Difference between revisions of "Melanoma"

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'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]].'''
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<span id="BackToTop"></span>
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Is there a regimen missing from this list?  Would you like to share a different dosage/schedule or an additional reference for a regimen?  Have you noticed an error?  Do you have an idea that will help the site grow to better meet your needs and the needs of many others?  You are [[How_to_contribute|invited to contribute to the site]].
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[[#top|Back to Top]]
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</div>
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{{#lst:Editorial board transclusions|mel}}
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''Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the [[Melanoma_-_historical|historical regimens page]]. For placebo or observational studies in this condition, please visit [[Melanoma - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''<br>
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<big>'''Note: some melanoma regimens can be found on dedicated pages:'''
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*'''[[Melanoma,_BRAF-mutated|BRAF-mutated melanoma]]'''
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*'''[[Melanoma,_KIT-mutated|KIT-mutated melanoma]]'''
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*'''[[Melanoma,_NRAS-mutated|NRAS-mutated melanoma]]'''
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*'''[[CNS melanoma]]'''
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*'''[[Uveal melanoma]]'''
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</big>
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
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|<div style="background-color: #66FF66; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} regimens on this page</b></font></div>
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|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div>
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<div style="background-color: #66CCFF; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} variants on this page</b></font></div>
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<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
 
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{{TOC limit|limit=3}}
 
{{TOC limit|limit=3}}
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=Guidelines=
 +
'''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.'''
 +
==ASCO==
 +
*'''2022:''' Seth et al. [https://doi.org/10.1200/jco.22.00944 Systemic Therapy for Melanoma: ASCO Guideline Rapid Recommendation Update] [https://www.ncbi.nlm.nih.gov/pubmed/35658488 PubMed]
 +
**'''2020:''' Seth et al. [https://doi.org/10.1200/jco.20.00198 Systemic Therapy for Melanoma: ASCO Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/32228358 PubMed]
 +
 +
==EDF/EADO/EORTC==
 +
*'''2016:''' Garbe et al. [https://doi.org/10.1016/j.ejca.2016.05.005 Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline - Update 2016] [https://www.ncbi.nlm.nih.gov/pubmed/27367293 PubMed]
 +
==[https://www.esmo.org/ ESMO]==
 +
*'''2020:''' Keilholz et al. [https://doi.org/10.1016/j.annonc.2020.07.004 ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee] [https://www.ncbi.nlm.nih.gov/pubmed/32763453 PubMed]
 +
*'''2020:''' Michielin et al. [https://doi.org/10.1016/j.annonc.2020.07.005 ESMO consensus conference recommendations on the management of locoregional melanoma: under the auspices of the ESMO Guidelines Committee]  [https://www.ncbi.nlm.nih.gov/pubmed/32763452 PubMed]
 +
 +
*'''2019:''' Michielin et al. [https://academic.oup.com/annonc/article/30/12/1884/5578477 Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/31566661 PubMed]
 +
**'''2015:''' Dummer et al. [http://annonc.oxfordjournals.org/content/26/suppl_5/v126.full.pdf+html Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.] [https://pubmed.ncbi.nlm.nih.gov/26314774/ PubMed]
 +
**'''2012:''' Dummer et al. [https://doi.org/10.1093/annonc/mds229 Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/22997461/ PubMed]
 +
**'''2010:''' Dummer et al. [https://doi.org/10.1093/annonc/mdq188 Melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/20555080/ PubMed]
 +
**'''2009:''' Dummer et al. [https://doi.org/10.1093/annonc/mdp152 Cutaneous malignant melanoma: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454433/ PubMed]
 +
**'''2008:''' Dummer et al. [https://doi.org/10.1093/annonc/mdn100 Cutaneous malignant melanoma: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/18456782/ PubMed]
 +
**'''2007:''' Jost. [https://doi.org/10.1093/annonc/mdm045 Cutaneous malignant melanoma: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/17491056/ PubMed]
 +
**'''2005:''' Jost et al. [https://doi.org/10.1093/annonc/mdi809 ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of cutaneous malignant melanoma] [https://pubmed.ncbi.nlm.nih.gov/15888761/ PubMed]
 +
**'''2003:''' Jost. [https://doi.org/10.1093/annonc/mdg294 ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of cutaneous malignant melanoma] [https://pubmed.ncbi.nlm.nih.gov/12853340/ PubMed]
 +
 +
==[https://melanoma-inc.org/ INMC]==
 +
*'''2019:''' Amaria et al. [https://doi.org/10.1016/S1470-2045(19)30332-8 Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium] [https://www.ncbi.nlm.nih.gov/pubmed/31267972 PubMed]
 +
==NCCN==
 +
*[https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492 NCCN Guidelines - Melanoma: Cutaneous]
 +
**'''2019:''' Coit et al. [https://doi.org/10.6004/Jnccn.2019.0018 Cutaneous Melanoma, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/30959471/ PubMed]
 +
**'''2016:''' Coit et al. [https://doi.org/10.6004/Jnccn.2016.0051 Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/27059193/ PubMed]
 +
**'''2014:''' Coit et al. [https://doi.org/10.6004/jnccn.2014.0066 Melanoma, Version 4.2014] [https://pubmed.ncbi.nlm.nih.gov/24812131/ PubMed]
 +
**'''2013:''' Coit et al. [https://doi.org/10.6004/Jnccn.2013.0055 Melanoma, version 2.2013: featured updates to the NCCN guidelines.] [https://pubmed.ncbi.nlm.nih.gov/23584343/ PubMed]
 +
**'''2012:''' Coit et al. [https://doi.org/10.6004/Jnccn.2012.0036 Melanoma.] [https://pubmed.ncbi.nlm.nih.gov/22393197/ PubMed]
 +
**'''2012:''' Pfister et al. [https://doi.org/10.6004/Jnccn.2012.0033 Mucosal melanoma of the head and neck.] [https://pubmed.ncbi.nlm.nih.gov/22393194/ PubMed]
 +
**'''2009:''' Coit et al. [https://doi.org/10.6004/Jnccn.2009.0020 Melanoma.] [https://pubmed.ncbi.nlm.nih.gov/19401060/ PubMed]
 +
**'''2006:''' Houghton et al. [https://doi.org/10.6004/Jnccn.2006.0057 Melanoma.] [https://pubmed.ncbi.nlm.nih.gov/16884669/ PubMed]
 +
**'''2004:''' Author not listed. [https://doi.org/10.6004/Jnccn.2004.0003 Melanoma. Clinical practice guidelines in oncology.] [https://pubmed.ncbi.nlm.nih.gov/19777694/ PubMed]
  
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=Adjuvant therapy=
+
==SITC==
 +
*'''2018:''' Sullivan et al. [http://dx.doi.org/10.1186/s40425-018-0362-6 An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy for the treatment of cutaneous melanoma: version 2.0] [https://pubmed.ncbi.nlm.nih.gov/29848375/ PubMed]
 +
**'''2013:''' Kaufman et al. [https://doi.org/10.1038/nrclinonc.2013.153 The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma] [https://pubmed.ncbi.nlm.nih.gov/23982524/ PubMed]
  
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==Interferon alfa-2a (Roferon-A) {{#subobject:67406e|Regimen=1}}==
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=Perioperative therapy=
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{| class="wikitable" style="float:right; margin-left: 5px;"
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''This section contains protocols with a pre-planned neoadjuvant (preoperative) and adjuvant (postoperative) component.''
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|-
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==Pembrolizumab monotherapy {{#subobject:0a3e71|Regimen=1}}==
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|[[#toc|back to top]]
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<div class="toccolours" style="background-color:#c8a2c8">
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|}
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{| class="wikitable sortable" style="width: 100%; text-align:center;"  
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===Regimen #1 {{#subobject:65fe20|Variant=1}}===
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!style="width: 20%"|Study
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{| border="1" style="text-align:center;" !align="left"  
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!style="width: 20%"|Dates of enrollment
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|'''Study'''
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!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
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|[[Levels_of_Evidence#Evidence|'''Evidence''']]
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!style="width: 20%"|Comparator
−
|'''Comparator'''
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!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(97)12445-X/abstract Grob et al. 1998]
+
|[https://doi.org/10.1056/NEJMoa2211437 Patel et al 2023 (SWOG S1801)]
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|<span
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|2019-02 to 2022-05
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style="background:#00CD00;
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| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
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padding:3px 6px 3px 6px;
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|Adjuvant [[#Pembrolizumab_monotherapy_2|Pembrolizumab]]
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border-color:black;
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| style="background-color:#1a9850" |Superior EFS (primary endpoint)<br>EFS24: 72% vs 49%<br>(HR 0.59, 95% CI 0.40-0.86)
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border-width:2px;
 
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border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Placebo_.28Observation.29|Observation]]
 
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Eligibility criteria====
 +
*Resectable stage IIIB to IV melanoma without brain metastasis
 +
</div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Neoadjuvant {{#subobject:bd92fe|Variant=1}}===
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 +
'''21-day cycle for 3 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Definitive===
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Local therapy====
 +
*[[Surgery#Surgical_resection|Complete resection]]
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Adjuvant===
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 +
'''21-day cycle for 15 cycles'''
 +
</div></div></div>
 +
===References===
 +
#'''SWOG S1801:''' Patel SP, Othus M, Chen Y, Wright GP Jr, Yost KJ, Hyngstrom JR, Hu-Lieskovan S, Lao CD, Fecher LA, Truong TG, Eisenstein JL, Chandra S, Sosman JA, Kendra KL, Wu RC, Devoe CE, Deutsch GB, Hegde A, Khalil M, Mangla A, Reese AM, Ross MI, Poklepovic AS, Phan GQ, Onitilo AA, Yasar DG, Powers BC, Doolittle GC, In GK, Kokot N, Gibney GT, Atkins MB, Shaheen M, Warneke JA, Ikeguchi A, Najera JE, Chmielowski B, Crompton JG, Floyd JD, Hsueh E, Margolin KA, Chow WA, Grossmann KF, Dietrich E, Prieto VG, Lowe MC, Buchbinder EI, Kirkwood JM, Korde L, Moon J, Sharon E, Sondak VK, Ribas A; SWOG. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023 Mar 2;388(9):813-823. [https://doi.org/10.1056/NEJMoa2211437 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/36856617/ PubMed] [https://clinicaltrials.gov/study/NCT03698019 NCT03698019]
  
−
*[[Interferon alfa-2a (Roferon-A)]] 3,000,000 international units SC three times per week
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=Neoadjuvant response criteria=
 +
*'''2018:''' Tetzlaff et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096739/ Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma]
  
−
'''18-month course'''
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=Adjuvant therapy=
−
 
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==Cisplatin & Temozolomide {{#subobject:63gh1g|Regimen=1}}==
−
===Regimen #2 {{#subobject:ae58d1|Variant=1}}===
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<div class="toccolours" style="background-color:#eeeeee">
−
{| border="1" style="text-align:center;" !align="left"  
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===Regimen {{#subobject:1jizga|Variant=1}}===
−
|'''Study'''
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{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
! style="width: 20%" |Study
−
|'''Comparator'''
+
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="2" |[https://doi.org/10.1158/1078-0432.ccr-13-0739 Lian et al. 2013]
 +
| rowspan="2" |2007-2009
 +
| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
 +
|1. [[Melanoma_-_historical#Interferon_alfa-2b_monotherapy|Interferon alfa-2b]]
 +
| style="background-color:#1a9850" |Superior RFS (co-primary endpoint)
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/16/4/1425.long Pehamberger et al. 1998]
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|2. [[Melanoma_-_null_regimens#Observation|Observation]]
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|<span
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| style="background-color:#1a9850" |Superior OS (co-primary endpoint)
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style="background:#00CD00;
 
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padding:3px 6px 3px 6px;
 
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border-color:black;
 
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border-width:2px;
 
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border-style:solid;">Phase III</span>
 
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|[[Melanoma#Placebo_.28Observation.29|Observation]]
 
 
|-
 
|-
 
|}
 
|}
−
 
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<div class="toccolours" style="background-color:#cbd5e8">
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====Induction phase====
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====Preceding treatment====
−
*[[Interferon alfa-2a (Roferon-A)]] 3,000,000 international units SC once per day
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*[[Surgery#Melanoma_surgery|Surgery]]
−
 
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</div>
−
'''21-day course, then proceed to maintenance phase'''
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<div class="toccolours" style="background-color:#b3e2cd">
−
 
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====Chemotherapy====
−
====Maintenance phase====
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*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once per day on days 1 to 3
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*[[Interferon alfa-2a (Roferon-A)]] 3,000,000 international units SC three times per week
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*[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup>/day PO on days 1 to 5
−
 
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'''21-day cycle for 6 cycles'''
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'''49-week course (to complete a total 1-year treatment when added to the induction phase)'''
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</div></div>
−
 
 
 
===References===
 
===References===
−
# Pehamberger H, Soyer HP, Steiner A, Kofler R, Binder M, Mischer P, Pachinger W, Auböck J, Fritsch P, Kerl H, Wolff K. Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group. J Clin Oncol. 1998 Apr;16(4):1425-9. [http://jco.ascopubs.org/content/16/4/1425.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/9552047 PubMed]
+
#Lian B, Si L, Cui C, Chi Z, Sheng X, Mao L, Li S, Kong Y, Tang B, Guo J. Phase II randomized trial comparing high-dose IFN-α2b with temozolomide plus cisplatin as systemic adjuvant therapy for resected mucosal melanoma. Clin Cancer Res. 2013 Aug 15;19(16):4488-98. Epub 2013 Jul 5. [https://doi.org/10.1158/1078-0432.ccr-13-0739 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23833309/ PubMed] ChiCTR-TRC-11001798
−
# Grob JJ, Dreno B, de la Salmonière P, Delaunay M, Cupissol D, Guillot B, Souteyrand P, Sassolas B, Cesarini JP, Lionnet S, Lok C, Chastang C, Bonerandi JJ. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. French Cooperative Group on Melanoma. Lancet. 1998 Jun 27;351(9120):1905-10. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(97)12445-X/abstract link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/9654256 PubMed]
 
  
−
==Interferon alfa-2b (Intron-A) {{#subobject:86bbbb|Regimen=1}}==
+
==Ipilimumab monotherapy {{#subobject:89bbc6|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
===Example orders===
 +
*[[Example orders for Ipilimumab (Yervoy) in melanoma]]
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 3 mg/kg x 1 year {{#subobject:f9bac45|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7030886/ Tarhini et al. 2019 (ECOG E1609)]
 +
| rowspan="2" |2011-2014
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|1. [[Melanoma_-_historical#Interferon_alfa-2b_monotherapy|Interferon alfa-2b]]
 +
| style="background-color:#91cf60" |Seems to have superior OS (co-primary endpoint)<br>OS60: 72% vs 67%<br>(HR 0.78, 95.6% CI 0.61-0.99)
 +
|-
 +
|2. [[#Ipilimumab_monotherapy|Ipilimumab]]; 10 mg/kg
 +
| style="background-color:#d3d3d3" |Not reported
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Example orders===
+
<div class="toccolours" style="background-color:#fdcdac">
−
*[[Example orders for adjuvant Interferon alfa-2b (Intron-A) in melanoma]]
+
====Eligibility criteria====
−
 
+
*Stage IIIB, IIIC, or IV melanoma
−
===Regimen #1 {{#subobject:9dcc46|Variant=1}}===
+
</div>
−
{| border="1" style="text-align:center;" !align="left"  
+
<div class="toccolours" style="background-color:#cbd5e8">
−
|'''Study'''
+
====Preceding treatment====
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
*[[Surgery#Surgical_resection|Complete resection]]
−
|'''Comparator'''
+
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Ipilimumab (Yervoy)]] 3 mg/kg IV once on day 1
 +
'''21-day cycle for 4 cycles, then 12-week cycle for up to 4 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 10 mg/kg x 1 year {{#subobject:f92245|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7030886/ Tarhini et al. 2019 (ECOG E1609)]
 +
| rowspan="2" |2011-2014
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|1. [[Melanoma_-_historical#Interferon_alfa-2b_monotherapy|Interferon alfa-2b]]
 +
| style="background-color:#ffffbf" |Did not meet co-primary endpoint of OS
 +
|-
 +
|2. [[#Ipilimumab_monotherapy|Ipilimumab]]; 3 mg/kg
 +
| style="background-color:#d3d3d3" |Not reported
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/14/1/7.long Kirkwood et al. 1996 (ECOG EST 1684)]
+
|[https://doi.org/10.1056/NEJMoa1709030 Weber et al. 2017 (CheckMate 238)]
−
|<span
+
|2015-03-30 to 2015-11-30
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[Melanoma#Nivolumab_monotherapy|Nivolumab]]
−
border-color:black;
+
| style="background-color:#d73027" |Inferior RFS
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Placebo_.28Observation.29|Observation]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''Note: 12-month recurrence-free survival (RFS) in this arm of CheckMate 238 was 61% overall; Stage IIIB or IIIC: 62% (95% CI: 56-66.5); Stage IV: 57.5% (95% CI: 46-67). In the experimental arm, it was 70.5% overall; Stage IIIB or IIIC: 72% (95% CI, 67-77); Stage IV: 63% (95% CI, 52-72.5).''
−
====Induction phase====
+
<div class="toccolours" style="background-color:#fdcdac">
−
*[[Interferon alfa-2b (Intron-A)]] 20,000,000 units/m2 IV five times per week
+
====Eligibility criteria====
−
 
+
*Stage IIIB, IIIC, or IV melanoma
−
'''4-week course, then proceed to maintenance phase'''
+
</div>
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
====Maintenance phase====
+
====Preceding treatment====
−
*[[Interferon alfa-2b (Intron-A)]] 10,000,000 units/m2 SC three times per week
+
*[[Surgery#Surgical_resection|Complete resection]]
−
 
+
</div>
−
'''48-week course'''
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Immunotherapy====
−
===Regimen #2 {{#subobject:1eabea|Variant=1}}===
+
*[[Ipilimumab (Yervoy)]] 10 mg/kg IV once on day 1
−
{| border="1" style="text-align:center;" !align="left"  
+
'''21-day cycle for 4 cycles, then 12-week cycle for up to 4 cycles'''
−
|'''Study'''
+
</div></div><br>
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
<div class="toccolours" style="background-color:#eeeeee">
−
|'''Comparator'''
+
===Regimen variant #3, 3 years {{#subobject:a17a88|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 +
|-
 +
|}
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 17%" |Study
 +
! style="width: 15%" |Dates of enrollment
 +
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 17%" |Comparator
 +
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(15)70122-1 Eggermont et al. 2015 (EORTC 18071)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-76-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
 
|-
 
|-
−
|[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363881/ Cameron et al. 2001 (The Scottish study)]
+
|} -->
−
|<span
+
|2008-2011
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
−
padding:3px 6px 3px 6px;
+
|[[Melanoma_-_null_regimens#Placebo|Placebo]]
−
border-color:black;
+
| style="background-color:#1a9850" |Superior RFS<sup>1</sup> (primary endpoint)<br>RFS60: 40.8% vs 30.3%<br>(HR 0.76, 95% CI 0.64-0.89)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>OS60: 65.4% vs 54.4%<br>(HR 0.72, 95.1% CI 0.58-0.88)
−
border-width:2px;
+
| style="background-color:#eeee01" |Similar HRQoL<sup>2</sup>
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Placebo_.28Observation.29|Observation]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''<sup>1</sup>Reported efficacy is based on the 2016 update.''<br>
−
''Note: The PubMed version of Cameron et al. 2001's abstract says that interferon alfa-2b is given "twice weekly," in contrast to what the actual paper says, "thrice weekly."''
+
''<sup>2</sup>While there was a statistically significant difference in EORTC QLC-C30 scores in EORTC 18071 (in favor of placebo), this difference did not meet the pre-determined threshold for clinical relevance.''
−
*[[Interferon alfa-2b (Intron-A)]] 3,000,000 units SC three times per week
+
<div class="toccolours" style="background-color:#fdcdac">
−
 
+
====Eligibility criteria====
−
'''6-month course'''
+
*Stage III cutaneous melanoma
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Surgical_resection|Complete resection]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Ipilimumab (Yervoy)]] 10 mg/kg IV over 90 minutes once on day 1
 +
'''21-day cycle for 4 cycles, then 12-week cycle for 12 cycles (3 years)'''
 +
</div></div>
  
 
===References===
 
===References===
−
# Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996 Jan;14(1):7-17. [http://jco.ascopubs.org/content/14/1/7.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/8558223 PubMed]
+
#'''EORTC 18071:''' Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Konto C, Hoos A, de Pril V, Karra Gurunath R, de Schaetzen G, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 May;16(5):522-30. Epub 2015 Mar 31. Erratum: Lancet Oncol. 2015 Jun;16(6):e262. Epub 2015 May 27. [https://doi.org/10.1016/S1470-2045(15)70122-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25840693/ PubMed] [https://clinicaltrials.gov/study/NCT00636168 NCT00636168]
−
# Cameron DA, Cornbleet MC, Mackie RM, Hunter JA, Gore M, Hancock B, Smyth JF; Scottish Melanoma Group. Adjuvant interferon alpha 2b in high risk melanoma - the Scottish study. Br J Cancer. 2001 May 4;84(9):1146-9. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363881/ link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/11379605 PubMed]
+
##'''Update:''' Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel JC, Hodi FS, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016 Nov 10;375(19):1845-1855. Epub 2016 Oct 7. [https://doi.org/10.1056/NEJMoa1611299 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5648545/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27717298/ PubMed]
 +
##'''HRQoL analysis:''' Coens C, Suciu S, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bottomley A, Kotapati S, de Pril V, Testori A, Eggermont AM. Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol. 2017 Mar;18(3):393-403. Epub 2017 Feb 3. [https://doi.org/10.1016/s1470-2045(17)30015-3 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5636622/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28162999/ PubMed]
 +
##'''Update:''' Eggermont AMM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Hosein F, de Pril V, Kicinski M, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial. Eur J Cancer. 2019 Sep;119:1-10. Epub 2019 Aug 7. [https://doi.org/10.1016/j.ejca.2019.07.001 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31400634/ PubMed]
 +
#'''CheckMate 238:''' Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. Epub 2017 Sep 10. [https://doi.org/10.1056/NEJMoa1709030 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28891423/ PubMed] [https://clinicaltrials.gov/study/NCT02388906 NCT02388906]
 +
##'''Update:''' Ascierto PA, Del Vecchio M, Mandalá M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Márquez-Rodas I, Butler MO, Maio M, Middleton MR, de la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Khushalani NI, Queirolo P, Lobo M, de Pril V, Loffredo J, Larkin J, Weber J. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1465-1477. Epub 2020 Sep 19. [https://doi.org/10.1016/s1470-2045(20)30494-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32961119/ PubMed]
 +
#'''ECOG E1609:''' Tarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol. 2020 Feb 20;38(6):567-575. Epub 2019 Dec 27. [https://doi.org/10.1200/JCO.19.01381 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7030886/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31880964/ PubMed] [https://clinicaltrials.gov/study/NCT01274338 NCT01274338]
 +
##'''HRQoL analysis:''' McLouth LE, Zheng Y, Smith S, Hodi FS, Rao UN, Cohen GI, Amatruda TT, Dakhil SR, Curti BD, Nakhoul I, Chandana SR, Bane CL, Marinier DE, Lee SJ, Sondak VK, Kirkwood JM, Tarhini AA, Wagner LI. Patient-reported tolerability of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk stage III-IV melanoma in phase III trial E1609. Qual Life Res. 2023 Jan;32(1):183-196. Epub 2022 Aug 27. [https://doi.org/10.1007/s11136-022-03226-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9839512/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/36029412/ PubMed]
 +
#'''SWOG S1404:''' Grossmann KF, Othus M, Patel SP, Tarhini AA, Sondak VK, Knopp MV, Petrella TM, Truong TG, Khushalani NI, Cohen JV, Buchbinder EI, Kendra K, Funchain P, Lewis KD, Conry RM, Chmielowski B, Kudchadkar RR, Johnson DB, Li H, Moon J, Eroglu Z, Gastman B, Kovacsovics-Bankowski M, Gunturu KS, Ebbinghaus SW, Ahsan S, Ibrahim N, Sharon E, Korde LA, Kirkwood JM, Ribas A. Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma. Cancer Discov. 2022 Mar 1;12(3):644-653. [https://doi.org/10.1158/2159-8290.cd-21-1141 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904282/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34764195/ PubMed] [https://clinicaltrials.gov/study/NCT02506153 NCT02506153]
 +
##'''HRQoL analysis:''' Unger JM, Darke A, Othus M, Truong TG, Khushalani N, Kendra K, Lewis KD, Faller B, Funchain P, Buchbinder EI, Tarhini AA, Kirkwood JM, Sharon E, Sondak V, Guild SR, Grossmann K, Ribas A, Patel SP. Effectiveness of Adjuvant Pembrolizumab vs High-Dose Interferon or Ipilimumab for Quality-of-Life Outcomes in Patients With Resected Melanoma: A Secondary Analysis of the SWOG S1404 Randomized Clinical Trial. JAMA Oncol. 2023 Feb 1;9(2):251-260. [https://doi.org/10.1001/jamaoncol.2022.5486 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9685550/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/36416836/ PubMed]
  
−
==Ipilimumab (Yervoy) {{#subobject:PYR2|Regimen=1}}==
+
==Ipilimumab & Nivolumab {{#subobject:28103f|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:6cf5ae|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30417-7 Zimmer et al. 2020 (IMMUNED)]
 +
| rowspan="2" |2015-2018
 +
| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
 +
|1. [[#Nivolumab_monotherapy|Nivolumab]]
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|2. [[Melanoma_-_null_regimens#Placebo|Placebo]]
 +
| style="background-color:#91cf60" |Superior RFS (primary endpoint)<br>Median RFS: NYR vs 12.4 mo<br>(HR 0.23, 97.5% CI 0.12-0.45)<br><br>Seems to have superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: NYR vs NYR<br>(HR 0.41, 95% CI 0.17-0.99)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
''<sup>1</sup>Reported efficacy is based on the 2022 update.''
−
===Example orders===
+
<div class="toccolours" style="background-color:#fdcdac">
−
*[[Example orders for Ipilimumab (Yervoy) in melanoma]]
+
====Eligibility criteria====
−
 
+
*Stage IV melanoma
−
===Regimen {{#subobject:PYV2|Variant=1}}===
+
</div>
−
{| border="1" style="text-align:center;" !align="left"  
+
<div class="toccolours" style="background-color:#cbd5e8">
−
|'''Study'''
+
====Preceding treatment====
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
*[[Surgery#Surgical_resection|Resection]] or definitive [[Regimen_classes#Radiotherapy-based_regimen|radiotherapy]], with NED
−
|'''Comparator'''
+
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Ipilimumab (Yervoy)]] as follows:
 +
**Cycles 1 to 4: 3 mg/kg IV once on day 1
 +
*[[Nivolumab (Opdivo)]] as follows:
 +
**Cycles 1 to 4: 1 mg/kg IV once on day 1,
 +
**Cycles 5 to 24: 3 mg/kg IV once on day 1
 +
'''21-day cycle for 4 cycles, then 14-day cycle for 20 cycles (1 year)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2 {{#subobject:jg8cxe|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70122-1/abstract Eggermont et al. 2015 (EORTC 18071)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9870220/ Weber et al. 2022 (CheckMate 915)]
−
|<span
+
|2017-04 to 2018-06
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
padding:3px 6px 3px 6px;
+
|[[#Nivolumab_monotherapy|Nivolumab]]
−
border-color:black;
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS<br>RFS24: 64.6% vs 63.2%<br>(HR 0.92, 97.295% CI 0.77-1.09)
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Placebo_.28Observation.29|Placebo]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority in this setting.''
−
====Induction phase====
+
<div class="toccolours" style="background-color:#fdcdac">
−
*[[Ipilimumab (Yervoy)]] 10 mg/kg IV once on day 1
+
====Eligibility criteria====
−
 
+
*Stage IIIB, IIIC, IIID, or IV melanoma
−
'''21-day cycles x 4 doses'''
+
</div>
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
====Maintenance phase====
+
====Preceding treatment====
−
*[[Ipilimumab (Yervoy)]] 10 mg/kg IV once on day 1
+
*[[Surgery#Surgical_resection|Complete resection]]
−
 
+
</div>
−
'''3-month cycles x up to 3 years or disease recurrence or unacceptable toxicity'''
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Ipilimumab (Yervoy)]] 1 mg/kg IV once on day 1
 +
*[[Nivolumab (Opdivo)]] 240 mg IV once per day on days 1, 15, 29
 +
'''42-day cycle for 9 cycles (1 year)'''
 +
</div></div>
  
 
===References===
 
===References===
−
# Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Konto C, Hoos A, de Pril V, Gurunath RK, de Schaetzen G, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 May;16(5):522-30. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70122-1/abstract link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/25840693 PubMed]
+
#'''IMMUNED:''' Zimmer L, Livingstone E, Hassel JC, Fluck M, Eigentler T, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kieker F, Dippel E, Rösch A, Simon JC, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020 May 16;395(10236):1558-1568. [https://doi.org/10.1016/s0140-6736(20)30417-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32416781/ PubMed] [https://clinicaltrials.gov/study/NCT02523313 NCT02523313]
−
## '''Correction:''' Eggermont AM, Chiarion-Sileni V, Grob JJ. Correction to Lancet Oncol 2015; 16: 522-30. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):e262. Epub 2015 May 27. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70271-8/abstract link to correction] [http://www.ncbi.nlm.nih.gov/pubmed/26065611 PubMed]
+
##'''Update:''' Livingstone E, Zimmer L, Hassel JC, Fluck M, Eigentler TK, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kiecker F, Dippel E, Roesch A, Ziemer M, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab alone versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): final results of a randomised, double-blind, phase 2 trial. Lancet. 2022 Oct 1;400(10358):1117-1129. Epub 2022 Sep 10. [https://doi.org/10.1016/s0140-6736(22)01654-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36099927/ PubMed]
 +
#'''CheckMate 915:''' Weber JS, Schadendorf D, Del Vecchio M, Larkin J, Atkinson V, Schenker M, Pigozzo J, Gogas H, Dalle S, Meyer N, Ascierto PA, Sandhu S, Eigentler T, Gutzmer R, Hassel JC, Robert C, Carlino MS, Di Giacomo AM, Butler MO, Muñoz-Couselo E, Brown MP, Rutkowski P, Haydon A, Grob JJ, Schachter J, Queirolo P, de la Cruz-Merino L, van der Westhuizen A, Menzies AM, Re S, Bas T, de Pril V, Braverman J, Tenney DJ, Tang H, Long GV. Adjuvant Therapy of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Patients With Resected Stage IIIB-D or Stage IV Melanoma (CheckMate 915). J Clin Oncol. 2023 Jan 20;41(3):517-527. Epub 2022 Sep 26. [https://doi.org/10.1200/jco.22.00533 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9870220/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/36162037/ PubMed] [https://clinicaltrials.gov/study/NCT03068455 NCT03068455]
  
−
==Peginterferon alfa-2b (Sylatron) {{#subobject:42f282|Regimen=1}}==
+
==Nivolumab monotherapy {{#subobject:2b3899|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 240 mg flat dose {{#subobject:igj2d5|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9870220/ Weber et al. 2022 (CheckMate 915)]
 +
|2017-04 to 2018-06
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Ipilimumab_.26_Nivolumab|Ipilimumab & Nivolumab]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:934e7d|Variant=1}}===
+
<div class="toccolours" style="background-color:#fdcdac">
−
{| border="1" style="text-align:center;" !align="left"  
+
====Eligibility criteria====
−
|'''Study'''
+
*Stage IIIB, IIIC, IIID, or IV melanoma
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
</div>
−
|'''Comparator'''
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Surgical_resection|Complete resection]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Nivolumab (Opdivo)]] 240 mg IV once on day 1
 +
'''14-day cycle for up to 26 cycles (1 year)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 480 mg flat dose {{#subobject:iy5335|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61033-8/abstract Eggermont et al. 2008 (EORTC 18991)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10667090/ Kirkwood et al. 2023 (CheckMate 76K)]
−
|<span
+
|2019-10-28 to 2021-11-03
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
−
padding:3px 6px 3px 6px;
+
|[[Melanoma_-_null_regimens#Placebo|Placebo]]
−
border-color:black;
+
| style="background-color:#1a9850" |Superior RFS (primary endpoint)<br>RFS12: 89 vs 79.4%<br>(HR 0.42, 95% CI 0.30-0.59)
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Placebo_.28Observation.29|Observation]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#fdcdac">
−
''Patients enrolled in EORTC 18991 had resected stage III melanoma.''
+
====Eligibility criteria====
−
 
+
*Stage IIB or IIC melanoma
−
====Induction phase====
+
</div>
−
*[[Peginterferon alfa-2b (Sylatron)]] 6 mcg/kg SC once per week
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
'''8-week course, then proceed to maintenance phase'''
+
*[[Surgery#Surgical_resection|Complete resection]]
−
 
+
</div>
−
====Maintenance phase====
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Peginterferon alfa-2b (Sylatron)]] 3 mcg/kg SC once per week
+
====Immunotherapy====
−
 
+
*[[Nivolumab (Opdivo)]] 480 mg IV once on day 1
−
'''Given for up to 5 years of therapy if [[performance status|ECOG performance status]] remained 0 or 1'''
+
'''28-day cycle for 13 cycles (1 year)'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, weight-based {{#subobject:a228d5|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa1709030 Weber et al. 2017 (CheckMate 238)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-174-1 <span style="color:white;">ESMO-MCBS (C)</span>]'''
 +
|-
 +
|} -->
 +
|2015-03-30 to 2015-11-30
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
 +
|[[Melanoma#Ipilimumab_monotherapy|Ipilimumab]]
 +
| style="background-color:#1a9850" |Superior RFS (primary endpoint)<br>RFS12: 70.5% vs 60.8%<br>(HR 0.65, 97.56% CI 0.51-0.83)
 +
|-
 +
| rowspan="2" |[https://doi.org/10.1016/s0140-6736(20)30417-7 Zimmer et al. 2020 (IMMUNED)]
 +
| rowspan="2" |2015-2018
 +
| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
 +
|1. [[#Ipilimumab_.26_Nivolumab|Ipilimumab & Nivolumab]]
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|2. [[Melanoma_-_null_regimens#Placebo|Placebo]]
 +
| style="background-color:#1a9850" |Superior RFS (primary endpoint)<br>Median RFS: 12.4 vs 6.4 mo<br>(HR 0.56, 97.5% CI 0.33-0.94)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Eligibility criteria====
 +
*CheckMate 238: Stage IIIB, IIIC, or IV melanoma
 +
*IMMUNED: Stage IV melanoma
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*CheckMate 238: [[Surgery#Surgical_resection|Complete resection]]
 +
*IMMUNED: [[Surgery#Surgical_resection|Resection]] or definitive [[Regimen_classes#Radiotherapy-based_regimen|radiotherapy]], with NED
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
 +
'''14-day cycle for up to 26 cycles (1 year)'''
 +
</div></div>
 
===References===
 
===References===
−
# Eggermont AM, Suciu S, Santinami M, Testori A, Kruit WH, Marsden J, Punt CJ, Salès F, Gore M, Mackie R, Kusic Z, Dummer R, Hauschild A, Musat E, Spatz A, Keilholz U; EORTC Melanoma Group. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet. 2008 Jul 12;372(9633):117-26. doi: 10.1016/S0140-6736(08)61033-8. [http://www.sciencedirect.com/science/article/pii/S0140673608610338 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18620949 PubMed]
+
#'''CheckMate 238:''' Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. Epub 2017 Sep 10. [https://doi.org/10.1056/NEJMoa1709030 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28891423/ PubMed] [https://clinicaltrials.gov/study/NCT02388906 NCT02388906]
−
## '''Update:''' Eggermont AM, Suciu S, Testori A, Santinami M, Kruit WH, Marsden J, Punt CJ, Salès F, Dummer R, Robert C, Schadendorf D, Patel PM, de Schaetzen G, Spatz A, Keilholz U. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol. 2012 Nov 1;30(31):3810-8. doi: 10.1200/JCO.2011.41.3799. Epub 2012 Sep 24. [http://jco.ascopubs.org/content/30/31/3810.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23008300 PubMed]
+
##'''Update:''' Ascierto PA, Del Vecchio M, Mandalá M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Márquez-Rodas I, Butler MO, Maio M, Middleton MR, de la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Khushalani NI, Queirolo P, Lobo M, de Pril V, Loffredo J, Larkin J, Weber J. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1465-1477. Epub 2020 Sep 19. [https://doi.org/10.1016/s1470-2045(20)30494-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32961119/ PubMed]
 +
#'''IMMUNED:''' Zimmer L, Livingstone E, Hassel JC, Fluck M, Eigentler T, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kieker F, Dippel E, Rösch A, Simon JC, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020 May 16;395(10236):1558-1568. [https://doi.org/10.1016/s0140-6736(20)30417-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32416781/ PubMed] [https://clinicaltrials.gov/study/NCT02523313 NCT02523313]
 +
#'''CheckMate 915:''' Weber JS, Schadendorf D, Del Vecchio M, Larkin J, Atkinson V, Schenker M, Pigozzo J, Gogas H, Dalle S, Meyer N, Ascierto PA, Sandhu S, Eigentler T, Gutzmer R, Hassel JC, Robert C, Carlino MS, Di Giacomo AM, Butler MO, Muñoz-Couselo E, Brown MP, Rutkowski P, Haydon A, Grob JJ, Schachter J, Queirolo P, de la Cruz-Merino L, van der Westhuizen A, Menzies AM, Re S, Bas T, de Pril V, Braverman J, Tenney DJ, Tang H, Long GV. Adjuvant Therapy of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Patients With Resected Stage IIIB-D or Stage IV Melanoma (CheckMate 915). J Clin Oncol. 2023 Jan 20;41(3):517-527. Epub 2022 Sep 26. [https://doi.org/10.1200/jco.22.00533 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9870220/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/36162037/ PubMed] [https://clinicaltrials.gov/study/NCT03068455 NCT03068455]
 +
#'''CheckMate 76K:''' Kirkwood JM, Del Vecchio M, Weber J, Hoeller C, Grob JJ, Mohr P, Loquai C, Dutriaux C, Chiarion-Sileni V, Mackiewicz J, Rutkowski P, Arenberger P, Quereux G, Meniawy TM, Ascierto PA, Menzies AM, Durani P, Lobo M, Campigotto F, Gastman B, Long GV. Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial. Nat Med. 2023 Nov;29(11):2835-2843. Epub 2023 Oct 16. Erratum in: Nat Med. 2023 Nov 3. [https://doi.org/10.1038/s41591-023-02583-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10667090/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37845511/ PubMed] [https://clinicaltrials.gov/study/NCT04099251 NCT04099251]
 +
#'''PIVOT-12:''' [https://clinicaltrials.gov/study/NCT04410445 NCT04410445]
  
−
==Placebo (Observation) {{#subobject:98ba83|Regimen=1}}==
+
==Pembrolizumab monotherapy {{#subobject:0a3e71|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
{| class="wikitable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
===Regimen variant #1, adult dosing {{#subobject:bd92fe|Variant=1}}===
−
===Regimen {{#subobject:dab4f3|Variant=1}}===
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
{| border="1" style="text-align:center;" !align="left"  
+
! style="width: 20%" |Study
−
|'''Study'''
+
! style="width: 20%" |Dates of enrollment
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
|'''Comparator'''
+
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/14/1/7.long Kirkwood et al. 1996 (ECOG EST 1684)]
+
|[https://doi.org/10.1056/NEJMoa1802357 Eggermont et al. 2018 (KEYNOTE-054)]
−
|<span
+
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
−
style="background:#00CD00;
+
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-173-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Interferon_alfa-2b_.28Intron-A.29|Interferon alfa-2b]]
 
 
|-
 
|-
−
!colspan="4" align="center"|
+
|} -->
 +
|2015-08 to 2016-11
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[Melanoma_-_null_regimens#Placebo|Placebo]]
 +
| style="background-color:#1a9850" |Superior RFS<sup>1</sup> (primary endpoint)<br>RFS60: 55.4% vs 38.3%<br>(HR 0.61, 95% CI 0.51-0.72)
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/16/4/1425.long Pehamberger et al. 1998]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904282/ Grossmann et al. 2022 (SWOG S1404)]
−
|<span
+
|2015-2017
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
−
padding:3px 6px 3px 6px;
+
|1. [[Melanoma_-_historical#Interferon_alfa-2b_monotherapy|HD-Interferon alfa-2b]]<br>2. [[#Ipilimumab_monotherapy|Ipilimumab]]
−
border-color:black;
+
| style="background-color:#1a9850" |Superior RFS (co-primary endpoint)<br>(HR 0.77, 99.62% CI 0.59-0.99)
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Interferon_alfa-2a_.28Roferon-A.29|Interferon alfa-2a]]
 
 
|-
 
|-
−
!colspan="4" align="center"|
+
|[https://doi.org/10.1016/s0140-6736(22)00562-1 Luke et al. 2022 (KEYNOTE-716)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-339-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
 
|-
 
|-
−
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(97)12445-X/abstract Grob et al. 1998]
+
|} -->
−
|<span
+
|2018-2020
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
−
padding:3px 6px 3px 6px;
+
|[[Melanoma_-_null_regimens#Placebo|Placebo]]
−
border-color:black;
+
| style="background-color:#1a9850" |Superior RFS<sup>2</sup> (primary endpoint)<br>Median RFS: 37.2 mo vs NYR<br>(HR 0.64, 95% CI 0.50-0.84)
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Interferon_alfa-2a_.28Roferon-A.29|Interferon alfa-2a]]
 
 
|-
 
|-
−
!colspan="4" align="center"|
+
|[https://doi.org/10.1056/NEJMoa2211437 Patel et al 2023 (SWOG S1801)]
 +
|2019-02 to 2022-05
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|Perioperative [[#Pembrolizumab_monotherapy|Pembrolizumab]]
 +
| style="background-color:#d73027" |Inferior EFS
 
|-
 
|-
−
|[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363881/ Cameron et al. 2001 (The Scottish study)]
+
|[https://doi.org/10.1016/s0140-6736(23)02268-7 Weber et al. 2024 (KEYNOTE-942)]
−
|<span
+
|2019-07-18 to 2021-09-30
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[#Pembrolizumab_.26_mRNA-4157_777|Pembrolizumab & mRNA-4157]]
−
border-color:black;
+
| style="background-color:#fee08b" |Might have inferior RFS (primary endpoint)<br>RFS18: 62% vs 79%<br>(HR 1.78, 95% CI 0.98-3.24)
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Interferon_alfa-2b_.28Intron-A.29|Interferon alfa-2b]]
 
 
|-
 
|-
−
!colspan="4" align="center"|
+
|}
 +
''<sup>1</sup>Reported efficacy for KEYNOTE-054 is based on the 2022 update.''<br>
 +
''<sup>2</sup>Reported efficacy for KEYNOTE-716 is based on the 2022 update.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Eligibility criteria====
 +
*KEYNOTE-942: completely resected stage IIIB to IV
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*KEYNOTE-716: [[Surgery#Lymphadenectomy|Complete regional lymphadenectomy]], within 13 weeks
 +
*SWOG S1404: [[Surgery#Surgical_resection|Complete resection]], within 14 weeks
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 +
'''21-day cycle for 18 cycles (1 year)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
 
