Difference between revisions of "Staging page"

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[[#top|Back to Top]]
 
[[#top|Back to Top]]
 
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{{#lst:Section editor transclusions|gi}}
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{{#lst:Section editor transclusions|rcc}}
 +
''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]]. For placebo or observational studies in this condition, please visit [[Renal cell carcinoma - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''
 +
<br>There are several related dedicated pages:
 +
*'''Histology-specific:'''
 +
**'''[[Clear cell renal cell carcinoma]]'''
 +
**'''[[Non-clear cell renal cell carcinoma]]'''
 +
***'''[[Papillary renal cell carcinoma]]'''
 +
***'''[[Sarcomatoid renal cell carcinoma]]'''
 +
*'''Biomarker-specific:'''
 +
**'''[[Renal_cell_carcinoma,_VHL-associated|RCC, VHL-associated]]'''
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
|-
 
|-
 
|<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>
 
|<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>
 
<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>
 
<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}}
 
{{TOC limit|limit=3}}
−
 
 
=Guidelines=
 
=Guidelines=
 
==[http://www.esmo.org/ ESMO]==
 
==[http://www.esmo.org/ ESMO]==
−
*'''2021:''' Rao et al. [https://doi.org/10.1016/j.annonc.2021.06.015 Anal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
+
*'''2021:''' Powles et al. [https://doi.org/10.1016/j.annonc.2021.09.014 ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma]
 +
*'''2019:''' Escudier et al. [https://doi.org/10.1093/annonc/mdz056 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
 
===Older===
 
===Older===
−
*'''2014:''' Glynne-Jones et al. [https://doi.org/10.1016/j.ejso.2014.07.030 Anal cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
+
*'''2016:''' Escudier et al. [https://doi.org/10.1093/annonc/mdw328 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/27664262 PubMed]
 +
*'''2014:''' Escudier et al. [https://doi.org/10.1093/annonc/mdu259 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
 +
*'''2012:''' Escudier et al. [https://doi.org/10.1093/annonc/mds227 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
 +
*'''2010:''' Escudier et al. [https://doi.org/10.1093/annonc/mdq206 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://doi.org/10.1016/S1470-2045(18)30125-6 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 PMC article] [https://pubmed.ncbi.nlm.nih.gov/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://doi.org/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://pubmed.ncbi.nlm.nih.gov/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]
 +
*[https://www.mdcalc.com/ucla-integrated-staging-system-uiss-renal-cell-carcinoma-rcc UCLA Integrated Staging System (UISS) for Renal Cell Carcinoma (RCC)]
 +
**ref: Zisman A, Pantuck AJ, Dorey F, Said JW, Shvarts O, Quintana D, Gitlitz BJ, deKernion JB, Figlin RA, Belldegrun AS. Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol. 2001 Mar 15;19(6):1649-57. [https://pubmed.ncbi.nlm.nih.gov/11250993/ PubMed]
 +
*Leibovich prognostic model
 +
**ref: Leibovich BC, Lohse CM, Cheville JC, Zaid HB, Boorjian SA, Frank I, Thompson RH, Parker WP. Predicting Oncologic Outcomes in Renal Cell Carcinoma After Surgery. Eur Urol. 2018 May;73(5):772-780. Epub 2018 Feb 3. [https://pubmed.ncbi.nlm.nih.gov/29398265/ PubMed]
 +
 
 +
=Adjuvant therapy=
 +
==Sunitinib monotherapy {{#subobject:cf6852|Regimen=1}}==
 +
 
 +
===Regimen {{#subobject:3c0a01|Variant=1}}===
 +
{| class="wikitable sortable" 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 3 (E-esc)
 +
|1. [[Renal_cell_carcinoma_-_null_regimens#Placebo|Placebo]]<br> 2. [[#Sorafenib_monotherapy_99|Sorafenib]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa1611406 Ravaud et al. 2016 (S-TRAC)]
 +
|2007-2011
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[Renal_cell_carcinoma_-_null_regimens#Placebo|Placebo]]
 +
| style="background-color:#91cf60" |Seems to have superior DFS<br>Median DFS: 6.8 vs 5.6 yr<br>(HR 0.76, 95% CI 0.59-0.98)
 +
| style="background-color:#d73027" |More toxicity
 +
|-
 +
|}
 +
====Preceding treatment====
 +
*[[Surgery#Renal_cell_carcinoma_surgery|Surgery]]
 +
====Targeted therapy====
 +
*[[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://doi.org/10.1016/S0140-6736(16)00559-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878938/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/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://doi.org/10.1056/NEJMoa1611406 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27718781 PubMed] NCT00375674
 +
##'''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 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28967554 PubMed]
 +
=Metastatic disease, first-line=
 +
==Atezolizumab & Bevacizumab {{#subobject:af0d04|Regimen=1}}==
 +
 
 +
===Regimen {{#subobject:34c462|Variant=1}}===
 +
{| class="wikitable sortable" 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/10.1016/S0140-6736(19)30723-8 Rini et al. 2019 (IMmotion151)]
 +
|2015-2016
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Sunitinib_monotherapy_2|Sunitinib]]
 +
| style="background-color:#91cf60" |Seems to have superior PFS<sup>1</sup><br>Median PFS: 11.2 vs 7.7 mo<br>(HR 0.74, 95% CI 0.57-0.96)
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy is for the PD-L1-positive subgroup, which was the predefined co-primary endpoint.''
 +
====Immunotherapy====
 +
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1
 +
====Targeted therapy====
 +
*[[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://doi.org/10.1016/S0140-6736(19)30723-8 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31079938 PubMed] NCT02420821
 +
##'''Update:''' Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Alekseev BY, Lee JL, Suarez C, Stroyakovskiy D, De Giorgi U, Donskov F, Mellado B, Banchereau R, Hamidi H, Khan O, Craine V, Huseni M, Flinn N, Dubey S, Rini BI. Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol. 2022 Feb 1;8(2):275-280. [https://doi.org/10.1001/jamaoncol.2021.5981 link to original article] [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8855230/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34940781/ PubMed]
 +
 
 +
==Axitinib monotherapy {{#subobject:e83fa|Regimen=1}}==
 +
 
 +
===Regimen {{#subobject:90ba4d|Variant=1}}===
 +
{| class="wikitable sortable" 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://doi.org/10.1016/S1470-2045(13)70465-0 Hutson et al. 2013 (A4061051)]
 +
|2010-2011
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Sorafenib_monotherapy|Sorafenib]]
 +
| style="background-color:#d9ef8b" |Might have superior PFS<sup>1</sup> <br>(HR 0.77, 95% CI 0.56-1.05)
 +
|32%
 +
|15%
 +
|-
 +
|}
 +
''<sup>1</sup>In the 2016 update, there was no difference in OS, which was a secondary endpoint. Reported efficacy here is from the primary (2013) analysis.''
 +
====Targeted therapy====
 +
*[[Axitinib (Inlyta)]] as follows:
 +
**Starting dose: 5 mg PO twice per day for at least 2 weeks
 +
**Then if tolerated and BP not greater than 150/90: 7 mg PO twice per day
 +
**Then if tolerated and BP not greater than 150/90: 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://doi.org/10.1016/S1470-2045(13)70465-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24206640 PubMed] NCT00920816
 +
##'''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 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27498023 PubMed]
 +
==Axitinib & Avelumab {{#subobject:e83faz|Regimen=1}}==
 +
 
 +
===Regimen variant #1, weight-based dosing {{#subobject:88ca4d|Variant=1}}===
 +
{| class="wikitable sortable" 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 3 (E-RT-esc)
 +
|[[#Sunitinib_monotherapy_2|Sunitinib]]
 +
| style="background-color:#1a9850" |Superior PFS<sup>1</sup><br>Median PFS: 13.3 vs 8 mo<br>(HR 0.69, 95% CI 0.57-0.83)
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy is for the overall population and is based on the 2020 update.''<br>
 +
''Note: this is not the FDA-recommended dose.''
 +
====Targeted therapy====
 +
*[[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.''
 +
====Targeted therapy====
 +
*[[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://doi.org/10.1056/NEJMoa1816047 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716603/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30779531/ PubMed] NCT02684006
 +
##'''Update:''' Choueiri TK, Motzer RJ, Rini BI, Haanen J, Campbell MT, Venugopal B, Kollmannsberger C, Gravis-Mescam G, Uemura M, Lee JL, Grimm MO, Gurney H, Schmidinger M, Larkin J, Atkins MB, Pal SK, Wang J, Mariani M, Krishnaswami S, Cislo P, Chudnovsky A, Fowst C, Huang B, di Pietro A, Albiges L. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020 Aug;31(8):1030-1039. Epub 2020 Apr 25. [https://doi.org/10.1016/j.annonc.2020.04.010 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32339648/ PubMed]
 +
==Axitinib & Pembrolizumab {{#subobject:e83gac|Regimen=1}}==
 +
 
 +
===Regimen {{#subobject:22bc4d|Variant=1}}===
 +
{| class="wikitable sortable" 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/10.1056/NEJMoa1816714 Rini et al. 2019 (KEYNOTE-426)]
 +
|2016-2018
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[#Sunitinib_monotherapy_2|Sunitinib]]
 +
| style="background-color:#1a9850" |Superior OS<sup>1</sup><br>Median OS: NYR vs 36 mo<br>(HR 0.68, 95% CI 0.55-0.85)
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy is based on the 2020 update.''
 +
====Targeted therapy====
 +
*[[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://doi.org/10.1056/NEJMoa1816714 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30779529 PubMed] NCT02853331
 +
##'''Update:''' Powles T, Plimack ER, Soulières D, Waddell T, Stus V, Gafanov R, Nosov D, Pouliot F, Melichar B, Vynnychenko I, Azevedo SJ, Borchiellini D, McDermott RS, Bedke J, Tamada S, Yin L, Chen M, Molife LR, Atkins MB, Rini BI. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1563-1573. Epub 2020 Oct 23. Erratum in: Lancet Oncol. 2020 Dec;21(12):e553. [https://doi.org/10.1016/S1470-2045(20)30436-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33284113 PubMed]
 +
==Bevacizumab monotherapy {{#subobject:29beb2|Regimen=1}}==
 +
 
 +
===Regimen {{#subobject:433717|Variant=1}}===
 +
{| class="wikitable sortable" 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://doi.org/10.1200/jco.2007.11.5154 Bukowski et al. 2007]
 +
|2004
 +
| style="background-color:#1a9851" |Randomized Phase 2 (C)
 +
|[[#Erlotinib_.26_Bevacizumab|Erlotinib & Bevacizumab]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoints of ORR/PFS
 +
|13%
 +
|14%
 +
|-
 +
|}
 +
====Targeted therapy====
 +
*[[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. [https://doi.org/10.1200/jco.2007.11.5154 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17876014 PubMed]
 +
==Bevacizumab & Interferon alfa-2a {{#subobject:808d58|Regimen=1}}==
 +
 
 +
===Regimen variant #1, 1 year of interferon {{#subobject:dbebac|Variant=1}}===
 +
{| class="wikitable sortable" 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/10.1016/S0140-6736(07)61904-7 Escudier et al. 2007 (AVOREN)]
 +
|2004-2005
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<sup>1</sup><br>Median OS: 23.3 vs 21.3 mo<br>(HR 0.91, 95% CI 0.76-1.10)
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy for AVOREN is based on the 2010 update.''<br>
 +
''Note: Timing below reflects starting treatment on a Monday.''
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
 +
====Immunotherapy====
 +
*[[Interferon alfa-2a (Roferon-A)]] as follows:
 +
**Cycles 1 to 26: 9,000,000 units SC once per day on days 1, 3, 5, 8, 10, 12 (3 times per week)
 +
'''14-day cycles'''
 +
====Dose modifications====
 +
*[[Interferon alfa-2a (Roferon-A)]] dose can be reduced to 3,000,000 or 6,000,000 units SC 3 times per week based on tolerability
 +
===Regimen variant #2, indefinite {{#subobject:d136cc|Variant=1}}===
 +
{| class="wikitable sortable" 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/PMC2651074/ Rini et al. 2008 (CALGB 90206)]
 +
|2003-2005
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
 +
| style="background-color:#d9ef8b" |Might have superior OS<sup>1</sup><br>Median OS: 18.3 vs 17.4 mo<br>(HR 0.86, 95% CI 0.73-1.01)
 +
|-
 +
|[https://doi.org/10.1200/JCO.2013.50.5305 Rini et al. 2013 (INTORACT)]
 +
|2008-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Temsirolimus_.26_Bevacizumab_99|Temsirolimus & Bevacizumab]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy for CALGB 90206 is based on the 2010 update and is based on a stratified analysis.''<br>
 +
''Note: Timing below reflects starting treatment on a Monday.''
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
 +
====Immunotherapy====
 +
*[[Interferon alfa-2a (Roferon-A)]] 9,000,000 units SC once per day on days 1, 3, 5, 8, 10, 12 (3 times per week)
 +
'''14-day cycles'''
 +
====Dose modifications====
 +
*[[Interferon alfa-2a (Roferon-A)]] dose can be reduced to 3,000,000 or 6,000,000 units SC 3 times per week based on tolerability
 +
 
 +
===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://doi.org/10.1016/S0140-6736(07)61904-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18156031 PubMed] NCT00738530
 +
##'''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. [https://doi.org/10.1200/jco.2009.26.7849 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/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. [https://doi.org/10.1200/jco.2008.16.9847 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651074/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18936475 PubMed] NCT00072046
 +
##'''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. [https://doi.org/10.1200/jco.2009.26.5561 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860433/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/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 dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24297945 PubMed] NCT00631371
 +
 
 +
==Cabozantinib monotherapy {{#subobject:e3ff16|Regimen=1}}==
 +
 
 +
===Regimen {{#subobject:a0ee63|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 +
|-
 +
|}
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 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 3 (E-RT-switch-ic)
 +
|[[#Sunitinib_monotherapy_2|Sunitinib]]
 +
| style="background-color:#1a9850" |Superior PFS<sup>1</sup><br>Median PFS: 8.6 vs 5.3 mo<br>(HR 0.48, 95% CI 0.31-0.74)
 +
|-
 +
|}
 +
''<sup>1</sup>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.''
 +
====Targeted therapy====
 +
*[[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; Alliance. 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 dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455807/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28199818 PubMed] NCT01835158
 +
##'''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 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057479/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29550566 PubMed]
 +
#'''PIVOT-09:''' NCT03729245
 +
 
 +
==Cabozantinib & Nivolumab {{#subobject:e3igp6|Regimen=1}}==
 +
 
 +
===Regimen variant #1, bi-weekly nivolumab {{#subobject:ajg89a|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 +
|-
 +
|}
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 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/10.1056/nejmoa2026982 Choueiri et al. 2021 (CheckMate 9ER)]
 +
|2017-2019
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[#Sunitinib_monotherapy_2|Sunitinib]]
 +
| style="background-color:#1a9850" |Superior OS<sup>1</sup><br>Median OS: 37.7 vs 34.3 mo<br>(HR 0.70, 95% CI 0.55-0.90)
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy is based on the 2022 update.''
 +
====Targeted therapy====
 +
*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 40 mg PO once per day
 +
====Immunotherapy====
 +
*[[Nivolumab (Opdivo)]] as follows:
 +
**Cycles 1 to 52: 240 mg IV over 30 minutes once on day 1
 +
'''14-day cycles'''
 +
===Regimen variant #2, monthly nivolumab {{#subobject:aj9iya|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 +
|-
 +
|}
 +
''Note: this dosing does not appear to have been used in a trial, but is recommended by the FDA.''
 +
====Targeted therapy====
 +
*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 40 mg PO once per day
 +
====Immunotherapy====
 +
*[[Nivolumab (Opdivo)]] as follows:
 +
**Cycles 1 to 26: 480 mg IV over 30 minutes once on day 1
 +
'''28-day cycles'''
 +
===References===
 +
#'''CheckMate 9ER:''' Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, Oyervides Juárez VM, Hsieh JJ, Basso U, Shah AY, Suárez C, Hamzaj A, Goh JC, Barrios C, Richardet M, Porta C, Kowalyszyn R, Feregrino JP, Żołnierek J, Pook D, Kessler ER, Tomita Y, Mizuno R, Bedke J, Zhang J, Maurer MA, Simsek B, Ejzykowicz F, Schwab GM, Apolo AB, Motzer RJ; CheckMate 9ER Investigators. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841. [https://doi.org/10.1056/nejmoa2026982 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33657295/ PubMed] NCT03141177
 +
##'''Update:''' Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, Suárez C, Hamzaj A, Porta C, Hocking CM, Kessler ER, Gurney H, Tomita Y, Bedke J, Zhang J, Simsek B, Scheffold C, Apolo AB, Choueiri TK. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Jun 7:S1470-2045(22)00290-X. Epub ahead of print. [https://doi.org/10.1016/s1470-2045(22)00290-x link to original article] [https://pubmed.ncbi.nlm.nih.gov/35688173/ PubMed]
 +
 
 +
==Erlotinib & Bevacizumab {{#subobject:1a1b7b|Regimen=1}}==
 +
 
 +
===Regimen {{#subobject:1e7b71|Variant=1}}===
 +
{| class="wikitable sortable" 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.2007.11.5154 Bukowski et al. 2007]
 +
|2004
 +
| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
 +
|[[#Bevacizumab_monotherapy|Bevacizumab]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoints of ORR/PFS
 +
|-
 +
|}
 +
====Targeted therapy====
 +
*[[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. [https://doi.org/10.1200/jco.2007.11.5154 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17876014 PubMed]
 +
==Everolimus monotherapy {{#subobject:b3af63|Regimen=1}}==
 +
 
 +
===Regimen {{#subobject:474ade|Variant=1}}===
 +
{| class="wikitable sortable" 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/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
 +
|2009-2011
 +
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 +
|[[#Sunitinib_monotherapy_2|Sunitinib]]
 +
| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
 +
|-
 +
|}
 +
====Targeted therapy====
 +
*[[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===
 +
 
 +
#'''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. [https://doi.org/10.1200/jco.2013.54.6911 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25049330 PubMed] NCT00903175
  
−
==[https://www.nccn.org/ NCCN]==
+
==Everolimus & Lenvatinib {{#subobject:e83gac|Regimen=1}}==
−
*[https://www.nccn.org/professionals/physician_gls/pdf/anal.pdf NCCN Guidelines - Anal Carcinoma]
 
