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]].''' | '''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]].''' | ||
− | Is there a regimen missing from this list? | + | 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]]. |
+ | |||
+ | <big>'''Note: biomarker-specific regimens have been moved to dedicated pages: | ||
+ | *'''[[Melanoma,_BRAF-mutated|Melanoma, BRAF-mutated]] | ||
+ | </big> | ||
{| class="wikitable" style="float:right; margin-right: 5px;" | {| class="wikitable" style="float:right; margin-right: 5px;" | ||
|- | |- | ||
− | |<div style="background-color: #66FF66; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] | + | |<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> |
− | <div style="background-color: #66CCFF; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] | + | <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> |
|} | |} | ||
{{TOC limit|limit=3}} | {{TOC limit|limit=3}} | ||
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|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(97)12445-X/fulltext Grob et al. 1998] | |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(97)12445-X/fulltext Grob et al. 1998] | ||
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
− | |[[ | + | |[[#Placebo_.28Observation.29|Observation]] |
|style="background-color:#d9ef8b"|Might have superior OS | |style="background-color:#d9ef8b"|Might have superior OS | ||
|- | |- | ||
Line 51: | Line 55: | ||
|[http://jco.ascopubs.org/content/16/4/1425.long Pehamberger et al. 1998] | |[http://jco.ascopubs.org/content/16/4/1425.long Pehamberger et al. 1998] | ||
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
− | |[[ | + | |[[#Placebo_.28Observation.29|Observation]] |
|style="background-color:#91cf60"|Seems to have superior DFS | |style="background-color:#91cf60"|Seems to have superior DFS | ||
|- | |- | ||
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|[http://jco.ascopubs.org/content/14/1/7.long Kirkwood et al. 1996 (ECOG EST 1684)] | |[http://jco.ascopubs.org/content/14/1/7.long Kirkwood et al. 1996 (ECOG EST 1684)] | ||
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
− | |[[ | + | |[[#Placebo_.28Observation.29|Observation]] |
|style="background-color:#91cf60"|Seems to have superior OS | |style="background-color:#91cf60"|Seems to have superior OS | ||
|- | |- | ||
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|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363881/ Cameron et al. 2001 (The Scottish study)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363881/ Cameron et al. 2001 (The Scottish study)] | ||
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
− | |[[ | + | |[[#Placebo_.28Observation.29|Observation]] |
|style="background-color:#ffffbf"|Seems not superior | |style="background-color:#ffffbf"|Seems not superior | ||
|- | |- | ||
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|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61033-8/fulltext Eggermont et al. 2008 (EORTC 18991)] | |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61033-8/fulltext Eggermont et al. 2008 (EORTC 18991)] | ||
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
− | |[[ | + | |[[#Placebo_.28Observation.29|Observation]] |
|style="background-color:#91cf60"|Seems to have superior RFS | |style="background-color:#91cf60"|Seems to have superior RFS | ||
|- | |- | ||
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|[http://jco.ascopubs.org/content/14/1/7.long Kirkwood et al. 1996 (ECOG EST 1684)] | |[http://jco.ascopubs.org/content/14/1/7.long Kirkwood et al. 1996 (ECOG EST 1684)] | ||
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
− | |[[ | + | |[[#Interferon_alfa-2b_monotherapy|Interferon alfa-2b]] |
|style="background-color:#fc8d59"|Seems to have inferior OS | |style="background-color:#fc8d59"|Seems to have inferior OS | ||
|- | |- | ||
|[http://jco.ascopubs.org/content/16/4/1425.long Pehamberger et al. 1998] | |[http://jco.ascopubs.org/content/16/4/1425.long Pehamberger et al. 1998] | ||
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
− | |[[ | + | |[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]] |
|style="background-color:#fc8d59"|Seems to have inferior DFS | |style="background-color:#fc8d59"|Seems to have inferior DFS | ||
|- | |- | ||
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(97)12445-X/fulltext Grob et al. 1998] | |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(97)12445-X/fulltext Grob et al. 1998] | ||
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
− | |[[ | + | |[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]] |
|style="background-color:#fee08b"|Might have inferior OS | |style="background-color:#fee08b"|Might have inferior OS | ||
|- | |- | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363881/ Cameron et al. 2001 (The Scottish study)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2363881/ Cameron et al. 2001 (The Scottish study)] | ||
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
− | |[[ | + | |[[#Interferon_alfa-2b_monotherapy|Interferon alfa-2b]] |
|style="background-color:#ffffbf"|Seems not superior | |style="background-color:#ffffbf"|Seems not superior | ||
|- | |- | ||
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61033-8/fulltext Eggermont et al. 2008 (EORTC 18991)] | |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61033-8/fulltext Eggermont et al. 2008 (EORTC 18991)] | ||
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
− | |[[ | + | |[[#Peginterferon_alfa-2b_monotherapy|Pegylated interferon alfa-2b]] |
|style="background-color:#fc8d59"|Seems to have inferior RFS | |style="background-color:#fc8d59"|Seems to have inferior RFS | ||
|- | |- | ||
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70122-1/fulltext Eggermont et al. 2015 (EORTC 18071)] | |[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70122-1/fulltext Eggermont et al. 2015 (EORTC 18071)] | ||
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
− | |[[ | + | |[[#Ipilimumab_monotherapy|Ipilimumab]] |
|style="background-color:#d73027"|Inferior OS | |style="background-color:#d73027"|Inferior OS | ||
|- | |- | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455684/ Agarwala et al. 2017 (ECOG E1697)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455684/ Agarwala et al. 2017 (ECOG E1697)] | ||
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
− | |[[ | + | |[[#Interferon_alfa-2b_monotherapy|Interferon alfa-2b]] |
|style="background-color:#ffffbf"|Seems not superior | |style="background-color:#ffffbf"|Seems not superior | ||
|- | |- | ||
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**Initially: 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 | **Initially: 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. | **Thereafter: 10<sup>8</sup> pfu/mL SC intralesional injection once every 2 weeks. | ||
− | **Total volume given per treatment session was up to 4.0 mL. | + | **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." |
'''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.''' | '''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.''' | ||
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|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089063/ Kottschade et al. 2013 (N0775)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089063/ Kottschade et al. 2013 (N0775)] | ||
|style="background-color:#00cd00"|Randomized Phase II | |style="background-color:#00cd00"|Randomized Phase II | ||
− | |[[ | + | |[[#Temozolomide_.26_Bevacizumab|Temozolomide & Bevacizumab]] |
|style="background-color:#91cf60"|Seems to have superior PFS6 | |style="background-color:#91cf60"|Seems to have superior PFS6 | ||
|- | |- | ||
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|[http://jco.ascopubs.org/content/27/17/2823.long Hauschild et al. 2009] | |[http://jco.ascopubs.org/content/27/17/2823.long Hauschild et al. 2009] | ||
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
− | |[[ | + | |[[#Carboplatin.2C_Paclitaxel.2C_Sorafenib|Carboplatin, Paclitaxel, Sorafenib]] |
|style="background-color:#ffffbf"|Seems not superior | |style="background-color:#ffffbf"|Seems not superior | ||
|- | |- | ||
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878104/ Flaherty et al. 2013 (ECOG E2603)] | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878104/ Flaherty et al. 2013 (ECOG E2603)] | ||
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
− | |[[ | + | |[[#Carboplatin.2C_Paclitaxel.2C_Sorafenib|Carboplatin, Paclitaxel, Sorafenib]] |
|style="background-color:#ffffbf"|Seems not superior | |style="background-color:#ffffbf"|Seems not superior | ||
|- | |- | ||
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# 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''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645104/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19001327 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''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645104/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19001327 PubMed] | ||
− | == | + | ==Dacarbazine monotherapy {{#subobject:d3599b|Regimen=1}}== |
{| class="wikitable" style="float:right; margin-left: 5px;" | {| class="wikitable" style="float:right; margin-left: 5px;" | ||
|- | |- | ||
|[[#top|back to top]] | |[[#top|back to top]] | ||
|} | |} | ||
− | ===Regimen {{#subobject: | + | ===Example orders=== |
+ | *[[Example orders for Dacarbazine (DTIC) in melanoma]] | ||
+ | |||
+ | ===Regimen #1 {{#subobject:bede4c|Variant=1}}=== | ||
{| border="1" style="text-align:center;" !align="left" | {| border="1" style="text-align:center;" !align="left" | ||
|'''Study''' | |'''Study''' | ||
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|'''Comparator''' | |'''Comparator''' | ||
|[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | |[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549296/ Chapman et al. 2011 (BRIM-3)] | ||
+ | |style="background-color:#00cd00"|Phase III | ||
+ | |[[Melanoma,_BRAF-mutated#Vemurafenib_monotherapy|Vemurafenib]] | ||
+ | |style="background-color:#d73027"|Inferior OS | ||
|- | |- | ||
|[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60868-X/fulltext Hauschild et al. 2012 (BREAK-3)] | |[http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60868-X/fulltext Hauschild et al. 2012 (BREAK-3)] | ||
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
− | |[[Melanoma | + | |[[Melanoma,_BRAF-mutated#Dabrafenib_monotherapy|Dabrafenib]] |
− | |||
− | |||
− | |||
− | |||
− | |||
|style="background-color:#d73027"|Inferior PFS | |style="background-color:#d73027"|Inferior PFS | ||
|- | |- | ||
− | + | |[http://www.nejm.org/doi/full/10.1056/NEJMoa1203421 Flaherty et al. 2012 (METRIC)] | |
− | + | |style="background-color:#00cd00"|Phase III | |
− | + | |[[Melanoma,_BRAF-mutated#Trametinib_monotherapy|Trametinib]] | |
− | |||
− | |||
− | |[http://www.nejm.org/doi/full/10.1056/ | ||
− | |style="background-color:#00cd00"| | ||
− | |[[Melanoma# | ||
|style="background-color:#fc8d59"|Seems to have inferior OS | |style="background-color:#fc8d59"|Seems to have inferior OS | ||
|- | |- | ||
− | | | + | |[http://www.nejm.org/doi/full/10.1056/NEJMoa1412082 Robert et al. 2014 (CheckMate 066)] |
− | + | |style="background-color:#00cd00"|Phase III | |
− | + | |[[#Nivolumab_monotherapy|Nivolumab]] | |
− | + | |style="background-color:#d73027"|Inferior OS | |
− | |||
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− | |[ | + | |[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70076-8/fulltext Weber et al. 2015 (CheckMate 037)] |
− | + | |style="background-color:#00cd00"|Phase III | |
− | + | |[[#Nivolumab_monotherapy|Nivolumab]] | |
− | + | |style="background-color:#d73027"|Inferior ORR | |
− | | | ||
− | |[[ | ||
− | | | ||
− | |||
|- | |- | ||
− | |[ | + | |[http://annonc.oxfordjournals.org/content/26/11/2267.long Hersh et al. 2015] |
− | |style="background-color:#00cd00"| | + | |style="background-color:#00cd00"|Phase III |
− | | | + | |nab-Paclitaxel |