 +
===Regimen variant #2, pediatric dosing {{#subobject:ug1xfe|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61033-8/abstract Eggermont et al. 2008 (EORTC 18991)]
+
|[https://doi.org/10.1016/s0140-6736(22)00562-1 Luke et al. 2022 (KEYNOTE-716)]
−
|<span
+
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
−
style="background:#00CD00;
+
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-339-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Peginterferon_alfa-2b_.28Sylatron.29|Pegylated interferon alfa-2b]]
 
 
|-
 
|-
−
!colspan="4" align="center"|
+
|} -->
−
|-
+
|2018-2020
−
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70122-1/abstract Eggermont et al. 2015 (EORTC 18071)]
+
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
−
|<span
+
|[[Melanoma_-_null_regimens#Placebo|Placebo]]
−
style="background:#00CD00;
+
| style="background-color:#1a9850" |Superior RFS<sup>2</sup> (primary endpoint)<br>Median RFS: 37.2 mo vs NYR<br>(HR 0.64, 95% CI 0.50-0.84)
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Ipilimumab_.28Yervoy.29|Ipilimumab]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''<sup>1</sup>Reported efficacy is based on the 2022 update.''
−
''No active antineoplastic treatment.  Placed here because one or more randomized clinical trials included a placebo or observation arm in this disease context.''
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
 +
*KEYNOTE-716: [[Surgery#Lymphadenectomy|Complete regional lymphadenectomy]], within 13 weeks
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Pembrolizumab (Keytruda)]] 2 mg/kg (maximum dose of 200 mg) IV once on day 1
 +
'''21-day cycle for 18 cycles (1 year)'''
 +
</div></div>
 
===References===
 
===References===
−
# Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996 Jan;14(1):7-17. [http://jco.ascopubs.org/content/14/1/7.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/8558223 PubMed]
+
#'''KEYNOTE-054:''' Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Maio M, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan P, Ibrahim N, Marreaud S, van Akkooi ACJ, Suciu S, Robert C. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018 May 10;378(19):1789-1801. Epub 2018 Apr 15. [https://doi.org/10.1056/NEJMoa1802357 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29658430/ PubMed] [https://clinicaltrials.gov/study/NCT02362594 NCT02362594]
−
# Pehamberger H, Soyer HP, Steiner A, Kofler R, Binder M, Mischer P, Pachinger W, Auböck J, Fritsch P, Kerl H, Wolff K. Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group. J Clin Oncol. 1998 Apr;16(4):1425-9. [http://jco.ascopubs.org/content/16/4/1425.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/9552047 PubMed]
+
##'''Update:''' Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C. Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial. J Clin Oncol. 2020 Nov 20;38(33):3925-3936. Epub 2020 Sep 18. [https://doi.org/10.1200/jco.20.02110 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676886/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32946353/ PubMed]
−
# Grob JJ, Dreno B, de la Salmonière P, Delaunay M, Cupissol D, Guillot B, Souteyrand P, Sassolas B, Cesarini JP, Lionnet S, Lok C, Chastang C, Bonerandi JJ. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. French Cooperative Group on Melanoma. Lancet. 1998 Jun 27;351(9120):1905-10. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(97)12445-X/abstract link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/9654256 PubMed]
+
##'''Update:''' Eggermont AMM, Blank CU, Mandalà M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C; EORTC Melanoma Group. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 May;22(5):643-654. Epub 2021 Apr 12. [https://doi.org/10.1016/s1470-2045(21)00065-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33857412/ PubMed]
−
# Cameron DA, Cornbleet MC, Mackie RM, Hunter JA, Gore M, Hancock B, Smyth JF; Scottish Melanoma Group. Adjuvant interferon alpha 2b in high risk melanoma - the Scottish study. Br J Cancer. 2001 May 4;84(9):1146-9. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363881/ link to PMC article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/11379605 PubMed]
+
##'''HRQoL analysis:''' Bottomley A, Coens C, Mierzynska J, Blank CU, Mandalà M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Puig S, Ascierto PA, Larkin J, Lorigan PC, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C, Eggermont AMM; EORTC Melanoma Group. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 May;22(5):655-664. Epub 2021 Apr 12. [https://doi.org/10.1016/s1470-2045(21)00081-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33857414/ PubMed]
−
# Eggermont AM, Suciu S, Santinami M, Testori A, Kruit WH, Marsden J, Punt CJ, Salès F, Gore M, Mackie R, Kusic Z, Dummer R, Hauschild A, Musat E, Spatz A, Keilholz U; EORTC Melanoma Group. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet. 2008 Jul 12;372(9633):117-26. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61033-8/abstract link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18620949 PubMed]
+
##'''Update:''' Eggermont AMM, Kicinski M, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Boers-Sonderen M, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, van Akkooi ACJ, Lorigan P, Grebennik D, Krepler C, Marreaud S, Suciu S, Robert C. Five-Year Analysis of Adjuvant Pembrolizumab or Placebo in Stage III Melanoma. NEJM Evid. 2022 Nov;1(11):EVIDoa2200214. Epub 2022 Sep 10. [https://doi.org/10.1056/EVIDoa2200214 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38319852/ PubMed]
−
## '''Update:''' Eggermont AM, Suciu S, Testori A, Santinami M, Kruit WH, Marsden J, Punt CJ, Salès F, Dummer R, Robert C, Schadendorf D, Patel PM, de Schaetzen G, Spatz A, Keilholz U. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol. 2012 Nov 1;30(31):3810-8. Epub 2012 Sep 24. [http://jco.ascopubs.org/content/30/31/3810.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23008300 PubMed]
+
#'''KEYNOTE-716:''' Luke JJ, Rutkowski P, Queirolo P, Del Vecchio M, Mackiewicz J, Chiarion-Sileni V, de la Cruz Merino L, Khattak MA, Schadendorf D, Long GV, Ascierto PA, Mandala M, De Galitiis F, Haydon A, Dummer R, Grob JJ, Robert C, Carlino MS, Mohr P, Poklepovic A, Sondak VK, Scolyer RA, Kirkwood JM, Chen K, Diede SJ, Ahsan S, Ibrahim N, Eggermont AMM; KEYNOTE-716 Investigators. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet. 2022 Apr 30;399(10336):1718-1729. Epub 2022 Apr 1. [https://doi.org/10.1016/s0140-6736(22)00562-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35367007/ PubMed] [https://clinicaltrials.gov/study/NCT03553836 NCT03553836]
−
# Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Konto C, Hoos A, de Pril V, Gurunath RK, de Schaetzen G, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 May;16(5):522-30. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70122-1/abstract link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/25840693 PubMed]
+
##'''HRQoL analysis:''' Khattak MA, Luke JJ, Long GV, Ascierto PA, Rutkowski P, Schadendorf D, Robert C, Grob JJ, de la Cruz Merino L, Del Vecchio M, Spagnolo F, Mackiewicz J, Chiarion-Sileni V, Carlino MS, Mohr P, De Galitiis F, Ross MI, Eroglu Z, Chen K, Jiang R, Fukunaga-Kalabis M, Krepler C, Eggermont AMM, Kirkwood JM. Adjuvant pembrolizumab versus placebo in resected high-risk stage II melanoma: Health-related quality of life from the randomized phase 3 KEYNOTE-716 study. Eur J Cancer. 2022 Nov;176:207-217. Epub 2022 Oct 3. [https://doi.org/10.1016/j.ejca.2022.08.004 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36202690/ PubMed]
−
## '''Correction:''' Eggermont AM, Chiarion-Sileni V, Grob JJ. Correction to Lancet Oncol 2015; 16: 522-30. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):e262. Epub 2015 May 27. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70271-8/abstract link to correction] [http://www.ncbi.nlm.nih.gov/pubmed/26065611 PubMed]
+
##'''Update:''' Long GV, Luke JJ, Khattak MA, de la Cruz Merino L, Del Vecchio M, Rutkowski P, Spagnolo F, Mackiewicz J, Chiarion-Sileni V, Kirkwood JM, Robert C, Grob JJ, de Galitiis F, Schadendorf D, Carlino MS, Mohr P, Dummer R, Gershenwald JE, Yoon CH, Wu XL, Fukunaga-Kalabis M, Krepler C, Eggermont AMM, Ascierto PA; KEYNOTE-716 Investigators. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma (KEYNOTE-716): distant metastasis-free survival results of a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol. 2022 Nov;23(11):1378-1388. Epub 2022 Oct 18. [https://doi.org/10.1016/s1470-2045(22)00559-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36265502/ PubMed]
 +
##'''Update:''' Luke JJ, Ascierto PA, Khattak MA, de la Cruz Merino L, Del Vecchio M, Rutkowski P, Spagnolo F, Mackiewicz J, Chiarion-Sileni V, Kirkwood JM, Robert C, Grob JJ, de Galitiis F, Schadendorf D, Carlino MS, Wu XL, Fukunaga-Kalabis M, Krepler C, Eggermont AMM, Long GV. Pembrolizumab Versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma: Final Analysis of Distant Metastasis-Free Survival in the Phase III KEYNOTE-716 Study. J Clin Oncol. 2024 May 10;42(14):1619-1624. Epub 2024 Mar 7. [https://doi.org/10.1200/jco.23.02355 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38452313/ PubMed]
 +
#'''SWOG S1404:''' Grossmann KF, Othus M, Patel SP, Tarhini AA, Sondak VK, Knopp MV, Petrella TM, Truong TG, Khushalani NI, Cohen JV, Buchbinder EI, Kendra K, Funchain P, Lewis KD, Conry RM, Chmielowski B, Kudchadkar RR, Johnson DB, Li H, Moon J, Eroglu Z, Gastman B, Kovacsovics-Bankowski M, Gunturu KS, Ebbinghaus SW, Ahsan S, Ibrahim N, Sharon E, Korde LA, Kirkwood JM, Ribas A. Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma. Cancer Discov. 2022 Mar 1;12(3):644-653. [https://doi.org/10.1158/2159-8290.cd-21-1141 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904282/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34764195/ PubMed] [https://clinicaltrials.gov/study/NCT02506153 NCT02506153]
 +
##'''HRQoL analysis:''' Unger JM, Darke A, Othus M, Truong TG, Khushalani N, Kendra K, Lewis KD, Faller B, Funchain P, Buchbinder EI, Tarhini AA, Kirkwood JM, Sharon E, Sondak V, Guild SR, Grossmann K, Ribas A, Patel SP. Effectiveness of Adjuvant Pembrolizumab vs High-Dose Interferon or Ipilimumab for Quality-of-Life Outcomes in Patients With Resected Melanoma: A Secondary Analysis of the SWOG S1404 Randomized Clinical Trial. JAMA Oncol. 2023 Feb 1;9(2):251-260. [https://doi.org/10.1001/jamaoncol.2022.5486 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9685550/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/36416836/ PubMed]
 +
#'''SWOG S1801:''' Patel SP, Othus M, Chen Y, Wright GP Jr, Yost KJ, Hyngstrom JR, Hu-Lieskovan S, Lao CD, Fecher LA, Truong TG, Eisenstein JL, Chandra S, Sosman JA, Kendra KL, Wu RC, Devoe CE, Deutsch GB, Hegde A, Khalil M, Mangla A, Reese AM, Ross MI, Poklepovic AS, Phan GQ, Onitilo AA, Yasar DG, Powers BC, Doolittle GC, In GK, Kokot N, Gibney GT, Atkins MB, Shaheen M, Warneke JA, Ikeguchi A, Najera JE, Chmielowski B, Crompton JG, Floyd JD, Hsueh E, Margolin KA, Chow WA, Grossmann KF, Dietrich E, Prieto VG, Lowe MC, Buchbinder EI, Kirkwood JM, Korde L, Moon J, Sharon E, Sondak VK, Ribas A; SWOG. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023 Mar 2;388(9):813-823. [https://doi.org/10.1056/NEJMoa2211437 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/36856617/ PubMed] [https://clinicaltrials.gov/study/NCT03698019 NCT03698019]
 +
#'''KEYNOTE-942:''' Weber JS, Carlino MS, Khattak A, Meniawy T, Ansstas G, Taylor MH, Kim KB, McKean M, Long GV, Sullivan RJ, Faries M, Tran TT, Cowey CL, Pecora A, Shaheen M, Segar J, Medina T, Atkinson V, Gibney GT, Luke JJ, Thomas S, Buchbinder EI, Healy JA, Huang M, Morrissey M, Feldman I, Sehgal V, Robert-Tissot C, Hou P, Zhu L, Brown M, Aanur P, Meehan RS, Zaks T. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet. 2024 Feb 17;403(10427):632-644. Epub 2024 Jan 18. [https://doi.org/10.1016/s0140-6736(23)02268-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38246194/ PubMed] [https://clinicaltrials.gov/study/NCT03897881 NCT03897881]
  
 
=Local therapy=
 
=Local therapy=
−
==Talimogene laherparepvec (Imlygic) {{#subobject:PYR1|Regimen=1}}==
+
==Talimogene laherparepvec monotherapy {{#subobject:PYR1|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#toc|back to top]]
 
−
|}
 
−
 
 
 
===Regimen {{#subobject:PYV1|Variant=1}}===
 
===Regimen {{#subobject:PYV1|Variant=1}}===
−
{| border="1" style="text-align:center;" !align="left"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
|'''Study'''
+
! style="width: 20%" |Study
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
! style="width: 20%" |Dates of enrollment
−
|'''Comparator'''
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/33/25/2780.long Andtbacka et al. 2015]
+
|[https://doi.org/10.1200/jco.2014.58.3377 Andtbacka et al. 2015 (OPTiM)]
−
|<span
+
|2009-2011
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
−
padding:3px 6px 3px 6px;
+
|[[Melanoma_-_historical#Sargramostim_monotherapy|GM-CSF]]
−
border-color:black;
+
| style="background-color:#1a9850" |Superior DRR (primary endpoint)<br><br>Seems to have superior OS<sup>1</sup> (secondary endpoint)<br>(HR 0.79, 95% CI 0.62-1.00)
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|GM-CSF
 
 
|-
 
|-
 
|}
 
|}
 +
''<sup>1</sup>Reported efficacy is based on the 2019 update.''<br>
 +
''Note: Talimogene laherparepvec was injected directly into unresectable cutaneous, subcutaneous, and nodal melanoma lesions. Treatment continued until progression of disease, unacceptable toxicity, lack of response by 12 months, or disappearance of all injectable lesions.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Local therapy====
 +
*[[Talimogene laherparepvec (Imlygic)]] as follows:
 +
**Initially, to seroconvert HSV-seronegative patients: 1,000,000 pfu/mL SC intralesional injection once on day 1
 +
**Thereafter: 100,000,000 pfu/mL SC intralesional injection once on day 1
 +
**Total volume given per treatment session was up to 4.0 mL. "Injected volume per lesion ranged from 0.1 mL for lesions less than 0.5 cm to 4.0 mL for lesions greater than 5 cm in longest diameter."
 +
'''21-day course, then 14-day cycle for at least 12 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
  
−
''In Andtbacka et al. 2015, Talimogene laherparepvec (Imlygic) was injected directly into unresectable cutaneous, subcutaneous, and nodal melanoma lesions.''
+
====Subsequent treatment====
−
*[[Talimogene laherparepvec (Imlygic)]] 10<sup>6</sup> pfu/mL (to seroconvert HSV-seronegative patients) SC intralesional injection once on day 1, then 10<sup>8</sup> pfu/mL SC intralesional injection once on day 22. Thereafter, 10<sup>8</sup> pfu/mL SC intralesional injection once every 2 weeks.
+
*Patients with stable or responding disease after 1 year of therapy could continue treatment for another 6 months
−
**Total volume given per treatment session was up to 4.0 mL.  "Injected volume per lesion ranged from 0.1 mL for lesions < 0.5 cm to 4.0 mL for lesions > 5 cm in longest diameter."
+
</div></div>
−
 
 
−
'''Generally given for at least 24 weeks. Treatment continued until progression of disease, unacceptable toxicity, lack of response by 12 months, or disappearance of all injectable lesions.''' Patients with stable or responding disease after 1 year of therapy could continue treatment for another 6 months.
 
−
 
 
 
===References===
 
===References===
−
# Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780-8. [http://jco.ascopubs.org/content/33/25/2780.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/26014293 PubMed]
+
<!-- Presented in part at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013, and 50th ASCO Annual Meeting, Chicago, IL, May 30-June 3, 2014. -->
−
 
+
#'''OPTiM:''' Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780-8. Epub 2015 May 26. [https://doi.org/10.1200/jco.2014.58.3377 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26014293/ PubMed] [https://clinicaltrials.gov/study/NCT00769704 NCT00769704]
−
=Metastatic or unresectable disease=
+
##'''Update:''' Andtbacka RHI, Collichio F, Harrington KJ, Middleton MR, Downey G, Ӧhrling K, Kaufman HL. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma. J Immunother Cancer. 2019 Jun 6;7(1):145. [https://jitc.biomedcentral.com/articles/10.1186/s40425-019-0623-z link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554874/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31171039/ PubMed]
  
 +
=Metastatic or unresectable disease, first-line=
 
==ABC {{#subobject:ddf2d4|Regimen=1}}==
 
==ABC {{#subobject:ddf2d4|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#toc|back to top]]
 
−
|}
 
 
ABC: '''<u>A</u>'''braxane (Paclitaxel nanoparticle albumin-bound), '''<u>B</u>'''evacizumab, '''<u>C</u>'''arboplatin
 
ABC: '''<u>A</u>'''braxane (Paclitaxel nanoparticle albumin-bound), '''<u>B</u>'''evacizumab, '''<u>C</u>'''arboplatin
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:318c66|Variant=1}}===
 
===Regimen {{#subobject:318c66|Variant=1}}===
−
{| border="1" style="text-align:center;" !align="left"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
|'''Study'''
+
! style="width: 20%" |Study
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
! style="width: 20%" |Dates of enrollment
−
|'''Comparator'''
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://onlinelibrary.wiley.com/doi/10.1002/cncr.27760/full Kottschade et al. 2013 (N0775)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089063/ Kottschade et al. 2013 (N0775)]
−
|<span
+
|2008-2010
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
−
padding:3px 6px 3px 6px;
+
|[[#Temozolomide_.26_Bevacizumab|Temozolomide & Bevacizumab]]
−
border-color:black;
+
| style="background-color:#91cf60" |Seems to have superior PFS6 (primary endpoint)
−
border-width:2px;
 
−
border-style:solid;">Randomized Phase II</span>
 
−
|[[Melanoma#Temozolomide_.26_Bevacizumab_.28TB.29|Temozolomide & Bevacizumab]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''Note: The doses listed here are the amended starting doses.''
−
''The doses listed here are the amended starting doses.''
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 80 mg/m2 IV once per day on days 1, 8, 15
+
====Chemotherapy====
 +
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 +
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
 +
====Targeted therapy====
 
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
 
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
 +
'''28-day cycles'''
 +
</div></div>
 +
===References===
 +
<!-- This study was presented at the American Society for Clinical Oncology 2011 Annual Meeting, June 3 to 7, Chicago, Illinois, as a poster discussion. -->
 +
#'''N0775:''' Kottschade LA, Suman VJ, Perez DG, McWilliams RR, Kaur JS, Amatruda TT 3rd, Geoffroy FJ, Gross HM, Cohen PA, Jaslowski AJ, Kosel ML, Markovic SN; North Central Cancer Treatment Group. A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N0775. Cancer. 2013 Feb 1;119(3):586-92. Epub 2012 Aug 22. [https://doi.org/10.1002/cncr.27760 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089063/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22915053/ PubMed] [https://clinicaltrials.gov/study/NCT00626405 NCT00626405]
 +
==Carboplatin & Paclitaxel (CP) {{#subobject:hbq571|Regimen=1}}==
 +
CP: '''<u>C</u>'''arboplatin & '''<u>P</u>'''aclitaxel
 +
<br>PC: '''<u>P</u>'''aclitaxel & '''<u>C</u>'''arboplatin
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 5/175 {{#subobject:6ahg7c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.20.00902 Yan et al. 2021 (BCH-MM-131101)]
 +
|2014-2017
 +
| style="background-color:#1a9851" |Randomized Phase 2 (C)
 +
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Bevacizumab|CP & Bevacizumab]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
 
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
−
 
+
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
−
'''28-day cycles, given until progression of disease'''
+
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2 {{#subobject:6a8ye2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878104/ Flaherty et al. 2013 (ECOG E2603)]
 +
|2005-2008
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Sorafenib|CP & Sorafenib]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Carboplatin (Paraplatin)]] as follows:
 +
**Cycles 1 to 4: AUC 6 IV over 30 minutes once on day 1, '''given second'''
 +
**Cycle 5 up to 10: AUC 5 IV over 30 minutes once on day 1, '''given second'''
 +
*[[Paclitaxel (Taxol)]] as follows:
 +
**Cycles 1 to 4: 225 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
 +
**Cycle 5 up to 10: 175 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
 +
'''21-day cycle for up to 10 cycles'''
 +
</div></div>
  
 
===References===
 
===References===
−
# Kottschade LA, Suman VJ, Perez DG, McWilliams RR, Kaur JS, Amatruda TT 3rd, Geoffroy FJ, Gross HM, Cohen PA, Jaslowski AJ, Kosel ML, Markovic SN. A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma : a North Central Cancer Treatment Group study, N0775. Cancer. 2013 Feb 1;119(3):586-92. Epub 2012 Aug 22. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.27760/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22915053 PubMed]
+
#'''ECOG E2603:''' Flaherty KT, Lee SJ, Zhao F, Schuchter LM, Flaherty L, Kefford R, Atkins MB, Leming P, Kirkwood JM. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol. 2013 Jan 20;31(3):373-9. Epub 2012 Dec 17. [https://doi.org/10.1200/jco.2012.42.1529 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878104/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23248256/ PubMed] [https://clinicaltrials.gov/study/NCT00110019 NCT00110019]
−
 
+
#'''BCH-MM-131101:''' Yan X, Sheng X, Chi Z, Si L, Cui C, Kong Y, Tang B, Mao L, Wang X, Lian B, Li S, Bai X, Zhou L, Dai J, Yao H, Guo J. Randomized Phase II Study of Bevacizumab in Combination With Carboplatin Plus Paclitaxel in Patients With Previously Untreated Advanced Mucosal Melanoma. J Clin Oncol. 2021 Mar 10;39(8):881-889. Epub 2021 Jan 14. [https://doi.org/10.1200/jco.20.00902 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33444116/ PubMed] [https://clinicaltrials.gov/study/NCT02023710 NCT02023710]
−
==CP - Carboplatin & Paclitaxel {{#subobject:610571|Regimen=1}}==
+
==Carboplatin & Paclitaxel (CP) & Bevacizumab {{#subobject:hjgb71|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
CPB: '''<u>C</u>'''arboplatin, '''<u>P</u>'''aclitaxel, '''<u>B</u>'''evacizumab
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:6trg7c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.20.00902 Yan et al. 2021 (BCH-MM-131101)]
 +
|2014-2017
 +
| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
 +
|[[#Carboplatin_.26_Paclitaxel_.28CP.29|CP]]
 +
| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)<br>Median OS: 14 vs 9 mo<br>(HR 0.61, 95% CI 0.41-0.92)<br><br>Superior PFS (primary endpoint)<br>Median PFS: 4.8 vs 3 mo<br>(HR 0.46, 95% CI 0.31-0.695)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
CP: '''<u>C</u>'''arboplatin, '''<u>P</u>'''aclitaxel
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
===Regimen #1, Rao et al. 2006 {{#subobject:5edf1c|Variant=1}}===
+
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
−
Level of Evidence:
+
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
−
<span
+
====Targeted therapy====
−
style="background:#ff0000;
+
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1 & 15
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Retrospective</span>
 
−
 
 
−
*[[Carboplatin (Paraplatin)]] AUC 2 IV once per day on days 1, 8, 15
 
−
*[[Paclitaxel (Taxol)]] 100 mg/m2 IV once per day on days 1, 8, 15
 
−
 
 
 
'''28-day cycles'''
 
'''28-day cycles'''
 +
</div></div>
  
−
===Regimen #2, Rao et al. 2006 {{#subobject:6fddea|Variant=1}}===
+
===References===
−
Level of Evidence:
+
#'''BCH-MM-131101:''' Yan X, Sheng X, Chi Z, Si L, Cui C, Kong Y, Tang B, Mao L, Wang X, Lian B, Li S, Bai X, Zhou L, Dai J, Yao H, Guo J. Randomized Phase II Study of Bevacizumab in Combination With Carboplatin Plus Paclitaxel in Patients With Previously Untreated Advanced Mucosal Melanoma. J Clin Oncol. 2021 Mar 10;39(8):881-889. Epub 2021 Jan 14. [https://doi.org/10.1200/jco.20.00902 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33444116/ PubMed] [https://clinicaltrials.gov/study/NCT02023710 NCT02023710]
−
<span
+
==Carboplatin & nab-Paclitaxel {{#subobject:a013af|Regimen=1}}==
−
style="background:#ff0000;
+
<div class="toccolours" style="background-color:#eeeeee">
−
padding:3px 6px 3px 6px;
+
===Regimen {{#subobject:d78d72|Variant=1}}===
−
border-color:black;
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
border-width:2px;
+
! style="width: 33%" |Study
−
border-style:solid;">Retrospective</span>
+
! style="width: 33%" |Dates of enrollment
−
 
+
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
+
|-
−
*[[Paclitaxel (Taxol)]] 175 to 200 mg/m2 IV once on day 1
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116030/ Kottschade et al. 2011 (N057E1)]
−
 
+
|2006-2007
−
'''21-day cycles'''
+
| style="background-color:#91cf61" |Phase 2
−
 
+
|-
−
===Regimen #3 {{#subobject:6a83f2|Variant=1}}===
+
|}
−
{| border="1" style="text-align:center;" !align="left"  
+
<div class="toccolours" style="background-color:#b3e2cd">
−
|'''Study'''
+
====Chemotherapy====
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
*[[Carboplatin (Paraplatin)]] AUC 2 IV once per day on days 1, 8, 15, '''given second'''
−
|'''Comparator'''
+
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, '''given first'''
 +
====Supportive therapy====
 +
*"All patients received standard supportive care, including antiemetics, antibiotics, blood/platelet transfusions, erythropoietin, and colony-stimulating factors at the discretion of the treating physician."
 +
'''28-day cycle for up to 8 cycles;''' patients without progressive disease or excessive toxicity could receive additional therapy per physician discretion
 +
</div></div>
 +
===References===
 +
#'''N057E1:''' Kottschade LA, Suman VJ, Amatruda T 3rd, McWilliams RR, Mattar BI, Nikcevich DA, Behrens R, Fitch TR, Jaslowski AJ, Markovic SN; North Central Cancer Treatment Group. A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, N057E(1). Cancer. 2011 Apr 15;117(8):1704-10. Epub 2010 Nov 8. [https://doi.org/10.1002/cncr.25659 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116030/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21472717/ PubMed] [https://clinicaltrials.gov/study/NCT00404235 NCT00404235]
 +
==Cisplatin & Dacarbazine {{#subobject:1c1243|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:fc0483|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/27/17/2823.long Hauschild et al. 2009]
+
|[https://doi.org/10.1200/jco.2002.20.6.1600 Ridolfi et al. 2002]
−
|<span
+
|1997-1999
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[Melanoma_-_historical#Cisplatin.2C_Dacarbazine.2C_IL-2.2C_IFN_alfa-2b_.2B.2F-_Carmustine|Cisplatin, Dacarbazine, IL-2, IFN alfa-2b +/- Carmustine]]
−
border-color:black;
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Carboplatin.2C_Paclitaxel.2C_Sorafenib|Carboplatin, Paclitaxel, Sorafenib]]
 
 
|-
 
|-
−
!colspan="4" align="center"|
+
|}
 +
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
*[[Dacarbazine (DTIC)]] 800 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 cycles'''
 +
</div></div>
 +
===References===
 +
#Ridolfi R, Chiarion-Sileni V, Guida M, Romanini A, Labianca R, Freschi A, Lo Re G, Nortilli R, Brugnara S, Vitali P, Nanni O; Italian Melanoma Intergroup. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol. 2002 Mar 15;20(6):1600-7. [https://doi.org/10.1200/jco.2002.20.6.1600 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11896110/ PubMed]
 +
==Cisplatin, Dacarbazine, Paclitaxel {{#subobject:12c753|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:9b0171|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Dates of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/31/3/373.long Flaherty et al. 2013 (E2603)]
+
|[https://doi.org/10.1097/coc.0b013e3181942a1f Papadopoulos et al. 2009]
−
|<span
+
|2000-04 to 2002-09
−
style="background:#00CD00;
+
| style="background-color:#91cf61" |Phase 1/2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Carboplatin.2C_Paclitaxel.2C_Sorafenib|Carboplatin, Paclitaxel, Sorafenib]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''Note: This is the suggested phase 2 dosing.''
−
*[[Carboplatin (Paraplatin)]] AUC 6 IV over 30 minutes once on day 1, '''given second'''
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Paclitaxel (Taxol)]] 225 mg/m2 IV over 3 hours once on day 1, '''given first'''
+
====Chemotherapy====
−
 
+
*[[Cisplatin (Platinol)]] 20 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 4
−
'''21-day cycle x 4 cycles, then'''
+
*[[Dacarbazine (DTIC)]] 800 mg/m<sup>2</sup> IV once on day 1
−
 
+
*[[Paclitaxel (Taxol)]] 120 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 8
−
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 30 minutes once on day 1, '''given second'''
+
'''21-day cycles (see note)'''
−
*[[Paclitaxel (Taxol)]] 175 mg/m2 IV over 3 hours once on day 1, '''given first'''
+
</div></div>
−
 
 
−
'''21-day cycle x 6 cycles, until progression of disease, or unacceptable toxicity'''
 
−
 
 
 
===References===
 
===References===
−
# Rao RD, Holtan SG, Ingle JN, Croghan GA, Kottschade LA, Creagan ET, Kaur JS, Pitot HC, Markovic SN. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer. 2006 Jan 15;106(2):375-82. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.21611/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16342250 PubMed]
+
#Papadopoulos NE, Bedikian A, Ring S, Kim KB, Hwu WJ, Gerber DL, Homsi J, Hwu P. Phase I/II study of a cisplatin-taxol-dacarbazine regimen in metastatic melanoma. Am J Clin Oncol. 2009 Oct;32(5):509-14. [https://doi.org/10.1097/coc.0b013e3181942a1f link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19506454/ PubMed]
−
# Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermont A, Grabbe S, Gonzalez R, Gille J, Peschel C, Schadendorf D, Garbe C, O'Day S, Daud A, White JM, Xia C, Patel K, Kirkwood JM, Keilholz U. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009 Jun 10;27(17):2823-30. Epub 2009 Apr 6. [http://jco.ascopubs.org/content/27/17/2823.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19349552 PubMed]
 
−
# Flaherty KT, Lee SJ, Zhao F, Schuchter LM, Flaherty L, Kefford R, Atkins MB, Leming P, Kirkwood JM. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol. 2013 Jan 20;31(3):373-9. Epub 2012 Dec 17. [http://jco.ascopubs.org/content/31/3/373.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23248256 PubMed]
 
−
# Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70076-8/fulltext link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/25795410 PubMed]
 
  
−
==Carboplatin & Paclitaxel, nanoparticle albumin-bound {{#subobject:a013af|Regimen=1}}==
+
==CVD (Vindesine) {{#subobject:9gt161|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
CVD: '''<u>C</u>'''isplatin, '''<u>V</u>'''indesine, '''<u>D</u>'''acarbazine
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, q3wk {{#subobject:6bgtye|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdl007 Bajetta et al. 2006]
 +
|1999-2003
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Regimen_classes#Biochemotherapy|Biochemotherapy]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 3
 +
*[[Vindesine (Eldisine)]] 2.5 mg/m<sup>2</sup> IV once on day 1
 +
*[[Dacarbazine (DTIC)]] 250 mg/m<sup>2</sup> IV once per day on days 1 to 3
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, q4wk {{#subobject:6b20de|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/s0959-8049(98)00068-9 Jungnelius et al. 1998]
 +
|NR
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Melanoma#Dacarbazine_.26_Vindesine|Dacarbazine & Vindesine]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
===Regimen, Kottschade et al. 2011 (N057E(1)) {{#subobject:d78d72|Variant=1}}===
+
====Chemotherapy====
−
*[[Carboplatin (Paraplatin)]] AUC 2 IV once per day on days 1, 8, 15, given second
+
*[[Cisplatin (Platinol)]] as follows:
−
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m2 IV over 30 minutes once per day on days 1, 8, 15, given first
+
**Cycles 1 to 3: 100 mg/m<sup>2</sup> IV over 30 minutes once on day 1
−
 
+
*[[Vindesine (Eldisine)]] 3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
−
'''28-day cycles x up to 8 cycles;''' patients without progressive disease or excessive toxicity could receive additional therapy per physician discretion
+
*[[Dacarbazine (DTIC)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5
−
 
+
'''28-day cycles'''
−
Supportive medications:
+
</div></div>
−
*"All patients received standard supportive care, including antiemetics, antibiotics, blood/platelet transfusions, erythropoietin, and colony-stimulating factors at the discretion of the treating physician."
 
−
 
 
 
===References===
 
===References===
−
# Kottschade LA, Suman VJ, Amatruda T 3rd, McWilliams RR, Mattar BI, Nikcevich DA, Behrens R, Fitch TR, Jaslowski AJ, Markovic SN. A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma : a North Central Cancer Treatment Group Study, N057E(1). Cancer. 2011 Apr 15;117(8):1704-10. doi: 10.1002/cncr.25659. Epub 2010 Nov 8. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.25659/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21472717 PubMed]
+
#Jungnelius U, Ringborg U, Aamdal S, Mattsson J, Stierner U, Ingvar C, Malmström P, Andersson R, Karlsson M, Willman K, Wist E, Bjelkengren G, Westberg R. Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma: a randomised phase III trial. Eur J Cancer. 1998 Aug;34(9):1368-74. [https://doi.org/10.1016/s0959-8049(98)00068-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9849419/ PubMed]
 +
#Bajetta E, Del Vecchio M, Nova P, Fusi A, Daponte A, Sertoli MR, Queirolo P, Taveggia P, Bernengo MG, Legha SS, Formisano B, Cascinelli N. Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon-alpha2b in metastatic melanoma. Ann Oncol. 2006 Apr;17(4):571-7. Epub 2006 Feb 9. [https://doi.org/10.1093/annonc/mdl007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16469753/ PubMed]
  
−
==Carboplatin, Paclitaxel, Sorafenib {{#subobject:1f09b1|Regimen=1}}==
+
==Dacarbazine monotherapy {{#subobject:d8ug9b|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
===Example orders===
 +
*[[Example orders for Dacarbazine (DTIC) in melanoma]]
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 850 mg/m<sup>2</sup> q3wk {{#subobject:b6dcb3|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa1104621 Robert et al. 2011 (CA184-024)]
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Dacarbazine_.26_Ipilimumab|Dacarbazine & Ipilimumab]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|}
 +
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Dacarbazine (DTIC)]] 850 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 850 mg/m<sup>2</sup> q4wk {{#subobject:954862|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdj138 Schadendorf et al. 2006]
 +
|2000-2003
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|Autologous peptide-pulsed monocyte-derived dendritic cells
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|}
 +
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Dacarbazine (DTIC)]] 850 mg/m<sup>2</sup> IV once on day 1
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 900 mg/m<sup>2</sup> q3wk {{#subobject:a17084|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598549/ Daponte et al. 2013 (SICOG 0109)]
 +
|2002-2007
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Dacarbazine_.26_Fotemustine_999|Dacarbazine & Fotemustine]]<br>2. [[#Dacarbazine_.26_Interferon_alfa-2b_999|Dacarbazine & IFN alfa-2b]]<br> 3. [[#Dacarbazine.2C_Fotemustine.2C_Interferon_alfa-2b_999|Dacarbazine, Fotemustine, IFN alfa-2b]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
−
===Regimen {{#subobject:316044|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
{| border="1" style="text-align:center;" !align="left"  
+
====Chemotherapy====
−
|'''Study'''
+
*[[Dacarbazine (DTIC)]] 900 mg/m<sup>2</sup> IV once on day 1
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
'''21-day cycles'''
−
|'''Comparator'''
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 1000 mg/m<sup>2</sup> q3wk {{#subobject:beug4c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.1999.17.9.2745 Chapman et al. 1999]
 +
|1991-1997
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Dartmouth_regimen_333|Dartmouth regimen]]
 +
| style="background-color:#fee08b" |Might have inferior ORR
 +
|-
 +
|[https://doi.org/10.1200/jco.2006.06.0483 Bedikian et al. 2006 (AGENDA)]
 +
|2000-2003
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Dacarbazine_.26_Oblimersen_777|Dacarbazine & Oblimersen]]
 +
| style="background-color:#fee08b" |Might have inferior OS<br>Median OS: 7.8 vs 9 mo<br>(HR 1.15, 95% CI 0.99-1.33)
 +
|-
 +
|[https://doi.org/10.1200/JCO.2007.11.9941 Testori et al. 2008 (C-100-21)]
 +
|2002-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Vitespen_monotherapy_999|Vitespen]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303777/ Bedikian et al. 2010]
 +
|2002-2007
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#DHA-paclitaxel_monotherapy_999|DHA-paclitaxel]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878048/ Ribas et al. 2013 (A3671009)]
 +
|2006-03 to 2007-07
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Tremelimumab_monotherapy_999|Tremelimumab]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652683/ Ugurel et al. 2017 (ChemoSensMM)]
 +
|2008-2012
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|Chemosensitivity-directed therapy:<br>1. [[#Cisplatin_.26_Paclitaxel_999|Cisplatin & Paclitaxel]]<br>2. [[#Cytarabine_.26_Treosulfan_999|Cytarabine & Treosulfan]]<br>3. [[#Gemcitabine_.26_Treosulfan|Gemcitabine & Treosulfan]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279094/ Hersh et al. 2015 (CA033)]
 +
|2009-04 to 2011-06
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]
 +
| style="background-color:#fc8d59" |Seems to have inferior PFS
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa1412082 Robert et al. 2014 (CheckMate 066)]
 +
|2013-01 to 2014-02
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Nivolumab_monotherapy_2|Nivolumab]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Dacarbazine (DTIC)]] 1000 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #5, 1000 mg/m<sup>2</sup>, split doses, q4wk {{#subobject:3f3475|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/27/17/2823.long Hauschild et al. 2009]
+
|[https://doi.org/10.1200/jco.1998.16.5.1743 Falkson et al. 2003 (ECOG E3690)]
−
|<span
+
|NR
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|1. [[#Dacarbazine_.26_Interferon_alfa-2b_888|DTIC & Interferon]]<br>2. [[Melanoma_-_historical#Dacarbazine_.26_Tamoxifen|DTIC & Tamoxifen]]<br> 3. [[#Dacarbazine.2C_Interferon_alfa-2b.2C_Tamoxifen_888|DTIC, Interferon, Tamoxifen]]
−
border-color:black;
+
| style="background-color:#fc8d59" |Seems to have inferior ORR
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#CP_-_Carboplatin_.26_Paclitaxel|Carboplatin & Paclitaxel]]
 
 
|-
 
|-
−
!colspan="4" align="center"|
+
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Dacarbazine (DTIC)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #6, 1250 mg/m<sup>2</sup>, split doses, q3wk {{#subobject:4bacb3|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/31/3/373.long Flaherty et al. 2013 (E2603)]
+
|[https://doi.org/10.1200/jco.2000.18.1.158 Middleton et al. 2000b]
−
|<span
+
|1995-1997
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[#Temozolomide_monotherapy|Temozolomide]]
−
border-color:black;
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#CP_-_Carboplatin_.26_Paclitaxel|Carboplatin & Paclitaxel]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
''Hauschild et al. 2009 and Flaherty et al. 2013 (E2603) were negative studies.  They did not show improved outcomes for Carboplatin, Paclitaxel, Sorafenib as compared to Carboplatin and Paclitaxel.''
+
====Chemotherapy====
−
*[[Carboplatin (Paraplatin)]] AUC 6 IV over 30 minutes once on day 1, given second
+
*[[Dacarbazine (DTIC)]] 250 mg/m<sup>2</sup> IV over 20 to 30 minutes once per day on days 1 to 5
−
*[[Paclitaxel (Taxol)]] 225 mg/m2 IV over 3 hours once on day 1, given first
+
'''21-day cycles'''
−
*[[Sorafenib (Nexavar)]] 400 mg PO BID on days 2 to 19
+
</div></div><br>
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
'''21-day cycles x 4 cycles, then'''
+
===Regimen variant #7, 1250 mg/m<sup>2</sup>, split doses, q4wk {{#subobject:f3110c|Variant=1}}===
−
 