  
−
=Definitive chemoradiotherapy for locally advanced disease=
+
===Regimen {{#subobject:22bc4d|Variant=1}}===
−
==Capecitabine, Mitomycin, RT {{#subobject:6a7b17 |Regimen=1}}==
+
{| class="wikitable sortable" 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://doi.org/10.1056/NEJMoa2035716 Motzer et al. 2021 (CLEAR)]
 +
|rowspan=2|2016-2019
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|1. [[#Lenvatinib_.26_Pembrolizumab|Lenvatinib & Pembrolizumab]]
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|2. [[#Sunitinib_monotherapy_2|Sunitinib]]
 +
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: 14.7 vs 9.2 mo<br>(HR 0.65, 95% CI 0.53-0.80)
 +
|-
 +
|}
 +
====Targeted therapy====
 +
*[[Everolimus (Afinitor)]] 5 mg PO once per day
 +
*[[Lenvatinib (Lenvima)]] 18 mg PO once per day
 +
'''21-day cycles'''
 +
===References===
 +
#'''CLEAR:''' Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. [https://doi.org/10.1056/NEJMoa2035716 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33616314/ PubMed] NCT02811861
 +
==Gemcitabine & Sunitinib {{#subobject:ec76af|Regimen=1}}==
  
−
<div class="toccolours" style="background-color:#eeeeee">
+
===Regimen variant #1 {{#subobject:py1|Variant=1}}===
−
===Regimen {{#subobject:9368b2|Variant=1}}===
+
{| class="wikitable" style="width: 60%; text-align:center;"
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
! style="width: 33%" |Study
−
!style="width: 33%"|Study
+
! style="width: 33%" |Years of enrollment
−
!style="width: 33%"|Years of enrollment
+
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
 
|-
 
|-
−
|[https://doi.org/10.1016/S0360-3016(07)04703-7 Glynne-Jones et al. 2008 (EXTRA)]
+
|[https://doi.org/10.1002/cncr.29503 Michaelson et al. 2015 (MGH 07-212)]
−
|2004-2006
+
|2007-2013
 
| style="background-color:#91cf61" |Phase 2
 
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
 
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Capecitabine (Xeloda)]] 825 mg/m<sup>2</sup> PO twice per day on radiation days
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
*[[Mitomycin (Mutamycin)]] 12 mg/m<sup>2</sup> IV once on day 1
+
====Targeted therapy====
−
====Radiotherapy====
+
*[[Sunitinib (Sutent)]] 37.5 mg PO once per day on days 1 to 14
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]]: 1.8 Gy per day x 28 fractions (total dose: 50.4 Gy)
+
'''21-day cycles'''
−
 
+
===Regimen variant #2 {{#subobject:e9a6b9|Variant=1}}===
−
'''6-week course'''
+
{| class="wikitable" style="width: 40%; text-align:center;"
−
</div></div>
+
! style="width: 50%" |Study
 +
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1111/j.1464-410X.2011.10096.x 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
 +
====Targeted therapy====
 +
*[[Sunitinib (Sutent)]] 37.5 mg PO once per day on days 2 to 15
 +
'''21-day cycles'''
 
===References===
 
===References===
−
# '''EXTRA:''' Glynne-Jones R, Meadows H, Wan S, Gollins S, Leslie M, Levine E, McDonald AC, Myint S, Samuel L, Sebag-Montefiore D; National Cancer Research Institute Anal Sub Group; NCRI Colorectal Clinical Oncology Group. EXTRA--a multicenter phase II study of chemoradiation using a 5 day per week oral regimen of capecitabine and intravenous mitomycin C in anal cancer. Int J Radiat Oncol Biol Phys. 2008 Sep 1;72(1):119-26. Epub 2008 May 9. [https://doi.org/10.1016/S0360-3016(07)04703-7 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/18472366 PubMed]
+
#'''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://doi.org/10.1111/j.1464-410X.2011.10096.x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/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://doi.org/10.1002/cncr.29503 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26058385 PubMed] NCT00556049
  
−
==Cisplatin & Fluorouracil (CF) & RT {{#subobject:6c5a17 |Regimen=1}}==
+
==High-dose Interleukin-2 {{#subobject:d95f4e|Regimen=1}}==
  
−
CF & RT: '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
+
HD IL-2: '''<u>H</u>'''igh-'''<u>D</u>'''ose '''<u>I</u>'''nter'''<u>L</u>'''eukin-'''<u>2</u>'''
−
<div class="toccolours" style="background-color:#eeeeee">
+
===Example orders===
−
===Regimen {{#subobject:6d1962 |Variant=1}}===
+
*[[Example orders for High-dose (HD) IL-2 in renal cancer]]
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
===Regimen variant #1, 1.8 MU/kg/day, intermittent {{#subobject:ca472e|Variant=1}}===
−
!style="width: 20%"|Study
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
!style="width: 20%"|Years of enrollment
+
! style="width: 20%" |Study
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |Years of enrollment
−
!style="width: 20%"|Comparator
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.1996.14.12.3121 Doci et al. 1996]
+
|[https://jamanetwork.com/journals/jama/article-abstract/368156 Rosenberg et al. 1994]
−
|1991-1995
+
|1985-1992
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#91cf61" |Non-randomized
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[http://jama.ama-assn.org/content/299/16/1914.full Ajani et al. 2008 (RTOG 98-11)]
+
|[https://doi.org/10.1200/JCO.1995.13.3.688 Fyfe et al. 1995]
−
|1998-2005
+
|NR
−
|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
+
| style="background-color:#91cf61" |Phase 2 (RT)
−
|[[Anal_cancer#Fluorouracil.2C_Mitomycin.2C_RT|Fluorouracil, Mitomycin, RT]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior OS<sup>1</sup>
 
−
|-
 
−
|[https://doi.org/10.1200/JCO.2011.35.4837 Peiffert et al. 2012 (ACCORD 03)]
 
−
|1999-2005
 
−
| style="background-color:#91cf61" |Non-randomized portion of phase 3 RCT
 
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[https://doi.org/10.1016/S1470-2045(13)70086-X James et al. 2013 (ACT II)]
+
|[https://doi.org/10.1200/jco.2005.03.206 McDermott et al. 2005]
−
|2001-2008
+
|1997-2000
−
|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
+
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[Anal_cancer#Fluorouracil.2C_Mitomycin.2C_RT|Fluorouracil, Mitomycin, RT]]
+
|[[#Interferon_alfa-2a_.26_Interleukin-2_99|Subcutaneous IL-2 & Interferon]]
−
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR rate at 26 weeks
+
| 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 therapy====
 +
*[[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 sortable" 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://doi.org/10.1200/JCO.1994.12.8.1572 Yang et al. 1994]
 +
| rowspan="2" |1991-1993
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (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: reported 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: 40%; 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
 
|-
 
|-
 
|}
 
|}
−
''<sup>1</sup>Reported efficacy for RTOG 98-11 is based on the 2012 update.''<br>
+
====Immunotherapy====
−
''Included for reference purposes only.''
+
*[[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)
−
<div class="toccolours" style="background-color:#b3e2cd">
+
**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
−
====Chemotherapy====
+
====Supportive therapy====
−
*[[Cisplatin (Platinol)]]
+
*"Routine administration of antipyretics, anti-inflammatories, antiemetics, antidiarrheals, and H2 antagonists."
−
*[[Fluorouracil (5-FU)]]
+
====Subsequent treatment====
−
====Radiotherapy====
+
*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)
−
*[[External beam radiotherapy]]
+
===Regimen variant #4, 5 MU/m<sup>2</sup>/day, CI {{#subobject:bd04b6|Variant=1}}===
 +
{| class="wikitable sortable" 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.1999.17.8.2521 Figlin et al. 1999]
 +
|1994-1997
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Interleukin-2_.26_TILs_77|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. [https://jamanetwork.com/journals/jama/article-abstract/368156 link to original article] [https://pubmed.ncbi.nlm.nih.gov/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://doi.org/10.1200/JCO.1994.12.8.1572 link to original article] [https://pubmed.ncbi.nlm.nih.gov/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. [https://doi.org/10.1200/jco.2003.02.122 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275327/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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 dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/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. [https://doi.org/10.1200/jco.2005.03.206 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/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://doi.org/10.1002/cncr.23552 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486432/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18457330 PubMed]
 +
==Low-dose Interleukin-2 {{#subobject:a2e938|Regimen=1}}==
  
−
</div></div>
+
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 sortable" 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://doi.org/10.1200/JCO.1994.12.8.1572 Yang et al. 1994]
 +
| rowspan="2" |1991-1993
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|1. [[#High-dose_Interleukin-2|High-dose IL-2]]
 +
| style="background-color:#fc8d59" |Seems to have inferior ORR
 +
|-
 +
|2. [[#Low-dose_Interleukin-2|LD IL-2]]; SC
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|}
 +
''Note: efficacy is based on the 2003 update.''
 +
====Immunotherapy====
 +
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] as follows:
 +
**Week 1: 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 sortable" 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://doi.org/10.1200/JCO.1994.12.8.1572 Yang et al. 1994]
 +
| rowspan="2" |1991-1993
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|1. [[#High-dose_Interleukin-2|High-dose IL-2]]
 +
| style="background-color:#fc8d59" |Seems to have inferior ORR
 +
|-
 +
|2. [[#Low-dose_Interleukin-2|LD IL-2]]; IV
 +
| 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===
 
===References===
−
#Doci R, Zucali R, La Monica G, Meroni E, Kenda R, Eboli M, Lozza L. Primary chemoradiation therapy with fluorouracil and cisplatin for cancer of the anus: results in 35 consecutive patients. J Clin Oncol. 1996 Dec;14(12):3121-5. [https://doi.org/10.1200/jco.1996.14.12.3121 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8955657/ 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://doi.org/10.1200/JCO.1994.12.8.1572 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8040669 PubMed]
−
# '''RTOG 98-11:''' Ajani JA, Winter KA, Gunderson LL, Pedersen J, Benson AB 3rd, Thomas CR Jr, Mayer RJ, Haddock MG, Rich TA, Willett C. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA. 2008 Apr 23;299(16):1914-21. [http://jama.ama-assn.org/content/299/16/1914.full link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18430910 PubMed] NCT00003596
+
##'''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. [https://doi.org/10.1200/jco.2003.02.122 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275327/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12915604 PubMed]
−
## '''Update:''' Gunderson LL, Winter KA, Ajani JA, Pedersen JE, Moughan J, Benson AB 3rd, Thomas CR Jr, Mayer RJ, Haddock MG, Rich TA, Willett CG. Long-term update of US GI intergroup RTOG 98-11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin. J Clin Oncol. 2012 Dec 10;30(35):4344-51. Epub 2012 Nov 13. [https://doi.org/10.1200/JCO.2012.43.8085 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3515768/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23150707 PubMed]
+
==Interferon alfa-2a monotherapy {{#subobject:8f04d6|Regimen=1}}==
−
# '''ACCORD 03:''' Peiffert D, Tournier-Rangeard L, Gérard JP, Lemanski C, François E, Giovannini M, Cvitkovic F, Mirabel X, Bouché O, Luporsi E, Conroy T, Montoto-Grillot C, Mornex F, Lusinchi A, Hannoun-Lévi JM, Seitz JF, Adenis A, Hennequin C, Denis B, Ducreux M. Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial. J Clin Oncol. 2012 Jun 1;30(16):1941-8. Epub 2012 Apr 23. Erratum in: J Clin Oncol. 2012 Nov 1;30(31):3903. [https://doi.org/10.1200/JCO.2011.35.4837 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22529257 PubMed] NCT00003652
 
−
# '''ACT II:''' James RD, Glynne-Jones R, Meadows HM, Cunningham D, Myint AS, Saunders MP, Maughan T, McDonald A, Essapen S, Leslie M, Falk S, Wilson C, Gollins S, Begum R, Ledermann J, Kadalayil L, Sebag-Montefiore D. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2×2 factorial trial. Lancet Oncol. 2013 May;14(6):516-24. Epub 2013 Apr 9. [https://doi.org/10.1016/S1470-2045(13)70086-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23578724 PubMed] NCT00025090
 
  
−
==Fluorouracil, Mitomycin, RT {{#subobject:744af9|Regimen=1}}==
+
===Regimen variant #1, 5 MU 5x per week {{#subobject:f49d4e|Variant=1}}===
 +
{| class="wikitable sortable" 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 3 (C)
 +
|[[#Cimetidine.2C_Coumarin.2C_Interferon_alfa-2a_99|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 sortable" 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/10.1016/S0140-6736(07)61904-7 Escudier et al. 2007 (AVOREN)]
 +
|2004-2005
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Bevacizumab_.26_Interferon_alfa-2a|Bevacizumab & Interferon alfa-2a]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<sup>1</sup>
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651074/ Rini et al. 2008 (CALGB 90206)]
 +
|2003-2005
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Bevacizumab_.26_Interferon_alfa-2a|Bevacizumab & Interferon alfa-2a]]
 +
| style="background-color:#fee08b" |Might have inferior OS<sup>2</sup>
 +
|-
 +
|[https://doi.org/10.1200/jco.2008.19.3342 Escudier et al. 2009]
 +
|2005
 +
| style="background-color:#1a9851" |Randomized Phase 2 (C)
 +
|[[#Sorafenib_monotherapy|Sorafenib]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835851/ Gore et al. 2010 (MRC RE04/EORTC GU 30012)]
 +
|2001-2006
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Fluorouracil.2C_Interferon_alfa-2a.2C_Interleukin-2_99|5-FU, Interferon alfa-2a, IL-2]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|[http://clincancerres.aacrjournals.org/content/22/13/3172.long Hawkins et al. 2016 (Active Biotech 06762004)]
 +
|2007-2010
 +
| style="background-color:#1a9851" |Phase 2/3 (C)
 +
|[[#Naptumomab estafenatox_.26_Inteferon_alfa_77|Naptumomab estafenatox + IFNα]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy for AVOREN is based on the 2010 update.''<br>
 +
''<sup>2</sup>Reported efficacy for CALGB 90206 is based on the 2010 update and is based on a stratified analysis.''
 +
====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'''
  
−
<div class="toccolours" style="background-color:#eeeeee">
+
===Regimen variant #3, 9 MU daily, with lead-in {{#subobject:5f04fc|Variant=1}}===
−
===Regimen variant #1, 3750/12/45 {{#subobject:6hdc9c |Variant=1}}===
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
{| class="wikitable sortable" 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
+
! 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]]
+
|-
 +
|[https://doi.org/10.1200/JCO.2000.18.16.2972 Motzer et al. 2000]
 +
|1994-1996
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Interferon_alfa_.26_13-CRA_77|IFN alfa & 13-CRA]]
 +
| style="background-color:#ffffbf" |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 {{#subobject:2c65a4|Variant=1}}===
 +
{| class="wikitable sortable" 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/10.1056/NEJMoa065044 Motzer et al. 2007 (A618-1034)]
 +
|2004-2005
 +
| style="background-color:#1a9851" |Phase 3 (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 sortable" 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/10.1016/S0140-6736(98)03544-2 Ritchie et al. 1999 (MRC RE01)]
 +
|1992-1997
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
 +
|[[#Medroxyprogesterone_monotherapy_88|MPA]]
 +
| style="background-color:#91cf60" |Seems to have superior OS
 
|-
 
|-
−
|[https://doi.org/10.1016/S0140-6736(96)03409-5 Northover et al. 1996 (ACT I)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835851/ Gore et al. 2010 (MRC RE04/EORTC GU 30012)]
−
|1987-1994
+
|2001-2006
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
+
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[Anal_cancer#Radiation_therapy|Radiation]]
+
|[[#Fluorouracil.2C_Interferon_alfa-2a.2C_Interleukin-2_99|5-FU, Interferon alfa-2a, IL-2]]
−
|style="background-color:#1a9850"|Superior local failure rate
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 
|-
 
|-
 
|}
 
|}
−
''Because there were a few different schedules used in UKCCCR Anal Cancer Trial Working Party 1996 and the update (Northover et al. 2010), there is some variability in potential schedules.''
+
====Immunotherapy====
−
<div class="toccolours" style="background-color:#b3e2cd">
+
*[[Interferon alfa-2a (Roferon-A)]] 10,000,000 units SC 3 times per week
−
====Chemotherapy====
+
**In MRC RE01, the first two doses were 5,000,000 units
−
*[[Fluorouracil (5-FU)]] 750 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m<sup>2</sup>)
+
'''12-week course (MRC RE01) or continued indefinitely (MRC RE04/EORTC GU 30012)'''
−
*[[Mitomycin (Mutamycin)]] 12 mg/m<sup>2</sup> (maximum dose of 20 mg) IV bolus once on day 1
+
===Regimen variant #6, 18 MU TIW, with lead-in {{#subobject:b28245|Variant=1}}===
−
====Radiotherapy====
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]]: 1.8 or 2.25 Gy fractions x 20 or 25 fractions (total dose: 45 Gy), given over 4 to 5 weeks; see Northover et al. 2010 for details, including information about boost radiation therapy
+
! 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.a058185 Fosså et al. 1992]
 +
|1985-1986
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Interferon_alfa-2a_.26_Vinblastine_99|IFN alfa-2a & Vinblastine]]
 +
| style="background-color:#ffffbf" |Did not meet efficacy endpoints
 +
|-
 +
| rowspan="2" |[https://doi.org/10.1056/NEJMoa066838 Hudes et al. 2007 (ARCC)]
 +
| rowspan="2" |2003-2005
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Interferon_alfa-2a_.26_Temsirolimus_99|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://pubmed.ncbi.nlm.nih.gov/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 dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/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://doi.org/10.1016/S0140-6736(98)03544-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://doi.org/10.1056/NEJMoa065044 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17215529 PubMed] NCT00098657
 +
##'''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. [https://doi.org/10.1200/jco.2008.20.1293 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646307/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19487381 PubMed] content property of [https://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://doi.org/10.1056/NEJMoa066838 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17538086 PubMed] NCT00065468
 +
#'''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://doi.org/10.1016/S0140-6736(07)61904-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18156031 PubMed] NCT00738530
 +
##'''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. [https://doi.org/10.1200/jco.2009.26.7849 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/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. [https://doi.org/10.1200/jco.2008.16.9847 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651074/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18936475 PubMed] NCT00072046
 +
##'''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. [https://doi.org/10.1200/jco.2009.26.5561 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860433/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/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. [https://doi.org/10.1200/jco.2008.19.3342 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19171708 PubMed] NCT00117637
 +
#'''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://doi.org/10.1016/S0140-6736(09)61921-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835851/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20153039 PubMed] NCT00053820
 +
#'''Active Biotech 06762004:''' 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 dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26851187 PubMed] NCT00420888
 +
==Ipilimumab & Nivolumab {{#subobject:7bc416|Regimen=1}}==
  