− | |style="background-color:# | + | |style="background-color:#fc8d59"|Seems to have inferior PFS |
|- | |- | ||
− | |[http://www. | + | |[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30180-8/fulltext Dummer et al. 2017 (NEMO)] |
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
− | |[[ | + | |[[Binimetinib_(MEK162)|Binimetinib]] |
− | |style="background-color:# | + | |style="background-color:#d73027"|Inferior PFS |
|- | |- | ||
|} | |} | ||
+ | ''Patients in '''BRIM-3''' had a BRAF p.V600E mutation detected. Patients in '''NEMO''' had NRAS mutations.'' | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Dacarbazine (DTIC)]] 1000 mg/m<sup>2</sup> IV once on day 1 |
− | |||
− | ''' | + | '''21-day cycles, given until progression of disease or unacceptable toxicity''' |
− | === | + | ===Regimen #2 {{#subobject:b6dcb|Variant=1}}=== |
− | + | {| border="1" style="text-align:center;" !align="left" | |
− | + | |'''Study''' | |
− | + | |[[Levels_of_Evidence#Evidence|'''Evidence''']] | |
− | + | |'''Comparator''' | |
− | + | |[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | |
− | + | |- | |
+ | |[http://www.nejm.org/doi/full/10.1056/NEJMoa1104621 Robert et al. 2011 (CA184-024)] | ||
+ | |style="background-color:#00cd00"|Phase III | ||
+ | |[[#Dacarbazine_.26_Ipilimumab|Dacarbazine & Ipilimumab]] | ||
+ | |style="background-color:#d73027"|Inferior OS | ||
|- | |- | ||
− | |||
|} | |} | ||
− | === | + | ====Chemotherapy==== |
− | *[[ | + | *[[Dacarbazine (DTIC)]] 850 mg/m<sup>2</sup> IV once on day 1 |
+ | |||
+ | '''21-day cycle for 8 cycles''' | ||
− | ===Regimen # | + | ===Regimen #3 {{#subobject:4bacb|Variant=1}}=== |
{| border="1" style="text-align:center;" !align="left" | {| border="1" style="text-align:center;" !align="left" | ||
|'''Study''' | |'''Study''' | ||
Line 764: | Line 754: | ||
|[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | |[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | ||
|- | |- | ||
− | |[ | + | |[http://jco.ascopubs.org/content/18/1/158.long Middleton et al. 2000] |
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
− | |[[ | + | |[[#Temozolomide_monotherapy|Temozolomide]] |
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|style="background-color:#fc8d59"|Seems to have inferior PFS | |style="background-color:#fc8d59"|Seems to have inferior PFS | ||
− | |||
− | |||
− | |||
− | |||
− | |||
|- | |- | ||
|} | |} | ||
− | |||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Dacarbazine (DTIC)]] | + | *[[Dacarbazine (DTIC)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5 |
'''21-day cycles, given until progression of disease or unacceptable toxicity''' | '''21-day cycles, given until progression of disease or unacceptable toxicity''' | ||
− | ===Regimen # | + | ===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. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. [http://jco.ascopubs.org/content/18/1/158.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10623706 PubMed] | ||
+ | # 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''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549296/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21639808 PubMed] | ||
+ | ## '''Update:''' McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, Ribas A, Hogg D, Hamid O, Ascierto PA, Garbe C, Testori A, Maio M, Lorigan P, Lebbé C, Jouary T, Schadendorf D, O'Day SJ, Kirkwood JM, Eggermont AM, Dréno B, Sosman JA, Flaherty KT, Yin M, Caro I, Cheng S, Trunzer K, Hauschild A. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014 Mar;15(3):323-32. Epub 2014 Feb 7. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382632/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24508103 PubMed] | ||
+ | # 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''' [https://www.ncbi.nlm.nih.gov/pubmed/21639810 PubMed] | ||
+ | ## '''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. [http://jco.ascopubs.org/content/33/10/1191.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25713437 PubMed] | ||
+ | # 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/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22735384 PubMed] | ||
+ | # 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''' [https://www.ncbi.nlm.nih.gov/pubmed/22663011 PubMed] | ||
+ | # 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''' [https://www.ncbi.nlm.nih.gov/pubmed/25399552 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] [https://www.ncbi.nlm.nih.gov/pubmed/25795410 PubMed] | ||
+ | # 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. [http://annonc.oxfordjournals.org/content/26/11/2267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26410620 PubMed] | ||
+ | # Dummer R, Schadendorf D, Ascierto PA, Arance A, Dutriaux C, Di Giacomo AM, Rutkowski P, Del Vecchio M, Gutzmer R, Mandala M, Thomas L, Demidov L, Garbe C, Hogg D, Liszkay G, Queirolo P, Wasserman E, Ford J, Weill M, Sirulnik LA, Jehl V, Bozón V, Long GV, Flaherty K. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Apr;18(4):435-445. Epub 2017 Mar 8. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30180-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28284557 PubMed] | ||
+ | |||
+ | ==Dacarbazine & Ipilimumab {{#subobject:5754a8|Regimen=1}}== | ||
+ | {| class="wikitable" style="float:right; margin-left: 5px;" | ||
+ | |- | ||
+ | |[[#top|back to top]] | ||
+ | |} | ||
+ | ===Regimen {{#subobject:7b4884|Variant=1}}=== | ||
{| border="1" style="text-align:center;" !align="left" | {| border="1" style="text-align:center;" !align="left" | ||
|'''Study''' | |'''Study''' | ||
Line 815: | Line 792: | ||
|[http://www.nejm.org/doi/full/10.1056/NEJMoa1104621 Robert et al. 2011 (CA184-024)] | |[http://www.nejm.org/doi/full/10.1056/NEJMoa1104621 Robert et al. 2011 (CA184-024)] | ||
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
− | |[[ | + | |[[#Dacarbazine_monotherapy|Dacarbazine]] |
− | |style="background-color:# | + | |style="background-color:#1a9850"|Superior OS |
|- | |- | ||
|} | |} | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
+ | *[[Ipilimumab (Yervoy)]] as follows: | ||
+ | **Cycles 1 to 4: 10 mg/kg IV once on day 1 | ||
*[[Dacarbazine (DTIC)]] 850 mg/m<sup>2</sup> IV once on day 1 | *[[Dacarbazine (DTIC)]] 850 mg/m<sup>2</sup> IV once on day 1 | ||
'''21-day cycle for 8 cycles''' | '''21-day cycle for 8 cycles''' | ||
− | ===Regimen # | + | ''If patient has stable disease or objective response, proceed to [[#Ipilimumab_monotherapy_3|maintenance ipilimumab]].'' |
+ | |||
+ | ===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''' [https://www.ncbi.nlm.nih.gov/pubmed/21639810 PubMed] | ||
+ | ## '''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. [http://jco.ascopubs.org/content/33/10/1191.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25713437 PubMed] | ||
+ | |||
+ | ==Docetaxel monotherapy {{#subobject:bd3e54|Regimen=1}}== | ||
+ | {| class="wikitable" style="float:right; margin-left: 5px;" | ||
+ | |- | ||
+ | |[[#top|back to top]] | ||
+ | |} | ||
+ | |||
+ | ===Regimen {{#subobject:46549|Variant=1}}=== | ||
{| border="1" style="text-align:center;" !align="left" | {| border="1" style="text-align:center;" !align="left" | ||
|'''Study''' | |'''Study''' | ||
|[[Levels_of_Evidence#Evidence|'''Evidence''']] | |[[Levels_of_Evidence#Evidence|'''Evidence''']] | ||
− | |||
− | |||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pubmed/7654429 Aamdal et al. 1994] |
− | |style="background-color:# | + | |style="background-color:#eeee00"|Phase II |
− | |||
− | |||
|- | |- | ||
|} | |} | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1 |
+ | |||
+ | ====Supportive medications==== | ||
+ | *"No prophylactic treatment with steroids or antihistamines was given." | ||
− | '''21-day cycles | + | '''21-day cycles''' |
===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''' [https://www.ncbi.nlm.nih.gov/pubmed/7654429 PubMed] |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | == | + | ==High-dose (HD) IL-2 {{#subobject:771c23|Regimen=1}}== |
{| class="wikitable" style="float:right; margin-left: 5px;" | {| class="wikitable" style="float:right; margin-left: 5px;" | ||
|- | |- | ||
|[[#top|back to top]] | |[[#top|back to top]] | ||
|} | |} | ||
− | ===Regimen {{#subobject: | + | |
+ | ===Example orders=== | ||
+ | *[[Example orders for High-dose (HD) IL-2 in melanoma]] | ||
+ | |||
+ | ===Regimen {{#subobject:4efbce|Variant=1}}=== | ||
{| border="1" style="text-align:center;" !align="left" | {| border="1" style="text-align:center;" !align="left" | ||
|'''Study''' | |'''Study''' | ||
|[[Levels_of_Evidence#Evidence|'''Evidence''']] | |[[Levels_of_Evidence#Evidence|'''Evidence''']] | ||
− | |||
− | |||
|- | |- | ||
− | |[http:// | + | |[http://jco.ascopubs.org/content/17/7/2105.long Atkins et al. 1999] |
− | |style="background-color:# | + | |style="background-color:#eeee00"|Phase II |
− | |||
− | |||
|- | |- | ||
|} | |} | ||
− | ==== | + | ====Immunotherapy==== |
− | *[[ | + | *[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 600,000 or 720,000 units/kg IV 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 | |
− | * | ||
− | ''' | + | '''6 to 12 weeks per cycle for up to 5 cycles''' |
− | + | ====Supportive medications==== | |
+ | *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. | ||
===References=== | ===References=== | ||
− | # | + | # 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] [https://www.ncbi.nlm.nih.gov/pubmed/8120958 PubMed] |
− | ## '''Update:''' | + | # 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''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/10685652 PubMed] | ||
− | == | + | ==Imatinib monotherapy {{#subobject:8686d5|Regimen=1}}== |
{| class="wikitable" style="float:right; margin-left: 5px;" | {| class="wikitable" style="float:right; margin-left: 5px;" | ||
|- | |- | ||
|[[#top|back to top]] | |[[#top|back to top]] | ||
|} | |} | ||
− | + | ===Regimen #1 {{#subobject:662612|Variant=1}}=== | |
− | ===Regimen {{#subobject: | ||
{| border="1" style="text-align:center;" !align="left" | {| border="1" style="text-align:center;" !align="left" | ||
|'''Study''' | |'''Study''' | ||
|[[Levels_of_Evidence#Evidence|'''Evidence''']] | |[[Levels_of_Evidence#Evidence|'''Evidence''']] | ||
|- | |- | ||
− | |[https://www.ncbi.nlm.nih.gov/ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878082/ Hodi et al. 2013] |
|style="background-color:#eeee00"|Phase II | |style="background-color:#eeee00"|Phase II | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | ''Patients had melanomas arising from mucosal, acral, and chronically sun-damaged skin with KIT mutations or amplifications.'' |
− | *[[ | + | ====Starting dose==== |
+ | *[[Imatinib (Gleevec)]] 400 mg PO once per day | ||
− | + | '''Given until disease progression; then proceed to higher dose:''' | |
− | |||
− | + | ====Higher dose==== | |
+ | *[[Imatinib (Gleevec)]] 400 mg PO BID | ||
− | + | '''Given until disease progression''' | |
− | |||
− | == | + | ===Regimen #2 {{#subobject:d1f61b|Variant=1}}=== |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
{| border="1" style="text-align:center;" !align="left" | {| border="1" style="text-align:center;" !align="left" | ||
|'''Study''' | |'''Study''' | ||
|[[Levels_of_Evidence#Evidence|'''Evidence''']] | |[[Levels_of_Evidence#Evidence|'''Evidence''']] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986039/ Carvajal et al. 2011] |
|style="background-color:#eeee00"|Phase II | |style="background-color:#eeee00"|Phase II | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | ''Patients had melanomas arising from mucosal, acral, and chronically sun-damaged skin with KIT mutations or amplifications.'' |
− | *[[ | + | ====Chemotherapy==== |
− | + | *[[Imatinib (Gleevec)]] 400 mg PO BID | |
− | ''' | + | '''Given until disease progression''' |
− | |||
− | |||
− | |||
===References=== | ===References=== | ||
− | # | + | # Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman RA, Teitcher J, Panageas KS, Busam KJ, Chmielowski B, Lutzky J, Pavlick AC, Fusco A, Cane L, Takebe N, Vemula S, Bouvier N, Bastian BC, Schwartz GK. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011 Jun 8;305(22):2327-34. '''contains protocol'' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986039/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21642685 PubMed] |
− | # | + | # 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 Sep 10;31(26):3182-90. Epub 2013 Jun 17. [http://jco.ascopubs.org/content/31/26/3182.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878082/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23775962 PubMed] |
− | |||
− | == | + | ==Ipilimumab monotherapy {{#subobject:fab3f4|Regimen=1}}== |
{| class="wikitable" style="float:right; margin-left: 5px;" | {| class="wikitable" style="float:right; margin-left: 5px;" | ||
|- | |- | ||
|[[#top|back to top]] | |[[#top|back to top]] | ||
|} | |} | ||
− | ===Regimen #1 {{#subobject: | + | |
+ | ===Example orders=== | ||
+ | *[[Example orders for Ipilimumab (Yervoy) in melanoma]] | ||
+ | |||
+ | ===Regimen #1 {{#subobject:33786a|Variant=1}}=== | ||
{| border="1" style="text-align:center;" !align="left" | {| border="1" style="text-align:center;" !align="left" | ||
|'''Study''' | |'''Study''' | ||
|[[Levels_of_Evidence#Evidence|'''Evidence''']] | |[[Levels_of_Evidence#Evidence|'''Evidence''']] | ||
+ | |'''Comparator''' | ||
+ | |[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | ||
+ | |[[Levels_of_Evidence#Toxicity|'''Toxicity''']] | ||
|- | |- | ||
− | |[https://www.ncbi.nlm.nih.gov/pmc/articles/ | + | |rowspan=2 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549297/ Hodi et al. 2010 (MDX010-20)] |
− | |style="background-color:# | + | |rowspan=2 style="background-color:#00cd00"|Phase III |
+ | |Ipilimumab & gp100 peptide vaccine | ||
+ | |style="background-color:#ffffbf"|Seems not superior | ||
+ | |style="background-color:#d3d3d3"| | ||
|- | |- | ||
− | | | + | |gp100 peptide vaccine |
− | + | |style="background-color:#1a9850"|Superior OS | |
− | + | |style="background-color:#d3d3d3"| | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
|- | |- | ||
− | |[ | + | |rowspan=2|[http://www.nejm.org/doi/full/10.1056/NEJMoa1503093 Robert et al. 2015 (KEYNOTE-006)] |
− | |style="background-color:# | + | |rowspan=2 style="background-color:#00cd00"|Phase III |
+ | |[[#Pembrolizumab_monotherapy|Pembrolizumab 10 mg/kg q2wks]] | ||
+ | |style="background-color:#d73027"|Inferior OS | ||
+ | |style="background-color:#d3d3d3"| | ||
|- | |- | ||
− | | | + | |[[#Pembrolizumab_monotherapy|Pembrolizumab 10 mg/kg q3wks]] |
− | + | |style="background-color:#d73027"|Inferior OS | |
− | ==== | + | |style="background-color:#d3d3d3"| |
− | *[[ | + | |- |
+ | |[http://www.nejm.org/doi/full/10.1056/NEJMoa1414428 Postow et al. 2015 (CheckMate 069)] | ||
+ | |style="background-color:#00cd00"|Phase III | ||
+ | |[[#Ipilimumab_.26_Nivolumab|Ipilimumab & Nivolumab]] | ||
+ | |style="background-color:#d73027"|Inferior PFS | ||
+ | |style="background-color:#d3d3d3"| | ||
+ | |- | ||
+ | |rowspan=2 |[http://www.nejm.org/doi/full/10.1056/NEJMoa1504030 Larkin et al. 2015 (CheckMate 067)] | ||
+ | |rowspan=2 style="background-color:#00cd00"|Phase III | ||
+ | |[[#Ipilimumab_.26_Nivolumab|Ipilimumab & Nivolumab]] | ||
+ | |style="background-color:#d73027"|Inferior PFS | ||
+ | |style="background-color:#eeee00"|Equivalent HRQoL | ||
+ | |- | ||
+ | |[[#Nivolumab_monotherapy|Nivolumab]] | ||
+ | |style="background-color:#d73027"|Inferior PFS | ||
+ | |style="background-color:#eeee00"|Equivalent HRQoL | ||
+ | |- | ||
+ | |} | ||
+ | ====Immunotherapy==== | ||
+ | *[[Ipilimumab (Yervoy)]] 3 mg/kg IV once on day 1 | ||
− | ''' | + | '''21-day cycle for 4 cycles''' |
− | + | ===Regimen #2 {{#subobject:7e975b|Variant=1}}=== | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | ===Regimen # | ||
{| border="1" style="text-align:center;" !align="left" | {| border="1" style="text-align:center;" !align="left" | ||
|'''Study''' | |'''Study''' | ||
|[[Levels_of_Evidence#Evidence|'''Evidence''']] | |[[Levels_of_Evidence#Evidence|'''Evidence''']] | ||
− | |||
− | |||
− | |||
|- | |- | ||
− | + | |[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970334-1/fulltext Wolchok et al. 2010] | |
− | | | + | |style="background-color:#eeee00"|Phase II |
− | |||
− | |||
− | |||
|- | |- | ||
− | | | + | |[http://annonc.oxfordjournals.org/content/21/8/1712.long O'Day et al. 2010] |
− | + | |style="background-color:#eeee00"|Phase II | |
− | |style="background-color:# | ||
|- | |- | ||
− | + | |[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70090-6/abstract Margolin et al. 2012] | |
− | | | + | |style="background-color:#eeee00"|Phase II |
− | |||
− | |||
− | |||
|- | |- | ||
− | |[[ | + | |} |
− | + | ''Note: In '''Wolchok et al. 2010''', lower doses including 3 mg/kg (the FDA approved dose) were investigated, but the 10 mg/kg dose was recommended.'' | |
− | + | ====Immunotherapy==== | |
− | + | *[[Ipilimumab (Yervoy)]] 10 mg/kg IV over 90 minutes once on day 1 | |
− | + | ||
− | |style=" | + | '''21-day cycle for 4 cycles''' |
− | |[[# | + | |
− | | | + | ''Patients in '''O'Day et al. 2010''' and '''Margolin et al. 2012''' who were clinically stable could proceed to [[#Ipilimumab_monotherapy_3|ipilimumab maintenance]].'' |
− | |style=" | + | |
+ | ===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''' [https://www.ncbi.nlm.nih.gov/pubmed/20004617 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. Erratum in: N Engl J Med. 2010 Sep 23;363(13):1290. [http://www.nejm.org/doi/full/10.1056/NEJMoa1003466 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549297/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20525992 PubMed] | ||
+ | ## '''Update:''' 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. [http://annonc.oxfordjournals.org/content/24/10/2694.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23942774 PubMed] | ||
+ | # 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''' [https://www.ncbi.nlm.nih.gov/pubmed/20147741 PubMed] | ||
+ | # 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. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70090-6/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22456429 PubMed] | ||
+ | # 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''' [https://www.ncbi.nlm.nih.gov/pubmed/25891173 PubMed] | ||
+ | ## '''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 Aug 16. [Epub ahead of print] [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31601-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28822576 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] [https://www.ncbi.nlm.nih.gov/pubmed/25891304 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. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30366-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27622997 PubMed] | ||
+ | # 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1504030 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26027431 PubMed] | ||
+ | ## '''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. [http://www.ejcancer.com/article/S0959-8049(17)30995-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28651159 PubMed] | ||
+ | |||
+ | ==Ipilimumab & Nivolumab {{#subobject:517ff0|Regimen=1}}== | ||
+ | {| class="wikitable" style="float:right; margin-left: 5px;" | ||
+ | |- | ||
+ | |[[#top|back to top]] | ||
+ | |} | ||
+ | ===Regimen #1 {{#subobject:3a481c|Variant=1}}=== | ||
+ | {| border="1" style="text-align:center;" !align="left" | ||
+ | |'''Study''' | ||
+ | |[[Levels_of_Evidence#Evidence|'''Evidence''']] | ||
+ | |'''Comparator''' | ||
+ | |[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | ||
+ | |[[Levels_of_Evidence#Toxicity|'''Toxicity''']] | ||
|- | |- | ||
|rowspan=2 |[http://www.nejm.org/doi/full/10.1056/NEJMoa1504030 Larkin et al. 2015 (CheckMate 067)] | |rowspan=2 |[http://www.nejm.org/doi/full/10.1056/NEJMoa1504030 Larkin et al. 2015 (CheckMate 067)] | ||
|rowspan=2 style="background-color:#00cd00"|Phase III | |rowspan=2 style="background-color:#00cd00"|Phase III | ||
− | |[[# | + | |[[#Ipilimumab_monotherapy_2|Ipilimumab]] |
− | |style="background-color:# | + | |style="background-color:#1a9850"|Superior PFS |
|style="background-color:#eeee00"|Equivalent HRQoL | |style="background-color:#eeee00"|Equivalent HRQoL | ||
|- | |- | ||
|[[#Nivolumab_monotherapy|Nivolumab]] | |[[#Nivolumab_monotherapy|Nivolumab]] | ||
− | |style="background-color:# | + | |style="background-color:#1a9850"|Superior PFS |
|style="background-color:#eeee00"|Equivalent HRQoL | |style="background-color:#eeee00"|Equivalent HRQoL | ||
|- | |- | ||
|} | |} | ||
− | ====Immunotherapy==== | + | ====Immunotherapy, part 1==== |
*[[Ipilimumab (Yervoy)]] 3 mg/kg IV once on day 1 | *[[Ipilimumab (Yervoy)]] 3 mg/kg IV once on day 1 | ||
+ | *[[Nivolumab (Opdivo)]] 1 mg/kg IV once on day 1 | ||
+ | |||
+ | '''21-day cycle for 4 cycles, followed by:''' | ||
− | ''' | + | ====Immunotherapy, part 2==== |
+ | *[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1 | ||
+ | **Notably, on 9/13/16 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. | ||
+ | |||
+ | '''14-day cycles''' | ||
− | ===Regimen #2 {{#subobject: | + | ===Regimen #2 {{#subobject:fa55a8|Variant=1}}=== |
{| border="1" style="text-align:center;" !align="left" | {| border="1" style="text-align:center;" !align="left" | ||
|'''Study''' | |'''Study''' | ||
|[[Levels_of_Evidence#Evidence|'''Evidence''']] | |[[Levels_of_Evidence#Evidence|'''Evidence''']] | ||
+ | |'''Comparator''' | ||
+ | |[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | ||
|- | |- | ||
− | |[http://www. | + | |[http://www.nejm.org/doi/full/10.1056/NEJMoa1414428 Postow et al. 2015 (CheckMate 069)] |
− | |style="background-color:# | + | |style="background-color:#00cd00"|Phase III |
− | + | |[[#Ipilimumab_monotherapy_2|Ipilimumab]] | |
− | |[ | + | |style="background-color:#1a9850"|Superior PFS |
− | |||
− | |||
− | |||
− | |style="background-color:# | ||
− | |||
|} | |} | ||
− | '' | + | ''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."'' |
− | ====Immunotherapy==== | + | ====Immunotherapy, part 1==== |
− | *[[ | + | *[[Ipilimumab (Yervoy)]] 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, followed by:''' | ||
+ | |||
+ | ====Immunotherapy, part 2==== | ||
+ | *[[Nivolumab (Opdivo)]] 1 mg/kg IV once on day 1 | ||
'''21-day cycle for 4 cycles''' | '''21-day cycle for 4 cycles''' | ||
− | '' | + | ''Treatment followed by [[#Ipilimumab_.26_Nivolumab_2|ipilimumab & nivolumab maintenance]].'' |
===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] [https://www.ncbi.nlm.nih.gov/pubmed/23724867 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] [https://www.ncbi.nlm.nih.gov/pubmed/25891304 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] [https://www.ncbi.nlm.nih.gov/pubmed/25891304 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. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30366-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27622997 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. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30366-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27622997 PubMed] | ||
Line 1,083: | Line 1,075: | ||
## '''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. [http://www.ejcancer.com/article/S0959-8049(17)30995-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28651159 PubMed] | ## '''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. [http://www.ejcancer.com/article/S0959-8049(17)30995-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28651159 PubMed] | ||
− | ==Ipilimumab | + | ==Ipilimumab, then Nivolumab {{#subobject:184810|Regimen=1}}== |
{| class="wikitable" style="float:right; margin-left: 5px;" | {| class="wikitable" style="float:right; margin-left: 5px;" | ||
|- | |- | ||
|[[#top|back to top]] | |[[#top|back to top]] | ||
|} | |} | ||
− | ===Regimen | + | ===Regimen {{#subobject:8347ab|Variant=1}}=== |
