Difference between revisions of "Renal cell carcinoma - null regimens"

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The purpose of this page is to provide references to "null therapy" such as placebo and observation. While not clinically relevant, these references provide further insight into the historical development of the treatment landscape. See the [[Renal cell carcinoma|main RCC page]] for current regimens.
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{| class="wikitable" style="text-align:center; width:50%;"
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! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''
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|-
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| style="background-color:#F0F0F0" |[[File:ChenEddy Sept2016.jpg|frameless|upright=0.3|center]]
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|<big>[[User:Eddychen|Eddy J. Chen, MD]]<br>Massachusetts General Hospital<br>Boston, MA</big>
 +
|-
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|}
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''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Renal_cell_carcinoma_-_historical|historical regimens page]]. If you still can't find it, please let us know so we can add it!''.
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{| class="wikitable" style="float:right; margin-right: 5px;"
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|-
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|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div>
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<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
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|}
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{{TOC limit|limit=3}}
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 +
=Guidelines=
 +
==EAU==
 +
*'''2016:''' Powles et al. [http://www.europeanurology.com/article/S0302-2838(15)00998-7/fulltext Updated EAU guidelines for clear cell renal cancer patients who fail VEGF targeted therapy] [https://www.ncbi.nlm.nih.gov/pubmed/26508312 PubMed]
 +
 
 +
==[http://www.esmo.org/ ESMO]==
 +
*'''2019:''' Escudier et al. [https://academic.oup.com/annonc/article-abstract/30/5/706/5345645 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
 +
===Older===
 +
*'''2016:''' Escudier et al. [https://www.esmo.org/Guidelines/Genitourinary-Cancers/Renal-Cell-Carcinoma Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/27664262 PubMed]
 +
*'''2014:''' Escudier et al. [https://academic.oup.com/annonc/article/25/suppl_3/iii49/160101 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
 +
*'''2012:''' Escudier et al. [https://academic.oup.com/annonc/article/23/suppl_7/vii65/144122 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
 +
*'''2010:''' Escudier et al. [https://academic.oup.com/annonc/article/21/suppl_5/v137/194178 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
 +
 
 +
==[https://www.nccn.org/ NCCN]==
 +
*[https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf NCCN Guidelines - Kidney Cancer]
 +
 
 +
==[http://www.siog.org/ SIOG]==
 +
*'''2018:''' Kanesvaran et al. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30125-6/fulltext Elderly patients with metastatic renal cell carcinoma: position paper from the International Society of Geriatric Oncology]
 +
 
 +
= Risk Stratification Calculators =
 +
* [https://www.mdcalc.com/heng-score-metastatic-renal-cell-carcinoma-rcc-prognosis International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) calculator]
 +
** ref: Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, Mackenzie M, Wood L, Donskov F, Tan MH, Rha SY, Agarwal N, Kollmannsberger C, Rini BI, Choueiri TK; External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013 Feb;14(2):141-8. Epub 2013 Jan 9. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144042/ link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23312463 PubMed]
 +
 
 +
* [https://www.mdcalc.com/memorial-sloan-kettering-cancer-center-mskcc-motzer-score-metastatic-renal-cell-carcinoma-rcc Memorial Sloan Kettering Cancer Center (MSKCC) calculator]
 +
** ref: Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002 Jan 1;20(1):289-96. [https://ascopubs.org/doi/abs/10.1200/JCO.2002.20.1.289?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11773181 PubMed]
 +
 
 +
* [https://rgulati.shinyapps.io/rcc-risk-calculator/ Mortality and complication risk calculator for a patients with clinical T1 renal cortical mass ≤ 7 cm] (Dr. Sarah P. Psutka)
 +
** ref: Psutka SP et al., A clinical decision aid to support personalized treatment selection for patients with stage T1 renal masses: Results from a multi-institutional competing risks analysis including performance status and comorbidity. Working paper. [https://www.urotoday.com/conference-highlights/asco-gu-2020/asco-gu-2020-kidney-cancer/119296-asco-gu-2020-a-novel-clinical-decision-aid-to-support-personalized-treatment-selection-for-patients-with-ct1-renal-cortical-masses-results-from-a-multi-institutional-competing-risks-analysis-including-performance-status-and-comorbidity.html link to news article]
  
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{{TOC limit|limit=3}}
 
 
=Adjuvant therapy=
 
=Adjuvant therapy=
−
==Observation==
+
==Sunitinib monotherapy {{#subobject:cf6852|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:3c0a01|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Years of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878938/ Haas et al. 2016 (ECOG-ACRIN E2805)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase III (E-esc)
 +
|[[Renal_cell_carcinoma_-_null_regimens#Placebo|Placebo]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|
 +
|-
 +
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1611406 Ravaud et al. 2016 (S-TRAC)]
 +
|2007-2011
 +
| style="background-color:#1a9851" |Phase III (E-RT-esc)
 +
|[[Renal_cell_carcinoma_-_null_regimens#Placebo|Placebo]]
 +
| style="background-color:#91cf60" |Seems to have superior DFS
 +
| style="background-color:#d73027" |More toxicity
 +
|-
 +
|}
 +
====Preceding treatment====
 +
*[[Surgery#Renal_cell_carcinoma_surgery|Surgery]]
 +
====Chemotherapy====
 +
*[[Sunitinib (Sutent)]] 50 mg PO once per day on days 1 to 28
 +
 
 +
'''42-day cycle for up to 9 cycles (1 year)'''
 +
 
 +
===References===
 +
# '''ECOG-ACRIN E2805:''' Haas NB, Manola J, Uzzo RG, Flaherty KT, Wood CG, Kane C, Jewett M, Dutcher JP, Atkins MB, Pins M, Wilding G, Cella D, Wagner L, Matin S, Kuzel TM, Sexton WJ, Wong YN, Choueiri TK, Pili R, Puzanov I, Kohli M, Stadler W, Carducci M, Coomes R, DiPaola RS. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016 May 14;387(10032):2008-16. Epub 2016 Mar 9. Erratum in: Lancet. 2016 May 14;387(10032):1998. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00559-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878938/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26969090 PubMed] NCT00326898
 +
# '''S-TRAC:''' Ravaud A, Motzer RJ, Pandha HS, George DJ, Pantuck AJ, Patel A, Chang YH, Escudier B, Donskov F, Magheli A, Carteni G, Laguerre B, Tomczak P, Breza J, Gerletti P, Lechuga M, Lin X, Martini JF, Ramaswamy K, Casey M, Staehler M, Patard JJ; S-TRAC Investigators. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016 Dec 8;375(23):2246-2254. Epub 2016 Oct 9. [https://www.nejm.org/doi/full/10.1056/NEJMoa1611406 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27718781 PubMed]
 +
## '''Update:''' Motzer RJ, Ravaud A, Patard JJ, Pandha HS, George DJ, Patel A, Chang YH, Escudier B, Donskov F, Magheli A, Carteni G, Laguerre B, Tomczak P, Breza J, Gerletti P, Lechuga M, Lin X, Casey M, Serfass L, Pantuck AJ, Staehler M. Adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy: subgroup analyses and updated overall survival results. Eur Urol. 2018 Jan;73(1):62-68. Epub 2017 Sep 26. [http://www.europeanurology.com/article/S0302-2838(17)30772-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28967554 PubMed]
 +
 
 +
=Metastatic disease, first-line=
 +
==Atezolizumab & Bevacizumab {{#subobject:af0d04|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:34c462|Variant=1}}===
−
{| class="wikitable" style="width: 100%; text-align:center;"
+
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 25%"|Study
 +
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 25%"|Comparator
 +
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30723-8/fulltext Rini et al. 2019 (IMmotion151)]
 +
| style="background-color:#1a9851" |Phase III (E-esc)
 +
|[[#Sunitinib_monotherapy_2|Sunitinib]]
 +
| style="background-color:#91cf60" |Seems to have superior PFS
 +
|-
 +
|}
 +
====Immunotherapy====
 +
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1
 +
====Chemotherapy====
 +
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
 +
 
 +
'''21-day cycles'''
 +
 
 +
===References===
 +
# '''IMmotion151:''' Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30723-8/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/31079938 PubMed]
 +
 
 +
==Axitinib monotherapy {{#subobject:e83fa|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
 
 +
===Regimen {{#subobject:90ba4d|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
 
!style="width: 20%"|Years of enrollment
 
!style="width: 20%"|Years of enrollment
Line 15: Line 126:
 
!style="width: 20%"|Comparator
 
!style="width: 20%"|Comparator
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
![[Overall response rate|ORR]]
 +
!Comparator [[Overall response rate|ORR]]
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.2003.02.005 Messing et al. 2003 (INT-0079)]
+
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70465-0/fulltext Hutson et al. 2013 (A4061051)]
−
|1987-1992
+
|2010-2011
 +
| style="background-color:#1a9851" |Phase III (E-switch-ic)
 +
|[[#Sorafenib_monotherapy|Sorafenib]]
 +
| style="background-color:#d9ef8b" |Might have superior PFS (*)
 +
|32%
 +
|15%
 +
|-
 +
|}
 +
''Note: in the 2016 update, there is no difference in OS.''
 +
====Chemotherapy====
 +
*[[Axitinib (Inlyta)]] as follows:
 +
**5 mg PO twice per day for at least 2 weeks
 +
**Then if tolerated and BP not greater than 150/90, increased to 7 mg PO twice per day
 +
**Then if tolerated and BP not greater than 150/90, increased to 10 mg PO twice per day
 +
**Dose can be reduced to 2 to 3 mg PO twice per day if needed based on tolerability
 +
 
 +
'''Continued indefinitely'''
 +
===References===
 +
# '''A4061051:''' Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, Rosbrook B, Chen C, Kim S, Vogelzang NJ. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1287-94. Epub 2013 Oct 25. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70465-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24206640 PubMed]
 +
## '''Update:''' Hutson TE, Al-Shukri S, Stus VP, Lipatov ON, Shparyk Y, Bair AH, Rosbrook B, Andrews GI, Vogelzang NJ. Axitinib versus sorafenib in first-line metastatic renal cell carcinoma: Overall survival from a randomized phase III trial. Clin Genitourin Cancer. 2017 Feb;15(1):72-76. Epub 2016 May 27. [http://www.clinical-genitourinary-cancer.com/article/S1558-7673(16)30134-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27498023 PubMed]
 +
 
 +
==Axitinib & Avelumab {{#subobject:e83faz|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen variant #1, weight-based dosing {{#subobject:88ca4d|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716603/ Motzer et al. 2019 (JAVELIN Renal 101)]
 +
|2016-2017
 +
| style="background-color:#1a9851" |Phase III (E-RT-esc)
 +
|[[#Sunitinib_monotherapy_2|Sunitinib]]
 +
| style="background-color:#1a9850" |Superior PFS
 +
|-
 +
|}
 +
''Note: this is not the FDA-recommended dose.''
 +
====Chemotherapy====
 +
*[[Axitinib (Inlyta)]] 5 mg PO twice per day
 +
====Immunotherapy====
 +
*[[Avelumab (Bavencio)]] 10 mg/kg IV once on day 1
 +
'''14-day cycles'''
 +
 
 +
===Regimen variant #2, flat dosing {{#subobject:33ca4d|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 +
|-
 +
|}
 +
''Note: this is not the dose described in Motzer et al. 2019.''
 +
====Chemotherapy====
 +
*[[Axitinib (Inlyta)]] 5 mg PO twice per day
 +
====Immunotherapy====
 +
*[[Avelumab (Bavencio)]] 800 mg IV once on day 1
 +
'''14-day cycles'''
 +
===References===
 +
# '''JAVELIN Renal 101:''' Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M, Lee JL, Vasiliev A, Miller WH Jr, Gurney H, Schmidinger M, Larkin J, Atkins MB, Bedke J, Alekseev B, Wang J, Mariani M, Robbins PB, Chudnovsky A, Fowst C, Hariharan S, Huang B, di Pietro A, Choueiri TK. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1103-1115. Epub 2019 Feb 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1816047 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716603/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30779531 PubMed]
 +
 
 +
==Axitinib & Pembrolizumab {{#subobject:e83gac|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:22bc4d|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1816714 Rini et al. 2019 (KEYNOTE-426)]
 +
|2016-2018
 +
| style="background-color:#1a9851" |Phase III (E-RT-esc)
 +
|[[#Sunitinib_monotherapy_2|Sunitinib]]
 +
| style="background-color:#1a9850" |Superior OS
 +
|-
 +
|}
 +
====Chemotherapy====
 +
*[[Axitinib (Inlyta)]] 5 mg PO twice per day
 +
====Immunotherapy====
 +
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 +
'''21-day cycles'''
 +
 
 +
===References===
 +
# '''KEYNOTE-426:''' Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, Vynnychenko I, Kryzhanivska A, Bondarenko I, Azevedo SJ, Borchiellini D, Szczylik C, Markus M, McDermott RS, Bedke J, Tartas S, Chang YH, Tamada S, Shou Q, Perini RF, Chen M, Atkins MB, Powles T; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116-1127. Epub 2019 Feb 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1816714 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30779529 PubMed]
 +
 
 +
==Bevacizumab monotherapy {{#subobject:29beb2|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:433717|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
![[Overall response rate|ORR]]
 +
!Comparator [[Overall response rate|ORR]]
 +
|-
 +
|[http://jco.ascopubs.org/content/25/29/4536.full Bukowski et al. 2007]
 +
|2004
 +
| style="background-color:#1a9851" |Randomized Phase II (C)
 +
|[[#Erlotinib_.26_Bevacizumab|Erlotinib & Bevacizumab]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoints of ORR/PFS
 +
|13%
 +
|14%
 +
|-
 +
|}
 +
====Chemotherapy====
 +
*[[Bevacizumab (Avastin)]] 10 mg/kg IV over 90 minutes once on day 1
 +
**Can subsequently be reduced to 60 and 30 minute infusions as tolerated
 +
 
 +
'''14-day cycle for up to 52 cycles (2 years)'''
 +
 
 +
===References===
 +
# Bukowski RM, Kabbinavar FF, Figlin RA, Flaherty K, Srinivas S, Vaishampayan U, Drabkin HA, Dutcher J, Ryba S, Xia Q, Scappaticci FA, McDermott D. Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol. 2007 Oct 10;25(29):4536-41. Epub 2007 Sep 17. [http://jco.ascopubs.org/content/25/29/4536.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17876014 PubMed]
 +
 
 +
==Bevacizumab & Interferon alfa-2a {{#subobject:808d58|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen variant #1, 1 year {{#subobject:dbebac|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61904-7/fulltext Escudier et al. 2007 (AVOREN)]
 +
|2004-2005
 +
| style="background-color:#1a9851" |Phase III (E-RT-esc)
 +
|[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (*)
 +
|-
 +
|}
 +
''Note: Reported efficacy for AVOREN is based on the 2010 update.''
 +
====Chemotherapy====
 +
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
 +
====Immunotherapy====
 +
*[[Interferon alfa-2a (Roferon-A)]] 9,000,000 units SC 3 times per week
 +
**Dose can be reduced to 3,000,000 or 6,000,000 units SC 3 times per week based on tolerability
 +
 
 +
'''14-day cycle for up to 26 cycles (1 year)'''
 +
====Subsequent treatment====
 +
*[[#Bevacizumab_monotherapy_2|Bevacizumab maintenance]]
 +
 
 +
===Regimen variant #2, indefinite {{#subobject:d136cc|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651074/ Rini et al. 2008 (CALGB 90206)]
 +
| style="background-color:#1a9851" |Phase III (E-esc)
 +
|[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
 +
| style="background-color:#d9ef8b" |Might have superior OS (*)
 +
|-
 +
|[https://doi.org/10.1200/JCO.2013.50.5305 Rini et al. 2013 (INTORACT)]
 
| style="background-color:#1a9851" |Phase III (C)
 
| style="background-color:#1a9851" |Phase III (C)
−
|Interferon alfa-NL
+
|Temsirolimus & Bevacizumab
−
| style="background-color:#d9ef8b" |Might have superior OS
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|}
 +
''Note: Reported efficacy for CALGB 90206 is based on the 2010 update.''
 +
====Chemotherapy====
 +
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
 +
====Immunotherapy====
 +
*[[Interferon alfa-2a (Roferon-A)]] 9,000,000 units SC 3 times per week
 +
**Dose can be reduced to 3,000,000 or 6,000,000 units SC 3 times per week based on tolerability
 +
 
 +
'''14-day cycles'''
 +
 
 +
===References===
 +
# '''AVOREN:''' Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007 Dec 22;370(9605):2103-11. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61904-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18156031 PubMed]
 +
## '''Update:''' Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, Sneller V. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010 May 1;28(13):2144-50. Epub 2010 Apr 5. [http://jco.ascopubs.org/content/28/13/2144.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20368553 PubMed]
 +
# '''CALGB 90206:''' Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008 Nov 20;26(33):5422-8. Epub 2008 Oct 20. [http://jco.ascopubs.org/content/26/33/5422.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651074/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18936475 PubMed]
 +
## '''Update:''' Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010 May 1;28(13):2137-43. Epub 2010 Apr 5. [http://jco.ascopubs.org/content/28/13/2137.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860433/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20368558 PubMed]
 +
# '''INTORACT:''' Rini BI, Bellmunt J, Clancy J, Wang K, Niethammer AG, Hariharan S, Escudier B. Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol. 2014 Mar 10;32(8):752-9. Epub 2013 Dec 2. [https://doi.org/10.1200/JCO.2013.50.5305 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24297945 PubMed]
 +
 
 +
==Cabozantinib monotherapy {{#subobject:e3ff16|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:a0ee63|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 +
|-
 +
|}
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455807/ Choueiri et al. 2016 (CABOSUN)]
 +
|2013-2015
 +
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
 +
|[[#Sunitinib_monotherapy_2|Sunitinib]]
 +
| style="background-color:#1a9850" |Superior PFS (*)
 +
|-
 +
|}
 +
''Note: reported efficacy is based on the 2018 update; in this update, independent review gave an ORR of 20% (95% CI 12-31%) in the experimental arm and 9% (95% CI 4-18%) in the control arm.''
 +
====Chemotherapy====
 +
*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 60 mg PO once per day
 +
 
 +
'''Continued indefinitely'''
 +
 
 +
===References===
 +
# '''CABOSUN:''' Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, Feldman DR, Olencki T, Picus J, Small EJ, Dakhil S, George DJ, Morris MJ. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol. 2017 Feb 20;35(6):591-597. Epub 2016 Nov 14. [https://doi.org/10.1200/JCO.2016.70.7398 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455807/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28199818 PubMed]
 +
## '''Update:''' Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, Walsh M, Olencki T, Picus J, Small EJ, Dakhil S, Feldman DR, Mangeshkar M, Scheffold C, George D, Morris MJ. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer. 2018 May;94:115-125. Epub 2018 Mar 20. [https://www.ejcancer.com/article/S0959-8049(18)30181-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057479/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29550566 PubMed]
 +
 
 +
==Doxorubicin & Gemcitabine {{#subobject:bad0b3|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:bdc472|Variant=1}}===
 +
{| class="wikitable" style="width: 50%; text-align:center;"
 +
! style="width: 50%" |Study
 +
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[http://www.springerlink.com/content/dnk52234n2567m5h/?MUD=MP Haas et al. 2012 (ECOG 8802)]
 +
| style="background-color:#91cf61" |Phase II
 +
|-
 +
|}
 +
''Patients had disease with sarcomatoid features.''
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV push once on day 1
 +
*[[Gemcitabine (Gemzar)]] 1500 mg/m<sup>2</sup> IV over 30 minutes once on day 1
 +
====Supportive medications====
 +
*One of the following:
 +
**[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 2 or 3, given until day 10
 +
**[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 2
 +
 
 +
'''14-day cycle for 6 to 9 cycles (cumulative doxorubicin dose of 300 to 450 mg/m<sup>2</sup>, depending on cardiac function)'''
 +
 
 +
===References===
 +
# '''ECOG 8802:''' Haas NB, Lin X, Manola J, Pins M, Liu G, McDermott D, Nanus D, Heath E, Wilding G, Dutcher J. A phase II trial of doxorubicin and gemcitabine in renal cell carcinoma with sarcomatoid features: ECOG 8802. Med Oncol. 2012 Jun;29(2):761-7. Epub 2011 Feb 6. [http://www.springerlink.com/content/dnk52234n2567m5h/?MUD=MP link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566570/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21298497 PubMed]
 +
 
 +
==Erlotinib monotherapy {{#subobject:862d0a|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:79bb24|Variant=1}}===
 +
{| class="wikitable" style="width: 75%; text-align:center;"
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2793000/ Gordon et al. 2009 (SWOG S0317)]
 +
| style="background-color:#91cf61" |Phase II
 +
|11% (95% CI 3-24%)
 +
|-
 +
|}
 +
====Chemotherapy====
 +
*[[Erlotinib (Tarceva)]] 150 mg PO once per day, given 1 hour before or 2 hours after meals
 +
 
 +
'''Continued indefinitely'''
 +
 
 +
===References===
 +
# '''SWOG S0317:''' Gordon MS, Hussey M, Nagle RB, Lara PN Jr, Mack PC, Dutcher J, Samlowski W, Clark JI, Quinn DI, Pan CX, Crawford D. Phase II study of erlotinib in patients with locally advanced or metastatic papillary histology renal cell cancer: SWOG S0317. J Clin Oncol. 2009 Dec 1;27(34):5788-93. Epub 2009 Nov 2. [http://jco.ascopubs.org/content/27/34/5788.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2793000/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19884559 PubMed]
 +
 
 +
==Erlotinib & Bevacizumab {{#subobject:1a1b7b|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:1e7b71|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[http://jco.ascopubs.org/content/25/29/4536.full Bukowski et al. 2007]
 +
|2004
 +
| style="background-color:#1a9851" |Randomized Phase II (E-esc)
 +
|[[#Bevacizumab_monotherapy|Bevacizumab]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoints of ORR/PFS
 +
|-
 +
|}
 +
====Chemotherapy====
 +
*[[Erlotinib (Tarceva)]] 150 mg PO once per day
 +
*[[Bevacizumab (Avastin)]] 10 mg/kg IV over 90 minutes once on day 1
 +
**Can subsequently be reduced to 60 and 30 minute infusions as tolerated
 +
 
 +
'''14-day cycle for up to 52 cycles (2 years)'''
 +
 
 +
===References===
 +
# Bukowski RM, Kabbinavar FF, Figlin RA, Flaherty K, Srinivas S, Vaishampayan U, Drabkin HA, Dutcher J, Ryba S, Xia Q, Scappaticci FA, McDermott D. Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol. 2007 Oct 10;25(29):4536-41. Epub 2007 Sep 17. [http://jco.ascopubs.org/content/25/29/4536.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17876014 PubMed]
 +
 
 +
==Everolimus monotherapy {{#subobject:b3af63|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:474ade|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[http://jco.ascopubs.org/content/32/25/2765.long Motzer et al. 2014 (RECORD-3)]
 +
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
 +
|[[#Sunitinib_monotherapy_2|Sunitinib]]
 +
| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879109/ Tannir et al. 2015 (ESPN)]
 +
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
 +
|[[#Sunitinib_monotherapy_2|Sunitinib]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00515-X/fulltext Armstrong et al. 2016 (ASPEN)]
 +
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
 +
|[[#Sunitinib_monotherapy_2|Sunitinib]]
 +
| style="background-color:#fee08b" |Might have inferior PFS
 +
|-
 +
|}
 +
====Chemotherapy====
 +
*[[Everolimus (Afinitor)]] 10 mg PO once per day
 +
**Dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability
 +
 
