Difference between revisions of "Renal cell carcinoma"

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''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Renal_cell_carcinoma_-_historical|historical regimens page]]. 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!''
 
''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:
 
<br>There are several related dedicated pages:
−
 
 
*'''Histology-specific:'''
 
*'''Histology-specific:'''
 
**'''[[Papillary renal cell carcinoma]]'''
 
**'''[[Papillary renal cell carcinoma]]'''
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*'''Biomarker-specific:'''
 
*'''Biomarker-specific:'''
 
**'''[[Renal_cell_carcinoma,_VHL-associated|RCC, VHL-associated]]'''
 
**'''[[Renal_cell_carcinoma,_VHL-associated|RCC, VHL-associated]]'''
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{{TOC limit|limit=3}}
 
{{TOC limit|limit=3}}
−
 
 
=Guidelines=
 
=Guidelines=
 
==EAU==
 
==EAU==
−
 
 
*'''2016:''' Powles et al. [http://www.europeanurology.com/article/S0302-2838(15)00998-7/fulltext Updated EAU guidelines for clear cell renal cancer patients who fail VEGF targeted therapy] [https://pubmed.ncbi.nlm.nih.gov/26508312 PubMed]
 
*'''2016:''' Powles et al. [http://www.europeanurology.com/article/S0302-2838(15)00998-7/fulltext Updated EAU guidelines for clear cell renal cancer patients who fail VEGF targeted therapy] [https://pubmed.ncbi.nlm.nih.gov/26508312 PubMed]
−
 
 
==[http://www.esmo.org/ ESMO]==
 
==[http://www.esmo.org/ ESMO]==
 
*'''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]
 
*'''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]
 
*'''2021:''' Powles [https://doi.org/10.1016/j.annonc.2020.11.016 Recent eUpdate to the ESMO Clinical Practice Guidelines on renal cell carcinoma on cabozantinib and nivolumab for first-line clear cell renal cancer: Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
 
*'''2021:''' Powles [https://doi.org/10.1016/j.annonc.2020.11.016 Recent eUpdate to the ESMO Clinical Practice Guidelines on renal cell carcinoma on cabozantinib and nivolumab for first-line clear cell renal cancer: Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
 
*'''2019:''' Escudier et al. [https://doi.org/10.1093/annonc/mdz056 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
 
*'''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===
−
 
 
*'''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]
 
*'''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]
 
*'''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]
 
*'''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]
 
*'''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/ NCCN]==
−
 
 
*[https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf NCCN Guidelines - Kidney Cancer]
 
*[https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf NCCN Guidelines - Kidney Cancer]
−
 
 
==[http://www.siog.org/ SIOG]==
 
==[http://www.siog.org/ SIOG]==
−
 
 
*'''2018:''' Kanesvaran et al. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30125-6/fulltext Elderly patients with metastatic renal cell carcinoma: position paper from the International Society of Geriatric Oncology]
 
*'''2018:''' Kanesvaran et al. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30125-6/fulltext Elderly patients with metastatic renal cell carcinoma: position paper from the International Society of Geriatric Oncology]
−
 
 
=Risk Stratification Calculators=
 
=Risk Stratification Calculators=
−
 
+
*[https://www.mdcalc.com/heng-score-metastatic-renal-cell-carcinoma-rcc-prognosis International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) calculator]
−
*[https://www.mdcalc.com/heng-score-metastatic-renal-cell-carcinoma-rcc-prognosis International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) calculator]  
 
 
**ref: Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, Mackenzie M, Wood L, Donskov F, Tan MH, Rha SY, Agarwal N, Kollmannsberger C, Rini BI, Choueiri TK; External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013 Feb;14(2):141-8. Epub 2013 Jan 9. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144042/ link to original article] [https://pubmed.ncbi.nlm.nih.gov/23312463 PubMed]
 
**ref: Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, Mackenzie M, Wood L, Donskov F, Tan MH, Rha SY, Agarwal N, Kollmannsberger C, Rini BI, Choueiri TK; External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013 Feb;14(2):141-8. Epub 2013 Jan 9. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144042/ link to original article] [https://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]  
+
*[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]
 
**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)
 
*[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]
 
**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. doi: 10.1200/JCO.2001.19.6.1649. PMID: 11250993. [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. doi: 10.1016/j.eururo.2018.01.005. Epub 2018 Feb 3. PMID: 29398265. [https://pubmed.ncbi.nlm.nih.gov/29398265/ PubMed]
 
=Adjuvant therapy=
 
=Adjuvant therapy=
 
==Pembrolizumab monotherapy {{#subobject:gadc52|Regimen=1}}==
 
==Pembrolizumab monotherapy {{#subobject:gadc52|Regimen=1}}==
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{| 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
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====Immunotherapy====
 
====Immunotherapy====
 
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
−
 
 
'''21-day cycle for up to 17 cycles (1 year)'''
 
'''21-day cycle for up to 17 cycles (1 year)'''
−
 
 
===Regimen variant #2, 400 mg q6wk {{#subobject:63y5a01|Variant=1}}===
 
===Regimen variant #2, 400 mg q6wk {{#subobject:63y5a01|Variant=1}}===
 
{| class="wikitable" style="color:white; background-color:#404040"
 
{| class="wikitable" style="color:white; background-color:#404040"
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====Immunotherapy====
 
====Immunotherapy====
 
*[[Pembrolizumab (Keytruda)]] 400 mg IV once on day 1
 
*[[Pembrolizumab (Keytruda)]] 400 mg IV once on day 1
−
 
 
'''42-day cycle for up to 8 cycles (1 year)'''
 
'''42-day cycle for up to 8 cycles (1 year)'''
−
 
 
===References===
 
===References===
 
# '''KEYNOTE-564:''' Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Chang YH, Hajek J, Symeonides SN, Lee JL, Sarwar N, Thiery-Vuillemin A, Gross-Goupil M, Mahave M, Haas NB, Sawrycki P, Gurney H, Chevreau C, Melichar B, Kopyltsov E, Alva A, Burke JM, Doshi G, Topart D, Oudard S, Hammers H, Kitamura H, Bedke J, Perini RF, Zhang P, Imai K, Willemann-Rogerio J, Quinn DI, Powles T; KEYNOTE-564 Investigators. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med. 2021 Aug 19;385(8):683-694. [https://doi.org/10.1056/nejmoa2106391 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/34407342/ PubMed] NCT03142334
 
# '''KEYNOTE-564:''' Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Chang YH, Hajek J, Symeonides SN, Lee JL, Sarwar N, Thiery-Vuillemin A, Gross-Goupil M, Mahave M, Haas NB, Sawrycki P, Gurney H, Chevreau C, Melichar B, Kopyltsov E, Alva A, Burke JM, Doshi G, Topart D, Oudard S, Hammers H, Kitamura H, Bedke J, Perini RF, Zhang P, Imai K, Willemann-Rogerio J, Quinn DI, Powles T; KEYNOTE-564 Investigators. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med. 2021 Aug 19;385(8):683-694. [https://doi.org/10.1056/nejmoa2106391 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/34407342/ PubMed] NCT03142334
−
 
 
==Sunitinib monotherapy {{#subobject:cf6852|Regimen=1}}==
 
==Sunitinib monotherapy {{#subobject:cf6852|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
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===Regimen {{#subobject:3c0a01|Variant=1}}===
 
===Regimen {{#subobject:3c0a01|Variant=1}}===
−
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{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
! style="width: 17%" |Study
 
! style="width: 17%" |Study
 
! style="width: 15%" |Years of enrollment
 
! style="width: 15%" |Years of enrollment
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====Preceding treatment====
 
====Preceding treatment====
−
 
 
*[[Surgery#Renal_cell_carcinoma_surgery|Surgery]]
 
*[[Surgery#Renal_cell_carcinoma_surgery|Surgery]]
−
 
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Sunitinib (Sutent)]] 50 mg PO once per day on days 1 to 28
 