{| border="1" style="text-align:center;" !align="left" | {| border="1" style="text-align:center;" !align="left" | ||
|'''Study''' | |'''Study''' | ||
Line 1,094: | Line 1,086: | ||
|'''Comparator''' | |'''Comparator''' | ||
|[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | |[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | ||
− | |||
|- | |- | ||
− | + | |[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30126-7/fulltext Weber et al. 2016 (CheckMate 064)] | |
− | | | + | |style="background-color:#00cd00"|Randomized Phase II |
− | |[[# | + | |[[#Nivolumab.2C_then_Ipilimumab|Nivolumab, then Ipilimumab]] |
− | |style="background-color:# | + | |style="background-color:#fc8d59"|Seems to have inferior OS |
− | |||
− | |||
− | |||
− | |||
− | |||
|- | |- | ||
|} | |} | ||
====Immunotherapy, part 1==== | ====Immunotherapy, part 1==== | ||
*[[Ipilimumab (Yervoy)]] 3 mg/kg IV once on day 1 | *[[Ipilimumab (Yervoy)]] 3 mg/kg IV once on day 1 | ||
− | |||
'''21-day cycle for 4 cycles, followed by:''' | '''21-day cycle for 4 cycles, followed by:''' | ||
Line 1,117: | Line 1,102: | ||
**Notably, on 9/13/16 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. | **Notably, on 9/13/16 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. | ||
− | '''14-day cycles''' | + | '''14-day cycle for 6 cycles''' |
+ | |||
+ | ''Treatment followed by [[#Nivolumab_monotherapy_2|maintenance nivolumab]].'' | ||
− | ===Regimen # | + | ===References=== |
− | {| border="1" style="text-align:center;" !align="left" | + | # 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. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30126-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474305/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27269740 PubMed] |
− | |'''Study''' | + | |
+ | ==Nivolumab monotherapy {{#subobject:6a44dd|Regimen=1}}== | ||
+ | {| class="wikitable" style="float:right; margin-left: 5px;" | ||
+ | |- | ||
+ | |[[#top|back to top]] | ||
+ | |} | ||
+ | ===Regimen #1 {{#subobject:722e51|Variant=1}}=== | ||
+ | {| border="1" style="text-align:center;" !align="left" | ||
+ | |'''Study''' | ||
|[[Levels_of_Evidence#Evidence|'''Evidence''']] | |[[Levels_of_Evidence#Evidence|'''Evidence''']] | ||
|'''Comparator''' | |'''Comparator''' | ||
|[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | |[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | ||
+ | |[[Levels_of_Evidence#Toxicity|'''Toxicity''']] | ||
|- | |- | ||
− | |[http://www.nejm.org/doi/full/10.1056/ | + | |[http://www.nejm.org/doi/full/10.1056/NEJMoa1412082 Robert et al. 2014 (CheckMate 066)] |
+ | |style="background-color:#00cd00"|Phase III | ||
+ | |[[#Dacarbazine_monotherapy|Dacarbazine]] | ||
+ | |style="background-color:#1a9850"|Superior OS | ||
+ | | | ||
+ | |- | ||
+ | |[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70076-8/fulltext Weber et al. 2015 (CheckMate 037)] | ||
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
+ | |[[#Dacarbazine_monotherapy|Dacarbazine]]<br> [[#Carboplatin_.26_Paclitaxel|Carboplatin & Paclitaxel]] | ||
+ | |style="background-color:#1a9850"|Superior ORR | ||
+ | | | ||
+ | |- | ||
+ | |rowspan=2 |[http://www.nejm.org/doi/full/10.1056/NEJMoa1504030 Larkin et al. 2015 (CheckMate 067)] | ||
+ | |rowspan=2 style="background-color:#00cd00"|Phase III | ||
|[[#Ipilimumab_monotherapy_2|Ipilimumab]] | |[[#Ipilimumab_monotherapy_2|Ipilimumab]] | ||
|style="background-color:#1a9850"|Superior PFS | |style="background-color:#1a9850"|Superior PFS | ||
− | | | + | |style="background-color:#eeee00"|Equivalent HRQoL |
− | + | |- | |
− | ====Immunotherapy | + | |[[#Ipilimumab_.26_Nivolumab|Ipilimumab & Nivolumab]] |
− | *[[ | + | |style="background-color:#d73027"|Inferior PFS |
− | *[ | + | |style="background-color:#eeee00"|Equivalent HRQoL |
+ | |- | ||
+ | |} | ||
+ | ====Immunotherapy==== | ||
+ | *[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1 | ||
+ | **Notably, on 9/13/16 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. | ||
− | ''' | + | '''14-day cycles, given until progression of disease or unacceptable toxicity''' |
− | + | ||
− | ====Immunotherapy | + | ===Regimen #2 {{#subobject:1ec35|Variant=1}}=== |
− | *[[Nivolumab (Opdivo)]] | + | {| border="1" style="text-align:center;" !align="left" |
− | + | |'''Study''' | |
− | ''' | + | |[[Levels_of_Evidence#Evidence|'''Evidence''']] |
− | + | |- | |
− | ''Treatment followed by [[# | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837092/ Weber et al. 2013] |
+ | |style="background-color:#ff0000"|Phase I | ||
+ | |- | ||
+ | |} | ||
+ | ====Immunotherapy==== | ||
+ | *[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1 | ||
+ | **Notably, on 9/13/16 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. | ||
+ | |||
+ | '''14-day cycle for 12 cycles | ||
+ | |||
+ | ''Treatment followed by [[#Nivolumab_monotherapy_2|maintenance nivolumab]].'' | ||
===References=== | ===References=== | ||
− | # '''Phase I:''' | + | # '''Phase I:''' 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. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837092/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24145345 PubMed] |
− | # | + | # 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''' [https://www.ncbi.nlm.nih.gov/pubmed/25399552 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] [https://www.ncbi.nlm.nih.gov/pubmed/25795410 PubMed] |
# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1504030 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26027431 PubMed] | # 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1504030 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26027431 PubMed] | ||
## '''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. [http://www.ejcancer.com/article/S0959-8049(17)30995-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28651159 PubMed] | ## '''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. [http://www.ejcancer.com/article/S0959-8049(17)30995-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28651159 PubMed] | ||
− | == | + | ==Nivolumab, then Ipilimumab {{#subobject:1145b9|Regimen=1}}== |
{| class="wikitable" style="float:right; margin-left: 5px;" | {| class="wikitable" style="float:right; margin-left: 5px;" | ||
|- | |- | ||
|[[#top|back to top]] | |[[#top|back to top]] | ||
|} | |} | ||
− | ===Regimen {{#subobject: | + | ===Regimen {{#subobject:61d1da|Variant=1}}=== |
{| border="1" style="text-align:center;" !align="left" | {| border="1" style="text-align:center;" !align="left" | ||
|'''Study''' | |'''Study''' | ||
Line 1,166: | Line 1,189: | ||
|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30126-7/fulltext Weber et al. 2016 (CheckMate 064)] | |[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30126-7/fulltext Weber et al. 2016 (CheckMate 064)] | ||
|style="background-color:#00cd00"|Randomized Phase II | |style="background-color:#00cd00"|Randomized Phase II | ||
− | |[[# | + | |[[#Ipilimumab.2C_then_Nivolumab|Ipilimumab, then Nivolumab]] |
− | |style="background-color:# | + | |style="background-color:#91cf60"|Seems to have superior OS |
|- | |- | ||
|} | |} | ||
====Immunotherapy, part 1==== | ====Immunotherapy, part 1==== | ||
− | *[[ | + | *[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1 |
+ | **Notably, on 9/13/16 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. | ||
− | ''' | + | '''14-day cycle for 6 cycles, followed by:''' |
====Immunotherapy, part 2==== | ====Immunotherapy, part 2==== | ||
− | *[[ | + | *[[Ipilimumab (Yervoy)]] 3 mg/kg IV once on day 1 |
− | |||
− | ''' | + | '''21-day cycle for 4 cycles''' |
''Treatment followed by [[#Nivolumab_monotherapy_2|maintenance nivolumab]].'' | ''Treatment followed by [[#Nivolumab_monotherapy_2|maintenance nivolumab]].'' | ||
Line 1,186: | Line 1,209: | ||
# 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. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30126-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474305/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27269740 PubMed] | # 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. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30126-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474305/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27269740 PubMed] | ||
− | == | + | ==Paclitaxel monotherapy {{#subobject:bfd5b|Regimen=1}}== |
{| class="wikitable" style="float:right; margin-left: 5px;" | {| class="wikitable" style="float:right; margin-left: 5px;" | ||
|- | |- | ||
|[[#top|back to top]] | |[[#top|back to top]] | ||
|} | |} | ||
− | ===Regimen #1 {{#subobject: | + | |
+ | ===Example orders=== | ||
+ | *[[Example orders for Paclitaxel (Taxol) in melanoma]] | ||
+ | |||
+ | ===Regimen #1 {{#subobject:100b77|Variant=1}}=== | ||
{| border="1" style="text-align:center;" !align="left" | {| border="1" style="text-align:center;" !align="left" | ||
|'''Study''' | |'''Study''' | ||
Line 1,197: | Line 1,224: | ||
|'''Comparator''' | |'''Comparator''' | ||
|[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | |[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | ||
− | |||
|- | |- | ||
− | |[http://www.nejm.org/doi/full/10.1056/ | + | |[http://www.nejm.org/doi/full/10.1056/NEJMoa1203421 Flaherty et al. 2012 (METRIC)] |
|style="background-color:#00cd00"|Phase III | |style="background-color:#00cd00"|Phase III | ||
− | |[[Melanoma# | + | |[[Melanoma,_BRAF-mutated#Trametinib_monotherapy|Trametinib]] |
− | |style="background-color:# | + | |style="background-color:#fc8d59"|Seems to have inferior OS |
− | |||
|- | |- | ||
− | | | + | |} |
− | + | ''This was a therapy option for patients in the control arm of METRIC.'' | |
− | + | ====Chemotherapy==== | |
− | + | *[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1 | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | ==== | ||
− | *[[ | ||
− | |||
− | ''' | + | '''21-day cycles''' |
− | ===Regimen #2 {{#subobject: | + | ===Regimen #2 {{#subobject:d13282|Variant=1}}=== |
{| border="1" style="text-align:center;" !align="left" | {| border="1" style="text-align:center;" !align="left" | ||
|'''Study''' | |'''Study''' | ||
|[[Levels_of_Evidence#Evidence|'''Evidence''']] | |[[Levels_of_Evidence#Evidence|'''Evidence''']] | ||
+ | |'''Comparator''' | ||
+ | |[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | ||
|- | |- | ||
− | |[ | + | |[http://jco.ascopubs.org/content/31/9/1211.long O'Day et al. 2013 (SYMMETRY)] |
− | |style="background-color:# | + | |style="background-color:#00cd00"|Phase III |
+ | |Elesclomol & Paclitaxel | ||
+ | |style="background-color:#ffffbf"|Seems not superior | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | ''This was the control arm of SYMMETRY, which was a negative study.'' |
− | *[[ | + | ====Chemotherapy==== |
− | + | *[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15 | |
− | ''' | + | '''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''' [https://www.ncbi.nlm.nih.gov/pubmed/22663011 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''' [https://www.ncbi.nlm.nih.gov/pubmed/23401447 PubMed] | |
− | # | ||
− | |||
− | |||
− | == | + | ==Paclitaxel, nanoparticle albumin-bound monotherapy {{#subobject:1748f5|Regimen=1}}== |
{| class="wikitable" style="float:right; margin-left: 5px;" | {| class="wikitable" style="float:right; margin-left: 5px;" | ||
|- | |- | ||
|[[#top|back to top]] | |[[#top|back to top]] | ||
|} | |} | ||
− | ===Regimen {{#subobject: | + | ===Regimen #1 {{#subobject:df0a74|Variant=1}}=== |
{| border="1" style="text-align:center;" !align="left" | {| border="1" style="text-align:center;" !align="left" | ||
|'''Study''' | |'''Study''' | ||
Line 1,264: | Line 1,272: | ||
|[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | |[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | ||
|- | |- | ||
− | |[http:// | + | |[http://onlinelibrary.wiley.com/doi/10.1002/cncr.24720/abstract Hersh et al. 2012] |
− | |style="background-color:#00cd00"| | + | |style="background-color:#eeee00"|Phase II |
− | |[[# | + | |style="background-color:#d3d3d3"| |