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
*[[Carboplatin (Paraplatin)]] AUC 5 IV over 30 minutes once on day 1, given second
+
! style="width: 20%" |Study
−
*[[Paclitaxel (Taxol)]] 175 mg/m2 IV over 3 hours once on day 1, given first
+
! style="width: 20%" |Dates of enrollment
−
*[[Sorafenib (Nexavar)]] 400 mg PO BID on days 2 to 19
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
 
+
! style="width: 20%" |Comparator
−
'''21-day cycles x 6 cycles, until progression of disease, or unacceptable toxicity; then proceed to sorafenib monotherapy'''
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
 
+
|-
−
====Sorafenib monotherapy====
+
|[https://doi.org/10.1200/JCO.2004.04.165 Avril et al. 2004]
−
*[[Sorafenib (Nexavar)]] 400 mg PO BID on days 1 to 21
+
|1998-2000
−
 
+
| style="background-color:#1a9851" |Phase 3 (C)
−
'''21-day cycles, given until progression of disease or unacceptable toxicity'''
+
|[[#Fotemustine_monotherapy|Fotemustine]]
−
 
+
| style="background-color:#fc8d59" |Seems to have inferior ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Dacarbazine (DTIC)]] 250 mg/m<sup>2</sup> IV over 20 to 30 minutes once per day on days 1 to 5
 +
'''28-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermont A, Grabbe S, Gonzalez R, Gille J, Peschel C, Schadendorf D, Garbe C, O'Day S, Daud A, White JM, Xia C, Patel K, Kirkwood JM, Keilholz U. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009 Jun 10;27(17):2823-30. Epub 2009 Apr 6. [http://jco.ascopubs.org/content/27/17/2823.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19349552 PubMed]
+
#'''ECOG E3690:''' Falkson CI, Ibrahim J, Kirkwood JM, Coates AS, Atkins MB, Blum RH; [[Study_Groups#ECOG|ECOG]]. Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol. 1998 May;16(5):1743-51. [https://doi.org/10.1200/jco.1998.16.5.1743 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9586887/ PubMed]
−
# Flaherty KT, Lee SJ, Zhao F, Schuchter LM, Flaherty L, Kefford R, Atkins MB, Leming P, Kirkwood JM. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol. 2013 Jan 20;31(3):373-9. doi: 10.1200/JCO.2012.42.1529. Epub 2012 Dec 17. [http://jco.ascopubs.org/content/31/3/373.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23248256 PubMed]
+
#Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro AN, Panageas KS, Begg CB, Agarwala SS, Schuchter LM, Ernstoff MS, Houghton AN, Kirkwood JM. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999 Sep;17(9):2745-51. [https://doi.org/10.1200/jco.1999.17.9.2745 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10561349/ PubMed]
 +
#Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. [https://doi.org/10.1200/jco.2000.18.1.158 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10623706/ PubMed]
 +
#Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saïag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004 Mar 15;22(6):1118-25. [https://doi.org/10.1200/JCO.2004.04.165 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15020614/ PubMed]
 +
#Schadendorf D, Ugurel S, Schuler-Thurner B, Nestle FO, Enk A, Bröcker EB, Grabbe S, Rittgen W, Edler L, Sucker A, Zimpfer-Rechner C, Berger T, Kamarashev J, Burg G, Jonuleit H, Tüttenberg A, Becker JC, Keikavoussi P, Kämpgen E, Schuler G; DeCOG. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol. 2006 Apr;17(4):563-70. Epub 2006 Jan 17. [https://doi.org/10.1093/annonc/mdj138 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16418308/ PubMed]
 +
#'''AGENDA:''' Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, Pavlick AC, DeConti R, Hersh EM, Hersey P, Kirkwood JM, Haluska FG; Oblimersen Melanoma Study Group. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol. 2006 Oct 10;24(29):4738-45. Epub 2006 Sep 11. [https://doi.org/10.1200/jco.2006.06.0483 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16966688/ PubMed] [https://clinicaltrials.gov/study/NCT00518895 NCT00518895]
 +
#'''C-100-21:''' Testori A, Richards J, Whitman E, Mann GB, Lutzky J, Camacho L, Parmiani G, Tosti G, Kirkwood JM, Hoos A, Yuh L, Gupta R, Srivastava PK; C-100-21 Study Group. Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: the C-100-21 Study Group. J Clin Oncol. 2008 Feb 20;26(6):955-62. Erratum in: J Clin Oncol. 2008 Aug 1;26(22): 3819. [https://doi.org/10.1200/JCO.2007.11.9941 link to original article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/18281670/ PubMed]
 +
#Bedikian AY, DeConti RC, Conry R, Agarwala S, Papadopoulos N, Kim KB, Ernstoff M. Phase 3 study of docosahexaenoic acid-paclitaxel versus dacarbazine in patients with metastatic malignant melanoma. Ann Oncol. 2011 Apr;22(4):787-93. Epub 2010 Sep 20. [https://doi.org/10.1093/annonc/mdq438 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303777/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20855467/ PubMed]
 +
#'''CA184-024:''' Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. [https://doi.org/10.1056/NEJMoa1104621 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21639810/ PubMed] [https://clinicaltrials.gov/study/NCT00324155 NCT00324155]
 +
##'''Update:''' Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, Garbe C, Chiarion-Sileni V, Testori A, Chen TT, Tschaika M, Wolchok JD. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6. Epub 2015 Feb 23. [https://doi.org/10.1200/jco.2014.56.6018 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5795709/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25713437/ PubMed]
 +
<!-- Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, 2008, and 25th Annual Meeting of the International Society for Biological Therapy of Cancer, Washington, DC, October 2-4, 2010. -->
 +
#'''A3671009:''' Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G, Lorigan P, Kendra KL, Maio M, Trefzer U, Smylie M, McArthur GA, Dreno B, Nathan PD, Mackiewicz J, Kirkwood JM, Gomez-Navarro J, Huang B, Pavlov D, Hauschild A. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013 Feb 10;31(5):616-22. Epub 2013 Jan 7. [https://doi.org/10.1200/JCO.2012.44.6112 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878048/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23295794/ PubMed] [https://clinicaltrials.gov/study/NCT00257205 NCT00257205]
 +
#'''SICOG 0109:''' Daponte A, Signoriello S, Maiorino L, Massidda B, Simeone E, Grimaldi AM, Caracò C, Palmieri G, Cossu A, Botti G, Petrillo A, Lastoria S, Cavalcanti E, Aprea P, Mozzillo N, Gallo C, Comella G, Ascierto PA; Southern Italy Cooperative Oncology Group. Phase III randomized study of fotemustine and dacarbazine versus dacarbazine with or without interferon-α in advanced malignant melanoma. J Transl Med. 2013 Feb 13;11:38. [https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-11-38 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598549/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23402397/ PubMed] [https://clinicaltrials.gov/study/NCT01359956 NCT01359956]
 +
#'''CheckMate 066:''' Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. Epub 2014 Nov 16. [https://doi.org/10.1056/NEJMoa1412082 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25399552/ PubMed] [https://clinicaltrials.gov/study/NCT01721772 NCT01721772]
 +
##'''Update:''' Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Ny L, Arance A, Svane IM, Schadendorf D, Gogas H, Saci A, Jiang J, Rizzo J, Atkinson V. Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol. 2019 Feb 1;5(2):187-194. Epub 2018 Oct 25.  [https://jamanetwork.com/journals/jamaoncology/article-abstract/2707224 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439558/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30422243/ PubMed]
 +
##'''Update:''' Robert C, Long GV, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Rutkowski P, Hassel JC, McNeil CM, Kalinka EA, Lebbé C, Charles J, Hernberg MM, Savage KJ, Chiarion-Sileni V, Mihalcioiu C, Mauch C, Arance A, Cognetti F, Ny L, Schmidt H, Schadendorf D, Gogas H, Zoco J, Re S, Ascierto PA, Atkinson V. Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma. J Clin Oncol. 2020 Nov 20;38(33):3937-3946. Epub 2020 Sep 30. [https://doi.org/10.1200/jco.20.00995 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676881/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32997575/ PubMed]
 +
#'''CA033:''' Hersh EM, Del Vecchio M, Brown MP, Kefford R, Loquai C, Testori A, Bhatia S, Gutzmer R, Conry R, Haydon A, Robert C, Ernst S, Homsi J, Grob JJ, Kendra K, Agarwala SS, Li M, Clawson A, Brachmann C, Karnoub M, Elias I, Renschler MF, Hauschild A. A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann Oncol. 2015 Nov;26(11):2267-74. Epub 2015 Sep 26. [https://doi.org/10.1093/annonc/mdv324 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279094/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26410620/ PubMed] [https://clinicaltrials.gov/study/NCT00864253 NCT00864253]
 +
#'''ChemoSensMM:''' Ugurel S, Loquai C, Terheyden P, Schadendorf D, Richtig E, Utikal J, Gutzmer R, Rass K, Sunderkötter C, Stein A, Fluck M, Kaatz M, Trefzer U, Kähler K, Stadler R, Berking C, Höller C, Kerschke L, Edler L, Kopp-Schneider A, Becker JC. Chemosensitivity-directed therapy compared to dacarbazine in chemo-naive advanced metastatic melanoma: a multicenter randomized phase-3 DeCOG trial. Oncotarget. 2017 Jun 27;8(44):76029-76043. eCollection 2017 Sep 29. [https://doi.org/10.18632/oncotarget.18635 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652683/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29100289/ PubMed] [https://clinicaltrials.gov/study/NCT00779714 NCT00779714]
  
−
==Cisplatin, Dacarbazine +/- Carmustine {{#subobject:1c1243|Regimen=1}}==
+
==Dacarbazine & Ipilimumab {{#subobject:5754a8|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:7b4884|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa1104621 Robert et al. 2011 (CA184-024)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-90-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
 +
|-
 +
|} -->
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Dacarbazine_monotherapy|Dacarbazine]]
 +
| style="background-color:#1a9850" |Superior OS<sup>1</sup> (primary endpoint)<br>Median OS: 11.2 vs 9.1 mo<br>(HR 0.69, 95% CI 0.57-0.84)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:fc0483|Variant=1}}===
+
''<sup>1</sup>Reported efficacy is based on the 2015 update.''
−
{| border="1" style="text-align:center;" !align="left"  
+
<div class="toccolours" style="background-color:#b3e2cd">
−
|'''Study'''
+
====Chemotherapy====
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
*[[Dacarbazine (DTIC)]] as follows:
−
|'''Comparator'''
+
**Cycles 1 to 8: 850 mg/m<sup>2</sup> IV once on day 1
 +
====Immunotherapy====
 +
*[[Ipilimumab (Yervoy)]] as follows:
 +
**Cycles 1 to 4: 10 mg/kg IV once on day 1
 +
**Cycle 9 onwards: 10 mg/kg IV once on day 1
 +
'''21-day cycle for 8 cycles, then 12-week cycles'''
 +
</div></div>
 +
===References===
 +
#'''CA184-024:''' Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. [https://doi.org/10.1056/NEJMoa1104621 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21639810/ PubMed] [https://clinicaltrials.gov/study/NCT00324155 NCT00324155]
 +
##'''Update:''' Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, Garbe C, Chiarion-Sileni V, Testori A, Chen TT, Tschaika M, Wolchok JD. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6. Epub 2015 Feb 23. [https://doi.org/10.1200/jco.2014.56.6018 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5795709/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25713437/ PubMed]
 +
==Dacarbazine & Vindesine {{#subobject:97ve61|Regimen=1}}==
 +
DV: '''<u>D</u>'''acarbazine & '''<u>V</u>'''indesine
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:6b20de|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/20/6/1600.long Ridolfi et al. 2002]
+
|[https://doi.org/10.1016/s0959-8049(98)00068-9 Jungnelius et al. 1998]
−
|<span
+
|NR
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[Melanoma_-_historical#CVD_.28Vindesine.29|CVD]]
−
border-color:black;
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[#Cisplatin.2C_Dacarbazine.2C_IL-2.2C_IFN_alfa-2b_.2B.2F-_Carmustine|Cisplatin, Dacarbazine, IL-2, IFN alfa-2b +/- Carmustine]]
 
 
|-
 
|-
 
|}
 
|}
−
*[[Cisplatin (Platinol)]] 75 mg/m2 IV once on day 1
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Dacarbazine (DTIC)]] 800 mg/m2 IV once on day 1
+
====Chemotherapy====
−
*Optional: [[Carmustine (BiCNU)]] 100 mg/m2 (note: in Ridolfi et al. 2002, in contrast to the treatment text, figure 1 lists a dosage of 150 mg/m2) IV once on day 1
+
*[[Dacarbazine (DTIC)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5
−
 
+
*[[Vindesine (Eldisine)]] 3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
−
'''21-day cycle x 6 cycles'''
+
'''28-day cycles'''
 +
</div></div>
 +
===References===
 +
#Jungnelius U, Ringborg U, Aamdal S, Mattsson J, Stierner U, Ingvar C, Malmström P, Andersson R, Karlsson M, Willman K, Wist E, Bjelkengren G, Westberg R. Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma: a randomised phase III trial. Eur J Cancer. 1998 Aug;34(9):1368-74. [https://doi.org/10.1016/s0959-8049(98)00068-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9849419/ PubMed]
  
 +
==Fotemustine monotherapy {{#subobject:92d0c6|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:ff4f50|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2004.04.165 Avril et al. 2004]
 +
|1998-2000
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Dacarbazine_monotherapy_2|Dacarbazine]]
 +
| style="background-color:#91cf60" |Seems to have superior ORR (primary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fotemustine (Muphoran)]] as follows:
 +
**Cycle 1: 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 +
**Cycle 2 onwards: 100 mg/m<sup>2</sup> IV once on day 1
 +
'''8-week course, then 21-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Ridolfi R, Chiarion-Sileni V, Guida M, Romanini A, Labianca R, Freschi A, Lo Re G, Nortilli R, Brugnara S, Vitali P, Nanni O; Italian Melanoma Intergroup. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol. 2002 Mar 15;20(6):1600-7. [http://jco.ascopubs.org/content/20/6/1600.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/11896110 PubMed]
+
#Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saïag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004 Mar 15;22(6):1118-25. [https://doi.org/10.1200/JCO.2004.04.165 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15020614/ PubMed]
−
 
+
==Ipilimumab monotherapy {{#subobject:cbz3f4|Regimen=1}}==
−
==Cisplatin, Dacarbazine, IL-2, IFN alfa-2b +/- Carmustine {{#subobject:d23e47|Regimen=1}}==
+
===Example orders===
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
*[[Example orders for Ipilimumab (Yervoy) in melanoma]]
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:33ug6a|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:a3dd35|Variant=1}}===
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
{| border="1" style="text-align:center;" !align="left"  
+
! style="width: 17%" |Study
−
|'''Study'''
+
! style="width: 15%" |Dates of enrollment
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
|'''Comparator'''
+
! style="width: 17%" |Comparator
 +
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5698905/ Larkin et al. 2015 (CheckMate 067)]
 +
| rowspan="2" |2013-07 to 2014-03
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Ipilimumab_.26_Nivolumab_2|Ipilimumab & Nivolumab]]
 +
| style="background-color:#d73027" |Inferior OS<sup>1</sup>
 +
| style="background-color:#eeee01" |Equivalent HRQoL
 +
|-
 +
|2. [[#Nivolumab_monotherapy_2|Nivolumab]]
 +
| style="background-color:#d73027" |Inferior OS<sup>1</sup>
 +
| style="background-color:#eeee01" |Equivalent HRQoL
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/20/6/1600.long Ridolfi et al. 2002]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5744258/ Postow et al. 2015 (CheckMate 069)]
−
|<span
+
|2013-09-16 to 2014-02-06
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[#Ipilimumab_.26_Nivolumab_2|Ipilimumab & Nivolumab]]
−
border-color:black;
+
| style="background-color:#d73027" |Inferior PFS
−
border-width:2px;
+
| style="background-color:#d3d3d3" |
−
border-style:solid;">Phase III</span>
 
−
|[[#Cisplatin.2C_Dacarbazine_.2B.2F-_Carmustine|Cisplatin, Dacarbazine +/- Carmustine]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''<sup>1</sup>Reported efficacy for CheckMate 067 is based on the 2021 update.''
−
*[[Cisplatin (Platinol)]] 75 mg/m2 IV once on day 1
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Dacarbazine (DTIC)]] 800 mg/m2 IV once on day 1
+
====Immunotherapy====
−
*Optional: [[Carmustine (BiCNU)]] 100 mg/m2 (note: in Ridolfi et al. 2002, in contrast to the treatment text, figure 1 lists a dosage of 150 mg/m2) IV once on day 1
+
*[[Ipilimumab (Yervoy)]] 3 mg/kg IV over 90 minutes once on day 1
−
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 4,500,000 units/m2 (Ridolfi et al. 2002 did not clearly specify the frequency and whether this dose was per day or total) SC on days 3 to 5, 8 to 12
+
'''21-day cycle for 4 cycles'''
−
*[[Interferon alfa-2b (Intron-A)]] 3,000,000 units/m2 (Ridolfi et al. 2002 did not clearly specify the frequency and whether this dose was per day or total) IM on days 3 to 5 of week 1, then 3 times per week on all later weeks
+
</div></div>
−
 
 
−
'''21-day cycles x 6 cycles'''
 
−
 
 
 
===References===
 
===References===
−
# Ridolfi R, Chiarion-Sileni V, Guida M, Romanini A, Labianca R, Freschi A, Lo Re G, Nortilli R, Brugnara S, Vitali P, Nanni O; Italian Melanoma Intergroup. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol. 2002 Mar 15;20(6):1600-7. [http://jco.ascopubs.org/content/20/6/1600.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/11896110 PubMed]
+
#'''CheckMate 069:''' Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. [https://doi.org/10.1056/NEJMoa1414428 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5744258/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25891304/ PubMed] [https://clinicaltrials.gov/study/NCT01927419 NCT01927419]
−
 
+
##'''Update:''' Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. Epub 2016 Sep 9. [https://doi.org/10.1016/S1470-2045(16)30366-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5630525/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27622997/ PubMed]
−
==Cisplatin, Paclitaxel, Dacarbazine {{#subobject:12c753|Regimen=1}}==
+
#'''CheckMate 067:''' Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. [https://doi.org/10.1056/NEJMoa1504030 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5698905/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26027431/ PubMed] [https://clinicaltrials.gov/study/NCT01844505 NCT01844505]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
##'''HRQoL analysis:''' Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. [https://doi.org/10.1016/j.ejca.2017.05.031 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5737813/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28651159/ PubMed]
 +
##'''Update:''' Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017 Oct 5;377(14):1345-1356. Epub 2017 Sep 11. Erratum in: N Engl J Med. 2018 Nov 29;379(22):2185. [https://doi.org/10.1056/nejmoa1709684 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5706778/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28889792/ PubMed]
 +
##'''Update:''' Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. [https://doi.org/10.1016/S1470-2045(18)30700-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30361170/ PubMed]
 +
##'''Update:''' Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. [https://doi.org/10.1056/NEJMoa1910836 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31562797/ PubMed]
 +
##'''Update:''' Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Butler MO, Hill A, Márquez-Rodas I, Haanen JBAG, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bas T, Ritchings C, Larkin J, Hodi FS. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol. 2022 Jan 10;40(2):127-137. Epub 2021 Nov 24. [https://doi.org/10.1200/jco.21.02229 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718224/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34818112/ PubMed]
 +
==Ipilimumab & Nivolumab {{#subobject:51gu10|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:3a481c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 17%" |Study
 +
! style="width: 15%" |Dates of enrollment
 +
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 17%" |Comparator
 +
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5698905/ Larkin et al. 2015 (CheckMate 067)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-77-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
 +
|-
 +
|} -->
 +
| rowspan="2" |2013-07 to 2014-03
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|1. [[#Ipilimumab_monotherapy_2|Ipilimumab]]
 +
| style="background-color:#1a9850" |Superior OS<sup>1</sup> (co-primary endpoint)<br>Median OS: 72.1 vs 19.9 mo<br>(HR 0.42, 95% CI 0.35-0.51)
 +
| style="background-color:#eeee01" |Equivalent HRQoL
 +
|-
 +
|2. [[#Nivolumab_monotherapy_2|Nivolumab]]
 +
| style="background-color:#91cf60" |Seems to have superior PFS<sup>1</sup> (co-primary endpoint)<br>Median PFS: 11.5 vs 6.9 mo<br>(HR 0.79, 95% CI 0.65-0.97)
 +
| style="background-color:#eeee01" |Equivalent HRQoL
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen, Papadopoulos et al. 2009 {{#subobject:9b0171|Variant=1}}===
+
''<sup>1</sup>Reported efficacy is based on the 2021 update.''<br>
−
Level of Evidence:
+
''Note: on 2016-09-13 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.''
−
<span
+
<div class="toccolours" style="background-color:#b3e2cd">
−
style="background:#EEEE00;
+
====Immunotherapy====
−
padding:3px 6px 3px 6px;
+
*[[Ipilimumab (Yervoy)]] as follows:
−
border-color:black;
+
**Cycles 1 to 4: 3 mg/kg IV once on day 1
−
border-width:2px;
+
*[[Nivolumab (Opdivo)]] as follows:
−
border-style:solid;">Phase II</span>
+
**Cycles 1 to 4: 1 mg/kg IV once on day 1
−
 
+
**Cycle 5 onwards: 3 mg/kg IV once on day 1
−
*[[Cisplatin (Platinol)]] 20 mg/m2 IV once per day on days 1 to 4
+
'''21-day cycle for 4 cycles, then 14-day cycles'''
−
*[[Paclitaxel (Taxol)]] 100-120 mg/m2 IV once per day on days 1 & 8
+
</div></div><br>
−
*[[Dacarbazine (DTIC)]] 800 mg/m2 IV once on day 1
+
<div class="toccolours" style="background-color:#eeeeee">
−
 
+
===Regimen variant #2, "NIVO1+IPI3", weight-based maintenance {{#subobject:fa88a8|Variant=1}}===
−
===References===
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
# Papadopoulos NE, Bedikian A, Ring S, Kim KB, Hwu WJ, Gerber DL, Homsi J, Hwu P. Phase I/II Study of a Cisplatin-Taxol-Dacarbazine Regimen in Metastatic Melanoma. Am J Clin Oncol. 2009 Oct;32(5):509-14. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=2009&issue=10000&article=00011&type=abstract link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19506454 PubMed]
+
! style="width: 20%" |Study
−
 
+
! style="width: 20%" |Dates of enrollment
−
==CVD - Cisplatin, Vinblastine, Dacarbazine {{#subobject:435c97|Regimen=1}}==
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5744258/ Postow et al. 2015 (CheckMate 069)]
 +
|2013-09-16 to 2014-02-06
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Ipilimumab_monotherapy_2|Ipilimumab]]
 +
| style="background-color:#1a9850" |Superior PFS (secondary endpoint)<br>Median PFS: NYR vs 4.4 mo<br>(HR 0.40, 95% CI 0.23-0.68)<br><br>Superior ORR (primary endpoint)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
CVD: '''<u>C</u>'''isplatin, '''<u>V</u>'''inblastine, '''<u>D</u>'''acarbazine
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Ipilimumab (Yervoy)]] as follows:
 +
**Cycles 1 to 4: 3 mg/kg IV once on day 1, '''given second'''
 +
*[[Nivolumab (Opdivo)]] 1 mg/kg IV once on day 1, '''given first'''
 +
'''21-day cycle for 4 cycles, then 14-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
−
===Regimen #1 {{#subobject:e9c736|Variant=1}}===
+
===Regimen variant #3, "NIVO1+IPI3", flat-dose maintenance {{#subobject:3ab34c|Variant=1}}===
−
{| border="1" style="text-align:center;" !align="left"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
|'''Study'''
+
! style="width: 17%" |Study
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
! style="width: 15%" |Dates of enrollment
−
|'''Comparator'''
+
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 17%" |Comparator
 +
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/26/35/5748.long Atkins et al. 2008 (ECOG E3695)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6455714/ Lebbé et al. 2019 (CheckMate 511)]
−
|<span
+
|2016-04-04 to 2017-03-27
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3b/4 (C)
−
padding:3px 6px 3px 6px;
+
|[[#Ipilimumab_.26_Nivolumab_2|Ipilimumab & Nivolumab]]; NIVO3+IPI1
−
border-color:black;
+
| style="background-color:#d3d3d3" |Not evaluated
−
border-width:2px;
+
| style="background-color:#d73027" |More grade 3 to 5 TRAEs
−
border-style:solid;">Phase III</span>
 
−
|[[#CVD.2C_IL-2.2C_IFN_alfa-2b_-_sequential_biochemotherapy|Sequential biochemotherapy]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Cisplatin (Platinol)]] 20 mg/m2 IV over 30 minutes once per day on days 1 to 4, '''given first'''
+
====Immunotherapy====
−
*[[Vinblastine (Velban)]] 1.2 mg/m2 IV push once per day on days 1 to 4, '''given second'''
+
*[[Ipilimumab (Yervoy)]] as follows:
−
*[[Dacarbazine (DTIC)]] 800 mg/m2 IV over 1 hour once on day 1, '''given third'''
+
**Cycles 1 to 4: 3 mg/kg IV once on day 1
−
 
+
*[[Nivolumab (Opdivo)]] as follows:
−
'''21-day cycle x up to 4 cycles'''
+
**Cycles 1 to 4: 1 mg/kg IV once on day 1
−
 
+
**Cycle 5 onwards: 480 mg IV once on day 1
−
Supportive medications:
+
'''21-day cycle for 4 cycles, then 28-day cycles'''
−
*[[Antiemesis|Antiemetics]] and [[Dexamethasone (Decadron)]] premedication for chemotherapy
+
</div></div><br>
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen #2 {{#subobject:353d3a|Variant=1}}===
+
===Regimen variant #4, "NIVO3+IPI1", flat-dose maintenance {{#subobject:3a48jc|Variant=1}}===
−
{| border="1" style="text-align:center;" !align="left"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
|'''Study'''
+
! style="width: 17%" |Study
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
! style="width: 15%" |Dates of enrollment
−
|'''Comparator'''
+
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 17%" |Comparator
 +
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
|-
 
|-
−
|[http://www.ncbi.nlm.nih.gov/pubmed/11956264 Eton et al. 2002]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6455714/ Lebbé et al. 2019 (CheckMate 511)]
−
|<span
+
|2016-04-04 to 2017-03-27
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3b/4 (E-switch-ic)
−
padding:3px 6px 3px 6px;
+
|[[#Ipilimumab_.26_Nivolumab_2|Ipilimumab & Nivolumab]]; NIVO1+IPI3
−
border-color:black;
+
| style="background-color:#d3d3d3" |Not evaluated
−
border-width:2px;
+
| style="background-color:#1a9850" |Fewer grade 3 to 5 TRAEs
−
border-style:solid;">Phase III</span>
 
−
|[[#CVD.2C_IL-2.2C_IFN_alfa-2b_-_sequential_biochemotherapy|Sequential biochemotherapy]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Cisplatin (Platinol)]] 20 mg/m2 IV once per day on days 1 to 4, 22 to 25
+
====Immunotherapy====
−
*[[Vinblastine (Velban)]] 2 mg/m2 IV once per day on days 1 to 4, 22 to 25
+
*[[Ipilimumab (Yervoy)]] as follows:
−
*[[Dacarbazine (DTIC)]] 800 mg/m2 IV once per day on days 1 & 22
+
**Cycles 1 to 4: 1 mg/kg IV once on day 1
−
 
+
*[[Nivolumab (Opdivo)]] as follows:
−
'''6-week cycle x up to 5 cycles'''
+
**Cycles 1 to 4: 3 mg/kg IV once on day 1
−
 
+
**Cycle 5 onwards: 480 mg IV once on day 1
 +
'''21-day cycle for 4 cycles, then 28-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Eton O, Legha SS, Bedikian AY, Lee JJ, Buzaid AC, Hodges C, Ring SE, Papadopoulos NE, Plager C, East MJ, Zhan F, Benjamin RS. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol. 2002 Apr 15;20(8):2045-52. [http://jco.ascopubs.org/content/20/8/2045.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/11956264 PubMed] content property of [http://hemonc.org HemOnc.org]
+
#'''CheckMate 069:''' Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. [https://doi.org/10.1056/NEJMoa1414428 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5744258/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25891304/ PubMed] [https://clinicaltrials.gov/study/NCT01927419 NCT01927419]
−
# Atkins MB, Hsu J, Lee S, Cohen GI, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM; Eastern Cooperative Oncology Group. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2008 Dec 10;26(35):5748-54. Epub 2008 Nov 10. [http://jco.ascopubs.org/content/26/35/5748.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19001327 PubMed]
+
##'''Update:''' Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. Epub 2016 Sep 9. [https://doi.org/10.1016/S1470-2045(16)30366-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5630525/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27622997/ PubMed]
−
 
+
#'''CheckMate 067:''' Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. [https://doi.org/10.1056/NEJMoa1504030 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5698905/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26027431/ PubMed] [https://clinicaltrials.gov/study/NCT01844505 NCT01844505]
−
==CVD, IL-2, IFN alfa-2b - sequential biochemotherapy {{#subobject:53ae36|Regimen=1}}==
+
##'''HRQoL analysis:''' Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. [https://doi.org/10.1016/j.ejca.2017.05.031 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5737813/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28651159/ PubMed]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
##'''Update:''' Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017 Oct 5;377(14):1345-1356. Epub 2017 Sep 11. Erratum in: N Engl J Med. 2018 Nov 29;379(22):2185. [https://doi.org/10.1056/nejmoa1709684 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5706778/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28889792/ PubMed]
 +
##'''Update:''' Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. [https://doi.org/10.1016/S1470-2045(18)30700-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30361170/ PubMed]
 +
##'''Update:''' Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. [https://doi.org/10.1056/NEJMoa1910836 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31562797/ PubMed]
 +
##'''Update:''' Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Butler MO, Hill A, Márquez-Rodas I, Haanen JBAG, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bas T, Ritchings C, Larkin J, Hodi FS. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol. 2022 Jan 10;40(2):127-137. Epub 2021 Nov 24.[https://doi.org/10.1200/jco.21.02229 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718224/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34818112/ PubMed]
 +
#'''CheckMate 511:''' Lebbé C, Meyer N, Mortier L, Marquez-Rodas I, Robert C, Rutkowski P, Menzies AM, Eigentler T, Ascierto PA, Smylie M, Schadendorf D, Ajaz M, Svane IM, Gonzalez R, Rollin L, Lord-Bessen J, Saci A, Grigoryeva E, Pigozzo J. Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial. J Clin Oncol. 2019 Apr 10;37(11):867-875. Epub 2019 Feb 27. [https://doi.org/10.1200/jco.18.01998 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6455714/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30811280/ PubMed] [https://clinicaltrials.gov/study/NCT02714218 NCT02714218]
 +
==Nivolumab monotherapy {{#subobject:6aoobd|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, q2wk {{#subobject:2gze51|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 17%" |Study
 +
! style="width: 15%" |Dates of enrollment
 +
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 17%" |Comparator
 +
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
|-
 
|-
−
|[[#toc|back to top]]
+
|[https://doi.org/10.1056/NEJMoa1412082 Robert et al. 2014 (CheckMate 066)]
−
|}
+
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
−
CVD: '''<u>C</u>'''isplatin, '''<u>V</u>'''inblastine, '''<u>D</u>'''acarbazine
+
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-89-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
−
 
 
−
===Example orders===
 
−
*[[Example orders for CVD, IL-2, IFN alfa-2b - sequential biochemotherapy in melanoma]]
 
−
 
 
−
===Regimen #1 {{#subobject:a7741a|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"  
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
 
|-
 
|-
−
|[http://clincancerres.aacrjournals.org/content/6/6/2201.long McDermott et al. 2000]
+
|} -->
−
|<span
+
|2013-01 to 2014-02
−
style="background:#eeee00;
+
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
−
padding:3px 6px 3px 6px;
+
|[[#Dacarbazine_monotherapy|Dacarbazine]]
−
border-color:black;
+
| style="background-color:#1a9850" |Superior OS<sup>1</sup> (primary endpoint)<br>OS60: 39% vs 17%<br>(HR 0.50, 95% CI 0.40-0.63)
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|
 
|
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/26/35/5748.long Atkins et al. 2008 (ECOG E3695)]
+
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5698905/ Larkin et al. 2015 (CheckMate 067)]
−
|<span  
+
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
−
style="background:#00CD00;
+
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-77-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
−
padding:3px 6px 3px 6px;
+
|-
−
border-color:black;
+
|} -->
−
border-width:2px;
+
| rowspan="2" |2013-07 to 2014-03
−
border-style:solid;">Phase III</span>
+
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
−
|[[#CVD_-_Cisplatin.2C_Vinblastine.2C_Dacarbazine|CVD]]
+
|1. [[#Ipilimumab_monotherapy_2|Ipilimumab]]
 +
| style="background-color:#1a9850" |Superior OS<sup>2</sup> (co-primary endpoint)<br>Median OS: 36.9 vs 19.9 mo<br>(HR 0.53, 95% CI 0.44-0.64)
 +
| style="background-color:#eeee01" |Equivalent HRQoL
 +
|-
 +
|2. [[#Ipilimumab_.26_Nivolumab_2|Ipilimumab & Nivolumab]]
 +
| style="background-color:#d73027" |Inferior PFS (co-primary endpoint)
 +
| style="background-color:#eeee01" |Equivalent HRQoL
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy for CheckMate 066 is based on the 2020 update.''<br>
 +
''<sup>2</sup>Reported efficacy for CheckMate 067 is based on the 2021 update.''<br>
 +
''Note: on 2016-09-13 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
 +
'''14-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, q3wk {{#subobject:7gce52|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.23.00172 Diab et al. 2023 (PIVOT IO 001)]
 +
|2018-10-10 to 2021-12-17
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Bempegaldesleukin_monotherapy_999|Bempegaldesleukin]]
 +
| style="background-color:#91cf60" |Seems to have superior ORR (co-primary endpoint)<br><br>Did not meet co-primary endpoint of PFS
 
|-
 
|-
 
|}
 
|}
−
 
+
''Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
−
*[[Cisplatin (Platinol)]] 20 mg/m2 IV over 30 minutes once per day on days 1 to 4, '''given first'''
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Vinblastine (Velban)]] 1.2 mg/m2 IV push once per day on days 1 to 4, '''given second'''
+
====Immunotherapy====
−
*[[Dacarbazine (DTIC)]] 800 mg/m2 IV over 1 hour once on day 1, '''given third'''
+
*[[Nivolumab (Opdivo)]] 360 mg IV once on day 1
−
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 9,000,000 units/m2/day IV continuous infusion over 96 hours on days 1 to 4
+
'''21-day cycles'''
−
*[[Interferon alfa-2b (Intron-A)]] 5,000,000 units/m2 SC once per day on days 1 to 5, 8, 10, 12; ''doses on days 8, 10, 12 are given as outpatient doses''
+
</div></div><br>
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
'''21-day cycle x up to 4 cycles'''
+
===Regimen variant #3, q4wk {{#subobject:2gze52|Variant=1}}===
−
 
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
Supportive medications:
+
!style="width: 20%"|Study
−
*All antihypertensive therapy discontinued at least 24 hours before each cycle
+
!style="width: 20%"|Dates of enrollment
−
*[[Cephalexin (Keflex)]] or [[Ciprofloxacin (Cipro)]] 250 mg PO BID on days 1 to 14
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day on days 7 to 16, or until ANC >10,000
+
!style="width: 20%"|Comparator
−
*[[Ondansetron (Zofran)]] 32 mg IV once per day
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
*[[Lorazepam (Ativan)]] 1 mg PO/IV every 6 hours
 
−
*[[Acetaminophen (Tylenol)]] 650 mg PO every 6 hours
 
−
*[[Ranitidine (Zantac)]] 150 mg PO every 12 hours
 
−
*[[Hydroxyzine (Atarax)]] 25 to 50 mg PO or Diphenhydramine (Benadryl) 25 mg PO every 6 hours for pruritis
 
−
*[[Meperidine (Demerol)]] 25 to 50 mg IV every 3 hours for chills and rigors
 
−
*Antidiarrheals & anxiolytics as needed
 
−
 
 
−
===Regimen #2 {{#subobject:118ce0|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"  
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
 
|-
 
|-
−
|[http://www.ncbi.nlm.nih.gov/pubmed/11956264 Eton et al. 2002]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9844513/ Tawbi et al. 2022 (RELATIVITY-047)]
−
|<span
+
|2018-2020
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 2/3 (C)
−
padding:3px 6px 3px 6px;
+
|[[#Nivolumab_.26_Relatlimab|Nivolumab & Relatlimab]]
−
border-color:black;
+
| style="background-color:#d73027" |Inferior PFS
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[#CVD_-_Cisplatin.2C_Vinblastine.2C_Dacarbazine|CVD]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Cisplatin (Platinol)]] 20 mg/m2 IV once per day on days 1 to 4, 22 to 25
+
====Immunotherapy====
−
*[[Vinblastine (Velban)]] 1.5 mg/m2 IV once per day on days 1 to 4, 22 to 25
+
*[[Nivolumab (Opdivo)]] 480 mg IV once on day 1
−
*[[Dacarbazine (DTIC)]] 800 mg/m2 IV once per day on days 1 & 22
+
'''28-day cycles'''
−
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 9,000,000 units/m2/day IV continuous infusion over 96 hours on days 5 to 8, 17 to 20, 26 to 29
+
</div></div>
−
*[[Interferon alfa-2b (Intron-A)]] 5,000,000 units/m2 SC once per day on days 5 to 9, 17 to 21, 26 to 30
 
−
 
 
−
'''6-week cycle x up to 5 cycles'''
 
−
 
 
 