*[[Sunitinib (Sutent)]] 50 mg PO once per day on days 1 to 28
−
 
 
'''42-day cycle for up to 9 cycles (1 year)'''
 
'''42-day cycle for up to 9 cycles (1 year)'''
−
 
 
===References===
 
===References===
−
 
 
#'''ECOG-ACRIN E2805:''' Haas NB, Manola J, Uzzo RG, Flaherty KT, Wood CG, Kane C, Jewett M, Dutcher JP, Atkins MB, Pins M, Wilding G, Cella D, Wagner L, Matin S, Kuzel TM, Sexton WJ, Wong YN, Choueiri TK, Pili R, Puzanov I, Kohli M, Stadler W, Carducci M, Coomes R, DiPaola RS. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016 May 14;387(10032):2008-16. Epub 2016 Mar 9. Erratum in: Lancet. 2016 May 14;387(10032):1998. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00559-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878938/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26969090 PubMed] NCT00326898
 
#'''ECOG-ACRIN E2805:''' Haas NB, Manola J, Uzzo RG, Flaherty KT, Wood CG, Kane C, Jewett M, Dutcher JP, Atkins MB, Pins M, Wilding G, Cella D, Wagner L, Matin S, Kuzel TM, Sexton WJ, Wong YN, Choueiri TK, Pili R, Puzanov I, Kohli M, Stadler W, Carducci M, Coomes R, DiPaola RS. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016 May 14;387(10032):2008-16. Epub 2016 Mar 9. Erratum in: Lancet. 2016 May 14;387(10032):1998. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00559-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878938/ link to PMC article] [https://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://www.nejm.org/doi/full/10.1056/NEJMoa1611406 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27718781 PubMed] NCT00375674
 
#'''S-TRAC:''' Ravaud A, Motzer RJ, Pandha HS, George DJ, Pantuck AJ, Patel A, Chang YH, Escudier B, Donskov F, Magheli A, Carteni G, Laguerre B, Tomczak P, Breza J, Gerletti P, Lechuga M, Lin X, Martini JF, Ramaswamy K, Casey M, Staehler M, Patard JJ; S-TRAC Investigators. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016 Dec 8;375(23):2246-2254. Epub 2016 Oct 9. [https://www.nejm.org/doi/full/10.1056/NEJMoa1611406 link to original article] '''contains verified protocol''' [https://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/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28967554 PubMed]
 
##'''Update:''' Motzer RJ, Ravaud A, Patard JJ, Pandha HS, George DJ, Patel A, Chang YH, Escudier B, Donskov F, Magheli A, Carteni G, Laguerre B, Tomczak P, Breza J, Gerletti P, Lechuga M, Lin X, Casey M, Serfass L, Pantuck AJ, Staehler M. Adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy: subgroup analyses and updated overall survival results. Eur Urol. 2018 Jan;73(1):62-68. Epub 2017 Sep 26. [http://www.europeanurology.com/article/S0302-2838(17)30772-8/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/28967554 PubMed]
−
 
 
=Metastatic disease, first-line=
 
=Metastatic disease, first-line=
 
==Atezolizumab & Bevacizumab {{#subobject:af0d04|Regimen=1}}==
 
==Atezolizumab & Bevacizumab {{#subobject:af0d04|Regimen=1}}==
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===Regimen {{#subobject:34c462|Variant=1}}===
 
===Regimen {{#subobject:34c462|Variant=1}}===
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! style="width: 20%" |Study
 
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! style="width: 20%" |Years of enrollment
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''<sup>1</sup>Reported efficacy is for the PD-L1-positive subgroup, which was the predefined co-primary endpoint.''
 
''<sup>1</sup>Reported efficacy is for the PD-L1-positive subgroup, which was the predefined co-primary endpoint.''
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1
 
*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1
−
 
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
 
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
−
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
 
===References===
 
===References===
−
 
 
#'''IMmotion151:''' Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30723-8/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/31079938 PubMed] NCT02420821
 
#'''IMmotion151:''' Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30723-8/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/31079938 PubMed] NCT02420821
−
 
 
==Axitinib monotherapy {{#subobject:e83fa|Regimen=1}}==
 
==Axitinib monotherapy {{#subobject:e83fa|Regimen=1}}==
 
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|[[#top|back to top]]
 
|[[#top|back to top]]
 
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===Regimen {{#subobject:90ba4d|Variant=1}}===
 
===Regimen {{#subobject:90ba4d|Variant=1}}===
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! style="width: 20%" |Years of enrollment
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''<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.''
 
''<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====
 
====Targeted therapy====
−
 
 
*[[Axitinib (Inlyta)]] as follows:
 
*[[Axitinib (Inlyta)]] as follows:
 
**Starting dose: 5 mg PO twice per day for at least 2 weeks
 
**Starting dose: 5 mg PO twice per day for at least 2 weeks
Line 220: Line 189:
 
**Then if tolerated and BP not greater than 150/90: 10 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
 
**Dose can be reduced to 2 to 3 mg PO twice per day if needed based on tolerability
−
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
 
===References===
 
===References===
−
 
 
#'''A4061051:''' Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, Rosbrook B, Chen C, Kim S, Vogelzang NJ. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1287-94. Epub 2013 Oct 25. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70465-0/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24206640 PubMed] NCT00920816
 
#'''A4061051:''' Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, Rosbrook B, Chen C, Kim S, Vogelzang NJ. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1287-94. Epub 2013 Oct 25. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70465-0/fulltext link to original article] '''contains protocol''' [https://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/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/27498023 PubMed]
 
##'''Update:''' Hutson TE, Al-Shukri S, Stus VP, Lipatov ON, Shparyk Y, Bair AH, Rosbrook B, Andrews GI, Vogelzang NJ. Axitinib versus sorafenib in first-line metastatic renal cell carcinoma: Overall survival from a randomized phase III trial. Clin Genitourin Cancer. 2017 Feb;15(1):72-76. Epub 2016 May 27. [http://www.clinical-genitourinary-cancer.com/article/S1558-7673(16)30134-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/27498023 PubMed]
−
 
 
==Axitinib & Avelumab {{#subobject:e83faz|Regimen=1}}==
 
==Axitinib & Avelumab {{#subobject:e83faz|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 233: Line 199:
 
|}
 
|}
 
===Regimen variant #1, weight-based dosing {{#subobject:88ca4d|Variant=1}}===
 
===Regimen variant #1, weight-based dosing {{#subobject:88ca4d|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
Line 250: Line 216:
 
''Note: this is not the FDA-recommended dose.''
 
''Note: this is not the FDA-recommended dose.''
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Axitinib (Inlyta)]] 5 mg PO twice per day
 
*[[Axitinib (Inlyta)]] 5 mg PO twice per day
−
 
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Avelumab (Bavencio)]] 10 mg/kg IV once on day 1
 
*[[Avelumab (Bavencio)]] 10 mg/kg IV once on day 1
−
 
 
'''14-day cycles'''
 
'''14-day cycles'''
−
 
 
===Regimen variant #2, flat dosing {{#subobject:33ca4d|Variant=1}}===
 
===Regimen variant #2, flat dosing {{#subobject:33ca4d|Variant=1}}===
 
{| class="wikitable" style="color:white; background-color:#404040"
 
{| class="wikitable" style="color:white; background-color:#404040"
Line 266: Line 227:
 
''Note: this is not the dose described in Motzer et al. 2019.''
 