− | |style="background-color:#91cf60"|Seems to have superior | + | |style="background-color:#d3d3d3"| |
+ | |- | ||
+ | |[http://annonc.oxfordjournals.org/content/26/11/2267.long Hersh et al. 2015] | ||
+ | |style="background-color:#00cd00"|Phase III | ||
+ | |[[#Dacarbazine_monotherapy|Dacarbazine]] | ||
+ | |style="background-color:#91cf60"|Seems to have superior PFS | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | ====Chemotherapy==== |
− | *[[ | + | *[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 150 mg/m<sup>2</sup> IV once per day on days 1, 8, 15 |
− | |||
− | ''' | + | '''28-day cycles''' |
− | ==== | + | ===Regimen #2 {{#subobject:f13d6e|Variant=1}}=== |
− | *[[ | + | {| border="1" style="text-align:center;" !align="left" |
− | + | |'''Study''' | |
− | ''' | + | |[[Levels_of_Evidence#Evidence|'''Evidence''']] |
− | + | |- | |
− | + | |[http://onlinelibrary.wiley.com/doi/10.1002/cncr.24720/abstract Hersh et al. 2012] | |
+ | |style="background-color:#eeee00"|Phase II | ||
+ | |- | ||
+ | |} | ||
+ | ''Note: this dose was intended for previously treated patients.'' | ||
+ | ====Chemotherapy==== | ||
+ | *[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15 | ||
+ | |||
+ | '''28-day cycles''' | ||
===References=== | ===References=== | ||
− | # | + | # 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. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.24720/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19877111 PubMed] |
+ | # 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. [http://annonc.oxfordjournals.org/content/26/11/2267.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26410620 PubMed] | ||
− | == | + | ==Pembrolizumab monotherapy {{#subobject:78d8cc|Regimen=1}}== |
{| class="wikitable" style="float:right; margin-left: 5px;" | {| class="wikitable" style="float:right; margin-left: 5px;" | ||
|- | |- | ||
Line 1,292: | Line 1,313: | ||
|} | |} | ||
− | + | ===Regimen #1, 10 mg/kg q2wk {{#subobject:2829cd|Variant=1}}=== | |
− | |||
− | |||
− | ===Regimen #1 {{#subobject: | ||
{| border="1" style="text-align:center;" !align="left" | {| border="1" style="text-align:center;" !align="left" | ||
|'''Study''' | |'''Study''' | ||
Line 1,302: | Line 1,320: | ||
|[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | |[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | ||
|- | |- | ||
− | |[http://www.nejm.org/doi/full/10.1056/ | + | |rowspan=2|[http://www.nejm.org/doi/full/10.1056/NEJMoa1503093 Robert et al. 2015 (KEYNOTE-006)] |
− | |style="background-color:#00cd00"|Phase III | + | |rowspan=2 style="background-color:#00cd00"|Phase III |
− | |[[ | + | |[[#Ipilimumab_monotherapy_2|Ipilimumab]] |
− | |style="background-color:# | + | |style="background-color:#1a9850"|Superior OS |
|- | |- | ||
− | |} | + | |Pembrolizumab 10 mg/kg q3wk |
− | + | |style="background-color:#ffffbf"|Seems not superior | |
− | ==== | + | |- |
− | *[[ | + | |} |
+ | ====Immunotherapy==== | ||
+ | *[[Pembrolizumab (Keytruda)]] 10 mg/kg IV once on day 1 | ||
− | ''' | + | '''14-day cycles, given until progression of disease or unacceptable toxicity''' |
− | ===Regimen #2 {{#subobject: | + | ===Regimen #2, 10 mg/kg q3wk {{#subobject:e60ce6|Variant=1}}=== |
{| border="1" style="text-align:center;" !align="left" | {| border="1" style="text-align:center;" !align="left" | ||
|'''Study''' | |'''Study''' | ||
Line 1,321: | Line 1,341: | ||
|[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | |[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | ||
|- | |- | ||
− | |[http:// | + | |rowspan=2|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00083-2/fulltext Ribas et al. 2015 (KEYNOTE-002)] |
− | |style="background-color:#00cd00"|Phase | + | |rowspan=2 style="background-color:#00cd00"|Randomized Phase II |
− | | | + | |Investigator-choice chemotherapy |
+ | |style="background-color:#1a9850"|Superior PFS | ||
+ | |- | ||
+ | |Pembrolizumab 2 mg/kg | ||
|style="background-color:#ffffbf"|Seems not superior | |style="background-color:#ffffbf"|Seems not superior | ||
|- | |- | ||
− | |} | + | |rowspan=2|[http://www.nejm.org/doi/full/10.1056/NEJMoa1503093 Robert et al. 2015 (KEYNOTE-006)] |
− | + | |rowspan=2 style="background-color:#00cd00"|Phase III | |
− | ==== | + | |[[#Ipilimumab_monotherapy_2|Ipilimumab]] |
− | *[[ | + | |style="background-color:#1a9850"|Superior OS |
+ | |- | ||
+ | |Pembrolizumab 10 mg/kg q2wk | ||
+ | |style="background-color:#ffffbf"|Seems not superior | ||
+ | |- | ||
+ | |} | ||
+ | ====Immunotherapy==== | ||
+ | *[[Pembrolizumab (Keytruda)]] 10 mg/kg IV over 30 minutes once on day 1 | ||
− | ''' | + | '''21-day cycles, given until progression of disease or unacceptable toxicity''' |
− | === | + | ===Regimen #3, 2 mg/kg q3wk {{#subobject:25a9fe|Variant=1}}=== |
− | # | ||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
{| border="1" style="text-align:center;" !align="left" | {| border="1" style="text-align:center;" !align="left" | ||
|'''Study''' | |'''Study''' | ||
Line 1,349: | Line 1,370: | ||
|[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | |[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | ||
|- | |- | ||
− | |[http:// | + | |rowspan=2|[http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00083-2/fulltext Ribas et al. 2015 (KEYNOTE-002)] |
− | |style="background-color:# | + | |rowspan=2 style="background-color:#00cd00"|Randomized Phase II |
− | | | + | |Investigator-choice chemotherapy |
− | |style="background-color:# | + | |style="background-color:#1a9850"|Superior PFS |
|- | |- | ||
− | | | + | |Pembrolizumab 10 mg/kg q3wk |
− | + | |style="background-color:#ffffbf"|Seems not superior | |
− | |||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | ''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.'' |
− | *[[ | + | ====Immunotherapy==== |
+ | *[[Pembrolizumab (Keytruda)]] 2 mg/kg IV over 30 minutes once on day 1 | ||
− | ''' | + | '''21-day cycles, given until progression of disease or unacceptable toxicity''' |
− | === | + | ===References=== |
− | + | # 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1305133 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126516/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23724846 PubMed] | |
− | + | # '''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/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25034862 PubMed] | |
− | + | # 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''' [https://www.ncbi.nlm.nih.gov/pubmed/26115796 PubMed] | |
− | + | # 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''' [https://www.ncbi.nlm.nih.gov/pubmed/25891173 PubMed] | |
− | + | ## '''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 Aug 16. [Epub ahead of print] [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31601-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28822576 PubMed] | |
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{| class="wikitable" style="float:right; margin-left: 5px;" | {| class="wikitable" style="float:right; margin-left: 5px;" | ||
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− | + | ===Regimen {{#subobject:6e73a5|Variant=1}}=== | |
− | ===Regimen | ||
{| border="1" style="text-align:center;" !align="left" | {| border="1" style="text-align:center;" !align="left" | ||
|'''Study''' | |'''Study''' | ||
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|[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | |[[Levels_of_Evidence#Efficacy|'''Efficacy''']] | ||
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− | + | |[http://jco.ascopubs.org/content/18/1/158.long Middleton et al. 2000] | |
− | | | + | |style="background-color:#00cd00"|Phase III |
− | |[[# | + | |[[#Dacarbazine_monotherapy|Dacarbazine]] |
− | |style="background-color:# | + | |style="background-color:#91cf60"|Seems to have superior PFS |
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− | | | + | |} |
− | |style=" | + | ====Chemotherapy==== |
+ | *[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> 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. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. [http://jco.ascopubs.org/content/18/1/158.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10623706 PubMed] | ||
+ | |||
+ | ==Temozolomide & Bevacizumab {{#subobject:511376|Regimen=1}}== | ||
+ | {| class="wikitable" style="float:right; margin-left: 5px;" | ||
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+ | |[[#top|back to top]] | ||
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− | + | TB: '''<u>T</u>'''emozolomide & '''<u>B</u>'''evacizumab | |
− | + | ===Regimen {{#subobject:42ead6|Variant=1}}=== | |
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− | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089063/ Kottschade et al. 2013 (N0775)] | |
− | + | |style="background-color:#00cd00"|Randomized Phase II | |
− | + | |[[#ABC|ABC]] | |
− | + | |style="background-color:#fc8d59"|Seems to have inferior PFS6 | |
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− | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089063/ Kottschade et al. 2013 (N0775)] | ||
− | |style="background-color:#00cd00"|Randomized Phase II | ||
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====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once per day on days 1 to 5 |
+ | *[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15 | ||
− | ''' | + | '''28-day cycles, given until progression of disease''' |
===References=== | ===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. --> | |
− | + | # 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''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089063/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22915053 PubMed] | |
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=Maintenance immunotherapy for metastatic or unresectable disease= | =Maintenance immunotherapy for metastatic or unresectable disease= | ||
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====Supportive medications==== | ====Supportive medications==== | ||
− | *[[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 | + | *[[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) |
*[[Ondansetron (Zofran)]] 32 mg IV or [[Granisetron (Kytril)]] 2 mg IV once per day | *[[Ondansetron (Zofran)]] 32 mg IV or [[Granisetron (Kytril)]] 2 mg IV once per day | ||
*[[Omeprazole (Prilosec)]] 20 mg PO QPM | *[[Omeprazole (Prilosec)]] 20 mg PO QPM | ||
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====Preceding treatment==== | ====Preceding treatment==== | ||
*'''O'Day et al. 2010''' and '''Margolin et al. 2012:''' [[#Ipilimumab_monotherapy_2|Ipilimumab induction]] | *'''O'Day et al. 2010''' and '''Margolin et al. 2012:''' [[#Ipilimumab_monotherapy_2|Ipilimumab induction]] | ||
− | *'''CA184-024:''' [[ | + | *'''CA184-024:''' [[#Dacarbazine_.26_Ipilimumab|Dacarbazine & Ipilimumab]] |
====Immunotherapy==== | ====Immunotherapy==== | ||
*[[Ipilimumab (Yervoy)]] 10 mg/kg IV once on day 1 | *[[Ipilimumab (Yervoy)]] 10 mg/kg IV once on day 1 | ||
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===References=== | ===References=== | ||
− | # '''Phase I:''' 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. | + | # '''Phase I:''' 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. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837092/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24145345 PubMed] |
# 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. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30126-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474305/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27269740 PubMed] | # 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. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30126-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474305/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27269740 PubMed] | ||
Revision as of 20:45, 6 November 2017
Use of this site is subject to you reading and agreeing with the terms set forth in the disclaimer.