 +
'''Continued indefinitely'''
 +
====Subsequent treatment====
 +
*RECORD-3, upon progression: [[#Sunitinib_monotherapy_3|Sunitinib]]
 +
 
 +
===References===
 +
<!-- # '''Abstract:''' Robert John Motzer, Carlos H. Barrios, Tae Min Kim, Silvia Falcon, Thomas Cosgriff, W. Graydon Harker, Kenneth B. Pittman, Roberto Sabbatini, Sun Young Rha, Thomas W. Flaig, Ray D. Page, Sevil E. Bavbek, J. Thaddeus Beck, Poulam M Patel, Edward Schiff, Alexandra Vaury, Julie Niolat, Sven Gogov, Ozlem Anak, Jennifer Knox. Record-3: Phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC). 2013 ASCO Annual Meeting abstract 4504. [http://meetinglibrary.asco.org/content/113103-132 link to abstract] -->
 +
# '''RECORD-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [http://jco.ascopubs.org/content/32/25/2765.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25049330 PubMed]
 +
# '''ESPN:''' Tannir NM, Jonasch E, Albiges L, Altinmakas E, Ng CS, Matin SF, Wang X, Qiao W, Dubauskas Lim Z, Tamboli P, Rao P, Sircar K, Karam JA, McDermott DF, Wood CG, Choueiri TK. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol. 2016 May;69(5):866-74. Epub 2015 Nov 26. [http://www.europeanurology.com/article/S0302-2838(15)01083-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879109/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26626617 PubMed]
 +
# Armstrong AJ, Halabi S, Eisen T, Broderick S, Stadler WM, Jones RJ, Garcia JA, Vaishampayan UN, Picus J, Hawkins RE, Hainsworth JD, Kollmannsberger CK, Logan TF, Puzanov I, Pickering LM, Ryan CW, Protheroe A, Lusk CM, Oberg S, George DJ. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016 Mar;17(3):378-88. Epub 2016 Jan 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00515-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26794930 PubMed]
 +
 
 +
==Gemcitabine & Sunitinib {{#subobject:ec76af|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen variant #1 {{#subobject:py1|Variant=1}}===
 +
{| class="wikitable" style="width: 50%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.29503/abstract Michaelson et al. 2015 (MGH 07-212)]
 +
|2007-2013
 +
| style="background-color:#91cf61" |Phase II
 +
|-
 +
|}
 +
''Patients had disease with sarcomatoid features.''
 +
====Chemotherapy====
 +
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Sunitinib (Sutent)]] 37.5 mg PO once per day on days 1 to 14
 +
 
 +
'''21-day cycles'''
 +
 
 +
===Regimen variant #2 {{#subobject:e9a6b9|Variant=1}}===
 +
{| class="wikitable" style="width: 50%; text-align:center;"
 +
! style="width: 50%" |Study
 +
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2011.10096.x/full Pandya et al. 2011]
 +
| style="background-color:#ffffbe" |Retrospective
 +
|-
 +
|}
 +
====Chemotherapy====
 +
*[[Gemcitabine (Gemzar)]] 750 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1 & 8
 +
*[[Sunitinib (Sutent)]] 37.5 mg PO once per day on days 2 to 15
 +
 
 +
'''21-day cycles'''
 +
 
 +
===References===
 +
# '''Retrospective:''' Pandya SS, Mier JW, McDermott DF, Cho DC. Addition of gemcitabine at the time of sunitinib resistance in metastatic renal cell cancer. BJU Int. 2011 Oct;108(8 Pt 2):E245-9. Epub 2011 Feb 14. [https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2011.10096.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21320274 PubMed]
 +
# '''MGH 07-212:''' Michaelson MD, McKay RR, Werner L, Atkins MB, Van Allen EM, Olivier KM, Song J, Signoretti S, McDermott DF, Choueiri TK. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer. 2015 Oct 1;121(19):3435-43. Epub 2015 Jun 8. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.29503/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26058385 PubMed]
 +
 
 +
==High-dose Interleukin-2 {{#subobject:d95f4e|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
HD IL-2: '''<u>H</u>'''igh-'''<u>D</u>'''ose '''<u>I</u>'''nter'''<u>L</u>'''eukin-'''<u>2</u>'''
 +
===Example orders===
 +
*[[Example orders for High-dose (HD) IL-2 in renal cancer]]
 +
 
 +
===Regimen variant #1, 1.8 MU/kg/day, intermittent {{#subobject:ca472e|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[http://jamanetwork.com/journals/jama/article-abstract/368156 Rosenberg et al. 1994]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#91cf61" |Non-randomized
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/JCO.1995.13.3.688 Fyfe et al. 1995]
 +
|NR
 +
| style="background-color:#91cf61" |Phase II (RT)
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[http://jco.ascopubs.org/content/23/1/133.long McDermott et al. 2005]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#1a9851" |Phase III (C)
 +
|Subcutaneous IL-2 & Interferon
 +
| style="background-color:#d9ef8b" |Might have superior PFS
 +
|-
 +
|}
 +
====Immunotherapy====
 +
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 600,000 units/kg IV every 8 hours for up to 14 doses per week, on days 1 to 5, 15 to 19
 +
 
 +
====Supportive medications====
 +
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10, 15 to 24
 +
*All antihypertensive therapy discontinued at least 24 hours before each cycle
 +
*[[Acetaminophen (Tylenol)]] 650 mg PO every 4 hours
 +
*[[Indomethacin (Indocin)]] 25 mg PO every 6 hours
 +
*[[Ranitidine (Zantac)]] 150 mg PO or [[Famotidine (Pepcid)]] 20 mg PO every 12 hours
 +
*[[Hydroxyzine (Atarax)]] 25 to 50 mg PO every 6 hours or [[Diphenhydramine (Benadryl)]] 25 mg PO every (note: frequency was blank in reference) hours for pruritis
 +
*[[Meperidine (Demerol)]] 25 to 50 mg PO every 6 hours for chills and rigors
 +
*"An antidiarrheal agent, antiemetics, anxiolytics, diuretics, and vasopressors as needed"
 +
 
 +
'''28-day cycle for up to 3 cycles'''
 +
 
 +
===Regimen variant #2, 2.16 MU/kg/day, intermittent, goal 10.8 MU {{#subobject:9867a|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="2" |[https://ascopubs.org/doi/abs/10.1200/JCO.1994.12.8.1572 Yang et al. 1994]
 +
| rowspan="2" style="background-color:#1a9851" |Phase III (C)
 +
|1. [[#Low-dose_Interleukin-2|LD IL-2 (IV)]]
 +
| style="background-color:#91cf60" |Seems to have superior ORR
 +
|-
 +
|2. [[#Low-dose_Interleukin-2|LD IL-2 (SC)]]
 +
| style="background-color:#91cf60" |Seems to have superior ORR
 +
|-
 +
|}
 +
''Note: efficacy is based on the 2003 update.''
 +
====Immunotherapy====
 +
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours for up to 15 doses
 +
**Then after 7 to 10 days of rest, [[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours for up to 15 doses is given again
 +
 
 +
'''8-week cycle for up to 2 cycles'''
 +
 
 +
===Regimen variant #3, 2.16 MU/kg/day, intermittent, goal 8.64 MU {{#subobject:9a662|Variant=1}}===
 +
{| class="wikitable" style="width: 50%; text-align:center;"
 +
! style="width: 50%" |Study
 +
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486432/ Klapper et al. 2008]
 +
| style="background-color:#ffffbe" |Retrospective
 +
|-
 +
|}
 +
====Immunotherapy====
 +
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours for up to 12 doses (reduced from originally up to 15 doses due to few patients tolerating 15 doses)
 +
**Then after 10 to 15 days of rest, [[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours for up to 12 doses is given again
 +
 
 +
====Supportive medications====
 +
*"Routine administration of antipyretics, anti-inflammatories, antiemetics, antidiarrheals, and H2 antagonists."
 +
 
 +
====Subsequent treatment====
 +
*After this one course of treatments--defined by the paper as "two cycles"--patients with stable to improved disease would receive additional courses of treatments every 2 months (no maximum number of courses listed)
 +
 
 +
===Regimen variant #4, 5 MU/m<sup>2</sup>/day, CI {{#subobject:bd04b6|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1999.17.8.2521 Figlin et al. 1999]
 +
| style="background-color:#1a9851" |Phase III (C)
 +
|IL-2 & CD8+ TILs
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|}
 +
====Immunotherapy====
 +
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 5,000,000 units/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on days 1, 8, 15, 22 (total dose per cycle: 80 MU/m<sup>2</sup>)
 +
 
 +
'''8-week cycles'''
 +
 
 +
===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]
 +
# Yang JC, Topalian SL, Parkinson D, Schwartzentruber DJ, Weber JS, Ettinghausen SE, White DE, Steinberg SM, Cole DJ, Kim HI, Levin R, Guleria A, MacFarlane MP, White RL, Einhorn JH, Seipp CA, Rosenberg SA. Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol. 1994 Aug;12(8):1572-6. [https://ascopubs.org/doi/abs/10.1200/JCO.1994.12.8.1572 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8040669 PubMed]
 +
## '''Update:''' Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. [http://jco.ascopubs.org/content/21/16/3127.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275327/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275327/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/12915604 PubMed]
 +
# Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995 Mar;13(3):688-96. [https://doi.org/10.1200/JCO.1995.13.3.688 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7884429 PubMed]
 +
# Figlin RA, Thompson JA, Bukowski RM, Vogelzang NJ, Novick AC, Lange P, Steinberg GD, Belldegrun AS. Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol. 1999 Aug;17(8):2521-9. [https://doi.org/10.1200/JCO.1999.17.8.2521 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10561318 PubMed]
 +
# McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, Kirkwood JM, Gordon MS, Sosman JA, Ernstoff MS, Tretter CP, Urba WJ, Smith JW, Margolin KA, Mier JW, Gollob JA, Dutcher JP, Atkins MB. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005 Jan 1;23(1):133-41. [http://jco.ascopubs.org/content/23/1/133.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15625368 PubMed]
 +
# '''Retrospective:''' Klapper JA, Downey SG, Smith FO, Yang JC, Hughes MS, Kammula US, Sherry RM, Royal RE, Steinberg SM, Rosenberg S. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma : a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008 Jul 15;113(2):293-301. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.23552/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486432/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18457330 PubMed]
 +
 
 +
==Low-dose Interleukin-2 {{#subobject:a2e938|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
LD IL-2: '''<u>L</u>'''ow-'''<u>D</u>'''ose '''<u>I</u>'''nter'''<u>L</u>'''eukin-'''<u>2</u>'''
 +
===Regimen variant #1, Intravenous {{#subobject:445b6c|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="2" |[https://ascopubs.org/doi/abs/10.1200/JCO.1994.12.8.1572 Yang et al. 1994]
 +
| rowspan="2" style="background-color:#1a9851" |Phase III (E-de-esc)
 +
|1. [[#High-dose_Interleukin-2|High-dose IL-2]]
 +
| style="background-color:#fc8d59" |Seems to have inferior ORR
 +
|-
 +
|2. Subcutaneous LD IL-2
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|}
 +
''Note: efficacy is based on the 2003 update.''
 +
====Immunotherapy====
 +
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] as follows:
 +
**72,000 units/kg IV every 8 hours for up to 15 doses
 +
**Then after 7 to 10 days of rest: 72,000 units/kg IV every 8 hours for up to 15 doses is given again
 +
 
 +
'''8-week cycle for up to 2 cycles'''
 +
 
 +
===Regimen variant #2, Subcutaneous {{#subobject:cbb5b2|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="2" |[https://ascopubs.org/doi/abs/10.1200/JCO.1994.12.8.1572 Yang et al. 1994]
 +
| rowspan="2" style="background-color:#1a9851" |Phase III (E-de-esc)
 +
|1. [[#High-dose_Interleukin-2|High-dose IL-2]]
 +
| style="background-color:#fc8d59" |Seems to have inferior ORR
 +
|-
 +
|2. Intravenous LD IL-2
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|}
 +
''Note: this arm was added to the trial after the interim results were announced in 1994.''
 +
====Immunotherapy====
 +
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] as follows:
 +
**Week 1: 250,000 units/kg SC once per day for 5 days
 +
**Weeks 2 to 6: 125,000 units/kg SC once per day for 5 days per week
 +
 
 +
'''8-week cycle for up to 2 cycles'''
 +
 
 +
===References===
 +
# Yang JC, Topalian SL, Parkinson D, Schwartzentruber DJ, Weber JS, Ettinghausen SE, White DE, Steinberg SM, Cole DJ, Kim HI, Levin R, Guleria A, MacFarlane MP, White RL, Einhorn JH, Seipp CA, Rosenberg SA. Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol. 1994 Aug;12(8):1572-6. [https://ascopubs.org/doi/abs/10.1200/JCO.1994.12.8.1572 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8040669 PubMed]
 +
## '''Update:''' Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. [http://jco.ascopubs.org/content/21/16/3127.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275327/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275327/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/12915604 PubMed]
 +
 
 +
==Interferon alfa-2a monotherapy {{#subobject:8f04d6|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen variant #1, 5 MU 5x per week {{#subobject:f49d4e|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/oxfordjournals.annonc.a059097 Sagaster et al. 1995]
 +
|NR-1992
 +
| style="background-color:#1a9851" |Phase III (C)
 +
|Cimetidine, Coumarin, IFN alfa-2a
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|}
 +
====Immunotherapy====
 +
*[[Interferon alfa-2a (Roferon-A)]] 5,000,000 units SC 5 times per week
 +
 
 +
'''Continued indefinitely'''
 +
 
 +
===Regimen variant #2, 9 MU TIW {{#subobject:524ccc|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61904-7/fulltext Escudier et al. 2007 (AVOREN)]
 +
|2004-2005
 +
| style="background-color:#1a9851" |Phase III (C)
 +
|[[#Bevacizumab_.26_Interferon_alfa-2a|Bevacizumab & Interferon alfa-2a]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (*)
 
|-
 
|-
−
|[https://journals.lww.com/immunotherapy-journal/fulltext/2014/11000/Adjuvant_Low_Dose_Interleukin_2__IL_2__Plus.2.aspx Passalacqua et al. 2014 (POLAR-01)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651074/ Rini et al. 2008 (CALGB 90206)]
−
|1994-2006
+
|{{#subobject:xx|ToDo=1}}
 
| style="background-color:#1a9851" |Phase III (C)
 
| style="background-color:#1a9851" |Phase III (C)
−
|IFN & IL-2
+
|[[#Bevacizumab_.26_Interferon_alfa-2a|Bevacizumab & Interferon alfa-2a]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
+
| style="background-color:#fee08b" |Might have inferior OS (*)
 +
|-
 +
|[http://jco.ascopubs.org/content/27/8/1280.long Escudier et al. 2009]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#1a9851" |Randomized Phase II (C)
 +
|[[#Sorafenib_monotherapy|Sorafenib]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.2003.02.014 Clark et al. 2003]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835851/ Gore et al. 2010 (MRC RE04/EORTC GU 30012)]
−
|1997-2002
+
|{{#subobject:xx|ToDo=1}}
 
| style="background-color:#1a9851" |Phase III (C)
 
| style="background-color:#1a9851" |Phase III (C)
−
|High-dose IL-2
+
|5-FU, Interferon alfa-2a, IL-2
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS24
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|[http://clincancerres.aacrjournals.org/content/22/13/3172.long Hawkins et al. 2016]
 +
|2007-2010
 +
| style="background-color:#1a9851" |Phase II/III (C)
 +
|Naptumomab estafenatox + IFNα
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|}
 +
''Note: reported efficacy for AVOREN is based on the 2010 update. Reported efficacy for CALGB 90206 is based on the 2010 update.''
 +
====Immunotherapy====
 +
*[[Interferon alfa-2a (Roferon-A)]] 9,000,000 units SC 3 times per week
 +
**Some protocols: Dose can be reduced to 3 or 6,000,000 units SC 3 times per week based on tolerability
 +
 
 +
'''Given for varying lengths of time; see individual trials'''
 +
 
 +
===Regimen variant #3, 9 MU daily, with lead-in {{#subobject:5f04fc|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(04)15590-6/fulltext Jocham et al. 2004]
+
|[https://doi.org/10.1200/JCO.2000.18.16.2972 Motzer et al. 2000]
−
|1997-1998
 
 
| style="background-color:#1a9851" |Phase III (C)
 
| style="background-color:#1a9851" |Phase III (C)
−
|Renal tumor cell vaccine
+
|IFN alfa & 13-CRA
−
| style="background-color:#fc8d59" |Seems to have inferior TTP
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 
|-
 
|-
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60697-2/fulltext Wood et al. 2008 (C-100-12 Part I)]
+
|}
−
|NR
+
====Immunotherapy====
 +
*[[Interferon alfa-2a (Roferon-A)]] as follows:
 +
**Week 1: 3,000,000 units SC once per day
 +
**Week 2 (if prior dose tolerated): 6,000,000 units SC once per day
 +
**Week 3 onwards (if prior dose tolerated): 9,000,000 units SC once per day
 +
 
 +
'''Continued indefinitely'''
 +
 
 +
===Regimen variant #4, 9 MU TIW, with lead-in {{#subobject:2c65a4|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.nejm.org/doi/full/10.1056/NEJMoa065044 Motzer et al. 2007 (A618-1034)]
 +
|2004-2005
 +
| style="background-color:#1a9851" |Phase III (C)
 +
|[[#Sunitinib_monotherapy_2|Sunitinib]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
====Immunotherapy====
 +
*[[Interferon alfa-2a (Roferon-A)]] as follows:
 +
**Week 1: 3,000,000 units SC 3 times per week
 +
**Week 2 (if prior dose tolerated): 6,000,000 units SC 3 times per week
 +
**Week 3 onwards (if prior dose tolerated): 9,000,000 units SC 3 times per week
 +
 
 +
'''Continued indefinitely'''
 +
 
 +
===Regimen variant #5, 10 MU TIW {{#subobject:800dd5|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03544-2/fulltext Ritchie et al. 1999 (MRC RE01)]
 +
| style="background-color:#1a9851" |Phase III (E-switch-ooc)
 +
|MPA
 +
| style="background-color:#91cf60" |Seems to have superior OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835851/ Gore et al. 2010 (MRC RE04/EORTC GU 30012)]
 
| style="background-color:#1a9851" |Phase III (C)
 
| style="background-color:#1a9851" |Phase III (C)
−
|Vitespen
+
|Chemoimmunotherapy
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|}
 +
====Immunotherapy====
 +
*[[Interferon alfa-2a (Roferon-A)]] 10,000,000 units SC 3 times per week
 +
**In MRC RE01, the first two doses were 5,000,000 units
 +
 
 +
'''12-week course (MRC RE01) or continued indefinitely (MRC RE04/EORTC GU 30012)'''
 +
 
 +
===Regimen variant #6, 18 MU TIW, with lead-in {{#subobject:b28245|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ejcancer.com/article/S0959-8049(13)00787-9/fulltext Aitchison et al. 2013 (EORTC 30955)]
+
|[https://doi.org/10.1093/oxfordjournals.annonc.a058185 Fosså et al. 1992]
−
|1998-2007
+
|1985-1986
 +
|style="background-color:#1a9851" |Phase III (C)
 +
|IFN alfa-2a & Vinblastine
 +
| style="background-color:#ffffbf" |Did not meet efficacy endpoints
 +
|-
 +
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa066838 Hudes et al. 2007 (ARCC)]
 +
| rowspan="2" |2003-2005
 +
| rowspan="2" style="background-color:#1a9851" |Phase III (C)
 +
|1. Interferon alfa-2a & Temsirolimus
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|2. [[#Temsirolimus_monotherapy|Temsirolimus]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|}
 +
====Immunotherapy====
 +
*[[Interferon alfa-2a (Roferon-A)]] as follows:
 +
**Week 1: 3,000,000 units SC 3 times per week
 +
**Week 2 (if prior dose tolerated): 9,000,000 units SC 3 times per week
 +
**Week 3 onwards (if prior dose tolerated): 18,000,000 units SC 3 times per week
 +
***If higher doses cannot be tolerated, highest tolerable doses of 3,000,000, 4,500,500, or 6,000,000 units can be used
 +
 
 +
'''Continued indefinitely'''
 +
 
 +
===References===
 +
# Fosså SD, Martinelli G, Otto U, Schneider G, Wander H, Oberling F, Bauer HW, Achtnicht U, Holdener EE. Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: results of a European multi-center phase III study. Ann Oncol. 1992 Apr;3(4):301-5. [https://doi.org/10.1093/oxfordjournals.annonc.a058185 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/1390305 PubMed]
 +
# Sagaster P, Micksche M, Flamm J, Ludwig H. Randomised study using IFN-alpha versus IFN-alpha plus coumarin and cimetidine for treatment of advanced renal cell cancer. Ann Oncol. 1995 Dec;6(10):999-1003. [https://doi.org/10.1093/oxfordjournals.annonc.a059097 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8750152 PubMed]
 +
# '''MRC RE01:''' Ritchie A, Griffiths G, Parmar M; Medical Research Council Renal Cancer Collaborators. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet. 1999 Jan 2;353(9146):14-7. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03544-2/fulltext link to original article] '''contans protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10023944 PubMed]
 +
# Motzer RJ, Murphy BA, Bacik J, Schwartz LH, Nanus DM, Mariani T, Loehrer P, Wilding G, Fairclough DL, Cella D, Mazumdar M. Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol. 2000 Aug;18(16):2972-80. [https://doi.org/10.1200/JCO.2000.18.16.2972 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10944130 PubMed]
 +
# '''A618-1034:''' Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. [https://www.nejm.org/doi/full/10.1056/NEJMoa065044 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17215529 PubMed]
 +
## '''Update:''' Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Aug 1;27(22):3584-90. Epub 2009 Jun 1. [http://jco.ascopubs.org/content/27/22/3584.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646307/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19487381 PubMed] content property of [http://hemonc.org HemOnc.org]
 +
# '''ARCC:''' Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. [https://www.nejm.org/doi/full/10.1056/NEJMoa066838 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538086 PubMed]
 +
# '''AVOREN:''' Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007 Dec 22;370(9605):2103-11. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61904-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18156031 PubMed]
 +
## '''Update:''' Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, Sneller V. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010 May 1;28(13):2144-50. Epub 2010 Apr 5. [http://jco.ascopubs.org/content/28/13/2144.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20368553 PubMed]
 +
# '''CALGB 90206:''' Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008 Nov 20;26(33):5422-8. Epub 2008 Oct 20. [http://jco.ascopubs.org/content/26/33/5422.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651074/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18936475 PubMed]
 +
## '''Update:''' Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010 May 1;28(13):2137-43. Epub 2010 Apr 5. [http://jco.ascopubs.org/content/28/13/2137.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860433/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20368558 PubMed]
 +
# Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, Negrier S, Laferriere N, Scheuring UJ, Cella D, Shah S, Bukowski RM. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Mar 10;27(8):1280-9. Epub 2009 Jan 26. Erratum in: J Clin Oncol. 2009 May 1; 27(13):2305. [http://jco.ascopubs.org/content/27/8/1280.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19171708 PubMed]
 +
# '''MRC RE04/EORTC GU 30012:''' Gore ME, Griffin CL, Hancock B, Patel PM, Pyle L, Aitchison M, James N, Oliver RT, Mardiak J, Hussain T, Sylvester R, Parmar MK, Royston P, Mulders PF. Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial. Lancet. 2010 Feb 20;375(9715):641-8. Epub 2010 Feb 10. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61921-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835851/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20153039 PubMed]
 +
# Hawkins RE, Gore M, Shparyk Y, Bondar V, Gladkov O, Ganev T, Harza M, Polenkov S, Bondarenko I, Karlov P, Karyakin O, Khasanov R, Hedlund G, Forsberg G, Nordle Ö, Eisen T. A randomized phase II/III study of naptumomab estafenatox + IFNα versus IFNα in renal cell carcinoma: final analysis with baseline biomarker subgroup and trend analysis. Clin Cancer Res. 2016 Jul 1;22(13):3172-81. Epub 2016 Feb 5. [http://clincancerres.aacrjournals.org/content/22/13/3172.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26851187 PubMed]
 +
 