''Note: this is not the dose described in Motzer et al. 2019.''
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Axitinib (Inlyta)]] 5 mg PO twice per day
 
*[[Axitinib (Inlyta)]] 5 mg PO twice per day
−
 
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Avelumab (Bavencio)]] 800 mg IV once on day 1
 
*[[Avelumab (Bavencio)]] 800 mg IV once on day 1
−
 
 
'''14-day cycles'''
 
'''14-day cycles'''
 
===References===
 
===References===
−
 
 
#'''JAVELIN Renal 101:''' Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M, Lee JL, Vasiliev A, Miller WH Jr, Gurney H, Schmidinger M, Larkin J, Atkins MB, Bedke J, Alekseev B, Wang J, Mariani M, Robbins PB, Chudnovsky A, Fowst C, Hariharan S, Huang B, di Pietro A, Choueiri TK. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1103-1115. Epub 2019 Feb 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1816047 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716603/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30779531/ PubMed] NCT02684006
 
#'''JAVELIN Renal 101:''' Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M, Lee JL, Vasiliev A, Miller WH Jr, Gurney H, Schmidinger M, Larkin J, Atkins MB, Bedke J, Alekseev B, Wang J, Mariani M, Robbins PB, Chudnovsky A, Fowst C, Hariharan S, Huang B, di Pietro A, Choueiri TK. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1103-1115. Epub 2019 Feb 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1816047 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716603/ link to PMC article] [https://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]
 
##'''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}}==
 
==Axitinib & Pembrolizumab {{#subobject:e83gac|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 285: Line 240:
 
|}
 
|}
 
===Regimen {{#subobject:22bc4d|Variant=1}}===
 
===Regimen {{#subobject:22bc4d|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
Line 301: Line 256:
 
''<sup>1</sup>Reported efficacy is based on the 2020 update.''
 
''<sup>1</sup>Reported efficacy is based on the 2020 update.''
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Axitinib (Inlyta)]] 5 mg PO twice per day
 
*[[Axitinib (Inlyta)]] 5 mg PO twice per day
−
 
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
−
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
 
===References===
 
===References===
−
 
 
#'''KEYNOTE-426:''' Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, Vynnychenko I, Kryzhanivska A, Bondarenko I, Azevedo SJ, Borchiellini D, Szczylik C, Markus M, McDermott RS, Bedke J, Tartas S, Chang YH, Tamada S, Shou Q, Perini RF, Chen M, Atkins MB, Powles T; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116-1127. Epub 2019 Feb 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1816714 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/30779529 PubMed] NCT02853331
 
#'''KEYNOTE-426:''' Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, Vynnychenko I, Kryzhanivska A, Bondarenko I, Azevedo SJ, Borchiellini D, Szczylik C, Markus M, McDermott RS, Bedke J, Tartas S, Chang YH, Tamada S, Shou Q, Perini RF, Chen M, Atkins MB, Powles T; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116-1127. Epub 2019 Feb 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1816714 link to original article] '''contains protocol''' [https://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]
 
##'''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}}==
 
==Bevacizumab monotherapy {{#subobject:29beb2|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 321: Line 269:
 
|}
 
|}
 
===Regimen {{#subobject:433717|Variant=1}}===
 
===Regimen {{#subobject:433717|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
Line 340: Line 288:
 
|}
 
|}
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Bevacizumab (Avastin)]] 10 mg/kg IV over 90 minutes once on day 1
 
*[[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
 
**Can subsequently be reduced to 60 and 30 minute infusions as tolerated
−
 
 
'''14-day cycle for up to 52 cycles (2 years)'''
 
'''14-day cycle for up to 52 cycles (2 years)'''
−
 
 
===References===
 
===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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17876014 PubMed]
 
#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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17876014 PubMed]
−
 
 
==Bevacizumab & Interferon alfa-2a {{#subobject:808d58|Regimen=1}}==
 
==Bevacizumab & Interferon alfa-2a {{#subobject:808d58|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 356: Line 299:
 
|}
 
|}
 
===Regimen variant #1, 1 year of interferon {{#subobject:dbebac|Variant=1}}===
 
===Regimen variant #1, 1 year of interferon {{#subobject:dbebac|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
Line 373: Line 316:
 
''Note: Timing below reflects starting treatment on a Monday.''
 
''Note: Timing below reflects starting treatment on a Monday.''
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
 
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
−
 
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Interferon alfa-2a (Roferon-A)]] as follows:
 
*[[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)  
 
**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'''
 
'''14-day cycles'''
−
 
 
====Dose modifications====
 
====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
 
*[[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}}===
 
===Regimen variant #2, indefinite {{#subobject:d136cc|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
Line 409: Line 347:
 
''Note: Timing below reflects starting treatment on a Monday.''
 
''Note: Timing below reflects starting treatment on a Monday.''
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
 
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
−
 
 
====Immunotherapy====
 
====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)
 
*[[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'''
 
'''14-day cycles'''
−
 
 
====Dose modifications====
 
====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
 
*[[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===
 
===References===
−
 
 
#'''AVOREN:''' Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007 Dec 22;370(9605):2103-11. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61904-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/18156031 PubMed] NCT00738530
 
#'''AVOREN:''' Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007 Dec 22;370(9605):2103-11. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61904-7/fulltext link to original article] [https://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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20368553 PubMed]
 
##'''Update:''' Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, Sneller V. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010 May 1;28(13):2144-50. Epub 2010 Apr 5. [https://doi.org/10.1200/jco.2009.26.7849 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20368553 PubMed]
Line 428: Line 359:
 
##'''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]
 
##'''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 protocol''' [https://pubmed.ncbi.nlm.nih.gov/24297945 PubMed] NCT00631371
 
#'''INTORACT:''' Rini BI, Bellmunt J, Clancy J, Wang K, Niethammer AG, Hariharan S, Escudier B. Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol. 2014 Mar 10;32(8):752-9. Epub 2013 Dec 2. [https://doi.org/10.1200/JCO.2013.50.5305 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24297945 PubMed] NCT00631371
−
 
 
==Cabozantinib monotherapy {{#subobject:e3ff16|Regimen=1}}==
 
==Cabozantinib monotherapy {{#subobject:e3ff16|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 439: Line 369:
 
|-
 
|-
 
|}
 
|}
−
{| 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
Line 455: Line 385:
 
''<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.''
 
''<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====
 
====Targeted therapy====
−
 
 
*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 60 mg PO once per day
 
*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 60 mg PO once per day
−
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
−
 
 
===References===
 
===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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455807/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28199818 PubMed] NCT01835158
 
#'''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 verified protocol''' [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/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057479/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29550566 PubMed]
 
##'''Update:''' Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, Walsh M, Olencki T, Picus J, Small EJ, Dakhil S, Feldman DR, Mangeshkar M, Scheffold C, George D, Morris MJ. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer. 2018 May;94:115-125. Epub 2018 Mar 20. [https://www.ejcancer.com/article/S0959-8049(18)30181-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057479/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29550566 PubMed]
−
 
 
==Cabozantinib & Nivolumab {{#subobject:e3igp6|Regimen=1}}==
 
==Cabozantinib & Nivolumab {{#subobject:e3igp6|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 475: Line 400:
 
|-
 
|-
 
|}
 
|}
−
{| 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
Line 490: Line 415:
 
|}
 
|}
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 40 mg PO once per day
 
*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 40 mg PO once per day
−
 
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Nivolumab (Opdivo)]] as follows:
 
*[[Nivolumab (Opdivo)]] as follows:
 
**Cycles 1 to 52: 240 mg IV over 30 minutes once on day 1
 
**Cycles 1 to 52: 240 mg IV over 30 minutes once on day 1
−
 
 
'''14-day cycles'''
 
'''14-day cycles'''
−
 
 
===Regimen variant #2, monthly nivolumab {{#subobject:aj9iya|Variant=1}}===
 
===Regimen variant #2, monthly nivolumab {{#subobject:aj9iya|Variant=1}}===
 
{| class="wikitable" style="color:white; background-color:#404040"
 
{| class="wikitable" style="color:white; background-color:#404040"
Line 507: Line 427:
 
''Note: this dosing does not appear to have been used in a trial, but is recommended by the FDA.''
 