−
'''28-day cycle for 2 cycles'''
+
===Regimen variant #1 {{#subobject:aa43c1|Variant=1}}===
−
</div></div><br>
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
<div class="toccolours" style="background-color:#eeeeee">
+
! style="width: 20%" |Study
−
===Regimen variant #2, 3750/15/45 {{#subobject:cf4334 |Variant=1}}===
+
! style="width: 20%" |Years of enrollment
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Study
+
! style="width: 20%" |Comparator
−
!style="width: 20%"|Years of enrollment
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
!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.1997.15.5.2040 Bartelink et al. 1997 (EORTC 22861)]
+
|[https://doi.org/10.1056/NEJMoa1712126 Motzer et al. 2018 (CheckMate 214)]
−
|1987-1994
+
|2014-2016
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
+
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
−
|[[Anal_cancer#Radiation_therapy|Radiation]]
+
|[[#Sunitinib_monotherapy_2|Sunitinib]]
−
|style="background-color:#1a9850"|Superior local failure rate
+
| style="background-color:#1a9850" |Superior OS<sup>1</sup><br>OS42: 56% vs 47%<br>(HR 0.72, 95% CI 0.61-0.86)
 
|-
 
|-
 
|}
 
|}
−
''Note: mitomycin is only given with cycle 1.''
+
''<sup>1</sup>Reported efficacy is for the ITT population per the 2020 update.''<br>
−
<div class="toccolours" style="background-color:#b3e2cd">
+
''Note: while this is the dosing studied in CheckMate 214, it is not the FDA-recommended dosing.''
−
====Chemotherapy====
+
====Immunotherapy====
−
*[[Fluorouracil (5-FU)]] 750 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m<sup>2</sup>)
+
*[[Ipilimumab (Yervoy)]] as follows:
−
*[[Mitomycin (Mutamycin)]] as follows:
+
**Cycles 1 to 4: 1 mg/kg IV over 30 minutes once on day 1
−
**Cycle 1: 15 mg/m<sup>2</sup> IV bolus once on day 1
+
*[[Nivolumab (Opdivo)]] 3 mg/kg IV over 60 minutes once on day 1
−
====Radiotherapy====
+
'''21-day cycle for 4 cycles, then 14-day cycles'''
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]]: 1.8 Gy x 25 fractions (total dose: 45 Gy)
+
===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====
 +
*[[Ipilimumab (Yervoy)]] as follows:
 +
**Cycles 1 to 4: 1 mg/kg IV once on day 1, '''given second'''
 +
*[[Nivolumab (Opdivo)]] as follows:
 +
**Cycles 1 to 4: 3 mg/kg IV once on day 1, '''given first'''
 +
**Cycle 5 onwards: 240 mg IV once on day 1
 +
'''21-day cycle for 4 cycles, then 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====
 +
*[[Ipilimumab (Yervoy)]] as follows:
 +
**Cycles 1 to 4: 1 mg/kg IV once on day 1, '''given second'''
 +
*[[Nivolumab (Opdivo)]] as follows:
 +
**Cycles 1 to 4: 3 mg/kg IV once on day 1, '''given first'''
 +
**Cycle 5 onwards: 480 mg IV once on day 1
 +
'''21-day cycle for 4 cycles, then 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://doi.org/10.1056/NEJMoa1712126 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29562145 PubMed] NCT02231749
 +
##'''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://doi.org/10.1016/S1470-2045(19)30413-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31427204 PubMed]
 +
##'''Update:''' Motzer RJ, Escudier B, McDermott DF, Arén Frontera O, Melichar B, Powles T, Donskov F, Plimack ER, Barthélémy P, Hammers HJ, George S, Grünwald V, Porta C, Neiman V, Ravaud A, Choueiri TK, Rini BI, Salman P, Kollmannsberger CK, Tykodi SS, Grimm MO, Gurney H, Leibowitz-Amit R, Geertsen PF, Amin A, Tomita Y, McHenry MB, Saggi SS, Tannir NM. Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer. 2020 Jul;8(2):e000891. Erratum in: J Immunother Cancer. 2021 May;9(5). [https://doi.org/10.1136/jitc-2020-000891 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7359377/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32661118/ PubMed]
 +
##'''Update:''' Albiges L, Tannir NM, Burotto M, McDermott D, Plimack ER, Barthélémy P, Porta C, Powles T, Donskov F, George S, Kollmannsberger CK, Gurney H, Grimm MO, Tomita Y, Castellano D, Rini BI, Choueiri TK, Saggi SS, McHenry MB, Motzer RJ. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020 Nov;5(6):e001079. [https://doi.org/10.1136/esmoopen-2020-001079 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7703447/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33246931/ PubMed]
 +
#'''PDIGREE:''' NCT03793166
 +
#'''COSMIC-313:''' NCT03937219
 +
==Lenvatinib & Pembrolizumab {{#subobject:e83gac|Regimen=1}}==
  
−
'''28-day cycle for 2 cycles'''
+
===Regimen variant #1 {{#subobject:22bc4d|Variant=1}}===
−
</div></div><br>
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
<div class="toccolours" style="background-color:#eeeeee">
+
! style="width: 20%" |Study
−
===Regimen variant #3, 4000/10/45 {{#subobject:8659c6 |Variant=1}}===
+
! style="width: 20%" |Years of enrollment
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Study
+
! style="width: 20%" |Comparator
−
!style="width: 20%"|Years of enrollment
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
|-
−
!style="width: 20%"|Comparator
+
|rowspan=2|[https://doi.org/10.1056/NEJMoa2035716 Motzer et al. 2021 (CLEAR)]
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
|rowspan=2|2016-2019
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|1. [[#Everolimus_.26_Lenvatinib|Everolimus & Lenvatinib]]
 +
| style="background-color:#d3d3d3" |Not reported
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.1996.14.9.2527 Flam et al. 1996 (ECOG E1289)]
+
|2. [[#Sunitinib_monotherapy_2|Sunitinib]]
−
|1988-1991
+
| style="background-color:#1a9850" |Superior OS<br>Median OS: NYR vs NYR<br>(HR 0.66, 95% CI 0.49-0.88)
−
|style="background-color:#1a9851"|Phase 3 (C)
+
|-
−
|[[Stub#5-FU_.26_RT|5-FU & RT]]
+
|}
−
| style="background-color:#1a9850" |Superior DFS
+
====Targeted therapy====
 +
*[[Lenvatinib (Lenvima)]] 20 mg PO once per day
 +
====Immunotherapy====
 +
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 +
'''21-day cycles'''
 +
 
 +
===Regimen variant #2 {{#subobject:22bug8|Variant=1}}===
 +
{| class="wikitable sortable" 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://jama.ama-assn.org/content/299/16/1914.full Ajani et al. 2008 (RTOG 98-11)]
+
|Awaiting publication (MK-6482-012)
−
|1998-2005
+
|2021-ongoing
−
|style="background-color:#1a9851"|Phase 3 (C)
+
|style="background-color:#1a9851" |Phase 3 (C)
−
|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|CF & RT]]
+
|1. [[#Belzutifan.2C_Lenvatinib.2C_Pembrolizumab_77|Belzutifan, Lenvatinib, Pembrolizumab]]<br>2. [[#Lenvatinib.2C_Quavonlimab.2C_Pembrolizumab_77|Lenvatinib, Quavonlimab, Pembrolizumab]]
−
|style="background-color:#91cf60"|Seems to have superior OS<sup>1</sup>
+
| style="background-color:#d3d3d3" |Awaiting results
 
|-
 
|-
 
|}
 
|}
−
''<sup>1</sup>Reported efficacy for RTOG 98-11 is based on the 2012 update.''
+
====Targeted therapy====
−
<div class="toccolours" style="background-color:#b3e2cd">
+
*[[Lenvatinib (Lenvima)]] 20 mg PO once per day
−
====Chemotherapy====
+
====Immunotherapy====
−
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+
*[[Pembrolizumab (Keytruda)]] as follows:
−
*[[Mitomycin (Mutamycin)]] 10 mg/m<sup>2</sup> (maximum dose of 20 mg) IV bolus once on day 1
+
**Cycles 1 to 18: 400 mg IV once on day 1
−
====Radiotherapy====
+
 
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]]; at a minimum: 1.8 Gy per day x 25 fractions (total dose: 45 Gy), given over 5 weeks; see articles for additional details
+
'''42-day cycles'''
 +
 
 +
===References===
 +
#'''CLEAR:''' Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. [https://doi.org/10.1056/NEJMoa2035716 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33616314/ PubMed] NCT02811861
 +
#'''MK-6482-012:''' NCT04736706
 +
 
 +
==Pazopanib monotherapy {{#subobject:443024|Regimen=1}}==
  
−
'''28-day cycle for 2 cycles'''
+
===Regimen {{#subobject:d6c07c|Variant=1}}===
−
</div></div><br>
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
<div class="toccolours" style="background-color:#eeeeee">
+
! style="width: 20%" |Study
−
===Regimen variant #4, 4000/12/45 {{#subobject:63839c |Variant=1}}===
+
! style="width: 20%" |Years of enrollment
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Study
+
! style="width: 20%" |Comparator
−
!style="width: 20%"|Years of enrollment
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
![[Overall response rate|ORR]]
−
!style="width: 20%"|Comparator
+
!Comparator [[Overall response rate|ORR]]
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
|-
 +
|[https://doi.org/10.1200/jco.2008.21.6994 Hutson et al. 2009 (VEG102616)]
 +
|2005-2006
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|
 +
|
 +
|-
 +
|[https://doi.org/10.1200/jco.2009.23.9764 Sternberg et al. 2010 (VEG105192)]
 +
|2006-2007
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[Renal_cell_carcinoma_-_null_regimens#Placebo_2|Placebo]]
 +
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: 9.2 vs 4.2 mo<br>(HR 0.46, 95% CI 0.34-0.62)
 +
|30% (95% CI 25-36%)
 +
|3% (95% CI 0-6%)
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa1303989 Motzer et al. 2013 (COMPARZ)]
 +
|2008-2011
 +
| style="background-color:#1a9851" |Phase 3 (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://doi.org/10.1016/S0140-6736(96)03409-5 Northover et al. 1996 (ACT I)]
+
|[https://jamanetwork.com/journals/jamaoncology/fullarticle/2588465 Cirkel et al. 2017 (ROPETAR)]
−
|1987-1994
+
|2012-2014
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
+
| style="background-color:#1a9851" |Randomized (C)
−
|[[Anal_cancer#Radiation_therapy|Radiation]]
+
|[[#Pazopanib.2FEverolimus_99|Pazopanib/Everolimus]]
−
|style="background-color:#1a9850"|Superior local failure rate
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|
 +
|
 
|-
 
|-
 
|}
 
|}
−
''Because there were a few different schedules used in UKCCCR Anal Cancer Trial Working Party 1996 and the update (Northover et al. 2010), there is some variability in potential schedules.''
+
====Targeted therapy====
−
<div class="toccolours" style="background-color:#b3e2cd">
+
*[[Pazopanib (Votrient)]] 800 mg PO once per day, given 1 hour before or 2 hours after meals
−
====Chemotherapy====
+
**Dose may be decreased to 600 mg or 400 mg PO once per day depending on tolerability
−
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1, '''initiated at least 2 hours before the first radiation fraction''' (total dose per cycle: 4000 mg/m<sup>2</sup>)
+
'''Continued indefinitely'''
−
*[[Mitomycin (Mutamycin)]] 12 mg/m<sup>2</sup> (maximum dose of 20 mg) IV bolus once on day 1
+
===References===
−
====Radiotherapy====
+
#'''VEG102616:''' 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. [https://doi.org/10.1200/jco.2008.21.6994 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20008644 PubMed] NCT00244764
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]]: 1.8 or 2.25 Gy fractions x 20 or 25 fractions (total dose: 45 Gy), given over 4 to 5 weeks; see Northover et al. 2010 for details, including information about boost radiation therapy
+
#'''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. [https://doi.org/10.1200/jco.2009.23.9764 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20100962 PubMed] NCT00334282
 +
##'''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 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/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://doi.org/10.1056/NEJMoa1303989 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23964934 PubMed] NCT00720941
 +
##'''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://doi.org/10.1056/NEJMc1400731 link to letter] [https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/24687826 PubMed] NCT01064310
 +
#'''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 dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27918762 PubMed] NCT01408004
 +
==Regorafenib monotherapy {{#subobject:183793|Regimen=1}}==
  
−
'''28-day cycle for 2 cycles'''
+
===Regimen {{#subobject:a55057|Variant=1}}===
−
</div></div><br>
+
{| class="wikitable sortable" style="width: 80%; text-align:center;"
−
<div class="toccolours" style="background-color:#eeeeee">
+
!style="width: 25%"|Study
−
===Regimen variant #5, 4000/12/50.4 {{#subobject:6382ac |Variant=1}}===
+
!style="width: 25%"|Years of enrollment
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Study
+
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
−
!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/10.1016/S1470-2045(13)70086-X James et al. 2013 (ACT II)]
+
|[https://doi.org/10.1016/S1470-2045(12)70364-9 Eisen et al. 2012 (Bayer 11726)]
−
|2001-2008
+
|2008-2011
−
|style="background-color:#1a9851"|Phase 3 (C)
+
| style="background-color:#91cf61" |Phase 2
−
|[[#Cisplatin_.26_Fluorouracil_.28CF.29_.26_RT|Cisplatin, Fluorouracil, RT]]
+
|ORR: 40% (90% CI 28-53%)
−
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR rate at 26 weeks
 
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
+
====Targeted therapy====
−
====Chemotherapy====
+
*[[Regorafenib (Stivarga)]] 160 mg PO once per day on days 1 to 21, given while fasting or after a light meal
−
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+
'''28-day cycles'''
−
*[[Mitomycin (Mutamycin)]] 12 mg/m<sup>2</sup> (maximum dose of 20 mg) IV bolus once on day 1
+
===References===
−
====Radiotherapy====
+
#'''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://doi.org/10.1016/S1470-2045(12)70364-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22959186 PubMed] NCT00664326
−
*Concurrent [[External_beam_radiotherapy|radiation therapy]]: 1.8 Gy per day x 28 fractions (total dose: 50.4 Gy), given over 5.5 weeks; see paper for details
+
==Sorafenib monotherapy {{#subobject:fe45b0|Regimen=1}}==
  
−
'''28-day cycle for 2 cycles'''
+
===Regimen {{#subobject:90ba4d|Variant=1}}===
−
</div>
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
<div class="toccolours" style="background-color:#cbd5e7">
+
! 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://doi.org/10.1200/jco.2008.19.3342 Escudier et al. 2009]
 +
|2005
 +
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ooc)
 +
|[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|5%
 +
|9%
 +
|-
 +
|[https://doi.org/10.1002/cncr.24864 Stadler et al. 2010 (ARCCS)]
 +
|2005-2006
 +
| style="background-color:#91cf61" |Non-randomized
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569677/ Motzer et al. 2013 (AV-951-09-902)]
 +
|2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Tivozanib_monotherapy|Tivozanib]]
 +
| style="background-color:#fc8d59" |Seems to have inferior PFS
 +
|
 +
|
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(13)70465-0 Hutson et al. 2013 (A4061051)]
 +
|2010-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Axitinib_monotherapy|Axitinib]]
 +
| style="background-color:#fee08b" |Might have inferior PFS<sup>1</sup>
 +
|15%
 +
|32%
 +
|-
 +
|[https://doi.org/10.1016/j.clgc.2020.01.001 Tomita et al. 2020 (CROSS-J-RCC)]
 +
|2010-2012
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Sunitinib_monotherapy_2|Sunitinib]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|
 +
|
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2018.11.001 Retz et al. 2018 (SWITCH-II)]
 +
|2012-NR in abstract
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Pazopanib_monotherapy|Pazopanib]]
 +
| style="background-color:#ffffbf" |Inconclusive whether non-inferior tPFS
 +
|-
 +
|}
 +
''<sup>1</sup>In the 2016 update to A4061051, there was no difference in OS, which was a secondary endpoint. Reported efficacy here is from the primary (2013) analysis.''
 +
====Targeted therapy====
 +
*[[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'''
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*[[#Cisplatin_.26_Fluorouracil_.28CF.29_88|CF]] maintenance versus [[#Observation_88|no further treatment]]
+
*SWITCH-II, upon progression: [[#Pazopanib_monotherapy_2|Pazopanib]]
−
 