===References===
 
===References===
−
# McDermott DF, Mier JW, Lawrence DP, van den Brink MR, Clancy MA, Rubin KM, Atkins MB. A phase II pilot trial of concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin 2, and interferon alpha-2B in patients with metastatic melanoma. Clin Cancer Res. 2000 Jun;6(6):2201-8. [http://clincancerres.aacrjournals.org/content/6/6/2201.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/10873069 PubMed]
+
#'''CheckMate 066:''' Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. Epub 2014 Nov 16. [https://doi.org/10.1056/NEJMoa1412082 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25399552/ PubMed] [https://clinicaltrials.gov/study/NCT01721772 NCT01721772]
−
# Eton O, Legha SS, Bedikian AY, Lee JJ, Buzaid AC, Hodges C, Ring SE, Papadopoulos NE, Plager C, East MJ, Zhan F, Benjamin RS. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol. 2002 Apr 15;20(8):2045-52. [http://jco.ascopubs.org/content/20/8/2045.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/11956264 PubMed]
+
##'''Update:''' Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Ny L, Arance A, Svane IM, Schadendorf D, Gogas H, Saci A, Jiang J, Rizzo J, Atkinson V. Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol. 2019 Feb 1;5(2):187-194. Epub 2018 Oct 25.  [https://jamanetwork.com/journals/jamaoncology/article-abstract/2707224 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439558/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30422243/ PubMed]
−
# Atkins MB, Hsu J, Lee S, Cohen GI, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM; Eastern Cooperative Oncology Group. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2008 Dec 10;26(35):5748-54. Epub 2008 Nov 10. [http://jco.ascopubs.org/content/26/35/5748.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19001327 PubMed]
+
##'''Update:''' Robert C, Long GV, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Rutkowski P, Hassel JC, McNeil CM, Kalinka EA, Lebbé C, Charles J, Hernberg MM, Savage KJ, Chiarion-Sileni V, Mihalcioiu C, Mauch C, Arance A, Cognetti F, Ny L, Schmidt H, Schadendorf D, Gogas H, Zoco J, Re S, Ascierto PA, Atkinson V. Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma. J Clin Oncol. 2020 Nov 20;38(33):3937-3946. Epub 2020 Sep 30. [https://doi.org/10.1200/jco.20.00995 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676881/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32997575/ PubMed]
 +
#'''CheckMate 067:''' Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. [https://doi.org/10.1056/NEJMoa1504030 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5698905/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26027431/ PubMed] [https://clinicaltrials.gov/study/NCT01844505 NCT01844505]
 +
##'''HRQoL analysis:''' Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. [https://doi.org/10.1016/j.ejca.2017.05.031 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5737813/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28651159/ PubMed]
 +
##'''Update:''' Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017 Oct 5;377(14):1345-1356. Epub 2017 Sep 11. Erratum in: N Engl J Med. 2018 Nov 29;379(22):2185. [https://doi.org/10.1056/nejmoa1709684 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5706778/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28889792/ PubMed]
 +
##'''Update:''' Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. [https://doi.org/10.1016/S1470-2045(18)30700-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30361170/ PubMed]
 +
##'''Update:''' Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. [https://doi.org/10.1056/NEJMoa1910836 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31562797/ PubMed]
 +
##'''Update:''' Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Butler MO, Hill A, Márquez-Rodas I, Haanen JBAG, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bas T, Ritchings C, Larkin J, Hodi FS. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol. 2022 Jan 10;40(2):127-137. Epub 2021 Nov 24. [https://doi.org/10.1200/jco.21.02229 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718224/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34818112/ PubMed]
 +
#'''RELATIVITY-047:''' Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, Dalle S, Arance A, Grob JJ, Srivastava S, Abaskharoun M, Hamilton M, Keidel S, Simonsen KL, Sobiesk AM, Li B, Hodi FS, Long GV; RELATIVITY-047 Investigators. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022 Jan 6;386(1):24-34. [https://doi.org/10.1056/nejmoa2109970 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9844513/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34986285/ PubMed] [https://clinicaltrials.gov/study/NCT03470922 NCT03470922]
 +
##'''Update:''' Long GV, Hodi FS, Lipson EJ, Schadendorf D, Ascierto PA, Matamala L, Salman P, Gutiérrez EC, Rutkowski P, Gogas HJ, Lao CD, Menezes JJD, Dalle S, Arance A, Grob JJ, Keidel S, Shaikh A, Sobiesk AM, Dolfi S, Tawbi HA. Overall Survival and Response with Nivolumab and Relatlimab in Advanced Melanoma. NEJM Evidence. 2023 Apr;2(4):EVIDoa2200239. Epub 2023 Mar 22. [https://pubmed.ncbi.nlm.nih.gov/38320023/ PubMed] [https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200239 link to original article]
 +
#'''PIVOT IO 001:''' Diab A, Gogas H, Sandhu S, Long GV, Ascierto PA, Larkin J, Sznol M, Franke F, Ciuleanu TE, Pereira C, Muñoz Couselo E, Bronzon Damian F, Schenker M, Perfetti A, Lebbe C, Quéreux G, Meier F, Curti BD, Rojas C, Arriaga Y, Yang H, Zhou M, Ravimohan S, Statkevich P, Tagliaferri MA, Khushalani NI. Bempegaldesleukin Plus Nivolumab in Untreated Advanced Melanoma: The Open-Label, Phase III PIVOT IO 001 Trial Results. J Clin Oncol. 2023 Oct 20;41(30):4756-4767. Epub 2023 Aug 31. [https://doi.org/10.1200/jco.23.00172 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37651676/ PubMed] [https://clinicaltrials.gov/study/NCT03635983 NCT03635983]
  
−
==Dabrafenib (Tafinlar) {{#subobject:8f3562|Regimen=1}}==
+
==Nivolumab & Relatlimab {{#subobject:6abj1d|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:2gzt44|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:fa5aa0|Variant=1}}===
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
{| border="1" style="text-align:center;" !align="left"  
+
!style="width: 20%"|Study
−
|'''Study'''
+
!style="width: 20%"|Dates of enrollment
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
|'''Comparator'''
+
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60868-X/abstract Hauschild et al. 2012]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9844513/ Tawbi et al. 2022 (RELATIVITY-047)]
−
|<span
+
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
−
style="background:#00CD00;
+
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-330-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Dacarbazine_.28DTIC.29|Dacarbazine]]
 
 
|-
 
|-
−
!colspan="4" align="center"|
+
|} -->
 +
|2018-2020
 +
| style="background-color:#1a9851" |Phase 2/3 (E-RT-esc)
 +
|[[#Nivolumab_monotherapy_2|Nivolumab]]
 +
| style="background-color:#1a9850" |Superior PFS<sup>1</sup> (primary endpoint)<br>Median PFS: 10.2 vs 4.6 mo<br>(HR 0.78, 95% CI 0.64-0.94)<br><br>Might have superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: NYR vs 34.1 mo<br>(HR 0.80, 95% CI 0.64-1.01)
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1210093 Flaherty et al. 2012]
+
|}
−
|<span
+
''<sup>1</sup>Reported efficacy is based on the 2023 update.''
−
style="background:#00CD00;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
padding:3px 6px 3px 6px;
+
====Immunotherapy====
−
border-color:black;
+
*[[Nivolumab and relatlimab (Opdualag)]] 480/160 mg IV once on day 1
−
border-width:2px;
+
'''28-day cycles'''
−
border-style:solid;">Phase III</span>
+
</div></div>
−
|[[Melanoma#Dabrafenib_.26_Trametinib|Dabrafenib & Trametinib]]
+
===References===
 +
#'''RELATIVITY-047:''' Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, Dalle S, Arance A, Grob JJ, Srivastava S, Abaskharoun M, Hamilton M, Keidel S, Simonsen KL, Sobiesk AM, Li B, Hodi FS, Long GV; RELATIVITY-047 Investigators. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022 Jan 6;386(1):24-34. [https://doi.org/10.1056/nejmoa2109970 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9844513/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34986285/ PubMed] [https://clinicaltrials.gov/study/NCT03470922 NCT03470922]
 +
##'''Update:''' Long GV, Hodi FS, Lipson EJ, Schadendorf D, Ascierto PA, Matamala L, Salman P, Gutiérrez EC, Rutkowski P, Gogas HJ, Lao CD, Menezes JJD, Dalle S, Arance A, Grob JJ, Keidel S, Shaikh A, Sobiesk AM, Dolfi S, Tawbi HA. Overall Survival and Response with Nivolumab and Relatlimab in Advanced Melanoma. NEJM Evidence. 2023 Apr;2(4):EVIDoa2200239. Epub 2023 Mar 22. [https://pubmed.ncbi.nlm.nih.gov/38320023/ PubMed] [https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200239 link to original article]
 +
 
 +
==Pembrolizumab monotherapy {{#subobject:78ub8c|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:25acnp|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
!colspan="4" align="center"|
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9870217/ Chesney et al. 2022 (MASTERKEY-265)]
 +
|2016-2018
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#T-VEC_.26_Pembrolizumab_333|T-VEC & Pembrolizumab]]
 +
| style="background-color:#fee08b" |Might have inferior PFS<br>Median PFS: 8.5 vs 14.3 mo<br>(HR 1.16, 95% CI 0.96-1.41)
 
|-
 
|-
−
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70431-X/abstract Long et al. 2012 (BREAK-MB)]
+
|[https://doi.org/10.1016/j.annonc.2020.12.004 Gogas et al. 2020 (IMspire170)]
−
|<span
+
|2017-2019
−
style="background:#eeee00;
+
| style="background-color:#1a9851" |Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[#Cobimetinib_.26_Atezolizumab_999|Cobimetinib & Atezolizumab]]
−
border-color:black;
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br>Median PFS: 5.7 vs 5.5 mo<br>(HR 0.87, 95% CI 0.67-1.14)
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
−
|
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
''Patients enrolled in these trials were BRAF-mutated.''
+
====Immunotherapy====
−
*[[Dabrafenib (Tafinlar)]] 150 mg PO BID
+
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
−
 
+
'''21-day cycles'''
−
'''Given until progression of disease'''
+
</div></div>
−
 
 
 
===References===
 
===References===
−
# Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012 Jul 28;380(9839):358-65. Epub 2012 Jun 25. [http://www.sciencedirect.com/science/article/pii/S014067361260868X link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22735384 PubMed]
+
#'''IMspire170:''' Gogas H, Dréno B, Larkin J, Demidov L, Stroyakovskiy D, Eroglu Z, Francesco Ferrucci P, Pigozzo J, Rutkowski P, Mackiewicz J, Rooney I, Voulgari A, Troutman S, Pitcher B, Guo Y, Yan Y, Castro M, Mulla S, Flaherty K, Arance A. Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study. Ann Oncol. 2021 Mar;32(3):384-394. Epub 2020 Dec 10. [https://doi.org/10.1016/j.annonc.2020.12.004 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33309774/ PubMed] [https://clinicaltrials.gov/study/NCT03273153 NCT03273153]
−
# Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012 Nov;367(18):1694-703. Epub 2012 Sep 29. [http://www.nejm.org/doi/full/10.1056/NEJMoa1210093 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23020132 PubMed]
+
#'''MASTERKEY-265:''' Chesney JA, Ribas A, Long GV, Kirkwood JM, Dummer R, Puzanov I, Hoeller C, Gajewski TF, Gutzmer R, Rutkowski P, Demidov L, Arenberger P, Shin SJ, Ferrucci PF, Haydon A, Hyngstrom J, van Thienen JV, Haferkamp S, Guilera JM, Rapoport BL, VanderWalde A, Diede SJ, Anderson JR, Treichel S, Chan EL, Bhatta S, Gansert J, Hodi FS, Gogas H. Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma. J Clin Oncol. 2023 Jan 20;41(3):528-540. Epub 2022 Aug 23. [https://doi.org/10.1200/jco.22.00343 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9870217/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35998300/ PubMed] [https://clinicaltrials.gov/study/NCT02263508 NCT02263508]
−
# Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, Puzanov I, Hauschild A, Robert C, Algazi A, Mortier L, Tawbi H, Wilhelm T, Zimmer L, Switzky J, Swann S, Martin AM, Guckert M, Goodman V, Streit M, Kirkwood JM, Schadendorf D. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Nov;13(11):1087-95. Epub 2012 Oct 8. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70431-X/abstract link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23051966 PubMed]
 
  
−
==Dabrafenib & Trametinib {{#subobject:7d3694|Regimen=1}}==
+
==Temozolomide & Bevacizumab {{#subobject:511376|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
TB: '''<u>T</u>'''emozolomide & '''<u>B</u>'''evacizumab
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:42ead6|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089063/ Kottschade et al. 2013 (N0775)]
 +
|2008-2010
 +
| style="background-color:#1a9851" |Randomized Phase 2 (E-de-esc)
 +
|[[#ABC|ABC]]
 +
| style="background-color:#fc8d59" |Seems to have inferior PFS6 (primary endpoint)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:23212f|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
{| border="1" style="text-align:center;" !align="left"  
+
====Chemotherapy====
−
|'''Study'''
+
*[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once per day on days 1 to 5
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
====Targeted therapy====
−
|'''Comparator'''
+
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
 +
'''28-day cycles'''
 +
</div></div>
 +
===References===
 +
<!-- This study was presented at the American Society for Clinical Oncology 2011 Annual Meeting, June 3 to 7, Chicago, Illinois, as a poster discussion. -->
 +
#'''N0775:''' Kottschade LA, Suman VJ, Perez DG, McWilliams RR, Kaur JS, Amatruda TT 3rd, Geoffroy FJ, Gross HM, Cohen PA, Jaslowski AJ, Kosel ML, Markovic SN; North Central Cancer Treatment Group. A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N0775. Cancer. 2013 Feb 1;119(3):586-92. Epub 2012 Aug 22. [https://doi.org/10.1002/cncr.27760 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089063/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22915053/ PubMed] [https://clinicaltrials.gov/study/NCT00626405 NCT00626405]
 +
=Maintenance after first-line therapy=
 +
==IL-2 & GM-CSF {{#subobject:fa72a9|Regimen=1}}==
 +
===Example orders===
 +
*[[Example orders for IL-2 maintenance biotherapy in melanoma]]
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:2ed5d3|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Dates of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1210093 Flaherty et al. 2012]
+
|[http://clincancerres.aacrjournals.org/content/8/9/2775.long O'Day et al. 2002]
−
|<span
+
|1998-2000
−
style="background:#00CD00;
+
| style="background-color:#91cf61" |Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Dabrafenib_.28Tafinlar.29|Dabrafenib]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''Note: timing below is based on the assumption that all cycles begin on a Monday.''
−
''Patients enrolled in Flaherty et al. 2012 were BRAF-mutated.''
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
*[[Dabrafenib (Tafinlar)]] 150 mg PO BID
+
*Induction [[Regimen_classes#Biochemotherapy|biochemotherapy]]
−
*[[Trametinib (Mekinist)]] 2 mg PO once per day
+
</div>
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
'''Continued until progression'''
+
====Immunotherapy, low-dose portion (cycles 1, 4, 7, 9, 11)====
−
 
+
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 1,000,000 units/m<sup>2</sup> SC once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26
 +
====Growth factor therapy, low-dose portion (cycles 1, 4, 7, 9, 11)====
 +
*[[Sargramostim (Leukine)]] 125 mcg/m<sup>2</sup> SC once per day on days 1 to 14
 +
====Immunotherapy, pulse portion (cycles 2, 3, 5, 6, 8, 10, 12)====
 +
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 18,000,000 units/m<sup>2</sup> IV continuous infusion over 6 hours, started on day 1, then 18,000,000 units/m<sup>2</sup> IV continuous infusion over 12 hours, then 18,000,000 units/m<sup>2</sup> IV continuous infusion over 24 hours, then 1,000,000 units/m<sup>2</sup> SC once per day on days 3 to 5, 8 to 12, 15 to 19, 22 to 26
 +
====Growth factor therapy, pulse portion (cycles 2, 3, 5, 6, 8, 10, 12)====
 +
*[[Sargramostim (Leukine)]] 125 mcg/m<sup>2</sup> SC once per day on days 3 to 17 (note: this was possibly a typo in O'Day et al. 2002 since shifting the schedule 2 days forward would be days 3 to 16)
 +
====Supportive therapy, pulse portion (cycles 2, 3, 5, 6, 8, 10, 12)====
 +
*One of the following 5-HT3 agonists:
 +
**[[Ondansetron (Zofran)]] 32 mg IV once per day
 +
**[[Granisetron]] 2 mg IV once per day
 +
*[[Omeprazole (Prilosec)]] 20 mg PO once every evening
 +
*[[Acetaminophen (Tylenol)]] 650 mg PO once every 4 hours, starting prior to IL-2 and continuing on days 1 & 2
 +
*[[Meperidine (Demerol)]] 25 mg IV once every 6 hours as needed for chills and rigors
 +
'''28-day cycle for 12 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012 Nov;367(18):1694-703. Epub 2012 Sep 29. [http://www.nejm.org/doi/full/10.1056/NEJMoa1210093 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23020132 PubMed]
+
#O'Day SJ, Boasberg PD, Piro L, Kristedja TS, Wang HJ, Martin M, Deck R, Ames P, Shinn K, Kim H, Fournier P, Gammon G. Maintenance biotherapy for metastatic melanoma with interleukin-2 and granulocyte macrophage-colony stimulating factor improves survival for patients responding to induction concurrent biochemotherapy. Clin Cancer Res. 2002 Sep;8(9):2775-81. [http://clincancerres.aacrjournals.org/content/8/9/2775.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12231516/ PubMed]
  
−
==Dacarbazine (DTIC) {{#subobject:d3599b|Regimen=1}}==
+
=Metastatic or unresectable disease, second-line=
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
==Carboplatin & Paclitaxel (CP) {{#subobject:610571|Regimen=1}}==
 +
CP: '''<u>C</u>'''arboplatin & '''<u>P</u>'''aclitaxel
 +
<br>PC: '''<u>P</u>'''aclitaxel & '''<u>C</u>'''arboplatin
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, AUC 2/100 {{#subobject:5edf1c|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"  
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1002/cncr.21611 Rao et al. 2006]
 +
| style="background-color:#ffffbe" |Retrospective
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Example orders===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Example orders for Dacarbazine (DTIC) in melanoma]]
+
====Chemotherapy====
−
 
+
*[[Carboplatin (Paraplatin)]] AUC 2 IV once per day on days 1, 8, 15
−
===Regimen #1 {{#subobject:bede4c|Variant=1}}===
+
*[[Paclitaxel (Taxol)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
−
{| border="1" style="text-align:center;" !align="left"  
+
'''28-day cycles'''
−
|'''Study'''
+
</div></div><br>
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
<div class="toccolours" style="background-color:#eeeeee">
−
|'''Comparator'''
+
===Regimen variant #2, AUC 6/175 {{#subobject:06b48b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1103782 Chapman et al. 2011 (BRIM-3)]
+
|[https://doi.org/10.1016/S1470-2045(15)70076-8 Weber et al. 2015 (CheckMate 037)]
−
|<span
+
|2012-2014
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[#Nivolumab_monotherapy_3|Nivolumab]]
−
border-color:black;
+
| style="background-color:#d73027" |Inferior ORR
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Vemurafenib_.28Zelboraf.29|Vemurafenib]]
 
 
|-
 
|-
−
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60868-X/abstract Hauschild et al. 2012]
+
|}
−
|<span
+
''Note: this study did not meet the co-primary endpoint of OS.''
−
style="background:#00CD00;
+
<div class="toccolours" style="background-color:#fdcdac">
−
padding:3px 6px 3px 6px;
+
====Prior treatment criteria====
−
border-color:black;
+
*CheckMate 037, BRAF WT: Exposure to ipilimumab
−
border-width:2px;
+
*CheckMate 037, BRAF p.V600: Exposure to ipilimumab and BRAF inhibitor
−
border-style:solid;">Phase III</span>
+
</div>
−
|[[Melanoma#Dabrafenib_.28Tafinlar.29|Dabrafenib]]
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Carboplatin (Paraplatin)]] AUC 6 IV once on day 1
 +
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, AUC 6/225 x 4, then AUC 5/175 {{#subobject:6a83f2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1203421 Flaherty et al. 2012 (METRIC)]
+
|[https://doi.org/10.1200/jco.2007.15.7636 Hauschild et al. 2009 (Bayer 11718)]
−
|<span
+
|2005-05 to 2006-05
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Sorafenib|CP & Sorafenib]]
−
border-color:black;
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Trametinib_.28Mekinist.29|Trametinib]]
 
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1412082 Robert et al. 2014]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878104/ Flaherty et al. 2013 (ECOG E2603)]
−
|<span
+
|2005-2008
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[Stub#Carboplatin_.26_Paclitaxel_.28CP.29_.26_Sorafenib|CP & Sorafenib]]
−
border-color:black;
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Nivolumab_.28Opdivo.29|Nivolumab]]
 
 
|-
 
|-
−
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70076-8/fulltext Weber et al. 2015 (CheckMate 037)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ Ribas et al. 2015 (KEYNOTE-002)]
−
|<span
+
|2012-11-30 to 2013-11-13
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Randomized Phase 2 (C)
−
padding:3px 6px 3px 6px;
+
|1. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 2 mg/kg q3wk<br>2. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 10 mg/kg q3wk
−
border-color:black;
+
| style="background-color:#d73027" |Inferior PFS
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[#Nivolumab_.28Opdivo.29|Nivolumab]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#fdcdac">
−
''Patients in BRIM-3 had a BRAF p.V600E mutation detected.''
+
====Prior treatment criteria====
−
 
+
*Bayer 11718: Exposure to a [[Regimen_classes#Dacarbazine-based_regimen|dacarbazine-]] or [[Regimen_classes#Temozolomide-based_regimen|temozolomide-containing regimen]]
−
*[[Dacarbazine (DTIC)]] 1000 mg/m2 IV once on day 1
+
*ECOG E2603: No chemotherapy or [[:Category:MEK_inhibitors|MAP kinase pathway–targeted drugs]]
−
 
+
</div>
−
'''21-day cycles, given until progression of disease or unacceptable toxicity'''
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
===Regimen #2 {{#subobject:b6dcb|Variant=1}}===
+
*[[Carboplatin (Paraplatin)]] as follows:
−
{| border="1" style="text-align:center;" !align="left"  
+
**Cycles 1 to 4: AUC 6 IV over 30 minutes once on day 1, '''given second'''
−
|'''Study'''
+
**Cycle 5 up to 10: AUC 5 IV over 30 minutes once on day 1, '''given second'''
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
*[[Paclitaxel (Taxol)]] as follows:
−
|'''Comparator'''
+
**Cycles 1 to 4: 225 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
 +
**Cycle 5 up to 10: 175 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
 +
'''21-day cycle for up to 10 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 200/100, 6 out of 8 weeks {{#subobject:64b1c2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1104621 Robert et al. 2011]
+
|[https://doi.org/10.1097/00008390-200310000-00012 Zimpfer-Rechner et al. 2003]
−
|<span
+
|1998-2000
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
−
padding:3px 6px 3px 6px;
+
|[[#Paclitaxel_monotherapy|Paclitaxel]]
−
border-color:black;
+
| style="background-color:#ffffbf" |Did not meet primary efficacy endpoints
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Dacarbazine_.26_Ipilimumab|Dacarbazine & Ipilimumab]]
 
 
|-
 
|-
 
|}
 
|}
 +
''Note: This was an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Carboplatin (Paraplatin)]] 200 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
 +
*[[Paclitaxel (Taxol)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
 +
'''8-week cycles'''
 +
</div></div>
 +
===References===
 +
#Zimpfer-Rechner C, Hofmann U, Figl R, Becker JC, Trefzer U, Keller I, Hauschild A, Schadendorf D; Dermatologic Cooperative Oncology Group. Randomized phase II study of weekly paclitaxel versus paclitaxel and carboplatin as second-line therapy in disseminated melanoma: a multicentre trial of the Dermatologic Co-operative Oncology Group (DeCOG). Melanoma Res. 2003 Oct;13(5):531-6. [https://doi.org/10.1097/00008390-200310000-00012 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/14512795/ PubMed]
 +
#'''Retrospective:''' Rao RD, Holtan SG, Ingle JN, Croghan GA, Kottschade LA, Creagan ET, Kaur JS, Pitot HC, Markovic SN. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer. 2006 Jan 15;106(2):375-82. [https://doi.org/10.1002/cncr.21611 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16342250/ PubMed]
 +
<!-- Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL. -->
 +
#'''Bayer 11718:''' Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermont A, Grabbe S, Gonzalez R, Gille J, Peschel C, Schadendorf D, Garbe C, O'Day S, Daud A, White JM, Xia C, Patel K, Kirkwood JM, Keilholz U. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009 Jun 10;27(17):2823-30. Epub 2009 Apr 6. [https://doi.org/10.1200/jco.2007.15.7636 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19349552/ PubMed] [https://clinicaltrials.gov/study/NCT00111007 NCT00111007]
 +
#'''CheckMate 037:''' Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. [https://doi.org/10.1016/S1470-2045(15)70076-8 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25795410/ PubMed] [https://clinicaltrials.gov/study/NCT01721746 NCT01721746]
 +
##'''Update:''' Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. [https://doi.org/10.1200/JCO.2016.71.8023 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6804912/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28671856/ PubMed]
 +
#'''KEYNOTE-002:''' Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. [https://doi.org/10.1016/S1470-2045(15)00083-2 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26115796/ PubMed] [https://clinicaltrials.gov/study/NCT01704287 NCT01704287]
 +
##'''HRQoL analysis:''' Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. [https://doi.org/10.1016/j.ejca.2016.07.018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27596353/ PubMed]
 +
##'''Update:''' Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. [https://doi.org/10.1016/j.ejca.2017.07.022 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28961465/ PubMed]
  
−
*[[Dacarbazine (DTIC)]] 850 mg/m2 IV once on day 1
+
==Carboplatin & nab-Paclitaxel {{#subobject:a013af|Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
'''21-day cycle x 8 cycles'''
+
===Regimen {{#subobject:d78d72|Variant=1}}===
−
 
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
===Regimen #3 {{#subobject:4bacb|Variant=1}}===
+
! style="width: 33%" |Study
−
{| border="1" style="text-align:center;" !align="left"  
+
! style="width: 33%" |Dates of enrollment
−
|'''Study'''
+
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/18/1/158.long Middleton et al. 2000]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116030/ Kottschade et al. 2011 (N057E1)]
−
|<span
+
|2006-2007
−
style="background:#00CD00;
+
| style="background-color:#91cf61" |Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Temozolomide_.28Temodar.29|Temozolomide]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Dacarbazine (DTIC)]] 250 mg/m2 IV over 30 minutes once per day on days 1 to 5
+
====Chemotherapy====
−
 
+
*[[Carboplatin (Paraplatin)]] AUC 2 IV once per day on days 1, 8, 15, '''given second'''
−
'''21-day cycles, given until progression of disease or unacceptable toxicity'''
+
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, '''given first'''
−
 
+
====Supportive therapy====
 +
*"All patients received standard supportive care, including antiemetics, antibiotics, blood/platelet transfusions, erythropoietin, and colony-stimulating factors at the discretion of the treating physician."
 +
'''28-day cycle for up to 8 cycles;''' patients without progressive disease or excessive toxicity could receive additional therapy per physician discretion
 +
</div></div>
 
===References===
 
===References===
−
# Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. [http://jco.ascopubs.org/content/18/1/158.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/10623706 PubMed]
+
#'''N057E1:''' Kottschade LA, Suman VJ, Amatruda T 3rd, McWilliams RR, Mattar BI, Nikcevich DA, Behrens R, Fitch TR, Jaslowski AJ, Markovic SN; North Central Cancer Treatment Group. A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, N057E(1). Cancer. 2011 Apr 15;117(8):1704-10. Epub 2010 Nov 8. [https://doi.org/10.1002/cncr.25659 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116030/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21472717/ PubMed] [https://clinicaltrials.gov/study/NCT00404235 NCT00404235]
−
# Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun 30;364(26):2507-16. Epub 2011 Jun 5. [http://www.nejm.org/doi/full/10.1056/NEJMoa1103782 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21639808 PubMed]
+
==Lifileucel & IL-2 {{#subobject:f33e1b|Regimen=1}}==
−
# Robert C, Thomas L, Bondarenko I, O'Day S, M D JW, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. [http://www.nejm.org/doi/full/10.1056/NEJMoa1104621 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21639810 PubMed]
+
TILs: '''<u>T</u>'''umor '''<u>I</u>'''nfiltrating '''<u>L</u>'''ymphocyte'''<u>s</u>'''
−
# Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012 Jul 28;380(9839):358-65. Epub 2012 Jun 25. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60868-X/abstract link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22735384 PubMed]
+
<div class="toccolours" style="background-color:#eeeeee">
−
# Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12;367(2):107-14. Epub 2012 Jun 4. [http://www.nejm.org/doi/full/10.1056/NEJMoa1203421 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22663011 PubMed]
+
===Regimen {{#subobject:12350b|Variant=1}}===
−
# Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in Previously Untreated Melanoma without BRAF Mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. Epub 2014 Nov 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1412082 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/25399552 PubMed]
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
# Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70076-8/fulltext link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/25795410 PubMed]
+
!style="width: 33%"|Study
−
 
+
!style="width: 33%"|Dates of enrollment
−
==Dacarbazine & Ipilimumab {{#subobject:5754a8|Regimen=1}}==
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376325/ Sarnaik et al. 2021 (C-144-01)]
 +
|2017-2019
 +
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:7b4884|Variant=1}}===
+
<div class="toccolours" style="background-color:#cbd5e8">
−
{| border="1" style="text-align:center;" !align="left"  
+
====Preceding treatment====
−
|'''Study'''
+
*[[Chimeric_antigen_receptor_T_cells_(CAR-T)#Cyclophosphamide_.26_Fludarabine_.28FC.29|FC]] lymphodepletion
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
</div>
−
|'''Comparator'''
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Lifileuecel (Contego)]] administered 24 hours after last dose of fludarabine
 +
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 600,000 units/kg IV over 15 minutes every 8 to 12 hours as tolerated for up to 6 doses, starting 3 to 24 hours after completing lifileucel infusion
 +
</div></div>
 +
===References===
 +
# '''C-144-01:''' Sarnaik AA, Hamid O, Khushalani NI, Lewis KD, Medina T, Kluger HM, Thomas SS, Domingo-Musibay E, Pavlick AC, Whitman ED, Martin-Algarra S, Corrie P, Curti BD, Oláh J, Lutzky J, Weber JS, Larkin JMG, Shi W, Takamura T, Jagasia M, Qin H, Wu X, Chartier C, Graf Finckenstein F, Fardis M, Kirkwood JM, Chesney JA. Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma. J Clin Oncol. 2021 Aug 20;39(24):2656-2666. Epub 2021 May 12. Erratum in: J Clin Oncol. 2021 Sep 10;39(26):2972. [https://doi.org/10.1200/jco.21.00612 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376325/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33979178/ PubMed] [https://clinicaltrials.gov/study/NCT02360579 NCT02360579]
 +
 
 +
==Toripalimab monotherapy {{#subobject:cbc31b|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:acb46b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1104621 Robert et al. 2011]
+
|[https://clinicaltrials.gov/study/NCT03013101 Awaiting publication (Junshi-JS001-BJZL-II)]
−
|<span
+
|2016-NR
−
style="background:#00CD00;
+
| style="background-color:#91cf61" |Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Dacarbazine_.28DTIC.29|Dacarbazine]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Ipilimumab (Yervoy)]] 10 mg/kg IV once on day 1
+
====Immunotherapy====
−
*[[Dacarbazine (DTIC)]] 850 mg/m2 IV once on day 1
+
*[[Toripalimab (Loqtorzi)]] 3 mg/kg IV once on day 1
−
 
+
'''14-day cycles'''
−
'''21-day cycle x 4 cycles, then:'''
+
</div></div>
−
 
 
−
*[[Dacarbazine (DTIC)]] 850 mg/m2 IV once on day 1
 
−
 
 
−
'''21-day cycle x 4 cycles'''
 
−
 
 
−
''If patient has stable disease or objective response, proceed to [[Melanoma#Ipilimumab_.28Yervoy.29_2|maintenance ipilimumab]].''
 
−
 
 
 
===References===
 
===References===
−
# Robert C, Thomas L, Bondarenko I, O'Day S, M D JW, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. [http://www.nejm.org/doi/full/10.1056/NEJMoa1104621 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21639810 PubMed]
+
#'''Junshi-JS001-BJZL-II:''' '''contains dosing details on CT.gov''' [https://clinicaltrials.gov/study/NCT03013101 NCT03013101]
  
−
==Docetaxel (Taxotere) {{#subobject:bd3e54|Regimen=1}}==
+
=Metastatic or unresectable disease=
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
''Note: these regimens have not yet been classified by line of treatment.''
 +
==Dacarbazine monotherapy {{#subobject:d3599b|Regimen=1}}==
 +
===Example orders===
 +
*[[Example orders for Dacarbazine (DTIC) in melanoma]]
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 850 mg/m<sup>2</sup> q3wk {{#subobject:b6dcb|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://pubmed.ncbi.nlm.nih.gov/7459898 Pritchard et al. 1980]
 +
|NR in abstract
 +
| style="background-color:#91cf61" |Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Dacarbazine (DTIC)]] 850 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 1000 mg/m<sup>2</sup> q3wk {{#subobject:bede4c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2011.04.030 Patel et al. 2011 (EORTC 18032)]
 +
|2004-2007
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Temozolomide_monotherapy|Temozolomide]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ Ribas et al. 2015 (KEYNOTE-002)]
 +
|2012-11-30 to 2013-11-13
 +
| style="background-color:#1a9851" |Randomized Phase 2 (C)
 +
|1. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 2 mg/kg q3wk<br>2. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 10 mg/kg q3wk
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(15)70076-8 Weber et al. 2015 (CheckMate 037)]
 +
|2012-2014
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Nivolumab_monotherapy_3|Nivolumab]]
 +
| style="background-color:#d73027" |Inferior ORR
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
 +
''Note: CheckMate 037 did not meet the co-primary endpoint of OS.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Prior treatment criteria====
 +
*CheckMate 037, BRAF WT: Exposure to ipilimumab
 +
*CheckMate 037, BRAF p.V600: Exposure to ipilimumab and BRAF inhibitor
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Dacarbazine (DTIC)]] 1000 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
−
===Regimen {{#subobject:46549|Variant=1}}===
+
===Regimen variant #3, 1250 mg/m<sup>2</sup>, split doses, q3wk {{#subobject:4bacb|Variant=1}}===
−
{| border="1" style="text-align:center;" !align="left"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
|'''Study'''
+
! style="width: 20%" |Study
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.ncbi.nlm.nih.gov/pubmed/7654429 Aamdal et al. 1994]
+
|[https://doi.org/10.1056/NEJM199208203270803 Cocconi et al. 1992]
−
|<span
+
|1983-1988
−
style="background:#EEEE00;
+
| style="background-color:#1a9851" |Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[Melanoma_-_historical#Dacarbazine_.26_Tamoxifen|Dacarbazine & Tamoxifen]]
−
border-color:black;
+
| style="background-color:#fc8d59" |Seems to have inferior OS
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#fdcdac">
−
*[[Docetaxel (Taxotere)]] 100 mg/m2 IV over 60 minutes once on day 1
+
====Prior treatment criteria====
−
 
+
*Cocconi et al. 1992: No previous treatment with dacarbazine or tamoxifen
−
Supportive medications:
+
</div>
−
*"No prophylactic treatment with steroids or antihistamines was given."
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
 +
*[[Dacarbazine (DTIC)]] 250 mg/m<sup>2</sup> IV over 20 to 30 minutes once per day on days 1 to 5
 
'''21-day cycles'''
 
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 2500 mg/m<sup>2</sup>, split doses, q4wk {{#subobject:ac310c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1984.2.3.164 Luikart et al. 1984]
 +
|NR
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#BVP_999|BVP]]
 +
| style="background-color:#ffffbf" |Did not meet efficacy endpoints
 +
|-
 +
|}
 +
''Note: This is the first phase 3 RCT published in the Journal of Clinical Oncology.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Dacarbazine (DTIC)]] 250 mg/m<sup>2</sup> IV once per day on days 1 to 10
 +
'''28-day cycles'''
 +
</div></div>
  
 
===References===
 
===References===
−
# Aamdal S, Wolff I, Kaplan S, Paridaens R, Kerger J, Schachter J, Wanders J, Franklin HR, Verweij J. Docetaxel (Taxotere) in advanced malignant melanoma: a phase II study of the EORTC Early Clinical Trials Group. Eur J Cancer. 1994;30A(8):1061-4. '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/7654429 PubMed]
+
#Pritchard KI, Quirt IC, Cowan DH, Osoba D, Kutas GJ. DTIC therapy in metastatic malignant melanoma: a simplified dose schedule. Cancer Treat Rep. 1980 Oct-Nov;64(10-11):1123-6. [https://pubmed.ncbi.nlm.nih.gov/7459898/ PubMed]
 +
#Luikart SD, Kennealey GT, Kirkwood JM. Randomized phase III trial of vinblastine, bleomycin, and cis-dichlorodiammine-platinum versus dacarbazine in malignant melanoma. J Clin Oncol. 1984 Mar;2(3):164-8. [https://doi.org/10.1200/JCO.1984.2.3.164 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/6199481/ PubMed]
 +
#Cocconi G, Bella M, Calabresi F, Tonato M, Canaletti R, Boni C, Buzzi F, Ceci G, Corgna E, Costa P, Lottici R, Papadia F, Sofra MC, Bacchi M. Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen. N Engl J Med. 1992 Aug 20;327(8):516-23. [https://doi.org/10.1056/NEJM199208203270803 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1635566/ PubMed]
 +
#'''EORTC 18032:''' Patel PM, Suciu S, Mortier L, Kruit WH, Robert C, Schadendorf D, Trefzer U, Punt CJ, Dummer R, Davidson N, Becker J, Conry R, Thompson JA, Hwu WJ, Engelen K, Agarwala SS, Keilholz U, Eggermont AM, Spatz A; [[Study_Groups#EORTC|EORTC]] Melanoma Group. Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). Eur J Cancer. 2011 Jul;47(10):1476-83. Epub 2011 May 18. [https://doi.org/10.1016/j.ejca.2011.04.030 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21600759/ PubMed] [https://clinicaltrials.gov/study/NCT00091572 NCT00091572]
 +
#'''CheckMate 037:''' Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. [https://doi.org/10.1016/S1470-2045(15)70076-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25795410/ PubMed] [https://clinicaltrials.gov/study/NCT01721746 NCT01721746]
 +
##'''Update:''' Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. [https://doi.org/10.1200/JCO.2016.71.8023 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6804912/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28671856/ PubMed]
 +
#'''KEYNOTE-002:''' Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. [https://doi.org/10.1016/S1470-2045(15)00083-2 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26115796/ PubMed] [https://clinicaltrials.gov/study/NCT01704287 NCT01704287]
 +
##'''HRQoL analysis:''' Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. [https://doi.org/10.1016/j.ejca.2016.07.018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27596353/ PubMed]
 +
##'''Update:''' Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. [https://doi.org/10.1016/j.ejca.2017.07.022 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28961465/ PubMed]
  
−
==High-dose (HD) IL-2 {{#subobject:771c23|Regimen=1}}==
+
==Docetaxel monotherapy {{#subobject:bd3e54|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:46549|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1016/0959-8049(94)90456-1 Aamdal et al. 1994]
 +
|NR
 +
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
====Supportive therapy====
 +
*"No prophylactic treatment with steroids or antihistamines was given."
 +
'''21-day cycles'''
 +
</div></div>
 +
===References===
 +
#Aamdal S, Wolff I, Kaplan S, Paridaens R, Kerger J, Schachter J, Wanders J, Franklin HR, Verweij J; [[Study_Groups#EORTC|EORTC]] Early Clinical Trials Group. Docetaxel (Taxotere) in advanced malignant melanoma: a phase II study of the EORTC Early Clinical Trials Group. Eur J Cancer. 1994;30A(8):1061-4. [https://doi.org/10.1016/0959-8049(94)90456-1 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/7654429/ PubMed]
  
 +
==High-dose Interleukin-2 {{#subobject:771c23|Regimen=1}}==
 +
HD IL-2: '''<u>H</u>'''igh-'''<u>D</u>'''ose '''<u>I</u>'''nter'''<u>L</u>'''eukin-'''<u>2</u>'''
 
===Example orders===
 
===Example orders===
 
*[[Example orders for High-dose (HD) IL-2 in melanoma]]
 
*[[Example orders for High-dose (HD) IL-2 in melanoma]]
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen, Atkins et al. 1999 {{#subobject:4efbce|Variant=1}}===
+
===Regimen variant #1, 600k, up to 3 cycles {{#subobject:4efbce|Variant=1}}===
−
Level of Evidence:
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
<span
+
! style="width: 20%" |Study
−
style="background:#EEEE00;
+
! style="width: 20%" |Dates of enrollment
−
padding:3px 6px 3px 6px;
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
border-color:black;
+
! style="width: 20%" |Comparator
−
border-width:2px;
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
border-style:solid;">Phase II</span>
+
|-
−
 
+
|[https://doi.org/10.1200/JCO.1993.11.10.1969 Sparano et al. 1993]
−
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 600,000 or 720,000 units/kg IV every 8 hours x up to 14 doses per week, on days 1 to 5
+
|NR
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#High-dose_Interleukin-2_.26_Interferon_alfa-2a_999|HD IL-2 & IFN alfa-2a]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS50%
 +
|-
 +
|}
 +
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 600,000 units/kg IV over 15 minutes every 8 hours as tolerated on days 1 to 5, 15 to 19 (up to 28 total doses per cycle)
 +
====Supportive therapy====
 +
*Included:
 +
*[[Acetaminophen (Tylenol)]]
 +
*[[Indomethacin (Indocin)]]
 +
*[[Meperidine (Demerol)]]
 +
*[[Ranitidine (Zantac)]]
 +
*[[Cimetidine (Tagamet)]]
 +
*[[Hydroxyzine (Atarax)]]
 +
*[[Diphenhydramine (Benadryl)]]
 +
*Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.
 +
'''12-week cycle for up to 3 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 600k, up to 5 cycles {{#subobject:4ehg1e|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Dates of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.1999.17.7.2105 Atkins et al. 1999]
 +
|1985-1993
 +
| style="background-color:#91cf61" |Phase 2 (RT)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 600,000 units/kg IV over 15 minutes every 8 hours for up to 14 doses per week, on days 1 to 5
 
**After a 6 to 9 day rest period, another 14 doses per week given over 5 days is given as described above
 
**After a 6 to 9 day rest period, another 14 doses per week given over 5 days is given as described above
−
 
+
====Supportive therapy====
−
'''6 to 12 weeks per cycle x up to 5 cycles'''
+
*Included:
−
 
+
*[[Acetaminophen (Tylenol)]]
−
Supportive medications:
+
*[[Indomethacin (Indocin)]]
−
*Included Acetaminophen (Tylenol), Indomethacin (Indocin), Meperidine (Demerol), Ranitidine (Zantac), Cimetidine (Tagamet), Hydroxyzine (Atarax), Diphenhydramine (Benadryl), dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.
+
*[[Meperidine (Demerol)]]
−
 
+
*[[Ranitidine (Zantac)]]
−
===References===
+
*[[Cimetidine (Tagamet)]]
−
# Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999 Jul;17(7):2105-16. [http://jco.ascopubs.org/content/17/7/2105.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/10561265 PubMed]
+
*[[Hydroxyzine (Atarax)]]
−
## '''Update:''' Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000 Feb;6 Suppl 1:S11-4. [http://www.ncbi.nlm.nih.gov/pubmed/10685652 PubMed]
+
*[[Diphenhydramine (Benadryl)]]
−
 