''Note: this dosing does not appear to have been used in a trial, but is recommended by the FDA.''
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 40 mg PO once per day
 
*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 40 mg PO once per day
−
 
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Nivolumab (Opdivo)]] as follows:
 
*[[Nivolumab (Opdivo)]] as follows:
 
**Cycles 1 to 26: 480 mg IV over 30 minutes once on day 1
 
**Cycles 1 to 26: 480 mg IV over 30 minutes once on day 1
−
 
 
'''28-day cycles'''
 
'''28-day cycles'''
−
 
 
===References===
 
===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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33657295/ PubMed] NCT03141177
 
#'''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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33657295/ PubMed] NCT03141177
−
 
 
==Erlotinib & Bevacizumab {{#subobject:1a1b7b|Regimen=1}}==
 
==Erlotinib & Bevacizumab {{#subobject:1a1b7b|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 527: Line 440:
 
|}
 
|}
 
===Regimen {{#subobject:1e7b71|Variant=1}}===
 
===Regimen {{#subobject:1e7b71|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
Line 542: Line 455:
 
|}
 
|}
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Erlotinib (Tarceva)]] 150 mg PO once per day
 
*[[Erlotinib (Tarceva)]] 150 mg PO once per day
 
*[[Bevacizumab (Avastin)]] 10 mg/kg IV over 90 minutes once on day 1
 
*[[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
 
**Can subsequently be reduced to 60 and 30 minute infusions as tolerated
−
 
 
'''14-day cycle for up to 52 cycles (2 years)'''
 
'''14-day cycle for up to 52 cycles (2 years)'''
−
 
 
===References===
 
===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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17876014 PubMed]
 
#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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17876014 PubMed]
−
 
 
==Everolimus monotherapy {{#subobject:b3af63|Regimen=1}}==
 
==Everolimus monotherapy {{#subobject:b3af63|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 559: Line 467:
 
|}
 
|}
 
===Regimen {{#subobject:474ade|Variant=1}}===
 
===Regimen {{#subobject:474ade|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
Line 566: Line 474:
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
 
|2009-2011
 
|2009-2011
 
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
Line 587: Line 495:
 
''Note: ASPEN should not be confused with the trial by the same name in Waldenström macroglobulinemia.''
 
''Note: ASPEN should not be confused with the trial by the same name in Waldenström macroglobulinemia.''
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Everolimus (Afinitor)]] 10 mg PO once per day
 
*[[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
 
**Dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability
−
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
 
====Subsequent treatment====
 
====Subsequent treatment====
−
 
 
*RECORD-3, upon progression: [[#Sunitinib_monotherapy_3|Sunitinib]]
 
*RECORD-3, upon progression: [[#Sunitinib_monotherapy_3|Sunitinib]]
−
 
 
===References===
 
===References===
−
<!-- # '''Abstract:''' Robert John Motzer, Carlos H. Barrios, Tae Min Kim, Silvia Falcon, Thomas Cosgriff, W. Graydon Harker, Kenneth B. Pittman, Roberto Sabbatini, Sun Young Rha, Thomas W. Flaig, Ray D. Page, Sevil E. Bavbek, J. Thaddeus Beck, Poulam M Patel, Edward Schiff, Alexandra Vaury, Julie Niolat, Sven Gogov, Ozlem Anak, Jennifer Knox. Record-3: Phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC). 2013 ASCO Annual Meeting abstract 4504. [http://meetinglibrary.asco.org/content/113103-132 link to abstract] -->
 
  
−
#'''RECORD-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [https://doi.org/10.1200/jco.2013.54.6911 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25049330 PubMed] NCT00903175
+
#'''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
 
#'''ESPN:''' Tannir NM, Jonasch E, Albiges L, Altinmakas E, Ng CS, Matin SF, Wang X, Qiao W, Dubauskas Lim Z, Tamboli P, Rao P, Sircar K, Karam JA, McDermott DF, Wood CG, Choueiri TK. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol. 2016 May;69(5):866-74. Epub 2015 Nov 26. [http://www.europeanurology.com/article/S0302-2838(15)01083-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879109/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26626617 PubMed] NCT01185366
 
#'''ESPN:''' Tannir NM, Jonasch E, Albiges L, Altinmakas E, Ng CS, Matin SF, Wang X, Qiao W, Dubauskas Lim Z, Tamboli P, Rao P, Sircar K, Karam JA, McDermott DF, Wood CG, Choueiri TK. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol. 2016 May;69(5):866-74. Epub 2015 Nov 26. [http://www.europeanurology.com/article/S0302-2838(15)01083-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879109/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26626617 PubMed] NCT01185366
 
#'''ASPEN:''' Armstrong AJ, Halabi S, Eisen T, Broderick S, Stadler WM, Jones RJ, Garcia JA, Vaishampayan UN, Picus J, Hawkins RE, Hainsworth JD, Kollmannsberger CK, Logan TF, Puzanov I, Pickering LM, Ryan CW, Protheroe A, Lusk CM, Oberg S, George DJ. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016 Mar;17(3):378-88. Epub 2016 Jan 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00515-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/26794930 PubMed] NCT01108445
 
#'''ASPEN:''' Armstrong AJ, Halabi S, Eisen T, Broderick S, Stadler WM, Jones RJ, Garcia JA, Vaishampayan UN, Picus J, Hawkins RE, Hainsworth JD, Kollmannsberger CK, Logan TF, Puzanov I, Pickering LM, Ryan CW, Protheroe A, Lusk CM, Oberg S, George DJ. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016 Mar;17(3):378-88. Epub 2016 Jan 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00515-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/26794930 PubMed] NCT01108445
−
 
 
==Everolimus & Lenvatinib {{#subobject:e83gac|Regimen=1}}==
 
==Everolimus & Lenvatinib {{#subobject:e83gac|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 609: Line 511:
 
|}
 
|}
 
===Regimen {{#subobject:22bc4d|Variant=1}}===
 
===Regimen {{#subobject:22bc4d|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
Line 627: Line 529:
 
|}
 
|}
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Everolimus (Afinitor)]] 5 mg PO once per day
 
*[[Everolimus (Afinitor)]] 5 mg PO once per day
 
*[[Lenvatinib (Lenvima)]] 18 mg PO once per day
 
*[[Lenvatinib (Lenvima)]] 18 mg PO once per day
−
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
 
===References===
 
===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://www.nejm.org/doi/full/10.1056/NEJMoa2035716 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33616314/ PubMed] NCT02811861
 
#'''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://www.nejm.org/doi/full/10.1056/NEJMoa2035716 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33616314/ PubMed] NCT02811861
−
 
 
==Gemcitabine & Sunitinib {{#subobject:ec76af|Regimen=1}}==
 
==Gemcitabine & Sunitinib {{#subobject:ec76af|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 643: Line 540:
 
|}
 
|}
 
===Regimen variant #1 {{#subobject:py1|Variant=1}}===
 
===Regimen variant #1 {{#subobject:py1|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"
 
! style="width: 33%" |Study
 
! style="width: 33%" |Study
 
! style="width: 33%" |Years of enrollment
 
! style="width: 33%" |Years of enrollment
Line 654: Line 551:
 
|}
 
|}
 
====Chemotherapy====
 
====Chemotherapy====
−
 
 
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
 
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Sunitinib (Sutent)]] 37.5 mg PO once per day on days 1 to 14
 
*[[Sunitinib (Sutent)]] 37.5 mg PO once per day on days 1 to 14
−
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
 
===Regimen variant #2 {{#subobject:e9a6b9|Variant=1}}===
 
===Regimen variant #2 {{#subobject:e9a6b9|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"
 
! style="width: 50%" |Study
 
! style="width: 50%" |Study
 
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
Line 673: Line 565:
 
|}
 
|}
 
====Chemotherapy====
 
====Chemotherapy====
−
 
 
*[[Gemcitabine (Gemzar)]] 750 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1 & 8
 