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 invited to contribute to the site.
Note: biomarker-specific regimens have been moved to dedicated pages:
40 regimens on this page
76 variants on this page
|
Guidelines
ESMO
- Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PubMed
NCCN
Adjuvant therapy
Interferon alfa-2a monotherapy
back to top |
Regimen #1
Study | Evidence | Comparator | Efficacy |
Grob et al. 1998 | Phase III | Observation | Might have superior OS |
Immunotherapy
- Interferon alfa-2a (Roferon-A) 3,000,000 international units SC three times per week
18-month course
Regimen #2
Study | Evidence | Comparator | Efficacy |
Pehamberger et al. 1998 | Phase III | Observation | Seems to have superior DFS |
Immunotherapy
- Interferon alfa-2a (Roferon-A) as follows:
- Weeks 1 to 3: 3,000,000 international units SC once per day (21 doses total)
- Weeks 4 to 52: 3,000,000 international units SC three times per week
12-month course
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. link to original article contains verified protocol 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. link to original article contains verified protocol PubMed
Interferon alfa-2b monotherapy
back to top |
Example orders
Regimen #1, 12-month course
Study | Evidence | Comparator | Efficacy |
Kirkwood et al. 1996 (ECOG EST 1684) | Phase III | Observation | Seems to have superior OS |
Immunotherapy
- Interferon alfa-2b (Intron-A) as follows:
- Weeks 1 to 4: 20,000,000 units/m2 IV five times per week
- Weeks 5 to 52: 10,000,000 units/m2 SC three times per week
12-month course
Regimen #2, 6-month course
Study | Evidence | Comparator | Efficacy |
Cameron et al. 2001 (The Scottish study) | Phase III | Observation | Seems not superior |
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."
Immunotherapy
- Interferon alfa-2b (Intron-A) 3,000,000 units SC three times per week
6-month course
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. link to original article contains verified protocol 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. link to original article contains verified protocol link to PMC article PubMed
- Eggermont AM, Suciu S, MacKie R, Ruka W, Testori A, Kruit W, Punt CJ, Delauney M, Sales F, Groenewegen G, Ruiter DJ, Jagiello I, Stoitchkov K, Keilholz U, Lienard D; EORTC Melanoma Group. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet. 2005 Oct 1;366(9492):1189-96. link to original article PubMed
- Update: Eggermont AM, Suciu S, Rutkowski P, Kruit WH, Punt CJ, Dummer R, Salès F, Keilholz U, de Schaetzen G, Testori A; EORTC Melanoma Group. Long term follow up of the EORTC 18952 trial of adjuvant therapy in resected stage IIB-III cutaneous melanoma patients comparing intermediate doses of interferon-alpha-2b (IFN) with observation: Ulceration of primary is key determinant for IFN-sensitivity. Eur J Cancer. 2016 Mar;55:111-21. link to SD article PubMed
- Flaherty LE, Othus M, Atkins MB, Tuthill RJ, Thompson JA, Vetto JT, Haluska FG, Pappo AS, Sosman JA, Redman BG, Moon J, Ribas A, Kirkwood JM, Sondak VK. Southwest Oncology Group S0008: a phase III trial of high-dose interferon Alfa-2b versus cisplatin, vinblastine, and dacarbazine, plus interleukin-2 and interferon in patients with high-risk melanoma--an intergroup study of cancer and leukemia Group B, Children's Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. J Clin Oncol. 2014 Nov 20;32(33):3771-8. Epub 2014 Oct 20. link to PMC article PubMed
- Agarwala SS, Lee SJ, Yip W, Rao UN, Tarhini AA, Cohen GI, Reintgen DS, Evans TL, Brell JM, Albertini MR, Atkins MB, Dakhil SR, Conry RM, Sosman JA, Flaherty LE, Sondak VK, Carson WE, Smylie MG, Pappo AS, Kefford RF, Kirkwood JM. Phase III Randomized Study of 4 Weeks of High-Dose Interferon-α-2b in Stage T2bNO, T3a-bNO, T4a-bNO, and T1-4N1a-2a (microscopic) Melanoma: A Trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E1697). J Clin Oncol. 2017 Mar 10;35(8):885-892. Epub 2017 Jan 30. link to original article link to PMC article PubMed
Ipilimumab monotherapy
Ipilimumab (Yervoy) for melanoma, adjuvant
Nivolumab monotherapy
Nivolumab (Opdivo) for melanoma, adjuvant
Peginterferon alfa-2b monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
Eggermont et al. 2008 (EORTC 18991) | Phase III | Observation | Seems to have superior RFS |
Patients enrolled in EORTC 18991 had resected stage III melanoma.
Immunotherapy
- Peginterferon alfa-2b (Sylatron) as follows:
- Weeks 1 to 8: 6 mcg/kg SC once per week
- Week 9 onwards: 3 mcg/kg SC once per week
Given for up to 5 years of therapy if ECOG performance status remained 0 or 1
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. link to original article contains verified protocol 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. link to original article contains verified protocol PubMed
Placebo (Observation)
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
Kirkwood et al. 1996 (ECOG EST 1684) | Phase III | Interferon alfa-2b | Seems to have inferior OS |
Pehamberger et al. 1998 | Phase III | Interferon alfa-2a | Seems to have inferior DFS |
Grob et al. 1998 | Phase III | Interferon alfa-2a | Might have inferior OS |
Cameron et al. 2001 (The Scottish study) | Phase III | Interferon alfa-2b | Seems not superior |
Eggermont et al. 2008 (EORTC 18991) | Phase III | Pegylated interferon alfa-2b | Seems to have inferior RFS |
Eggermont et al. 2015 (EORTC 18071) | Phase III | Ipilimumab | Inferior OS |
Agarwala et al. 2017 (ECOG E1697) | Phase III | Interferon alfa-2b | Seems not superior |
No active antineoplastic treatment after primary resection. Placed here because one or more randomized clinical trials included a placebo or observation arm in this disease context.
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. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol 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. link to original article contains verified protocol 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. link to original article contains verified protocol link to PMC article PubMed
- Eggermont AM, Suciu S, MacKie R, Ruka W, Testori A, Kruit W, Punt CJ, Delauney M, Sales F, Groenewegen G, Ruiter DJ, Jagiello I, Stoitchkov K, Keilholz U, Lienard D; EORTC Melanoma Group. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet. 2005 Oct 1;366(9492):1189-96. link to original article PubMed
- Update: Eggermont AM, Suciu S, Rutkowski P, Kruit WH, Punt CJ, Dummer R, Salès F, Keilholz U, de Schaetzen G, Testori A; EORTC Melanoma Group. Long term follow up of the EORTC 18952 trial of adjuvant therapy in resected stage IIB-III cutaneous melanoma patients comparing intermediate doses of interferon-alpha-2b (IFN) with observation: Ulceration of primary is key determinant for IFN-sensitivity. Eur J Cancer. 2016 Mar;55:111-21. link to SD article 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. link to original article contains verified protocol 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. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol 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. link to correction PubMed
- Update: Eggermont AM1, Chiarion-Sileni V1, Grob JJ1, Dummer R1, Wolchok JD1, Schmidt H1, Hamid O1, Robert C1, Ascierto PA1, Richards JM1, Lebbé C1, Ferraresi V1, Smylie M1, Weber JS1, Maio M1, Bastholt L1, Mortier L1, Thomas L1, Tahir S1, Hauschild A1, Hassel JC1, Hodi FS1, Taitt C1, de Pril V1, de Schaetzen G1, Suciu S1, Testori A1. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med. 2016 Nov;375(19):1845-55. Epub 2016 Oct 7. link to original article contains verified protocol PubMed
- Agarwala SS, Lee SJ, Yip W, Rao UN, Tarhini AA, Cohen GI, Reintgen DS, Evans TL, Brell JM, Albertini MR, Atkins MB, Dakhil SR, Conry RM, Sosman JA, Flaherty LE, Sondak VK, Carson WE, Smylie MG, Pappo AS, Kefford RF, Kirkwood JM. Phase III Randomized Study of 4 Weeks of High-Dose Interferon-α-2b in Stage T2bNO, T3a-bNO, T4a-bNO, and T1-4N1a-2a (microscopic) Melanoma: A Trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E1697). J Clin Oncol. 2017 Mar 10;35(8):885-892. Epub 2017 Jan 30. link to original article link to PMC article PubMed
Local therapy
Talimogene laherparepvec monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
Andtbacka et al. 2015 | Phase III | GM-CSF | Superior DRR |
Talimogene laherparepvec was injected directly into unresectable cutaneous, subcutaneous, and nodal melanoma lesions.
Therapy
- Talimogene laherparepvec (Imlygic) as follows:
- Initially: 106 pfu/mL (to seroconvert HSV-seronegative patients) SC intralesional injection once on day 1, then 108 pfu/mL SC intralesional injection once on day 22
- Thereafter: 108 pfu/mL SC intralesional injection once every 2 weeks.
- 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."
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
- 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. link to original article contains verified protocol PubMed
Metastatic or unresectable disease
ABC
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ABC: Abraxane (Paclitaxel nanoparticle albumin-bound), Bevacizumab, Carboplatin
Regimen
Study | Evidence | Comparator | Efficacy |
Kottschade et al. 2013 (N0775) | Randomized Phase II | Temozolomide & Bevacizumab | Seems to have superior PFS6 |
The doses listed here are the amended starting doses.