 +
==Interferon alfa-2a & Interleukin-2 {{#subobject:77d26e|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:89bca8|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.nejm.org/doi/full/10.1056/NEJM199804303381805 Negrier et al. 1998]
 +
| style="background-color:#1a9851" |Phase III (E-esc)
 +
|1. [[#High-dose_Interleukin-2|HD IL-2]]<br> 2. [[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
 +
| style="background-color:#1a9850" |Superior EFS
 +
|-
 +
|[https://link.springer.com/article/10.1007%2Fs00262-009-0773-9 Passalacqua et al. 2009]
 
| style="background-color:#1a9851" |Phase III (C)
 
| style="background-color:#1a9851" |Phase III (C)
−
|5-FU, IFN, IL-2
+
|Maintenance IFN & IL-2
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 
|-
 
|-
 
|}
 
|}
−
''No treatment after surgery.''
+
''Of historic interest.''
 +
====Immunotherapy====
 +
*[[Interferon alfa-2a (Roferon-A)]]
 +
*[[Aldesleukin (Proleukin)]]
 +
===References===
 +
# Negrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C, Ravaud A, Mercatello A, Peny J, Mousseau M, Philip T, Tursz T; Groupe Français d'Immunothérapie. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. N Engl J Med. 1998 Apr 30;338(18):1272-8. [https://www.nejm.org/doi/full/10.1056/NEJM199804303381805 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9562581 PubMed]
 +
# Passalacqua R, Buzio C, Buti S, Porta C, Labianca R, Pezzuolo D, Camisa R, Sabbatini R, Benecchi L, Messina C, Cengarle R, Vaglio A, Dalla Chiesa M, Tomasello G, Caminiti C. Phase III, randomised, multicentre trial of maintenance immunotherapy with low-dose interleukin-2 and interferon-alpha for metastatic renal cell cancer. Cancer Immunol Immunother. 2010 Apr;59(4):553-61. Epub 2009 Sep 25. [https://link.springer.com/article/10.1007%2Fs00262-009-0773-9 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19779715 PubMed]
 +
 
 +
==Interferon alfa-2b monotherapy {{#subobject:6b5be6|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:39f1ab|Variant=1}}===
 +
{| class="wikitable" style="width: 50%; text-align:center;"
 +
! style="width: 50%" |Study
 +
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06103-7/fulltext Mickisch et al. 2001 (EORTC 30947)]
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 +
|-
 +
|[https://www.nejm.org/doi/full/10.1056/NEJMoa003013 Flanigan et al. 2001 (SWOG 8949)]
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 +
|-
 +
|}
 +
''Of historic interest.''
 
====Preceding treatment====
 
====Preceding treatment====
−
*[[Surgery#Renal_cell_carcinoma_surgery|Surgery]]
+
*[[Surgery#Renal_cell_carcinoma_surgery|Nephrectomy]] versus no preceding treatment
 +
 
 +
====Immunotherapy====
 +
*[[Interferon alfa-2b (Intron-A)]]
 +
 
 +
===References===
 +
# '''EORTC 30947:''' Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R; European Organisation for Research and Treatment of Cancer (EORTC) Genitourinary Group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001 Sep 22;358(9286):966-70. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06103-7/fulltext link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/11583750 PubMed]
 +
# '''SWOG 8949:''' Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, Caton JR Jr, Munshi N, Crawford ED. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001 Dec 6;345(23):1655-9. [https://www.nejm.org/doi/full/10.1056/NEJMoa003013 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11759643 PubMed]
 +
 
 +
==Ipilimumab & Nivolumab {{#subobject:7bc416|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen variant #1 {{#subobject:aa43c1|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1712126 Motzer et al. 2018 (CheckMate 214)]
 +
|2014-2016
 +
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)
 +
|[[#Sunitinib_monotherapy_2|Sunitinib]]
 +
| style="background-color:#1a9850" |Superior OS
 +
|-
 +
|}
 +
''Note: while this is the dosing studied in CheckMate 214, it is not the FDA-recommended dosing.''
 +
====Immunotherapy, part 1====
 +
*[[Ipilimumab (Yervoy)]] 1 mg/kg IV over 30 minutes once on day 1
 +
*[[Nivolumab (Opdivo)]] 3 mg/kg IV over 60 minutes once on day 1
 +
 
 +
'''21-day cycle for 4 cycles, followed by:'''
 +
 
 +
====Immunotherapy, part 2====
 +
*[[Nivolumab (Opdivo)]] 3 mg/kg IV over 60 minutes once on day 1
 +
 
 +
'''14-day cycles'''
 +
 
 +
===Regimen variant #2 {{#subobject:2fc613|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 +
|-
 +
|}
 +
''Note: while this one of two FDA-recommended dosing options, we are not aware of any particular published trial using this dosing.''
 +
====Immunotherapy, part 1====
 +
*[[Ipilimumab (Yervoy)]] 1 mg/kg IV once on day 1, '''given second'''
 +
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1, '''given first'''
 +
 
 +
'''21-day cycle for 4 cycles, followed by:'''
 +
 
 +
====Immunotherapy, part 2====
 +
*[[Nivolumab (Opdivo)]] 240 mg IV once on day 1
 +
 
 +
'''14-day cycles'''
 +
 
 +
===Regimen variant #3 {{#subobject:1d722d|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 +
|-
 +
|}
 +
''Note: while this one of two FDA-recommended dosing options, we are not aware of any particular published trial using this dosing.''
 +
====Immunotherapy, part 1====
 +
*[[Ipilimumab (Yervoy)]] 1 mg/kg IV once on day 1, '''given second'''
 +
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1, '''given first'''
 +
 
 +
'''21-day cycle for 4 cycles, followed by:'''
 +
 
 +
====Immunotherapy, part 2====
 +
*[[Nivolumab (Opdivo)]] 480 mg IV once on day 1
 +
 
 +
'''28-day cycles'''
 +
 
 +
===References===
 +
# '''CheckMate 214:''' Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. Epub 2018 Mar 21. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712126 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29562145 PubMed]
 +
## '''Update:''' Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, Salman P, Escudier B, Beuselinck B, Amin A, Porta C, George S, Neiman V, Bracarda S, Tykodi SS, Barthélémy P, Leibowitz-Amit R, Plimack ER, Oosting SF, Redman B, Melichar B, Powles T, Nathan P, Oudard S, Pook D, Choueiri TK, Donskov F, Grimm MO, Gurney H, Heng DYC, Kollmannsberger CK, Harrison MR, Tomita Y, Duran I, Grünwald V, McHenry MB, Mekan S, Tannir NM; CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019 Oct;20(10):1370-1385. Epub 2019 Aug 16. Erratum in: Lancet Oncol. 2019 Aug 21. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30413-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31427204 PubMed]
 +
 
 +
==Pazopanib monotherapy {{#subobject:443024|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:d6c07c|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
![[Overall response rate|ORR]]
 +
!Comparator [[Overall response rate|ORR]]
 +
|-
 +
|[http://jco.ascopubs.org/content/28/3/475.long Hutson et al. 2010]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#91cf61" |Phase II
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|
 +
|
 +
|-
 +
|[http://jco.ascopubs.org/content/28/6/1061.long Sternberg et al. 2010 (VEG105192)]
 +
|2006-2007
 +
| style="background-color:#1a9851" |Phase III (E-RT-esc)
 +
|[[Renal_cell_carcinoma_-_null_regimens#Placebo_2|Placebo]]
 +
| style="background-color:#1a9850" |Superior PFS
 +
|30% (95% CI 25-36%)
 +
|3% (95% CI 0-6%)
 +
|-
 +
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1303989 Motzer et al. 2013 (COMPARZ)]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#1a9851" |Phase III (E-switch-ic)
 +
|[[#Sunitinib_monotherapy_2|Sunitinib]]
 +
| style="background-color:#eeee01" |Non-inferior PFS
 +
|31% (95% CI 27-34%)
 +
|25% (95% CI 21-28%)
 +
|-
 +
|[https://jamanetwork.com/journals/jamaoncology/fullarticle/2588465 Cirkel et al. 2017 (ROPETAR)]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#1a9851" |Randomized (C)
 +
|Pazopanib/Everolimus
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|
 +
|
 +
|-
 +
|}
 +
====Chemotherapy====
 +
*[[Pazopanib (Votrient)]] 800 mg PO once per day, given 1 hour before or 2 hours after meals
 +
**Dose may be decreased to 600 mg or 400 mg PO once per day depending on tolerability
 +
 
 +
'''Continued indefinitely'''
 +
 
 +
===References===
 +
# Hutson TE, Davis ID, Machiels JP, De Souza PL, Rottey S, Hong BF, Epstein RJ, Baker KL, McCann L, Crofts T, Pandite L, Figlin RA. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2010 Jan 20;28(3):475-80. Epub 2009 Dec 14. [http://jco.ascopubs.org/content/28/3/475.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20008644 PubMed]
 +
# '''VEG105192:''' Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarbá JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010 Feb 20;28(6):1061-8. Epub 2010 Jan 25. [http://jco.ascopubs.org/content/28/6/1061.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20100962 PubMed]
 +
## '''Update:''' Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, Zarba JJ, Gladkov OA, Lee E, Szczylik C, McCann L, Rubin SD, Chen M, Davis ID. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013 Apr;49(6):1287-96. Epub 2013 Jan 12. [https://www.ejcancer.com/article/S0959-8049(12)00980-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23321547 PubMed]
 +
# '''COMPARZ:''' Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, Jin J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R, Pandite LN, Choueiri TK. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013 Aug 22;369(8):722-31. [https://www.nejm.org/doi/full/10.1056/NEJMoa1303989 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23964934 PubMed]
 +
## '''Update:''' Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med. 2014 May 1;370(18):1769-70. [https://www.nejm.org/doi/full/10.1056/NEJMc1400731 link to letter] [https://www.ncbi.nlm.nih.gov/pubmed/24785224 PubMed]
 +
# '''HRQoL analysis:''' Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U, Parikh O, Hawkins R, Sevin E, Négrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol. 2014 May 10;32(14):1412-8. Epub 2014 Mar 31. [https://doi.org/10.1200/JCO.2013.50.8267 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24687826 PubMed]
 +
# '''ROPETAR:''' Cirkel GA, Hamberg P, Sleijfer S, Loosveld OJL, Dercksen MW, Los M, Polee MB, van den Berkmortel F, Aarts MJ, Beerepoot LV, Groenewegen G, Lolkema MP, Tascilar M, Portielje JEA, Peters FPJ, Klümpen HJ, van der Noort V, Haanen JBAG, Voest EE; Dutch WIN-O Consortium. Alternating treatment with pazopanib and everolimus vs continuous pazopanib to delay disease progression in patients with metastatic clear cell renal cell cancer: the ROPETAR randomized clinical trial. JAMA Oncol. 2017 Apr 1;3(4):501-508. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2588465 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27918762 PubMed]
 +
 
 +
==Regorafenib monotherapy {{#subobject:183793|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:a55057|Variant=1}}===
 +
{| class="wikitable" style="width: 75%; text-align:center;"
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 +
|-
 +
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70364-9/fulltext Eisen et al. 2012 (Bayer 11726)]
 +
| style="background-color:#91cf61" |Phase II
 +
|40% (90% CI 28-53%)
 +
|-
 +
|}
 +
====Chemotherapy====
 +
*[[Regorafenib (Stivarga)]] 160 mg PO once per day on days 1 to 21, given while fasting or after a light meal
 +
 
 +
'''28-day cycles'''
 +
 
 +
===References===
 +
# '''Bayer 11726:''' Eisen T, Joensuu H, Nathan PD, Harper PG, Wojtukiewicz MZ, Nicholson S, Bahl A, Tomczak P, Pyrhonen S, Fife K, Bono P, Boxall J, Wagner A, Jeffers M, Lin T, Quinn DI. Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial. Lancet Oncol. 2012 Oct;13(10):1055-62. Epub 2012 Sep 6. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70364-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22959186 PubMed]
 +
 
 +
==Sorafenib monotherapy {{#subobject:fe45b0|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:b76687|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
===Regimen {{#subobject:90ba4d|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
![[Overall response rate|ORR]]
 +
!Comparator [[Overall response rate|ORR]]
 +
|-
 +
|[http://jco.ascopubs.org/content/27/8/1280.long Escudier et al. 2009]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ooc)
 +
|[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|5%
 +
|9%
 +
|-
 +
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.24864/abstract Stadler et al. 2010 (ARCCS)]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#91cf61" |Non-randomized
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569677/ Motzer et al. 2013 (AV-951-09-902)]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#1a9851" |Phase III (C)
 +
|Tivozanib
 +
| style="background-color:#fc8d59" |Seems to have inferior PFS
 +
|
 +
|
 +
|-
 +
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70465-0/fulltext Hutson et al. 2013 (A4061051)]
 +
|2010-2011
 +
| style="background-color:#1a9851" |Phase III (C)
 +
|[[#Axitinib_monotherapy|Axitinib]]
 +
| style="background-color:#fee08b" |Might have inferior PFS (*)
 +
|15%
 +
|32%
 +
|-
 +
|}
 +
''Note: in the 2016 update to A4061051, there is no difference in OS.''
 +
====Chemotherapy====
 +
*[[Sorafenib (Nexavar)]] 400 mg PO twice per day
 +
**Can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity
 +
 
 +
'''Continued indefinitely'''
  
 
===References===
 
===References===
−
# '''INT-0079:''' Messing EM, Manola J, Wilding G, Propert K, Fleischmann J, Crawford ED, Pontes JE, Hahn R, Trump D; Eastern Cooperative Oncology Group/Intergroup trial. Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: an Eastern Cooperative Oncology Group/Intergroup trial. J Clin Oncol. 2003 Apr 1;21(7):1214-22. [https://doi.org/10.1200/JCO.2003.02.005 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12663707 PubMed]
+
# Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, Negrier S, Laferriere N, Scheuring UJ, Cella D, Shah S, Bukowski RM. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Mar 10;27(8):1280-9. Epub 2009 Jan 26. Erratum in: J Clin Oncol. 2009 May 1; 27(13):2305. [http://jco.ascopubs.org/content/27/8/1280.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19171708 PubMed]
−
# Clark JI, Atkins MB, Urba WJ, Creech S, Figlin RA, Dutcher JP, Flaherty L, Sosman JA, Logan TF, White R, Weiss GR, Redman BG, Tretter CP, McDermott D, Smith JW, Gordon MS, Margolin KA. Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine working group randomized trial. J Clin Oncol. 2003 Aug 15;21(16):3133-40. Epub 2003 Jun 16. [https://doi.org/10.1200/JCO.2003.02.014 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12810695 PubMed]
+
# Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010 Mar 1;116(5):1272-80. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.24864/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20082451 PubMed]
−
# Jocham D, Richter A, Hoffmann L, Iwig K, Fahlenkamp D, Zakrzewski G, Schmitt E, Dannenberg T, Lehmacher W, von Wietersheim J, Doehn C. Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial. Lancet. 2004 Feb 21;363(9409):594-9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(04)15590-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14987883 PubMed]
+
# '''AV-951-09-902:''' Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, Tomczak P, Lyulko O, Alyasova A, Harza M, Kogan M, Alekseev BY, Sternberg CN, Szczylik C, Cella D, Ivanescu C, Krivoshik A, Strahs A, Esteves B, Berkenblit A, Hutson TE. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013 Oct 20;31(30):3791-9. Epub 2013 Sep 9. [https://doi.org/10.1200/JCO.2012.47.4940 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569677/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24019545 PubMed]
−
# '''C-100-12 Part I:''' Wood C, Srivastava P, Bukowski R, Lacombe L, Gorelov AI, Gorelov S, Mulders P, Zielinski H, Hoos A, Teofilovici F, Isakov L, Flanigan R, Figlin R, Gupta R, Escudier B; C-100-12 RCC Study Group. An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial. Lancet. 2008 Jul 12;372(9633):145-54. Epub 2008 Jul 3. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60697-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18602688 PubMed] NCT00033904
+
# '''A4061051:''' Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, Rosbrook B, Chen C, Kim S, Vogelzang NJ. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1287-94. Epub 2013 Oct 25. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70465-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24206640 PubMed]
−
# '''EORTC 30955:''' Aitchison M, Bray CA, Van Poppel H, Sylvester R, Graham J, Innes C, McMahon L, Vasey PA. Adjuvant 5-flurouracil, alpha-interferon and interleukin-2 versus observation in patients at high risk of recurrence after nephrectomy for renal cell carcinoma: results of a phase III randomised European Organisation for Research and Treatment of Cancer (Genito-Urinary Cancers Group)/National Cancer Research Institute trial. Eur J Cancer. 2014 Jan;50(1):70-7. Epub 2013 Sep 25. [https://www.ejcancer.com/article/S0959-8049(13)00787-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24074763 PubMed]
+
## '''Update:''' Hutson TE, Al-Shukri S, Stus VP, Lipatov ON, Shparyk Y, Bair AH, Rosbrook B, Andrews GI, Vogelzang NJ. Axitinib versus sorafenib in first-line metastatic renal cell carcinoma: Overall survival from a randomized phase III trial. Clin Genitourin Cancer. 2017 Feb;15(1):72-76. Epub 2016 May 27. [http://www.clinical-genitourinary-cancer.com/article/S1558-7673(16)30134-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27498023 PubMed]
−
# '''POLAR-01:''' Passalacqua R, Caminiti C, Buti S, Porta C, Camisa R, Braglia L, Tomasello G, Vaglio A, Labianca R, Rondini E, Sabbatini R, Nastasi G, Artioli F, Prati A, Potenzoni M, Pezzuolo D, Oliva E, Alberici F, Buzio C; POLAR-01 Trial Investigators; GOIRC. Adjuvant low-dose interleukin-2 (IL-2) plus interferon-α (IFN-α) in operable renal cell carcinoma (RCC): a phase III, randomized, multicentre trial of the Italian Oncology Group for Clinical Research (GOIRC). J Immunother. 2014 Nov-Dec;37(9):440-7. Erratum in: J Immunother. 2015 Jun;38(5):216. [https://journals.lww.com/immunotherapy-journal/fulltext/2014/11000/Adjuvant_Low_Dose_Interleukin_2__IL_2__Plus.2.aspx link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25304727 PubMed] NCT00502034
 
  
−
==Placebo==
+
==Sunitinib monotherapy {{#subobject:b4a97a|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:92e618|Variant=1}}===
 
{| class="wikitable" style="width: 100%; text-align:center;"  
 
{| class="wikitable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 20%"|Comparator
 
!style="width: 20%"|Comparator
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
!style="width: 20%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
+
![[Overall response rate|ORR]]
 +
!Comparator [[Overall response rate|ORR]]
 +
|-
 +
|[https://www.nejm.org/doi/full/10.1056/NEJMoa065044 Motzer et al. 2007 (A618-1034)]
 +
|2004-2005
 +
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)
 +
|[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
 +
| style="background-color:#1a9850" |Superior PFS
 +
|31%
 +
|6%
 +
|-
 +
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970162-7/fulltext Gore et al. 2009 (A618-1037)]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#91cf61" |Non-randomized
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|17%
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[http://clincancerres.aacrjournals.org/content/16/22/5539 Amato et al. 2010 (TroVax Renal Immunotherapy Survival Trial)]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#1a9851" |Phase III (C)
 +
|Sunitinib & MVA-5T4
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|
 +
|
 +
|-
 +
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1303989 Motzer et al. 2013 (COMPARZ)]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#1a9851" |Phase III (C)
 +
|[[#Pazopanib_monotherapy|Pazopanib]]
 +
| style="background-color:#eeee01" |Non-inferior PFS
 +
|25% (95% CI 21-28%)
 +
|31% (95% CI 27-34%)
 +
|-
 +
|[http://jco.ascopubs.org/content/32/25/2765.long Motzer et al. 2014 (RECORD-3)]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
 +
|[[#Everolimus_monotherapy|Everolimus]]
 +
| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
 +
|
 +
|
 +
|-
 +
|[https://www.europeanurology.com/article/S0302-2838(15)00319-X/fulltext Eichelberg et al. 2015 (SWITCH)]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#1a9851" |Phase III (C)
 +
|[[#Sorafenib_monotherapy|Sorafenib]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|
 +
|
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879109/ Tannir et al. 2015 (ESPN)]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
 +
|[[#Everolimus_monotherapy|Everolimus]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|
 +
|
 
|-
 
|-
−
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878938/ Haas et al. 2016 (ECOG-ACRIN E2805)]
+
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00515-X/fulltext Armstrong et al. 2016 (ASPEN)]
−
| rowspan="2" style="background-color:#1a9851" |Phase III (C)
+
|{{#subobject:xx|ToDo=1}}
−
|1. Sorafenib
+
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
+
|[[#Everolimus_monotherapy|Everolimus]]
 +
| style="background-color:#d9ef8b" |Might have superior PFS
 +
|
 
|
 
|
 
|-
 
|-
−
|2. [[Renal_cell_carcinoma#Sunitinib_monotherapy|Sunitinib]]
+
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30408-9/fulltext Rini et al. 2016 (IMPRINT)]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
+
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#1a9851" |Phase III (C)
 +
|Sunitinib & IMA901
 +
| style="background-color:#d9ef8b" |Might have superior OS
 +
|
 
|
 
|
 
|-
 
|-
−
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1611406 Ravaud et al. 2016 (S-TRAC)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455807/ Choueiri et al. 2016 (CABOSUN)]
 +
|2013-2015
 
| style="background-color:#1a9851" |Phase III (C)
 
| style="background-color:#1a9851" |Phase III (C)
−
|[[Renal_cell_carcinoma#Sunitinib_monotherapy|Sunitinib]]
+
|[[#Cabozantinib_monotherapy|Cabozantinib]]
−
| style="background-color:#fc8d59" |Seems to have inferior DFS
+
| style="background-color:#d73027" |Inferior PFS
−
| style="background-color:#1a9850" |Less toxicity
+
|
 +
|
 
|-
 
|-
−
|[https://jamanetwork.com/journals/jamaoncology/fullarticle/2575469 Chamie et al. 2017 (ARISER)]
+
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1712126 Motzer et al. 2018 (CheckMate 214)]
 +
|2014-2016
 
| style="background-color:#1a9851" |Phase III (C)
 
| style="background-color:#1a9851" |Phase III (C)
−
|Girentuximab
+
|[[#Ipilimumab_.26_Nivolumab|Ipilimumab & Nivolumab]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoints of DFS/OS
+
| style="background-color:#d73027" |Inferior OS
 +
|
 
|
 
|
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.2017.73.5324 Motzer et al. 2017 (PROTECT)]
+
|[https://www.nejm.org/doi/10.1056/NEJMoa1803675 Méjean et al. 2018 (CARMENA)]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#1a9851" |Phase III (E-de-esc)
 +
|Nephrectomy & Sunitinib
 +
| style="background-color:#eeee01" |Non-inferior OS
 +
|
 +
|
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716603/ Motzer et al. 2019 (JAVELIN Renal 101)]
 +
|2016-2017
 +
| style="background-color:#1a9851" |Phase III (C)
 +
|[[#Axitinib_.26_Avelumab|Axitinib & Avelumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|
 +
|
 +
|-
 +
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1816714 Rini et al. 2019 (KEYNOTE-426)]
 +
|2016-2018
 
| style="background-color:#1a9851" |Phase III (C)
 
| style="background-color:#1a9851" |Phase III (C)
−
|Pazopanib
+
|[[#Axitinib_.26_Pembrolizumab|Axitinib & Pembrolizumab]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
+
| style="background-color:#d73027" |Inferior OS
 +
|
 
|
 
|
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311952/ Gross-Goupil et al. 2018 (ATLAS-RCC)]
+
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30723-8/fulltext Rini et al. 2019 (IMmotion151)]
−
|2012-2016
+
|{{#subobject:xx|ToDo=1}}
 
| style="background-color:#1a9851" |Phase III (C)
 
| style="background-color:#1a9851" |Phase III (C)
−
|Axitinib
+
|[[#Atezolizumab_.26_Bevacizumab|Atezolizumab & Bevacizumab]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
+
| style="background-color:#fc8d59" |Seems to have inferior PFS
 +
|
 +
|
 +
|-
 +
|}
 +
''Note: reported efficacy for CABOSUN is based on the 2018 update.''
 +
====Chemotherapy====
 +
*[[Sunitinib (Sutent)]] 50 mg PO once per day on days 1 to 28
 +
**Per some references, dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability
 +
 