*[[Gemcitabine (Gemzar)]] 750 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1 & 8
−
 
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Sunitinib (Sutent)]] 37.5 mg PO once per day on days 2 to 15
 
*[[Sunitinib (Sutent)]] 37.5 mg PO once per day on days 2 to 15
−
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
 
===References===
 
===References===
−
 
 
#'''Retrospective:''' Pandya SS, Mier JW, McDermott DF, Cho DC. Addition of gemcitabine at the time of sunitinib resistance in metastatic renal cell cancer. BJU Int. 2011 Oct;108(8 Pt 2):E245-9. Epub 2011 Feb 14. [https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2011.10096.x/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21320274 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://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2011.10096.x/full link to original article] '''contains verified protocol''' [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://onlinelibrary.wiley.com/doi/10.1002/cncr.29503/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/26058385 PubMed] NCT00556049
 
#'''MGH 07-212:''' Michaelson MD, McKay RR, Werner L, Atkins MB, Van Allen EM, Olivier KM, Song J, Signoretti S, McDermott DF, Choueiri TK. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer. 2015 Oct 1;121(19):3435-43. Epub 2015 Jun 8. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.29503/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/26058385 PubMed] NCT00556049
−
 
 
==High-dose Interleukin-2 {{#subobject:d95f4e|Regimen=1}}==
 
==High-dose Interleukin-2 {{#subobject:d95f4e|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 694: Line 579:
 
HD IL-2: '''<u>H</u>'''igh-'''<u>D</u>'''ose '''<u>I</u>'''nter'''<u>L</u>'''eukin-'''<u>2</u>'''
 
HD IL-2: '''<u>H</u>'''igh-'''<u>D</u>'''ose '''<u>I</u>'''nter'''<u>L</u>'''eukin-'''<u>2</u>'''
 
===Example orders===
 
===Example orders===
−
 
 
*[[Example orders for High-dose (HD) IL-2 in renal cancer]]
 
*[[Example orders for High-dose (HD) IL-2 in renal cancer]]
−
 
 
===Regimen variant #1, 1.8 MU/kg/day, intermittent {{#subobject:ca472e|Variant=1}}===
 
===Regimen variant #1, 1.8 MU/kg/day, intermittent {{#subobject:ca472e|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
Line 705: Line 588:
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://jamanetwork.com/journals/jama/article-abstract/368156 Rosenberg et al. 1994]
+
|[https://jamanetwork.com/journals/jama/article-abstract/368156 Rosenberg et al. 1994]
 
|1985-1992
 
|1985-1992
 
| style="background-color:#91cf61" |Non-randomized
 
| style="background-color:#91cf61" |Non-randomized
Line 725: Line 608:
 
|}
 
|}
 
====Immunotherapy====
 
====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
 
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 600,000 units/kg IV every 8 hours for up to 14 doses per week, on days 1 to 5, 15 to 19
−
 
 
====Supportive medications====
 
====Supportive medications====
−
 
 
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10, 15 to 24
 
*[[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
 
*All antihypertensive therapy discontinued at least 24 hours before each cycle
Line 738: Line 618:
 
*[[Meperidine (Demerol)]] 25 to 50 mg PO every 6 hours for chills and rigors
 
*[[Meperidine (Demerol)]] 25 to 50 mg PO every 6 hours for chills and rigors
 
*"An antidiarrheal agent, antiemetics, anxiolytics, diuretics, and vasopressors as needed"
 
*"An antidiarrheal agent, antiemetics, anxiolytics, diuretics, and vasopressors as needed"
−
 
 
'''28-day cycle for up to 3 cycles'''
 
'''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}}===
 
===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;"  
+
{| 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
Line 761: Line 639:
 
''Note: reported efficacy is based on the 2003 update.''
 
''Note: reported efficacy is based on the 2003 update.''
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours for up to 15 doses
 
*[[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
 
**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'''
 
'''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}}===
 
===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;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"
 
! style="width: 50%" |Study
 
! style="width: 50%" |Study
 
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
Line 777: Line 652:
 
|}
 
|}
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours for up to 12 doses (reduced from originally up to 15 doses due to few patients tolerating 15 doses)
 
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours for up to 12 doses (reduced from originally up to 15 doses due to few patients tolerating 15 doses)
 
**Then after 10 to 15 days of rest, [[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours for up to 12 doses is given again
 
**Then after 10 to 15 days of rest, [[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours for up to 12 doses is given again
−
 
 
====Supportive medications====
 
====Supportive medications====
−
 
 
*"Routine administration of antipyretics, anti-inflammatories, antiemetics, antidiarrheals, and H2 antagonists."
 
*"Routine administration of antipyretics, anti-inflammatories, antiemetics, antidiarrheals, and H2 antagonists."
−
 
 
====Subsequent treatment====
 
====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)
 
*After this one course of treatments--defined by the paper as "two cycles"--patients with stable to improved disease would receive additional courses of treatments every 2 months (no maximum number of courses listed)
−
 
 
===Regimen variant #4, 5 MU/m<sup>2</sup>/day, CI {{#subobject:bd04b6|Variant=1}}===
 
===Regimen variant #4, 5 MU/m<sup>2</sup>/day, CI {{#subobject:bd04b6|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
Line 805: Line 674:
 
|}
 
|}
 
====Immunotherapy====
 
====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>)
 
*[[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'''
 
'''8-week cycles'''
−
 
 
===References===
 
===References===
−
 
+
#Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994 Mar 23-30;271(12):907-13. [https://jamanetwork.com/journals/jama/article-abstract/368156 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8120958 PubMed]
−
#Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994 Mar 23-30;271(12):907-13. [http://jamanetwork.com/journals/jama/article-abstract/368156 link to original article] [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]
 
#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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12915604 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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12915604 PubMed]
Line 819: Line 684:
 
#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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15625368 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 verified protocol''' [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://onlinelibrary.wiley.com/doi/10.1002/cncr.23552/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486432/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18457330 PubMed]
 
#'''Retrospective:''' Klapper JA, Downey SG, Smith FO, Yang JC, Hughes MS, Kammula US, Sherry RM, Royal RE, Steinberg SM, Rosenberg S. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma : a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008 Jul 15;113(2):293-301. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.23552/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486432/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18457330 PubMed]
−
 
 
==Low-dose Interleukin-2 {{#subobject:a2e938|Regimen=1}}==
 
==Low-dose Interleukin-2 {{#subobject:a2e938|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 827: Line 691:
 
LD IL-2: '''<u>L</u>'''ow-'''<u>D</u>'''ose '''<u>I</u>'''nter'''<u>L</u>'''eukin-'''<u>2</u>'''
 
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}}===
 
===Regimen variant #1, Intravenous {{#subobject:445b6c|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
Line 846: Line 710:
 
''Note: efficacy is based on the 2003 update.''
 
''Note: efficacy is based on the 2003 update.''
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] as follows:
 
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] as follows:
 
**Week 1: 72,000 units/kg IV every 8 hours for up to 15 doses
 
**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
 
**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'''
 
'''8-week cycle for up to 2 cycles'''
−
 
 
===Regimen variant #2, Subcutaneous {{#subobject:cbb5b2|Variant=1}}===
 
===Regimen variant #2, Subcutaneous {{#subobject:cbb5b2|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
Line 873: Line 734:
 
''Note: this arm was added to the trial after the interim results were announced in 1994.''
 