+
*Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.
−
==IL-2 maintenance biotherapy {{#subobject:fa72a9|Regimen=1}}==
+
'''6- to 12-week cycle for up to 5 cycles'''
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 720k, up to 3 cycles {{#subobject:4efbce|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Dates of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[http://jamanetwork.com/journals/jama/article-abstract/368156 Rosenberg et al. 1994]
 +
|1985-1992
 +
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Example orders===
+
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
−
*[[Example orders for IL-2 maintenance biotherapy in melanoma]]
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Immunotherapy====
−
===Regimen, O'Day et al. 2002 {{#subobject:2ed5d3|Variant=1}}===
+
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV over 15 minutes every 8 hours as tolerated on days 1 to 5, 15 to 19 (up to 30 total doses per cycle)
−
Level of Evidence:
+
====Supportive therapy====
−
<span
+
*Included:
−
style="background:#EEEE00;
+
*[[Acetaminophen (Tylenol)]]
−
padding:3px 6px 3px 6px;
+
*[[Indomethacin (Indocin)]]
−
border-color:black;
+
*[[Meperidine (Demerol)]]
−
border-width:2px;
+
*[[Ranitidine (Zantac)]]
−
border-style:solid;">Phase II</span>
+
*[[Cimetidine (Tagamet)]]
−
 
+
*[[Hydroxyzine (Atarax)]]
−
====Low-dose cycles 1, 4, 7, 9, 11====
+
*[[Diphenhydramine (Benadryl)]]
−
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 1,000,000 units/m2 SC once per day every Monday to Friday on days 1 to 28
+
*Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.
−
 
+
'''2-month cycle for up to 3 cycles'''
−
'''28-day cycles x a total of 12 cycles after being combined with the pulse cycles below'''
+
</div></div><br>
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
Supportive medications:
+
===Regimen variant #4, 720k, up to 5 cycles {{#subobject:4jbaq1|Variant=1}}===
−
*[[Sargramostim (Leukine)]] 125 mcg/m2 SC once per day on days 1 to 14
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
 
+
! style="width: 33%" |Study
−
====Pulse cycles 2, 3, 5, 6, 8, 10, 12====
+
! style="width: 33%" |Dates of enrollment
−
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 18,000,000 units/m2 IV continuous infusion over 6 hours, then 18,000,000 units/m2 IV continuous infusion over 12 hours, then 18,000,000 units/m2 IV continuous infusion over 24 hours on days 1 to 2
+
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
**Then as an outpatient: [[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 1,000,000 units/m2 SC once per day every Monday to Friday on days 3 to 28
+
|-
−
 
+
|[https://doi.org/10.1200/jco.1999.17.7.2105 Atkins et al. 1999]
−
'''28-day cycles x a total of 12 cycles after being combined with the low dose cycles above'''
+
|1985-1993
−
 
+
| style="background-color:#91cf61" |Phase 2 (RT)
−
Supportive medications:
 
−
*[[Sargramostim (Leukine)]] 125 mcg/m2 SC once per day on days 3 to 17 (note: this was possibly a typo in O'Day et al. 2002  since shifting the schedule 2 days forward would be days 3 to 16)
 
−
*Ondansetron (Zofran) 32 mg IV or Granisetron (Kytril) 2 mg IV once per day
 
−
*Omeprazole (Prilosec) 20 mg PO QPM
 
−
*Acetaminophen (Tylenol) 650 mg PO every 4 hours, starting prior to IL-2 and continuing on days 1-2
 
−
*Meperidine (Demerol) 25 mg IV every 6 hours as needed for chills and rigors
 
−
 
 
−
===References===
 
−
# O'Day SJ, Boasberg PD, Piro L, Kristedja TS, Wang HJ, Martin M, Deck R, Ames P, Shinn K, Kim H, Fournier P, Gammon G. Maintenance biotherapy for metastatic melanoma with interleukin-2 and granulocyte macrophage-colony stimulating factor improves survival for patients responding to induction concurrent biochemotherapy. Clin Cancer Res. 2002 Sep;8(9):2775-81. [http://clincancerres.aacrjournals.org/content/8/9/2775.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12231516 PubMed]
 
−
 
 
−
==Imatinib (Gleevec) {{#subobject:8686d5|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen, Hodi et al. 2013 {{#subobject:662612|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Immunotherapy====
−
<span
+
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV over 15 minutes every 8 hours for up to 14 doses per week, on days 1 to 5
−
style="background:#EEEE00;
+
**After a 6 to 9 day rest period, another 14 doses per week given over 5 days is given as described above
−
padding:3px 6px 3px 6px;
+
====Supportive therapy====
−
border-color:black;
+
*Included:
−
border-width:2px;
+
*[[Acetaminophen (Tylenol)]]
−
border-style:solid;">Phase II</span>
+
*[[Indomethacin (Indocin)]]
−
 
+
*[[Meperidine (Demerol)]]
−
''Patients in Hodi et al. 2013 had melanomas arising from mucosal, acral, and chronically sun-damaged (CSD) skin with KIT mutations or amplifications.''
+
*[[Ranitidine (Zantac)]]
−
====Starting dose====
+
*[[Cimetidine (Tagamet)]]
−
*[[Imatinib (Gleevec)]] 400 mg PO once per day
+
*[[Hydroxyzine (Atarax)]]
−
 
+
*[[Diphenhydramine (Benadryl)]]
−
'''given until disease progression; then proceed to higher dose'''
+
*Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.
−
 
+
'''6- to 12-week cycle for up to 5 cycles'''
−
====Higher dose====
+
</div></div><br>
−
*[[Imatinib (Gleevec)]] 400 mg PO BID
+
<div class="toccolours" style="background-color:#eeeeee">
−
 
+
===Regimen variant #5, 720k, indefinite {{#subobject:61ghce|Variant=1}}===
−
'''given until disease progression'''
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
 
+
! style="width: 20%" |Study
−
===References===
+
! style="width: 20%" |Dates of enrollment
−
# Hodi FS, Corless CL, Giobbie-Hurder A, Fletcher JA, Zhu M, Marino-Enriquez A, Friedlander P, Gonzalez R, Weber JS, Gajewski TF, O'Day SJ, Kim KB, Lawrence D, Flaherty KT, Luke JJ, Collichio FA, Ernstoff MS, Heinrich MC, Beadling C, Zukotynski KA, Yap JT, Van den Abbeele AD, Demetri GD, Fisher DE. Imatinib for Melanomas Harboring Mutationally Activated or Amplified KIT Arising on Mucosal, Acral, and Chronically Sun-Damaged Skin. J Clin Oncol. 2013 Jun 17. [Epub ahead of print] [http://jco.ascopubs.org/content/early/2013/06/17/JCO.2012.47.7836.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23775962 PubMed]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
 
+
! style="width: 20%" |Comparator
−
==Ipilimumab (Yervoy) {{#subobject:fab3f4|Regimen=1}}==
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517182/ Schwartzentruber et al. 2011 (NCI-2012-02897)]
 +
|2000-2007
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#High-dose_Interleukin-2_.26_gp100_vaccine_888|HD IL-2 & gp100 vaccine]]
 +
| style="background-color:#fc8d59" |Seems to have inferior clinical response
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours as tolerated on days 1 to 4, 22 to 25 (up to 24 total doses per cycle)
 +
====Supportive therapy====
 +
*Included:
 +
*[[Acetaminophen (Tylenol)]]
 +
*[[Indomethacin (Indocin)]]
 +
*[[Meperidine (Demerol)]]
 +
*[[Ranitidine (Zantac)]]
 +
*[[Cimetidine (Tagamet)]]
 +
*[[Hydroxyzine (Atarax)]]
 +
*[[Diphenhydramine (Benadryl)]]
 +
*Dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.
 +
'''7-week cycles'''
 +
</div></div>
 +
===References===
 +
#Sparano JA, Fisher RI, Sunderland M, Margolin K, Ernest ML, Sznol M, Atkins MB, Dutcher JP, Micetich KC, Weiss GR, Doroshow JH, Aronson FR, Rubinstein LV, Mier JW. Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol. 1993 Oct;11(10):1969-77. [https://doi.org/10.1200/JCO.1993.11.10.1969 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8410122/ PubMed]
 +
#Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994 Mar 23-30;271(12):907-13. [http://jamanetwork.com/journals/jama/article-abstract/368156 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8120958/ PubMed]
 +
#Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999 Jul;17(7):2105-16. [https://doi.org/10.1200/jco.1999.17.7.2105 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10561265/ PubMed]
 +
##'''Update:''' Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000 Feb;6 Suppl 1:S11-4. [https://pubmed.ncbi.nlm.nih.gov/10685652/ PubMed]
 +
#'''NCI-2012-02897:''' Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, Gailani F, Riley L, Conlon K, Pockaj B, Kendra KL, White RL, Gonzalez R, Kuzel TM, Curti B, Leming PD, Whitman ED, Balkissoon J, Reintgen DS, Kaufman H, Marincola FM, Merino MJ, Rosenberg SA, Choyke P, Vena D, Hwu P. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011 Jun 2;364(22):2119-27. [https://doi.org/10.1056/NEJMoa1012863 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517182/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21631324/ PubMed] [https://clinicaltrials.gov/study/NCT00019682 NCT00019682]
 +
==Ipilimumab monotherapy {{#subobject:fab3f4|Regimen=1}}==
 
===Example orders===
 
===Example orders===
 
*[[Example orders for Ipilimumab (Yervoy) in melanoma]]
 
*[[Example orders for Ipilimumab (Yervoy) in melanoma]]
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen #1 {{#subobject:33786a|Variant=1}}===
+
===Regimen variant #1, 3 mg/kg {{#subobject:33786a|Variant=1}}===
−
{| border="1" style="text-align:center;" !align="left"  
+
{| class="wikitable" style="color:white; background-color:#404040"
−
|'''Study'''
+
|<small>'''FDA-recommended dose'''</small>
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
|-
−
|[[Overall response rate|'''ORR''']]
+
|}
−
|'''Comparator'''
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
|Comparator [[Overall response rate|'''ORR''']]
+
! style="width: 20%" |Study
−
|Pt Population
+
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549297/ Hodi et al. 2010 (MDX010-20)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-81-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
 +
|-
 +
|} -->
 +
| rowspan="2" |2004-2008
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
 +
|1. [[#Ipilimumab_.26_gp100_vaccine_999|Ipilimumab & gp100 peptide vaccine]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|2. [[#gp100_vaccine_888|gp100 peptide vaccine]]
 +
| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 10 vs 6.4 mo<br>(HR 0.68, 95% CI 0.55-0.85)
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1003466 Hodi et al. 2010]
+
|[https://doi.org/10.1016/S1470-2045(17)30231-0 Ascierto et al. 2017 (CA184-169)]
−
|<span
+
|2012-02-29 to 2012-07-09
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[#Ipilimumab_monotherapy_3|Ipilimumab]]; 10 mg/kg
−
border-color:black;
+
| style="background-color:#fc8d59" |Seems to have inferior OS
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|10.9% (95% CI 6.3 - 17.4)
 
−
|Ipilimumab & gp100 peptide vaccine<br> gp100 peptide vaccine
 
−
|5.7% (95% CI 3.7 - 8.4)<br>1.5% (95% CI 0.2 - 5.2)
 
−
|Pretreated (chemo, IL-2)
 
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1503093 Robert et al. 2015 (KEYNOTE-006)]
+
| rowspan="2" |[https://doi.org/10.1056/NEJMoa1503093 Robert et al. 2015 (KEYNOTE-006)]
−
|<span
+
| rowspan="2" |2013-09-18 to 2014-03-03
−
style="background:#00cd00;
+
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|1. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 10 mg/kg q2wks
−
border-color:black;
+
| style="background-color:#d73027" |Inferior OS
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|
 
−
|[[#Pembrolizumab_.28Keytruda.29|Pembrolizumab]]
 
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1414428 Postow et al. 2015]
+
|2. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 10 mg/kg q3wks
−
|<span
+
| style="background-color:#d73027" |Inferior OS
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|
 
−
|[[#Ipilimumab_.26_Nivolumab|Ipilimumab & Nivolumab]]
 
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Prior treatment criteria====
 +
*KEYNOTE-006: No more than 1 line of systemic therapy for advanced disease
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Ipilimumab (Yervoy)]] 3 mg/kg IV over 90 minutes once on day 1
 +
'''21-day cycle for 4 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
−
*[[Ipilimumab (Yervoy)]] 3 mg/kg IV once on day 1
+
===Regimen variant #2, 10 mg/kg limited duration {{#subobject:7e975b|Variant=1}}===
−
 
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
'''21-day cycle x 4 cycles'''
+
! style="width: 20%" |Study
−
 
+
! style="width: 20%" |Dates of enrollment
−
===Regimen #2 {{#subobject:7e975b|Variant=1}}===
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
{| border="1" style="text-align:center;" !align="left"  
+
! style="width: 20%" |Comparator
−
|'''Study'''
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
|-
 +
|[https://doi.org/10.1200/JCO.2008.16.1927 Weber et al. 2008]
 +
|2003-2005
 +
| style="background-color:#91cf61" |Phase 1/2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045%2809%2970334-1 Wolchok et al. 2010 (CA184-022)]
 +
|2006-2007
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336189/ Hodi et al. 2014 (ECOG E1608)]
 +
|2010-2011
 +
| style="background-color:#1a9851" |Randomized Phase 2 (C)
 +
|[[#Ipilimumab_.26_Sargramostim_888|Ipilimumab & GM-CSF]]
 +
| style="background-color:#d73027" |Inferior OS
 
|-
 
|-
−
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970334-1/fulltext Wolchok et al. 2010]
+
|[https://doi.org/10.1016/S1470-2045(17)30231-0 Ascierto et al. 2017 (CA184-169)]
−
|<span
+
|2012-02-29 to 2012-07-09
−
style="background:#EEEE00;
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
padding:3px 6px 3px 6px;
+
|[[#Ipilimumab_monotherapy_3|Ipilimumab]]; 3 mg/kg
−
border-color:black;
+
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup> (primary endpoint)<br>Median OS: 15.7 vs 11.5 mo<br>(HR 0.84, 95% CI 0.71-0.99)
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''<sup>1</sup>Reported efficacy is based on the 2020 update.''<br>
 +
''Note: In CA184-022, lower doses including 3 mg/kg (the FDA approved dose) were investigated, but the 10 mg/kg dose was recommended.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 
*[[Ipilimumab (Yervoy)]] 10 mg/kg IV over 90 minutes once on day 1
 
*[[Ipilimumab (Yervoy)]] 10 mg/kg IV over 90 minutes once on day 1
−
**Lower doses including 3 mg/kg (the FDA approved dose) were investigated, but the 10 mg/kg dose was recommended in this study
+
'''21-day cycle for 4 cycles'''
−
 
+
</div></div><br>
−
'''21-day cycle x 4 cycles'''
+
<div class="toccolours" style="background-color:#eeeeee">
−
 
+
===Regimen variant #3, 10 mg/kg with maintenance {{#subobject:7e98hgv|Variant=1}}===
−
===Regimen #3 {{#subobject:a9b395|Variant=1}}===
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
{| border="1" style="text-align:center;" !align="left"  
+
! style="width: 33%" |Study
−
|'''Study'''
+
! style="width: 33%" |Dates of enrollment
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdq013 O'Day et al. 2010 (CA184-008)]
 +
|2006-2007
 +
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
−
|[http://annonc.oxfordjournals.org/content/21/8/1712.long O'Day et al. 2010]
+
|[https://doi.org/10.1016/S1470-2045(12)70090-6 Margolin et al. 2012 (CA184-042)]
−
|<span
+
|2008-2009
−
style="background:#EEEE00;
+
| style="background-color:#91cf61" |Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
====Induction phase====
+
====Immunotherapy====
−
*[[Ipilimumab (Yervoy)]] 10 mg/kg IV over 90 minutes once on day 1
 
−
 
 
−
'''21-day cycle x 4 cycles'''
 
−
 
 
−
====Maintenance phase====
 
 
*[[Ipilimumab (Yervoy)]] 10 mg/kg IV over 90 minutes once on day 1
 
*[[Ipilimumab (Yervoy)]] 10 mg/kg IV over 90 minutes once on day 1
−
 
+
'''21-day cycle for 4 cycles, then 12-week cycles'''
−
'''12-week cycles, given until progression of disease or unacceptable toxicity; starts 12 weeks after completion of induction phase'''
+
</div></div>
−
 
 
 
===References===
 
===References===
−
# Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, Waterfield W, Schadendorf D, Smylie M, Guthrie T Jr, Grob JJ, Chesney J, Chin K, Chen K, Hoos A, O'Day SJ, Lebbé C. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010 Feb;11(2):155-64. Epub 2009 Dec 8. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970334-1/fulltext link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20004617 PubMed]
+
#Weber JS, O'Day S, Urba W, Powderly J, Nichol G, Yellin M, Snively J, Hersh E. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008 Dec 20;26(36):5950-6. Epub 2008 Nov 17. [https://doi.org/10.1200/JCO.2008.16.1927 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19018089/ PubMed]
−
# Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. Epub 2010 Jun 5. [http://www.nejm.org/doi/full/10.1056/NEJMoa1003466 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20525992 PubMed]
+
#'''CA184-022:''' Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, Waterfield W, Schadendorf D, Smylie M, Guthrie T Jr, Grob JJ, Chesney J, Chin K, Chen K, Hoos A, O'Day SJ, Lebbé C. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010 Feb;11(2):155-64. Epub 2009 Dec 8. [https://doi.org/10.1016/S1470-2045%2809%2970334-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20004617/ PubMed] [https://clinicaltrials.gov/study/NCT00289640 NCT00289640]
−
# O'Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, Queirolo P, Lundgren L, Mikhailov S, Roman L, Verschraegen C, Humphrey R, Ibrahim R, de Pril V, Hoos A, Wolchok JD. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010 Aug;21(8):1712-7. Epub 2010 Feb 10. [http://annonc.oxfordjournals.org/content/21/8/1712.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20147741 PubMed]
+
#'''MDX010-20:''' Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. Epub 2010 Jun 5. Erratum in: N Engl J Med. 2010 Sep 23;363(13):1290. [https://doi.org/10.1056/NEJMoa1003466 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549297/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20525992/ PubMed] [https://clinicaltrials.gov/study/NCT00094653 NCT00094653]
−
# Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19.[http://www.nejm.org/doi/full/10.1056/NEJMoa1503093 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/25891173 PubMed]
+
##'''HRQoL analysis:''' Revicki DA, van den Eertwegh AJ, Lorigan P, Lebbe C, Linette G, Ottensmeier CH, Safikhani S, Messina M, Hoos A, Wagner S, Kotapati S. Health related quality of life outcomes for unresectable stage III or IV melanoma patients receiving ipilimumab treatment. Health Qual Life Outcomes. 2012 Jun 13;10:66. [https://doi.org/10.1186/1477-7525-10-66 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc3426458/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22694829/ PubMed]
−
# Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. [http://www.nejm.org/doi/full/10.1056/NEJMoa1414428 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/25891304 PubMed]
+
##'''Subgroup analysis:''' McDermott D, Haanen J, Chen TT, Lorigan P, O'Day S; MDX010-20 Investigators. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol. 2013 Oct;24(10):2694-8. Epub 2013 Aug 13. [https://doi.org/10.1093/annonc/mdt291 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23942774/ PubMed]
−
 
+
#'''CA184-008:''' O'Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, Queirolo P, Lundgren L, Mikhailov S, Roman L, Verschraegen C, Humphrey R, Ibrahim R, de Pril V, Hoos A, Wolchok JD. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010 Aug;21(8):1712-7. Epub 2010 Feb 10. [https://doi.org/10.1093/annonc/mdq013 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20147741/ PubMed] [https://clinicaltrials.gov/study/NCT00289627 NCT00289627]
 +
#'''CA184-042:''' Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012 May;13(5):459-65. Epub 2012 Mar 27. [https://doi.org/10.1016/S1470-2045(12)70090-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22456429/ PubMed] [https://clinicaltrials.gov/study/NCT00623766 NCT00623766]
 +
#'''ECOG E1608:''' Hodi FS, Lee S, McDermott DF, Rao UN, Butterfield LH, Tarhini AA, Leming P, Puzanov I, Shin D, Kirkwood JM. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014 Nov 5;312(17):1744-53. [https://jamanetwork.com/journals/jama/fullarticle/1920969 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336189/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25369488/ PubMed] [https://clinicaltrials.gov/study/NCT01134614 NCT01134614]
 +
#'''KEYNOTE-006:''' Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19. [https://doi.org/10.1056/NEJMoa1503093 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25891173/ PubMed] [https://clinicaltrials.gov/study/NCT01866319 NCT01866319]
 +
##'''Update:''' Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-1862. Epub 2017 Aug 16. [https://doi.org/10.1016/S0140-6736(17)31601-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/28822576/ PubMed]
 +
##'''PRO analysis:''' Petrella TM, Robert C, Richtig E, Miller WH Jr, Masucci GV, Walpole E, Lebbe C, Steven N, Middleton MR, Hille D, Zhou W, Ibrahim N, Cebon J. Patient-reported outcomes in KEYNOTE-006, a randomised study of pembrolizumab versus ipilimumab in patients with advanced melanoma. Eur J Cancer. 2017 Nov;86:115-124. Epub 2017 Oct 4. [https://doi.org/10.1016/j.ejca.2017.08.032 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28987768/ PubMed]
 +
##'''Update:''' Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Su SC, Krepler C, Ibrahim N, Long GV. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019 Sep;20(9):1239-1251. Epub 2019 Jul 22. [https://doi.org/10.1016/S1470-2045(19)30388-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31345627/ PubMed]
 +
##'''Update:''' Robert C, Carlino MS, McNeil C, Ribas A, Grob JJ, Schachter J, Nyakas M, Kee D, Petrella TM, Blaustein A, Lotem M, Arance A, Daud AI, Hamid O, Larkin J, Anderson J, Krepler C, Grebennik D, Long GV. Seven-Year Follow-Up of the Phase III KEYNOTE-006 Study: Pembrolizumab Versus Ipilimumab in Advanced Melanoma. J Clin Oncol. 2023 Aug 20;41(24):3998-4003. Epub 2023 Jun 22. [https://doi.org/10.1200/jco.22.01599 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37348035/ PubMed]
 +
#'''CA184-169:''' Ascierto PA, Del Vecchio M, Robert C, Mackiewicz A, Chiarion-Sileni V, Arance A, Lebbé C, Bastholt L, Hamid O, Rutkowski P, McNeil C, Garbe C, Loquai C, Dreno B, Thomas L, Grob JJ, Liszkay G, Nyakas M, Gutzmer R, Pikiel J, Grange F, Hoeller C, Ferraresi V, Smylie M, Schadendorf D, Mortier L, Svane IM, Hennicken D, Qureshi A, Maio M. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2017 May;18(5):611-622. Epub 2017 Mar 27. [https://doi.org/10.1016/S1470-2045(17)30231-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28359784/ PubMed] [https://clinicaltrials.gov/study/NCT01515189 NCT01515189]
 +
##'''Update:''' Ascierto PA, Del Vecchio M, Mackiewicz A, Robert C, Chiarion-Sileni V, Arance A, Lebbé C, Svane IM, McNeil C, Rutkowski P, Loquai C, Mortier L, Hamid O, Bastholt L, Dreno B, Schadendorf D, Garbe C, Nyakas M, Grob JJ, Thomas L, Liszkay G, Smylie M, Hoeller C, Ferraresi V, Grange F, Gutzmer R, Pikiel J, Hosein F, Simsek B, Maio M. Overall survival at 5 years of follow-up in a phase III trial comparing ipilimumab 10 mg/kg with 3 mg/kg in patients with advanced melanoma. J Immunother Cancer. 2020 Jun;8(1):e000391. Erratum in: J Immunother Cancer. 2020 Jul;8(2). [https://doi.org/10.1136/jitc-2019-000391 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7279645/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32503946/ PubMed]
 +
#'''M14TIL:''' [https://clinicaltrials.gov/study/NCT02278887 NCT02278887]
 
==Ipilimumab & Nivolumab {{#subobject:517ff0|Regimen=1}}==
 
==Ipilimumab & Nivolumab {{#subobject:517ff0|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#toc|back to top]]
 
−
|}
 
 
===Regimen {{#subobject:fa55a8|Variant=1}}===
 
===Regimen {{#subobject:fa55a8|Variant=1}}===
−
{| border="1" style="text-align:center;" !align="left"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
|'''Study'''
+
! style="width: 33%" |Study
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
! style="width: 33%" |Dates of enrollment
−
|'''Comparator'''
+
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1414428 Postow et al. 2015]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5698004/ Wolchok et al. 2013 (CheckMate 004)]
−
|<span
+
|2009-2013
−
style="background:#00CD00;
+
| style="background-color:#ffffbe" |Phase 1
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[#Ipilimumab_.28Yervoy.29_2|Ipilimumab]]
 
 
|-
 
|-
 
|}
 
|}
−
''These doses were from the cohort deemed by Wolchok et al. 2013 as being "the maximum doses that were associated with an acceptable level of adverse events."''
+
''Note: These doses were from the cohort deemed by CheckMate 004 as being "the maximum doses that were associated with an acceptable level of adverse events."''
−
====Induction therapy====
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Ipilimumab (Yervoy)]] 3 mg/kg IV once on day 1, given second
+
====Immunotherapy====
−
*[[Nivolumab (Opdivo)]] 1 mg/kg IV once on day 1, given first
+
*[[Ipilimumab (Yervoy)]] as follows:
−
 
+
**Cycles 1 to 4: 3 mg/kg IV once on day 1, '''given second'''
−
'''21-day cycle x 4 cycles, then proceed to Nivolumab only phase'''
+
*[[Nivolumab (Opdivo)]] 1 mg/kg IV once on day 1, '''given first'''
−
 
+
'''21-day cycle for 8 cycles'''
−
====Nivolumab only phase====
+
</div>
−
*[[Nivolumab (Opdivo)]] 1 mg/kg IV once on day 1
+
<div class="toccolours" style="background-color:#cbd5e7">
−
 
+
====Subsequent treatment====
−
'''21-day cycle x 4 cycles, then proceed to maintenance therapy'''
+
*[[#Ipilimumab_.26_Nivolumab_3|Ipilimumab & nivolumab]] maintenance
−
 
+
</div></div>
−
====Maintenance therapy====
 
−
*[[Ipilimumab (Yervoy)]] 3 mg/kg IV once on day 1, given second
 
−
*[[Nivolumab (Opdivo)]] 1 mg/kg IV once on day 1, given first
 
−
 
 
−
'''12-week cycle x 8 cycles'''
 
−
 
 
 
===References===
 
===References===
−
# '''Phase I:''' Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33. [http://www.nejm.org/doi/full/10.1056/NEJMoa1302369 link to original article] '''contains verified protocol''' [http://www.nejm.org/doi/suppl/10.1056/NEJMoa1302369/suppl_file/nejmoa1302369_appendix.pdf link to supplementary appendix] [http://www.ncbi.nlm.nih.gov/pubmed/23724867 PubMed]
+
#'''CheckMate 004:''' Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33. Epub 2013 Jun 2. [https://doi.org/10.1056/NEJMoa1302369 link to original article] '''contains dosing details in manuscript''' [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1302369/suppl_file/nejmoa1302369_appendix.pdf link to supplementary appendix] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5698004/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23724867/ PubMed] [https://clinicaltrials.gov/study/NCT01024231 NCT01024231]
−
# Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. [http://www.nejm.org/doi/full/10.1056/NEJMoa1414428 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/25891304 PubMed]
 
  
−
==Nivolumab (Opdivo) {{#subobject:6a44dd|Regimen=1}}==
+
==Ipilimumab-Nivolumab {{#subobject:184810|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:8347ab|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(16)30126-7 Weber et al. 2016 (CheckMate 064)]
 +
|2013-2014
 +
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 +
|[[#Nivolumab-Ipilimumab|Nivolumab, then Ipilimumab]]
 +
| style="background-color:#d73027" |Inferior OS (secondary endpoint)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen #1 {{#subobject:722e51|Variant=1}}===
+
''Note: on 2016-09-13 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.''
−
{| border="1" style="text-align:center;" !align="left"  
+
<div class="toccolours" style="background-color:#b3e2cd">
−
|'''Study'''
+
====Immunotherapy====
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
*[[Ipilimumab (Yervoy)]] as follows:
−
|'''Comparator'''
+
**Cycles 1 to 4: 3 mg/kg IV once on day 1
 +
*[[Nivolumab (Opdivo)]] as follows:
 +
**Cycle 5 onwards: 3 mg/kg IV once on day 1
 +
'''21-day cycle for 4 cycles, then 14-day cycles'''
 +
</div></div>
 +
===References===
 +
#'''CheckMate 064:''' Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP, Logan TF, Schuchter LM, Nair S, Fecher L, Buchbinder EI, Berghorn E, Ruisi M, Kong G, Jiang J, Horak C, Hodi FS. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol. 2016 Jul;17(7):943-55. Epub 2016 Jun 4. [https://doi.org/10.1016/S1470-2045(16)30126-7 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474305/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27269740/ PubMed] [https://clinicaltrials.gov/study/NCT01783938 NCT01783938]
 +
==Nivolumab monotherapy {{#subobject:6a44dd|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, limited duration {{#subobject:1ec35|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Dates of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837092/ Weber et al. 2013 (MCC-15400)]
 +
|2010-2012
 +
| style="background-color:#ffffbe" |Phase 1
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1412082 Robert et al. 2014]
+
|}
−
|<span
+
''Note: on 2016-09-13 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data. It is not clear from the manuscript whether the maintenance is 2 years or if the total course is 2 years.''
−
style="background:#00CD00;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
padding:3px 6px 3px 6px;
+
====Immunotherapy====
−
border-color:black;
+
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
−
border-width:2px;
+
'''14-day cycle for 12 cycles, then 12-week cycle for 8 cycles (see note)'''
−
border-style:solid;">Phase III</span>
+
</div></div><br>
−
|[[Melanoma#Dacarbazine_.28DTIC.29|Dacarbazine]]
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, indefinite {{#subobject:722e51|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70076-8/fulltext Weber et al. 2015 (CheckMate 037)]
+
|[https://doi.org/10.1016/S1470-2045(15)70076-8 Weber et al. 2015 (CheckMate 037)]
−
|<span
+
|2012-2014
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
−
padding:3px 6px 3px 6px;
+
|Investigator's choice of:<br>1a. [[#Dacarbazine_monotherapy_2|Dacarbazine]]<br>1b. [[#Carboplatin_.26_Paclitaxel_.28CP.29_2|Carboplatin & Paclitaxel]]
−
border-color:black;
+
| style="background-color:#1a9850" |Superior ORR (co-primary endpoint)
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Dacarbazine_.28DTIC.29|Dacarbazine]]<br> [[#CP_-_Carboplatin_.26_Paclitaxel|Carboplatin & Paclitaxel]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''Note: CheckMate 037 did not meet the co-primary endpoint of OS. On 2016-09-13 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Prior treatment criteria====
 +
*CheckMate 037, BRAF WT: Exposure to ipilimumab
 +
*CheckMate 037, BRAF p.V600: Exposure to ipilimumab and BRAF inhibitor
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
 
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
−
 
+
'''14-day cycles'''
−
'''2-week cycles, given until progression of disease or unacceptable toxicity'''
+
</div></div>
−
 
 
−
===Regimen #2, Weber et al. 2013 {{#subobject:1ec35|Variant=1}}===
 
−
Level of Evidence:
 
−
<span style="background:#ff0000; padding:3px 6px 3px 6px; border-color:black; border-width:2px; border-style:solid;">Phase I</span>
 
−
 
 
−
====Induction therapy====
 
−
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
 
−
 
 
−
'''2-week cycles x 12 cycles, then proceed to maintenance therapy'''
 
−
 
 
−
====Maintenance therapy====
 
−
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
 
−
 
 
−
'''12-week cycles x 2 years'''
 
  
 
===References===
 
===References===
−
# Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, Zhao X, Martinez AJ, Wang W, Gibney G, Kroeger J, Eysmans C, Sarnaik AA, Chen YA. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013 Dec 1;31(34):4311-8. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837092/ link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/24145345 PubMed]
+
#'''MCC-15400:''' Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, Zhao X, Martinez AJ, Wang W, Gibney G, Kroeger J, Eysmans C, Sarnaik AA, Chen YA. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013 Dec 1;31(34):4311-8. Epub 2013 Oct 21. [https://doi.org/10.1200/JCO.2013.51.4802 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837092/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24145345/ PubMed] [https://clinicaltrials.gov/study/NCT01176461 NCT01176461]
−
# Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in Previously Untreated Melanoma without BRAF Mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. Epub 2014 Nov 16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1412082 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/25399552 PubMed]
+
#'''CheckMate 037:''' Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. [https://doi.org/10.1016/S1470-2045(15)70076-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25795410/ PubMed] [https://clinicaltrials.gov/study/NCT01721746 NCT01721746]
−
# Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70076-8/fulltext link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/25795410 PubMed]
+
##'''Update:''' Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. [https://doi.org/10.1200/JCO.2016.71.8023 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6804912/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28671856/ PubMed]
  
−
==Paclitaxel (Taxol) {{#subobject:bfd5b|Regimen=1}}==
+
==Nivolumab-Ipilimumab {{#subobject:1145b9|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:61d1da|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(16)30126-7 Weber et al. 2016 (CheckMate 064)]
 +
|2013-2014
 +
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 +
|[[#Ipilimumab-Nivolumab|Ipilimumab, then Nivolumab]]
 +
| style="background-color:#1a9850" |Superior OS (secondary endpoint)<br>Median OS: NYR vs 16.9 mo<br>(HR 0.48, 95% CI 0.29-0.80)
 +
| style="background-color:#eeee01" |Similar rate of grade 3-5 TRAEs (primary endpoint)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
''Note: on 2016-09-13 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Nivolumab (Opdivo)]] as follows:
 +
**Cycles 1 to 6: 3 mg/kg IV once on day 1
 +
**Cycle 11 onwards: 3 mg/kg IV once on day 1
 +
*[[Ipilimumab (Yervoy)]] as follows:
 +
**Cycles 7 to 10: 3 mg/kg IV once on day 1
 +
'''14-day cycle for 6 cycles, then 21-day cycle for 4 cycles, then 14-day cycles'''
 +
</div></div>
 +
===References===
 +
#'''CheckMate 064:''' Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP, Logan TF, Schuchter LM, Nair S, Fecher L, Buchbinder EI, Berghorn E, Ruisi M, Kong G, Jiang J, Horak C, Hodi FS. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol. 2016 Jul;17(7):943-55. Epub 2016 Jun 4. [https://doi.org/10.1016/S1470-2045(16)30126-7 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474305/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27269740/ PubMed] [https://clinicaltrials.gov/study/NCT01783938 NCT01783938]
 +
==Paclitaxel monotherapy {{#subobject:bfd5b|Regimen=1}}==
 
===Example orders===
 
===Example orders===
 
*[[Example orders for Paclitaxel (Taxol) in melanoma]]
 
*[[Example orders for Paclitaxel (Taxol) in melanoma]]
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen #1 {{#subobject:100b77|Variant=1}}===
+
===Regimen variant #1, 80 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:d13282|Variant=1}}===
−
{| border="1" style="text-align:center;" !align="left"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
|'''Study'''
+
! style="width: 20%" |Study
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
! style="width: 20%" |Dates of enrollment
−
|'''Comparator'''
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2012.44.5585 O'Day et al. 2013 (SYMMETRY)]
 +
|2007-2009
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Elesclomol_.26_Paclitaxel_999|Elesclomol & Paclitaxel]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|[https://doi.org/10.1002/cncr.28635 Hamid et al. 2014 (SUMMIT-1)]
 +
|2009-NR
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Tasisulam_monotherapy_999|Tasisulam]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|}
 +
''Note: This was the control arm of SYMMETRY, which was a negative study. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 175 mg/m<sup>2</sup> q3wk {{#subobject:2839uq|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1203421 Flaherty et al. 2012 (METRIC)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ Ribas et al. 2015 (KEYNOTE-002)]
−
|<span
+
|2012-11-30 to 2013-11-13
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Randomized Phase 2 (C)
−
padding:3px 6px 3px 6px;
+
|1. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 2 mg/kg q3wk<br>2. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 10 mg/kg q3wk
−
border-color:black;
+
| style="background-color:#d73027" |Inferior PFS
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Trametinib_.28Mekinist.29|Trametinib]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
''This was a therapy option for patients in the control arm of METRIC.''
+
====Chemotherapy====
−
*[[Paclitaxel (Taxol)]] 175 mg/m2 IV once on day 1
+
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
−
 
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div><br>
−
===Regimen #2 {{#subobject:d13282|Variant=1}}===
+
<div class="toccolours" style="background-color:#eeeeee">
−
{| border="1" style="text-align:center;" !align="left"  
+
===Regimen variant #3, 250 mg/m<sup>2</sup> q3wk {{#subobject:283bc4|Variant=1}}===
−
|'''Study'''
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
!style="width: 33%"|Study
−
|'''Comparator'''
+
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/31/9/1211.long O'Day et al. 2013 (SYMMETRY)]
+
|[https://doi.org/10.1002/1097-0142(19900601)65:11%3C2478::AID-CNCR2820651114%3E3.0.CO;2-S Legha et al. 1990]
−
|<span
+
|NR
−
style="background:#00CD00;
+
| style="background-color:#91cf61" |Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|Elesclomol & Paclitaxel
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
''This was the control arm of SYMMETRY, which was a negative study.''
+
====Chemotherapy====
−
 
+
*[[Paclitaxel (Taxol)]] 250 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
−
*[[Paclitaxel (Taxol)]] 80 mg/m2 IV once per day on days 1, 8, 15
+
'''21-day cycles'''
−
 
+
</div></div>
−
'''28-day cycles, given until progression of disease or unacceptable toxicity'''
 
−
 
 
 
===References===
 
===References===
−
# Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12;367(2):107-14. Epub 2012 Jun 4. [http://www.nejm.org/doi/full/10.1056/NEJMoa1203421 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22663011 PubMed]
+
#Legha SS, Ring S, Papadopoulos N, Raber M, Benjamin RS. A phase II trial of taxol in metastatic melanoma. Cancer. 1990 Jun 1;65(11):2478-81. [https://doi.org/10.1002/1097-0142(19900601)65:11%3C2478::AID-CNCR2820651114%3E3.0.CO;2-S link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/1970948/ PubMed]
−
# O'Day SJ, Eggermont AM, Chiarion-Sileni V, Kefford R, Grob JJ, Mortier L, Robert C, Schachter J, Testori A, Mackiewicz J, Friedlander P, Garbe C, Ugurel S, Collichio F, Guo W, Lufkin J, Bahcall S, Vukovic V, Hauschild A. Final results of phase III SYMMETRY study: randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma. J Clin Oncol. 2013 Mar 20;31(9):1211-8. Epub 2013 Feb 11. [http://jco.ascopubs.org/content/31/9/1211.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23401447 PubMed]
+
#'''SYMMETRY:''' O'Day SJ, Eggermont AM, Chiarion-Sileni V, Kefford R, Grob JJ, Mortier L, Robert C, Schachter J, Testori A, Mackiewicz J, Friedlander P, Garbe C, Ugurel S, Collichio F, Guo W, Lufkin J, Bahcall S, Vukovic V, Hauschild A. Final results of phase III SYMMETRY study: randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma. J Clin Oncol. 2013 Mar 20;31(9):1211-8. Epub 2013 Feb 11. [https://doi.org/10.1200/jco.2012.44.5585 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23401447/ PubMed] [https://clinicaltrials.gov/study/NCT00522834 NCT00522834]
 +
#'''SUMMIT-1:''' Hamid O, Ilaria R Jr, Garbe C, Wolter P, Maio M, Hutson TE, Arance A, Lorigan P, Lee J, Hauschild A, Mohr P, Hahka-Kemppinen M, Kaiser C, Turner PK, Conti I, Grob JJ. A randomized, open-label clinical trial of tasisulam sodium versus paclitaxel as second-line treatment in patients with metastatic melanoma. Cancer. 2014 Jul 1;120(13):2016-24. Epub 2014 Mar 26. [https://doi.org/10.1002/cncr.28635 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24676877/ PubMed] [https://clinicaltrials.gov/study/NCT01006252 NCT01006252]
 +
#'''KEYNOTE-002:''' Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. [https://doi.org/10.1016/S1470-2045(15)00083-2 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26115796/ PubMed] [https://clinicaltrials.gov/study/NCT01704287 NCT01704287]
 +
##'''HRQoL analysis:''' Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. [https://doi.org/10.1016/j.ejca.2016.07.018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27596353/ PubMed]
 +
##'''Update:''' Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. [https://doi.org/10.1016/j.ejca.2017.07.022 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28961465/ PubMed]
  