 
−
</div></div>
 
 
===References===
 
===References===
−
# '''ECOG E1289:''' Flam M, John M, Pajak TF, Petrelli N, Myerson R, Doggett S, Quivey J, Rotman M, Kerman H, Coia L, Murray K; RTOG; ECOG. Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol. 1996 Sep;14(9):2527-39. [https://doi.org/10.1200/JCO.1996.14.9.2527 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8823332 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. [https://doi.org/10.1200/jco.2008.19.3342 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19171708 PubMed] NCT00117637
−
# '''ACT I:''' Northover JMA, Arnott SJ, Cunningham D, Gallagher J, Gray R, Hardcastle J, Houghton J, James RD, Lennon TA, Meadows HM, Mossman J, Morgan DAL, Plowman PN, Slevin M; UKCCCR Anal Cancer Trial Working Party; UK Co-ordinating Committee on Cancer Research. Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. Lancet. 1996 Oct 19;348(9034):1049-54. [https://doi.org/10.1016/S0140-6736(96)03409-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8874455 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://doi.org/10.1002/cncr.24864 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20082451 PubMed] NCT00111020
−
## '''Update:''' Northover J, Glynne-Jones R, Sebag-Montefiore D, James R, Meadows H, Wan S, Jitlal M, Ledermann J. Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I). Br J Cancer. 2010 Mar 30;102(7):1123-8. Epub 2010 Mar 16. [https://doi.org/10.1038/sj.bjc.6605605 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2853094/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20354531 PubMed] content property of [http://hemonc.org HemOnc.org]
+
#'''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 dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24019545 PubMed] NCT01030783
−
# '''EORTC 22861:''' Bartelink H, Roelofsen F, Eschwege F, Rougier P, Bosset JF, Gonzalez DG, Peiffert D, van Glabbeke M, Pierart M; European Organisation for Research and Treatment of Cancer Radiotherapy Group; EORTC Gastrointestinal Cooperative Group. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organisation for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol. 1997 May;15(5):2040-9. [https://doi.org/10.1200/JCO.1997.15.5.2040 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/9164216 PubMed]
+
#'''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://doi.org/10.1016/S1470-2045(13)70465-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24206640 PubMed] NCT00920816
−
# '''RTOG 98-11:''' Ajani JA, Winter KA, Gunderson LL, Pedersen J, Benson AB 3rd, Thomas CR Jr, Mayer RJ, Haddock MG, Rich TA, Willett C. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA. 2008 Apr 23;299(16):1914-21. [http://jama.ama-assn.org/content/299/16/1914.full link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18430910 PubMed] NCT00003596
+
##'''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 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27498023 PubMed]
−
## '''Update:''' Gunderson LL, Winter KA, Ajani JA, Pedersen JE, Moughan J, Benson AB 3rd, Thomas CR Jr, Mayer RJ, Haddock MG, Rich TA, Willett CG. Long-term update of US GI intergroup RTOG 98-11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin. J Clin Oncol. 2012 Dec 10;30(35):4344-51. Epub 2012 Nov 13. [https://doi.org/10.1200/JCO.2012.43.8085 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3515768/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23150707 PubMed]
+
#'''SWITCH-II:''' Retz M, Bedke J, Bögemann M, Grimm MO, Zimmermann U, Müller L, Leiber C, Teber D, Wirth M, Bolenz C, van Alphen R, De Santis M, Beeker A, Lehmann J, Indorf M, Frank M, Bokemeyer C, Gschwend JE. SWITCH II: Phase III randomized, sequential, open-label study to evaluate the efficacy and safety of sorafenib-pazopanib versus pazopanib-sorafenib in the treatment of advanced or metastatic renal cell carcinoma (AUO AN 33/11). Eur J Cancer. 2019 Jan;107:37-45. Epub 2018 Dec 7. [https://doi.org/10.1016/j.ejca.2018.11.001 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30529901/ PubMed] NCT01613846
−
# '''ACT II:''' James RD, Glynne-Jones R, Meadows HM, Cunningham D, Myint AS, Saunders MP, Maughan T, McDonald A, Essapen S, Leslie M, Falk S, Wilson C, Gollins S, Begum R, Ledermann J, Kadalayil L, Sebag-Montefiore D. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2×2 factorial trial. Lancet Oncol. 2013 May;14(6):516-24. Epub 2013 Apr 9. [https://doi.org/10.1016/S1470-2045(13)70086-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23578724 PubMed] NCT00025090
+
#'''CROSS-J-RCC:''' Tomita Y, Naito S, Sassa N, Takahashi A, Kondo T, Koie T, Obara W, Kobayashi Y, Teishima J, Takahashi M, Matsuyama H, Ueda T, Yamaguchi K, Kishida T, Shiroki R, Saika T, Shinohara N, Oya M, Kanayama HO. Sunitinib Versus Sorafenib as Initial Targeted Therapy for mCC-RCC With Favorable/Intermediate Risk: Multicenter Randomized Trial CROSS-J-RCC. Clin Genitourin Cancer. 2020 Aug;18(4):e374-e385. Epub 2020 Mar 6. [https://doi.org/10.1016/j.clgc.2020.01.001 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32466961/ PubMed] NCT01481870
 +
==Sunitinib monotherapy {{#subobject:b4a97a|Regimen=1}}==
  
−
==Radiation therapy {{#subobject:f4d6d6|Regimen=1}}==
+
===Regimen variant #1, 4 out of 6 weeks {{#subobject:92e618|Variant=1}}===
 +
{| class="wikitable sortable" 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://doi.org/10.1056/NEJMoa065044 Motzer et al. 2007 (A618-1034)]
 +
|2004-2005
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
 +
|[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
 +
| style="background-color:#d9ef8b" |Might have superior OS<sup>1</sup><br>Median OS: 26.4 vs 21.8 mo<br>(HR 0.82, 95% CI 0.67-1.001)
 +
|31%
 +
|6%
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045%2809%2970162-7 Gore et al. 2009 (A618-1037)]
 +
|2005-2007
 +
| 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)]
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#MVA-5T4_.26_Sunitinib_77|Sunitinib & MVA-5T4]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br>Median OS: 19.2 vs 20.1 mo<br>(HR 0.93, 95% CI 0.76-1.16)
 +
|
 +
|
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa1303989 Motzer et al. 2013 (COMPARZ)]
 +
|2008-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Pazopanib_monotherapy|Pazopanib]]
 +
| style="background-color:#eeee01" |Non-inferior PFS
 +
|25% (95% CI 21-28%)
 +
|31% (95% CI 27-34%)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
 +
|2009-2011
 +
| style="background-color:#1a9851" |Randomized Phase 2 (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 Eichelberg et al. 2015 (SWITCH)]
 +
|2009-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Sorafenib_monotherapy|Sorafenib]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|
 +
|
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa1803675 Méjean et al. 2018 (CARMENA)]
 +
|2009-2017
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|Nephrectomy, then [[#Sunitinib_monotherapy_2|Sunitinib]]
 +
| style="background-color:#eeee01" |Non-inferior OS<br>Median OS: 18.4 vs 13.9 mo<br>(HR 0.89, 95% CI 0.71-1.10)
 +
|
 +
|
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(16)30408-9 Rini et al. 2016 (IMPRINT)]
 +
|2010-2012
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#IMA901_.26_Sunitinib_77|Sunitinib & IMA901]]
 +
| style="background-color:#d9ef8b" |Might have superior OS<br>Median OS: NYR vs 33.2 mo<br>(HR 0.75, 95% CI 0.54-1.04)
 +
|
 +
|
 +
|-
 +
|[https://doi.org/10.1016/j.clgc.2020.01.001 Tomita et al. 2020 (CROSS-J-RCC)]
 +
|2010-2012
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Sorafenib_monotherapy|Sorafenib]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|
 +
|
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455807/ Choueiri et al. 2016 (CABOSUN)]
 +
|2013-2015
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cabozantinib_monotherapy|Cabozantinib]]
 +
| style="background-color:#d73027" |Inferior PFS<sup>2</sup>
 +
|
 +
|
 +
|-
 +
|[https://doi.org/10.1158/1078-0432.ccr-19-2427 Figlin et al. 2020 (ADAPT)]
 +
|2013-2016
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Rocapuldencel-T_.26_Sunitinib_77|Rocapuldencel-T & Sunitinib]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br>Median OS: 32.4 vs 27.7 mo<br>(HR 0.91, 95% CI 0.71-1.20)
 +
|
 +
|
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa1712126 Motzer et al. 2018 (CheckMate 214)]
 +
|2014-2016
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Ipilimumab_.26_Nivolumab|Ipilimumab & Nivolumab]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|
 +
|
 +
|-
 +
|[https://doi.org/10.1016/S0140-6736(19)30723-8 Rini et al. 2019 (IMmotion151)]
 +
|2015-2016
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Atezolizumab_.26_Bevacizumab|Atezolizumab & Bevacizumab]]
 +
| style="background-color:#fc8d59" |Seems to have inferior PFS
 +
|
 +
|
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716603/ Motzer et al. 2019 (JAVELIN Renal 101)]
 +
|2016-2017
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Axitinib_.26_Avelumab|Axitinib & Avelumab]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS<sup>3</sup>
 +
|
 +
|
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa1816714 Rini et al. 2019 (KEYNOTE-426)]
 +
|2016-2018
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Axitinib_.26_Pembrolizumab|Axitinib & Pembrolizumab]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|
 +
|
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2026982 Choueiri et al. 2021 (CheckMate 9ER)]
 +
|2017-2019
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cabozantinib_.26_Nivolumab|Cabozantinib & Nivolumab]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|
 +
|
 +
|-
 +
|rowspan=2|[https://doi.org/10.1056/NEJMoa2035716 Motzer et al. 2021 (CLEAR)]
 +
|rowspan=2|2016-2019
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Everolimus_.26_Lenvatinib|Everolimus & Lenvatinib]]
 +
|style="background-color:#d73027" |Inferior PFS
 +
|36.1%
 +
|53.5%
 +
|-
 +
|2. [[#Lenvatinib_.26_Pembrolizumab|Lenvatinib & Pembrolizumab]]
 +
|style="background-color:#d73027" |Inferior OS
 +
|36.1%
 +
|71.0%
 +
|-
 +
|Awaiting publication (JS001-036-III-RCC)
 +
|2020-ongoing
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Axitinb_.26_Toripalimab_77|Axitinib & Toripalimab]]
 +
|style="background-color:#d3d3d3" |Awaiting results
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy for A618-1034 is based on the 2009 update.''<br>
 +
''<sup>2</sup>Reported efficacy for CABOSUN is based on the 2018 update.''<br>
 +
''<sup>3</sup>Reported efficacy for Javelin Renal 101 is based on the 2020 update, although the authors state that OS data remains immature.''
 +
====Targeted therapy====
 +
*[[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]]
  
−
<div class="toccolours" style="background-color:#eeeeee">
+
===Regimen variant #2, 2 out of 4 weeks {{#subobject:92ejg8|Variant=1}}===
−
===Regimen {{#subobject:57260e |Variant=1}}===
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
{| class="wikitable sortable" 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
+
! 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]]
 
 
|-
 
|-
−
|[https://doi.org/10.1016/S0140-6736(96)03409-5 Northover et al. 1996 (ACT I)]
+
|Awaiting publication (TQB2450-III-07)
−
|1987-1994
+
|2020-ongoing
−
|style="background-color:#1a9851"|Phase 3 (C)
+
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[#Fluorouracil.2C_Mitomycin.2C_RT|Fluorouracil, Mitomycin, RT]]
+
|[[#Anlotinib_.26_TQB2450_77|Anlotinib & TQB2450]]
−
|style="background-color:#d73027"|Inferior local failure rate
+
|style="background-color:#d3d3d3" |Awaiting results
 
|-
 
|-
 
|}
 
|}
−
''Inferior to combined modality therapy; included for reference purposes only.''
+
====Targeted therapy====
−
<div class="toccolours" style="background-color:#b3e2cd">
+
*[[Sunitinib (Sutent)]] 50 mg PO once per day on days 1 to 14
−
====Radiotherapy====
+
'''28-day cycles'''
−
*[[External beam radiotherapy]]
 
  
−
</div></div>
 
 
===References===
 
===References===
−
# '''ACT I:''' Northover JMA, Arnott SJ, Cunningham D, Gallagher J, Gray R, Hardcastle J, Houghton J, James RD, Lennon TA, Meadows HM, Mossman J, Morgan DAL, Plowman PN, Slevin M; UKCCCR Anal Cancer Trial Working Party; UK Co-ordinating Committee on Cancer Research. Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. Lancet. 1996 Oct 19;348(9034):1049-54. [https://doi.org/10.1016/S0140-6736(96)03409-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8874455 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://doi.org/10.1056/NEJMoa065044 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17215529 PubMed] NCT00098657
−
## '''Update:''' Northover J, Glynne-Jones R, Sebag-Montefiore D, James R, Meadows H, Wan S, Jitlal M, Ledermann J. Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I). Br J Cancer. 2010 Mar 30;102(7):1123-8. Epub 2010 Mar 16. [https://doi.org/10.1038/sj.bjc.6605605 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2853094/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20354531 PubMed] content property of [http://hemonc.org HemOnc.org]
+
##'''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. [https://doi.org/10.1200/jco.2008.20.1293 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646307/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19487381 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://doi.org/10.1016/S1470-2045%2809%2970162-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19615940 PubMed] NCT00130897
 +
#'''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 dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20881001 PubMed] NCT00397345
 +
#'''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://doi.org/10.1056/NEJMoa1303989 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23964934 PubMed] NCT00720941
 +
##'''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://doi.org/10.1056/NEJMc1400731 link to letter] [https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/24687826 PubMed] NCT01064310
 +
#'''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. [https://doi.org/10.1200/jco.2013.54.6911 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25049330 PubMed] NCT00903175
 +
#'''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 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25952317 PubMed] NCT00732914
 +
#'''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://doi.org/10.1016/S1470-2045(16)30408-9 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27720136 PubMed] NCT01265901
 +
#'''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 dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455807/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28199818 PubMed] NCT01835158
 +
##'''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 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057479/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/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://doi.org/10.1056/NEJMoa1712126 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29562145 PubMed] NCT02231749
 +
##'''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://doi.org/10.1016/S1470-2045(19)30413-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31427204 PubMed]
 +
##'''Update:''' Motzer RJ, Escudier B, McDermott DF, Arén Frontera O, Melichar B, Powles T, Donskov F, Plimack ER, Barthélémy P, Hammers HJ, George S, Grünwald V, Porta C, Neiman V, Ravaud A, Choueiri TK, Rini BI, Salman P, Kollmannsberger CK, Tykodi SS, Grimm MO, Gurney H, Leibowitz-Amit R, Geertsen PF, Amin A, Tomita Y, McHenry MB, Saggi SS, Tannir NM. Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer. 2020 Jul;8(2):e000891. Erratum in: J Immunother Cancer. 2021 May;9(5). [https://doi.org/10.1136/jitc-2020-000891 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7359377/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32661118/ PubMed]
 +
##'''Update:''' Albiges L, Tannir NM, Burotto M, McDermott D, Plimack ER, Barthélémy P, Porta C, Powles T, Donskov F, George S, Kollmannsberger CK, Gurney H, Grimm MO, Tomita Y, Castellano D, Rini BI, Choueiri TK, Saggi SS, McHenry MB, Motzer RJ. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020 Nov;5(6):e001079. [https://doi.org/10.1136/esmoopen-2020-001079 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7703447/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33246931/ 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://doi.org/10.1056/NEJMoa1803675 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29860937 PubMed] NCT00930033
 +
#'''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://doi.org/10.1056/NEJMoa1816047 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716603/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30779531/ PubMed] NCT02684006
 +
##'''Update:''' Choueiri TK, Motzer RJ, Rini BI, Haanen J, Campbell MT, Venugopal B, Kollmannsberger C, Gravis-Mescam G, Uemura M, Lee JL, Grimm MO, Gurney H, Schmidinger M, Larkin J, Atkins MB, Pal SK, Wang J, Mariani M, Krishnaswami S, Cislo P, Chudnovsky A, Fowst C, Huang B, di Pietro A, Albiges L. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020 Aug;31(8):1030-1039. Epub 2020 Apr 25. [https://doi.org/10.1016/j.annonc.2020.04.010 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32339648/ 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://doi.org/10.1056/NEJMoa1816714 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30779529 PubMed] NCT02853331
 +
##'''Update:''' Powles T, Plimack ER, Soulières D, Waddell T, Stus V, Gafanov R, Nosov D, Pouliot F, Melichar B, Vynnychenko I, Azevedo SJ, Borchiellini D, McDermott RS, Bedke J, Tamada S, Yin L, Chen M, Molife LR, Atkins MB, Rini BI. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1563-1573. Epub 2020 Oct 23. Erratum in: Lancet Oncol. 2020 Dec;21(12):e553. [https://doi.org/10.1016/S1470-2045(20)30436-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33284113 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://doi.org/10.1016/S0140-6736(19)30723-8 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31079938 PubMed] NCT02420821
 +
##'''Update:''' Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Alekseev BY, Lee JL, Suarez C, Stroyakovskiy D, De Giorgi U, Donskov F, Mellado B, Banchereau R, Hamidi H, Khan O, Craine V, Huseni M, Flinn N, Dubey S, Rini BI. Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol. 2022 Feb 1;8(2):275-280. [https://doi.org/10.1001/jamaoncol.2021.5981 link to original article] [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8855230/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34940781/ PubMed]
 +
#'''ADAPT:''' Figlin RA, Tannir NM, Uzzo RG, Tykodi SS, Chen DYT, Master V, Kapoor A, Vaena D, Lowrance W, Bratslavsky G, DeBenedette M, Gamble A, Plachco A, Norris MS, Horvatinovich J, Tcherepanova IY, Nicolette CA, Wood CG; ADAPT study group. Results of the ADAPT Phase 3 Study of Rocapuldencel-T in Combination with Sunitinib as First-Line Therapy in Patients with Metastatic Renal Cell Carcinoma. Clin Cancer Res. 2020 May 15;26(10):2327-2336. Epub 2020 Feb 7. [https://doi.org/10.1158/1078-0432.ccr-19-2427 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32034074/ PubMed] NCT01582672
 +
#'''CROSS-J-RCC:''' Tomita Y, Naito S, Sassa N, Takahashi A, Kondo T, Koie T, Obara W, Kobayashi Y, Teishima J, Takahashi M, Matsuyama H, Ueda T, Yamaguchi K, Kishida T, Shiroki R, Saika T, Shinohara N, Oya M, Kanayama HO. Sunitinib Versus Sorafenib as Initial Targeted Therapy for mCC-RCC With Favorable/Intermediate Risk: Multicenter Randomized Trial CROSS-J-RCC. Clin Genitourin Cancer. 2020 Aug;18(4):e374-e385. Epub 2020 Mar 6. [https://doi.org/10.1016/j.clgc.2020.01.001 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32466961/ PubMed] NCT01481870
 +
#'''CheckMate 9ER:''' Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, Oyervides Juárez VM, Hsieh JJ, Basso U, Shah AY, Suárez C, Hamzaj A, Goh JC, Barrios C, Richardet M, Porta C, Kowalyszyn R, Feregrino JP, Żołnierek J, Pook D, Kessler ER, Tomita Y, Mizuno R, Bedke J, Zhang J, Maurer MA, Simsek B, Ejzykowicz F, Schwab GM, Apolo AB, Motzer RJ; CheckMate 9ER Investigators. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841. [https://doi.org/10.1056/nejmoa2026982 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33657295/ PubMed] NCT03141177
 +
##'''Update:''' Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, Suárez C, Hamzaj A, Porta C, Hocking CM, Kessler ER, Gurney H, Tomita Y, Bedke J, Zhang J, Simsek B, Scheffold C, Apolo AB, Choueiri TK. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Jun 7:S1470-2045(22)00290-X. Epub ahead of print. [https://doi.org/10.1016/s1470-2045(22)00290-x link to original article] [https://pubmed.ncbi.nlm.nih.gov/35688173/ PubMed]
 +
#'''CLEAR:''' Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. [https://doi.org/10.1056/NEJMoa2035716 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/33616314/ PubMed] NCT02811861
 +
#'''KEYNOTE-679:''' NCT03260894
 +
#'''JS001-036-III-RCC:''' NCT04394975
 +
#'''PIVOT-09:''' NCT03729245
 +
#'''TQB2450-III-07:''' NCT04523272
  