 +
'''42-day cycles'''
 +
====Subsequent treatment====
 +
*SWITCH, upon progression: [[#Sorafenib_monotherapy_2|Sorafenib]]
 +
 
 +
===References===
 +
# '''A618-1034:''' Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. [https://www.nejm.org/doi/full/10.1056/NEJMoa065044 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17215529 PubMed]
 +
## '''Update:''' Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Aug 1;27(22):3584-90. Epub 2009 Jun 1. [http://jco.ascopubs.org/content/27/22/3584.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646307/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19487381 PubMed]
 +
# '''Retrospective:''' Choueiri TK, Plantade A, Elson P, Negrier S, Ravaud A, Oudard S, Zhou M, Rini BI, Bukowski RM, Escudier B. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol. 2008 Jan 1;26(1):127-31. [http://jco.ascopubs.org/content/26/1/127.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18165647 PubMed]
 +
# '''A618-1037:''' Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009 Aug;10(8):757-63. Epub 2009 Jul 15. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970162-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19615940 PubMed]
 +
# '''TroVax Renal Immunotherapy Survival Trial:''' Amato RJ, Hawkins RE, Kaufman HL, Thompson JA, Tomczak P, Szczylik C, McDonald M, Eastty S, Shingler WH, de Belin J, Goonewardena M, Naylor S, Harrop R. Vaccination of metastatic renal cancer patients with MVA-5T4: a randomized, double-blind, placebo-controlled phase III study. Clin Cancer Res. 2010 Nov 15;16(22):5539-47. Epub 2010 Sep 29. [http://clincancerres.aacrjournals.org/content/16/22/5539 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20881001 PubMed]
 +
# '''COMPARZ:''' Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, Jin J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R, Pandite LN, Choueiri TK. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013 Aug 22;369(8):722-31. [https://www.nejm.org/doi/full/10.1056/NEJMoa1303989 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23964934 PubMed]
 +
## '''Update:''' Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med. 2014 May 1;370(18):1769-70. [https://www.nejm.org/doi/full/10.1056/NEJMc1400731 link to letter] [https://www.ncbi.nlm.nih.gov/pubmed/24785224 PubMed]
 +
# '''HRQoL analysis:''' Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U, Parikh O, Hawkins R, Sevin E, Négrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol. 2014 May 10;32(14):1412-8. Epub 2014 Mar 31. [https://doi.org/10.1200/JCO.2013.50.8267 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24687826 PubMed]
 +
<!-- # '''Abstract:''' Robert John Motzer, Carlos H. Barrios, Tae Min Kim, Silvia Falcon, Thomas Cosgriff, W. Graydon Harker, Kenneth B. Pittman, Roberto Sabbatini, Sun Young Rha, Thomas W. Flaig, Ray D. Page, Sevil E. Bavbek, J. Thaddeus Beck, Poulam M Patel, Edward Schiff, Alexandra Vaury, Julie Niolat, Sven Gogov, Ozlem Anak, Jennifer Knox. Record-3: Phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC). 2013 ASCO Annual Meeting abstract 4504. [http://meetinglibrary.asco.org/content/113103-132 link to abstract] -->
 +
# '''RECORD-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [http://jco.ascopubs.org/content/32/25/2765.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25049330 PubMed]
 +
# '''SWITCH:''' Eichelberg C, Vervenne WL, De Santis M, Fischer von Weikersthal L, Goebell PJ, Lerchenmüller C, Zimmermann U, Bos MM, Freier W, Schirrmacher-Memmel S, Staehler M, Pahernik S, Los M, Schenck M, Flörcken A, van Arkel C, Hauswald K, Indorf M, Gottstein D, Michel MS. SWITCH: A Randomised, Sequential, Open-label Study to Evaluate the Efficacy and Safety of Sorafenib-sunitinib Versus Sunitinib-sorafenib in the Treatment of Metastatic Renal Cell Cancer. Eur Urol. 2015 Nov;68(5):837-47. Epub 2015 May 4. [https://www.europeanurology.com/article/S0302-2838(15)00319-X/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25952317 PubMed]
 +
# '''ESPN:''' Tannir NM, Jonasch E, Albiges L, Altinmakas E, Ng CS, Matin SF, Wang X, Qiao W, Dubauskas Lim Z, Tamboli P, Rao P, Sircar K, Karam JA, McDermott DF, Wood CG, Choueiri TK. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol. 2016 May;69(5):866-74. Epub 2015 Nov 26. [http://www.europeanurology.com/article/S0302-2838(15)01083-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879109/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26626617 PubMed]
 +
# '''ASPEN:''' Armstrong AJ, Halabi S, Eisen T, Broderick S, Stadler WM, Jones RJ, Garcia JA, Vaishampayan UN, Picus J, Hawkins RE, Hainsworth JD, Kollmannsberger CK, Logan TF, Puzanov I, Pickering LM, Ryan CW, Protheroe A, Lusk CM, Oberg S, George DJ. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016 Mar;17(3):378-88. Epub 2016 Jan 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00515-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26794930 PubMed]
 +
# '''IMPRINT:''' Rini BI, Stenzl A, Zdrojowy R, Kogan M, Shkolnik M, Oudard S, Weikert S, Bracarda S, Crabb SJ, Bedke J, Ludwig J, Maurer D, Mendrzyk R, Wagner C, Mahr A, Fritsche J, Weinschenk T, Walter S, Kirner A, Singh-Jasuja H, Reinhardt C, Eisen T. IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2016 Nov;17(11):1599-1611. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30408-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27720136 PubMed]
 +
# '''CABOSUN:''' Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, Feldman DR, Olencki T, Picus J, Small EJ, Dakhil S, George DJ, Morris MJ. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol. 2017 Feb 20;35(6):591-597. Epub 2016 Nov 14. [https://doi.org/10.1200/JCO.2016.70.7398 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455807/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28199818 PubMed]
 +
## '''Update:''' Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, Walsh M, Olencki T, Picus J, Small EJ, Dakhil S, Feldman DR, Mangeshkar M, Scheffold C, George D, Morris MJ. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer. 2018 May;94:115-125. Epub 2018 Mar 20. [https://www.ejcancer.com/article/S0959-8049(18)30181-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057479/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29550566 PubMed]
 +
# '''CheckMate 214:''' Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. Epub 2018 Mar 21. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712126 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29562145 PubMed]
 +
## '''Update:''' Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, Salman P, Escudier B, Beuselinck B, Amin A, Porta C, George S, Neiman V, Bracarda S, Tykodi SS, Barthélémy P, Leibowitz-Amit R, Plimack ER, Oosting SF, Redman B, Melichar B, Powles T, Nathan P, Oudard S, Pook D, Choueiri TK, Donskov F, Grimm MO, Gurney H, Heng DYC, Kollmannsberger CK, Harrison MR, Tomita Y, Duran I, Grünwald V, McHenry MB, Mekan S, Tannir NM; CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019 Oct;20(10):1370-1385. Epub 2019 Aug 16. Erratum in: Lancet Oncol. 2019 Aug 21. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30413-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31427204 PubMed]
 +
# '''CARMENA:''' Méjean A, Ravaud A, Thezenas S, Colas S, Beauval JB, Bensalah K, Geoffrois L, Thiery-Vuillemin A, Cormier L, Lang H, Guy L, Gravis G, Rolland F, Linassier C, Lechevallier E, Beisland C, Aitchison M, Oudard S, Patard JJ, Theodore C, Chevreau C, Laguerre B, Hubert J, Gross-Goupil M, Bernhard JC, Albiges L, Timsit MO, Lebret T, Escudier B. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018 Aug 2;379(5):417-427. Epub 2018 Jun 3. [https://www.nejm.org/doi/10.1056/NEJMoa1803675 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29860937 PubMed]
 +
# '''JAVELIN Renal 101:''' Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M, Lee JL, Vasiliev A, Miller WH Jr, Gurney H, Schmidinger M, Larkin J, Atkins MB, Bedke J, Alekseev B, Wang J, Mariani M, Robbins PB, Chudnovsky A, Fowst C, Hariharan S, Huang B, di Pietro A, Choueiri TK. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1103-1115. Epub 2019 Feb 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1816047 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716603/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30779531 PubMed]
 +
# '''KEYNOTE-426:''' Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, Vynnychenko I, Kryzhanivska A, Bondarenko I, Azevedo SJ, Borchiellini D, Szczylik C, Markus M, McDermott RS, Bedke J, Tartas S, Chang YH, Tamada S, Shou Q, Perini RF, Chen M, Atkins MB, Powles T; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116-1127. Epub 2019 Feb 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1816714 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30779529 PubMed]
 +
# '''IMmotion151:''' Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30723-8/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/31079938 PubMed]
 +
 
 +
==Temsirolimus monotherapy {{#subobject:8160ec|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:f56815|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
![[Overall response rate|ORR]]
 +
!Comparator [[Overall response rate|ORR]]
 +
|-
 +
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa066838 Hudes et al. 2007 (ARCC)]
 +
| rowspan="2" |2003-2005
 +
| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)
 +
|1. [[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
 +
| style="background-color:#1a9850" |Superior OS
 +
|9% (95% CI 5-12%)
 +
|5% (95% CI 2-8%)
 +
|-
 +
|2. Interferon alfa-2a & Temsirolimus
 +
| style="background-color:#d3d3d3" |Not reported
 +
|8% (95% CI 4-12%)
 
|
 
|
 
|-
 
|-
 
|}
 
|}
−
''No active antineoplastic treatment. Note that ATLAS should not be confused with the trials with the same name in breast cancer and in NSCLC.''
+
====Chemotherapy====
 +
*[[Temsirolimus (Torisel)]] 25 mg IV over 30 minutes once on day 1
 +
 
 +
====Supportive medications====
 +
*[[Diphenhydramine (Benadryl)]] (or similar H1 blocker) 25 to 50 mg IV once on day 1; 30 minutes prior to [[Temsirolimus (Torisel)]]
 +
 
 +
'''7-day cycles'''
 +
 
 +
===References===
 +
# '''ARCC:''' Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. [https://www.nejm.org/doi/full/10.1056/NEJMoa066838 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538086 PubMed]
 +
 
 +
=Maintenance after first-line therapy=
 +
==Bevacizumab monotherapy {{#subobject:6aea81|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:a2085a|Variant=1}}===
 +
{| class="wikitable" style="width: 50%; text-align:center;"
 +
! style="width: 50%" |Study
 +
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61904-7/fulltext Escudier et al. 2007 (AVOREN)]
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 +
|-
 +
|}
 
====Preceding treatment====
 
====Preceding treatment====
−
*[[Surgery#Renal_cell_carcinoma_surgery|Surgery]]
+
*[[#Bevacizumab_.26_Interferon_alfa-2a|Bevacizumab & IFN alfa-2a]] x 12 mo
 +
====Chemotherapy====
 +
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
 +
 
 +
'''14-day cycles'''
  
 
===References===
 
===References===
−
# '''ECOG-ACRIN E2805:''' Haas NB, Manola J, Uzzo RG, Flaherty KT, Wood CG, Kane C, Jewett M, Dutcher JP, Atkins MB, Pins M, Wilding G, Cella D, Wagner L, Matin S, Kuzel TM, Sexton WJ, Wong YN, Choueiri TK, Pili R, Puzanov I, Kohli M, Stadler W, Carducci M, Coomes R, DiPaola RS. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016 May 14;387(10032):2008-16. Epub 2016 Mar 9. Erratum in: Lancet. 2016 May 14;387(10032):1998. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00559-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878938/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26969090 PubMed]
+
# '''AVOREN:''' Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007 Dec 22;370(9605):2103-11. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61904-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18156031 PubMed]
−
# '''S-TRAC:''' Ravaud A, Motzer RJ, Pandha HS, George DJ, Pantuck AJ, Patel A, Chang YH, Escudier B, Donskov F, Magheli A, Carteni G, Laguerre B, Tomczak P, Breza J, Gerletti P, Lechuga M, Lin X, Martini JF, Ramaswamy K, Casey M, Staehler M, Patard JJ; S-TRAC Investigators. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016 Dec 8;375(23):2246-2254. Epub 2016 Oct 9. [https://www.nejm.org/doi/full/10.1056/NEJMoa1611406 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27718781 PubMed]
+
## '''Update:''' Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, Sneller V. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010 May 1;28(13):2144-50. Epub 2010 Apr 5. [http://jco.ascopubs.org/content/28/13/2144.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20368553 PubMed]
−
## '''Update:''' Motzer RJ, Ravaud A, Patard JJ, Pandha HS, George DJ, Patel A, Chang YH, Escudier B, Donskov F, Magheli A, Carteni G, Laguerre B, Tomczak P, Breza J, Gerletti P, Lechuga M, Lin X, Casey M, Serfass L, Pantuck AJ, Staehler M. Adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy: subgroup analyses and updated overall survival results. Eur Urol. 2018 Jan;73(1):62-68. Epub 2017 Sep 26. [http://www.europeanurology.com/article/S0302-2838(17)30772-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28967554 PubMed]
 
−
# '''ARISER:''' Chamie K, Donin NM, Klöpfer P, Bevan P, Fall B, Wilhelm O, Störkel S, Said J, Gambla M, Hawkins RE, Jankilevich G, Kapoor A, Kopyltsov E, Staehler M, Taari K, Wainstein AJA, Pantuck AJ, Belldegrun AS. Adjuvant weekly girentuximab following nephrectomy for high-risk renal cell carcinoma: The ARISER randomized clinical trial. JAMA Oncol. 2017 Jul 1;3(7):913-920. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2575469 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27787547 PubMed]
 
−
# '''PROTECT:''' Motzer RJ, Haas NB, Donskov F, Gross-Goupil M, Varlamov S, Kopyltsov E, Lee JL, Melichar B, Rini BI, Choueiri TK, Zemanova M, Wood LA, Reaume MN, Stenzl A, Chowdhury S, Lim HY, McDermott R, Michael A, Bao W, Carrasco-Alfonso MJ, Aimone P, Voi M, Doehn C, Russo P, Sternberg CN; PROTECT investigators. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. J Clin Oncol. 2017 Dec 10;35(35):3916-3923. Epub 2017 Sep 13. [https://doi.org/10.1200/JCO.2017.73.5324 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28902533 PubMed]
 
−
# '''ATLAS:''' Gross-Goupil M, Kwon TG, Eto M, Ye D, Miyake H, Seo SI, Byun SS, Lee JL, Master V, Jin J, DeBenedetto R, Linke R, Casey M, Rosbrook B, Lechuga M, Valota O, Grande E, Quinn DI. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial. Ann Oncol. 2018 Dec 1;29(12):2371-2378. Epub 2018 Oct 20. [https://doi.org/10.1093/annonc/mdy454 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311952/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30346481 PubMed]
 
  
−
=Metastatic disease, first-line=
+
=Metastatic disease, second-line=
−
==Placebo==
+
==Axitinib monotherapy {{#subobject:832684|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
|-
 
|-
Line 133: Line 1,407:
 
|}
 
|}
  
−
===Regimen===
+
===Regimen {{#subobject:a48a96|Variant=1}}===
 
{| class="wikitable" style="width: 100%; text-align:center;"  
 
{| class="wikitable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 141: Line 1,415:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.nejm.org/doi/full/10.1056/NEJM199804303381804 Gleave et al. 1998]
+
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961613-9/fulltext Rini et al. 2011 (AXIS)]
−
|1993-1995
+
|2008-2010
−
| style="background-color:#1a9851" |Phase III (C)
+
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
−
|Interferon gamma-1b
+
|[[#Sorafenib_monotherapy_2|Sorafenib]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
+
| style="background-color:#1a9850" |Superior PFS
 +
|-
 +
|}
 +
''In the 2013 update, ORR was 23% in this arm, and 12% in the control arm.''
 +
====Chemotherapy====
 +
*[[Axitinib (Inlyta)]] as follows:
 +
**5 mg PO twice per day for at least 2 weeks
 +
**Then if tolerated and BP not greater than 150/90, increased to 7 mg PO twice per day
 +
**Then if tolerated and BP not greater than 150/90, increased to 10 mg PO twice per day
 +
**Dose can be reduced to 2 to 3 mg PO twice per day if needed based on tolerability
 +
 
 +
'''Continued indefinitely'''
 +
 
 +
===References===
 +
# '''AXIS:''' Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011 Dec 3;378(9807):1931-9. Epub 2011 Nov 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961613-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22056247 PubMed]
 +
## '''Update:''' Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, Oudard S, Gore ME, Tarazi J, Hariharan S, Chen C, Rosbrook B, Kim S, Rini BI. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013 May;14(6):552-62. Epub 2013 Apr 15. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70093-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23598172 PubMed]
 +
## '''Subgroup analysis:''' Escudier B, Michaelson MD, Motzer RJ, Hutson TE, Clark JI, Lim HY, Porfiri E, Zalewski P, Kannourakis G, Staehler M, Tarazi J, Rosbrook B, Cisar L, Hariharan S, Kim S, Rini BI. Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial. Br J Cancer. 2014 Jun 10;110(12):2821-8. Epub 2014 May 13. [https://www.nature.com/articles/bjc2014244 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056058/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24823696 PubMed]
 +
 
 +
==Bevacizumab monotherapy {{#subobject:dc7874|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:24489f|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275324/ Yang et al. 2003]
 +
|1998-2001
 +
| style="background-color:#1a9851" |Randomized Phase II (E-esc)
 +
|[[Renal_cell_carcinoma_-_null_regimens#Placebo_3|Placebo]]
 +
| style="background-color:#1a9850" |Superior TTP
 +
|-
 +
|}
 +
====Chemotherapy====
 +
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
 +
 
 +
'''14-day cycles'''
 +
 
 +
===References===
 +
# Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003 Jul 31;349(5):427-34. [https://www.nejm.org/doi/full/10.1056/NEJMoa021491 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275324/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/12890841 PubMed]
 +
 
 +
==Cabozantinib monotherapy {{#subobject:pyr1|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:pyv1|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 +
|-
 +
|}
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
![[Overall response rate|ORR]]
 +
!Comparator [[Overall response rate|ORR]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ Choueiri et al. 2015 (METEOR)]
 +
|2013-2014
 +
| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
 +
|[[#Everolimus_monotherapy_2|Everolimus]]
 +
| style="background-color:#1a9850" |Superior OS
 +
| style="background-color:#88419d; color:white " |21% (95% CI 16-28%)
 +
| style="background-color:#6e016b; color:white " |5% (95% CI 2-9%)
 +
|-
 +
|}
 +
====Preceding treatment====
 +
*VEGFR TKI, with progression
 +
 
 +
====Chemotherapy====
 +
*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 60 mg PO once per day
 +
**At least 2 hours before or 1 hour after meals according to the [https://www.cabometyx.com/downloads/CABOMETYXUSPI.pdf Cabozantinib (Cabometyx) package insert]
 +
 
 +
'''Continued indefinitely'''
 +
 
 +
===References===
 +
# '''METEOR:''' Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1814-23. Epub 2015 Sep 25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1510016 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26406150 PubMed]
 +
## '''Update:''' Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, Hammers HJ, Donskov F, Roth BJ, Peltola K, Lee JL, Heng DY, Schmidinger M, Agarwal N, Sternberg CN, McDermott DF, Aftab DT, Hessel C, Scheffold C, Schwab G, Hutson TE, Pal S, Motzer RJ; METEOR investigators. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):917-27. Epub 2016 Jun 5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30107-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27279544 PubMed]
 +
## '''HRQoL analysis:''' Cella D, Escudier B, Tannir NM, Powles T, Donskov F, Peltola K, Schmidinger M, Heng DYC, Mainwaring PN, Hammers HJ, Lee JL, Roth BJ, Marteau F, Williams P, Baer J, Mangeshkar M, Scheffold C, Hutson TE, Pal S, Motzer RJ, Choueiri TK. Quality of life outcomes for cabozantinib versus everolimus in patients with metastatic renal cell carcinoma: METEOR phase III randomized trial. J Clin Oncol. 2018 Mar 10;36(8):757-764. Epub 2018 Jan 29. [https://doi.org/10.1200/JCO.2017.75.2170 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29377755 PubMed]
 +
## '''Update:''' Motzer RJ, Escudier B, Powles T, Scheffold C, Choueiri TK. Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer. 2018 May;118(9):1176-1178. Epub 2018 Mar 26. [https://www.nature.com/articles/s41416-018-0061-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943250/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29576624 PubMed]
 +
 