''Note: this arm was added to the trial after the interim results were announced in 1994.''
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] as follows:
 
*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] as follows:
 
**Week 1: 250,000 units/kg SC once per day for 5 days
 
**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
 
**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'''
 
'''8-week cycle for up to 2 cycles'''
−
 
 
===References===
 
===References===
−
 
 
#Yang JC, Topalian SL, Parkinson D, Schwartzentruber DJ, Weber JS, Ettinghausen SE, White DE, Steinberg SM, Cole DJ, Kim HI, Levin R, Guleria A, MacFarlane MP, White RL, Einhorn JH, Seipp CA, Rosenberg SA. Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol. 1994 Aug;12(8):1572-6. [https://doi.org/10.1200/JCO.1994.12.8.1572 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8040669 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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12915604 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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12915604 PubMed]
−
 
 
==Interferon alfa-2a monotherapy {{#subobject:8f04d6|Regimen=1}}==
 
==Interferon alfa-2a monotherapy {{#subobject:8f04d6|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 891: Line 747:
 
|}
 
|}
 
===Regimen variant #1, 5 MU 5x per week {{#subobject:f49d4e|Variant=1}}===
 
===Regimen variant #1, 5 MU 5x per week {{#subobject:f49d4e|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
Line 906: Line 762:
 
|}
 
|}
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Interferon alfa-2a (Roferon-A)]] 5,000,000 units SC 5 times per week
 
*[[Interferon alfa-2a (Roferon-A)]] 5,000,000 units SC 5 times per week
−
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
−
 
 
===Regimen variant #2, 9 MU TIW {{#subobject:524ccc|Variant=1}}===
 
===Regimen variant #2, 9 MU TIW {{#subobject:524ccc|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
Line 953: Line 806:
 
''<sup>2</sup>Reported efficacy for CALGB 90206 is based on the 2010 update and is based on a stratified analysis.''
 
''<sup>2</sup>Reported efficacy for CALGB 90206 is based on the 2010 update and is based on a stratified analysis.''
 
====Immunotherapy====
 
====Immunotherapy====
−
 
+
*[[Interferon alfa-2a (Roferon-A)]] 9,000,000 units SC 3 times per week
−
*[[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
 
**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'''
 
'''Given for varying lengths of time; see individual trials'''
−
 
 
===Regimen variant #3, 9 MU daily, with lead-in {{#subobject:5f04fc|Variant=1}}===
 
===Regimen variant #3, 9 MU daily, with lead-in {{#subobject:5f04fc|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
Line 975: Line 825:
 
|}
 
|}
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Interferon alfa-2a (Roferon-A)]] as follows:
 
*[[Interferon alfa-2a (Roferon-A)]] as follows:
 
**Week 1: 3,000,000 units SC once per day
 
**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 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
 
**Week 3 onwards (if prior dose tolerated): 9,000,000 units SC once per day
−
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
−
 
 
===Regimen variant #4, 9 MU TIW, with lead-in {{#subobject:2c65a4|Variant=1}}===
 
===Regimen variant #4, 9 MU TIW, with lead-in {{#subobject:2c65a4|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
Line 999: Line 846:
 
|}
 
|}
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Interferon alfa-2a (Roferon-A)]] as follows:
 
*[[Interferon alfa-2a (Roferon-A)]] as follows:
 
**Week 1: 3,000,000 units SC 3 times per week
 
**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 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
 
**Week 3 onwards (if prior dose tolerated): 9,000,000 units SC 3 times per week
−
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
−
 
 
===Regimen variant #5, 10 MU TIW {{#subobject:800dd5|Variant=1}}===
 
===Regimen variant #5, 10 MU TIW {{#subobject:800dd5|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
Line 1,029: Line 873:
 
|}
 
|}
 
====Immunotherapy====
 
====Immunotherapy====
−
 
+
*[[Interferon alfa-2a (Roferon-A)]] 10,000,000 units SC 3 times per week
−
*[[Interferon alfa-2a (Roferon-A)]] 10,000,000 units SC 3 times per week  
 
 
**In MRC RE01, the first two doses were 5,000,000 units
 
**In MRC RE01, the first two doses were 5,000,000 units
−
 
 
'''12-week course (MRC RE01) or continued indefinitely (MRC RE04/EORTC GU 30012)'''
 
'''12-week course (MRC RE01) or continued indefinitely (MRC RE04/EORTC GU 30012)'''
−
 
 
===Regimen variant #6, 18 MU TIW, with lead-in {{#subobject:b28245|Variant=1}}===
 
===Regimen variant #6, 18 MU TIW, with lead-in {{#subobject:b28245|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
Line 1,060: Line 901:
 
|}
 
|}
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Interferon alfa-2a (Roferon-A)]] as follows:
 
*[[Interferon alfa-2a (Roferon-A)]] as follows:
 
**Week 1: 3,000,000 units SC 3 times per week
 
**Week 1: 3,000,000 units SC 3 times per week
Line 1,066: Line 906:
 
**Week 3 onwards (if prior dose tolerated): 18,000,000 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
 
***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'''
 
'''Continued indefinitely'''
−
 
 
===References===
 
===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]
 
#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 protocol''' [https://pubmed.ncbi.nlm.nih.gov/8750152 PubMed]
 
#Sagaster P, Micksche M, Flamm J, Ludwig H. Randomised study using IFN-alpha versus IFN-alpha plus coumarin and cimetidine for treatment of advanced renal cell cancer. Ann Oncol. 1995 Dec;6(10):999-1003. [https://doi.org/10.1093/oxfordjournals.annonc.a059097 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/8750152 PubMed]
Line 1,076: Line 913:
 
#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]
 
#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://www.nejm.org/doi/full/10.1056/NEJMoa065044 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17215529 PubMed] NCT00098657
 
#'''A618-1034:''' Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. [https://www.nejm.org/doi/full/10.1056/NEJMoa065044 link to original article] '''contains verified protocol''' [https://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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646307/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19487381 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 verified protocol''' [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://www.nejm.org/doi/full/10.1056/NEJMoa066838 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17538086 PubMed] NCT00065468
 
#'''ARCC:''' Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. [https://www.nejm.org/doi/full/10.1056/NEJMoa066838 link to original article] '''contains verified protocol''' [https://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://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61904-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/18156031 PubMed] NCT00738530
 
#'''AVOREN:''' Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007 Dec 22;370(9605):2103-11. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61904-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/18156031 PubMed] NCT00738530
Line 1,085: Line 922:
 
#'''MRC RE04/EORTC GU 30012:''' Gore ME, Griffin CL, Hancock B, Patel PM, Pyle L, Aitchison M, James N, Oliver RT, Mardiak J, Hussain T, Sylvester R, Parmar MK, Royston P, Mulders PF. Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial. Lancet. 2010 Feb 20;375(9715):641-8. Epub 2010 Feb 10. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61921-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835851/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20153039 PubMed] NCT00053820
 
#'''MRC RE04/EORTC GU 30012:''' Gore ME, Griffin CL, Hancock B, Patel PM, Pyle L, Aitchison M, James N, Oliver RT, Mardiak J, Hussain T, Sylvester R, Parmar MK, Royston P, Mulders PF. Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial. Lancet. 2010 Feb 20;375(9715):641-8. Epub 2010 Feb 10. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61921-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835851/ link to PMC article] '''contains verified protocol''' [https://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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26851187 PubMed] NCT00420888
 
#'''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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26851187 PubMed] NCT00420888
−
 
 
==Interferon alfa-2b monotherapy {{#subobject:6b5be6|Regimen=1}}==
 
==Interferon alfa-2b monotherapy {{#subobject:6b5be6|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 1,092: Line 928:
 
|}
 
|}
 
===Regimen {{#subobject:39f1ab|Variant=1}}===
 
===Regimen {{#subobject:39f1ab|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"
 
! style="width: 50%" |Study
 
! style="width: 50%" |Study
 
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
Line 1,105: Line 941:
 
''Of historic interest.''
 
''Of historic interest.''
 