−
=Metastatic disease, first-line therapy=
+
==Temsirolimus monotherapy {{#subobject:8160ec|Regimen=1}}==
−
==Cisplatin & Fluorouracil (CF) {{#subobject:f83c8e|Regimen=1}}==
 
  
−
<div class="toccolours" style="background-color:#eeeeee">
+
===Regimen {{#subobject:f56815|Variant=1}}===
−
===Regimen variant #1, 100/5000 every 4 weeks {{#subobject:88896f |Variant=1}}===
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
! style="width: 20%" |Study
−
!style="width: 33%"|Study
+
! style="width: 20%" |Years of enrollment
−
!style="width: 33%"|Years of enrollment
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 33%"|[[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://www.jle.com/en/revues/medecine/bdc/e-docs/00/01/12/15/resume.phtml Faivre et al. 1999]
+
| rowspan="2" |[https://doi.org/10.1056/NEJMoa066838 Hudes et al. 2007 (ARCC)]
−
|NR in abstract
+
| rowspan="2" |2003-2005
−
|style="background-color:#ffffbe"|Pilot, <20 patients reported
+
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
 +
|1. [[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
 +
| style="background-color:#1a9850" |Superior OS<br>Median OS: 10.9 vs 7.3 mo<br>(HR 0.73, 95% CI 0.58-0.92)
 +
|9% (95% CI 5-12%)
 +
|5% (95% CI 2-8%)
 +
|-
 +
|2. [[#Interferon_alfa-2a_.26_Temsirolimus_99|Interferon alfa-2a & Temsirolimus]]
 +
| style="background-color:#d3d3d3" |Not reported
 +
|8% (95% CI 4-12%)
 +
|
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
+
====Targeted therapy====
−
====Chemotherapy====
+
*[[Temsirolimus (Torisel)]] 25 mg IV over 30 minutes once on day 1
−
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV once on day 2
+
====Supportive therapy====
−
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 5000 mg/m<sup>2</sup>)
+
*[[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://doi.org/10.1056/NEJMoa066838 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17538086 PubMed] NCT00065468
 +
 
 +
==Tivozanib monotherapy {{#subobject:f8qut0|Regimen=1}}==
  
 +
===Regimen {{#subobject:1yga4d|Variant=1}}===
 +
{| class="wikitable sortable" 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/PMC5569677/ Motzer et al. 2013 (AV-951-09-902)]
 +
|2010
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Sorafenib_monotherapy|Sorafenib]]
 +
| style="background-color:#91cf60" |Seems to have superior PFS<br>Median PFS: 11.9 vs 9.1 mo<br>(HR 0.80, 95% CI 0.64-0.993)
 +
|-
 +
|}
 +
====Targeted therapy====
 +
*[[Tivozanib (Fotivda)]] 1.5 mg PO once per day on days 1 to 21
 
'''28-day cycles'''
 
'''28-day cycles'''
−
</div></div><br>
+
===References===
−
<div class="toccolours" style="background-color:#eeeeee">
+
#'''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 dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24019545 PubMed] NCT01030783
−
===Regimen variant #2, 60/4000 every 3 weeks {{#subobject:77796f |Variant=1}}===
+
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
=Metastatic disease, second-line=
−
!style="width: 20%"|Study
+
==Axitinib monotherapy {{#subobject:832684|Regimen=1}}==
−
!style="width: 20%"|Years of enrollment
+
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
===Regimen {{#subobject:a48a96|Variant=1}}===
−
!style="width: 20%"|Comparator
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
! 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/pmc7406334/ Rao et al. 2020 (InterAACT)]
+
|[https://doi.org/10.1016/S0140-6736(11)61613-9 Rini et al. 2011 (AXIS)]
−
|2013-2017
+
|2008-2010
−
| style="background-color:#1a9851" |Randomized Phase 2 (C)
+
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
−
|[[#Carboplatin_.26_Paclitaxel_.28CP.29|Carboplatin & Paclitaxel]]
+
|[[#Sorafenib_monotherapy_2|Sorafenib]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
+
| style="background-color:#1a9850" |Superior PFS<sup>1</sup><br>Median PFS: 8.3 vs 5.7 mo<br>(HR 0.66, 95% CI 0.55-0.78)
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
+
''<sup>1</sup>Reported efficacy is based on the 2013 update. In this update, ORR was 23% in this arm, and 12% in the control arm. There was no statistically significant difference in overall survival.''
−
====Chemotherapy====
+
====Prior treatment criteria====
−
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1
+
*AXIS: Progression on first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines
−
*[[Fluorouracil (5-FU)]] 1000 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+
====Targeted therapy====
 +
*[[Axitinib (Inlyta)]] as follows:
 +
**Starting dose: 5 mg PO twice per day for at least 2 weeks
 +
**Then if tolerated and BP not greater than 150/90: 7 mg PO twice per day
 +
**Then if tolerated and BP not greater than 150/90: 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://doi.org/10.1016/S0140-6736(11)61613-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22056247 PubMed] NCT00678392
 +
##'''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://doi.org/10.1016/S1470-2045(13)70093-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/24823696 PubMed]
 +
==Bevacizumab monotherapy {{#subobject:dc7874|Regimen=1}}==
  
−
'''21-day cycles'''
+
===Regimen {{#subobject:24489f|Variant=1}}===
 +
{| class="wikitable sortable" 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 2 (E-esc)
 +
|[[Renal_cell_carcinoma_-_null_regimens#Placebo_3|Placebo]]
 +
| style="background-color:#1a9850" |Superior TTP
 +
|-
 +
|}
 +
====Prior treatment criteria====
 +
*Previous therapy with IL-2 or contraindication to IL-2
 +
====Targeted therapy====
 +
*[[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://doi.org/10.1056/NEJMoa021491 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275324/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/12890841 PubMed]
 +
==Cabozantinib monotherapy {{#subobject:pyr1|Regimen=1}}==
  
−
</div></div>
+
===Regimen {{#subobject:pyv1|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 +
|-
 +
|}
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 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 3 (E-RT-switch-ic)
 +
|[[#Everolimus_monotherapy_2|Everolimus]]
 +
| style="background-color:#1a9850" |Superior OS<sup>1</sup><br>Median OS: 21.4 vs 17.1 mo<br>(HR 0.70, 95% CI 0.58-0.85)
 +
| style="background-color:#88419d; color:white " |21% (95% CI 16-28%)
 +
| style="background-color:#6e016b; color:white " |5% (95% CI 2-9%)
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy is based on the 2018 update.''
 +
====Preceding treatment====
 +
*[[Regimen_classes#VEGFR_inhibitor_therapy|VEGFR TKI]], with progression
 +
====Targeted therapy====
 +
*[[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===
 
===References===
−
# Faivre C, Rougier P, Ducreux M, Mitry E, Lusinchi A, Lasser P, Elias D, Eschwege F. [5-fluorouracile and cisplatinum combination chemotherapy for metastatic squamous-cell anal cancer]. Bull Cancer. 1999 Oct;86(10):861-5. [http://www.jle.com/en/revues/medecine/bdc/e-docs/00/01/12/15/resume.phtml link to original article & English summary] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10572237 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://doi.org/10.1056/NEJMoa1510016 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26406150 PubMed] NCT01865747
−
<!-- # '''Abstract:''' Sclafani F et al. [InterAACT: An international multicenter open label randomized phase II advanced anal cancer trial comparing cisplatin (CDDP) plus 5-fluorouracil (5-FU) versus carboplatin (CBDCA) plus weekly paclitaxel (PTX) in patients with inoperable locally recurrent (ILR) or metastatic disease]. Journal of Clinical Oncology. 2015 33:3_suppl, TPS792-TPS792. [https://doi.org/10.1200/jco.2015.33.3_suppl.tps792 link to abstract] '''contains dosing details in abstract''' -->
+
##'''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://doi.org/10.1016/S1470-2045(16)30107-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27279544 PubMed]
−
#'''InterAAct:''' Rao S, Sclafani F, Eng C, Adams RA, Guren MG, Sebag-Montefiore D, Benson A, Bryant A, Peckitt C, Segelov E, Roy A, Seymour MT, Welch J, Saunders MP, Muirhead R, O'Dwyer P, Bridgewater J, Bhide S, Glynne-Jones R, Arnold D, Cunningham D. International Rare Cancers Initiative Multicenter Randomized Phase II Trial of Cisplatin and Fluorouracil Versus Carboplatin and Paclitaxel in Advanced Anal Cancer: InterAAct. J Clin Oncol. 2020 Aug 1;38(22):2510-2518. Epub 2020 Jun 12. [https://doi.org/10.1200/jco.19.03266 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7406334/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32530769/ PubMed] NCT02051868
+
##'''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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/29576624 PubMed]
 +
#'''CONTACT-03:''' NCT04338269
 +
#'''MK-6482-011:''' NCT04586231
  
−
==Carboplatin & Paclitaxel (CP) {{#subobject:1a2b3c|Regimen=1}}==
+
==Everolimus monotherapy {{#subobject:893557|Regimen=1}}==
  
−
<div class="toccolours" style="background-color:#eeeeee">
+
===Regimen {{#subobject:9d436d|Variant=1}}===
−
===Regimen {{#subobject:88896f |Variant=1}}===
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
{| class="wikitable sortable" 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
+
! 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]]
+
![[Overall response rate|ORR]]
 +
!Comparator [[Overall response rate|ORR]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7406334/ Rao et al. 2020 (InterAACT)]
+
|[https://doi.org/10.1016/S0140-6736(08)61039-9 Motzer et al. 2008 (RECORD-1)]
−
|2013-2017
+
|2006-2007
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[Renal_cell_carcinoma_-_null_regimens#Placebo_2|Placebo]]
 +
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: 4 vs 1.9 mo<br>(HR 0.30, 95% CI 0.22-0.40)
 +
|1%
 +
|0%
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
 +
|2009-2011
 
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
−
|[[#Cisplatin_.26_Fluorouracil_.28CF.29|CF]]
+
|[[#Sunitinib_monotherapy_3|Sunitinib]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
+
| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
 +
|
 +
|
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006123/ Motzer et al. 2015 (RECORD-4)]
 +
|2011-2013
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|
 +
|
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa1510665 Motzer et al. 2015 (CheckMate 025)]
 +
|2012-2014
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Nivolumab_monotherapy|Nivolumab]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|5%
 +
|25%
 +
|-
 +
| rowspan="2" |[https://doi.org/10.1016/S1470-2045(15)00290-9 Motzer et al. 2015 (E7080-G000-205)]
 +
| rowspan="2" |2012-2013
 +
| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (C)
 +
|1. [[#Everolimus_.26_Lenvatinib | Everolimus & Lenvatinib]]
 +
| 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 3 (C)
 +
|[[#Cabozantinib_monotherapy_2|Cabozantinib]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|5% (95% CI 2-9%)
 +
|21% (95% CI 16-28%)
 +
|-
 +
|rowspan=2|Awaiting publication (CONCEPT<sub>RCC</sub>)
 +
|rowspan=2|2016-2019
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Everolimus_.26_Vorolanib_77|Everolimus & Vorolanib]]
 +
| style="background-color:#fc8d59" |Seems to have inferior PFS
 +
|
 +
|
 +
|-
 +
|2. [[#Vorolanib_monotherapy_77|Vorolanib]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|
 +
|
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
+
''Note: 72% of patients in Checkmate 025 had anti-angiogenic therapy prior to progression.''
−
====Chemotherapy====
+
====Preceding treatment====
−
*[[Carboplatin (Paraplatin)]] AUC 5 IV once on day 1
+
*RECORD-1 & METEOR: [[Regimen_classes#VEGFR_inhibitor_therapy|VEGFR TKI]], with progression
−
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
+
*RECORD-3: [[#Sunitinib_monotherapy_2|Sunitinib]], with progression
 +
====Targeted therapy====
 +
*[[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://doi.org/10.1016/S0140-6736(08)61039-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18653228 PubMed] NCT00410124
 +
##'''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://doi.org/10.1002/cncr.25219 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20549832 PubMed]
 +
#'''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. [https://doi.org/10.1200/jco.2013.54.6911 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25049330 PubMed] NCT00903175
 +
#'''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://doi.org/10.1056/NEJMoa1510665 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26406148 PubMed] NCT01668784
 +
##'''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://doi.org/10.1016/S1470-2045(16)30125-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521044/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/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 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28262413 PubMed]
 +
##'''Subgroup analysis:''' 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://pubmed.ncbi.nlm.nih.gov/30941424 PubMed]
 +
##'''Update:''' Motzer RJ, Escudier B, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Plimack ER, Procopio G, McDermott DF, Castellano D, Choueiri TK, Donskov F, Gurney H, Oudard S, Richardet M, Peltola K, Alva AS, Carducci M, Wagstaff J, Chevreau C, Fukasawa S, Tomita Y, Gauler TC, Kollmannsberger CK, Schutz FA, Larkin J, Cella D, McHenry MB, Saggi SS, Tannir NM. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer. 2020 Sep 15;126(18):4156-4167. Epub 2020 Jul 16. [https://doi.org/10.1002/cncr.33033 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32673417 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://doi.org/10.1056/NEJMoa1510016 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26406150 PubMed] NCT01865747
 +
##'''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://doi.org/10.1016/S1470-2045(16)30107-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://doi.org/10.1016/S1470-2045(15)00290-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26482279 PubMed] NCT01136733
 +
##'''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://doi.org/10.1016/S1470-2045(15)00543-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/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 dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26681676 PubMed] NCT01491672
 +
#'''CONCEPT<sub>RCC</sub>:''' NCT03095040
  
−
'''28-day cycles'''
+
==Everolimus & Lenvatinib {{#subobject:21039d|Regimen=1}}==
  
−
</div></div>
+
===Regimen {{#subobject:71ef67|Variant=1}}===
 +
{| class="wikitable sortable" 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://doi.org/10.1016/S1470-2045(15)00290-9 Motzer et al. 2015 (E7080-G000-205)]
 +
| rowspan="2" |2012-2013
 +
| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (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.''
 +
====Targeted therapy====
 +
*[[Everolimus (Afinitor)]] 5 mg PO once per day
 +
*[[Lenvatinib (Lenvima)]] 18 mg PO once per day
 +
'''Continued indefinitely'''
 
===References===
 
===References===
−
<!-- # '''Abstract:''' Sclafani F et al. [InterAACT: An international multicenter open label randomized phase II advanced anal cancer trial comparing cisplatin (CDDP) plus 5-fluorouracil (5-FU) versus carboplatin (CBDCA) plus weekly paclitaxel (PTX) in patients with inoperable locally recurrent (ILR) or metastatic disease]. Journal of Clinical Oncology. 2015 33:3_suppl, TPS792-TPS792. [https://doi.org/10.1200/jco.2015.33.3_suppl.tps792 link to abstract] '''contains dosing details in abstract''' -->
+
#'''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://doi.org/10.1016/S1470-2045(15)00290-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26482279 PubMed] NCT01136733
−
#'''InterAAct:''' Rao S, Sclafani F, Eng C, Adams RA, Guren MG, Sebag-Montefiore D, Benson A, Bryant A, Peckitt C, Segelov E, Roy A, Seymour MT, Welch J, Saunders MP, Muirhead R, O'Dwyer P, Bridgewater J, Bhide S, Glynne-Jones R, Arnold D, Cunningham D. International Rare Cancers Initiative Multicenter Randomized Phase II Trial of Cisplatin and Fluorouracil Versus Carboplatin and Paclitaxel in Advanced Anal Cancer: InterAAct. J Clin Oncol. 2020 Aug 1;38(22):2510-2518. Epub 2020 Jun 12. [https://doi.org/10.1200/jco.19.03266 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7406334/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32530769/ PubMed] NCT02051868
+
##'''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://doi.org/10.1016/S1470-2045(15)00543-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26758760 PubMed]
−
#'''ECOG-ACRIN EA2176:''' NCT04444921
+
==Lenvatinib monotherapy {{#subobject:PYR3|Regimen=1}}==
  
−
==mDCF {{#subobject:70e20f|Regimen=1}}==
+
===Regimen {{#subobject:PYV3|Variant=1}}===
 +
{| class="wikitable sortable" 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://doi.org/10.1016/S1470-2045(15)00290-9 Motzer et al. 2015 (E7080-G000-205)]
 +
| rowspan="2" |2012-2013
 +
| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (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
 +
|-
 +
|}
 +
====Targeted therapy====
 +
*[[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://doi.org/10.1016/S1470-2045(15)00290-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26482279 PubMed] NCT01136733
 +
##'''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://doi.org/10.1016/S1470-2045(15)00543-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26758760 PubMed]
 +
==Nivolumab monotherapy {{#subobject:pyr2|Regimen=1}}==
  
−
mDCF: '''<u>m</u>'''odified '''<u>D</u>'''ocetaxel, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
+
===Regimen variant #1, 0.3 mg/kg q3wk {{#subobject:6d0807|Variant=1}}===
−
<div class="toccolours" style="background-color:#eeeeee">
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
===Regimen {{#subobject:323b13|Variant=1}}===
+
! style="width: 20%" |Study
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
! style="width: 20%" |Years of enrollment
−
!style="width: 33%"|Study
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 33%"|Years of enrollment
+
! style="width: 20%" |Comparator
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2014.59.0703 Motzer et al. 2015 (CheckMate 010)]
 +
|2011-2012
 +
| style="background-color:#1a9851" |Randomized Phase 2 (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 sortable" 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.2014.59.0703 Motzer et al. 2015 (CheckMate 010)]
 +
|2011-2012
 +
| style="background-color:#1a9851" |Randomized Phase 2 (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 sortable" 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://doi.org/10.1016/S1470-2045(18)30321-8 Kim et al. 2018 (Epitopes-HPV02)]
+
|[https://doi.org/10.1056/NEJMoa1510665 Motzer et al. 2015 (CheckMate 025)]
−
|2014-2016
+
|2012-2014
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
 +
|[[#Everolimus_monotherapy_2|Everolimus]]
 +
| style="background-color:#1a9850" |Superior OS<br>Median OS: 25 vs 19.6 mo<br>(HR 0.73, 98.5% CI 0.57-0.93)
 +
|25%
 +
|5%
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
+
====Immunotherapy====
−
====Chemotherapy====
+
*[[Nivolumab (Opdivo)]] 3 mg/kg IV over 60 minutes once on day 1
−
*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV once on day 1
+
**Notably, on 9/13/16 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
−
*[[Cisplatin (Platinol)]] 40 mg/m<sup>2</sup> IV once on day 1
+
'''14-day cycles'''
−
*[[Fluorouracil (5-FU)]] 1200 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 2400 mg/m<sup>2</sup>)
 