 +
==Everolimus monotherapy {{#subobject:893557|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:9d436d|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
![[Overall response rate|ORR]]
 +
!Comparator [[Overall response rate|ORR]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/28/6/1061.long Sternberg et al. 2010 (VEG105192)]
+
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2808%2961039-9/fulltext Motzer et al. 2008 (RECORD-1)]
 
|2006-2007
 
|2006-2007
 +
| style="background-color:#1a9851" |Phase III (E-RT-esc)
 +
|[[Renal_cell_carcinoma_-_null_regimens#Placebo_2|Placebo]]
 +
| style="background-color:#1a9850" |Superior PFS
 +
|1%
 +
|0%
 +
|-
 +
|[http://jco.ascopubs.org/content/32/25/2765.long Motzer et al. 2014 (RECORD-3)]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
 +
|[[#Sunitinib_monotherapy_3|Sunitinib]]
 +
| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
 +
|
 +
|
 +
|-
 +
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1510665 Motzer et al. 2015 (CheckMate 025)]
 +
|2012-2014
 
| style="background-color:#1a9851" |Phase III (C)
 
| style="background-color:#1a9851" |Phase III (C)
−
|[[Renal_cell_carcinoma#Pazopanib_monotherapy|Pazopanib]]
+
|[[#Nivolumab_monotherapy|Nivolumab]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|5%
 +
|25%
 +
|-
 +
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext Motzer et al. 2015 (E7080-G000-205)]
 +
|rowspan=2|2012-2013
 +
| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (C)
 +
|1. [[#Everolimus_.26_Lenvatinib | Everolimus & Lenvatinib]]
 
| style="background-color:#d73027" |Inferior PFS
 
| style="background-color:#d73027" |Inferior PFS
 +
|
 +
|
 +
|-
 +
|2. [[#Lenvatinib_monotherapy|Lenvatinib]]
 +
| style="background-color:#fc8d59" |Seems to have inferior PFS
 +
|
 +
|
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ Choueiri et al. 2015 (METEOR)]
 +
|2013-2014
 +
| style="background-color:#1a9851" |Phase III (C)
 +
|[[#Cabozantinib_monotherapy_2|Cabozantinib]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|5% (95% CI 2-9%)
 +
|21% (95% CI 16-28%)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006123/ Motzer et al. 2015 (RECORD-4)]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#91cf61" |Phase II
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|
 +
|
 +
|-
 +
|}
 +
''Note: 72% of patients in Checkmate 025 had anti-angiogenic therapy prior to progression.''
 +
====Preceding treatment====
 +
*RECORD-1 & METEOR: VEGFR TKI, with progression
 +
*RECORD-3: [[#Sunitinib_monotherapy_2|Sunitinib]], with progression
 +
====Chemotherapy====
 +
*[[Everolimus (Afinitor)]] 10 mg PO once per day
 +
**Dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability
 +
 +
'''Continued indefinitely'''
 +
 +
===References===
 +
# '''RECORD-1:''' Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008 Aug 9;372(9637):449-56. Epub 2008 Jul 22. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2808%2961039-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18653228 PubMed]
 +
## '''Update:''' Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A; RECORD-1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010 Sep 15;116(18):4256-65. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.25219/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20549832 PubMed]
 +
<!-- # '''Abstract:''' Robert John Motzer, Carlos H. Barrios, Tae Min Kim, Silvia Falcon, Thomas Cosgriff, W. Graydon Harker, Kenneth B. Pittman, Roberto Sabbatini, Sun Young Rha, Thomas W. Flaig, Ray D. Page, Sevil E. Bavbek, J. Thaddeus Beck, Poulam M Patel, Edward Schiff, Alexandra Vaury, Julie Niolat, Sven Gogov, Ozlem Anak, Jennifer Knox. Record-3: Phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC). 2013 ASCO Annual Meeting abstract 4504. [http://meetinglibrary.asco.org/content/113103-132 link to abstract] -->
 +
# '''RECORD-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [http://jco.ascopubs.org/content/32/25/2765.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25049330 PubMed]
 +
# '''CheckMate 025:''' Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803-13. Epub 2015 Sep 25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1510665 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26406148 PubMed]
 +
## '''HRQoL analysis:''' Cella D, Grünwald V, Nathan P, Doan J, Dastani H, Taylor F, Bennett B, DeRosa M, Berry S, Broglio K, Berghorn E, Motzer RJ. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):994-1003. Epub 2016 Jun 6. Erratum in: Lancet Oncol. 2016 Jul;17 (7):e270. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30125-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521044/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27283863 PubMed]
 +
## '''Subgroup analysis:''' Escudier B, Sharma P, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Gurney H, Donskov F, Peltola K, Wagstaff J, Gauler TC, Ueda T, Zhao H, Waxman IM, Motzer RJ; CheckMate 025 investigators. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol. 2017 Dec;72(6):962-971. Epub 2017 Mar 3. Erratum in: Eur Urol. 2018 Jan 3. [https://www.europeanurology.com/article/S0302-2838(17)30099-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28262413 PubMed]
 +
## '''Subgroup analysis and update:''' Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Saito M, Kimura G, Yonese J, Yao M, Uemura H. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the phase III CheckMate 025 study. Jpn J Clin Oncol. 2019 Jun 1;49(6):506-514. [https://academic.oup.com/jjco/article-abstract/49/6/506/5426435 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30941424 PubMed]
 +
# '''METEOR:''' Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1814-23. Epub 2015 Sep 25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1510016 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26406150 PubMed]
 +
## '''Update:''' Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, Hammers HJ, Donskov F, Roth BJ, Peltola K, Lee JL, Heng DY, Schmidinger M, Agarwal N, Sternberg CN, McDermott DF, Aftab DT, Hessel C, Scheffold C, Schwab G, Hutson TE, Pal S, Motzer RJ; METEOR investigators. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):917-27. Epub 2016 Jun 5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30107-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27279544 PubMed]
 +
## '''HRQoL analysis:''' Cella D, Escudier B, Tannir NM, Powles T, Donskov F, Peltola K, Schmidinger M, Heng DYC, Mainwaring PN, Hammers HJ, Lee JL, Roth BJ, Marteau F, Williams P, Baer J, Mangeshkar M, Scheffold C, Hutson TE, Pal S, Motzer RJ, Choueiri TK. Quality of life outcomes for cabozantinib versus everolimus in patients with metastatic renal cell carcinoma: METEOR phase III randomized trial. J Clin Oncol. 2018 Mar 10;36(8):757-764. Epub 2018 Jan 29. [https://doi.org/10.1200/JCO.2017.75.2170 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29377755 PubMed]
 +
## '''Update:''' Motzer RJ, Escudier B, Powles T, Scheffold C, Choueiri TK. Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer. 2018 May;118(9):1176-1178. Epub 2018 Mar 26. [https://www.nature.com/articles/s41416-018-0061-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943250/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29576624 PubMed]
 +
# '''E7080-G000-205:''' Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26482279 PubMed]
 +
## '''Update:''' Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 Jan;17(1):e4-5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00543-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26758760 PubMed]
 +
# '''RECORD-4:''' Motzer RJ, Alyasova A, Ye D, Karpenko A, Li H, Alekseev B, Xie L, Kurteva G, Kowalyszyn R, Karyakin O, Neron Y, Cosgriff T, Collins L, Brechenmacher T, Lin C, Morgan L, Yang L. Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4). Ann Oncol. 2016 Mar;27(3):441-8. Epub 2015 Dec 17. [https://doi.org/10.1093/annonc/mdv612 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006123/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26681676 PubMed]
 +
 +
==Everolimus & Lenvatinib {{#subobject:21039d|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:71ef67|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext Motzer et al. 2015 (E7080-G000-205)]
 +
|rowspan=2|2012-2013
 +
| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-RT-esc)
 +
|1. [[#Everolimus_monotherapy|Everolimus]]
 +
| style="background-color:#1a9850" |Superior PFS
 +
|-
 +
|2. [[#Lenvatinib_monotherapy|Lenvatinib]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 
|-
 
|-
 
|}
 
|}
 +
''Patients had progressed after [[:Category:VEGFR_inhibitors|VEGFR TKI]] treatment.''
 +
====Chemotherapy====
 +
*[[Everolimus (Afinitor)]] 5 mg PO once per day
 +
*[[Lenvatinib (Lenvima)]] 18 mg PO once per day
  
−
''No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.''
+
'''Continued indefinitely'''
  
 
===References===
 
===References===
−
# Gleave ME, Elhilali M, Fradet Y, Davis I, Venner P, Saad F, Klotz LH, Moore MJ, Paton V, Bajamonde A; Canadian Urologic Oncology Group. Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma. N Engl J Med. 1998 Apr 30;338(18):1265-71. [https://www.nejm.org/doi/full/10.1056/NEJM199804303381804 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9562580 PubMed]
+
# '''E7080-G000-205:''' Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26482279 PubMed]
−
# '''VEG105192:''' Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarbá JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010 Feb 20;28(6):1061-8. Epub 2010 Jan 25. [http://jco.ascopubs.org/content/28/6/1061.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20100962 PubMed]
+
## '''Update:''' Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 Jan;17(1):e4-5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00543-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26758760 PubMed]
−
## '''Update:''' Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, Zarba JJ, Gladkov OA, Lee E, Szczylik C, McCann L, Rubin SD, Chen M, Davis ID. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013 Apr;49(6):1287-96. Epub 2013 Jan 12. [https://www.ejcancer.com/article/S0959-8049(12)00980-X/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23321547 PubMed]
+
 
 +
==Lenvatinib monotherapy {{#subobject:PYR3|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:PYV3|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext Motzer et al. 2015 (E7080-G000-205)]
 +
|rowspan=2|2012-2013
 +
| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-RT-switch-ic)
 +
|1. [[#Everolimus_monotherapy|Everolimus]]
 +
| style="background-color:#91cf60" |Seems to have superior PFS
 +
|-
 +
|2. [[#Everolimus_.26_Lenvatinib | Everolimus & Lenvatinib]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|}
 +
====Chemotherapy====
 +
*[[Lenvatinib (Lenvima)]] 24 mg PO once per day
 +
 
 +
'''Continued indefinitely'''
 +
 
 +
===References===
 +
# '''E7080-G000-205:''' Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26482279 PubMed]
 +
## '''Update:''' Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 Jan;17(1):e4-5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00543-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26758760 PubMed]
  
−
=Metastatic disease, second-line=
+
==Nivolumab monotherapy {{#subobject:pyr2|Regimen=1}}==
−
==Placebo==
 
 
{| 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 variant #1, 0.3 mg/kg q3wk {{#subobject:6d0807|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2014.59.0703 Motzer et al. 2015 (CA209-010)]
 +
| style="background-color:#1a9851" |Randomized Phase II (E-de-esc)
 +
|1. [[#Nivolumab_monotherapy|Nivolumab]]; 2 mg/kg<br> 2. [[#Nivolumab_monotherapy|Nivolumab]]; 10 mg/kg
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|}
 +
====Immunotherapy====
 +
*[[Nivolumab (Opdivo)]] 0.3 mg/kg IV once on day 1
 +
 +
'''21-day cycles'''
 +
 +
===Regimen variant #2, 2 mg/kg q3wk {{#subobject:e0b43a|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2014.59.0703 Motzer et al. 2015 (CA209-010)]
 +
| style="background-color:#1a9851" |Randomized Phase II (E-esc)
 +
|1. [[#Nivolumab_monotherapy|Nivolumab]]; 0.3 mg/kg<br> 2. [[#Nivolumab_monotherapy|Nivolumab]]; 10 mg/kg
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|}
 +
====Immunotherapy====
 +
*[[Nivolumab (Opdivo)]] 2 mg/kg IV once on day 1
 +
 +
'''21-day cycles'''
 +
 +
===Regimen variant #3, 3 mg/kg q2wk {{#subobject:pyv2|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
![[Overall response rate|ORR]]
 +
!Comparator [[Overall response rate|ORR]]
 +
|-
 +
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1510665 Motzer et al. 2015 (CheckMate 025)]
 +
|2012-2014
 +
| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)
 +
|[[#Everolimus_monotherapy_2|Everolimus]]
 +
| style="background-color:#1a9850" |Superior OS
 +
|25%
 +
|5%
 +
|-
 +
|}
 +
====Immunotherapy====
 +
*[[Nivolumab (Opdivo)]] 3 mg/kg IV over 60 minutes 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===
+
===Regimen variant #4, 10 mg/kg q3wk {{#subobject:6f2515|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 25%" |Comparator
 +
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2014.59.0703 Motzer et al. 2015 (CA209-010)]
 +
| style="background-color:#1a9851" |Randomized Phase II (E-esc)
 +
|1.[[#Nivolumab_monotherapy|Nivolumab]]; 0.3 mg/kg<br> 2. [[#Nivolumab_monotherapy|Nivolumab]]; 2 mg/kg
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|}
 +
====Immunotherapy====
 +
*[[Nivolumab (Opdivo)]] 10 mg/kg IV once on day 1
 +
 
 +
'''21-day cycles'''
 +
===References===
 +
# '''CA209-010:''' Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, Vaishampayan UN, Drabkin HA, George S, Logan TF, Margolin KA, Plimack ER, Lambert AM, Waxman IM, Hammers HJ. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. 2015 May 1;33(13):1430-7. Epub 2014 Dec 1. [https://doi.org/10.1200/JCO.2014.59.0703 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806782/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25452452 PubMed]
 +
# '''CheckMate 025:''' Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803-13. Epub 2015 Sep 25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1510665 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26406148 PubMed]
 +
## '''HRQoL analysis:''' Cella D, Grünwald V, Nathan P, Doan J, Dastani H, Taylor F, Bennett B, DeRosa M, Berry S, Broglio K, Berghorn E, Motzer RJ. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):994-1003. Epub 2016 Jun 6. Erratum in: Lancet Oncol. 2016 Jul;17 (7):e270. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30125-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521044/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/27283863 PubMed]
 +
## '''Subgroup analysis:''' Escudier B, Sharma P, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Gurney H, Donskov F, Peltola K, Wagstaff J, Gauler TC, Ueda T, Zhao H, Waxman IM, Motzer RJ; CheckMate 025 investigators. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol. 2017 Dec;72(6):962-971. Epub 2017 Mar 3. Erratum in: Eur Urol. 2018 Jan 3. [https://www.europeanurology.com/article/S0302-2838(17)30099-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28262413 PubMed]
 +
## '''Subgroup analysis and update:''' Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Saito M, Kimura G, Yonese J, Yao M, Uemura H. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the phase III CheckMate 025 study. Jpn J Clin Oncol. 2019 Jun 1;49(6):506-514. [https://academic.oup.com/jjco/article-abstract/49/6/506/5426435 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30941424 PubMed]
 +
 
 +
==Pazopanib monotherapy {{#subobject:443024|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:d6c07c|Variant=1}}===
 
{| class="wikitable" style="width: 100%; text-align:center;"  
 
{| class="wikitable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 176: Line 1,772:
 
!style="width: 20%"|Comparator
 
!style="width: 20%"|Comparator
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
![[Overall response rate|ORR]]
 +
!Comparator [[Overall response rate|ORR]]
 +
|-
 +
|[http://jco.ascopubs.org/content/28/3/475.long Hutson et al. 2010]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#91cf61" |Phase II
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[http://jco.ascopubs.org/content/28/6/1061.long Sternberg et al. 2010 (VEG105192)]
 +
|2006-2007
 +
| style="background-color:#1a9851" |Phase III (E-esc)
 +
|[[Renal_cell_carcinoma_-_null_regimens#Placebo_3|Placebo]]
 +
| style="background-color:#1a9850" |Superior PFS
 +
|30% (95% CI 25-36%)
 +
|3% (95% CI 0-6%)
 +
|-
 +
|[http://www.clinical-genitourinary-cancer.com/article/S1558-7673(13)00052-9/abstract Hainsworth et al. 2013]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#91cf61" |Phase II
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|
 +
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275324/ Yang et al. 2003]
+
|}
−
|1998-2001
+
====Chemotherapy====
−
| style="background-color:#1a9851" |Randomized Phase II (C)
+
*[[Pazopanib (Votrient)]] 800 mg PO once per day, given 1 hour before or 2 hours after meals
−
|[[Renal_cell_carcinoma#Bevacizumab_monotherapy_3|Bevacizumab]]
+
**Dose may be decreased to 600 mg or 400 mg PO once per day depending on tolerability
−
| style="background-color:#d73027" |Inferior TTP
+
 
 +
'''Continued indefinitely'''
 +
 
 +
===References===
 +
# Hutson TE, Davis ID, Machiels JP, De Souza PL, Rottey S, Hong BF, Epstein RJ, Baker KL, McCann L, Crofts T, Pandite L, Figlin RA. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2010 Jan 20;28(3):475-80. Epub 2009 Dec 14. [http://jco.ascopubs.org/content/28/3/475.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20008644 PubMed]
 +
# '''VEG105192:''' Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarbá JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010 Feb 20;28(6):1061-8. Epub 2010 Jan 25. [http://jco.ascopubs.org/content/28/6/1061.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20100962 PubMed]
 +
## '''Update:''' Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, Zarba JJ, Gladkov OA, Lee E, Szczylik C, McCann L, Rubin SD, Chen M, Davis ID. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013 Apr;49(6):1287-96. Epub 2013 Jan 12. [https://www.ejcancer.com/article/S0959-8049(12)00980-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23321547 PubMed]
 +
# Hainsworth JD, Rubin MS, Arrowsmith ER, Khatcheressian J, Crane EJ, Franco LA. Pazopanib as second-line treatment after sunitinib or bevacizumab in patients with advanced renal cell carcinoma: a Sarah Cannon Oncology Research Consortium phase II trial. Clin Genitourin Cancer. 2013 Sep;11(3):270-5. Epub 2013 May 9. [http://www.clinical-genitourinary-cancer.com/article/S1558-7673(13)00052-9/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23665131 PubMed]
 +
 
 +
==Sorafenib monotherapy {{#subobject:6e18d8|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:a50d71|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
![[Overall response rate|ORR]]
 +
!Comparator [[Overall response rate|ORR]]
 
|-
 
|-
 
|[https://www.nejm.org/doi/full/10.1056/NEJMoa060655 Escudier et al. 2007 (TARGET<sub>RCC</sub>)]
 
|[https://www.nejm.org/doi/full/10.1056/NEJMoa060655 Escudier et al. 2007 (TARGET<sub>RCC</sub>)]
 
|2003-2005
 
|2003-2005
−
| style="background-color:#1a9851" |Phase III (C)
+
| style="background-color:#1a9851" |Phase III (E-RT-esc)
−
|[[Renal_cell_carcinoma#Sorafenib_monotherapy|Sorafenib]]
+
|[[Renal_cell_carcinoma_-_null_regimens#Placebo_2|Placebo]]
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (*)
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (*)
 +
|10%
 +
|2%
 +
|-
 +
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.24864/abstract Stadler et al. 2010 (ARCCS)]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#91cf61" |Non-randomized
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|
 +
|
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdq651 Beck et al. 2011 (EU-ARCCS)]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#91cf61" |Non-randomized
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|
 +
|
 
|-
 
|-
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2808%2961039-9/fulltext Motzer et al. 2008 (RECORD-1)]
+
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961613-9/fulltext Rini et al. 2011 (AXIS)]
−
|2006-2007
+
|2008-2010
 
| style="background-color:#1a9851" |Phase III (C)
 
| style="background-color:#1a9851" |Phase III (C)
−
|[[Renal_cell_carcinoma#Everolimus_monotherapy|Everolimus]]
+
|[[#Axitinib_monotherapy|Axitinib]]
 
| style="background-color:#d73027" |Inferior PFS
 
| style="background-color:#d73027" |Inferior PFS
 +
|9% (95% CI 7-13%)
 +
|19% (95% CI 15-24%)
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/28/6/1061.long Sternberg et al. 2010 (VEG105192)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569683/ Hutson et al. 2013 (INTORSECT)]
−
|2006-2007
+
|{{#subobject:xx|ToDo=1}}
 
| style="background-color:#1a9851" |Phase III (C)
 
| style="background-color:#1a9851" |Phase III (C)
−
|[[Renal_cell_carcinoma#Pazopanib_monotherapy|Pazopanib]]
+
|Temsirolimus
−
| style="background-color:#d73027" |Inferior PFS
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS (*)
 +
|
 +
|
 
|-
 
|-
 
|}
 
|}
−
''No active antineoplastic treatment. Note that TARGET should not be confused with the study by the same name in breast cancer. Reported efficacy for TARGET is based on the 2009 update.''
+
''Note that TARGET should not be confused with the study by the same name in breast cancer. Reported efficacy for TARGET is based on the 2009 update. While the primary endpoint (PFS) was not met in INTORSECT, the control arm actually had superior OS compared to the experimental arm.''
 +
====Chemotherapy====
 +
*[[Sorafenib (Nexavar)]] 400 mg PO twice per day
 +
**Can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity
 +
 
 +
'''Continued indefinitely'''
  
 
===References===
 
===References===
−
# Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003 Jul 31;349(5):427-34. [https://www.nejm.org/doi/full/10.1056/NEJMoa021491 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275324/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/12890841 PubMed]
 
 
# '''TARGET:''' Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):125-34. Erratum in: N Engl J Med. 2007 Jul 12;357(2):203. [https://www.nejm.org/doi/full/10.1056/NEJMoa060655 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17215530 PubMed]
 
# '''TARGET:''' Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):125-34. Erratum in: N Engl J Med. 2007 Jul 12;357(2):203. [https://www.nejm.org/doi/full/10.1056/NEJMoa060655 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17215530 PubMed]
 
## '''Update:''' Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, Negrier S, Chevreau C, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Anderson S, Hofilena G, Shan M, Pena C, Lathia C, Bukowski RM. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009 Jul 10;27(20):3312-8. Epub 2009 May 18. [https://doi.org/10.1200/JCO.2008.19.5511 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19451442 PubMed]
 
## '''Update:''' Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, Negrier S, Chevreau C, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Anderson S, Hofilena G, Shan M, Pena C, Lathia C, Bukowski RM. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009 Jul 10;27(20):3312-8. Epub 2009 May 18. [https://doi.org/10.1200/JCO.2008.19.5511 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19451442 PubMed]
 
## '''Subgroup analysis:''' Hutson TE, Bellmunt J, Porta C, Szczylik C, Staehler M, Nadel A, Anderson S, Bukowski R, Eisen T, Escudier B; Sorafenib TARGET Clinical Trial Group. Long-term safety of sorafenib in advanced renal cell carcinoma: follow-up of patients from phase III TARGET. Eur J Cancer. 2010 Sep;46(13):2432-40. Epub 2010 Jul 23. [https://www.ejcancer.com/article/S0959-8049(10)00637-4/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20656473 PubMed]
 