−
==Pembrolizumab (Keytruda) {{#subobject:78d8cc|Regimen=1}}==
+
==nab-Paclitaxel monotherapy {{#subobject:1748f5|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:df0a74|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1002/cncr.24720 Hersh et al. 2012]
 +
|NR
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279094/ Hersh et al. 2015 (CA033)]
 +
|2009-04 to 2011-06
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Dacarbazine_monotherapy_2|Dacarbazine]]
 +
| style="background-color:#91cf60" |Seems to have superior PFS (primary endpoint)<br>Median PFS: 4.8 vs 2.5 mo<br>(HR 0.79, 95.1% CI 0.63-0.99)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
===Regimen #1, 10 mg/kg q2wk {{#subobject:2829cd|Variant=1}}===
+
====Chemotherapy====
−
{| border="1" style="text-align:center;" !align="left"  
+
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 150 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
−
|'''Study'''
+
'''28-day cycles'''
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
</div></div><br>
−
|'''Comparator'''
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2 {{#subobject:f13d6e|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Dates of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00083-2/abstract Ribas et al. 2015 (KEYNOTE-002)]
+
|[https://doi.org/10.1002/cncr.24720 Hersh et al. 2012]
−
|<span
+
|NR
−
style="background:#00cd00;
+
| style="background-color:#91cf61" |Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Randomized Phase II</span>
 
−
|Investigator-choice chemotherapy<br> Pembrolizumab 10 mg/kg
 
−
|-
 
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1503093 Robert et al. 2015 (KEYNOTE-006)]
 
−
|<span
 
−
style="background:#00cd00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[#Ipilimumab_.28Yervoy.29_2|Ipilimumab]]<br> Pembrolizumab 10 mg/kg q3wk
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''Note: this dose was intended for previously treated patients.''
−
*[[Pembrolizumab (Keytruda)]] 10 mg/kg IV once on day 1
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
'''14-day cycles, given until progression of disease or unacceptable toxicity'''
+
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
−
 
+
'''28-day cycles'''
−
===Regimen #2, 10 mg/kg q3wk {{#subobject:e60ce6|Variant=1}}===
+
</div></div>
−
{| border="1" style="text-align:center;" !align="left"  
+
===References===
−
|'''Study'''
+
#Hersh EM, O'Day SJ, Ribas A, Samlowski WE, Gordon MS, Shechter DE, Clawson AA, Gonzalez R. A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. Cancer. 2010 Jan 1;116(1):155-63. [https://doi.org/10.1002/cncr.24720 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19877111/ PubMed]
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
#'''CA033:''' Hersh EM, Del Vecchio M, Brown MP, Kefford R, Loquai C, Testori A, Bhatia S, Gutzmer R, Conry R, Haydon A, Robert C, Ernst S, Homsi J, Grob JJ, Kendra K, Agarwala SS, Li M, Clawson A, Brachmann C, Karnoub M, Elias I, Renschler MF, Hauschild A. A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann Oncol. 2015 Nov;26(11):2267-74. Epub 2015 Sep 26. [https://doi.org/10.1093/annonc/mdv324 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279094/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26410620/ PubMed] [https://clinicaltrials.gov/study/NCT00864253 NCT00864253]
−
|'''Comparator'''
+
==Pembrolizumab monotherapy {{#subobject:78d8cc|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 2 mg/kg q3wk {{#subobject:25a9fe|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00083-2/abstract Ribas et al. 2015 (KEYNOTE-002)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126516/ Hamid et al. 2013 (KEYNOTE-001<sub>melanoma</sub>)]
−
|<span
+
|2011-2012
−
style="background:#00cd00;
+
| style="background-color:#91cf61" |Phase 1, >20 pts
−
padding:3px 6px 3px 6px;
+
| style="background-color:#d3d3d3" |
−
border-color:black;
+
| style="background-color:#d3d3d3" |
−
border-width:2px;
 
−
border-style:solid;">Randomized Phase II</span>
 
−
|Investigator-choice chemotherapy<br> Pembrolizumab 2 mg/kg
 
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1503093 Robert et al. 2015 (KEYNOTE-006)]
+
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ Ribas et al. 2015 (KEYNOTE-002)]
−
|<span
+
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
−
style="background:#00cd00;
+
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-91-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[#Ipilimumab_.28Yervoy.29_2|Ipilimumab]]<br> Pembrolizumab 10 mg/kg q2wk
 
 
|-
 
|-
−
|}
+
|} -->
−
 
+
| rowspan="2" |2012-11-30 to 2013-11-13
−
*[[Pembrolizumab (Keytruda)]] 10 mg/kg IV over 30 minutes once on day 1
+
| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (E-RT-switch-ooc)
−
 
+
|Investigator's choice of:<br>1a. [[#Carboplatin_.26_Paclitaxel_.28CP.29_2|Carboplatin & Paclitaxel]]<br>1b. [[#Dacarbazine_monotherapy_2|Dacarbazine]]<br>1c. [[#Paclitaxel_monotherapy|Paclitaxel]]<br>1d. [[#Temozolomide_monotherapy|Temozolomide]]
−
'''21-day cycles, given until progression of disease or unacceptable toxicity'''
+
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>PFS6: 34% vs 16%<br>(HR 0.57, 95% CI 0.45-0.73)
−
 
 
−
===Regimen #3, 2 mg/kg q3wk {{#subobject:25a9fe|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"  
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
 
|-
 
|-
−
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00083-2/abstract Ribas et al. 2015 (KEYNOTE-002)]
+
|2. [[#Pembrolizumab_monotherapy_3|Pembrolizumab]]; 10 mg/kg q3wk
−
|<span
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
−
style="background:#00cd00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Randomized Phase II</span>
 
−
|Investigator-choice chemotherapy<br> Pembrolizumab 10 mg/kg q3wk
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#fdcdac">
−
''Robert et al. 2014 and Ribas et al. 2015 investigated the 2 mg/kg and 10 mg/kg doses. 2 mg/kg is the FDA approved dose.''
+
====Prior treatment criteria====
 +
*KEYNOTE-002, BRAFwt: Failure of ipilimumab
 +
*KEYNOTE-002, BRAFmut: Failure of ipilimumab and previous treatment with a BRAF or MEK inhibitor or both
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 
*[[Pembrolizumab (Keytruda)]] 2 mg/kg IV over 30 minutes once on day 1
 
*[[Pembrolizumab (Keytruda)]] 2 mg/kg IV over 30 minutes once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
−
'''21-day cycles, given until progression of disease or unacceptable toxicity'''
+
===Regimen variant #2, 10 mg/kg q2wk {{#subobject:2829cd|Variant=1}}===
−
 
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
===References===
+
! style="width: 20%" |Study
−
# '''Phase I:''' Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Jul 14. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2960958-2/abstract link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/25034862 PubMed]
+
! style="width: 20%" |Dates of enrollment
−
# Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00083-2/fulltext link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/26115796 PubMed]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
# Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19.[http://www.nejm.org/doi/full/10.1056/NEJMoa1503093 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/25891173 PubMed]
+
! style="width: 20%" |Comparator
−
 
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
==Temozolomide (Temodar) {{#subobject:4e2652|Regimen=1}}==
+
|-
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126516/ Hamid et al. 2013 (KEYNOTE-001<sub>melanoma</sub>)]
 +
|2011-2012
 +
| style="background-color:#91cf61" |Phase 1, >20 pts
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[[#toc|back to top]]
+
| rowspan="2" |[https://doi.org/10.1056/NEJMoa1503093 Robert et al. 2015 (KEYNOTE-006)]
−
|}
+
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
−
===Regimen {{#subobject:6e73a5|Variant=1}}===
+
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-327-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
−
{| border="1" style="text-align:center;" !align="left"  
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/18/1/158.long Middleton et al. 2000]
+
|} -->
−
|<span
+
| rowspan="2" |2013-09-18 to 2014-03-03
−
style="background:#00CD00;
+
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
−
padding:3px 6px 3px 6px;
+
|1. [[#Ipilimumab_monotherapy_3|Ipilimumab]]
−
border-color:black;
+
| style="background-color:#1a9850" |Superior OS (co-primary endpoint)<br>OS12: 74.1% vs 58.2%<br>(HR 0.63, 95% CI 0.47-0.83)
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Dacarbazine_.28DTIC.29|Dacarbazine]]
 
 
|-
 
|-
−
|}
+
|2. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 10 mg/kg q3wk
−
 
+
| style="background-color:#ffffbf" |Did not meet co-primary endpoints of PFS/OS
−
*[[Temozolomide (Temodar)]] 200 mg/m2 PO once per day on days 1 to 5, taken while fasting
 
−
 
 
−
'''28-day cycles, given until progression of disease or unacceptable toxicity'''
 
−
 
 
−
===References===
 
−
# Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. [http://jco.ascopubs.org/content/18/1/158.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/10623706 PubMed]
 
−
 
 
−
==Temozolomide & Bevacizumab (TB) {{#subobject:511376|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:42ead6|Variant=1}}===
+
<div class="toccolours" style="background-color:#fdcdac">
−
{| border="1" style="text-align:center;" !align="left"  
+
====Prior treatment criteria====
−
|'''Study'''
+
*KEYNOTE-006: No more than 1 line of systemic therapy for advanced disease
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
</div>
−
|'''Comparator'''
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Pembrolizumab (Keytruda)]] 10 mg/kg IV once on day 1
 +
'''14-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 10 mg/kg q3wk {{#subobject:e60ce6|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://onlinelibrary.wiley.com/doi/10.1002/cncr.27760/full Kottschade et al. 2013 (N0775)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126516/ Hamid et al. 2013 (KEYNOTE-001<sub>melanoma</sub>)]
−
|<span
+
|2011-2012
−
style="background:#00CD00;
+
| style="background-color:#91cf61" |Phase 1, >20 pts
−
padding:3px 6px 3px 6px;
+
| style="background-color:#d3d3d3" |
−
border-color:black;
+
| style="background-color:#d3d3d3" |
−
border-width:2px;
 
−
border-style:solid;">Randomized Phase II</span>
 
−
|[[Melanoma#ABC|ABC]]
 
 
|-
 
|-
−
|}
+
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ Ribas et al. 2015 (KEYNOTE-002)]
−
 
+
| rowspan="2" |2012-11-30 to 2013-11-13
−
*[[Temozolomide (Temodar)]] 200 mg/m2 PO once per day on days 1 to 5
+
| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (E-RT-switch-ooc)
−
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
+
|Investigator's choice of:<br>1a. [[#Carboplatin_.26_Paclitaxel_.28CP.29|Carboplatin & Paclitaxel]]<br>1b. [[#Dacarbazine_monotherapy_2|Dacarbazine]]<br>1c. [[#Paclitaxel_monotherapy|Paclitaxel]]<br>1d. [[#Temozolomide_monotherapy|Temozolomide]]
−
 
+
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>PFS6: 38% vs 16%<br>(HR 0.50, 95% CI 0.39-0.64)
−
'''28-day cycles, given until progression of disease'''
 
−
 
 
−
===References===
 
−
# Kottschade LA, Suman VJ, Perez DG, McWilliams RR, Kaur JS, Amatruda TT 3rd, Geoffroy FJ, Gross HM, Cohen PA, Jaslowski AJ, Kosel ML, Markovic SN. A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma : a North Central Cancer Treatment Group study, N0775. Cancer. 2013 Feb 1;119(3):586-92. doi: 10.1002/cncr.27760. Epub 2012 Aug 22. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.27760/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22915053 PubMed]
 
−
 
 
−
==Trametinib (Mekinist) {{#subobject:9e1876|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
 
|-
 
|-
−
|[[#toc|back to top]]
+
|2. [[#Pembrolizumab_monotherapy_3|Pembrolizumab]]; 2 mg/kg
−
|}
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
−
===Regimen {{#subobject:abc29f|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"  
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1203421 Flaherty et al. 2012 (METRIC)]
+
| rowspan="2" |[https://doi.org/10.1056/NEJMoa1503093 Robert et al. 2015 (KEYNOTE-006)]
−
|<span
+
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
−
style="background:#00CD00;
+
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-327-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Dacarbazine_.28DTIC.29|Dacarbazine]]<br> [[Melanoma#Paclitaxel_.28Taxol.29|Paclitaxel]]
 
 
|-
 
|-
−
!colspan="4" align="center"|
+
|} -->
 +
| rowspan="2" |2013-09-18 to 2014-03-03
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
 +
|1. [[#Ipilimumab_monotherapy_3|Ipilimumab]]
 +
| style="background-color:#1a9850" |Superior OS (co-primary endpoint)<br>OS12: 68.4% vs 58.2%<br>(HR 0.69, 95% CI 0.52-0.90)
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/31/4/482.long Kim et al. 2012]
+
|2. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 10 mg/kg q2wk
−
|<span
+
| style="background-color:#ffffbf" |Did not meet co-primary endpoints of PFS/OS
−
style="background:#eeee00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
−
|
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#fdcdac">
−
*[[Trametinib (Mekinist)]] 2 mg PO once per day
+
====Prior treatment criteria====
−
 
+
*KEYNOTE-002, BRAFwt: Failure of ipilimumab
−
===References===
+
*KEYNOTE-002, BRAFmut: Failure of ipilimumab and previous treatment with a BRAF or MEK inhibitor or both
−
# Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12;367(2):107-14.  Epub 2012 Jun 4. [http://www.nejm.org/doi/full/10.1056/NEJMoa1203421 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22663011 PubMed]
+
*KEYNOTE-006: No more than 1 line of systemic therapy for advanced disease
−
# Falchook GS, Lewis KD, Infante JR, Gordon MS, Vogelzang NJ, DeMarini DJ, Sun P, Moy C, Szabo SA, Roadcap LT, Peddareddigari VG, Lebowitz PF, Le NT, Burris HA 3rd, Messersmith WA, O'Dwyer PJ, Kim KB, Flaherty K, Bendell JC, Gonzalez R, Kurzrock R, Fecher LA. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 2012 Aug;13(8):782-9. Epub 2012 Jul 16. [http://www.sciencedirect.com/science/article/pii/S1470204512702693 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22805292 PubMed]
+
</div>
−
# Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, Fecher LA, Millward M, McArthur GA, Hwu P, Gonzalez R, Ott PA, Long GV, Gardner OS, Ouellet D, Xu Y, DeMarini DJ, Le NT, Patel K, Lewis KD. Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol. 2013 Feb 1;31(4):482-9. Epub 2012 Dec 17. [http://jco.ascopubs.org/content/31/4/482.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23248257 PubMed]
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Immunotherapy====
−
==Vemurafenib (Zelboraf) {{#subobject:7652e9|Regimen=1}}==
+
*[[Pembrolizumab (Keytruda)]] 10 mg/kg IV over 30 minutes once on day 1
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
'''21-day cycles'''
−
|-
+
</div></div><br>
−
|[[#toc|back to top]]
+
<div class="toccolours" style="background-color:#eeeeee">
−
|}
+
===Regimen variant #4, 200 mg q3wk {{#subobject:e84ce6|Variant=1}}===
−
===Regimen {{#subobject:c639c3|Variant=1}}===
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
{| border="1" style="text-align:center;" !align="left"  
+
! style="width: 20%" |Study
−
|'''Study'''
+
! style="width: 20%" |Dates of enrollment
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
|'''Comparator'''
+
! style="width: 20%" |Comparator
−
|-
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1103782 Chapman et al. 2011 (BRIM-3)]
 
−
|<span
 
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Dacarbazine_.28DTIC.29|Dacarbazine]]
 
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1408868 Larkin et al. 2014 (coBRIM)]
+
|[https://doi.org/10.1016/S1470-2045(19)30274-8 Long et al. 2019 (ECHO-301/KEYNOTE-252)]
−
|<span
+
|2016-06-21 to 2017-08-07
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[#Epacadostat_.26_Pembrolizumab_999|Epacadostat & Pembrolizumab]]
−
border-color:black;
+
| style="background-color:#ffffbf" |Did not meet co-primary endpoints of PFS/OS
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Vemurafenib_.26_Cobimetinib|Vemurafenib & Cobimetinib]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#fdcdac">
−
''Patients enrolled in BRIM-3 had a BRAF p.V600E mutation detected.''
+
====Prior treatment criteria====
−
 
+
*ECHO-301/KEYNOTE-252: No previous treatment with PD-1 or PD-L1 checkpoint inhibitors
−
*[[Vemurafenib (Zelboraf)]] 960 mg PO BID
+
</div>
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
'''Given until progression of disease or unacceptable toxicity'''
+
====Immunotherapy====
−
 
+
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 +
'''21-day cycle for up to 35 cycles (2 years)'''
 +
</div></div>
 
===References===
 
===References===
−
# Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun 30;364(26):2507-16. Epub 2011 Jun 5. [http://www.nejm.org/doi/full/10.1056/NEJMoa1103782 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21639808 PubMed]
+
#'''KEYNOTE-001<sub>melanoma</sub>:''' Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013 Jul 11;369(2):134-44. Epub 2013 Jun 2. [https://doi.org/10.1056/NEJMoa1305133 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126516/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23724846/ PubMed] [https://clinicaltrials.gov/study/NCT01295827 NCT01295827]
−
# Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C, Sovak MA, Chang I, Choong N, Hack SP, McArthur GA, Ribas A. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014 Nov 13;371(20):1867-76. [http://www.nejm.org/doi/full/10.1056/NEJMoa1408868 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/25265494 PubMed]
+
##'''Update:''' Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Sep 20;384(9948):1109-17. Epub 2014 Jul 14. [https://doi.org/10.1016/S0140-6736(14)60958-2 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25034862/ PubMed]
 +
##'''Update:''' Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, Joshua AM, Patnaik A, Hwu WJ, Weber JS, Gangadhar TC, Hersey P, Dronca R, Joseph RW, Zarour H, Chmielowski B, Lawrence DP, Algazi A, Rizvi NA, Hoffner B, Mateus C, Gergich K, Lindia JA, Giannotti M, Li XN, Ebbinghaus S, Kang SP, Robert C. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016 Apr 19;315(15):1600-9. Erratum in: JAMA. 2016 Jun 14;315(22):2472. [https://jamanetwork.com/journals/jama/fullarticle/2514195 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27092830/ PubMed]
 +
##'''Update:''' Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph R, Weber JS, Dronca R, Mitchell TC, Patnaik A, Zarour HM, Joshua AM, Zhao Q, Jensen E, Ahsan S, Ibrahim N, Ribas A. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol. 2019 Apr 1;30(4):582-588. [https://doi.org/10.1093/annonc/mdz011 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503622/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30715153/ PubMed]
 +
#'''KEYNOTE-002:''' Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. [https://doi.org/10.1016/S1470-2045(15)00083-2 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26115796/ PubMed] [https://clinicaltrials.gov/study/NCT01704287 NCT01704287]
 +
##'''HRQoL analysis:''' Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. [https://doi.org/10.1016/j.ejca.2016.07.018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27596353/ PubMed]
 +
##'''Update:''' Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. [https://doi.org/10.1016/j.ejca.2017.07.022 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28961465/ PubMed]
 +
#'''KEYNOTE-006:''' Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19. [https://doi.org/10.1056/NEJMoa1503093 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25891173/ PubMed] [https://clinicaltrials.gov/study/NCT01866319 NCT01866319]
 +
##'''Update:''' Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-1862. Epub 2017 Aug 16. [https://doi.org/10.1016/S0140-6736(17)31601-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/28822576/ PubMed]
 +
##'''PRO analysis:''' Petrella TM, Robert C, Richtig E, Miller WH Jr, Masucci GV, Walpole E, Lebbe C, Steven N, Middleton MR, Hille D, Zhou W, Ibrahim N, Cebon J. Patient-reported outcomes in KEYNOTE-006, a randomised study of pembrolizumab versus ipilimumab in patients with advanced melanoma. Eur J Cancer. 2017 Nov;86:115-124. Epub 2017 Oct 4. [https://doi.org/10.1016/j.ejca.2017.08.032 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28987768/ PubMed]
 +
##'''Update:''' Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Su SC, Krepler C, Ibrahim N, Long GV. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019 Sep;20(9):1239-1251. Epub 2019 Jul 22. [https://doi.org/10.1016/S1470-2045(19)30388-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31345627/ PubMed]
 +
##'''Update:''' Robert C, Carlino MS, McNeil C, Ribas A, Grob JJ, Schachter J, Nyakas M, Kee D, Petrella TM, Blaustein A, Lotem M, Arance A, Daud AI, Hamid O, Larkin J, Anderson J, Krepler C, Grebennik D, Long GV. Seven-Year Follow-Up of the Phase III KEYNOTE-006 Study: Pembrolizumab Versus Ipilimumab in Advanced Melanoma. J Clin Oncol. 2023 Aug 20;41(24):3998-4003. Epub 2023 Jun 22. [https://doi.org/10.1200/jco.22.01599 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37348035/ PubMed]
 +
#'''ECHO-301/KEYNOTE-252:''' Long GV, Dummer R, Hamid O, Gajewski TF, Caglevic C, Dalle S, Arance A, Carlino MS, Grob JJ, Kim TM, Demidov L, Robert C, Larkin J, Anderson JR, Maleski J, Jones M, Diede SJ, Mitchell TC. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 2019 Aug;20(8):1083-1097. Epub 2019 Jun 17. [https://doi.org/10.1016/S1470-2045(19)30274-8 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31221619/ PubMed] [https://clinicaltrials.gov/study/NCT02752074 NCT02752074]
  
−
==Vemurafenib & Cobimetinib {{#subobject:PYR3|Regimen=1}}==
+
==Temozolomide monotherapy {{#subobject:4e2652|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:6e73a5|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Dates of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[[#toc|back to top]]
+
|[https://doi.org/10.1200/jco.2000.18.1.158 Middleton et al. 2000b]
−
|}
+
|1995-1997
−
===Regimen {{#subobject:PYV3|Variant=1}}===
+
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
−
{| border="1" style="text-align:center;" !align="left"
+
|[[#Dacarbazine_monotherapy_2|Dacarbazine]]
−
|'''Study'''
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|'''Comparator'''
 
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1408868 Larkin et al. 2014 (coBRIM)]
+
|[https://doi.org/10.1200/JCO.2005.01.1551 Kaufmann et al. 2005]
−
|<span
+
|1998-2001
−
style="background:#00CD00;
+
| style="background-color:#1a9851" |Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[#Temozolomide_.26_Interferon-alfa_888|Temozolomide & Interferon-alfa]]
−
border-color:black;
+
| style="background-color:#fc8d59" |Seems to have inferior ORR
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[Melanoma#Vemurafenib_.28Zelboraf.29|Vemurafenib]]
 
 
|-
 
|-
−
|}
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878048/ Ribas et al. 2013 (A3671009)]
−
 
+
|2006-03 to 2007-07
−
''Patients enrolled in coBRIM had a BRAF V600 mutation.''
+
| style="background-color:#1a9851" |Phase 3 (C)
−
 
+
|[[#Tremelimumab_monotherapy_999|Tremelimumab]]
−
*[[Vemurafenib (Zelboraf)]] 960 mg PO BID on days 1 to 28
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
−
*[[Cobimetinib (Cotellic)]] 60 mg PO once per day on days 1 to 21
 
−
 
 
−
'''28-day cycles, given until progression of disease or unacceptable toxicity'''
 
−
 
 
−
===References===
 
−
# Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C, Sovak MA, Chang I, Choong N, Hack SP, McArthur GA, Ribas A. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014 Nov 13;371(20):1867-76. [http://www.nejm.org/doi/full/10.1056/NEJMoa1408868 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/25265494 PubMed]
 
−
 
 
−
=Consolidation and/or maintenance after upfront therapy=
 
−
 
 
−
==Ipilimumab (Yervoy) {{#subobject:34ee90|Regimen=1}}==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#toc|back to top]]
 
−
|}
 
−
===Regimen {{#subobject:a89958|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"  
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
 
|-
 
|-
−
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1104621 Robert et al. 2011]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ Ribas et al. 2015 (KEYNOTE-002)]
−
|<span
+
|2012-11-30 to 2013-11-13
−
style="background:#eeee00;
+
| style="background-color:#1a9851" |Randomized Phase 2 (C)
−
padding:3px 6px 3px 6px;
+
|1. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 2 mg/kg q3wk<br>2. [[#Pembrolizumab_monotherapy_4|Pembrolizumab]]; 10 mg/kg q3wk
−
border-color:black;
+
| style="background-color:#d73027" |Inferior PFS
−
border-width:2px;
 
−
border-style:solid;">Non-randomized</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
''Treatment preceded by [[Melanoma#Dacarbazine_.26_Ipilimumab|dacarbazine & ipilimumab]].''
+
====Chemotherapy====
−
 
+
*[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once per day on days 1 to 5, taken while fasting
−
*[[Ipilimumab (Yervoy)]] 10 mg/kg IV once on day 1
+
'''28-day cycles'''
−
 
+
</div></div>
−
'''12-week cycles, given until progression of disease or unacceptable toxicity'''
 
−
 
 
 
===References===
 
===References===
−
# Robert C, Thomas L, Bondarenko I, O'Day S, M D JW, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. [http://www.nejm.org/doi/full/10.1056/NEJMoa1104621 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21639810 PubMed]
+
#Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. [https://doi.org/10.1200/jco.2000.18.1.158 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10623706/ PubMed]
 +
#Kaufmann R, Spieth K, Leiter U, Mauch C, von den Driesch P, Vogt T, Linse R, Tilgen W, Schadendorf D, Becker JC, Sebastian G, Krengel S, Kretschmer L, Garbe C, Dummer R; Dermatologic Cooperative Oncology Group. Temozolomide in combination with interferon-alfa versus temozolomide alone in patients with advanced metastatic melanoma: a randomized, phase III, multicenter study from the Dermatologic Cooperative Oncology Group. J Clin Oncol. 2005 Dec 10;23(35):9001-7. Epub 2005 Oct 31. [https://doi.org/10.1200/JCO.2005.01.1551 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16260697/ PubMed]
 +
<!-- Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, 2008, and 25th Annual Meeting of the International Society for Biological Therapy of Cancer, Washington, DC, October 2-4, 2010. -->
 +
#'''A3671009:''' Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G, Lorigan P, Kendra KL, Maio M, Trefzer U, Smylie M, McArthur GA, Dreno B, Nathan PD, Mackiewicz J, Kirkwood JM, Gomez-Navarro J, Huang B, Pavlov D, Hauschild A. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013 Feb 10;31(5):616-22. Epub 2013 Jan 7. [https://doi.org/10.1200/JCO.2012.44.6112 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878048/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23295794/ PubMed] [https://clinicaltrials.gov/study/NCT00257205 NCT00257205]
 +
#'''KEYNOTE-002:''' Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. [https://doi.org/10.1016/S1470-2045(15)00083-2 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9004487/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26115796/ PubMed] [https://clinicaltrials.gov/study/NCT01704287 NCT01704287]
 +
##'''HRQoL analysis:''' Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. [https://doi.org/10.1016/j.ejca.2016.07.018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27596353/ PubMed]
 +
##'''Update:''' Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. [https://doi.org/10.1016/j.ejca.2017.07.022 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28961465/ PubMed]
 +
[[Category:Melanoma regimens]]
 +
[[Category:Disease-specific pages]]
 +
[[Category:Skin cancers]]

Latest revision as of 17:50, 23 June 2024

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 Ryan Nguyen, DO
University of Illinois at Chicago
Chicago, IL, USA
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 Elizabeth Buchbinder, MD
Dana-Farber Cancer Institute
Boston, MA, USA
LinkedIn

Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
Note: some melanoma regimens can be found on dedicated pages:

39 regimens on this page
75 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASCO

EDF/EADO/EORTC

ESMO

INMC

NCCN

SITC

Perioperative therapy

This section contains protocols with a pre-planned neoadjuvant (preoperative) and adjuvant (postoperative) component.

Pembrolizumab monotherapy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Patel et al 2023 (SWOG S1801) 2019-02 to 2022-05 Phase 3 (E-switch-ic) Adjuvant Pembrolizumab Superior EFS (primary endpoint)
EFS24: 72% vs 49%
(HR 0.59, 95% CI 0.40-0.86)

Eligibility criteria

  • Resectable stage IIIB to IV melanoma without brain metastasis

Neoadjuvant

Immunotherapy

21-day cycle for 3 cycles


Definitive

Local therapy


Adjuvant

Immunotherapy

21-day cycle for 15 cycles

References

  1. SWOG S1801: Patel SP, Othus M, Chen Y, Wright GP Jr, Yost KJ, Hyngstrom JR, Hu-Lieskovan S, Lao CD, Fecher LA, Truong TG, Eisenstein JL, Chandra S, Sosman JA, Kendra KL, Wu RC, Devoe CE, Deutsch GB, Hegde A, Khalil M, Mangla A, Reese AM, Ross MI, Poklepovic AS, Phan GQ, Onitilo AA, Yasar DG, Powers BC, Doolittle GC, In GK, Kokot N, Gibney GT, Atkins MB, Shaheen M, Warneke JA, Ikeguchi A, Najera JE, Chmielowski B, Crompton JG, Floyd JD, Hsueh E, Margolin KA, Chow WA, Grossmann KF, Dietrich E, Prieto VG, Lowe MC, Buchbinder EI, Kirkwood JM, Korde L, Moon J, Sharon E, Sondak VK, Ribas A; SWOG. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023 Mar 2;388(9):813-823. link to original article contains dosing details in manuscript PubMed NCT03698019

Neoadjuvant response criteria

Adjuvant therapy

Cisplatin & Temozolomide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lian et al. 2013 2007-2009 Randomized Phase 2 (E-esc) 1. Interferon alfa-2b Superior RFS (co-primary endpoint)
2. Observation Superior OS (co-primary endpoint)

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles

References

  1. Lian B, Si L, Cui C, Chi Z, Sheng X, Mao L, Li S, Kong Y, Tang B, Guo J. Phase II randomized trial comparing high-dose IFN-α2b with temozolomide plus cisplatin as systemic adjuvant therapy for resected mucosal melanoma. Clin Cancer Res. 2013 Aug 15;19(16):4488-98. Epub 2013 Jul 5. link to original article contains dosing details in manuscript PubMed ChiCTR-TRC-11001798

Ipilimumab monotherapy

Example orders

Regimen variant #1, 3 mg/kg x 1 year

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tarhini et al. 2019 (ECOG E1609) 2011-2014 Phase 3 (E-switch-ic) 1. Interferon alfa-2b Seems to have superior OS (co-primary endpoint)
OS60: 72% vs 67%
(HR 0.78, 95.6% CI 0.61-0.99)
2. Ipilimumab; 10 mg/kg Not reported

Eligibility criteria

  • Stage IIIB, IIIC, or IV melanoma

Preceding treatment

Immunotherapy

21-day cycle for 4 cycles, then 12-week cycle for up to 4 cycles


Regimen variant #2, 10 mg/kg x 1 year

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tarhini et al. 2019 (ECOG E1609) 2011-2014 Phase 3 (E-switch-ic) 1. Interferon alfa-2b Did not meet co-primary endpoint of OS
2. Ipilimumab; 3 mg/kg Not reported
Weber et al. 2017 (CheckMate 238) 2015-03-30 to 2015-11-30 Phase 3 (C) Nivolumab Inferior RFS

Note: 12-month recurrence-free survival (RFS) in this arm of CheckMate 238 was 61% overall; Stage IIIB or IIIC: 62% (95% CI: 56-66.5); Stage IV: 57.5% (95% CI: 46-67). In the experimental arm, it was 70.5% overall; Stage IIIB or IIIC: 72% (95% CI, 67-77); Stage IV: 63% (95% CI, 52-72.5).

Eligibility criteria

  • Stage IIIB, IIIC, or IV melanoma

Preceding treatment

Immunotherapy

21-day cycle for 4 cycles, then 12-week cycle for up to 4 cycles


Regimen variant #3, 3 years

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Eggermont et al. 2015 (EORTC 18071) 2008-2011 Phase 3 (E-RT-esc) Placebo Superior RFS1 (primary endpoint)
RFS60: 40.8% vs 30.3%
(HR 0.76, 95% CI 0.64-0.89)

Superior OS1 (secondary endpoint)
OS60: 65.4% vs 54.4%
(HR 0.72, 95.1% CI 0.58-0.88) 		Similar HRQoL2

1Reported efficacy is based on the 2016 update.
2While there was a statistically significant difference in EORTC QLC-C30 scores in EORTC 18071 (in favor of placebo), this difference did not meet the pre-determined threshold for clinical relevance.

Eligibility criteria

  • Stage III cutaneous melanoma

Preceding treatment

Immunotherapy

21-day cycle for 4 cycles, then 12-week cycle for 12 cycles (3 years)

References

  1. EORTC 18071: Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Konto C, Hoos A, de Pril V, Karra Gurunath R, de Schaetzen G, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 May;16(5):522-30. Epub 2015 Mar 31. Erratum: Lancet Oncol. 2015 Jun;16(6):e262. Epub 2015 May 27. link to original article contains dosing details in manuscript PubMed NCT00636168
    1. Update: Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel JC, Hodi FS, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016 Nov 10;375(19):1845-1855. Epub 2016 Oct 7. link to original article contains dosing details in manuscript link to PMC article PubMed
    2. HRQoL analysis: Coens C, Suciu S, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bottomley A, Kotapati S, de Pril V, Testori A, Eggermont AM. Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol. 2017 Mar;18(3):393-403. Epub 2017 Feb 3. link to original article link to PMC article PubMed
    3. Update: Eggermont AMM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Hosein F, de Pril V, Kicinski M, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial. Eur J Cancer. 2019 Sep;119:1-10. Epub 2019 Aug 7. link to original article PubMed
  2. CheckMate 238: Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. Epub 2017 Sep 10. link to original article contains dosing details in manuscript PubMed NCT02388906
    1. Update: Ascierto PA, Del Vecchio M, Mandalá M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Márquez-Rodas I, Butler MO, Maio M, Middleton MR, de la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Khushalani NI, Queirolo P, Lobo M, de Pril V, Loffredo J, Larkin J, Weber J. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1465-1477. Epub 2020 Sep 19. link to original article PubMed
  3. ECOG E1609: Tarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol. 2020 Feb 20;38(6):567-575. Epub 2019 Dec 27. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01274338
    1. HRQoL analysis: McLouth LE, Zheng Y, Smith S, Hodi FS, Rao UN, Cohen GI, Amatruda TT, Dakhil SR, Curti BD, Nakhoul I, Chandana SR, Bane CL, Marinier DE, Lee SJ, Sondak VK, Kirkwood JM, Tarhini AA, Wagner LI. Patient-reported tolerability of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk stage III-IV melanoma in phase III trial E1609. Qual Life Res. 2023 Jan;32(1):183-196. Epub 2022 Aug 27. link to original article link to PMC article PubMed
  4. SWOG S1404: Grossmann KF, Othus M, Patel SP, Tarhini AA, Sondak VK, Knopp MV, Petrella TM, Truong TG, Khushalani NI, Cohen JV, Buchbinder EI, Kendra K, Funchain P, Lewis KD, Conry RM, Chmielowski B, Kudchadkar RR, Johnson DB, Li H, Moon J, Eroglu Z, Gastman B, Kovacsovics-Bankowski M, Gunturu KS, Ebbinghaus SW, Ahsan S, Ibrahim N, Sharon E, Korde LA, Kirkwood JM, Ribas A. Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma. Cancer Discov. 2022 Mar 1;12(3):644-653. link to original article link to PMC article PubMed NCT02506153
    1. HRQoL analysis: Unger JM, Darke A, Othus M, Truong TG, Khushalani N, Kendra K, Lewis KD, Faller B, Funchain P, Buchbinder EI, Tarhini AA, Kirkwood JM, Sharon E, Sondak V, Guild SR, Grossmann K, Ribas A, Patel SP. Effectiveness of Adjuvant Pembrolizumab vs High-Dose Interferon or Ipilimumab for Quality-of-Life Outcomes in Patients With Resected Melanoma: A Secondary Analysis of the SWOG S1404 Randomized Clinical Trial. JAMA Oncol. 2023 Feb 1;9(2):251-260. link to original article link to PMC article PubMed

Ipilimumab & Nivolumab

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zimmer et al. 2020 (IMMUNED) 2015-2018 Randomized Phase 2 (E-esc) 1. Nivolumab Not reported
2. Placebo Superior RFS (primary endpoint)
Median RFS: NYR vs 12.4 mo
(HR 0.23, 97.5% CI 0.12-0.45)

Seems to have superior OS1 (secondary endpoint)
Median OS: NYR vs NYR
(HR 0.41, 95% CI 0.17-0.99)

1Reported efficacy is based on the 2022 update.

Eligibility criteria

  • Stage IV melanoma

Preceding treatment

Immunotherapy

21-day cycle for 4 cycles, then 14-day cycle for 20 cycles (1 year)


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Weber et al. 2022 (CheckMate 915) 2017-04 to 2018-06 Phase 3 (E-esc) Nivolumab Did not meet primary endpoint of RFS
RFS24: 64.6% vs 63.2%
(HR 0.92, 97.295% CI 0.77-1.09)

Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority in this setting.

Eligibility criteria

  • Stage IIIB, IIIC, IIID, or IV melanoma

Preceding treatment

Immunotherapy

42-day cycle for 9 cycles (1 year)

References

  1. IMMUNED: Zimmer L, Livingstone E, Hassel JC, Fluck M, Eigentler T, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kieker F, Dippel E, Rösch A, Simon JC, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020 May 16;395(10236):1558-1568. link to original article contains dosing details in manuscript PubMed NCT02523313
    1. Update: Livingstone E, Zimmer L, Hassel JC, Fluck M, Eigentler TK, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kiecker F, Dippel E, Roesch A, Ziemer M, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab alone versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): final results of a randomised, double-blind, phase 2 trial. Lancet. 2022 Oct 1;400(10358):1117-1129. Epub 2022 Sep 10. link to original article PubMed
  2. CheckMate 915: Weber JS, Schadendorf D, Del Vecchio M, Larkin J, Atkinson V, Schenker M, Pigozzo J, Gogas H, Dalle S, Meyer N, Ascierto PA, Sandhu S, Eigentler T, Gutzmer R, Hassel JC, Robert C, Carlino MS, Di Giacomo AM, Butler MO, Muñoz-Couselo E, Brown MP, Rutkowski P, Haydon A, Grob JJ, Schachter J, Queirolo P, de la Cruz-Merino L, van der Westhuizen A, Menzies AM, Re S, Bas T, de Pril V, Braverman J, Tenney DJ, Tang H, Long GV. Adjuvant Therapy of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Patients With Resected Stage IIIB-D or Stage IV Melanoma (CheckMate 915). J Clin Oncol. 2023 Jan 20;41(3):517-527. Epub 2022 Sep 26. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03068455

Nivolumab monotherapy

Regimen variant #1, 240 mg flat dose

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Weber et al. 2022 (CheckMate 915) 2017-04 to 2018-06 Phase 3 (C) Ipilimumab & Nivolumab Did not meet primary endpoint of RFS

Eligibility criteria

  • Stage IIIB, IIIC, IIID, or IV melanoma

Preceding treatment

Immunotherapy

14-day cycle for up to 26 cycles (1 year)


Regimen variant #2, 480 mg flat dose

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kirkwood et al. 2023 (CheckMate 76K) 2019-10-28 to 2021-11-03 Phase 3 (E-RT-esc) Placebo Superior RFS (primary endpoint)
RFS12: 89 vs 79.4%
(HR 0.42, 95% CI 0.30-0.59)

Eligibility criteria

  • Stage IIB or IIC melanoma

Preceding treatment

Immunotherapy

28-day cycle for 13 cycles (1 year)


Regimen variant #3, weight-based

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Weber et al. 2017 (CheckMate 238) 2015-03-30 to 2015-11-30 Phase 3 (E-RT-switch-ic) Ipilimumab Superior RFS (primary endpoint)
RFS12: 70.5% vs 60.8%
(HR 0.65, 97.56% CI 0.51-0.83)
Zimmer et al. 2020 (IMMUNED) 2015-2018 Randomized Phase 2 (E-esc) 1. Ipilimumab & Nivolumab Not reported
2. Placebo Superior RFS (primary endpoint)
Median RFS: 12.4 vs 6.4 mo
(HR 0.56, 97.5% CI 0.33-0.94)

Eligibility criteria

  • CheckMate 238: Stage IIIB, IIIC, or IV melanoma
  • IMMUNED: Stage IV melanoma

Preceding treatment

Immunotherapy

14-day cycle for up to 26 cycles (1 year)

References

  1. CheckMate 238: Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. Epub 2017 Sep 10. link to original article contains dosing details in manuscript PubMed NCT02388906
    1. Update: Ascierto PA, Del Vecchio M, Mandalá M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Márquez-Rodas I, Butler MO, Maio M, Middleton MR, de la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Khushalani NI, Queirolo P, Lobo M, de Pril V, Loffredo J, Larkin J, Weber J. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1465-1477. Epub 2020 Sep 19. link to original article PubMed
  2. IMMUNED: Zimmer L, Livingstone E, Hassel JC, Fluck M, Eigentler T, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kieker F, Dippel E, Rösch A, Simon JC, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D; Dermatologic Cooperative Oncology Group. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020 May 16;395(10236):1558-1568. link to original article contains dosing details in manuscript PubMed NCT02523313
  3. CheckMate 915: Weber JS, Schadendorf D, Del Vecchio M, Larkin J, Atkinson V, Schenker M, Pigozzo J, Gogas H, Dalle S, Meyer N, Ascierto PA, Sandhu S, Eigentler T, Gutzmer R, Hassel JC, Robert C, Carlino MS, Di Giacomo AM, Butler MO, Muñoz-Couselo E, Brown MP, Rutkowski P, Haydon A, Grob JJ, Schachter J, Queirolo P, de la Cruz-Merino L, van der Westhuizen A, Menzies AM, Re S, Bas T, de Pril V, Braverman J, Tenney DJ, Tang H, Long GV. Adjuvant Therapy of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Patients With Resected Stage IIIB-D or Stage IV Melanoma (CheckMate 915). J Clin Oncol. 2023 Jan 20;41(3):517-527. Epub 2022 Sep 26. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03068455
  4. CheckMate 76K: Kirkwood JM, Del Vecchio M, Weber J, Hoeller C, Grob JJ, Mohr P, Loquai C, Dutriaux C, Chiarion-Sileni V, Mackiewicz J, Rutkowski P, Arenberger P, Quereux G, Meniawy TM, Ascierto PA, Menzies AM, Durani P, Lobo M, Campigotto F, Gastman B, Long GV. Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial. Nat Med. 2023 Nov;29(11):2835-2843. Epub 2023 Oct 16. Erratum in: Nat Med. 2023 Nov 3. link to original article link to PMC article PubMed NCT04099251
  5. PIVOT-12: NCT04410445

Pembrolizumab monotherapy

FDA-recommended dose

Regimen variant #1, adult dosing

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Eggermont et al. 2018 (KEYNOTE-054) 2015-08 to 2016-11 Phase 3 (E-RT-esc) Placebo Superior RFS1 (primary endpoint)
RFS60: 55.4% vs 38.3%
(HR 0.61, 95% CI 0.51-0.72)
Grossmann et al. 2022 (SWOG S1404) 2015-2017 Phase 3 (E-switch-ic) 1. HD-Interferon alfa-2b
2. Ipilimumab 		Superior RFS (co-primary endpoint)
(HR 0.77, 99.62% CI 0.59-0.99)
Luke et al. 2022 (KEYNOTE-716) 2018-2020 Phase 3 (E-RT-esc) Placebo Superior RFS2 (primary endpoint)
Median RFS: 37.2 mo vs NYR
(HR 0.64, 95% CI 0.50-0.84)
Patel et al 2023 (SWOG S1801) 2019-02 to 2022-05 Phase 3 (C) Perioperative Pembrolizumab Inferior EFS
Weber et al. 2024 (KEYNOTE-942) 2019-07-18 to 2021-09-30 Phase 3 (C) Pembrolizumab & mRNA-4157 Might have inferior RFS (primary endpoint)
RFS18: 62% vs 79%
(HR 1.78, 95% CI 0.98-3.24)

1Reported efficacy for KEYNOTE-054 is based on the 2022 update.
2Reported efficacy for KEYNOTE-716 is based on the 2022 update.