====Preceding treatment====
 
====Preceding treatment====
−
 
 
*[[Surgery#Renal_cell_carcinoma_surgery|Nephrectomy]] versus no preceding treatment
 
*[[Surgery#Renal_cell_carcinoma_surgery|Nephrectomy]] versus no preceding treatment
−
 
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Interferon alfa-2b (Intron-A)]]
 
*[[Interferon alfa-2b (Intron-A)]]
−
 
 
===References===
 
===References===
−
 
 
#'''EORTC 30947:''' Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R; [[Study_Groups#EORTC|EORTC]] Genitourinary Group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001 Sep 22;358(9286):966-70. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06103-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/11583750 PubMed]
 
#'''EORTC 30947:''' Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R; [[Study_Groups#EORTC|EORTC]] Genitourinary Group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001 Sep 22;358(9286):966-70. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06103-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/11583750 PubMed]
 
#'''SWOG 8949:''' Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, Caton JR Jr, Munshi N, Crawford ED. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001 Dec 6;345(23):1655-9. [https://www.nejm.org/doi/full/10.1056/NEJMoa003013 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11759643 PubMed]
 
#'''SWOG 8949:''' Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, Caton JR Jr, Munshi N, Crawford ED. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001 Dec 6;345(23):1655-9. [https://www.nejm.org/doi/full/10.1056/NEJMoa003013 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11759643 PubMed]
 
#'''ECOG E2898:''' NCT00005966
 
#'''ECOG E2898:''' NCT00005966
−
 
 
==Ipilimumab & Nivolumab {{#subobject:7bc416|Regimen=1}}==
 
==Ipilimumab & Nivolumab {{#subobject:7bc416|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 1,124: Line 954:
 
|}
 
|}
 
===Regimen variant #1 {{#subobject:aa43c1|Variant=1}}===
 
===Regimen variant #1 {{#subobject:aa43c1|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
Line 1,141: Line 971:
 
''Note: while this is the dosing studied in CheckMate 214, it is not the FDA-recommended dosing.''
 
''Note: while this is the dosing studied in CheckMate 214, it is not the FDA-recommended dosing.''
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Ipilimumab (Yervoy)]] as follows:
 
*[[Ipilimumab (Yervoy)]] as follows:
 
**Cycles 1 to 4: 1 mg/kg IV over 30 minutes once on day 1
 
**Cycles 1 to 4: 1 mg/kg IV over 30 minutes once on day 1
 
*[[Nivolumab (Opdivo)]] 3 mg/kg IV over 60 minutes once on day 1
 
*[[Nivolumab (Opdivo)]] 3 mg/kg IV over 60 minutes once on day 1
−
 
 
'''21-day cycle for 4 cycles, then 14-day cycles'''
 
'''21-day cycle for 4 cycles, then 14-day cycles'''
−
 
 
===Regimen variant #2 {{#subobject:2fc613|Variant=1}}===
 
===Regimen variant #2 {{#subobject:2fc613|Variant=1}}===
 
{| class="wikitable" style="color:white; background-color:#404040"
 
{| class="wikitable" style="color:white; background-color:#404040"
Line 1,155: Line 982:
 
''Note: while this one of two FDA-recommended dosing options, we are not aware of any particular published trial using this dosing.''
 
''Note: while this one of two FDA-recommended dosing options, we are not aware of any particular published trial using this dosing.''
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Ipilimumab (Yervoy)]] as follows:
 
*[[Ipilimumab (Yervoy)]] as follows:
 
**Cycles 1 to 4: 1 mg/kg IV once on day 1, '''given second'''
 
**Cycles 1 to 4: 1 mg/kg IV once on day 1, '''given second'''
Line 1,161: Line 987:
 
**Cycles 1 to 4: 3 mg/kg IV once on day 1, '''given first'''
 
**Cycles 1 to 4: 3 mg/kg IV once on day 1, '''given first'''
 
**Cycle 5 onwards: 240 mg IV once on day 1
 
**Cycle 5 onwards: 240 mg IV once on day 1
−
 
 
'''21-day cycle for 4 cycles, then 14-day cycles'''
 
'''21-day cycle for 4 cycles, then 14-day cycles'''
−
 
 
===Regimen variant #3 {{#subobject:1d722d|Variant=1}}===
 
===Regimen variant #3 {{#subobject:1d722d|Variant=1}}===
 
{| class="wikitable" style="color:white; background-color:#404040"
 
{| class="wikitable" style="color:white; background-color:#404040"
Line 1,171: Line 995:
 
''Note: while this one of two FDA-recommended dosing options, we are not aware of any particular published trial using this dosing.''
 
''Note: while this one of two FDA-recommended dosing options, we are not aware of any particular published trial using this dosing.''
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Ipilimumab (Yervoy)]] as follows:
 
*[[Ipilimumab (Yervoy)]] as follows:
 
**Cycles 1 to 4: 1 mg/kg IV once on day 1, '''given second'''
 
**Cycles 1 to 4: 1 mg/kg IV once on day 1, '''given second'''
Line 1,177: Line 1,000:
 
**Cycles 1 to 4: 3 mg/kg IV once on day 1, '''given first'''
 
**Cycles 1 to 4: 3 mg/kg IV once on day 1, '''given first'''
 
**Cycle 5 onwards: 480 mg IV once on day 1
 
**Cycle 5 onwards: 480 mg IV once on day 1
−
 
 
'''21-day cycle for 4 cycles, then 28-day cycles'''
 
'''21-day cycle for 4 cycles, then 28-day cycles'''
−
 
 
===References===
 
===References===
−
 
 
#'''CheckMate 214:''' Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. Epub 2018 Mar 21. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712126 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29562145 PubMed] NCT02231749
 
#'''CheckMate 214:''' Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. Epub 2018 Mar 21. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712126 link to original article] '''contains verified protocol''' [https://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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30413-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/31427204 PubMed]
 
##'''Update:''' Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, Salman P, Escudier B, Beuselinck B, Amin A, Porta C, George S, Neiman V, Bracarda S, Tykodi SS, Barthélémy P, Leibowitz-Amit R, Plimack ER, Oosting SF, Redman B, Melichar B, Powles T, Nathan P, Oudard S, Pook D, Choueiri TK, Donskov F, Grimm MO, Gurney H, Heng DYC, Kollmannsberger CK, Harrison MR, Tomita Y, Duran I, Grünwald V, McHenry MB, Mekan S, Tannir NM; CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019 Oct;20(10):1370-1385. Epub 2019 Aug 16. Erratum in: Lancet Oncol. 2019 Aug 21. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30413-9/fulltext link to original article] [https://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] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7359377/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32661118/ 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] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7703447/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33246931/ 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
 
#'''PDIGREE:''' NCT03793166
 
#'''COSMIC-313:''' NCT03937219
 
#'''COSMIC-313:''' NCT03937219
−
 
 
==Lenvatinib & Pembrolizumab {{#subobject:e83gac|Regimen=1}}==
 
==Lenvatinib & Pembrolizumab {{#subobject:e83gac|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 1,195: Line 1,014:
 
|}
 
|}
 
===Regimen {{#subobject:22bc4d|Variant=1}}===
 
===Regimen {{#subobject:22bc4d|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
Line 1,213: Line 1,032:
 
|}
 
|}
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Lenvatinib (Lenvima)]] 20 mg PO once per day
 
*[[Lenvatinib (Lenvima)]] 20 mg PO once per day
−
 
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
−
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
 
===References===
 
===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://www.nejm.org/doi/full/10.1056/NEJMoa2035716 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33616314/ PubMed] NCT02811861
 
#'''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://www.nejm.org/doi/full/10.1056/NEJMoa2035716 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33616314/ PubMed] NCT02811861
−
 
 
==Pazopanib monotherapy {{#subobject:443024|Regimen=1}}==
 
==Pazopanib monotherapy {{#subobject:443024|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 1,232: Line 1,044:
 
|}
 
|}
 
===Regimen {{#subobject:d6c07c|Variant=1}}===
 
===Regimen {{#subobject:d6c07c|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
Line 1,275: Line 1,087:
 
|}
 
|}
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Pazopanib (Votrient)]] 800 mg PO once per day, given 1 hour before or 2 hours after meals
 