  
−
'''14-day cycle for 8 cycles'''
+
===Regimen variant #4, 10 mg/kg q3wk {{#subobject:6f2515|Variant=1}}===
 +
{| class="wikitable sortable" 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.2014.59.0703 Motzer et al. 2015 (CheckMate 010)]
 +
|2011-2012
 +
| style="background-color:#1a9851" |Randomized Phase 2 (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'''
  
−
</div></div>
 
 
===References===
 
===References===
−
# '''Epitopes-HPV02:''' Kim S, François E, André T, Samalin E, Jary M, El Hajbi F, Baba-Hamed N, Pernot S, Kaminsky MC, Bouché O, Desrame J, Zoubir M, Ghiringhelli F, Parzy A, De La Fouchardiere C, Smith D, Deberne M, Spehner L, Badet N, Adotevi O, Anota A, Meurisse A, Vernerey D, Taieb J, Vendrely V, Buecher B, Borg C. Docetaxel, cisplatin, and fluorouracil chemotherapy for metastatic or unresectable locally recurrent anal squamous cell carcinoma (Epitopes-HPV02): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2018 Aug;19(8):1094-1106. Epub 2018 Jul 2. [https://doi.org/10.1016/S1470-2045(18)30321-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30042063 PubMed] NCT02402842
+
#'''CheckMate 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 dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25452452 PubMed] NCT01354431
 +
#'''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://doi.org/10.1056/NEJMoa1510665 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26406148 PubMed] NCT01668784
 +
##'''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://doi.org/10.1016/S1470-2045(16)30125-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521044/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/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 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28262413 PubMed]
 +
##'''Subgroup analysis:''' 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://pubmed.ncbi.nlm.nih.gov/30941424 PubMed]
 +
##'''Update:''' Motzer RJ, Escudier B, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Plimack ER, Procopio G, McDermott DF, Castellano D, Choueiri TK, Donskov F, Gurney H, Oudard S, Richardet M, Peltola K, Alva AS, Carducci M, Wagstaff J, Chevreau C, Fukasawa S, Tomita Y, Gauler TC, Kollmannsberger CK, Schutz FA, Larkin J, Cella D, McHenry MB, Saggi SS, Tannir NM. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer. 2020 Sep 15;126(18):4156-4167. Epub 2020 Jul 16. [https://doi.org/10.1002/cncr.33033 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32673417 PubMed]
  
−
=Metastatic disease, subsequent lines of therapy=
+
==Pazopanib monotherapy {{#subobject:443024|Regimen=1}}==
−
==Nivolumab monotherapy {{#subobject:09c0df|Regimen=1}}==
 
  
−
<div class="toccolours" style="background-color:#eeeeee">
+
===Regimen {{#subobject:d6c07c|Variant=1}}===
−
===Regimen {{#subobject:f2c946|Variant=1}}===
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
! style="width: 20%" |Study
−
!style="width: 33%"|Study
+
! style="width: 20%" |Years of enrollment
−
!style="width: 33%"|Years of enrollment
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 33%"|[[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://doi.org/10.1200/jco.2008.21.6994 Hutson et al. 2009 (VEG102616)]
 +
|2005-2006
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/jco.2009.23.9764 Sternberg et al. 2010 (VEG105192)]
 +
|2006-2007
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Renal_cell_carcinoma_-_null_regimens#Placebo_3|Placebo]]
 +
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: 9.2 vs 4.2 mo<br>(HR 0.46, 95% CI 0.34-0.62)
 +
|30% (95% CI 25-36%)
 +
|3% (95% CI 0-6%)
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809128/ Morris et al. 2017 (NCI9673)]
+
|[http://www.clinical-genitourinary-cancer.com/article/S1558-7673(13)00052-9 Hainsworth et al. 2013]
−
|2015
+
|2008-2011
 
| style="background-color:#91cf61" |Phase 2
 
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|
 +
| style="background-color:#d3d3d3" |
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
+
====Prior treatment criteria====
−
====Immunotherapy====
+
*VEG105192: Progression on 1 prior cytokine-based systemic therapy
−
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
+
====Targeted therapy====
 +
*[[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===
 +
#'''VEG102616:''' 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. [https://doi.org/10.1200/jco.2008.21.6994 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20008644 PubMed] NCT00244764
 +
#'''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. [https://doi.org/10.1200/jco.2009.23.9764 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20100962 PubMed] NCT00334282
 +
##'''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 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/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 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/23665131 PubMed]
 +
==Sorafenib monotherapy {{#subobject:6e18d8|Regimen=1}}==
  
−
'''14-day cycles'''
+
===Regimen {{#subobject:a50d71|Variant=1}}===
−
</div></div>
+
{| class="wikitable sortable" 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://doi.org/10.1056/NEJMoa060655 Escudier et al. 2007 (TARGET<sub>RCC</sub>)]
 +
|2003-2005
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[Renal_cell_carcinoma_-_null_regimens#Placebo_3|Placebo]]
 +
| style="background-color:#d9ef8b" |Might have superior OS<sup>1</sup><br>Median OS: 17.8 vs 15.2 mo<br>(HR 0.88, 95% CI 0.74-1.04)
 +
|
 +
|
 +
|-
 +
|[https://doi.org/10.1002/cncr.24864 Stadler et al. 2010 (ARCCS)]
 +
|2005-2006
 +
| style="background-color:#91cf61" |Non-randomized expanded access study
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|
 +
|
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdq651 Beck et al. 2011 (EU-ARCCS)]
 +
|2005-2007
 +
| style="background-color:#91cf61" |Non-randomized expanded access study
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|
 +
|
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569683/ Hutson et al. 2013 (INTORSECT)]
 +
|2007-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Temsirolimus_monotherapy_99|Temsirolimus]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<sup>2</sup><br>Median PFS: 3.9 vs 4.3 mo<br>(HR 1.15, 95% CI 0.93-1.41)
 +
|
 +
|
 +
|-
 +
|[https://doi.org/10.1016/S0140-6736(11)61613-9 Rini et al. 2011 (AXIS)]
 +
|2008-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Axitinib_monotherapy|Axitinib]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|9% (95% CI 7-13%)
 +
|19% (95% CI 15-24%)
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy for TARGET is based on the 2009 update.''<br>
 +
''<sup>2</sup>While the primary endpoint (PFS) was not met in INTORSECT, the control arm actually had superior OS compared to the experimental arm.''<br>
 +
====Prior treatment criteria====
 +
*TARGET<sub>RCC</sub>: 1 systemic treatment within the previous 8 months, with progression
 +
*INTORSECT: Progression on sunitinib
 +
*AXIS: Progression on first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines
 +
====Targeted therapy====
 +
*[[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===
−
# '''NCI9673:''' Morris VK, Salem ME, Nimeiri H, Iqbal S, Singh P, Ciombor K, Polite B, Deming D, Chan E, Wade JL, Xiao L, Bekaii-Saab T, Vence L, Blando J, Mahvash A, Foo WC, Ohaji C, Pasia M, Bland G, Ohinata A, Rogers J, Mehdizadeh A, Banks K, Lanman R, Wolff RA, Streicher H, Allison J, Sharma P, Eng C. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017 Apr;18(4):446-453. Epub 2017 Feb 18. [https://doi.org/10.1016/S1470-2045(17)30104-3 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809128/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28223062 PubMed] NCT02314169
+
# '''TARGET<sub>RCC</sub>:''' 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://doi.org/10.1056/NEJMoa060655 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17215530 PubMed] NCT00073307
 +
## '''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://pubmed.ncbi.nlm.nih.gov/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 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20656473 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://doi.org/10.1002/cncr.24864 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20082451 PubMed] NCT00111020
 +
#'''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 dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21324953 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://doi.org/10.1016/S0140-6736(11)61613-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22056247 PubMed] NCT00678392
 +
##'''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://doi.org/10.1016/S1470-2045(13)70093-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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 dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569683/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24297950 PubMed] NCT00474786
  
−
==Pembrolizumab monotherapy {{#subobject:82c0df|Regimen=1}}==
+
==Sunitinib monotherapy {{#subobject:f929da|Regimen=1}}==
  
−
<div class="toccolours" style="background-color:#eeeeee">
+
===Regimen {{#subobject:955949|Variant=1}}===
−
===Regimen {{#subobject:f2c123|Variant=1}}===
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
! style="width: 20%" |Study
−
!style="width: 33%"|Study
+
! style="width: 20%" |Years of enrollment
−
!style="width: 33%"|Years of enrollment
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 33%"|[[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 2 (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 2 (RT)
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045%2809%2970162-7 Gore et al. 2009 (A618-1037)]
 +
|2005-2007
 +
| style="background-color:#91cf61" |Non-randomized
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5406758/ Ott et al. 2017a (KEYNOTE-028)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
−
|2014
+
|2009-2011
−
| style="background-color:#91cf61" |Phase 1b, >20 pts in this subgroup
+
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 +
|[[#Everolimus_monotherapy|Everolimus]]
 +
| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
+
====Preceding treatment====
−
====Immunotherapy====
+
*RECORD-3: [[#Everolimus_monotherapy|Everolimus]]
−
*[[Pembrolizumab (Keytruda)]] 10 mg/kg IV once on day 1
+
====Targeted therapy====
 +
*[[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://pubmed.ncbi.nlm.nih.gov/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 dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16757724 PubMed] NCT00077974
 +
#'''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://doi.org/10.1016/S1470-2045%2809%2970162-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19615940 PubMed] NCT00130897
 +
#'''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. [https://doi.org/10.1200/jco.2013.54.6911 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25049330 PubMed] NCT00903175
  
−
'''14-day cycle for up to 52 cycles (2 years)'''
+
=Metastatic disease, third-line=
 +
==Sorafenib monotherapy {{#subobject:7b51ba|Regimen=1}}==
  
−
</div></div>
+
===Regimen {{#subobject:87cb7d|Variant=1}}===
 +
{| class="wikitable sortable" 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 3 (C)
 +
|[[#Dovitinib_monotherapy_77|Dovitinib]]
 +
| style="background-color:#fee08b" |Might have inferior PFS
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(19)30735-1 Rini et al. 2019 (TIVO-3)]
 +
|2016-2017
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Tivozanib_monotherapy_2|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.''
 +
====Targeted therapy====
 +
*[[Sorafenib (Nexavar)]] 400 mg PO twice per day
 +
'''Continued indefinitely'''
 
===References===
 
===References===
−
# '''KEYNOTE-028:''' Ott PA, Piha-Paul SA, Munster P, Pishvaian MJ, van Brummelen EMJ, Cohen RB, Gomez-Roca C, Ejadi S, Stein M, Chan E, Simonelli M, Morosky A, Saraf S, Emancipator K, Koshiji M, Bennouna J. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ann Oncol. 2017 May 1;28(5):1036-1041. [https://doi.org/10.1093/annonc/mdx029 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5406758/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28453692 PubMed] NCT02054806
+
#'''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://doi.org/10.1016/S1470-2045(14)70030-0 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719485/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24556040 PubMed] NCT01223027
 +
#'''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://doi.org/10.1016/S1470-2045(19)30735-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31810797 PubMed] NCT02627963
 +
##'''Update:''' Pal SK, Escudier BJ, Atkins MB, Hutson TE, Porta C, Verzoni E, Needle MN, Powers D, McDermott DF, Rini BI. Final Overall Survival Results from a Phase 3 Study to Compare Tivozanib to Sorafenib as Third- or Fourth-line Therapy in Subjects with Metastatic Renal Cell Carcinoma. Eur Urol. 2020 Dec;78(6):783-785. Epub 2020 Sep 13. [https://doi.org/10.1016/j.eururo.2020.08.007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32938569/ PubMed]
 +
==Tivozanib monotherapy {{#subobject:h7qut0|Regimen=1}}==
  
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[[Category:Anal cancer regimens]]
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===Regimen variant #1, 1.34 mg/day {{#subobject:1ug7ad|Variant=1}}===
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{| class="wikitable sortable" style="color:white; background-color:#404040"
 +
|<small>'''FDA-recommended dose'''</small>
 +
|-
 +
|}
 +
''Note: this is not the dose reported in the manuscript.''
 +
====Targeted therapy====
 +
*[[Tivozanib (Fotivda)]] 1.34 mg PO once per day on days 1 to 21
 +
'''28-day cycles'''
 +
===Regimen variant #2, 1.5 mg/day {{#subobject:1yq32d|Variant=1}}===
 +
{| class="wikitable sortable" 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]]
 +
|-
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|[https://doi.org/10.1016/S1470-2045(19)30735-1 Rini et al. 2019 (TIVO-3)]
 +
|2016-2017
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
 +
|[[#Sorafenib_monotherapy_3|Sorafenib]]
 +
| style="background-color:#91cf60" |Seems to have superior PFS<br>Median PFS: 5.6 vs 3.9 mo<br>(HR 0.73, 95% CI 0.56-0.94)
 +
|-
 +
|}
 +
====Targeted therapy====
 +
*[[Tivozanib (Fotivda)]] 1.5 mg PO once per day on days 1 to 21
 +
'''28-day cycles'''
 +
===References===
 +
#'''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://doi.org/10.1016/S1470-2045(19)30735-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31810797 PubMed] NCT02627963
 +
##'''Update:''' Pal SK, Escudier BJ, Atkins MB, Hutson TE, Porta C, Verzoni E, Needle MN, Powers D, McDermott DF, Rini BI. Final Overall Survival Results from a Phase 3 Study to Compare Tivozanib to Sorafenib as Third- or Fourth-line Therapy in Subjects with Metastatic Renal Cell Carcinoma. Eur Urol. 2020 Dec;78(6):783-785. Epub 2020 Sep 13. [https://doi.org/10.1016/j.eururo.2020.08.007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32938569/ PubMed]
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[[Category:Renal cell carcinoma regimens]]
 
[[Category:Disease-specific pages]]
 
[[Category:Disease-specific pages]]
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[[Category:Gastrointestinal cancers]]
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[[Category:Genitourinary cancers]]

Revision as of 11:24, 9 October 2022

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Section editor transclusions Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
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Guidelines

ESMO

Older

NCCN

SIOG

Risk Stratification Calculators

Adjuvant therapy

Sunitinib monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Haas et al. 2016 (ECOG-ACRIN E2805) 2006-2010 Phase 3 (E-esc) 1. Placebo
2. Sorafenib 		Did not meet primary endpoint of DFS
Ravaud et al. 2016 (S-TRAC) 2007-2011 Phase 3 (E-RT-esc) Placebo Seems to have superior DFS
Median DFS: 6.8 vs 5.6 yr
(HR 0.76, 95% CI 0.59-0.98) 		More toxicity

Preceding treatment

Targeted therapy

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 dosing details in manuscript PubMed NCT00375674
    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

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rini et al. 2019 (IMmotion151) 2015-2016 Phase 3 (E-esc) Sunitinib Seems to have superior PFS1
Median PFS: 11.2 vs 7.7 mo
(HR 0.74, 95% CI 0.57-0.96)

1Reported efficacy is for the PD-L1-positive subgroup, which was the predefined co-primary endpoint.

Immunotherapy

Targeted therapy

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 dosing details in abstract PubMed NCT02420821
    1. Update: Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Alekseev BY, Lee JL, Suarez C, Stroyakovskiy D, De Giorgi U, Donskov F, Mellado B, Banchereau R, Hamidi H, Khan O, Craine V, Huseni M, Flinn N, Dubey S, Rini BI. Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol. 2022 Feb 1;8(2):275-280. link to original article [link to PMC article PubMed

Axitinib monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Hutson et al. 2013 (A4061051) 2010-2011 Phase 3 (E-switch-ic) Sorafenib Might have superior PFS1
(HR 0.77, 95% CI 0.56-1.05) 		32% 15%

1In the 2016 update, there was no difference in OS, which was a secondary endpoint. Reported efficacy here is from the primary (2013) analysis.

Targeted therapy

  • Axitinib (Inlyta) as follows:
    • Starting dose: 5 mg PO twice per day for at least 2 weeks
    • Then if tolerated and BP not greater than 150/90: 7 mg PO twice per day
    • Then if tolerated and BP not greater than 150/90: 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 dosing details in abstract PubMed NCT00920816
    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

Regimen variant #1, weight-based dosing

Study Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2019 (JAVELIN Renal 101) 2016-2017 Phase 3 (E-RT-esc) Sunitinib Superior PFS1
Median PFS: 13.3 vs 8 mo
(HR 0.69, 95% CI 0.57-0.83)

1Reported efficacy is for the overall population and is based on the 2020 update.
Note: this is not the FDA-recommended dose.

Targeted therapy

Immunotherapy

14-day cycles

Regimen variant #2, flat dosing

FDA-recommended dose

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

Targeted therapy

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 dosing details in abstract link to PMC article PubMed NCT02684006
    1. Update: Choueiri TK, Motzer RJ, Rini BI, Haanen J, Campbell MT, Venugopal B, Kollmannsberger C, Gravis-Mescam G, Uemura M, Lee JL, Grimm MO, Gurney H, Schmidinger M, Larkin J, Atkins MB, Pal SK, Wang J, Mariani M, Krishnaswami S, Cislo P, Chudnovsky A, Fowst C, Huang B, di Pietro A, Albiges L. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020 Aug;31(8):1030-1039. Epub 2020 Apr 25. link to original article PubMed

Axitinib & Pembrolizumab

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rini et al. 2019 (KEYNOTE-426) 2016-2018 Phase 3 (E-RT-esc) Sunitinib Superior OS1
Median OS: NYR vs 36 mo
(HR 0.68, 95% CI 0.55-0.85)

1Reported efficacy is based on the 2020 update.