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 80 mg/m2 IV once per day on days 1, 8, 15
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
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. Epub 2012 Aug 22. link to original article contains verified protocol link to PMC article PubMed
Carboplatin & Paclitaxel
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CP: Carboplatin & Paclitaxel
Regimen #1
Study | Evidence | Comparator | Efficacy |
Weber et al. 2015 (CheckMate 037) | Phase III | Nivolumab | Inferior ORR |
Chemotherapy
- Carboplatin (Paraplatin) AUC 6 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycles
Regimen #2
Study | Evidence | Comparator | Efficacy |
Hauschild et al. 2009 | Phase III | Carboplatin, Paclitaxel, Sorafenib | Seems not superior |
Flaherty et al. 2013 (ECOG E2603) | Phase III | Carboplatin, Paclitaxel, Sorafenib | Seems not superior |
Chemotherapy
- Carboplatin (Paraplatin) as follows:
- Cycles 1 to 4: AUC 6 IV over 30 minutes once on day 1, given second
- Cycle 5 onwards: 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 onwards: 175 mg/m2 IV over 3 hours once on day 1, given first
21-day cycle for up to 10 cycles, until progression of disease, or unacceptable toxicity
Regimen #3
Study | Evidence |
Rao et al. 2006 | Retrospective |
Chemotherapy
- 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
Regimen #4
Study | Evidence |
Rao et al. 2006 | Retrospective |
Chemotherapy
- Carboplatin (Paraplatin) AUC 5 IV once on day 1
- Paclitaxel (Taxol) 175 to 200 mg/m2 IV once on day 1
21-day cycles
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. link to original article contains verified protocol 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. link to original article contains verified protocol 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. link to original article contains verified protocol link to PMC article 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. link to original article contains protocol PubMed
Carboplatin & Paclitaxel, nanoparticle albumin-bound
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Regimen
Study | Evidence |
Kottschade et al. 2011 (N057E(1)) | Phase II |
Chemotherapy
- Carboplatin (Paraplatin) AUC 2 IV once per day on days 1, 8, 15, given second
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 IV over 30 minutes once per day on days 1, 8, 15, given first
28-day cycle for up to 8 cycles; patients without progressive disease or excessive toxicity could receive additional therapy per physician discretion
Supportive medications
- "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
- 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. Epub 2010 Nov 8. link to original article contains verified protocol link to PMC article PubMed
Carboplatin, Paclitaxel, Sorafenib
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CPS: Carboplatin, Paclitaxel, Sorafenib
Regimen
Study | Evidence | Comparator | Efficacy |
Hauschild et al. 2009 | Phase III | Carboplatin & Paclitaxel | Seems not superior |
Flaherty et al. 2013 (ECOG E2603) | Phase III | Carboplatin & Paclitaxel | Seems not superior |
Chemotherapy
- Carboplatin (Paraplatin) as follows:
- Cycles 1 to 4: AUC 6 IV over 30 minutes once on day 1, given second
- Cycles 5 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
- Cycles 5 to 10: 175 mg/m2 IV over 3 hours once on day 1, given first
- Sorafenib (Nexavar) 400 mg PO BID on days 2 to 19
21-day cycle for 10 cycles, followed by:
Sorafenib monotherapy
- Sorafenib (Nexavar) 400 mg PO BID on days 1 to 21
21-day cycles, given until progression of disease or unacceptable toxicity
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. link to original article contains verified protocol 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. link to original article contains verified protocol link to PMC article PubMed
Cisplatin, Dacarbazine +/- Carmustine
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Regimen
Study | Evidence | Comparator | Efficacy |
Ridolfi et al. 2002 | Phase III | Cisplatin, Dacarbazine, IL-2, IFN alfa-2b +/- Carmustine | Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1
- Dacarbazine (DTIC) 800 mg/m2 IV once on day 1
- 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
21-day cycle for 6 cycles
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. link to original article contains verified protocol PubMed
Cisplatin, Dacarbazine, IL-2, IFN alfa-2b +/- Carmustine
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Regimen
Study | Evidence | Comparator | Efficacy |
Ridolfi et al. 2002 | Phase III | Cisplatin, Dacarbazine +/- Carmustine | Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1
- Dacarbazine (DTIC) 800 mg/m2 IV once on day 1
- 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
- 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
- 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
21-day cycle for 6 cycles
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. link to original article contains verified protocol PubMed
Cisplatin, Paclitaxel, Dacarbazine
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Regimen
Study | Evidence |
Papadopoulos et al. 2009 | Phase II |
Chemotherapy
- Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 to 4
- Paclitaxel (Taxol) 100-120 mg/m2 IV once per day on days 1 & 8
- Dacarbazine (DTIC) 800 mg/m2 IV once on day 1
References
- 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 protocol PubMed
CVD
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CVD: Cisplatin, Vinblastine, Dacarbazine
Regimen #1
Study | Evidence | Comparator | Efficacy |
Atkins et al. 2008 (ECOG E3695) | Phase III | Sequential biochemotherapy | Seems to have inferior PFS |
Chemotherapy
- Cisplatin (Platinol) 20 mg/m2 IV over 30 minutes once per day on days 1 to 4, given first
- Vinblastine (Velban) 1.2 mg/m2 IV push once per day on days 1 to 4, given second
- Dacarbazine (DTIC) 800 mg/m2 IV over 1 hour once on day 1, given third
21-day cycle for up to 4 cycles
Supportive medications
- Antiemetics and Dexamethasone (Decadron) premedication for chemotherapy
Regimen #2
Study | Evidence | Comparator | Efficacy |
Eton et al. 2002 | Phase III | Sequential biochemotherapy | Inferior TTP |
Chemotherapy
- Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 to 4, 22 to 25
- Vinblastine (Velban) 2 mg/m2 IV once per day on days 1 to 4, 22 to 25
- Dacarbazine (DTIC) 800 mg/m2 IV once per day on days 1 & 22
42-day cycle for up to 5 cycles
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. link to original article contains verified protocol PubMed content property of HemOnc.org
- 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. link to original article contains verified protocol link to PMC article PubMed
CVD, IL-2, IFN alfa-2b - sequential biochemotherapy
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CVD: Cisplatin, Vinblastine, Dacarbazine
Example orders
Regimen #1
Study | Evidence | Comparator | Efficacy |
McDermott et al. 2000 | Phase II | ||
Atkins et al. 2008 (ECOG E3695) | Phase III | CVD | Seems to have superior PFS |
Chemotherapy
- Cisplatin (Platinol) 20 mg/m2 IV over 30 minutes once per day on days 1 to 4, given first
- Vinblastine (Velban) 1.2 mg/m2 IV push once per day on days 1 to 4, given second
- Dacarbazine (DTIC) 800 mg/m2 IV over 1 hour once on day 1, given third
- IL-2 - Aldesleukin (Proleukin) 9,000,000 units/m2/day IV continuous infusion over 96 hours on days 1 to 4
- 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
Supportive medications
- All antihypertensive therapy discontinued at least 24 hours before each cycle
- Cephalexin (Keflex) or Ciprofloxacin (Cipro) 250 mg PO BID on days 1 to 14
- Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 7 to 16, or until ANC greater than 10,000
- Ondansetron (Zofran) 32 mg IV once per day
- 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
21-day cycle for up to 4 cycles
Regimen #2
Study | Evidence | Comparator | Efficacy |
Eton et al. 2002 | Phase III | CVD | Superior TTP |
Chemotherapy
- Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 to 4, 22 to 25
- Vinblastine (Velban) 1.5 mg/m2 IV once per day on days 1 to 4, 22 to 25
- Dacarbazine (DTIC) 800 mg/m2 IV once per day on days 1 & 22
- 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
- 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
42-day cycle for up to 5 cycles
References
- Legha SS, Ring S, Eton O, Bedikian A, Buzaid AC, Plager C, Papadopoulos N. Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma. J Clin Oncol. 1998 May;16(5):1752-9. link to original article PubMed
- 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. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol 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. link to original article contains verified protocol link to PMC article PubMed
Dacarbazine monotherapy
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Example orders
Regimen #1
Study | Evidence | Comparator | Efficacy |
Chapman et al. 2011 (BRIM-3) | Phase III | Vemurafenib | Inferior OS |
Hauschild et al. 2012 (BREAK-3) | Phase III | Dabrafenib | Inferior PFS |
Flaherty et al. 2012 (METRIC) | Phase III | Trametinib | Seems to have inferior OS |
Robert et al. 2014 (CheckMate 066) | Phase III | Nivolumab | Inferior OS |
Weber et al. 2015 (CheckMate 037) | Phase III | Nivolumab | Inferior ORR |
Hersh et al. 2015 | Phase III | nab-Paclitaxel | Seems to have inferior PFS |
Dummer et al. 2017 (NEMO) | Phase III | Binimetinib | Inferior PFS |
Patients in BRIM-3 had a BRAF p.V600E mutation detected. Patients in NEMO had NRAS mutations.
Chemotherapy
- Dacarbazine (DTIC) 1000 mg/m2 IV once on day 1
21-day cycles, given until progression of disease or unacceptable toxicity
Regimen #2
Study | Evidence | Comparator | Efficacy |
Robert et al. 2011 (CA184-024) | Phase III | Dacarbazine & Ipilimumab | Inferior OS |
Chemotherapy
- Dacarbazine (DTIC) 850 mg/m2 IV once on day 1
21-day cycle for 8 cycles
Regimen #3
Study | Evidence | Comparator | Efficacy |
Middleton et al. 2000 | Phase III | Temozolomide | Seems to have inferior PFS |
Chemotherapy
- Dacarbazine (DTIC) 250 mg/m2 IV over 30 minutes once per day on days 1 to 5
21-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. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol link to PMC article PubMed
- Update: McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, Ribas A, Hogg D, Hamid O, Ascierto PA, Garbe C, Testori A, Maio M, Lorigan P, Lebbé C, Jouary T, Schadendorf D, O'Day SJ, Kirkwood JM, Eggermont AM, Dréno B, Sosman JA, Flaherty KT, Yin M, Caro I, Cheng S, Trunzer K, Hauschild A. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014 Mar;15(3):323-32. Epub 2014 Feb 7. link to PMC article PubMed
- 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. link to original article contains verified protocol PubMed
- 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 PubMed
- 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. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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 verified protocol 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. link to original article PubMed
- 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 verified protocol PubMed
- Dummer R, Schadendorf D, Ascierto PA, Arance A, Dutriaux C, Di Giacomo AM, Rutkowski P, Del Vecchio M, Gutzmer R, Mandala M, Thomas L, Demidov L, Garbe C, Hogg D, Liszkay G, Queirolo P, Wasserman E, Ford J, Weill M, Sirulnik LA, Jehl V, Bozón V, Long GV, Flaherty K. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Apr;18(4):435-445. Epub 2017 Mar 8. link to original article PubMed
Dacarbazine & Ipilimumab
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Regimen
Study | Evidence | Comparator | Efficacy |
Robert et al. 2011 (CA184-024) | Phase III | Dacarbazine | Superior OS |
Chemotherapy
- Ipilimumab (Yervoy) as follows:
- Cycles 1 to 4: 10 mg/kg IV once on day 1
- Dacarbazine (DTIC) 850 mg/m2 IV once on day 1
21-day cycle for 8 cycles
If patient has stable disease or objective response, proceed to maintenance ipilimumab.
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. link to original article contains verified protocol PubMed
- 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 PubMed
Docetaxel monotherapy
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Regimen
Study | Evidence |
Aamdal et al. 1994 | Phase II |
Chemotherapy
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
Supportive medications
- "No prophylactic treatment with steroids or antihistamines was given."
21-day cycles
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 PubMed
High-dose (HD) IL-2
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Example orders
Regimen
Study | Evidence |
Atkins et al. 1999 | Phase II |
Immunotherapy
- IL-2 - Aldesleukin (Proleukin) 600,000 or 720,000 units/kg IV 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
6 to 12 weeks per cycle for up to 5 cycles
Supportive medications
- 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.
References
- 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 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. link to original article contains verified protocol 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. PubMed
Imatinib monotherapy
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Regimen #1
Study | Evidence |
Hodi et al. 2013 | Phase II |
Patients had melanomas arising from mucosal, acral, and chronically sun-damaged skin with KIT mutations or amplifications.
Starting dose
- Imatinib (Gleevec) 400 mg PO once per day
Given until disease progression; then proceed to higher dose:
Higher dose
- Imatinib (Gleevec) 400 mg PO BID
Given until disease progression
Regimen #2
Study | Evidence |
Carvajal et al. 2011 | Phase II |
Patients had melanomas arising from mucosal, acral, and chronically sun-damaged skin with KIT mutations or amplifications.