## '''Subgroup analysis:''' Hutson TE, Bellmunt J, Porta C, Szczylik C, Staehler M, Nadel A, Anderson S, Bukowski R, Eisen T, Escudier B; Sorafenib TARGET Clinical Trial Group. Long-term safety of sorafenib in advanced renal cell carcinoma: follow-up of patients from phase III TARGET. Eur J Cancer. 2010 Sep;46(13):2432-40. Epub 2010 Jul 23. [https://www.ejcancer.com/article/S0959-8049(10)00637-4/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20656473 PubMed]
−
# '''RECORD-1:''' Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008 Aug 9;372(9637):449-56. Epub 2008 Jul 22. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2808%2961039-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18653228 PubMed]
+
# '''ARCCS:''' Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010 Mar 1;116(5):1272-80. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.24864/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20082451 PubMed]
−
## '''Update:''' Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A; RECORD-1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010 Sep 15;116(18):4256-65. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.25219/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20549832 PubMed]
+
# '''EU-ARCCS:''' Beck J, Procopio G, Bajetta E, Keilholz U, Negrier S, Szczylik C, Bokemeyer C, Bracarda S, Richel DJ, Staehler M, Strauss UP, Mersmann S, Burock K, Escudier B. Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings. Ann Oncol. 2011 Aug;22(8):1812-23. Epub 2011 Feb 15. [https://doi.org/10.1093/annonc/mdq651 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21324953 PubMed]
−
# '''VEG105192:''' Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarbá JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010 Feb 20;28(6):1061-8. Epub 2010 Jan 25. [http://jco.ascopubs.org/content/28/6/1061.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20100962 PubMed]
+
# '''AXIS:''' Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011 Dec 3;378(9807):1931-9. Epub 2011 Nov 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961613-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22056247 PubMed]
−
## '''Update:''' Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, Zarba JJ, Gladkov OA, Lee E, Szczylik C, McCann L, Rubin SD, Chen M, Davis ID. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013 Apr;49(6):1287-96. Epub 2013 Jan 12. [https://www.ejcancer.com/article/S0959-8049(12)00980-X/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23321547 PubMed]
+
## '''Update:''' Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, Oudard S, Gore ME, Tarazi J, Hariharan S, Chen C, Rosbrook B, Kim S, Rini BI. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013 May;14(6):552-62. Epub 2013 Apr 15. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70093-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23598172 PubMed]
 +
## '''Subgroup analysis:''' Escudier B, Michaelson MD, Motzer RJ, Hutson TE, Clark JI, Lim HY, Porfiri E, Zalewski P, Kannourakis G, Staehler M, Tarazi J, Rosbrook B, Cisar L, Hariharan S, Kim S, Rini BI. Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial. Br J Cancer. 2014 Jun 10;110(12):2821-8. Epub 2014 May 13. [https://www.nature.com/articles/bjc2014244 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056058/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24823696 PubMed]
 +
# '''INTORSECT:''' Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, Senico P, Niethammer A, Lu DR, Hariharan S, Motzer RJ. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Mar 10;32(8):760-7. Epub 2013 Dec 2. [https://doi.org/10.1200/JCO.2013.50.3961 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569683/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24297950 PubMed]
 +
 
 +
==Sunitinib monotherapy {{#subobject:f929da|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:955949|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.02.2574 Motzer et al. 2005 (RTKC-0511-014)]
 +
|2003
 +
| style="background-color:#91cf61" |Phase II (RT)
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://jamanetwork.com/journals/jama/fullarticle/202955 Motzer et al. 2006 (A618-1006)]
 +
|2004
 +
| style="background-color:#91cf61" |Phase II (RT)
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970162-7/fulltext Gore et al. 2009 (A618-1037)]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#91cf61" |Non-randomized
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[http://jco.ascopubs.org/content/32/25/2765.long Motzer et al. 2014 (RECORD-3)]
 +
|{{#subobject:xx|ToDo=1}}
 +
| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
 +
|[[#Everolimus_monotherapy|Everolimus]]
 +
| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
 +
|-
 +
|}
 +
====Preceding treatment====
 +
*RECORD-3: [[#Everolimus_monotherapy|Everolimus]]
 +
====Chemotherapy====
 +
*[[Sunitinib (Sutent)]] 50 mg PO once per day on days 1 to 28
 +
**Dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability
 +
 
 +
'''42-day cycles'''
 +
 
 +
===References===
 +
# '''RTKC-0511-014:''' Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006 Jan 1;24(1):16-24. Epub 2005 Dec 5. [https://doi.org/10.1200/JCO.2005.02.2574 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16330672 PubMed]
 +
# '''A618-1006:''' Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, Redman BG, Margolin KA, Merchan JR, Wilding G, Ginsberg MS, Bacik J, Kim ST, Baum CM, Michaelson MD. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006 Jun 7;295(21):2516-24. [https://jamanetwork.com/journals/jama/fullarticle/202955 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16757724 PubMed]
 +
# '''A618-1037:''' Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009 Aug;10(8):757-63. Epub 2009 Jul 15. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970162-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19615940 PubMed]
 +
<!-- # '''Abstract:''' Robert John Motzer, Carlos H. Barrios, Tae Min Kim, Silvia Falcon, Thomas Cosgriff, W. Graydon Harker, Kenneth B. Pittman, Roberto Sabbatini, Sun Young Rha, Thomas W. Flaig, Ray D. Page, Sevil E. Bavbek, J. Thaddeus Beck, Poulam M Patel, Edward Schiff, Alexandra Vaury, Julie Niolat, Sven Gogov, Ozlem Anak, Jennifer Knox. Record-3: Phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC). 2013 ASCO Annual Meeting abstract 4504. [http://meetinglibrary.asco.org/content/113103-132 link to abstract] -->
 +
# '''RECORD-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [http://jco.ascopubs.org/content/32/25/2765.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25049330 PubMed]
 +
 
 +
=Metastatic disease, third-line=
 +
 
 +
==Sorafenib monotherapy {{#subobject:7b51ba|Regimen=1}}==
 +
{| class="wikitable" style="float:right; margin-left: 5px;"
 +
|-
 +
|[[#top|back to top]]
 +
|}
 +
===Regimen {{#subobject:87cb7d|Variant=1}}===
 +
{| class="wikitable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719485/ Motzer et al. 2014 (GOLD-RCC)]
 +
|2011-2012
 +
| style="background-color:#1a9851" |Phase III (C)
 +
|Dovitinib
 +
| style="background-color:#fee08b" |Might have inferior PFS
 +
|-
 +
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70030-0/fulltext Motzer et al. 2014 (GOLD-RCC)]
 +
|2016-2017
 +
| style="background-color:#1a9851" |Phase III (C)
 +
|Tivozanib
 +
| style="background-color:#fc8d59" |Seems to have inferior PFS
 +
|-
 +
|}
 +
''Note: GOLD should not be confused for the one with the same name in gastric cancer.''
 +
====Chemotherapy====
 +
*[[Sorafenib (Nexavar)]] 400 mg PO twice per day
 +
 
 +
'''Continued indefinitely'''
 +
===References===
 +
# '''GOLD:''' Motzer RJ, Porta C, Vogelzang NJ, Sternberg CN, Szczylik C, Zolnierek J, Kollmannsberger C, Rha SY, Bjarnason GA, Melichar B, De Giorgi U, Grünwald V, Davis ID, Lee JL, Esteban E, Urbanowitz G, Cai C, Squires M, Marker M, Shi MM, Escudier B. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Mar;15(3):286-96. Epub 2014 Feb 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70030-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719485/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24556040 PubMed]
 +
# '''TIVO-3:''' Rini BI, Pal SK, Escudier BJ, Atkins MB, Hutson TE, Porta C, Verzoni E, Needle MN, McDermott DF. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020 Jan;21(1):95-104. Epub 2019 Dec 3. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30735-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31810797 PubMed]
  
 
[[Category:Renal_cell_carcinoma regimens]]
 
[[Category:Renal_cell_carcinoma regimens]]
 
[[Category:Disease-specific pages]]
 
[[Category:Disease-specific pages]]
 
[[Category:Genitourinary cancers]]
 
[[Category:Genitourinary cancers]]
−
[[Category:Null regimens]]
 

Revision as of 15:12, 9 March 2020

Section editor
ChenEddy Sept2016.jpg
 Eddy J. Chen, MD
Massachusetts General Hospital
Boston, MA

Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. If you still can't find it, please let us know so we can add it!.

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Guidelines

EAU

ESMO

Older

NCCN

SIOG

Risk Stratification Calculators

Adjuvant therapy

Sunitinib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Haas et al. 2016 (ECOG-ACRIN E2805) 2006-2010 Phase III (E-esc) Placebo Did not meet primary endpoint of DFS
Ravaud et al. 2016 (S-TRAC) 2007-2011 Phase III (E-RT-esc) Placebo Seems to have superior DFS More toxicity

Preceding treatment

Chemotherapy

42-day cycle for up to 9 cycles (1 year)

References

  1. ECOG-ACRIN E2805: Haas NB, Manola J, Uzzo RG, Flaherty KT, Wood CG, Kane C, Jewett M, Dutcher JP, Atkins MB, Pins M, Wilding G, Cella D, Wagner L, Matin S, Kuzel TM, Sexton WJ, Wong YN, Choueiri TK, Pili R, Puzanov I, Kohli M, Stadler W, Carducci M, Coomes R, DiPaola RS. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016 May 14;387(10032):2008-16. Epub 2016 Mar 9. Erratum in: Lancet. 2016 May 14;387(10032):1998. link to original article link to PMC article PubMed NCT00326898
  2. S-TRAC: Ravaud A, Motzer RJ, Pandha HS, George DJ, Pantuck AJ, Patel A, Chang YH, Escudier B, Donskov F, Magheli A, Carteni G, Laguerre B, Tomczak P, Breza J, Gerletti P, Lechuga M, Lin X, Martini JF, Ramaswamy K, Casey M, Staehler M, Patard JJ; S-TRAC Investigators. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016 Dec 8;375(23):2246-2254. Epub 2016 Oct 9. link to original article contains verified protocol PubMed
    1. Update: Motzer RJ, Ravaud A, Patard JJ, Pandha HS, George DJ, Patel A, Chang YH, Escudier B, Donskov F, Magheli A, Carteni G, Laguerre B, Tomczak P, Breza J, Gerletti P, Lechuga M, Lin X, Casey M, Serfass L, Pantuck AJ, Staehler M. Adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy: subgroup analyses and updated overall survival results. Eur Urol. 2018 Jan;73(1):62-68. Epub 2017 Sep 26. link to original article PubMed

Metastatic disease, first-line

Atezolizumab & Bevacizumab

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Regimen

Study Evidence Comparator Comparative Efficacy
Rini et al. 2019 (IMmotion151) Phase III (E-esc) Sunitinib Seems to have superior PFS

Immunotherapy

Chemotherapy

21-day cycles

References

  1. IMmotion151: Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. link to original article contains protocol PubMed

Axitinib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Hutson et al. 2013 (A4061051) 2010-2011 Phase III (E-switch-ic) Sorafenib Might have superior PFS (*) 32% 15%

Note: in the 2016 update, there is no difference in OS.

Chemotherapy

  • Axitinib (Inlyta) as follows:
    • 5 mg PO twice per day for at least 2 weeks
    • Then if tolerated and BP not greater than 150/90, increased to 7 mg PO twice per day
    • Then if tolerated and BP not greater than 150/90, increased to 10 mg PO twice per day
    • Dose can be reduced to 2 to 3 mg PO twice per day if needed based on tolerability

Continued indefinitely

References

  1. A4061051: Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, Rosbrook B, Chen C, Kim S, Vogelzang NJ. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1287-94. Epub 2013 Oct 25. link to original article contains protocol PubMed
    1. Update: Hutson TE, Al-Shukri S, Stus VP, Lipatov ON, Shparyk Y, Bair AH, Rosbrook B, Andrews GI, Vogelzang NJ. Axitinib versus sorafenib in first-line metastatic renal cell carcinoma: Overall survival from a randomized phase III trial. Clin Genitourin Cancer. 2017 Feb;15(1):72-76. Epub 2016 May 27. link to original article PubMed

Axitinib & Avelumab

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Regimen variant #1, weight-based dosing

Study Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2019 (JAVELIN Renal 101) 2016-2017 Phase III (E-RT-esc) Sunitinib Superior PFS

Note: this is not the FDA-recommended dose.

Chemotherapy

Immunotherapy

14-day cycles

Regimen variant #2, flat dosing

FDA-recommended dose

Note: this is not the dose described in Motzer et al. 2019.

Chemotherapy

Immunotherapy

14-day cycles

References

  1. JAVELIN Renal 101: Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M, Lee JL, Vasiliev A, Miller WH Jr, Gurney H, Schmidinger M, Larkin J, Atkins MB, Bedke J, Alekseev B, Wang J, Mariani M, Robbins PB, Chudnovsky A, Fowst C, Hariharan S, Huang B, di Pietro A, Choueiri TK. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1103-1115. Epub 2019 Feb 16. link to original article contains protocol link to PMC article PubMed

Axitinib & Pembrolizumab

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rini et al. 2019 (KEYNOTE-426) 2016-2018 Phase III (E-RT-esc) Sunitinib Superior OS

Chemotherapy

Immunotherapy

21-day cycles

References

  1. KEYNOTE-426: Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, Vynnychenko I, Kryzhanivska A, Bondarenko I, Azevedo SJ, Borchiellini D, Szczylik C, Markus M, McDermott RS, Bedke J, Tartas S, Chang YH, Tamada S, Shou Q, Perini RF, Chen M, Atkins MB, Powles T; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116-1127. Epub 2019 Feb 16. link to original article contains protocol PubMed

Bevacizumab monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Bukowski et al. 2007 2004 Randomized Phase II (C) Erlotinib & Bevacizumab Did not meet primary endpoints of ORR/PFS 13% 14%

Chemotherapy

  • Bevacizumab (Avastin) 10 mg/kg IV over 90 minutes once on day 1
    • Can subsequently be reduced to 60 and 30 minute infusions as tolerated

14-day cycle for up to 52 cycles (2 years)

References

  1. Bukowski RM, Kabbinavar FF, Figlin RA, Flaherty K, Srinivas S, Vaishampayan U, Drabkin HA, Dutcher J, Ryba S, Xia Q, Scappaticci FA, McDermott D. Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol. 2007 Oct 10;25(29):4536-41. Epub 2007 Sep 17. link to original article contains verified protocol PubMed

Bevacizumab & Interferon alfa-2a

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Regimen variant #1, 1 year

Study Years of enrollment Evidence Comparator Comparative Efficacy
Escudier et al. 2007 (AVOREN) 2004-2005 Phase III (E-RT-esc) Interferon alfa-2a Did not meet primary endpoint of OS (*)

Note: Reported efficacy for AVOREN is based on the 2010 update.

Chemotherapy

Immunotherapy

  • Interferon alfa-2a (Roferon-A) 9,000,000 units SC 3 times per week
    • Dose can be reduced to 3,000,000 or 6,000,000 units SC 3 times per week based on tolerability

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

Subsequent treatment

Regimen variant #2, indefinite

Study Evidence Comparator Comparative Efficacy
Rini et al. 2008 (CALGB 90206) Phase III (E-esc) Interferon alfa-2a Might have superior OS (*)
Rini et al. 2013 (INTORACT) Phase III (C) Temsirolimus & Bevacizumab Did not meet primary endpoint of PFS

Note: Reported efficacy for CALGB 90206 is based on the 2010 update.

Chemotherapy

Immunotherapy

  • Interferon alfa-2a (Roferon-A) 9,000,000 units SC 3 times per week
    • Dose can be reduced to 3,000,000 or 6,000,000 units SC 3 times per week based on tolerability

14-day cycles

References

  1. AVOREN: Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007 Dec 22;370(9605):2103-11. link to original article PubMed
    1. Update: Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, Sneller V. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010 May 1;28(13):2144-50. Epub 2010 Apr 5. link to original article contains verified protocol PubMed
  2. CALGB 90206: Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008 Nov 20;26(33):5422-8. Epub 2008 Oct 20. link to original article link to PMC article PubMed
    1. Update: Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010 May 1;28(13):2137-43. Epub 2010 Apr 5. link to original article link to PMC article PubMed
  3. INTORACT: Rini BI, Bellmunt J, Clancy J, Wang K, Niethammer AG, Hariharan S, Escudier B. Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol. 2014 Mar 10;32(8):752-9. Epub 2013 Dec 2. link to original article contains protocol PubMed

Cabozantinib monotherapy

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Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Choueiri et al. 2016 (CABOSUN) 2013-2015 Phase III (E-RT-switch-ic) Sunitinib Superior PFS (*)

Note: reported efficacy is based on the 2018 update; in this update, independent review gave an ORR of 20% (95% CI 12-31%) in the experimental arm and 9% (95% CI 4-18%) in the control arm.

Chemotherapy

Continued indefinitely

References

  1. CABOSUN: Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, Feldman DR, Olencki T, Picus J, Small EJ, Dakhil S, George DJ, Morris MJ. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol. 2017 Feb 20;35(6):591-597. Epub 2016 Nov 14. link to original article contains verified protocol link to PMC article PubMed
    1. Update: Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, Walsh M, Olencki T, Picus J, Small EJ, Dakhil S, Feldman DR, Mangeshkar M, Scheffold C, George D, Morris MJ. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer. 2018 May;94:115-125. Epub 2018 Mar 20. link to original article contains verified protocol link to PMC article PubMed

Doxorubicin & Gemcitabine

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Regimen

Study Evidence
Haas et al. 2012 (ECOG 8802) Phase II

Patients had disease with sarcomatoid features.

Chemotherapy

Supportive medications

14-day cycle for 6 to 9 cycles (cumulative doxorubicin dose of 300 to 450 mg/m2, depending on cardiac function)

References

  1. ECOG 8802: Haas NB, Lin X, Manola J, Pins M, Liu G, McDermott D, Nanus D, Heath E, Wilding G, Dutcher J. A phase II trial of doxorubicin and gemcitabine in renal cell carcinoma with sarcomatoid features: ECOG 8802. Med Oncol. 2012 Jun;29(2):761-7. Epub 2011 Feb 6. link to original article contains verified protocol link to PMC article PubMed

Erlotinib monotherapy

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Regimen

Study Evidence Efficacy
Gordon et al. 2009 (SWOG S0317) Phase II 11% (95% CI 3-24%)

Chemotherapy

Continued indefinitely

References

  1. SWOG S0317: Gordon MS, Hussey M, Nagle RB, Lara PN Jr, Mack PC, Dutcher J, Samlowski W, Clark JI, Quinn DI, Pan CX, Crawford D. Phase II study of erlotinib in patients with locally advanced or metastatic papillary histology renal cell cancer: SWOG S0317. J Clin Oncol. 2009 Dec 1;27(34):5788-93. Epub 2009 Nov 2. link to original article contains verified protocol link to PMC article PubMed

Erlotinib & Bevacizumab

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bukowski et al. 2007 2004 Randomized Phase II (E-esc) Bevacizumab Did not meet primary endpoints of ORR/PFS

Chemotherapy

14-day cycle for up to 52 cycles (2 years)

References

  1. Bukowski RM, Kabbinavar FF, Figlin RA, Flaherty K, Srinivas S, Vaishampayan U, Drabkin HA, Dutcher J, Ryba S, Xia Q, Scappaticci FA, McDermott D. Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol. 2007 Oct 10;25(29):4536-41. Epub 2007 Sep 17. link to original article contains verified protocol PubMed

Everolimus monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Motzer et al. 2014 (RECORD-3) Randomized Phase II (E-switch-ic) Sunitinib Inconclusive whether non-inferior PFS
Tannir et al. 2015 (ESPN) Randomized Phase II (E-switch-ic) Sunitinib Did not meet primary endpoint of PFS
Armstrong et al. 2016 (ASPEN) Randomized Phase II (E-switch-ic) Sunitinib Might have inferior PFS

Chemotherapy

  • Everolimus (Afinitor) 10 mg PO once per day
    • Dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability

Continued indefinitely

Subsequent treatment

References

  1. RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article PubMed
  2. ESPN: Tannir NM, Jonasch E, Albiges L, Altinmakas E, Ng CS, Matin SF, Wang X, Qiao W, Dubauskas Lim Z, Tamboli P, Rao P, Sircar K, Karam JA, McDermott DF, Wood CG, Choueiri TK. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol. 2016 May;69(5):866-74. Epub 2015 Nov 26. link to original article link to PMC article PubMed
  3. Armstrong AJ, Halabi S, Eisen T, Broderick S, Stadler WM, Jones RJ, Garcia JA, Vaishampayan UN, Picus J, Hawkins RE, Hainsworth JD, Kollmannsberger CK, Logan TF, Puzanov I, Pickering LM, Ryan CW, Protheroe A, Lusk CM, Oberg S, George DJ. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016 Mar;17(3):378-88. Epub 2016 Jan 13. link to original article PubMed

Gemcitabine & Sunitinib

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Regimen variant #1

Study Years of enrollment Evidence
Michaelson et al. 2015 (MGH 07-212) 2007-2013 Phase II

Patients had disease with sarcomatoid features.

Chemotherapy

21-day cycles

Regimen variant #2

Study Evidence
Pandya et al. 2011 Retrospective

Chemotherapy

21-day cycles

References

  1. Retrospective: Pandya SS, Mier JW, McDermott DF, Cho DC. Addition of gemcitabine at the time of sunitinib resistance in metastatic renal cell cancer. BJU Int. 2011 Oct;108(8 Pt 2):E245-9. Epub 2011 Feb 14. link to original article contains verified protocol PubMed
  2. MGH 07-212: Michaelson MD, McKay RR, Werner L, Atkins MB, Van Allen EM, Olivier KM, Song J, Signoretti S, McDermott DF, Choueiri TK. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer. 2015 Oct 1;121(19):3435-43. Epub 2015 Jun 8. link to original article PubMed

High-dose Interleukin-2

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HD IL-2: High-Dose InterLeukin-2

Example orders

Regimen variant #1, 1.8 MU/kg/day, intermittent

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rosenberg et al. 1994 Non-randomized
Fyfe et al. 1995 NR Phase II (RT)
McDermott et al. 2005 Phase III (C) Subcutaneous IL-2 & Interferon Might have superior PFS

Immunotherapy

Supportive medications

28-day cycle for up to 3 cycles

Regimen variant #2, 2.16 MU/kg/day, intermittent, goal 10.8 MU

Study Evidence Comparator Comparative Efficacy
Yang et al. 1994 Phase III (C) 1. LD IL-2 (IV) Seems to have superior ORR
2. LD IL-2 (SC) Seems to have superior ORR

Note: efficacy is based on the 2003 update.

Immunotherapy

8-week cycle for up to 2 cycles

Regimen variant #3, 2.16 MU/kg/day, intermittent, goal 8.64 MU

Study Evidence
Klapper et al. 2008 Retrospective

Immunotherapy

Supportive medications

  • "Routine administration of antipyretics, anti-inflammatories, antiemetics, antidiarrheals, and H2 antagonists."

Subsequent treatment

  • After this one course of treatments--defined by the paper as "two cycles"--patients with stable to improved disease would receive additional courses of treatments every 2 months (no maximum number of courses listed)

Regimen variant #4, 5 MU/m2/day, CI

Study Evidence Comparator Comparative Efficacy
Figlin et al. 1999 Phase III (C) IL-2 & CD8+ TILs Did not meet primary endpoint of ORR

Immunotherapy

  • IL-2 - Aldesleukin (Proleukin) 5,000,000 units/m2/day IV continuous infusion over 96 hours, started on days 1, 8, 15, 22 (total dose per cycle: 80 MU/m2)

8-week cycles

References

  1. 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
  2. Yang JC, Topalian SL, Parkinson D, Schwartzentruber DJ, Weber JS, Ettinghausen SE, White DE, Steinberg SM, Cole DJ, Kim HI, Levin R, Guleria A, MacFarlane MP, White RL, Einhorn JH, Seipp CA, Rosenberg SA. Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol. 1994 Aug;12(8):1572-6. link to original article PubMed
    1. Update: Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. link to original article link to PMC article contains verified protocol link to PMC article PubMed
  3. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995 Mar;13(3):688-96. link to original article PubMed
  4. Figlin RA, Thompson JA, Bukowski RM, Vogelzang NJ, Novick AC, Lange P, Steinberg GD, Belldegrun AS. Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol. 1999 Aug;17(8):2521-9. link to original article contains verified protocol PubMed
  5. McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, Kirkwood JM, Gordon MS, Sosman JA, Ernstoff MS, Tretter CP, Urba WJ, Smith JW, Margolin KA, Mier JW, Gollob JA, Dutcher JP, Atkins MB. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005 Jan 1;23(1):133-41. link to original article contains verified protocol PubMed
  6. Retrospective: Klapper JA, Downey SG, Smith FO, Yang JC, Hughes MS, Kammula US, Sherry RM, Royal RE, Steinberg SM, Rosenberg S. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma : a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008 Jul 15;113(2):293-301. link to original article contains verified protocol link to PMC article PubMed

Low-dose Interleukin-2

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LD IL-2: Low-Dose InterLeukin-2

Regimen variant #1, Intravenous

Study Evidence Comparator Comparative Efficacy
Yang et al. 1994 Phase III (E-de-esc) 1. High-dose IL-2 Seems to have inferior ORR
2. Subcutaneous LD IL-2 Not reported

Note: efficacy is based on the 2003 update.