Targeted therapy

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 dosing details in abstract PubMed NCT02853331
    1. Update: Powles T, Plimack ER, Soulières D, Waddell T, Stus V, Gafanov R, Nosov D, Pouliot F, Melichar B, Vynnychenko I, Azevedo SJ, Borchiellini D, McDermott RS, Bedke J, Tamada S, Yin L, Chen M, Molife LR, Atkins MB, Rini BI. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1563-1573. Epub 2020 Oct 23. Erratum in: Lancet Oncol. 2020 Dec;21(12):e553. link to original article PubMed

Bevacizumab monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Bukowski et al. 2007 2004 Randomized Phase 2 (C) Erlotinib & Bevacizumab Did not meet primary endpoints of ORR/PFS 13% 14%

Targeted therapy

  • 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 dosing details in manuscript PubMed

Bevacizumab & Interferon alfa-2a

Regimen variant #1, 1 year of interferon

Study Years of enrollment Evidence Comparator Comparative Efficacy
Escudier et al. 2007 (AVOREN) 2004-2005 Phase 3 (E-RT-esc) Interferon alfa-2a Did not meet primary endpoint of OS1
Median OS: 23.3 vs 21.3 mo
(HR 0.91, 95% CI 0.76-1.10)

1Reported efficacy for AVOREN is based on the 2010 update.
Note: Timing below reflects starting treatment on a Monday.

Targeted therapy

Immunotherapy

14-day cycles

Dose modifications

Regimen variant #2, indefinite

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rini et al. 2008 (CALGB 90206) 2003-2005 Phase 3 (E-esc) Interferon alfa-2a Might have superior OS1
Median OS: 18.3 vs 17.4 mo
(HR 0.86, 95% CI 0.73-1.01)
Rini et al. 2013 (INTORACT) 2008-2010 Phase 3 (C) Temsirolimus & Bevacizumab Did not meet primary endpoint of PFS

1Reported efficacy for CALGB 90206 is based on the 2010 update and is based on a stratified analysis.
Note: Timing below reflects starting treatment on a Monday.

Targeted therapy

Immunotherapy

14-day cycles

Dose modifications

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 NCT00738530
    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 dosing details in manuscript 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 NCT00072046
    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 dosing details in abstract PubMed NCT00631371

Cabozantinib monotherapy

Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Choueiri et al. 2016 (CABOSUN) 2013-2015 Phase 3 (E-RT-switch-ic) Sunitinib Superior PFS1
Median PFS: 8.6 vs 5.3 mo
(HR 0.48, 95% CI 0.31-0.74)

1Reported 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.

Targeted therapy

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; Alliance. 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 dosing details in manuscript link to PMC article PubMed NCT01835158
    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 dosing details in manuscript link to PMC article PubMed
  2. PIVOT-09: NCT03729245

Cabozantinib & Nivolumab

Regimen variant #1, bi-weekly nivolumab

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Choueiri et al. 2021 (CheckMate 9ER) 2017-2019 Phase 3 (E-RT-esc) Sunitinib Superior OS1
Median OS: 37.7 vs 34.3 mo
(HR 0.70, 95% CI 0.55-0.90)

1Reported efficacy is based on the 2022 update.

Targeted therapy

Immunotherapy

14-day cycles

Regimen variant #2, monthly nivolumab

FDA-recommended dose

Note: this dosing does not appear to have been used in a trial, but is recommended by the FDA.

Targeted therapy

Immunotherapy

28-day cycles

References

  1. CheckMate 9ER: Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, Oyervides Juárez VM, Hsieh JJ, Basso U, Shah AY, Suárez C, Hamzaj A, Goh JC, Barrios C, Richardet M, Porta C, Kowalyszyn R, Feregrino JP, Żołnierek J, Pook D, Kessler ER, Tomita Y, Mizuno R, Bedke J, Zhang J, Maurer MA, Simsek B, Ejzykowicz F, Schwab GM, Apolo AB, Motzer RJ; CheckMate 9ER Investigators. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841. link to original article contains dosing details in manuscript PubMed NCT03141177
    1. Update: Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, Suárez C, Hamzaj A, Porta C, Hocking CM, Kessler ER, Gurney H, Tomita Y, Bedke J, Zhang J, Simsek B, Scheffold C, Apolo AB, Choueiri TK. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Jun 7:S1470-2045(22)00290-X. Epub ahead of print. link to original article PubMed

Erlotinib & Bevacizumab

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bukowski et al. 2007 2004 Randomized Phase 2 (E-esc) Bevacizumab Did not meet primary endpoints of ORR/PFS

Targeted therapy

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 dosing details in manuscript PubMed

Everolimus monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2014 (RECORD-3) 2009-2011 Randomized Phase 2 (E-switch-ic) Sunitinib Inconclusive whether non-inferior PFS

Targeted therapy

  • 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 link to PMC article PubMed NCT00903175

Everolimus & Lenvatinib

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2021 (CLEAR) 2016-2019 Phase 3 (E-RT-esc) 1. Lenvatinib & Pembrolizumab Not reported
2. Sunitinib Superior PFS
Median PFS: 14.7 vs 9.2 mo
(HR 0.65, 95% CI 0.53-0.80)

Targeted therapy

21-day cycles

References

  1. CLEAR: Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. link to original article contains dosing details in manuscript PubMed NCT02811861

Gemcitabine & Sunitinib

Regimen variant #1

Study Years of enrollment Evidence
Michaelson et al. 2015 (MGH 07-212) 2007-2013 Phase 2

Chemotherapy

Targeted therapy

21-day cycles

Regimen variant #2

Study Evidence
Pandya et al. 2011 Retrospective

Chemotherapy

Targeted therapy

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 dosing details in manuscript 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 NCT00556049

High-dose Interleukin-2

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 1985-1992 Non-randomized
Fyfe et al. 1995 NR Phase 2 (RT)
McDermott et al. 2005 1997-2000 Phase 3 (C) Subcutaneous IL-2 & Interferon Might have superior PFS

Immunotherapy

Supportive therapy

28-day cycle for up to 3 cycles

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

Study Years of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 1994 1991-1993 Phase 3 (C) 1. LD IL-2 (IV) Seems to have superior ORR
2. LD IL-2 (SC) Seems to have superior ORR

Note: reported 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 therapy

  • "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 Years of enrollment Evidence Comparator Comparative Efficacy
Figlin et al. 1999 1994-1997 Phase 3 (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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript link to PMC article PubMed

Low-dose Interleukin-2

LD IL-2: Low-Dose InterLeukin-2

Regimen variant #1, Intravenous

Study Years of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 1994 1991-1993 Phase 3 (E-de-esc) 1. High-dose IL-2 Seems to have inferior ORR
2. LD IL-2; SC Not reported

Note: efficacy is based on the 2003 update.

Immunotherapy

  • IL-2 - Aldesleukin (Proleukin) as follows:
    • Week 1: 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 Years of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 1994 1991-1993 Phase 3 (E-de-esc) 1. High-dose IL-2 Seems to have inferior ORR
2. LD IL-2; IV 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 dosing details in manuscript PubMed

Interferon alfa-2a monotherapy

Regimen variant #1, 5 MU 5x per week

Study Years of enrollment Evidence Comparator Comparative Efficacy
Sagaster et al. 1995 NR-1992 Phase 3 (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 3 (C) Bevacizumab & Interferon alfa-2a Did not meet primary endpoint of OS1
Rini et al. 2008 (CALGB 90206) 2003-2005 Phase 3 (C) Bevacizumab & Interferon alfa-2a Might have inferior OS2
Escudier et al. 2009 2005 Randomized Phase 2 (C) Sorafenib Did not meet primary endpoint of PFS
Gore et al. 2010 (MRC RE04/EORTC GU 30012) 2001-2006 Phase 3 (C) 5-FU, Interferon alfa-2a, IL-2 Did not meet primary endpoint of OS
Hawkins et al. 2016 (Active Biotech 06762004) 2007-2010 Phase 2/3 (C) Naptumomab estafenatox + IFNα Did not meet primary endpoint of OS

1Reported efficacy for AVOREN is based on the 2010 update.
2Reported efficacy for CALGB 90206 is based on the 2010 update and is based on a stratified analysis.

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 Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2000 1994-1996 Phase 3 (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 3 (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 Years of enrollment Evidence Comparator Comparative Efficacy
Ritchie et al. 1999 (MRC RE01) 1992-1997 Phase 3 (E-switch-ooc) MPA Seems to have superior OS
Gore et al. 2010 (MRC RE04/EORTC GU 30012) 2001-2006 Phase 3 (C) 5-FU, Interferon alfa-2a, IL-2 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 3 (C) IFN alfa-2a & Vinblastine Did not meet efficacy endpoints
Hudes et al. 2007 (ARCC) 2003-2005 Phase 3 (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 dosing details in abstract 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 contains dosing details in abstract 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 dosing details in manuscript PubMed NCT00098657
    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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00065468
  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 NCT00738530
    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 dosing details in manuscript 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 NCT00072046
    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 NCT00117637
  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 dosing details in manuscript PubMed NCT00053820
  11. Active Biotech 06762004: 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 dosing details in manuscript PubMed NCT00420888

Ipilimumab & Nivolumab

Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2018 (CheckMate 214) 2014-2016 Phase 3 (E-RT-switch-ooc) Sunitinib Superior OS1
OS42: 56% vs 47%
(HR 0.72, 95% CI 0.61-0.86)

1Reported efficacy is for the ITT population per the 2020 update.
Note: while this is the dosing studied in CheckMate 214, it is not the FDA-recommended dosing.

Immunotherapy

21-day cycle for 4 cycles, then 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

  • Ipilimumab (Yervoy) as follows:
    • Cycles 1 to 4: 1 mg/kg IV once on day 1, given second
  • Nivolumab (Opdivo) as follows:
    • Cycles 1 to 4: 3 mg/kg IV once on day 1, given first
    • Cycle 5 onwards: 240 mg IV once on day 1

21-day cycle for 4 cycles, then 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

  • Ipilimumab (Yervoy) as follows:
    • Cycles 1 to 4: 1 mg/kg IV once on day 1, given second
  • Nivolumab (Opdivo) as follows:
    • Cycles 1 to 4: 3 mg/kg IV once on day 1, given first
    • Cycle 5 onwards: 480 mg IV once on day 1

21-day cycle for 4 cycles, then 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 dosing details in manuscript PubMed NCT02231749
    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
    2. Update: Motzer RJ, Escudier B, McDermott DF, Arén Frontera O, Melichar B, Powles T, Donskov F, Plimack ER, Barthélémy P, Hammers HJ, George S, Grünwald V, Porta C, Neiman V, Ravaud A, Choueiri TK, Rini BI, Salman P, Kollmannsberger CK, Tykodi SS, Grimm MO, Gurney H, Leibowitz-Amit R, Geertsen PF, Amin A, Tomita Y, McHenry MB, Saggi SS, Tannir NM. Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer. 2020 Jul;8(2):e000891. Erratum in: J Immunother Cancer. 2021 May;9(5). link to original article link to PMC article PubMed
    3. Update: Albiges L, Tannir NM, Burotto M, McDermott D, Plimack ER, Barthélémy P, Porta C, Powles T, Donskov F, George S, Kollmannsberger CK, Gurney H, Grimm MO, Tomita Y, Castellano D, Rini BI, Choueiri TK, Saggi SS, McHenry MB, Motzer RJ. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020 Nov;5(6):e001079. link to original article link to PMC article PubMed
  2. PDIGREE: NCT03793166
  3. COSMIC-313: NCT03937219

Lenvatinib & Pembrolizumab

Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2021 (CLEAR) 2016-2019 Phase 3 (E-RT-esc) 1. Everolimus & Lenvatinib Not reported
2. Sunitinib Superior OS
Median OS: NYR vs NYR
(HR 0.66, 95% CI 0.49-0.88)

Targeted therapy

Immunotherapy

21-day cycles

Regimen variant #2

Study Years of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (MK-6482-012) 2021-ongoing Phase 3 (C) 1. Belzutifan, Lenvatinib, Pembrolizumab
2. Lenvatinib, Quavonlimab, Pembrolizumab 		Awaiting results

Targeted therapy

Immunotherapy

42-day cycles

References

  1. CLEAR: Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. link to original article contains dosing details in manuscript PubMed NCT02811861
  2. MK-6482-012: NCT04736706

Pazopanib monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Hutson et al. 2009 (VEG102616) 2005-2006 Phase 2
Sternberg et al. 2010 (VEG105192) 2006-2007 Phase 3 (E-RT-esc) Placebo Superior PFS
Median PFS: 9.2 vs 4.2 mo
(HR 0.46, 95% CI 0.34-0.62) 		30% (95% CI 25-36%) 3% (95% CI 0-6%)
Motzer et al. 2013 (COMPARZ) 2008-2011 Phase 3 (E-switch-ic) Sunitinib Non-inferior PFS 31% (95% CI 27-34%) 25% (95% CI 21-28%)
Cirkel et al. 2017 (ROPETAR) 2012-2014 Randomized (C) Pazopanib/Everolimus Did not meet primary endpoint of PFS

Targeted therapy

  • 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. VEG102616: 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 dosing details in manuscript PubMed NCT00244764
  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 dosing details in manuscript PubMed NCT00334282
    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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00720941
    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 NCT01064310
  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 dosing details in abstract PubMed NCT01408004

Regorafenib monotherapy

Regimen

Study Years of enrollment Evidence Efficacy
Eisen et al. 2012 (Bayer 11726) 2008-2011 Phase 2 ORR: 40% (90% CI 28-53%)

Targeted therapy

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 dosing details in manuscript PubMed NCT00664326

Sorafenib monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Escudier et al. 2009 2005 Randomized Phase 2 (E-switch-ooc) Interferon alfa-2a Did not meet primary endpoint of PFS 5% 9%
Stadler et al. 2010 (ARCCS) 2005-2006 Non-randomized
Motzer et al. 2013 (AV-951-09-902) 2010 Phase 3 (C) Tivozanib Seems to have inferior PFS
Hutson et al. 2013 (A4061051) 2010-2011 Phase 3 (C) Axitinib Might have inferior PFS1 15% 32%
Tomita et al. 2020 (CROSS-J-RCC) 2010-2012 Phase 3 (E-switch-ic) Sunitinib Did not meet primary endpoint of PFS
Retz et al. 2018 (SWITCH-II) 2012-NR in abstract Phase 3 (C) Pazopanib Inconclusive whether non-inferior tPFS

1In the 2016 update to A4061051, there was no difference in OS, which was a secondary endpoint. Reported efficacy here is from the primary (2013) analysis.

Targeted therapy

  • 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

Subsequent treatment

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 NCT00117637
  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 NCT00111020
  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 dosing details in manuscript PubMed NCT01030783
  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 dosing details in abstract PubMed NCT00920816
    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
  5. SWITCH-II: Retz M, Bedke J, Bögemann M, Grimm MO, Zimmermann U, Müller L, Leiber C, Teber D, Wirth M, Bolenz C, van Alphen R, De Santis M, Beeker A, Lehmann J, Indorf M, Frank M, Bokemeyer C, Gschwend JE. SWITCH II: Phase III randomized, sequential, open-label study to evaluate the efficacy and safety of sorafenib-pazopanib versus pazopanib-sorafenib in the treatment of advanced or metastatic renal cell carcinoma (AUO AN 33/11). Eur J Cancer. 2019 Jan;107:37-45. Epub 2018 Dec 7. link to original article contains dosing details in abstract PubMed NCT01613846
  6. CROSS-J-RCC: Tomita Y, Naito S, Sassa N, Takahashi A, Kondo T, Koie T, Obara W, Kobayashi Y, Teishima J, Takahashi M, Matsuyama H, Ueda T, Yamaguchi K, Kishida T, Shiroki R, Saika T, Shinohara N, Oya M, Kanayama HO. Sunitinib Versus Sorafenib as Initial Targeted Therapy for mCC-RCC With Favorable/Intermediate Risk: Multicenter Randomized Trial CROSS-J-RCC. Clin Genitourin Cancer. 2020 Aug;18(4):e374-e385. Epub 2020 Mar 6. link to original article PubMed NCT01481870

Sunitinib monotherapy

Regimen variant #1, 4 out of 6 weeks

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Motzer et al. 2007 (A618-1034) 2004-2005 Phase 3 (E-RT-switch-ooc) Interferon alfa-2a Might have superior OS1
Median OS: 26.4 vs 21.8 mo
(HR 0.82, 95% CI 0.67-1.001) 		31% 6%
Gore et al. 2009 (A618-1037) 2005-2007 Non-randomized 17%
Amato et al. 2010 (TroVax Renal Immunotherapy Survival Trial) 2006-2008 Phase 3 (C) Sunitinib & MVA-5T4 Did not meet primary endpoint of OS
Median OS: 19.2 vs 20.1 mo
(HR 0.93, 95% CI 0.76-1.16)
Motzer et al. 2013 (COMPARZ) 2008-2011 Phase 3 (C) Pazopanib Non-inferior PFS 25% (95% CI 21-28%) 31% (95% CI 27-34%)
Motzer et al. 2014 (RECORD-3) 2009-2011 Randomized Phase 2 (E-switch-ic) Everolimus Inconclusive whether non-inferior PFS
Eichelberg et al. 2015 (SWITCH) 2009-2011 Phase 3 (C) Sorafenib Did not meet primary endpoint of PFS
Méjean et al. 2018 (CARMENA) 2009-2017 Phase 3 (E-de-esc) Nephrectomy, then Sunitinib Non-inferior OS
Median OS: 18.4 vs 13.9 mo
(HR 0.89, 95% CI 0.71-1.10)
Rini et al. 2016 (IMPRINT) 2010-2012 Phase 3 (C) Sunitinib & IMA901 Might have superior OS
Median OS: NYR vs 33.2 mo
(HR 0.75, 95% CI 0.54-1.04)
Tomita et al. 2020 (CROSS-J-RCC) 2010-2012 Phase 3 (E-switch-ic) Sorafenib Did not meet primary endpoint of PFS
Choueiri et al. 2016 (CABOSUN) 2013-2015 Phase 3 (C) Cabozantinib Inferior PFS2
Figlin et al. 2020 (ADAPT) 2013-2016 Phase 3 (C) Rocapuldencel-T & Sunitinib Did not meet primary endpoint of OS
Median OS: 32.4 vs 27.7 mo
(HR 0.91, 95% CI 0.71-1.20)
Motzer et al. 2018 (CheckMate 214) 2014-2016 Phase 3 (C) Ipilimumab & Nivolumab Inferior OS
Rini et al. 2019 (IMmotion151) 2015-2016 Phase 3 (C) Atezolizumab & Bevacizumab Seems to have inferior PFS
Motzer et al. 2019 (JAVELIN Renal 101) 2016-2017 Phase 3 (C) Axitinib & Avelumab Seems to have inferior OS3
Rini et al. 2019 (KEYNOTE-426) 2016-2018 Phase 3 (C) Axitinib & Pembrolizumab Inferior OS
Choueiri et al. 2021 (CheckMate 9ER) 2017-2019 Phase 3 (C) Cabozantinib & Nivolumab Inferior OS
Motzer et al. 2021 (CLEAR) 2016-2019 Phase 3 (C) 1. Everolimus & Lenvatinib Inferior PFS 36.1% 53.5%
2. Lenvatinib & Pembrolizumab Inferior OS 36.1% 71.0%
Awaiting publication (JS001-036-III-RCC) 2020-ongoing Phase 3 (C) Axitinib & Toripalimab Awaiting results

1Reported efficacy for A618-1034 is based on the 2009 update.
2Reported efficacy for CABOSUN is based on the 2018 update.
3Reported efficacy for Javelin Renal 101 is based on the 2020 update, although the authors state that OS data remains immature.