Chemotherapy
- Imatinib (Gleevec) 400 mg PO BID
Given until disease progression
References
- Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman RA, Teitcher J, Panageas KS, Busam KJ, Chmielowski B, Lutzky J, Pavlick AC, Fusco A, Cane L, Takebe N, Vemula S, Bouvier N, Bastian BC, Schwartz GK. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011 Jun 8;305(22):2327-34. 'contains protocol link to PMC article PubMed
- 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 Sep 10;31(26):3182-90. Epub 2013 Jun 17. link to original article contains verified protocol link to PMC article PubMed
Ipilimumab monotherapy
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Example orders
Regimen #1
Study | Evidence | Comparator | Efficacy | Toxicity |
Hodi et al. 2010 (MDX010-20) | Phase III | Ipilimumab & gp100 peptide vaccine | Seems not superior | |
gp100 peptide vaccine | Superior OS | |||
Robert et al. 2015 (KEYNOTE-006) | Phase III | Pembrolizumab 10 mg/kg q2wks | Inferior OS | |
Pembrolizumab 10 mg/kg q3wks | Inferior OS | |||
Postow et al. 2015 (CheckMate 069) | Phase III | Ipilimumab & Nivolumab | Inferior PFS | |
Larkin et al. 2015 (CheckMate 067) | Phase III | Ipilimumab & Nivolumab | Inferior PFS | Equivalent HRQoL |
Nivolumab | Inferior PFS | Equivalent HRQoL |
Immunotherapy
- Ipilimumab (Yervoy) 3 mg/kg IV once on day 1
21-day cycle for 4 cycles
Regimen #2
Study | Evidence |
Wolchok et al. 2010 | Phase II |
O'Day et al. 2010 | Phase II |
Margolin et al. 2012 | Phase II |
Note: In Wolchok et al. 2010, lower doses including 3 mg/kg (the FDA approved dose) were investigated, but the 10 mg/kg dose was recommended.
Immunotherapy
- Ipilimumab (Yervoy) 10 mg/kg IV over 90 minutes once on day 1
21-day cycle for 4 cycles
Patients in O'Day et al. 2010 and Margolin et al. 2012 who were clinically stable could proceed to ipilimumab maintenance.
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. link to original article contains verified protocol 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. Erratum in: N Engl J Med. 2010 Sep 23;363(13):1290. link to original article contains verified protocol link to PMC article PubMed
- Update: 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
- 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 verified protocol PubMed
- 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 protocol PubMed
- 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 verified protocol PubMed
- 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 Aug 16. [Epub ahead of print] link to original article 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. link to original article 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. link to original article PubMed
- 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 verified protocol PubMed
- 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 PubMed
Ipilimumab & Nivolumab
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Regimen #1
Study | Evidence | Comparator | Efficacy | Toxicity |
Larkin et al. 2015 (CheckMate 067) | Phase III | Ipilimumab | Superior PFS | Equivalent HRQoL |
Nivolumab | Superior PFS | Equivalent HRQoL |
Immunotherapy, part 1
- Ipilimumab (Yervoy) 3 mg/kg IV once on day 1
- Nivolumab (Opdivo) 1 mg/kg IV once on day 1
21-day cycle for 4 cycles, followed by:
Immunotherapy, part 2
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
14-day cycles
Regimen #2
Study | Evidence | Comparator | Efficacy |
Postow et al. 2015 (CheckMate 069) | Phase III | Ipilimumab | Superior PFS |
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."
Immunotherapy, part 1
- Ipilimumab (Yervoy) 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, followed by:
Immunotherapy, part 2
- Nivolumab (Opdivo) 1 mg/kg IV once on day 1
21-day cycle for 4 cycles
Treatment followed by ipilimumab & nivolumab maintenance.
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. link to original article contains verified protocol link to supplementary appendix 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. link to original article 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. link to original article PubMed
- 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 verified protocol PubMed
- 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 PubMed
Ipilimumab, then Nivolumab
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Regimen
Study | Evidence | Comparator | Efficacy |
Weber et al. 2016 (CheckMate 064) | Randomized Phase II | Nivolumab, then Ipilimumab | Seems to have inferior OS |
Immunotherapy, part 1
- Ipilimumab (Yervoy) 3 mg/kg IV once on day 1
21-day cycle for 4 cycles, followed by:
Immunotherapy, part 2
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
14-day cycle for 6 cycles
Treatment followed by maintenance nivolumab.
References
- 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 protocol link to PMC article PubMed
Nivolumab monotherapy
back to top |
Regimen #1
Study | Evidence | Comparator | Efficacy | Toxicity |
Robert et al. 2014 (CheckMate 066) | Phase III | Dacarbazine | Superior OS | |
Weber et al. 2015 (CheckMate 037) | Phase III | Dacarbazine Carboplatin & Paclitaxel |
Superior ORR | |
Larkin et al. 2015 (CheckMate 067) | Phase III | Ipilimumab | Superior PFS | Equivalent HRQoL |
Ipilimumab & Nivolumab | Inferior PFS | Equivalent HRQoL |
Immunotherapy
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
14-day cycles, given until progression of disease or unacceptable toxicity
Regimen #2
Study | Evidence |
Weber et al. 2013 | Phase I |
Immunotherapy
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
14-day cycle for 12 cycles
Treatment followed by maintenance nivolumab.
References
- Phase I: 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. contains verified protocol link to PMC article PubMed
- 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 verified protocol 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. link to original article PubMed
- 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 verified protocol PubMed
- 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 PubMed
Nivolumab, then Ipilimumab
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
Weber et al. 2016 (CheckMate 064) | Randomized Phase II | Ipilimumab, then Nivolumab | Seems to have superior OS |
Immunotherapy, part 1
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
14-day cycle for 6 cycles, followed by:
Immunotherapy, part 2
- Ipilimumab (Yervoy) 3 mg/kg IV once on day 1
21-day cycle for 4 cycles
Treatment followed by maintenance nivolumab.
References
- 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 protocol link to PMC article PubMed
Paclitaxel monotherapy
back to top |
Example orders
Regimen #1
Study | Evidence | Comparator | Efficacy |
Flaherty et al. 2012 (METRIC) | Phase III | Trametinib | Seems to have inferior OS |
This was a therapy option for patients in the control arm of METRIC.
Chemotherapy
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycles
Regimen #2
Study | Evidence | Comparator | Efficacy |
O'Day et al. 2013 (SYMMETRY) | Phase III | Elesclomol & Paclitaxel | Seems not superior |
This was the control arm of SYMMETRY, which was a negative study.
Chemotherapy
- Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1, 8, 15
28-day cycles, given until progression of disease or unacceptable toxicity
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. link to original article contains verified protocol 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. link to original article contains verified protocol PubMed
Paclitaxel, nanoparticle albumin-bound monotherapy
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Regimen #1
Study | Evidence | Comparator | Efficacy |
Hersh et al. 2012 | Phase II | ||
Hersh et al. 2015 | Phase III | Dacarbazine | Seems to have superior PFS |
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 150 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Regimen #2
Study | Evidence |
Hersh et al. 2012 | Phase II |
Note: this dose was intended for previously treated patients.
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
References
- 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 protocol PubMed
- 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 verified protocol PubMed
Pembrolizumab monotherapy
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Regimen #1, 10 mg/kg q2wk
Study | Evidence | Comparator | Efficacy |
Robert et al. 2015 (KEYNOTE-006) | Phase III | Ipilimumab | Superior OS |
Pembrolizumab 10 mg/kg q3wk | Seems not superior |
Immunotherapy
- Pembrolizumab (Keytruda) 10 mg/kg IV once on day 1
14-day cycles, given until progression of disease or unacceptable toxicity
Regimen #2, 10 mg/kg q3wk
Study | Evidence | Comparator | Efficacy |
Ribas et al. 2015 (KEYNOTE-002) | Randomized Phase II | Investigator-choice chemotherapy | Superior PFS |
Pembrolizumab 2 mg/kg | Seems not superior | ||
Robert et al. 2015 (KEYNOTE-006) | Phase III | Ipilimumab | Superior OS |
Pembrolizumab 10 mg/kg q2wk | Seems not superior |
Immunotherapy
- Pembrolizumab (Keytruda) 10 mg/kg IV over 30 minutes once on day 1
21-day cycles, given until progression of disease or unacceptable toxicity
Regimen #3, 2 mg/kg q3wk
Study | Evidence | Comparator | Efficacy |
Ribas et al. 2015 (KEYNOTE-002) | Randomized Phase II | Investigator-choice chemotherapy | Superior PFS |
Pembrolizumab 10 mg/kg q3wk | Seems not superior |
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.
Immunotherapy
- Pembrolizumab (Keytruda) 2 mg/kg IV over 30 minutes once on day 1
21-day cycles, given until progression of disease or unacceptable toxicity
References
- 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
- 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. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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 verified protocol PubMed
- 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 Aug 16. [Epub ahead of print] link to original article PubMed
Temozolomide monotherapy
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Regimen
Study | Evidence | Comparator | Efficacy |
Middleton et al. 2000 | Phase III | Dacarbazine | Seems to have superior PFS |
Chemotherapy
- 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. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. link to original article contains verified protocol PubMed
Temozolomide & Bevacizumab
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TB: Temozolomide & Bevacizumab
Regimen
Study | Evidence | Comparator | Efficacy |
Kottschade et al. 2013 (N0775) | Randomized Phase II | ABC | Seems to have inferior PFS6 |
Chemotherapy
- Temozolomide (Temodar) 200 mg/m2 PO once per day on days 1 to 5
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
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. Epub 2012 Aug 22. link to original article contains verified protocol link to PMC article PubMed
Maintenance immunotherapy for metastatic or unresectable disease
IL-2 monotherapy
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Example orders
Regimen
Study | Evidence |
O'Day et al. 2002 | Phase II |
Immunotherapy, low-dose cycles (1, 4, 7, 9, 11)
- IL-2 - Aldesleukin (Proleukin) 1,000,000 units/m2 SC once per day every Monday to Friday on days 1 to 28
Supportive medications
- Sargramostim (Leukine) 125 mcg/m2 SC once per day on days 1 to 14
28-day cycles, alternating with pulse cycles:
Immunotherapy, pulse cycles (2, 3, 5, 6, 8, 10, 12)
- 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
- Then as an outpatient: 1,000,000 units/m2 SC once per day every Monday to Friday on days 3 to 28
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
28-day cycles, alternating with low-dose cycles, for a total of 12 cycles
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. link to original article contains verified protocol PubMed
Ipilimumab monotherapy
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Regimen
Study | Evidence |
O'Day et al. 2010 | Phase II |
Robert et al. 2011 (CA184-024) | Non-randomized portion of RCT |
Margolin et al. 2012 | Phase II |
Preceding treatment
- O'Day et al. 2010 and Margolin et al. 2012: Ipilimumab induction
- CA184-024: Dacarbazine & Ipilimumab
Immunotherapy
- Ipilimumab (Yervoy) 10 mg/kg IV once on day 1
12-week cycles, given until progression of disease or unacceptable toxicity
References
- 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 verified protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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 protocol PubMed
Ipilimumab & Nivolumab
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Regimen
Study | Evidence |
Postow et al. 2015 (CheckMate 069) | Non-randomized portion of RCT |
Preceding treatment
Immunotherapy
- 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 for 8 cycles
References
- 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 PubMed
Nivolumab monotherapy
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Regimen #1, indefinite
Study | Evidence |
Weber et al. 2016 (CheckMate 064) | Non-randomized portion of RCT |
Preceding treatment
Immunotherapy
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
14-day cycles, given until progression of disease or unacceptable toxicity
Regimen #2, 2-year course
Study | Evidence |
Weber et al. 2013 | Phase I |
Preceding treatment
Immunotherapy
- Nivolumab (Opdivo) 3 mg/kg IV once on day 1
- Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
12-week cycle for 2 years
References
- Phase I: 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. contains verified protocol link to PMC article PubMed
- 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 protocol link to PMC article PubMed