Eligibility criteria

  • KEYNOTE-942: completely resected stage IIIB to IV

Preceding treatment

Immunotherapy

21-day cycle for 18 cycles (1 year)


Regimen variant #2, pediatric dosing

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Luke et al. 2022 (KEYNOTE-716) 2018-2020 Phase 3 (E-RT-esc) Placebo Superior RFS2 (primary endpoint)
Median RFS: 37.2 mo vs NYR
(HR 0.64, 95% CI 0.50-0.84)

1Reported efficacy is based on the 2022 update.

Preceding treatment

Immunotherapy

21-day cycle for 18 cycles (1 year)

References

  1. KEYNOTE-054: Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Maio M, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan P, Ibrahim N, Marreaud S, van Akkooi ACJ, Suciu S, Robert C. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018 May 10;378(19):1789-1801. Epub 2018 Apr 15. link to original article contains dosing details in manuscript PubMed NCT02362594
    1. Update: Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C. Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial. J Clin Oncol. 2020 Nov 20;38(33):3925-3936. Epub 2020 Sep 18. link to original article link to PMC article PubMed
    2. Update: Eggermont AMM, Blank CU, Mandalà M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C; EORTC Melanoma Group. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 May;22(5):643-654. Epub 2021 Apr 12. link to original article PubMed
    3. HRQoL analysis: Bottomley A, Coens C, Mierzynska J, Blank CU, Mandalà M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Puig S, Ascierto PA, Larkin J, Lorigan PC, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C, Eggermont AMM; EORTC Melanoma Group. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 May;22(5):655-664. Epub 2021 Apr 12. link to original article PubMed
    4. Update: Eggermont AMM, Kicinski M, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Boers-Sonderen M, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, van Akkooi ACJ, Lorigan P, Grebennik D, Krepler C, Marreaud S, Suciu S, Robert C. Five-Year Analysis of Adjuvant Pembrolizumab or Placebo in Stage III Melanoma. NEJM Evid. 2022 Nov;1(11):EVIDoa2200214. Epub 2022 Sep 10. link to original article PubMed
  2. KEYNOTE-716: Luke JJ, Rutkowski P, Queirolo P, Del Vecchio M, Mackiewicz J, Chiarion-Sileni V, de la Cruz Merino L, Khattak MA, Schadendorf D, Long GV, Ascierto PA, Mandala M, De Galitiis F, Haydon A, Dummer R, Grob JJ, Robert C, Carlino MS, Mohr P, Poklepovic A, Sondak VK, Scolyer RA, Kirkwood JM, Chen K, Diede SJ, Ahsan S, Ibrahim N, Eggermont AMM; KEYNOTE-716 Investigators. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet. 2022 Apr 30;399(10336):1718-1729. Epub 2022 Apr 1. link to original article PubMed NCT03553836
    1. HRQoL analysis: Khattak MA, Luke JJ, Long GV, Ascierto PA, Rutkowski P, Schadendorf D, Robert C, Grob JJ, de la Cruz Merino L, Del Vecchio M, Spagnolo F, Mackiewicz J, Chiarion-Sileni V, Carlino MS, Mohr P, De Galitiis F, Ross MI, Eroglu Z, Chen K, Jiang R, Fukunaga-Kalabis M, Krepler C, Eggermont AMM, Kirkwood JM. Adjuvant pembrolizumab versus placebo in resected high-risk stage II melanoma: Health-related quality of life from the randomized phase 3 KEYNOTE-716 study. Eur J Cancer. 2022 Nov;176:207-217. Epub 2022 Oct 3. link to original article PubMed
    2. Update: Long GV, Luke JJ, Khattak MA, de la Cruz Merino L, Del Vecchio M, Rutkowski P, Spagnolo F, Mackiewicz J, Chiarion-Sileni V, Kirkwood JM, Robert C, Grob JJ, de Galitiis F, Schadendorf D, Carlino MS, Mohr P, Dummer R, Gershenwald JE, Yoon CH, Wu XL, Fukunaga-Kalabis M, Krepler C, Eggermont AMM, Ascierto PA; KEYNOTE-716 Investigators. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma (KEYNOTE-716): distant metastasis-free survival results of a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol. 2022 Nov;23(11):1378-1388. Epub 2022 Oct 18. link to original article PubMed
    3. Update: Luke JJ, Ascierto PA, Khattak MA, de la Cruz Merino L, Del Vecchio M, Rutkowski P, Spagnolo F, Mackiewicz J, Chiarion-Sileni V, Kirkwood JM, Robert C, Grob JJ, de Galitiis F, Schadendorf D, Carlino MS, Wu XL, Fukunaga-Kalabis M, Krepler C, Eggermont AMM, Long GV. Pembrolizumab Versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma: Final Analysis of Distant Metastasis-Free Survival in the Phase III KEYNOTE-716 Study. J Clin Oncol. 2024 May 10;42(14):1619-1624. Epub 2024 Mar 7. link to original article PubMed
  3. SWOG S1404: Grossmann KF, Othus M, Patel SP, Tarhini AA, Sondak VK, Knopp MV, Petrella TM, Truong TG, Khushalani NI, Cohen JV, Buchbinder EI, Kendra K, Funchain P, Lewis KD, Conry RM, Chmielowski B, Kudchadkar RR, Johnson DB, Li H, Moon J, Eroglu Z, Gastman B, Kovacsovics-Bankowski M, Gunturu KS, Ebbinghaus SW, Ahsan S, Ibrahim N, Sharon E, Korde LA, Kirkwood JM, Ribas A. Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma. Cancer Discov. 2022 Mar 1;12(3):644-653. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02506153
    1. HRQoL analysis: Unger JM, Darke A, Othus M, Truong TG, Khushalani N, Kendra K, Lewis KD, Faller B, Funchain P, Buchbinder EI, Tarhini AA, Kirkwood JM, Sharon E, Sondak V, Guild SR, Grossmann K, Ribas A, Patel SP. Effectiveness of Adjuvant Pembrolizumab vs High-Dose Interferon or Ipilimumab for Quality-of-Life Outcomes in Patients With Resected Melanoma: A Secondary Analysis of the SWOG S1404 Randomized Clinical Trial. JAMA Oncol. 2023 Feb 1;9(2):251-260. link to original article link to PMC article PubMed
  4. SWOG S1801: Patel SP, Othus M, Chen Y, Wright GP Jr, Yost KJ, Hyngstrom JR, Hu-Lieskovan S, Lao CD, Fecher LA, Truong TG, Eisenstein JL, Chandra S, Sosman JA, Kendra KL, Wu RC, Devoe CE, Deutsch GB, Hegde A, Khalil M, Mangla A, Reese AM, Ross MI, Poklepovic AS, Phan GQ, Onitilo AA, Yasar DG, Powers BC, Doolittle GC, In GK, Kokot N, Gibney GT, Atkins MB, Shaheen M, Warneke JA, Ikeguchi A, Najera JE, Chmielowski B, Crompton JG, Floyd JD, Hsueh E, Margolin KA, Chow WA, Grossmann KF, Dietrich E, Prieto VG, Lowe MC, Buchbinder EI, Kirkwood JM, Korde L, Moon J, Sharon E, Sondak VK, Ribas A; SWOG. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023 Mar 2;388(9):813-823. link to original article contains dosing details in manuscript PubMed NCT03698019
  5. KEYNOTE-942: Weber JS, Carlino MS, Khattak A, Meniawy T, Ansstas G, Taylor MH, Kim KB, McKean M, Long GV, Sullivan RJ, Faries M, Tran TT, Cowey CL, Pecora A, Shaheen M, Segar J, Medina T, Atkinson V, Gibney GT, Luke JJ, Thomas S, Buchbinder EI, Healy JA, Huang M, Morrissey M, Feldman I, Sehgal V, Robert-Tissot C, Hou P, Zhu L, Brown M, Aanur P, Meehan RS, Zaks T. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet. 2024 Feb 17;403(10427):632-644. Epub 2024 Jan 18. link to original article PubMed NCT03897881

Local therapy

Talimogene laherparepvec monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Andtbacka et al. 2015 (OPTiM) 2009-2011 Phase 3 (E-RT-switch-ooc) GM-CSF Superior DRR (primary endpoint)

Seems to have superior OS1 (secondary endpoint)
(HR 0.79, 95% CI 0.62-1.00)

1Reported efficacy is based on the 2019 update.
Note: Talimogene laherparepvec was injected directly into unresectable cutaneous, subcutaneous, and nodal melanoma lesions. Treatment continued until progression of disease, unacceptable toxicity, lack of response by 12 months, or disappearance of all injectable lesions.

Local therapy

  • Talimogene laherparepvec (Imlygic) as follows:
    • Initially, to seroconvert HSV-seronegative patients: 1,000,000 pfu/mL SC intralesional injection once on day 1
    • Thereafter: 100,000,000 pfu/mL SC intralesional injection once on day 1
    • Total volume given per treatment session was up to 4.0 mL. "Injected volume per lesion ranged from 0.1 mL for lesions less than 0.5 cm to 4.0 mL for lesions greater than 5 cm in longest diameter."

21-day course, then 14-day cycle for at least 12 cycles

Subsequent treatment

  • Patients with stable or responding disease after 1 year of therapy could continue treatment for another 6 months

References

  1. OPTiM: Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780-8. Epub 2015 May 26. link to original article contains dosing details in manuscript PubMed NCT00769704
    1. Update: Andtbacka RHI, Collichio F, Harrington KJ, Middleton MR, Downey G, Ӧhrling K, Kaufman HL. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma. J Immunother Cancer. 2019 Jun 6;7(1):145. link to original article link to PMC article PubMed

Metastatic or unresectable disease, first-line

ABC

ABC: Abraxane (Paclitaxel nanoparticle albumin-bound), Bevacizumab, Carboplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kottschade et al. 2013 (N0775) 2008-2010 Randomized Phase 2 (E-esc) Temozolomide & Bevacizumab Seems to have superior PFS6 (primary endpoint)

Note: The doses listed here are the amended starting doses.

Chemotherapy

Targeted therapy

28-day cycles

References

  1. N0775: Kottschade LA, Suman VJ, Perez DG, McWilliams RR, Kaur JS, Amatruda TT 3rd, Geoffroy FJ, Gross HM, Cohen PA, Jaslowski AJ, Kosel ML, Markovic SN; North Central Cancer Treatment Group. A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N0775. Cancer. 2013 Feb 1;119(3):586-92. Epub 2012 Aug 22. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00626405

Carboplatin & Paclitaxel (CP)

CP: Carboplatin & Paclitaxel
PC: Paclitaxel & Carboplatin

Regimen variant #1, 5/175

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yan et al. 2021 (BCH-MM-131101) 2014-2017 Randomized Phase 2 (C) CP & Bevacizumab Seems to have inferior OS

Chemotherapy

28-day cycles


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Flaherty et al. 2013 (ECOG E2603) 2005-2008 Phase 3 (C) CP & Sorafenib Did not meet primary endpoint of OS

Chemotherapy

  • Carboplatin (Paraplatin) as follows:
    • Cycles 1 to 4: AUC 6 IV over 30 minutes once on day 1, given second
    • Cycle 5 up to 10: AUC 5 IV over 30 minutes once on day 1, given second
  • Paclitaxel (Taxol) as follows:
    • Cycles 1 to 4: 225 mg/m2 IV over 3 hours once on day 1, given first
    • Cycle 5 up to 10: 175 mg/m2 IV over 3 hours once on day 1, given first

21-day cycle for up to 10 cycles

References

  1. ECOG E2603: Flaherty KT, Lee SJ, Zhao F, Schuchter LM, Flaherty L, Kefford R, Atkins MB, Leming P, Kirkwood JM. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol. 2013 Jan 20;31(3):373-9. Epub 2012 Dec 17. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00110019
  2. BCH-MM-131101: Yan X, Sheng X, Chi Z, Si L, Cui C, Kong Y, Tang B, Mao L, Wang X, Lian B, Li S, Bai X, Zhou L, Dai J, Yao H, Guo J. Randomized Phase II Study of Bevacizumab in Combination With Carboplatin Plus Paclitaxel in Patients With Previously Untreated Advanced Mucosal Melanoma. J Clin Oncol. 2021 Mar 10;39(8):881-889. Epub 2021 Jan 14. link to original article contains dosing details in manuscript PubMed NCT02023710

Carboplatin & Paclitaxel (CP) & Bevacizumab

CPB: Carboplatin, Paclitaxel, Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yan et al. 2021 (BCH-MM-131101) 2014-2017 Randomized Phase 2 (E-esc) CP Seems to have superior OS (secondary endpoint)
Median OS: 14 vs 9 mo
(HR 0.61, 95% CI 0.41-0.92)

Superior PFS (primary endpoint)
Median PFS: 4.8 vs 3 mo
(HR 0.46, 95% CI 0.31-0.695)

Chemotherapy

Targeted therapy

28-day cycles

References

  1. BCH-MM-131101: Yan X, Sheng X, Chi Z, Si L, Cui C, Kong Y, Tang B, Mao L, Wang X, Lian B, Li S, Bai X, Zhou L, Dai J, Yao H, Guo J. Randomized Phase II Study of Bevacizumab in Combination With Carboplatin Plus Paclitaxel in Patients With Previously Untreated Advanced Mucosal Melanoma. J Clin Oncol. 2021 Mar 10;39(8):881-889. Epub 2021 Jan 14. link to original article contains dosing details in manuscript PubMed NCT02023710

Carboplatin & nab-Paclitaxel

Regimen

Study Dates of enrollment Evidence
Kottschade et al. 2011 (N057E1) 2006-2007 Phase 2

Chemotherapy

Supportive therapy

  • "All patients received standard supportive care, including antiemetics, antibiotics, blood/platelet transfusions, erythropoietin, and colony-stimulating factors at the discretion of the treating physician."

28-day cycle for up to 8 cycles; patients without progressive disease or excessive toxicity could receive additional therapy per physician discretion

References

  1. N057E1: Kottschade LA, Suman VJ, Amatruda T 3rd, McWilliams RR, Mattar BI, Nikcevich DA, Behrens R, Fitch TR, Jaslowski AJ, Markovic SN; North Central Cancer Treatment Group. A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, N057E(1). Cancer. 2011 Apr 15;117(8):1704-10. Epub 2010 Nov 8. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00404235

Cisplatin & Dacarbazine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ridolfi et al. 2002 1997-1999 Phase 3 (C) Cisplatin, Dacarbazine, IL-2, IFN alfa-2b +/- Carmustine Did not meet primary endpoint of OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

21-day cycle for 6 cycles

References

  1. Ridolfi R, Chiarion-Sileni V, Guida M, Romanini A, Labianca R, Freschi A, Lo Re G, Nortilli R, Brugnara S, Vitali P, Nanni O; Italian Melanoma Intergroup. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol. 2002 Mar 15;20(6):1600-7. link to original article contains dosing details in manuscript PubMed

Cisplatin, Dacarbazine, Paclitaxel

Regimen

Study Dates of enrollment Evidence
Papadopoulos et al. 2009 2000-04 to 2002-09 Phase 1/2

Note: This is the suggested phase 2 dosing.

Chemotherapy

21-day cycles (see note)

References

  1. Papadopoulos NE, Bedikian A, Ring S, Kim KB, Hwu WJ, Gerber DL, Homsi J, Hwu P. Phase I/II study of a cisplatin-taxol-dacarbazine regimen in metastatic melanoma. Am J Clin Oncol. 2009 Oct;32(5):509-14. link to original article contains dosing details in manuscript PubMed

CVD (Vindesine)

CVD: Cisplatin, Vindesine, Dacarbazine

Regimen variant #1, q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bajetta et al. 2006 1999-2003 Phase 3 (C) Biochemotherapy Did not meet primary endpoint of OS

Chemotherapy

21-day cycles


Regimen variant #2, q4wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jungnelius et al. 1998 NR Phase 3 (E-esc) Dacarbazine & Vindesine Did not meet primary endpoint of OS

Chemotherapy

28-day cycles

References

  1. Jungnelius U, Ringborg U, Aamdal S, Mattsson J, Stierner U, Ingvar C, Malmström P, Andersson R, Karlsson M, Willman K, Wist E, Bjelkengren G, Westberg R. Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma: a randomised phase III trial. Eur J Cancer. 1998 Aug;34(9):1368-74. link to original article contains dosing details in manuscript PubMed
  2. Bajetta E, Del Vecchio M, Nova P, Fusi A, Daponte A, Sertoli MR, Queirolo P, Taveggia P, Bernengo MG, Legha SS, Formisano B, Cascinelli N. Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon-alpha2b in metastatic melanoma. Ann Oncol. 2006 Apr;17(4):571-7. Epub 2006 Feb 9. link to original article PubMed

Dacarbazine monotherapy

Example orders

Regimen variant #1, 850 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Robert et al. 2011 (CA184-024) 2006-2008 Phase 3 (C) Dacarbazine & Ipilimumab Inferior OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

21-day cycle for 8 cycles


Regimen variant #2, 850 mg/m2 q4wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Schadendorf et al. 2006 2000-2003 Phase 3 (C) Autologous peptide-pulsed monocyte-derived dendritic cells Did not meet primary endpoint of ORR

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

28-day cycles


Regimen variant #3, 900 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Daponte et al. 2013 (SICOG 0109) 2002-2007 Phase 3 (C) 1. Dacarbazine & Fotemustine
2. Dacarbazine & IFN alfa-2b
3. Dacarbazine, Fotemustine, IFN alfa-2b 		Did not meet primary endpoint of OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

21-day cycles


Regimen variant #4, 1000 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Chapman et al. 1999 1991-1997 Phase 3 (C) Dartmouth regimen Might have inferior ORR
Bedikian et al. 2006 (AGENDA) 2000-2003 Phase 3 (C) Dacarbazine & Oblimersen Might have inferior OS
Median OS: 7.8 vs 9 mo
(HR 1.15, 95% CI 0.99-1.33)
Testori et al. 2008 (C-100-21) 2002-2004 Phase 3 (C) Vitespen Did not meet primary endpoint of OS
Bedikian et al. 2010 2002-2007 Phase 3 (C) DHA-paclitaxel Did not meet primary endpoint of OS
Ribas et al. 2013 (A3671009) 2006-03 to 2007-07 Phase 3 (C) Tremelimumab Did not meet primary endpoint of OS
Ugurel et al. 2017 (ChemoSensMM) 2008-2012 Phase 3 (C) Chemosensitivity-directed therapy:
1. Cisplatin & Paclitaxel
2. Cytarabine & Treosulfan
3. Gemcitabine & Treosulfan 		Did not meet primary endpoint of OS
Hersh et al. 2015 (CA033) 2009-04 to 2011-06 Phase 3 (C) nab-Paclitaxel Seems to have inferior PFS
Robert et al. 2014 (CheckMate 066) 2013-01 to 2014-02 Phase 3 (C) Nivolumab Inferior OS

Chemotherapy

21-day cycles


Regimen variant #5, 1000 mg/m2, split doses, q4wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Falkson et al. 2003 (ECOG E3690) NR Phase 3 (C) 1. DTIC & Interferon
2. DTIC & Tamoxifen
3. DTIC, Interferon, Tamoxifen 		Seems to have inferior ORR

Chemotherapy

28-day cycles


Regimen variant #6, 1250 mg/m2, split doses, q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Middleton et al. 2000b 1995-1997 Phase 3 (C) Temozolomide Did not meet primary endpoint of OS

Chemotherapy

21-day cycles


Regimen variant #7, 1250 mg/m2, split doses, q4wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Avril et al. 2004 1998-2000 Phase 3 (C) Fotemustine Seems to have inferior ORR

Chemotherapy

28-day cycles

References

  1. ECOG E3690: Falkson CI, Ibrahim J, Kirkwood JM, Coates AS, Atkins MB, Blum RH; ECOG. Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol. 1998 May;16(5):1743-51. link to original article contains dosing details in manuscript PubMed
  2. Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro AN, Panageas KS, Begg CB, Agarwala SS, Schuchter LM, Ernstoff MS, Houghton AN, Kirkwood JM. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999 Sep;17(9):2745-51. link to original article contains dosing details in manuscript PubMed
  3. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. link to original article contains dosing details in manuscript PubMed
  4. Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saïag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004 Mar 15;22(6):1118-25. link to original article contains dosing details in manuscript PubMed
  5. Schadendorf D, Ugurel S, Schuler-Thurner B, Nestle FO, Enk A, Bröcker EB, Grabbe S, Rittgen W, Edler L, Sucker A, Zimpfer-Rechner C, Berger T, Kamarashev J, Burg G, Jonuleit H, Tüttenberg A, Becker JC, Keikavoussi P, Kämpgen E, Schuler G; DeCOG. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol. 2006 Apr;17(4):563-70. Epub 2006 Jan 17. link to original article contains dosing details in abstract PubMed
  6. AGENDA: Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, Pavlick AC, DeConti R, Hersh EM, Hersey P, Kirkwood JM, Haluska FG; Oblimersen Melanoma Study Group. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol. 2006 Oct 10;24(29):4738-45. Epub 2006 Sep 11. link to original article contains dosing details in manuscript PubMed NCT00518895
  7. C-100-21: Testori A, Richards J, Whitman E, Mann GB, Lutzky J, Camacho L, Parmiani G, Tosti G, Kirkwood JM, Hoos A, Yuh L, Gupta R, Srivastava PK; C-100-21 Study Group. Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: the C-100-21 Study Group. J Clin Oncol. 2008 Feb 20;26(6):955-62. Erratum in: J Clin Oncol. 2008 Aug 1;26(22): 3819. link to original article does not contain dosing details PubMed
  8. Bedikian AY, DeConti RC, Conry R, Agarwala S, Papadopoulos N, Kim KB, Ernstoff M. Phase 3 study of docosahexaenoic acid-paclitaxel versus dacarbazine in patients with metastatic malignant melanoma. Ann Oncol. 2011 Apr;22(4):787-93. Epub 2010 Sep 20. link to original article link to PMC article contains dosing details in manuscript PubMed
  9. CA184-024: Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. link to original article contains dosing details in manuscript PubMed NCT00324155
    1. Update: Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, Garbe C, Chiarion-Sileni V, Testori A, Chen TT, Tschaika M, Wolchok JD. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6. Epub 2015 Feb 23. link to original article link to PMC article PubMed
  10. A3671009: Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G, Lorigan P, Kendra KL, Maio M, Trefzer U, Smylie M, McArthur GA, Dreno B, Nathan PD, Mackiewicz J, Kirkwood JM, Gomez-Navarro J, Huang B, Pavlov D, Hauschild A. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013 Feb 10;31(5):616-22. Epub 2013 Jan 7. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00257205
  11. SICOG 0109: Daponte A, Signoriello S, Maiorino L, Massidda B, Simeone E, Grimaldi AM, Caracò C, Palmieri G, Cossu A, Botti G, Petrillo A, Lastoria S, Cavalcanti E, Aprea P, Mozzillo N, Gallo C, Comella G, Ascierto PA; Southern Italy Cooperative Oncology Group. Phase III randomized study of fotemustine and dacarbazine versus dacarbazine with or without interferon-α in advanced malignant melanoma. J Transl Med. 2013 Feb 13;11:38. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01359956
  12. CheckMate 066: Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. Epub 2014 Nov 16. link to original article contains dosing details in manuscript PubMed NCT01721772
    1. Update: Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Ny L, Arance A, Svane IM, Schadendorf D, Gogas H, Saci A, Jiang J, Rizzo J, Atkinson V. Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol. 2019 Feb 1;5(2):187-194. Epub 2018 Oct 25. link to original article link to PMC article PubMed
    2. Update: Robert C, Long GV, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Rutkowski P, Hassel JC, McNeil CM, Kalinka EA, Lebbé C, Charles J, Hernberg MM, Savage KJ, Chiarion-Sileni V, Mihalcioiu C, Mauch C, Arance A, Cognetti F, Ny L, Schmidt H, Schadendorf D, Gogas H, Zoco J, Re S, Ascierto PA, Atkinson V. Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma. J Clin Oncol. 2020 Nov 20;38(33):3937-3946. Epub 2020 Sep 30. link to original article link to PMC article PubMed
  13. CA033: Hersh EM, Del Vecchio M, Brown MP, Kefford R, Loquai C, Testori A, Bhatia S, Gutzmer R, Conry R, Haydon A, Robert C, Ernst S, Homsi J, Grob JJ, Kendra K, Agarwala SS, Li M, Clawson A, Brachmann C, Karnoub M, Elias I, Renschler MF, Hauschild A. A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann Oncol. 2015 Nov;26(11):2267-74. Epub 2015 Sep 26. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00864253
  14. ChemoSensMM: Ugurel S, Loquai C, Terheyden P, Schadendorf D, Richtig E, Utikal J, Gutzmer R, Rass K, Sunderkötter C, Stein A, Fluck M, Kaatz M, Trefzer U, Kähler K, Stadler R, Berking C, Höller C, Kerschke L, Edler L, Kopp-Schneider A, Becker JC. Chemosensitivity-directed therapy compared to dacarbazine in chemo-naive advanced metastatic melanoma: a multicenter randomized phase-3 DeCOG trial. Oncotarget. 2017 Jun 27;8(44):76029-76043. eCollection 2017 Sep 29. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00779714

Dacarbazine & Ipilimumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Robert et al. 2011 (CA184-024) 2006-2008 Phase 3 (E-esc) Dacarbazine Superior OS1 (primary endpoint)
Median OS: 11.2 vs 9.1 mo
(HR 0.69, 95% CI 0.57-0.84)

1Reported efficacy is based on the 2015 update.

Chemotherapy

Immunotherapy

  • Ipilimumab (Yervoy) as follows:
    • Cycles 1 to 4: 10 mg/kg IV once on day 1
    • Cycle 9 onwards: 10 mg/kg IV once on day 1

21-day cycle for 8 cycles, then 12-week cycles

References

  1. CA184-024: Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. link to original article contains dosing details in manuscript PubMed NCT00324155
    1. Update: Maio M, Grob JJ, Aamdal S, Bondarenko I, Robert C, Thomas L, Garbe C, Chiarion-Sileni V, Testori A, Chen TT, Tschaika M, Wolchok JD. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6. Epub 2015 Feb 23. link to original article link to PMC article PubMed

Dacarbazine & Vindesine

DV: Dacarbazine & Vindesine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jungnelius et al. 1998 NR Phase 3 (C) CVD Did not meet primary endpoint of OS

Chemotherapy

28-day cycles

References

  1. Jungnelius U, Ringborg U, Aamdal S, Mattsson J, Stierner U, Ingvar C, Malmström P, Andersson R, Karlsson M, Willman K, Wist E, Bjelkengren G, Westberg R. Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma: a randomised phase III trial. Eur J Cancer. 1998 Aug;34(9):1368-74. link to original article contains dosing details in manuscript PubMed

Fotemustine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Avril et al. 2004 1998-2000 Phase 3 (E-switch-ic) Dacarbazine Seems to have superior ORR (primary endpoint)

Chemotherapy

  • Fotemustine (Muphoran) as follows:
    • Cycle 1: 100 mg/m2 IV once per day on days 1, 8, 15
    • Cycle 2 onwards: 100 mg/m2 IV once on day 1

8-week course, then 21-day cycles

References

  1. Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saïag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004 Mar 15;22(6):1118-25. link to original article contains dosing details in manuscript PubMed

Ipilimumab monotherapy

Example orders

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Larkin et al. 2015 (CheckMate 067) 2013-07 to 2014-03 Phase 3 (C) 1. Ipilimumab & Nivolumab Inferior OS1 Equivalent HRQoL
2. Nivolumab Inferior OS1 Equivalent HRQoL
Postow et al. 2015 (CheckMate 069) 2013-09-16 to 2014-02-06 Phase 3 (C) Ipilimumab & Nivolumab Inferior PFS

1Reported efficacy for CheckMate 067 is based on the 2021 update.

Immunotherapy

21-day cycle for 4 cycles

References

  1. CheckMate 069: Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01927419
    1. Update: Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. Epub 2016 Sep 9. link to original article link to PMC article PubMed
  2. CheckMate 067: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01844505
    1. HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article link to PMC article PubMed
    2. Update: Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017 Oct 5;377(14):1345-1356. Epub 2017 Sep 11. Erratum in: N Engl J Med. 2018 Nov 29;379(22):2185. link to original article link to PMC article PubMed
    3. Update: Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. link to original article PubMed
    4. Update: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. link to original article PubMed
    5. Update: Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Butler MO, Hill A, Márquez-Rodas I, Haanen JBAG, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bas T, Ritchings C, Larkin J, Hodi FS. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol. 2022 Jan 10;40(2):127-137. Epub 2021 Nov 24. link to original article link to PMC article PubMed

Ipilimumab & Nivolumab

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Larkin et al. 2015 (CheckMate 067) 2013-07 to 2014-03 Phase 3 (E-RT-esc) 1. Ipilimumab Superior OS1 (co-primary endpoint)
Median OS: 72.1 vs 19.9 mo
(HR 0.42, 95% CI 0.35-0.51) 		Equivalent HRQoL
2. Nivolumab Seems to have superior PFS1 (co-primary endpoint)
Median PFS: 11.5 vs 6.9 mo
(HR 0.79, 95% CI 0.65-0.97) 		Equivalent HRQoL

1Reported efficacy is based on the 2021 update.
Note: on 2016-09-13 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

Immunotherapy

21-day cycle for 4 cycles, then 14-day cycles


Regimen variant #2, "NIVO1+IPI3", weight-based maintenance

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Postow et al. 2015 (CheckMate 069) 2013-09-16 to 2014-02-06 Phase 3 (E-esc) Ipilimumab Superior PFS (secondary endpoint)
Median PFS: NYR vs 4.4 mo
(HR 0.40, 95% CI 0.23-0.68)

Superior ORR (primary endpoint)

Immunotherapy

21-day cycle for 4 cycles, then 14-day cycles


Regimen variant #3, "NIVO1+IPI3", flat-dose maintenance

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Lebbé et al. 2019 (CheckMate 511) 2016-04-04 to 2017-03-27 Phase 3b/4 (C) Ipilimumab & Nivolumab; NIVO3+IPI1 Not evaluated More grade 3 to 5 TRAEs

Immunotherapy

21-day cycle for 4 cycles, then 28-day cycles


Regimen variant #4, "NIVO3+IPI1", flat-dose maintenance

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Lebbé et al. 2019 (CheckMate 511) 2016-04-04 to 2017-03-27 Phase 3b/4 (E-switch-ic) Ipilimumab & Nivolumab; NIVO1+IPI3 Not evaluated Fewer grade 3 to 5 TRAEs

Immunotherapy

21-day cycle for 4 cycles, then 28-day cycles

References

  1. CheckMate 069: Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17. Epub 2015 Apr 20. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01927419
    1. Update: Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568. Epub 2016 Sep 9. link to original article link to PMC article PubMed
  2. CheckMate 067: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01844505
    1. HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article link to PMC article PubMed
    2. Update: Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017 Oct 5;377(14):1345-1356. Epub 2017 Sep 11. Erratum in: N Engl J Med. 2018 Nov 29;379(22):2185. link to original article link to PMC article PubMed
    3. Update: Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. link to original article PubMed
    4. Update: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. link to original article PubMed
    5. Update: Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Butler MO, Hill A, Márquez-Rodas I, Haanen JBAG, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bas T, Ritchings C, Larkin J, Hodi FS. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol. 2022 Jan 10;40(2):127-137. Epub 2021 Nov 24.link to original article link to PMC article PubMed
  3. CheckMate 511: Lebbé C, Meyer N, Mortier L, Marquez-Rodas I, Robert C, Rutkowski P, Menzies AM, Eigentler T, Ascierto PA, Smylie M, Schadendorf D, Ajaz M, Svane IM, Gonzalez R, Rollin L, Lord-Bessen J, Saci A, Grigoryeva E, Pigozzo J. Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial. J Clin Oncol. 2019 Apr 10;37(11):867-875. Epub 2019 Feb 27. link to original article link to PMC article contains dosing details in abstract PubMed NCT02714218

Nivolumab monotherapy

Regimen variant #1, q2wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Robert et al. 2014 (CheckMate 066) 2013-01 to 2014-02 Phase 3 (E-RT-switch-ooc) Dacarbazine Superior OS1 (primary endpoint)
OS60: 39% vs 17%
(HR 0.50, 95% CI 0.40-0.63)
Larkin et al. 2015 (CheckMate 067) 2013-07 to 2014-03 Phase 3 (E-switch-ic) 1. Ipilimumab Superior OS2 (co-primary endpoint)
Median OS: 36.9 vs 19.9 mo
(HR 0.53, 95% CI 0.44-0.64) 		Equivalent HRQoL
2. Ipilimumab & Nivolumab Inferior PFS (co-primary endpoint) Equivalent HRQoL

1Reported efficacy for CheckMate 066 is based on the 2020 update.
2Reported efficacy for CheckMate 067 is based on the 2021 update.
Note: on 2016-09-13 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

Immunotherapy

14-day cycles


Regimen variant #2, q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Diab et al. 2023 (PIVOT IO 001) 2018-10-10 to 2021-12-17 Phase 3 (C) Bempegaldesleukin Seems to have superior ORR (co-primary endpoint)

Did not meet co-primary endpoint of PFS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Immunotherapy

21-day cycles


Regimen variant #3, q4wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tawbi et al. 2022 (RELATIVITY-047) 2018-2020 Phase 2/3 (C) Nivolumab & Relatlimab Inferior PFS

Immunotherapy

28-day cycles

References

  1. CheckMate 066: Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. Epub 2014 Nov 16. link to original article contains dosing details in manuscript PubMed NCT01721772
    1. Update: Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Ny L, Arance A, Svane IM, Schadendorf D, Gogas H, Saci A, Jiang J, Rizzo J, Atkinson V. Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol. 2019 Feb 1;5(2):187-194. Epub 2018 Oct 25. link to original article link to PMC article PubMed
    2. Update: Robert C, Long GV, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Rutkowski P, Hassel JC, McNeil CM, Kalinka EA, Lebbé C, Charles J, Hernberg MM, Savage KJ, Chiarion-Sileni V, Mihalcioiu C, Mauch C, Arance A, Cognetti F, Ny L, Schmidt H, Schadendorf D, Gogas H, Zoco J, Re S, Ascierto PA, Atkinson V. Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma. J Clin Oncol. 2020 Nov 20;38(33):3937-3946. Epub 2020 Sep 30. link to original article link to PMC article PubMed
  2. CheckMate 067: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. Epub 2015 May 31. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01844505
    1. HRQoL analysis: Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Wagstaff J, Callahan MK, Postow MA, Smylie M, Ferrucci PF, Dummer R, Hill A, Taylor F, Sabater J, Walker D, Kotapati S, Abernethy A, Long GV. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer. 2017 Sep;82:80-91. Epub 2017 Jun 23. link to original article link to PMC article PubMed
    2. Update: Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017 Oct 5;377(14):1345-1356. Epub 2017 Sep 11. Erratum in: N Engl J Med. 2018 Nov 29;379(22):2185. link to original article link to PMC article PubMed
    3. Update: Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-92. Epub 2018 Oct 18. link to original article PubMed
    4. Update: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Márquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019 Oct 17;381(16):1535-1546. Epub 2019 Sep 28. link to original article PubMed
    5. Update: Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Butler MO, Hill A, Márquez-Rodas I, Haanen JBAG, Guidoboni M, Maio M, Schöffski P, Carlino MS, Lebbé C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bas T, Ritchings C, Larkin J, Hodi FS. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol. 2022 Jan 10;40(2):127-137. Epub 2021 Nov 24. link to original article link to PMC article PubMed
  3. RELATIVITY-047: Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, Dalle S, Arance A, Grob JJ, Srivastava S, Abaskharoun M, Hamilton M, Keidel S, Simonsen KL, Sobiesk AM, Li B, Hodi FS, Long GV; RELATIVITY-047 Investigators. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022 Jan 6;386(1):24-34. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03470922
    1. Update: Long GV, Hodi FS, Lipson EJ, Schadendorf D, Ascierto PA, Matamala L, Salman P, Gutiérrez EC, Rutkowski P, Gogas HJ, Lao CD, Menezes JJD, Dalle S, Arance A, Grob JJ, Keidel S, Shaikh A, Sobiesk AM, Dolfi S, Tawbi HA. Overall Survival and Response with Nivolumab and Relatlimab in Advanced Melanoma. NEJM Evidence. 2023 Apr;2(4):EVIDoa2200239. Epub 2023 Mar 22. PubMed link to original article
  4. PIVOT IO 001: Diab A, Gogas H, Sandhu S, Long GV, Ascierto PA, Larkin J, Sznol M, Franke F, Ciuleanu TE, Pereira C, Muñoz Couselo E, Bronzon Damian F, Schenker M, Perfetti A, Lebbe C, Quéreux G, Meier F, Curti BD, Rojas C, Arriaga Y, Yang H, Zhou M, Ravimohan S, Statkevich P, Tagliaferri MA, Khushalani NI. Bempegaldesleukin Plus Nivolumab in Untreated Advanced Melanoma: The Open-Label, Phase III PIVOT IO 001 Trial Results. J Clin Oncol. 2023 Oct 20;41(30):4756-4767. Epub 2023 Aug 31. link to original article contains dosing details in manuscript PubMed NCT03635983

Nivolumab & Relatlimab

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tawbi et al. 2022 (RELATIVITY-047) 2018-2020 Phase 2/3 (E-RT-esc) Nivolumab Superior PFS1 (primary endpoint)
Median PFS: 10.2 vs 4.6 mo
(HR 0.78, 95% CI 0.64-0.94)

Might have superior OS1 (secondary endpoint)
Median OS: NYR vs 34.1 mo
(HR 0.80, 95% CI 0.64-1.01)

1Reported efficacy is based on the 2023 update.