Immunotherapy

  • IL-2 - Aldesleukin (Proleukin) as follows:
    • 72,000 units/kg IV every 8 hours for up to 15 doses
    • Then after 7 to 10 days of rest: 72,000 units/kg IV every 8 hours for up to 15 doses is given again

8-week cycle for up to 2 cycles

Regimen variant #2, Subcutaneous

Study Evidence Comparator Comparative Efficacy
Yang et al. 1994 Phase III (E-de-esc) 1. High-dose IL-2 Seems to have inferior ORR
2. Intravenous LD IL-2 Not reported

Note: this arm was added to the trial after the interim results were announced in 1994.

Immunotherapy

  • IL-2 - Aldesleukin (Proleukin) as follows:
    • Week 1: 250,000 units/kg SC once per day for 5 days
    • Weeks 2 to 6: 125,000 units/kg SC once per day for 5 days per week

8-week cycle for up to 2 cycles

References

  1. Yang JC, Topalian SL, Parkinson D, Schwartzentruber DJ, Weber JS, Ettinghausen SE, White DE, Steinberg SM, Cole DJ, Kim HI, Levin R, Guleria A, MacFarlane MP, White RL, Einhorn JH, Seipp CA, Rosenberg SA. Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol. 1994 Aug;12(8):1572-6. link to original article PubMed
    1. Update: Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. link to original article link to PMC article contains verified protocol link to PMC article PubMed

Interferon alfa-2a monotherapy

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Regimen variant #1, 5 MU 5x per week

Study Years of enrollment Evidence Comparator Comparative Efficacy
Sagaster et al. 1995 NR-1992 Phase III (C) Cimetidine, Coumarin, IFN alfa-2a Did not meet primary endpoint of ORR

Immunotherapy

Continued indefinitely

Regimen variant #2, 9 MU TIW

Study Years of enrollment Evidence Comparator Comparative Efficacy
Escudier et al. 2007 (AVOREN) 2004-2005 Phase III (C) Bevacizumab & Interferon alfa-2a Did not meet primary endpoint of OS (*)
Rini et al. 2008 (CALGB 90206) Phase III (C) Bevacizumab & Interferon alfa-2a Might have inferior OS (*)
Escudier et al. 2009 Randomized Phase II (C) Sorafenib Did not meet primary endpoint of PFS
Gore et al. 2010 (MRC RE04/EORTC GU 30012) Phase III (C) 5-FU, Interferon alfa-2a, IL-2 Did not meet primary endpoint of OS
Hawkins et al. 2016 2007-2010 Phase II/III (C) Naptumomab estafenatox + IFNα Did not meet primary endpoint of OS

Note: reported efficacy for AVOREN is based on the 2010 update. Reported efficacy for CALGB 90206 is based on the 2010 update.

Immunotherapy

  • Interferon alfa-2a (Roferon-A) 9,000,000 units SC 3 times per week
    • Some protocols: Dose can be reduced to 3 or 6,000,000 units SC 3 times per week based on tolerability

Given for varying lengths of time; see individual trials

Regimen variant #3, 9 MU daily, with lead-in

Study Evidence Comparator Comparative Efficacy
Motzer et al. 2000 Phase III (C) IFN alfa & 13-CRA Did not meet primary endpoint of ORR

Immunotherapy

  • Interferon alfa-2a (Roferon-A) as follows:
    • Week 1: 3,000,000 units SC once per day
    • Week 2 (if prior dose tolerated): 6,000,000 units SC once per day
    • Week 3 onwards (if prior dose tolerated): 9,000,000 units SC once per day

Continued indefinitely

Regimen variant #4, 9 MU TIW, with lead-in

Study Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2007 (A618-1034) 2004-2005 Phase III (C) Sunitinib Inferior PFS

Immunotherapy

  • Interferon alfa-2a (Roferon-A) as follows:
    • Week 1: 3,000,000 units SC 3 times per week
    • Week 2 (if prior dose tolerated): 6,000,000 units SC 3 times per week
    • Week 3 onwards (if prior dose tolerated): 9,000,000 units SC 3 times per week

Continued indefinitely

Regimen variant #5, 10 MU TIW

Study Evidence Comparator Comparative Efficacy
Ritchie et al. 1999 (MRC RE01) Phase III (E-switch-ooc) MPA Seems to have superior OS
Gore et al. 2010 (MRC RE04/EORTC GU 30012) Phase III (C) Chemoimmunotherapy Did not meet primary endpoint of OS

Immunotherapy

12-week course (MRC RE01) or continued indefinitely (MRC RE04/EORTC GU 30012)

Regimen variant #6, 18 MU TIW, with lead-in

Study Years of enrollment Evidence Comparator Comparative Efficacy
Fosså et al. 1992 1985-1986 Phase III (C) IFN alfa-2a & Vinblastine Did not meet efficacy endpoints
Hudes et al. 2007 (ARCC) 2003-2005 Phase III (C) 1. Interferon alfa-2a & Temsirolimus Did not meet primary endpoint of OS
2. Temsirolimus Inferior OS

Immunotherapy

  • Interferon alfa-2a (Roferon-A) as follows:
    • Week 1: 3,000,000 units SC 3 times per week
    • Week 2 (if prior dose tolerated): 9,000,000 units SC 3 times per week
    • Week 3 onwards (if prior dose tolerated): 18,000,000 units SC 3 times per week
      • If higher doses cannot be tolerated, highest tolerable doses of 3,000,000, 4,500,500, or 6,000,000 units can be used

Continued indefinitely

References

  1. Fosså SD, Martinelli G, Otto U, Schneider G, Wander H, Oberling F, Bauer HW, Achtnicht U, Holdener EE. Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: results of a European multi-center phase III study. Ann Oncol. 1992 Apr;3(4):301-5. link to original article PubMed
  2. Sagaster P, Micksche M, Flamm J, Ludwig H. Randomised study using IFN-alpha versus IFN-alpha plus coumarin and cimetidine for treatment of advanced renal cell cancer. Ann Oncol. 1995 Dec;6(10):999-1003. link to original article contains protocol PubMed
  3. MRC RE01: Ritchie A, Griffiths G, Parmar M; Medical Research Council Renal Cancer Collaborators. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet. 1999 Jan 2;353(9146):14-7. link to original article contans protocol PubMed
  4. Motzer RJ, Murphy BA, Bacik J, Schwartz LH, Nanus DM, Mariani T, Loehrer P, Wilding G, Fairclough DL, Cella D, Mazumdar M. Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol. 2000 Aug;18(16):2972-80. link to original article PubMed
  5. A618-1034: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. link to original article contains verified protocol PubMed
    1. Update: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Aug 1;27(22):3584-90. Epub 2009 Jun 1. link to original article contains verified protocol link to PMC article PubMed content property of HemOnc.org
  6. ARCC: Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. link to original article contains verified protocol PubMed
  7. AVOREN: Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007 Dec 22;370(9605):2103-11. link to original article PubMed
    1. Update: Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, Sneller V. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010 May 1;28(13):2144-50. Epub 2010 Apr 5. link to original article contains verified protocol PubMed
  8. CALGB 90206: Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008 Nov 20;26(33):5422-8. Epub 2008 Oct 20. link to original article link to PMC article PubMed
    1. Update: Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010 May 1;28(13):2137-43. Epub 2010 Apr 5. link to original article link to PMC article PubMed
  9. Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, Negrier S, Laferriere N, Scheuring UJ, Cella D, Shah S, Bukowski RM. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Mar 10;27(8):1280-9. Epub 2009 Jan 26. Erratum in: J Clin Oncol. 2009 May 1; 27(13):2305. link to original article PubMed
  10. MRC RE04/EORTC GU 30012: Gore ME, Griffin CL, Hancock B, Patel PM, Pyle L, Aitchison M, James N, Oliver RT, Mardiak J, Hussain T, Sylvester R, Parmar MK, Royston P, Mulders PF. Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial. Lancet. 2010 Feb 20;375(9715):641-8. Epub 2010 Feb 10. link to original article link to PMC article contains verified protocol PubMed
  11. Hawkins RE, Gore M, Shparyk Y, Bondar V, Gladkov O, Ganev T, Harza M, Polenkov S, Bondarenko I, Karlov P, Karyakin O, Khasanov R, Hedlund G, Forsberg G, Nordle Ö, Eisen T. A randomized phase II/III study of naptumomab estafenatox + IFNα versus IFNα in renal cell carcinoma: final analysis with baseline biomarker subgroup and trend analysis. Clin Cancer Res. 2016 Jul 1;22(13):3172-81. Epub 2016 Feb 5. link to original article contains verified protocol PubMed

Interferon alfa-2a & Interleukin-2

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Regimen

Study Evidence Comparator Comparative Efficacy
Negrier et al. 1998 Phase III (E-esc) 1. HD IL-2
2. Interferon alfa-2a 		Superior EFS
Passalacqua et al. 2009 Phase III (C) Maintenance IFN & IL-2 Did not meet primary endpoint of OS

Of historic interest.

Immunotherapy

References

  1. Negrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C, Ravaud A, Mercatello A, Peny J, Mousseau M, Philip T, Tursz T; Groupe Français d'Immunothérapie. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. N Engl J Med. 1998 Apr 30;338(18):1272-8. link to original article PubMed
  2. Passalacqua R, Buzio C, Buti S, Porta C, Labianca R, Pezzuolo D, Camisa R, Sabbatini R, Benecchi L, Messina C, Cengarle R, Vaglio A, Dalla Chiesa M, Tomasello G, Caminiti C. Phase III, randomised, multicentre trial of maintenance immunotherapy with low-dose interleukin-2 and interferon-alpha for metastatic renal cell cancer. Cancer Immunol Immunother. 2010 Apr;59(4):553-61. Epub 2009 Sep 25. link to original article PubMed

Interferon alfa-2b monotherapy

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Regimen

Study Evidence
Mickisch et al. 2001 (EORTC 30947) Non-randomized portion of RCT
Flanigan et al. 2001 (SWOG 8949) Non-randomized portion of RCT

Of historic interest.

Preceding treatment

Immunotherapy

References

  1. EORTC 30947: Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R; European Organisation for Research and Treatment of Cancer (EORTC) Genitourinary Group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001 Sep 22;358(9286):966-70. link to SD article PubMed
  2. SWOG 8949: Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, Caton JR Jr, Munshi N, Crawford ED. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001 Dec 6;345(23):1655-9. link to original article PubMed

Ipilimumab & Nivolumab

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Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2018 (CheckMate 214) 2014-2016 Phase III (E-RT-switch-ooc) Sunitinib Superior OS

Note: while this is the dosing studied in CheckMate 214, it is not the FDA-recommended dosing.

Immunotherapy, part 1

21-day cycle for 4 cycles, followed by:

Immunotherapy, part 2

14-day cycles

Regimen variant #2

FDA-recommended dose

Note: while this one of two FDA-recommended dosing options, we are not aware of any particular published trial using this dosing.

Immunotherapy, part 1

21-day cycle for 4 cycles, followed by:

Immunotherapy, part 2

14-day cycles

Regimen variant #3

FDA-recommended dose

Note: while this one of two FDA-recommended dosing options, we are not aware of any particular published trial using this dosing.

Immunotherapy, part 1

21-day cycle for 4 cycles, followed by:

Immunotherapy, part 2

28-day cycles

References

  1. CheckMate 214: Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. Epub 2018 Mar 21. link to original article contains verified protocol PubMed
    1. Update: Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, Salman P, Escudier B, Beuselinck B, Amin A, Porta C, George S, Neiman V, Bracarda S, Tykodi SS, Barthélémy P, Leibowitz-Amit R, Plimack ER, Oosting SF, Redman B, Melichar B, Powles T, Nathan P, Oudard S, Pook D, Choueiri TK, Donskov F, Grimm MO, Gurney H, Heng DYC, Kollmannsberger CK, Harrison MR, Tomita Y, Duran I, Grünwald V, McHenry MB, Mekan S, Tannir NM; CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019 Oct;20(10):1370-1385. Epub 2019 Aug 16. Erratum in: Lancet Oncol. 2019 Aug 21. link to original article PubMed

Pazopanib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Hutson et al. 2010 Phase II
Sternberg et al. 2010 (VEG105192) 2006-2007 Phase III (E-RT-esc) Placebo Superior PFS 30% (95% CI 25-36%) 3% (95% CI 0-6%)
Motzer et al. 2013 (COMPARZ) Phase III (E-switch-ic) Sunitinib Non-inferior PFS 31% (95% CI 27-34%) 25% (95% CI 21-28%)
Cirkel et al. 2017 (ROPETAR) Randomized (C) Pazopanib/Everolimus Did not meet primary endpoint of PFS

Chemotherapy

  • Pazopanib (Votrient) 800 mg PO once per day, given 1 hour before or 2 hours after meals
    • Dose may be decreased to 600 mg or 400 mg PO once per day depending on tolerability

Continued indefinitely

References

  1. Hutson TE, Davis ID, Machiels JP, De Souza PL, Rottey S, Hong BF, Epstein RJ, Baker KL, McCann L, Crofts T, Pandite L, Figlin RA. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2010 Jan 20;28(3):475-80. Epub 2009 Dec 14. link to original article contains verified protocol PubMed
  2. VEG105192: Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarbá JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010 Feb 20;28(6):1061-8. Epub 2010 Jan 25. link to original article contains verified protocol PubMed
    1. Update: Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, Zarba JJ, Gladkov OA, Lee E, Szczylik C, McCann L, Rubin SD, Chen M, Davis ID. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013 Apr;49(6):1287-96. Epub 2013 Jan 12. link to original article contains verified protocol PubMed
  3. COMPARZ: Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, Jin J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R, Pandite LN, Choueiri TK. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013 Aug 22;369(8):722-31. link to original article contains verified protocol PubMed
    1. Update: Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med. 2014 May 1;370(18):1769-70. link to letter PubMed
  4. HRQoL analysis: Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U, Parikh O, Hawkins R, Sevin E, Négrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol. 2014 May 10;32(14):1412-8. Epub 2014 Mar 31. link to original article PubMed
  5. ROPETAR: Cirkel GA, Hamberg P, Sleijfer S, Loosveld OJL, Dercksen MW, Los M, Polee MB, van den Berkmortel F, Aarts MJ, Beerepoot LV, Groenewegen G, Lolkema MP, Tascilar M, Portielje JEA, Peters FPJ, Klümpen HJ, van der Noort V, Haanen JBAG, Voest EE; Dutch WIN-O Consortium. Alternating treatment with pazopanib and everolimus vs continuous pazopanib to delay disease progression in patients with metastatic clear cell renal cell cancer: the ROPETAR randomized clinical trial. JAMA Oncol. 2017 Apr 1;3(4):501-508. link to original article contains protocol PubMed

Regorafenib monotherapy

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Regimen

Study Evidence Efficacy
Eisen et al. 2012 (Bayer 11726) Phase II 40% (90% CI 28-53%)

Chemotherapy

28-day cycles

References

  1. Bayer 11726: Eisen T, Joensuu H, Nathan PD, Harper PG, Wojtukiewicz MZ, Nicholson S, Bahl A, Tomczak P, Pyrhonen S, Fife K, Bono P, Boxall J, Wagner A, Jeffers M, Lin T, Quinn DI. Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial. Lancet Oncol. 2012 Oct;13(10):1055-62. Epub 2012 Sep 6. link to original article contains verified protocol PubMed

Sorafenib monotherapy

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Regimen

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Escudier et al. 2009 Randomized Phase II (E-switch-ooc) Interferon alfa-2a Did not meet primary endpoint of PFS 5% 9%
Stadler et al. 2010 (ARCCS) Non-randomized
Motzer et al. 2013 (AV-951-09-902) Phase III (C) Tivozanib Seems to have inferior PFS
Hutson et al. 2013 (A4061051) 2010-2011 Phase III (C) Axitinib Might have inferior PFS (*) 15% 32%

Note: in the 2016 update to A4061051, there is no difference in OS.

Chemotherapy

  • Sorafenib (Nexavar) 400 mg PO twice per day
    • Can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity

Continued indefinitely

References

  1. Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, Negrier S, Laferriere N, Scheuring UJ, Cella D, Shah S, Bukowski RM. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Mar 10;27(8):1280-9. Epub 2009 Jan 26. Erratum in: J Clin Oncol. 2009 May 1; 27(13):2305. link to original article PubMed
  2. Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010 Mar 1;116(5):1272-80. link to original article PubMed
  3. AV-951-09-902: Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, Tomczak P, Lyulko O, Alyasova A, Harza M, Kogan M, Alekseev BY, Sternberg CN, Szczylik C, Cella D, Ivanescu C, Krivoshik A, Strahs A, Esteves B, Berkenblit A, Hutson TE. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013 Oct 20;31(30):3791-9. Epub 2013 Sep 9. link to original article link to PMC article contains verified protocol PubMed
  4. A4061051: Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, Rosbrook B, Chen C, Kim S, Vogelzang NJ. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1287-94. Epub 2013 Oct 25. link to original article contains protocol PubMed
    1. Update: Hutson TE, Al-Shukri S, Stus VP, Lipatov ON, Shparyk Y, Bair AH, Rosbrook B, Andrews GI, Vogelzang NJ. Axitinib versus sorafenib in first-line metastatic renal cell carcinoma: Overall survival from a randomized phase III trial. Clin Genitourin Cancer. 2017 Feb;15(1):72-76. Epub 2016 May 27. link to original article PubMed

Sunitinib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Motzer et al. 2007 (A618-1034) 2004-2005 Phase III (E-RT-switch-ooc) Interferon alfa-2a Superior PFS 31% 6%
Gore et al. 2009 (A618-1037) Non-randomized 17%
Amato et al. 2010 (TroVax Renal Immunotherapy Survival Trial) Phase III (C) Sunitinib & MVA-5T4 Did not meet primary endpoint of OS
Motzer et al. 2013 (COMPARZ) Phase III (C) Pazopanib Non-inferior PFS 25% (95% CI 21-28%) 31% (95% CI 27-34%)
Motzer et al. 2014 (RECORD-3) Randomized Phase II (E-switch-ic) Everolimus Inconclusive whether non-inferior PFS
Eichelberg et al. 2015 (SWITCH) Phase III (C) Sorafenib Did not meet primary endpoint of PFS
Tannir et al. 2015 (ESPN) Randomized Phase II (E-switch-ic) Everolimus Did not meet primary endpoint of PFS
Armstrong et al. 2016 (ASPEN) Randomized Phase II (E-switch-ic) Everolimus Might have superior PFS
Rini et al. 2016 (IMPRINT) Phase III (C) Sunitinib & IMA901 Might have superior OS
Choueiri et al. 2016 (CABOSUN) 2013-2015 Phase III (C) Cabozantinib Inferior PFS
Motzer et al. 2018 (CheckMate 214) 2014-2016 Phase III (C) Ipilimumab & Nivolumab Inferior OS
Méjean et al. 2018 (CARMENA) Phase III (E-de-esc) Nephrectomy & Sunitinib Non-inferior OS
Motzer et al. 2019 (JAVELIN Renal 101) 2016-2017 Phase III (C) Axitinib & Avelumab Inferior PFS
Rini et al. 2019 (KEYNOTE-426) 2016-2018 Phase III (C) Axitinib & Pembrolizumab Inferior OS
Rini et al. 2019 (IMmotion151) Phase III (C) Atezolizumab & Bevacizumab Seems to have inferior PFS

Note: reported efficacy for CABOSUN is based on the 2018 update.