Targeted therapy

  • 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

Regimen variant #2, 2 out of 4 weeks

Study Years of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (TQB2450-III-07) 2020-ongoing Phase 3 (C) Anlotinib & TQB2450 Awaiting results

Targeted therapy

28-day cycles

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 dosing details in manuscript PubMed NCT00098657
    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 dosing details in manuscript link to PMC article PubMed
  2. 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 dosing details in manuscript PubMed NCT00130897
  3. 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 dosing details in manuscript PubMed NCT00397345
  4. 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 dosing details in manuscript PubMed NCT00720941
    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
  5. 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 NCT01064310
  6. 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 link to PMC article PubMed NCT00903175
  7. 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 dosing details in abstract PubMed NCT00732914
  8. 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 dosing details in abstract PubMed NCT01265901
  9. 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 dosing details in manuscript link to PMC article PubMed NCT01835158
    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 dosing details in manuscript link to PMC article PubMed
  10. 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 dosing details in manuscript PubMed NCT02231749
    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
    2. Update: Motzer RJ, Escudier B, McDermott DF, Arén Frontera O, Melichar B, Powles T, Donskov F, Plimack ER, Barthélémy P, Hammers HJ, George S, Grünwald V, Porta C, Neiman V, Ravaud A, Choueiri TK, Rini BI, Salman P, Kollmannsberger CK, Tykodi SS, Grimm MO, Gurney H, Leibowitz-Amit R, Geertsen PF, Amin A, Tomita Y, McHenry MB, Saggi SS, Tannir NM. Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer. 2020 Jul;8(2):e000891. Erratum in: J Immunother Cancer. 2021 May;9(5). link to original article link to PMC article PubMed
    3. Update: Albiges L, Tannir NM, Burotto M, McDermott D, Plimack ER, Barthélémy P, Porta C, Powles T, Donskov F, George S, Kollmannsberger CK, Gurney H, Grimm MO, Tomita Y, Castellano D, Rini BI, Choueiri TK, Saggi SS, McHenry MB, Motzer RJ. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020 Nov;5(6):e001079. link to original article link to PMC article PubMed
  11. 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 dosing details in abstract PubMed NCT00930033
  12. 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 dosing details in abstract link to PMC article PubMed NCT02684006
    1. Update: Choueiri TK, Motzer RJ, Rini BI, Haanen J, Campbell MT, Venugopal B, Kollmannsberger C, Gravis-Mescam G, Uemura M, Lee JL, Grimm MO, Gurney H, Schmidinger M, Larkin J, Atkins MB, Pal SK, Wang J, Mariani M, Krishnaswami S, Cislo P, Chudnovsky A, Fowst C, Huang B, di Pietro A, Albiges L. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020 Aug;31(8):1030-1039. Epub 2020 Apr 25. link to original article PubMed
  13. 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 dosing details in abstract PubMed NCT02853331
    1. Update: Powles T, Plimack ER, Soulières D, Waddell T, Stus V, Gafanov R, Nosov D, Pouliot F, Melichar B, Vynnychenko I, Azevedo SJ, Borchiellini D, McDermott RS, Bedke J, Tamada S, Yin L, Chen M, Molife LR, Atkins MB, Rini BI. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1563-1573. Epub 2020 Oct 23. Erratum in: Lancet Oncol. 2020 Dec;21(12):e553. link to original article PubMed
  14. 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 dosing details in abstract PubMed NCT02420821
    1. Update: Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Alekseev BY, Lee JL, Suarez C, Stroyakovskiy D, De Giorgi U, Donskov F, Mellado B, Banchereau R, Hamidi H, Khan O, Craine V, Huseni M, Flinn N, Dubey S, Rini BI. Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol. 2022 Feb 1;8(2):275-280. link to original article [link to PMC article PubMed
  15. ADAPT: Figlin RA, Tannir NM, Uzzo RG, Tykodi SS, Chen DYT, Master V, Kapoor A, Vaena D, Lowrance W, Bratslavsky G, DeBenedette M, Gamble A, Plachco A, Norris MS, Horvatinovich J, Tcherepanova IY, Nicolette CA, Wood CG; ADAPT study group. Results of the ADAPT Phase 3 Study of Rocapuldencel-T in Combination with Sunitinib as First-Line Therapy in Patients with Metastatic Renal Cell Carcinoma. Clin Cancer Res. 2020 May 15;26(10):2327-2336. Epub 2020 Feb 7. link to original article PubMed NCT01582672
  16. CROSS-J-RCC: Tomita Y, Naito S, Sassa N, Takahashi A, Kondo T, Koie T, Obara W, Kobayashi Y, Teishima J, Takahashi M, Matsuyama H, Ueda T, Yamaguchi K, Kishida T, Shiroki R, Saika T, Shinohara N, Oya M, Kanayama HO. Sunitinib Versus Sorafenib as Initial Targeted Therapy for mCC-RCC With Favorable/Intermediate Risk: Multicenter Randomized Trial CROSS-J-RCC. Clin Genitourin Cancer. 2020 Aug;18(4):e374-e385. Epub 2020 Mar 6. link to original article PubMed NCT01481870
  17. CheckMate 9ER: Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, Oyervides Juárez VM, Hsieh JJ, Basso U, Shah AY, Suárez C, Hamzaj A, Goh JC, Barrios C, Richardet M, Porta C, Kowalyszyn R, Feregrino JP, Żołnierek J, Pook D, Kessler ER, Tomita Y, Mizuno R, Bedke J, Zhang J, Maurer MA, Simsek B, Ejzykowicz F, Schwab GM, Apolo AB, Motzer RJ; CheckMate 9ER Investigators. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841. link to original article contains dosing details in manuscript PubMed NCT03141177
    1. Update: Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, Suárez C, Hamzaj A, Porta C, Hocking CM, Kessler ER, Gurney H, Tomita Y, Bedke J, Zhang J, Simsek B, Scheffold C, Apolo AB, Choueiri TK. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Jun 7:S1470-2045(22)00290-X. Epub ahead of print. link to original article PubMed
  18. CLEAR: Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. link to original article contains dosing details in abstract PubMed NCT02811861
  19. KEYNOTE-679: NCT03260894
  20. JS001-036-III-RCC: NCT04394975
  21. PIVOT-09: NCT03729245
  22. TQB2450-III-07: NCT04523272

Temsirolimus monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Hudes et al. 2007 (ARCC) 2003-2005 Phase 3 (E-RT-switch-ooc) 1. Interferon alfa-2a Superior OS
Median OS: 10.9 vs 7.3 mo
(HR 0.73, 95% CI 0.58-0.92) 		9% (95% CI 5-12%) 5% (95% CI 2-8%)
2. Interferon alfa-2a & Temsirolimus Not reported 8% (95% CI 4-12%)

Targeted therapy

Supportive therapy

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 dosing details in manuscript PubMed NCT00065468

Tivozanib monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2013 (AV-951-09-902) 2010 Phase 3 (E-switch-ic) Sorafenib Seems to have superior PFS
Median PFS: 11.9 vs 9.1 mo
(HR 0.80, 95% CI 0.64-0.993)

Targeted therapy

28-day cycles

References

  1. 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 dosing details in manuscript PubMed NCT01030783

Metastatic disease, second-line

Axitinib monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rini et al. 2011 (AXIS) 2008-2010 Phase 3 (E-RT-switch-ic) Sorafenib Superior PFS1
Median PFS: 8.3 vs 5.7 mo
(HR 0.66, 95% CI 0.55-0.78)

1Reported efficacy is based on the 2013 update. In this update, ORR was 23% in this arm, and 12% in the control arm. There was no statistically significant difference in overall survival.

Prior treatment criteria

  • AXIS: Progression on first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines

Targeted therapy

  • Axitinib (Inlyta) as follows:
    • Starting dose: 5 mg PO twice per day for at least 2 weeks
    • Then if tolerated and BP not greater than 150/90: 7 mg PO twice per day
    • Then if tolerated and BP not greater than 150/90: 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 dosing details in manuscript PubMed NCT00678392
    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 dosing details in manuscript 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

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 2003 1998-2001 Randomized Phase 2 (E-esc) Placebo Superior TTP

Prior treatment criteria

  • Previous therapy with IL-2 or contraindication to IL-2

Targeted therapy

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 dosing details in abstract link to PMC article PubMed

Cabozantinib monotherapy

Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Choueiri et al. 2015 (METEOR) 2013-2014 Phase 3 (E-RT-switch-ic) Everolimus Superior OS1
Median OS: 21.4 vs 17.1 mo
(HR 0.70, 95% CI 0.58-0.85) 		21% (95% CI 16-28%) 5% (95% CI 2-9%)

1Reported efficacy is based on the 2018 update.

Preceding treatment

Targeted therapy

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 dosing details in manuscript link to PMC article PubMed NCT01865747
    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
  2. CONTACT-03: NCT04338269
  3. MK-6482-011: NCT04586231

Everolimus monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Motzer et al. 2008 (RECORD-1) 2006-2007 Phase 3 (E-RT-esc) Placebo Superior PFS
Median PFS: 4 vs 1.9 mo
(HR 0.30, 95% CI 0.22-0.40) 		1% 0%
Motzer et al. 2014 (RECORD-3) 2009-2011 Randomized Phase 2 (E-switch-ic) Sunitinib Inconclusive whether non-inferior PFS
Motzer et al. 2015 (RECORD-4) 2011-2013 Phase 2
Motzer et al. 2015 (CheckMate 025) 2012-2014 Phase 3 (C) Nivolumab Inferior OS 5% 25%
Motzer et al. 2015 (E7080-G000-205) 2012-2013 Randomized Phase 2 (C) 1. Everolimus & Lenvatinib Inferior PFS
2. Lenvatinib Seems to have inferior PFS
Choueiri et al. 2015 (METEOR) 2013-2014 Phase 3 (C) Cabozantinib Inferior OS 5% (95% CI 2-9%) 21% (95% CI 16-28%)
Awaiting publication (CONCEPTRCC) 2016-2019 Phase 3 (C) 1. Everolimus & Vorolanib Seems to have inferior PFS
2. Vorolanib Did not meet primary endpoint of PFS

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

Preceding treatment

Targeted therapy

  • 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 dosing details in manuscript PubMed NCT00410124
    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 dosing details in manuscript 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 link to PMC article PubMed NCT00903175
  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 dosing details in manuscript PubMed NCT01668784
    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: 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. Update: Motzer RJ, Escudier B, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Plimack ER, Procopio G, McDermott DF, Castellano D, Choueiri TK, Donskov F, Gurney H, Oudard S, Richardet M, Peltola K, Alva AS, Carducci M, Wagstaff J, Chevreau C, Fukasawa S, Tomita Y, Gauler TC, Kollmannsberger CK, Schutz FA, Larkin J, Cella D, McHenry MB, Saggi SS, Tannir NM. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer. 2020 Sep 15;126(18):4156-4167. Epub 2020 Jul 16. 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 dosing details in manuscript link to PMC article PubMed NCT01865747
    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 dosing details in manuscript PubMed NCT01136733
    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 dosing details in abstract PubMed NCT01491672
  7. CONCEPTRCC: NCT03095040

Everolimus & Lenvatinib

Regimen

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

Patients had progressed after VEGFR TKI treatment.

Targeted therapy

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 dosing details in manuscript PubMed NCT01136733
    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

Regimen

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

Targeted therapy

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 dosing details in manuscript PubMed NCT01136733
    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

Regimen variant #1, 0.3 mg/kg q3wk

Study Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2015 (CheckMate 010) 2011-2012 Randomized Phase 2 (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 Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2015 (CheckMate 010) 2011-2012 Randomized Phase 2 (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 3 (E-RT-switch-ooc) Everolimus Superior OS
Median OS: 25 vs 19.6 mo
(HR 0.73, 98.5% CI 0.57-0.93) 		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 Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2015 (CheckMate 010) 2011-2012 Randomized Phase 2 (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. CheckMate 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 dosing details in manuscript PubMed NCT01354431
  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 dosing details in manuscript PubMed NCT01668784
    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: 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. Update: Motzer RJ, Escudier B, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Plimack ER, Procopio G, McDermott DF, Castellano D, Choueiri TK, Donskov F, Gurney H, Oudard S, Richardet M, Peltola K, Alva AS, Carducci M, Wagstaff J, Chevreau C, Fukasawa S, Tomita Y, Gauler TC, Kollmannsberger CK, Schutz FA, Larkin J, Cella D, McHenry MB, Saggi SS, Tannir NM. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer. 2020 Sep 15;126(18):4156-4167. Epub 2020 Jul 16. link to original article PubMed

Pazopanib monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Hutson et al. 2009 (VEG102616) 2005-2006 Phase 2
Sternberg et al. 2010 (VEG105192) 2006-2007 Phase 3 (E-esc) Placebo Superior PFS
Median PFS: 9.2 vs 4.2 mo
(HR 0.46, 95% CI 0.34-0.62) 		30% (95% CI 25-36%) 3% (95% CI 0-6%)
Hainsworth et al. 2013 2008-2011 Phase 2

Prior treatment criteria

  • VEG105192: Progression on 1 prior cytokine-based systemic therapy

Targeted therapy

  • 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. VEG102616: 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 dosing details in manuscript PubMed NCT00244764
  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 dosing details in manuscript PubMed NCT00334282
    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 dosing details in manuscript 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 dosing details in abstract PubMed

Sorafenib monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Escudier et al. 2007 (TARGETRCC) 2003-2005 Phase 3 (E-RT-esc) Placebo Might have superior OS1
Median OS: 17.8 vs 15.2 mo
(HR 0.88, 95% CI 0.74-1.04)
Stadler et al. 2010 (ARCCS) 2005-2006 Non-randomized expanded access study
Beck et al. 2011 (EU-ARCCS) 2005-2007 Non-randomized expanded access study
Hutson et al. 2013 (INTORSECT) 2007-2011 Phase 3 (C) Temsirolimus Did not meet primary endpoint of PFS2
Median PFS: 3.9 vs 4.3 mo
(HR 1.15, 95% CI 0.93-1.41)
Rini et al. 2011 (AXIS) 2008-2010 Phase 3 (C) Axitinib Inferior PFS 9% (95% CI 7-13%) 19% (95% CI 15-24%)

1Reported efficacy for TARGET is based on the 2009 update.
2While the primary endpoint (PFS) was not met in INTORSECT, the control arm actually had superior OS compared to the experimental arm.

Prior treatment criteria

  • TARGETRCC: 1 systemic treatment within the previous 8 months, with progression
  • INTORSECT: Progression on sunitinib
  • AXIS: Progression on first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines

Targeted therapy

  • 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. TARGETRCC: 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 dosing details in manuscript PubMed NCT00073307
    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 dosing details in manuscript 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 NCT00111020
  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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00678392
    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 dosing details in manuscript 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 dosing details in abstract link to PMC article PubMed NCT00474786

Sunitinib monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2005 (RTKC-0511-014) 2003 Phase 2 (RT)
Motzer et al. 2006 (A618-1006) 2004 Phase 2 (RT)
Gore et al. 2009 (A618-1037) 2005-2007 Non-randomized
Motzer et al. 2014 (RECORD-3) 2009-2011 Randomized Phase 2 (E-switch-ic) Everolimus Inconclusive whether non-inferior PFS

Preceding treatment

Targeted therapy

  • 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 dosing details in abstract PubMed NCT00077974
  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 dosing details in manuscript PubMed NCT00130897
  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 link to PMC article PubMed NCT00903175

Metastatic disease, third-line

Sorafenib monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2014 (GOLD-RCC) 2011-2012 Phase 3 (C) Dovitinib Might have inferior PFS
Rini et al. 2019 (TIVO-3) 2016-2017 Phase 3 (C) Tivozanib Seems to have inferior PFS

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

Targeted therapy

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 dosing details in abstract link to PMC article PubMed NCT01223027
  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 NCT02627963
    1. Update: Pal SK, Escudier BJ, Atkins MB, Hutson TE, Porta C, Verzoni E, Needle MN, Powers D, McDermott DF, Rini BI. Final Overall Survival Results from a Phase 3 Study to Compare Tivozanib to Sorafenib as Third- or Fourth-line Therapy in Subjects with Metastatic Renal Cell Carcinoma. Eur Urol. 2020 Dec;78(6):783-785. Epub 2020 Sep 13. link to original article PubMed

Tivozanib monotherapy

Regimen variant #1, 1.34 mg/day

FDA-recommended dose

Note: this is not the dose reported in the manuscript.

Targeted therapy

28-day cycles

Regimen variant #2, 1.5 mg/day

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rini et al. 2019 (TIVO-3) 2016-2017 Phase 3 (E-RT-switch-ic) Sorafenib Seems to have superior PFS
Median PFS: 5.6 vs 3.9 mo
(HR 0.73, 95% CI 0.56-0.94)

Targeted therapy

28-day cycles

References

  1. 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 contains dosing details in manuscript PubMed NCT02627963
    1. Update: Pal SK, Escudier BJ, Atkins MB, Hutson TE, Porta C, Verzoni E, Needle MN, Powers D, McDermott DF, Rini BI. Final Overall Survival Results from a Phase 3 Study to Compare Tivozanib to Sorafenib as Third- or Fourth-line Therapy in Subjects with Metastatic Renal Cell Carcinoma. Eur Urol. 2020 Dec;78(6):783-785. Epub 2020 Sep 13. link to original article PubMed
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