Immunotherapy

28-day cycles

References

  1. RELATIVITY-047: Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, Dalle S, Arance A, Grob JJ, Srivastava S, Abaskharoun M, Hamilton M, Keidel S, Simonsen KL, Sobiesk AM, Li B, Hodi FS, Long GV; RELATIVITY-047 Investigators. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022 Jan 6;386(1):24-34. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03470922
    1. Update: Long GV, Hodi FS, Lipson EJ, Schadendorf D, Ascierto PA, Matamala L, Salman P, Gutiérrez EC, Rutkowski P, Gogas HJ, Lao CD, Menezes JJD, Dalle S, Arance A, Grob JJ, Keidel S, Shaikh A, Sobiesk AM, Dolfi S, Tawbi HA. Overall Survival and Response with Nivolumab and Relatlimab in Advanced Melanoma. NEJM Evidence. 2023 Apr;2(4):EVIDoa2200239. Epub 2023 Mar 22. PubMed link to original article

Pembrolizumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Chesney et al. 2022 (MASTERKEY-265) 2016-2018 Phase 3 (C) T-VEC & Pembrolizumab Might have inferior PFS
Median PFS: 8.5 vs 14.3 mo
(HR 1.16, 95% CI 0.96-1.41)
Gogas et al. 2020 (IMspire170) 2017-2019 Phase 3 (C) Cobimetinib & Atezolizumab Did not meet primary endpoint of PFS
Median PFS: 5.7 vs 5.5 mo
(HR 0.87, 95% CI 0.67-1.14)

Immunotherapy

21-day cycles

References

  1. IMspire170: Gogas H, Dréno B, Larkin J, Demidov L, Stroyakovskiy D, Eroglu Z, Francesco Ferrucci P, Pigozzo J, Rutkowski P, Mackiewicz J, Rooney I, Voulgari A, Troutman S, Pitcher B, Guo Y, Yan Y, Castro M, Mulla S, Flaherty K, Arance A. Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study. Ann Oncol. 2021 Mar;32(3):384-394. Epub 2020 Dec 10. link to original article contains dosing details in manuscript PubMed NCT03273153
  2. MASTERKEY-265: Chesney JA, Ribas A, Long GV, Kirkwood JM, Dummer R, Puzanov I, Hoeller C, Gajewski TF, Gutzmer R, Rutkowski P, Demidov L, Arenberger P, Shin SJ, Ferrucci PF, Haydon A, Hyngstrom J, van Thienen JV, Haferkamp S, Guilera JM, Rapoport BL, VanderWalde A, Diede SJ, Anderson JR, Treichel S, Chan EL, Bhatta S, Gansert J, Hodi FS, Gogas H. Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma. J Clin Oncol. 2023 Jan 20;41(3):528-540. Epub 2022 Aug 23. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02263508

Temozolomide & Bevacizumab

TB: Temozolomide & Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kottschade et al. 2013 (N0775) 2008-2010 Randomized Phase 2 (E-de-esc) ABC Seems to have inferior PFS6 (primary endpoint)

Chemotherapy

Targeted therapy

28-day cycles

References

  1. N0775: Kottschade LA, Suman VJ, Perez DG, McWilliams RR, Kaur JS, Amatruda TT 3rd, Geoffroy FJ, Gross HM, Cohen PA, Jaslowski AJ, Kosel ML, Markovic SN; North Central Cancer Treatment Group. A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N0775. Cancer. 2013 Feb 1;119(3):586-92. Epub 2012 Aug 22. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00626405

Maintenance after first-line therapy

IL-2 & GM-CSF

Example orders

Regimen

Study Dates of enrollment Evidence
O'Day et al. 2002 1998-2000 Phase 2

Note: timing below is based on the assumption that all cycles begin on a Monday.

Preceding treatment

Immunotherapy, low-dose portion (cycles 1, 4, 7, 9, 11)

Growth factor therapy, low-dose portion (cycles 1, 4, 7, 9, 11)

Immunotherapy, pulse portion (cycles 2, 3, 5, 6, 8, 10, 12)

  • IL-2 - Aldesleukin (Proleukin) 18,000,000 units/m2 IV continuous infusion over 6 hours, started on day 1, then 18,000,000 units/m2 IV continuous infusion over 12 hours, then 18,000,000 units/m2 IV continuous infusion over 24 hours, then 1,000,000 units/m2 SC once per day on days 3 to 5, 8 to 12, 15 to 19, 22 to 26

Growth factor therapy, pulse portion (cycles 2, 3, 5, 6, 8, 10, 12)

  • Sargramostim (Leukine) 125 mcg/m2 SC once per day on days 3 to 17 (note: this was possibly a typo in O'Day et al. 2002 since shifting the schedule 2 days forward would be days 3 to 16)

Supportive therapy, pulse portion (cycles 2, 3, 5, 6, 8, 10, 12)

28-day cycle for 12 cycles

References

  1. O'Day SJ, Boasberg PD, Piro L, Kristedja TS, Wang HJ, Martin M, Deck R, Ames P, Shinn K, Kim H, Fournier P, Gammon G. Maintenance biotherapy for metastatic melanoma with interleukin-2 and granulocyte macrophage-colony stimulating factor improves survival for patients responding to induction concurrent biochemotherapy. Clin Cancer Res. 2002 Sep;8(9):2775-81. link to original article contains dosing details in manuscript PubMed

Metastatic or unresectable disease, second-line

Carboplatin & Paclitaxel (CP)

CP: Carboplatin & Paclitaxel
PC: Paclitaxel & Carboplatin

Regimen variant #1, AUC 2/100

Study Evidence
Rao et al. 2006 Retrospective

Chemotherapy

28-day cycles


Regimen variant #2, AUC 6/175

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Weber et al. 2015 (CheckMate 037) 2012-2014 Phase 3 (C) Nivolumab Inferior ORR

Note: this study did not meet the co-primary endpoint of OS.

Prior treatment criteria

  • CheckMate 037, BRAF WT: Exposure to ipilimumab
  • CheckMate 037, BRAF p.V600: Exposure to ipilimumab and BRAF inhibitor

Chemotherapy

21-day cycles


Regimen variant #3, AUC 6/225 x 4, then AUC 5/175

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hauschild et al. 2009 (Bayer 11718) 2005-05 to 2006-05 Phase 3 (C) CP & Sorafenib Did not meet primary endpoint of PFS
Flaherty et al. 2013 (ECOG E2603) 2005-2008 Phase 3 (C) CP & Sorafenib Did not meet primary endpoint of OS
Ribas et al. 2015 (KEYNOTE-002) 2012-11-30 to 2013-11-13 Randomized Phase 2 (C) 1. Pembrolizumab; 2 mg/kg q3wk
2. Pembrolizumab; 10 mg/kg q3wk 		Inferior PFS

Prior treatment criteria

Chemotherapy

  • Carboplatin (Paraplatin) as follows:
    • Cycles 1 to 4: AUC 6 IV over 30 minutes once on day 1, given second
    • Cycle 5 up to 10: AUC 5 IV over 30 minutes once on day 1, given second
  • Paclitaxel (Taxol) as follows:
    • Cycles 1 to 4: 225 mg/m2 IV over 3 hours once on day 1, given first
    • Cycle 5 up to 10: 175 mg/m2 IV over 3 hours once on day 1, given first

21-day cycle for up to 10 cycles


Regimen variant #4, 200/100, 6 out of 8 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zimpfer-Rechner et al. 2003 1998-2000 Randomized Phase 2 (E-esc) Paclitaxel Did not meet primary efficacy endpoints

Note: This was an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.

Chemotherapy

8-week cycles

References

  1. Zimpfer-Rechner C, Hofmann U, Figl R, Becker JC, Trefzer U, Keller I, Hauschild A, Schadendorf D; Dermatologic Cooperative Oncology Group. Randomized phase II study of weekly paclitaxel versus paclitaxel and carboplatin as second-line therapy in disseminated melanoma: a multicentre trial of the Dermatologic Co-operative Oncology Group (DeCOG). Melanoma Res. 2003 Oct;13(5):531-6. link to original article contains dosing details in abstract PubMed
  2. Retrospective: Rao RD, Holtan SG, Ingle JN, Croghan GA, Kottschade LA, Creagan ET, Kaur JS, Pitot HC, Markovic SN. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer. 2006 Jan 15;106(2):375-82. link to original article PubMed
  3. Bayer 11718: Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermont A, Grabbe S, Gonzalez R, Gille J, Peschel C, Schadendorf D, Garbe C, O'Day S, Daud A, White JM, Xia C, Patel K, Kirkwood JM, Keilholz U. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009 Jun 10;27(17):2823-30. Epub 2009 Apr 6. link to original article contains dosing details in manuscript PubMed NCT00111007
  4. CheckMate 037: Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. link to original article contains dosing details in abstract PubMed NCT01721746
    1. Update: Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. link to original article link to PMC article PubMed
  5. KEYNOTE-002: Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. link to original article contains dosing details in supplement link to PMC article PubMed NCT01704287
    1. HRQoL analysis: Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. link to original article PubMed
    2. Update: Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. link to original article PubMed

Carboplatin & nab-Paclitaxel

Regimen

Study Dates of enrollment Evidence
Kottschade et al. 2011 (N057E1) 2006-2007 Phase 2

Chemotherapy

Supportive therapy

  • "All patients received standard supportive care, including antiemetics, antibiotics, blood/platelet transfusions, erythropoietin, and colony-stimulating factors at the discretion of the treating physician."

28-day cycle for up to 8 cycles; patients without progressive disease or excessive toxicity could receive additional therapy per physician discretion

References

  1. N057E1: Kottschade LA, Suman VJ, Amatruda T 3rd, McWilliams RR, Mattar BI, Nikcevich DA, Behrens R, Fitch TR, Jaslowski AJ, Markovic SN; North Central Cancer Treatment Group. A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, N057E(1). Cancer. 2011 Apr 15;117(8):1704-10. Epub 2010 Nov 8. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00404235

Lifileucel & IL-2

TILs: Tumor Infiltrating Lymphocytes

Regimen

Study Dates of enrollment Evidence
Sarnaik et al. 2021 (C-144-01) 2017-2019 Phase 2

Preceding treatment

  • FC lymphodepletion

Immunotherapy

References

  1. C-144-01: Sarnaik AA, Hamid O, Khushalani NI, Lewis KD, Medina T, Kluger HM, Thomas SS, Domingo-Musibay E, Pavlick AC, Whitman ED, Martin-Algarra S, Corrie P, Curti BD, Oláh J, Lutzky J, Weber JS, Larkin JMG, Shi W, Takamura T, Jagasia M, Qin H, Wu X, Chartier C, Graf Finckenstein F, Fardis M, Kirkwood JM, Chesney JA. Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma. J Clin Oncol. 2021 Aug 20;39(24):2656-2666. Epub 2021 May 12. Erratum in: J Clin Oncol. 2021 Sep 10;39(26):2972. link to original article link to PMC article PubMed NCT02360579

Toripalimab monotherapy

Regimen

Study Dates of enrollment Evidence
Awaiting publication (Junshi-JS001-BJZL-II) 2016-NR Phase 2

Immunotherapy

14-day cycles

References

  1. Junshi-JS001-BJZL-II: contains dosing details on CT.gov NCT03013101

Metastatic or unresectable disease

Note: these regimens have not yet been classified by line of treatment.

Dacarbazine monotherapy

Example orders

Regimen variant #1, 850 mg/m2 q3wk

Study Dates of enrollment Evidence
Pritchard et al. 1980 NR in abstract Phase 2

Chemotherapy

21-day cycle for 8 cycles


Regimen variant #2, 1000 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Patel et al. 2011 (EORTC 18032) 2004-2007 Phase 3 (C) Temozolomide Did not meet primary endpoint of OS
Ribas et al. 2015 (KEYNOTE-002) 2012-11-30 to 2013-11-13 Randomized Phase 2 (C) 1. Pembrolizumab; 2 mg/kg q3wk
2. Pembrolizumab; 10 mg/kg q3wk 		Inferior PFS
Weber et al. 2015 (CheckMate 037) 2012-2014 Phase 3 (C) Nivolumab Inferior ORR

Note: CheckMate 037 did not meet the co-primary endpoint of OS.

Prior treatment criteria

  • CheckMate 037, BRAF WT: Exposure to ipilimumab
  • CheckMate 037, BRAF p.V600: Exposure to ipilimumab and BRAF inhibitor

Chemotherapy

21-day cycles


Regimen variant #3, 1250 mg/m2, split doses, q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cocconi et al. 1992 1983-1988 Phase 3 (C) Dacarbazine & Tamoxifen Seems to have inferior OS

Prior treatment criteria

  • Cocconi et al. 1992: No previous treatment with dacarbazine or tamoxifen

Chemotherapy

21-day cycles


Regimen variant #4, 2500 mg/m2, split doses, q4wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Luikart et al. 1984 NR Phase 3 (C) BVP Did not meet efficacy endpoints

Note: This is the first phase 3 RCT published in the Journal of Clinical Oncology.

Chemotherapy

28-day cycles

References

  1. Pritchard KI, Quirt IC, Cowan DH, Osoba D, Kutas GJ. DTIC therapy in metastatic malignant melanoma: a simplified dose schedule. Cancer Treat Rep. 1980 Oct-Nov;64(10-11):1123-6. PubMed
  2. Luikart SD, Kennealey GT, Kirkwood JM. Randomized phase III trial of vinblastine, bleomycin, and cis-dichlorodiammine-platinum versus dacarbazine in malignant melanoma. J Clin Oncol. 1984 Mar;2(3):164-8. link to original article contains dosing details in manuscript PubMed
  3. Cocconi G, Bella M, Calabresi F, Tonato M, Canaletti R, Boni C, Buzzi F, Ceci G, Corgna E, Costa P, Lottici R, Papadia F, Sofra MC, Bacchi M. Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen. N Engl J Med. 1992 Aug 20;327(8):516-23. link to original article contains dosing details in manuscript PubMed
  4. EORTC 18032: Patel PM, Suciu S, Mortier L, Kruit WH, Robert C, Schadendorf D, Trefzer U, Punt CJ, Dummer R, Davidson N, Becker J, Conry R, Thompson JA, Hwu WJ, Engelen K, Agarwala SS, Keilholz U, Eggermont AM, Spatz A; EORTC Melanoma Group. Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). Eur J Cancer. 2011 Jul;47(10):1476-83. Epub 2011 May 18. link to original article contains dosing details in abstract PubMed NCT00091572
  5. CheckMate 037: Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. link to original article PubMed NCT01721746
    1. Update: Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. link to original article link to PMC article PubMed
  6. KEYNOTE-002: Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. link to original article contains dosing details in supplement link to PMC article PubMed NCT01704287
    1. HRQoL analysis: Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. link to original article PubMed
    2. Update: Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. link to original article PubMed

Docetaxel monotherapy

Regimen

Study Dates of enrollment Evidence
Aamdal et al. 1994 NR Phase 2

Chemotherapy

Supportive therapy

  • "No prophylactic treatment with steroids or antihistamines was given."

21-day cycles

References

  1. Aamdal S, Wolff I, Kaplan S, Paridaens R, Kerger J, Schachter J, Wanders J, Franklin HR, Verweij J; EORTC Early Clinical Trials Group. Docetaxel (Taxotere) in advanced malignant melanoma: a phase II study of the EORTC Early Clinical Trials Group. Eur J Cancer. 1994;30A(8):1061-4. link to original article contains dosing details in abstract PubMed

High-dose Interleukin-2

HD IL-2: High-Dose InterLeukin-2

Example orders

Regimen variant #1, 600k, up to 3 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sparano et al. 1993 NR Phase 3 (C) HD IL-2 & IFN alfa-2a Did not meet primary endpoint of OS50%

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Immunotherapy

  • IL-2 - Aldesleukin (Proleukin) 600,000 units/kg IV over 15 minutes every 8 hours as tolerated on days 1 to 5, 15 to 19 (up to 28 total doses per cycle)

Supportive therapy

12-week cycle for up to 3 cycles


Regimen variant #2, 600k, up to 5 cycles

Study Dates of enrollment Evidence
Atkins et al. 1999 1985-1993 Phase 2 (RT)

Immunotherapy

  • IL-2 - Aldesleukin (Proleukin) 600,000 units/kg IV over 15 minutes every 8 hours for up to 14 doses per week, on days 1 to 5
    • After a 6 to 9 day rest period, another 14 doses per week given over 5 days is given as described above

Supportive therapy

6- to 12-week cycle for up to 5 cycles


Regimen variant #3, 720k, up to 3 cycles

Study Dates of enrollment Evidence
Rosenberg et al. 1994 1985-1992 Non-randomized

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Immunotherapy

  • IL-2 - Aldesleukin (Proleukin) 720,000 units/kg IV over 15 minutes every 8 hours as tolerated on days 1 to 5, 15 to 19 (up to 30 total doses per cycle)

Supportive therapy

2-month cycle for up to 3 cycles


Regimen variant #4, 720k, up to 5 cycles

Study Dates of enrollment Evidence
Atkins et al. 1999 1985-1993 Phase 2 (RT)

Immunotherapy

  • IL-2 - Aldesleukin (Proleukin) 720,000 units/kg IV over 15 minutes every 8 hours for up to 14 doses per week, on days 1 to 5
    • After a 6 to 9 day rest period, another 14 doses per week given over 5 days is given as described above

Supportive therapy

6- to 12-week cycle for up to 5 cycles


Regimen variant #5, 720k, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Schwartzentruber et al. 2011 (NCI-2012-02897) 2000-2007 Phase 3 (C) HD IL-2 & gp100 vaccine Seems to have inferior clinical response

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Immunotherapy

Supportive therapy

7-week cycles

References

  1. Sparano JA, Fisher RI, Sunderland M, Margolin K, Ernest ML, Sznol M, Atkins MB, Dutcher JP, Micetich KC, Weiss GR, Doroshow JH, Aronson FR, Rubinstein LV, Mier JW. Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol. 1993 Oct;11(10):1969-77. link to original article contains dosing details in manuscript PubMed
  2. Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994 Mar 23-30;271(12):907-13. link to original article contains dosing details in manuscript PubMed
  3. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999 Jul;17(7):2105-16. link to original article contains dosing details in manuscript PubMed
    1. Update: Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000 Feb;6 Suppl 1:S11-4. PubMed
  4. NCI-2012-02897: Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, Gailani F, Riley L, Conlon K, Pockaj B, Kendra KL, White RL, Gonzalez R, Kuzel TM, Curti B, Leming PD, Whitman ED, Balkissoon J, Reintgen DS, Kaufman H, Marincola FM, Merino MJ, Rosenberg SA, Choyke P, Vena D, Hwu P. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011 Jun 2;364(22):2119-27. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00019682

Ipilimumab monotherapy

Example orders

Regimen variant #1, 3 mg/kg

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hodi et al. 2010 (MDX010-20) 2004-2008 Phase 3 (E-RT-switch-ooc) 1. Ipilimumab & gp100 peptide vaccine Did not meet primary endpoint of OS
2. gp100 peptide vaccine Superior OS (primary endpoint)
Median OS: 10 vs 6.4 mo
(HR 0.68, 95% CI 0.55-0.85)
Ascierto et al. 2017 (CA184-169) 2012-02-29 to 2012-07-09 Phase 3 (C) Ipilimumab; 10 mg/kg Seems to have inferior OS
Robert et al. 2015 (KEYNOTE-006) 2013-09-18 to 2014-03-03 Phase 3 (C) 1. Pembrolizumab; 10 mg/kg q2wks Inferior OS
2. Pembrolizumab; 10 mg/kg q3wks Inferior OS

Prior treatment criteria

  • KEYNOTE-006: No more than 1 line of systemic therapy for advanced disease

Immunotherapy

21-day cycle for 4 cycles


Regimen variant #2, 10 mg/kg limited duration

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Weber et al. 2008 2003-2005 Phase 1/2
Wolchok et al. 2010 (CA184-022) 2006-2007 Phase 2
Hodi et al. 2014 (ECOG E1608) 2010-2011 Randomized Phase 2 (C) Ipilimumab & GM-CSF Inferior OS
Ascierto et al. 2017 (CA184-169) 2012-02-29 to 2012-07-09 Phase 3 (E-esc) Ipilimumab; 3 mg/kg Seems to have superior OS1 (primary endpoint)
Median OS: 15.7 vs 11.5 mo
(HR 0.84, 95% CI 0.71-0.99)

1Reported efficacy is based on the 2020 update.
Note: In CA184-022, lower doses including 3 mg/kg (the FDA approved dose) were investigated, but the 10 mg/kg dose was recommended.

Immunotherapy

21-day cycle for 4 cycles


Regimen variant #3, 10 mg/kg with maintenance

Study Dates of enrollment Evidence
O'Day et al. 2010 (CA184-008) 2006-2007 Phase 2
Margolin et al. 2012 (CA184-042) 2008-2009 Phase 2

Immunotherapy

21-day cycle for 4 cycles, then 12-week cycles

References

  1. Weber JS, O'Day S, Urba W, Powderly J, Nichol G, Yellin M, Snively J, Hersh E. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008 Dec 20;26(36):5950-6. Epub 2008 Nov 17. link to original article PubMed
  2. CA184-022: Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, Waterfield W, Schadendorf D, Smylie M, Guthrie T Jr, Grob JJ, Chesney J, Chin K, Chen K, Hoos A, O'Day SJ, Lebbé C. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010 Feb;11(2):155-64. Epub 2009 Dec 8. link to original article contains dosing details in manuscript PubMed NCT00289640
  3. MDX010-20: Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. Epub 2010 Jun 5. Erratum in: N Engl J Med. 2010 Sep 23;363(13):1290. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00094653
    1. HRQoL analysis: Revicki DA, van den Eertwegh AJ, Lorigan P, Lebbe C, Linette G, Ottensmeier CH, Safikhani S, Messina M, Hoos A, Wagner S, Kotapati S. Health related quality of life outcomes for unresectable stage III or IV melanoma patients receiving ipilimumab treatment. Health Qual Life Outcomes. 2012 Jun 13;10:66. link to original article link to PMC article PubMed
    2. Subgroup analysis: McDermott D, Haanen J, Chen TT, Lorigan P, O'Day S; MDX010-20 Investigators. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol. 2013 Oct;24(10):2694-8. Epub 2013 Aug 13. link to original article PubMed
  4. CA184-008: O'Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, Queirolo P, Lundgren L, Mikhailov S, Roman L, Verschraegen C, Humphrey R, Ibrahim R, de Pril V, Hoos A, Wolchok JD. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010 Aug;21(8):1712-7. Epub 2010 Feb 10. link to original article contains dosing details in manuscript PubMed NCT00289627
  5. CA184-042: Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012 May;13(5):459-65. Epub 2012 Mar 27. link to original article contains dosing details in abstract PubMed NCT00623766
  6. ECOG E1608: Hodi FS, Lee S, McDermott DF, Rao UN, Butterfield LH, Tarhini AA, Leming P, Puzanov I, Shin D, Kirkwood JM. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014 Nov 5;312(17):1744-53. link to original article link to PMC article contains dosing details in abstract PubMed NCT01134614
  7. KEYNOTE-006: Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19. link to original article contains dosing details in manuscript PubMed NCT01866319
    1. Update: Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-1862. Epub 2017 Aug 16. link to original article PubMed
    2. PRO analysis: Petrella TM, Robert C, Richtig E, Miller WH Jr, Masucci GV, Walpole E, Lebbe C, Steven N, Middleton MR, Hille D, Zhou W, Ibrahim N, Cebon J. Patient-reported outcomes in KEYNOTE-006, a randomised study of pembrolizumab versus ipilimumab in patients with advanced melanoma. Eur J Cancer. 2017 Nov;86:115-124. Epub 2017 Oct 4. link to original article PubMed
    3. Update: Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Su SC, Krepler C, Ibrahim N, Long GV. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019 Sep;20(9):1239-1251. Epub 2019 Jul 22. link to original article PubMed
    4. Update: Robert C, Carlino MS, McNeil C, Ribas A, Grob JJ, Schachter J, Nyakas M, Kee D, Petrella TM, Blaustein A, Lotem M, Arance A, Daud AI, Hamid O, Larkin J, Anderson J, Krepler C, Grebennik D, Long GV. Seven-Year Follow-Up of the Phase III KEYNOTE-006 Study: Pembrolizumab Versus Ipilimumab in Advanced Melanoma. J Clin Oncol. 2023 Aug 20;41(24):3998-4003. Epub 2023 Jun 22. link to original article PubMed
  8. CA184-169: Ascierto PA, Del Vecchio M, Robert C, Mackiewicz A, Chiarion-Sileni V, Arance A, Lebbé C, Bastholt L, Hamid O, Rutkowski P, McNeil C, Garbe C, Loquai C, Dreno B, Thomas L, Grob JJ, Liszkay G, Nyakas M, Gutzmer R, Pikiel J, Grange F, Hoeller C, Ferraresi V, Smylie M, Schadendorf D, Mortier L, Svane IM, Hennicken D, Qureshi A, Maio M. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2017 May;18(5):611-622. Epub 2017 Mar 27. link to original article PubMed NCT01515189
    1. Update: Ascierto PA, Del Vecchio M, Mackiewicz A, Robert C, Chiarion-Sileni V, Arance A, Lebbé C, Svane IM, McNeil C, Rutkowski P, Loquai C, Mortier L, Hamid O, Bastholt L, Dreno B, Schadendorf D, Garbe C, Nyakas M, Grob JJ, Thomas L, Liszkay G, Smylie M, Hoeller C, Ferraresi V, Grange F, Gutzmer R, Pikiel J, Hosein F, Simsek B, Maio M. Overall survival at 5 years of follow-up in a phase III trial comparing ipilimumab 10 mg/kg with 3 mg/kg in patients with advanced melanoma. J Immunother Cancer. 2020 Jun;8(1):e000391. Erratum in: J Immunother Cancer. 2020 Jul;8(2). link to original article link to PMC article PubMed
  9. M14TIL: NCT02278887

Ipilimumab & Nivolumab

Regimen

Study Dates of enrollment Evidence
Wolchok et al. 2013 (CheckMate 004) 2009-2013 Phase 1

Note: These doses were from the cohort deemed by CheckMate 004 as being "the maximum doses that were associated with an acceptable level of adverse events."

Immunotherapy

21-day cycle for 8 cycles

Subsequent treatment

References

  1. CheckMate 004: Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33. Epub 2013 Jun 2. link to original article contains dosing details in manuscript link to supplementary appendix link to PMC article PubMed NCT01024231

Ipilimumab-Nivolumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Weber et al. 2016 (CheckMate 064) 2013-2014 Randomized Phase 2 (E-switch-ic) Nivolumab, then Ipilimumab Inferior OS (secondary endpoint)

Note: on 2016-09-13 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

Immunotherapy

21-day cycle for 4 cycles, then 14-day cycles

References

  1. CheckMate 064: Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP, Logan TF, Schuchter LM, Nair S, Fecher L, Buchbinder EI, Berghorn E, Ruisi M, Kong G, Jiang J, Horak C, Hodi FS. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol. 2016 Jul;17(7):943-55. Epub 2016 Jun 4. link to original article contains dosing details in abstract link to PMC article PubMed NCT01783938

Nivolumab monotherapy

Regimen variant #1, limited duration

Study Dates of enrollment Evidence
Weber et al. 2013 (MCC-15400) 2010-2012 Phase 1

Note: on 2016-09-13 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data. It is not clear from the manuscript whether the maintenance is 2 years or if the total course is 2 years.

Immunotherapy

14-day cycle for 12 cycles, then 12-week cycle for 8 cycles (see note)


Regimen variant #2, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Weber et al. 2015 (CheckMate 037) 2012-2014 Phase 3 (E-RT-switch-ooc) Investigator's choice of:
1a. Dacarbazine
1b. Carboplatin & Paclitaxel 		Superior ORR (co-primary endpoint)

Note: CheckMate 037 did not meet the co-primary endpoint of OS. On 2016-09-13 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

Prior treatment criteria

  • CheckMate 037, BRAF WT: Exposure to ipilimumab
  • CheckMate 037, BRAF p.V600: Exposure to ipilimumab and BRAF inhibitor

Immunotherapy

14-day cycles

References

  1. MCC-15400: Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, Zhao X, Martinez AJ, Wang W, Gibney G, Kroeger J, Eysmans C, Sarnaik AA, Chen YA. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013 Dec 1;31(34):4311-8. Epub 2013 Oct 21. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01176461
  2. CheckMate 037: Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84. Epub 2015 Mar 18. link to original article PubMed NCT01721746
    1. Update: Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J. Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-390. Epub 2017 Jul 3. link to original article link to PMC article PubMed

Nivolumab-Ipilimumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Weber et al. 2016 (CheckMate 064) 2013-2014 Randomized Phase 2 (E-switch-ic) Ipilimumab, then Nivolumab Superior OS (secondary endpoint)
Median OS: NYR vs 16.9 mo
(HR 0.48, 95% CI 0.29-0.80) 		Similar rate of grade 3-5 TRAEs (primary endpoint)

Note: on 2016-09-13 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

Immunotherapy

  • Nivolumab (Opdivo) as follows:
    • Cycles 1 to 6: 3 mg/kg IV once on day 1
    • Cycle 11 onwards: 3 mg/kg IV once on day 1
  • Ipilimumab (Yervoy) as follows:
    • Cycles 7 to 10: 3 mg/kg IV once on day 1

14-day cycle for 6 cycles, then 21-day cycle for 4 cycles, then 14-day cycles

References

  1. CheckMate 064: Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP, Logan TF, Schuchter LM, Nair S, Fecher L, Buchbinder EI, Berghorn E, Ruisi M, Kong G, Jiang J, Horak C, Hodi FS. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol. 2016 Jul;17(7):943-55. Epub 2016 Jun 4. link to original article contains dosing details in abstract link to PMC article PubMed NCT01783938

Paclitaxel monotherapy

Example orders

Regimen variant #1, 80 mg/m2, 3 out of 4 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
O'Day et al. 2013 (SYMMETRY) 2007-2009 Phase 3 (C) Elesclomol & Paclitaxel Did not meet primary endpoint of PFS
Hamid et al. 2014 (SUMMIT-1) 2009-NR Phase 3 (C) Tasisulam Did not meet primary endpoint of OS

Note: This was the control arm of SYMMETRY, which was a negative study. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

28-day cycles


Regimen variant #2, 175 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ribas et al. 2015 (KEYNOTE-002) 2012-11-30 to 2013-11-13 Randomized Phase 2 (C) 1. Pembrolizumab; 2 mg/kg q3wk
2. Pembrolizumab; 10 mg/kg q3wk 		Inferior PFS

Chemotherapy

21-day cycles


Regimen variant #3, 250 mg/m2 q3wk

Study Dates of enrollment Evidence
Legha et al. 1990 NR Phase 2

Chemotherapy

21-day cycles

References

  1. Legha SS, Ring S, Papadopoulos N, Raber M, Benjamin RS. A phase II trial of taxol in metastatic melanoma. Cancer. 1990 Jun 1;65(11):2478-81. link to original article contains dosing details in abstract PubMed
  2. SYMMETRY: O'Day SJ, Eggermont AM, Chiarion-Sileni V, Kefford R, Grob JJ, Mortier L, Robert C, Schachter J, Testori A, Mackiewicz J, Friedlander P, Garbe C, Ugurel S, Collichio F, Guo W, Lufkin J, Bahcall S, Vukovic V, Hauschild A. Final results of phase III SYMMETRY study: randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma. J Clin Oncol. 2013 Mar 20;31(9):1211-8. Epub 2013 Feb 11. link to original article contains dosing details in manuscript PubMed NCT00522834
  3. SUMMIT-1: Hamid O, Ilaria R Jr, Garbe C, Wolter P, Maio M, Hutson TE, Arance A, Lorigan P, Lee J, Hauschild A, Mohr P, Hahka-Kemppinen M, Kaiser C, Turner PK, Conti I, Grob JJ. A randomized, open-label clinical trial of tasisulam sodium versus paclitaxel as second-line treatment in patients with metastatic melanoma. Cancer. 2014 Jul 1;120(13):2016-24. Epub 2014 Mar 26. link to original article contains dosing details in manuscript PubMed NCT01006252
  4. KEYNOTE-002: Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01704287
    1. HRQoL analysis: Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. link to original article PubMed
    2. Update: Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. link to original article PubMed

nab-Paclitaxel monotherapy

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hersh et al. 2012 NR Phase 2
Hersh et al. 2015 (CA033) 2009-04 to 2011-06 Phase 3 (E-switch-ic) Dacarbazine Seems to have superior PFS (primary endpoint)
Median PFS: 4.8 vs 2.5 mo
(HR 0.79, 95.1% CI 0.63-0.99)

Chemotherapy

28-day cycles


Regimen variant #2

Study Dates of enrollment Evidence
Hersh et al. 2012 NR Phase 2

Note: this dose was intended for previously treated patients.

Chemotherapy

28-day cycles

References

  1. Hersh EM, O'Day SJ, Ribas A, Samlowski WE, Gordon MS, Shechter DE, Clawson AA, Gonzalez R. A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. Cancer. 2010 Jan 1;116(1):155-63. link to original article contains dosing details in abstract PubMed
  2. CA033: Hersh EM, Del Vecchio M, Brown MP, Kefford R, Loquai C, Testori A, Bhatia S, Gutzmer R, Conry R, Haydon A, Robert C, Ernst S, Homsi J, Grob JJ, Kendra K, Agarwala SS, Li M, Clawson A, Brachmann C, Karnoub M, Elias I, Renschler MF, Hauschild A. A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann Oncol. 2015 Nov;26(11):2267-74. Epub 2015 Sep 26. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00864253

Pembrolizumab monotherapy

Regimen variant #1, 2 mg/kg q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hamid et al. 2013 (KEYNOTE-001melanoma) 2011-2012 Phase 1, >20 pts
Ribas et al. 2015 (KEYNOTE-002) 2012-11-30 to 2013-11-13 Randomized Phase 2 (E-RT-switch-ooc) Investigator's choice of:
1a. Carboplatin & Paclitaxel
1b. Dacarbazine
1c. Paclitaxel
1d. Temozolomide 		Superior PFS (primary endpoint)
PFS6: 34% vs 16%
(HR 0.57, 95% CI 0.45-0.73)
2. Pembrolizumab; 10 mg/kg q3wk Did not meet primary endpoint of PFS

Prior treatment criteria

  • KEYNOTE-002, BRAFwt: Failure of ipilimumab
  • KEYNOTE-002, BRAFmut: Failure of ipilimumab and previous treatment with a BRAF or MEK inhibitor or both

Immunotherapy

21-day cycles


Regimen variant #2, 10 mg/kg q2wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hamid et al. 2013 (KEYNOTE-001melanoma) 2011-2012 Phase 1, >20 pts
Robert et al. 2015 (KEYNOTE-006) 2013-09-18 to 2014-03-03 Phase 3 (E-RT-switch-ic) 1. Ipilimumab Superior OS (co-primary endpoint)
OS12: 74.1% vs 58.2%
(HR 0.63, 95% CI 0.47-0.83)
2. Pembrolizumab; 10 mg/kg q3wk Did not meet co-primary endpoints of PFS/OS

Prior treatment criteria

  • KEYNOTE-006: No more than 1 line of systemic therapy for advanced disease

Immunotherapy

14-day cycles


Regimen variant #3, 10 mg/kg q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hamid et al. 2013 (KEYNOTE-001melanoma) 2011-2012 Phase 1, >20 pts
Ribas et al. 2015 (KEYNOTE-002) 2012-11-30 to 2013-11-13 Randomized Phase 2 (E-RT-switch-ooc) Investigator's choice of:
1a. Carboplatin & Paclitaxel
1b. Dacarbazine
1c. Paclitaxel
1d. Temozolomide 		Superior PFS (primary endpoint)
PFS6: 38% vs 16%
(HR 0.50, 95% CI 0.39-0.64)
2. Pembrolizumab; 2 mg/kg Did not meet primary endpoint of PFS
Robert et al. 2015 (KEYNOTE-006) 2013-09-18 to 2014-03-03 Phase 3 (E-RT-switch-ic) 1. Ipilimumab Superior OS (co-primary endpoint)
OS12: 68.4% vs 58.2%
(HR 0.69, 95% CI 0.52-0.90)
2. Pembrolizumab; 10 mg/kg q2wk Did not meet co-primary endpoints of PFS/OS

Prior treatment criteria

  • KEYNOTE-002, BRAFwt: Failure of ipilimumab
  • KEYNOTE-002, BRAFmut: Failure of ipilimumab and previous treatment with a BRAF or MEK inhibitor or both
  • KEYNOTE-006: No more than 1 line of systemic therapy for advanced disease

Immunotherapy

21-day cycles


Regimen variant #4, 200 mg q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Long et al. 2019 (ECHO-301/KEYNOTE-252) 2016-06-21 to 2017-08-07 Phase 3 (C) Epacadostat & Pembrolizumab Did not meet co-primary endpoints of PFS/OS

Prior treatment criteria

  • ECHO-301/KEYNOTE-252: No previous treatment with PD-1 or PD-L1 checkpoint inhibitors

Immunotherapy

21-day cycle for up to 35 cycles (2 years)

References

  1. KEYNOTE-001melanoma: Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013 Jul 11;369(2):134-44. Epub 2013 Jun 2. link to original article link to PMC article PubMed NCT01295827
    1. Update: Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Sep 20;384(9948):1109-17. Epub 2014 Jul 14. link to original article contains dosing details in manuscript PubMed
    2. Update: Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, Joshua AM, Patnaik A, Hwu WJ, Weber JS, Gangadhar TC, Hersey P, Dronca R, Joseph RW, Zarour H, Chmielowski B, Lawrence DP, Algazi A, Rizvi NA, Hoffner B, Mateus C, Gergich K, Lindia JA, Giannotti M, Li XN, Ebbinghaus S, Kang SP, Robert C. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016 Apr 19;315(15):1600-9. Erratum in: JAMA. 2016 Jun 14;315(22):2472. link to original article PubMed
    3. Update: Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph R, Weber JS, Dronca R, Mitchell TC, Patnaik A, Zarour HM, Joshua AM, Zhao Q, Jensen E, Ahsan S, Ibrahim N, Ribas A. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol. 2019 Apr 1;30(4):582-588. link to original article link to PMC article PubMed
  2. KEYNOTE-002: Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01704287
    1. HRQoL analysis: Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. link to original article PubMed
    2. Update: Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. link to original article PubMed
  3. KEYNOTE-006: Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. Epub 2015 Apr 19. link to original article contains dosing details in manuscript PubMed NCT01866319
    1. Update: Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-1862. Epub 2017 Aug 16. link to original article PubMed
    2. PRO analysis: Petrella TM, Robert C, Richtig E, Miller WH Jr, Masucci GV, Walpole E, Lebbe C, Steven N, Middleton MR, Hille D, Zhou W, Ibrahim N, Cebon J. Patient-reported outcomes in KEYNOTE-006, a randomised study of pembrolizumab versus ipilimumab in patients with advanced melanoma. Eur J Cancer. 2017 Nov;86:115-124. Epub 2017 Oct 4. link to original article PubMed
    3. Update: Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Su SC, Krepler C, Ibrahim N, Long GV. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019 Sep;20(9):1239-1251. Epub 2019 Jul 22. link to original article PubMed
    4. Update: Robert C, Carlino MS, McNeil C, Ribas A, Grob JJ, Schachter J, Nyakas M, Kee D, Petrella TM, Blaustein A, Lotem M, Arance A, Daud AI, Hamid O, Larkin J, Anderson J, Krepler C, Grebennik D, Long GV. Seven-Year Follow-Up of the Phase III KEYNOTE-006 Study: Pembrolizumab Versus Ipilimumab in Advanced Melanoma. J Clin Oncol. 2023 Aug 20;41(24):3998-4003. Epub 2023 Jun 22. link to original article PubMed
  4. ECHO-301/KEYNOTE-252: Long GV, Dummer R, Hamid O, Gajewski TF, Caglevic C, Dalle S, Arance A, Carlino MS, Grob JJ, Kim TM, Demidov L, Robert C, Larkin J, Anderson JR, Maleski J, Jones M, Diede SJ, Mitchell TC. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 2019 Aug;20(8):1083-1097. Epub 2019 Jun 17. link to original article contains dosing details in abstract PubMed NCT02752074

Temozolomide monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Middleton et al. 2000b 1995-1997 Phase 3 (E-switch-ic) Dacarbazine Did not meet primary endpoint of OS
Kaufmann et al. 2005 1998-2001 Phase 3 (C) Temozolomide & Interferon-alfa Seems to have inferior ORR
Ribas et al. 2013 (A3671009) 2006-03 to 2007-07 Phase 3 (C) Tremelimumab Did not meet primary endpoint of OS
Ribas et al. 2015 (KEYNOTE-002) 2012-11-30 to 2013-11-13 Randomized Phase 2 (C) 1. Pembrolizumab; 2 mg/kg q3wk
2. Pembrolizumab; 10 mg/kg q3wk 		Inferior PFS

Chemotherapy

28-day cycles

References

  1. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. link to original article contains dosing details in manuscript PubMed
  2. Kaufmann R, Spieth K, Leiter U, Mauch C, von den Driesch P, Vogt T, Linse R, Tilgen W, Schadendorf D, Becker JC, Sebastian G, Krengel S, Kretschmer L, Garbe C, Dummer R; Dermatologic Cooperative Oncology Group. Temozolomide in combination with interferon-alfa versus temozolomide alone in patients with advanced metastatic melanoma: a randomized, phase III, multicenter study from the Dermatologic Cooperative Oncology Group. J Clin Oncol. 2005 Dec 10;23(35):9001-7. Epub 2005 Oct 31. link to original article contains dosing details in abstract PubMed
  3. A3671009: Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G, Lorigan P, Kendra KL, Maio M, Trefzer U, Smylie M, McArthur GA, Dreno B, Nathan PD, Mackiewicz J, Kirkwood JM, Gomez-Navarro J, Huang B, Pavlov D, Hauschild A. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013 Feb 10;31(5):616-22. Epub 2013 Jan 7. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00257205
  4. KEYNOTE-002: Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. Epub 2015 Jun 23. link to original article contains dosing details in supplement link to PMC article PubMed NCT01704287
    1. HRQoL analysis: Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, van den Eertwegh A, Cranmer L, O'Day S, Puzanov I, Schachter J, Blank C, Salama A, Loquai C, Mehnert JM, Hille D, Ebbinghaus S, Kang SP, Zhou W, Ribas A. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016 Nov;67:46-54. Epub 2016 Sep 2. link to original article PubMed
    2. Update: Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, Blank C, Cranmer LD, Robert C, Pavlick AC, Gonzalez R, Hodi FS, Ascierto PA, Salama AKS, Margolin KA, Gangadhar TC, Wei Z, Ebbinghaus S, Ibrahim N, Ribas A. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017 Nov;86:37-45. link to original article PubMed
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