Chemotherapy

  • Sunitinib (Sutent) 50 mg PO once per day on days 1 to 28
    • Per some references, dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability

42-day cycles

Subsequent treatment

References

  1. A618-1034: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. link to original article contains verified protocol PubMed
    1. Update: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Aug 1;27(22):3584-90. Epub 2009 Jun 1. link to original article contains verified protocol link to PMC article PubMed
  2. Retrospective: Choueiri TK, Plantade A, Elson P, Negrier S, Ravaud A, Oudard S, Zhou M, Rini BI, Bukowski RM, Escudier B. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol. 2008 Jan 1;26(1):127-31. link to original article PubMed
  3. A618-1037: Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009 Aug;10(8):757-63. Epub 2009 Jul 15. link to original article contains verified protocol PubMed
  4. TroVax Renal Immunotherapy Survival Trial: Amato RJ, Hawkins RE, Kaufman HL, Thompson JA, Tomczak P, Szczylik C, McDonald M, Eastty S, Shingler WH, de Belin J, Goonewardena M, Naylor S, Harrop R. Vaccination of metastatic renal cancer patients with MVA-5T4: a randomized, double-blind, placebo-controlled phase III study. Clin Cancer Res. 2010 Nov 15;16(22):5539-47. Epub 2010 Sep 29. link to original article contains verified protocol PubMed
  5. COMPARZ: Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, Jin J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R, Pandite LN, Choueiri TK. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013 Aug 22;369(8):722-31. link to original article contains verified protocol PubMed
    1. Update: Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med. 2014 May 1;370(18):1769-70. link to letter PubMed
  6. HRQoL analysis: Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U, Parikh O, Hawkins R, Sevin E, Négrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol. 2014 May 10;32(14):1412-8. Epub 2014 Mar 31. link to original article PubMed
  7. RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article PubMed
  8. SWITCH: Eichelberg C, Vervenne WL, De Santis M, Fischer von Weikersthal L, Goebell PJ, Lerchenmüller C, Zimmermann U, Bos MM, Freier W, Schirrmacher-Memmel S, Staehler M, Pahernik S, Los M, Schenck M, Flörcken A, van Arkel C, Hauswald K, Indorf M, Gottstein D, Michel MS. SWITCH: A Randomised, Sequential, Open-label Study to Evaluate the Efficacy and Safety of Sorafenib-sunitinib Versus Sunitinib-sorafenib in the Treatment of Metastatic Renal Cell Cancer. Eur Urol. 2015 Nov;68(5):837-47. Epub 2015 May 4. link to original article contains protocol PubMed
  9. ESPN: Tannir NM, Jonasch E, Albiges L, Altinmakas E, Ng CS, Matin SF, Wang X, Qiao W, Dubauskas Lim Z, Tamboli P, Rao P, Sircar K, Karam JA, McDermott DF, Wood CG, Choueiri TK. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol. 2016 May;69(5):866-74. Epub 2015 Nov 26. link to original article link to PMC article PubMed
  10. ASPEN: Armstrong AJ, Halabi S, Eisen T, Broderick S, Stadler WM, Jones RJ, Garcia JA, Vaishampayan UN, Picus J, Hawkins RE, Hainsworth JD, Kollmannsberger CK, Logan TF, Puzanov I, Pickering LM, Ryan CW, Protheroe A, Lusk CM, Oberg S, George DJ. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016 Mar;17(3):378-88. Epub 2016 Jan 13. link to original article PubMed
  11. IMPRINT: Rini BI, Stenzl A, Zdrojowy R, Kogan M, Shkolnik M, Oudard S, Weikert S, Bracarda S, Crabb SJ, Bedke J, Ludwig J, Maurer D, Mendrzyk R, Wagner C, Mahr A, Fritsche J, Weinschenk T, Walter S, Kirner A, Singh-Jasuja H, Reinhardt C, Eisen T. IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2016 Nov;17(11):1599-1611. link to original article contains protocol PubMed
  12. CABOSUN: Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, Feldman DR, Olencki T, Picus J, Small EJ, Dakhil S, George DJ, Morris MJ. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol. 2017 Feb 20;35(6):591-597. Epub 2016 Nov 14. link to original article contains verified protocol link to PMC article PubMed
    1. Update: Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, Walsh M, Olencki T, Picus J, Small EJ, Dakhil S, Feldman DR, Mangeshkar M, Scheffold C, George D, Morris MJ. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer. 2018 May;94:115-125. Epub 2018 Mar 20. link to original article contains verified protocol link to PMC article PubMed
  13. CheckMate 214: Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. Epub 2018 Mar 21. link to original article contains verified protocol PubMed
    1. Update: Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, Salman P, Escudier B, Beuselinck B, Amin A, Porta C, George S, Neiman V, Bracarda S, Tykodi SS, Barthélémy P, Leibowitz-Amit R, Plimack ER, Oosting SF, Redman B, Melichar B, Powles T, Nathan P, Oudard S, Pook D, Choueiri TK, Donskov F, Grimm MO, Gurney H, Heng DYC, Kollmannsberger CK, Harrison MR, Tomita Y, Duran I, Grünwald V, McHenry MB, Mekan S, Tannir NM; CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019 Oct;20(10):1370-1385. Epub 2019 Aug 16. Erratum in: Lancet Oncol. 2019 Aug 21. link to original article PubMed
  14. CARMENA: Méjean A, Ravaud A, Thezenas S, Colas S, Beauval JB, Bensalah K, Geoffrois L, Thiery-Vuillemin A, Cormier L, Lang H, Guy L, Gravis G, Rolland F, Linassier C, Lechevallier E, Beisland C, Aitchison M, Oudard S, Patard JJ, Theodore C, Chevreau C, Laguerre B, Hubert J, Gross-Goupil M, Bernhard JC, Albiges L, Timsit MO, Lebret T, Escudier B. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018 Aug 2;379(5):417-427. Epub 2018 Jun 3. link to original article contains protocol PubMed
  15. JAVELIN Renal 101: Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M, Lee JL, Vasiliev A, Miller WH Jr, Gurney H, Schmidinger M, Larkin J, Atkins MB, Bedke J, Alekseev B, Wang J, Mariani M, Robbins PB, Chudnovsky A, Fowst C, Hariharan S, Huang B, di Pietro A, Choueiri TK. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1103-1115. Epub 2019 Feb 16. link to original article contains protocol link to PMC article PubMed
  16. KEYNOTE-426: Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, Vynnychenko I, Kryzhanivska A, Bondarenko I, Azevedo SJ, Borchiellini D, Szczylik C, Markus M, McDermott RS, Bedke J, Tartas S, Chang YH, Tamada S, Shou Q, Perini RF, Chen M, Atkins MB, Powles T; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116-1127. Epub 2019 Feb 16. link to original article contains protocol PubMed
  17. IMmotion151: Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. link to original article contains protocol PubMed

Temsirolimus monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Hudes et al. 2007 (ARCC) 2003-2005 Phase III (E-RT-switch-ooc) 1. Interferon alfa-2a Superior OS 9% (95% CI 5-12%) 5% (95% CI 2-8%)
2. Interferon alfa-2a & Temsirolimus Not reported 8% (95% CI 4-12%)

Chemotherapy

Supportive medications

7-day cycles

References

  1. ARCC: Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. link to original article contains verified protocol PubMed

Maintenance after first-line therapy

Bevacizumab monotherapy

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Regimen

Study Evidence
Escudier et al. 2007 (AVOREN) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

14-day cycles

References

  1. AVOREN: Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007 Dec 22;370(9605):2103-11. link to original article PubMed
    1. Update: Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, Sneller V. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010 May 1;28(13):2144-50. Epub 2010 Apr 5. link to original article contains verified protocol PubMed

Metastatic disease, second-line

Axitinib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rini et al. 2011 (AXIS) 2008-2010 Phase III (E-RT-switch-ic) Sorafenib Superior PFS

In the 2013 update, ORR was 23% in this arm, and 12% in the control arm.

Chemotherapy

  • Axitinib (Inlyta) as follows:
    • 5 mg PO twice per day for at least 2 weeks
    • Then if tolerated and BP not greater than 150/90, increased to 7 mg PO twice per day
    • Then if tolerated and BP not greater than 150/90, increased to 10 mg PO twice per day
    • Dose can be reduced to 2 to 3 mg PO twice per day if needed based on tolerability

Continued indefinitely

References

  1. AXIS: Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011 Dec 3;378(9807):1931-9. Epub 2011 Nov 4. link to original article contains verified protocol PubMed
    1. Update: Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, Oudard S, Gore ME, Tarazi J, Hariharan S, Chen C, Rosbrook B, Kim S, Rini BI. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013 May;14(6):552-62. Epub 2013 Apr 15. link to original article contains verified protocol PubMed
    2. Subgroup analysis: Escudier B, Michaelson MD, Motzer RJ, Hutson TE, Clark JI, Lim HY, Porfiri E, Zalewski P, Kannourakis G, Staehler M, Tarazi J, Rosbrook B, Cisar L, Hariharan S, Kim S, Rini BI. Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial. Br J Cancer. 2014 Jun 10;110(12):2821-8. Epub 2014 May 13. link to original article link to PMC article PubMed

Bevacizumab monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 2003 1998-2001 Randomized Phase II (E-esc) Placebo Superior TTP

Chemotherapy

14-day cycles

References

  1. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003 Jul 31;349(5):427-34. link to original article contains protocol link to PMC article PubMed

Cabozantinib monotherapy

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Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Choueiri et al. 2015 (METEOR) 2013-2014 Phase III (E-RT-switch-ic) Everolimus Superior OS 21% (95% CI 16-28%) 5% (95% CI 2-9%)

Preceding treatment

  • VEGFR TKI, with progression

Chemotherapy

Continued indefinitely

References

  1. METEOR: Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1814-23. Epub 2015 Sep 25. link to original article contains verified protocol link to PMC article PubMed
    1. Update: Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, Hammers HJ, Donskov F, Roth BJ, Peltola K, Lee JL, Heng DY, Schmidinger M, Agarwal N, Sternberg CN, McDermott DF, Aftab DT, Hessel C, Scheffold C, Schwab G, Hutson TE, Pal S, Motzer RJ; METEOR investigators. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):917-27. Epub 2016 Jun 5. link to original article PubMed
    2. HRQoL analysis: Cella D, Escudier B, Tannir NM, Powles T, Donskov F, Peltola K, Schmidinger M, Heng DYC, Mainwaring PN, Hammers HJ, Lee JL, Roth BJ, Marteau F, Williams P, Baer J, Mangeshkar M, Scheffold C, Hutson TE, Pal S, Motzer RJ, Choueiri TK. Quality of life outcomes for cabozantinib versus everolimus in patients with metastatic renal cell carcinoma: METEOR phase III randomized trial. J Clin Oncol. 2018 Mar 10;36(8):757-764. Epub 2018 Jan 29. link to original article PubMed
    3. Update: Motzer RJ, Escudier B, Powles T, Scheffold C, Choueiri TK. Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer. 2018 May;118(9):1176-1178. Epub 2018 Mar 26. link to original article link to PMC article PubMed

Everolimus monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Motzer et al. 2008 (RECORD-1) 2006-2007 Phase III (E-RT-esc) Placebo Superior PFS 1% 0%
Motzer et al. 2014 (RECORD-3) Randomized Phase II (E-switch-ic) Sunitinib Inconclusive whether non-inferior PFS
Motzer et al. 2015 (CheckMate 025) 2012-2014 Phase III (C) Nivolumab Inferior OS 5% 25%
Motzer et al. 2015 (E7080-G000-205) 2012-2013 Randomized Phase II (C) 1. Everolimus & Lenvatinib Inferior PFS
2. Lenvatinib Seems to have inferior PFS
Choueiri et al. 2015 (METEOR) 2013-2014 Phase III (C) Cabozantinib Inferior OS 5% (95% CI 2-9%) 21% (95% CI 16-28%)
Motzer et al. 2015 (RECORD-4) Phase II

Note: 72% of patients in Checkmate 025 had anti-angiogenic therapy prior to progression.

Preceding treatment

  • RECORD-1 & METEOR: VEGFR TKI, with progression
  • RECORD-3: Sunitinib, with progression

Chemotherapy

  • Everolimus (Afinitor) 10 mg PO once per day
    • Dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability

Continued indefinitely

References

  1. RECORD-1: Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008 Aug 9;372(9637):449-56. Epub 2008 Jul 22. link to original article contains verified protocol PubMed
    1. Update: Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A; RECORD-1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010 Sep 15;116(18):4256-65. link to original article contains verified protocol PubMed
  2. RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article PubMed
  3. CheckMate 025: Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803-13. Epub 2015 Sep 25. link to original article contains verified protocol PubMed
    1. HRQoL analysis: Cella D, Grünwald V, Nathan P, Doan J, Dastani H, Taylor F, Bennett B, DeRosa M, Berry S, Broglio K, Berghorn E, Motzer RJ. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):994-1003. Epub 2016 Jun 6. Erratum in: Lancet Oncol. 2016 Jul;17 (7):e270. link to original article link to PMC article PubMed
    2. Subgroup analysis: Escudier B, Sharma P, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Gurney H, Donskov F, Peltola K, Wagstaff J, Gauler TC, Ueda T, Zhao H, Waxman IM, Motzer RJ; CheckMate 025 investigators. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol. 2017 Dec;72(6):962-971. Epub 2017 Mar 3. Erratum in: Eur Urol. 2018 Jan 3. link to original article PubMed
    3. Subgroup analysis and update: Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Saito M, Kimura G, Yonese J, Yao M, Uemura H. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the phase III CheckMate 025 study. Jpn J Clin Oncol. 2019 Jun 1;49(6):506-514. link to original article PubMed
  4. METEOR: Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1814-23. Epub 2015 Sep 25. link to original article contains verified protocol link to PMC article PubMed
    1. Update: Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, Hammers HJ, Donskov F, Roth BJ, Peltola K, Lee JL, Heng DY, Schmidinger M, Agarwal N, Sternberg CN, McDermott DF, Aftab DT, Hessel C, Scheffold C, Schwab G, Hutson TE, Pal S, Motzer RJ; METEOR investigators. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):917-27. Epub 2016 Jun 5. link to original article PubMed
    2. HRQoL analysis: Cella D, Escudier B, Tannir NM, Powles T, Donskov F, Peltola K, Schmidinger M, Heng DYC, Mainwaring PN, Hammers HJ, Lee JL, Roth BJ, Marteau F, Williams P, Baer J, Mangeshkar M, Scheffold C, Hutson TE, Pal S, Motzer RJ, Choueiri TK. Quality of life outcomes for cabozantinib versus everolimus in patients with metastatic renal cell carcinoma: METEOR phase III randomized trial. J Clin Oncol. 2018 Mar 10;36(8):757-764. Epub 2018 Jan 29. link to original article PubMed
    3. Update: Motzer RJ, Escudier B, Powles T, Scheffold C, Choueiri TK. Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer. 2018 May;118(9):1176-1178. Epub 2018 Mar 26. link to original article link to PMC article PubMed
  5. E7080-G000-205: Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. link to original article contains verified protocol PubMed
    1. Update: Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 Jan;17(1):e4-5. link to original article PubMed
  6. RECORD-4: Motzer RJ, Alyasova A, Ye D, Karpenko A, Li H, Alekseev B, Xie L, Kurteva G, Kowalyszyn R, Karyakin O, Neron Y, Cosgriff T, Collins L, Brechenmacher T, Lin C, Morgan L, Yang L. Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4). Ann Oncol. 2016 Mar;27(3):441-8. Epub 2015 Dec 17. link to original article link to PMC article contains protocol PubMed

Everolimus & Lenvatinib

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2015 (E7080-G000-205) 2012-2013 Randomized Phase II (E-RT-esc) 1. Everolimus Superior PFS
2. Lenvatinib Did not meet primary endpoint of PFS

Patients had progressed after VEGFR TKI treatment.

Chemotherapy

Continued indefinitely

References

  1. E7080-G000-205: Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. link to original article contains verified protocol PubMed
    1. Update: Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 Jan;17(1):e4-5. link to original article PubMed

Lenvatinib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2015 (E7080-G000-205) 2012-2013 Randomized Phase II (E-RT-switch-ic) 1. Everolimus Seems to have superior PFS
2. Everolimus & Lenvatinib Did not meet primary endpoint of PFS

Chemotherapy

Continued indefinitely

References

  1. E7080-G000-205: Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. link to original article contains verified protocol PubMed
    1. Update: Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 Jan;17(1):e4-5. link to original article PubMed

Nivolumab monotherapy

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Regimen variant #1, 0.3 mg/kg q3wk

Study Evidence Comparator Comparative Efficacy
Motzer et al. 2015 (CA209-010) Randomized Phase II (E-de-esc) 1. Nivolumab; 2 mg/kg
2. Nivolumab; 10 mg/kg 		Did not meet primary endpoint of PFS

Immunotherapy

21-day cycles

Regimen variant #2, 2 mg/kg q3wk

Study Evidence Comparator Comparative Efficacy
Motzer et al. 2015 (CA209-010) Randomized Phase II (E-esc) 1. Nivolumab; 0.3 mg/kg
2. Nivolumab; 10 mg/kg 		Did not meet primary endpoint of PFS

Immunotherapy

21-day cycles

Regimen variant #3, 3 mg/kg q2wk

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Motzer et al. 2015 (CheckMate 025) 2012-2014 Phase III (E-RT-switch-ooc) Everolimus Superior OS 25% 5%

Immunotherapy

  • Nivolumab (Opdivo) 3 mg/kg IV over 60 minutes 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 variant #4, 10 mg/kg q3wk

Study Evidence Comparator Comparative Efficacy
Motzer et al. 2015 (CA209-010) Randomized Phase II (E-esc) 1.Nivolumab; 0.3 mg/kg
2. Nivolumab; 2 mg/kg 		Did not meet primary endpoint of PFS

Immunotherapy

21-day cycles

References

  1. CA209-010: Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, Vaishampayan UN, Drabkin HA, George S, Logan TF, Margolin KA, Plimack ER, Lambert AM, Waxman IM, Hammers HJ. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. 2015 May 1;33(13):1430-7. Epub 2014 Dec 1. link to original article link to PMC article contains verified protocol PubMed
  2. CheckMate 025: Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803-13. Epub 2015 Sep 25. link to original article contains verified protocol PubMed
    1. HRQoL analysis: Cella D, Grünwald V, Nathan P, Doan J, Dastani H, Taylor F, Bennett B, DeRosa M, Berry S, Broglio K, Berghorn E, Motzer RJ. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):994-1003. Epub 2016 Jun 6. Erratum in: Lancet Oncol. 2016 Jul;17 (7):e270. link to original article link to PMC article PubMed
    2. Subgroup analysis: Escudier B, Sharma P, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Gurney H, Donskov F, Peltola K, Wagstaff J, Gauler TC, Ueda T, Zhao H, Waxman IM, Motzer RJ; CheckMate 025 investigators. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol. 2017 Dec;72(6):962-971. Epub 2017 Mar 3. Erratum in: Eur Urol. 2018 Jan 3. link to original article PubMed
    3. Subgroup analysis and update: Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Saito M, Kimura G, Yonese J, Yao M, Uemura H. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the phase III CheckMate 025 study. Jpn J Clin Oncol. 2019 Jun 1;49(6):506-514. link to original article PubMed

Pazopanib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Hutson et al. 2010 Phase II
Sternberg et al. 2010 (VEG105192) 2006-2007 Phase III (E-esc) Placebo Superior PFS 30% (95% CI 25-36%) 3% (95% CI 0-6%)
Hainsworth et al. 2013 Phase II

Chemotherapy

  • Pazopanib (Votrient) 800 mg PO once per day, given 1 hour before or 2 hours after meals
    • Dose may be decreased to 600 mg or 400 mg PO once per day depending on tolerability

Continued indefinitely

References

  1. Hutson TE, Davis ID, Machiels JP, De Souza PL, Rottey S, Hong BF, Epstein RJ, Baker KL, McCann L, Crofts T, Pandite L, Figlin RA. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2010 Jan 20;28(3):475-80. Epub 2009 Dec 14. link to original article contains verified protocol PubMed
  2. VEG105192: Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarbá JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010 Feb 20;28(6):1061-8. Epub 2010 Jan 25. link to original article contains verified protocol PubMed
    1. Update: Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, Zarba JJ, Gladkov OA, Lee E, Szczylik C, McCann L, Rubin SD, Chen M, Davis ID. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013 Apr;49(6):1287-96. Epub 2013 Jan 12. link to original article contains verified protocol PubMed
  3. Hainsworth JD, Rubin MS, Arrowsmith ER, Khatcheressian J, Crane EJ, Franco LA. Pazopanib as second-line treatment after sunitinib or bevacizumab in patients with advanced renal cell carcinoma: a Sarah Cannon Oncology Research Consortium phase II trial. Clin Genitourin Cancer. 2013 Sep;11(3):270-5. Epub 2013 May 9. link to original article contains protocol PubMed

Sorafenib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Escudier et al. 2007 (TARGETRCC) 2003-2005 Phase III (E-RT-esc) Placebo Did not meet primary endpoint of OS (*) 10% 2%
Stadler et al. 2010 (ARCCS) Non-randomized
Beck et al. 2011 (EU-ARCCS) Non-randomized
Rini et al. 2011 (AXIS) 2008-2010 Phase III (C) Axitinib Inferior PFS 9% (95% CI 7-13%) 19% (95% CI 15-24%)
Hutson et al. 2013 (INTORSECT) Phase III (C) Temsirolimus Did not meet primary endpoint of PFS (*)

Note that TARGET should not be confused with the study by the same name in breast cancer. Reported efficacy for TARGET is based on the 2009 update. While the primary endpoint (PFS) was not met in INTORSECT, the control arm actually had superior OS compared to the experimental arm.

Chemotherapy

  • Sorafenib (Nexavar) 400 mg PO twice per day
    • Can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity

Continued indefinitely

References

  1. TARGET: Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):125-34. Erratum in: N Engl J Med. 2007 Jul 12;357(2):203. link to original article contains verified protocol PubMed
    1. Update: Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, Negrier S, Chevreau C, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Anderson S, Hofilena G, Shan M, Pena C, Lathia C, Bukowski RM. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009 Jul 10;27(20):3312-8. Epub 2009 May 18. link to original article PubMed
    2. Subgroup analysis: Hutson TE, Bellmunt J, Porta C, Szczylik C, Staehler M, Nadel A, Anderson S, Bukowski R, Eisen T, Escudier B; Sorafenib TARGET Clinical Trial Group. Long-term safety of sorafenib in advanced renal cell carcinoma: follow-up of patients from phase III TARGET. Eur J Cancer. 2010 Sep;46(13):2432-40. Epub 2010 Jul 23. link to original article contains verified protocol PubMed
  2. ARCCS: Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010 Mar 1;116(5):1272-80. link to original article PubMed
  3. EU-ARCCS: Beck J, Procopio G, Bajetta E, Keilholz U, Negrier S, Szczylik C, Bokemeyer C, Bracarda S, Richel DJ, Staehler M, Strauss UP, Mersmann S, Burock K, Escudier B. Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings. Ann Oncol. 2011 Aug;22(8):1812-23. Epub 2011 Feb 15. link to original article contains verified protocol PubMed
  4. AXIS: Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011 Dec 3;378(9807):1931-9. Epub 2011 Nov 4. link to original article contains verified protocol PubMed
    1. Update: Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, Oudard S, Gore ME, Tarazi J, Hariharan S, Chen C, Rosbrook B, Kim S, Rini BI. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013 May;14(6):552-62. Epub 2013 Apr 15. link to original article contains verified protocol PubMed
    2. Subgroup analysis: Escudier B, Michaelson MD, Motzer RJ, Hutson TE, Clark JI, Lim HY, Porfiri E, Zalewski P, Kannourakis G, Staehler M, Tarazi J, Rosbrook B, Cisar L, Hariharan S, Kim S, Rini BI. Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial. Br J Cancer. 2014 Jun 10;110(12):2821-8. Epub 2014 May 13. link to original article link to PMC article PubMed
  5. INTORSECT: Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, Senico P, Niethammer A, Lu DR, Hariharan S, Motzer RJ. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Mar 10;32(8):760-7. Epub 2013 Dec 2. link to original article contains protocol link to PMC article PubMed

Sunitinib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2005 (RTKC-0511-014) 2003 Phase II (RT)
Motzer et al. 2006 (A618-1006) 2004 Phase II (RT)
Gore et al. 2009 (A618-1037) Non-randomized
Motzer et al. 2014 (RECORD-3) Randomized Phase II (E-switch-ic) Everolimus Inconclusive whether non-inferior PFS

Preceding treatment

Chemotherapy

  • Sunitinib (Sutent) 50 mg PO once per day on days 1 to 28
    • Dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability

42-day cycles

References

  1. RTKC-0511-014: Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006 Jan 1;24(1):16-24. Epub 2005 Dec 5. link to original article PubMed
  2. A618-1006: Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, Redman BG, Margolin KA, Merchan JR, Wilding G, Ginsberg MS, Bacik J, Kim ST, Baum CM, Michaelson MD. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006 Jun 7;295(21):2516-24. link to original article contains protocol PubMed
  3. A618-1037: Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009 Aug;10(8):757-63. Epub 2009 Jul 15. link to original article contains verified protocol PubMed
  4. RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article PubMed

Metastatic disease, third-line

Sorafenib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2014 (GOLD-RCC) 2011-2012 Phase III (C) Dovitinib Might have inferior PFS
Motzer et al. 2014 (GOLD-RCC) 2016-2017 Phase III (C) Tivozanib Seems to have inferior PFS

Note: GOLD should not be confused for the one with the same name in gastric cancer.

Chemotherapy

Continued indefinitely

References

  1. GOLD: Motzer RJ, Porta C, Vogelzang NJ, Sternberg CN, Szczylik C, Zolnierek J, Kollmannsberger C, Rha SY, Bjarnason GA, Melichar B, De Giorgi U, Grünwald V, Davis ID, Lee JL, Esteban E, Urbanowitz G, Cai C, Squires M, Marker M, Shi MM, Escudier B. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Mar;15(3):286-96. Epub 2014 Feb 17. link to original article contains protocol link to PMC article PubMed
  2. TIVO-3: Rini BI, Pal SK, Escudier BJ, Atkins MB, Hutson TE, Porta C, Verzoni E, Needle MN, McDermott DF. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020 Jan;21(1):95-104. Epub 2019 Dec 3. link to original article PubMed
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