*[[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
 
**Dose may be decreased to 600 mg or 400 mg PO once per day depending on tolerability
−
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
−
 
 
===References===
 
===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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20008644 PubMed] NCT00244764
 
#'''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 verified protocol''' [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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20100962 PubMed] NCT00334282
 
#'''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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20100962 PubMed] NCT00334282
Line 1,290: Line 1,098:
 
#'''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
 
#'''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 protocol''' [https://pubmed.ncbi.nlm.nih.gov/27918762 PubMed] NCT01408004
 
#'''ROPETAR:''' Cirkel GA, Hamberg P, Sleijfer S, Loosveld OJL, Dercksen MW, Los M, Polee MB, van den Berkmortel F, Aarts MJ, Beerepoot LV, Groenewegen G, Lolkema MP, Tascilar M, Portielje JEA, Peters FPJ, Klümpen HJ, van der Noort V, Haanen JBAG, Voest EE; Dutch WIN-O Consortium. Alternating treatment with pazopanib and everolimus vs continuous pazopanib to delay disease progression in patients with metastatic clear cell renal cell cancer: the ROPETAR randomized clinical trial. JAMA Oncol. 2017 Apr 1;3(4):501-508. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2588465 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/27918762 PubMed] NCT01408004
−
 
 
==Pembrolizumab monotherapy {{#subobject:18jguz|Regimen=1}}==
 
==Pembrolizumab monotherapy {{#subobject:18jguz|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 1,297: Line 1,104:
 
|}
 
|}
 
===Regimen {{#subobject:ahgz17|Variant=1}}===
 
===Regimen {{#subobject:ahgz17|Variant=1}}===
−
{| class="wikitable sortable" style="width: 80%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
!style="width: 25%"|Study
 
!style="width: 25%"|Study
 
!style="width: 25%"|Years of enrollment
 
!style="width: 25%"|Years of enrollment
Line 1,311: Line 1,118:
 
''Note: this reference describes the clear cell cohort of KEYNOTE-427.''
 
''Note: this reference describes the clear cell cohort of KEYNOTE-427.''
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
−
 
 
'''21-day cycle for up to 36 cycles (2 years)'''
 
'''21-day cycle for up to 36 cycles (2 years)'''
−
 
 
===References===
 
===References===
 
#'''KEYNOTE-427:''' McDermott DF, Lee JL, Bjarnason GA, Larkin JMG, Gafanov RA, Kochenderfer MD, Jensen NV, Donskov F, Malik J, Poprach A, Tykodi SS, Alonso-Gordoa T, Cho DC, Geertsen PF, Climent Duran MA, DiSimone C, Silverman RK, Perini RF, Schloss C, Atkins MB. Open-Label, Single-Arm Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Clear Cell Renal Cell Carcinoma. J Clin Oncol. 2021 Mar 20;39(9):1020-1028. Epub 2021 Feb 2. [https://doi.org/10.1200/jco.20.02363 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/33529051/ PubMed] NCT02853344
 
#'''KEYNOTE-427:''' McDermott DF, Lee JL, Bjarnason GA, Larkin JMG, Gafanov RA, Kochenderfer MD, Jensen NV, Donskov F, Malik J, Poprach A, Tykodi SS, Alonso-Gordoa T, Cho DC, Geertsen PF, Climent Duran MA, DiSimone C, Silverman RK, Perini RF, Schloss C, Atkins MB. Open-Label, Single-Arm Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Clear Cell Renal Cell Carcinoma. J Clin Oncol. 2021 Mar 20;39(9):1020-1028. Epub 2021 Feb 2. [https://doi.org/10.1200/jco.20.02363 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/33529051/ PubMed] NCT02853344
−
 
 
==Regorafenib monotherapy {{#subobject:183793|Regimen=1}}==
 
==Regorafenib monotherapy {{#subobject:183793|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 1,325: Line 1,128:
 
|}
 
|}
 
===Regimen {{#subobject:a55057|Variant=1}}===
 
===Regimen {{#subobject:a55057|Variant=1}}===
−
{| class="wikitable sortable" style="width: 80%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
!style="width: 25%"|Study
 
!style="width: 25%"|Study
 
!style="width: 25%"|Years of enrollment
 
!style="width: 25%"|Years of enrollment
Line 1,338: Line 1,141:
 
|}
 
|}
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Regorafenib (Stivarga)]] 160 mg PO once per day on days 1 to 21, given while fasting or after a light meal
 
*[[Regorafenib (Stivarga)]] 160 mg PO once per day on days 1 to 21, given while fasting or after a light meal
−
 
 
'''28-day cycles'''
 
'''28-day cycles'''
−
 
 
===References===
 
===References===
−
 
 
#'''Bayer 11726:''' Eisen T, Joensuu H, Nathan PD, Harper PG, Wojtukiewicz MZ, Nicholson S, Bahl A, Tomczak P, Pyrhonen S, Fife K, Bono P, Boxall J, Wagner A, Jeffers M, Lin T, Quinn DI. Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial. Lancet Oncol. 2012 Oct;13(10):1055-62. Epub 2012 Sep 6. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70364-9/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22959186 PubMed] NCT00664326
 
#'''Bayer 11726:''' Eisen T, Joensuu H, Nathan PD, Harper PG, Wojtukiewicz MZ, Nicholson S, Bahl A, Tomczak P, Pyrhonen S, Fife K, Bono P, Boxall J, Wagner A, Jeffers M, Lin T, Quinn DI. Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial. Lancet Oncol. 2012 Oct;13(10):1055-62. Epub 2012 Sep 6. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70364-9/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22959186 PubMed] NCT00664326
−
 
 
==Sorafenib monotherapy {{#subobject:fe45b0|Regimen=1}}==
 
==Sorafenib monotherapy {{#subobject:fe45b0|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 1,353: Line 1,151:
 
|}
 
|}
 
===Regimen {{#subobject:90ba4d|Variant=1}}===
 
===Regimen {{#subobject:90ba4d|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
Line 1,411: Line 1,209:
 
''<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.''
 
''<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====
 
====Targeted therapy====
−
 
 
*[[Sorafenib (Nexavar)]] 400 mg PO twice per day
 
*[[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
 
**Can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity
−
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
 
====Subsequent treatment====
 
====Subsequent treatment====
 
*SWITCH-II, upon progression: [[#Pazopanib_monotherapy_2|Pazopanib]]
 
*SWITCH-II, upon progression: [[#Pazopanib_monotherapy_2|Pazopanib]]
−
 
 
===References===
 
===References===
−
 
 
#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
 
#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
 
#'''ARCCS:''' Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010 Mar 1;116(5):1272-80. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.24864/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/20082451 PubMed] NCT00111020
 
#'''ARCCS:''' Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010 Mar 1;116(5):1272-80. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.24864/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/20082451 PubMed] NCT00111020
Line 1,427: Line 1,221:
 
##'''Update:''' Hutson TE, Al-Shukri S, Stus VP, Lipatov ON, Shparyk Y, Bair AH, Rosbrook B, Andrews GI, Vogelzang NJ. Axitinib versus sorafenib in first-line metastatic renal cell carcinoma: Overall survival from a randomized phase III trial. Clin Genitourin Cancer. 2017 Feb;15(1):72-76. Epub 2016 May 27. [http://www.clinical-genitourinary-cancer.com/article/S1558-7673(16)30134-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/27498023 PubMed]
 
##'''Update:''' Hutson TE, Al-Shukri S, Stus VP, Lipatov ON, Shparyk Y, Bair AH, Rosbrook B, Andrews GI, Vogelzang NJ. Axitinib versus sorafenib in first-line metastatic renal cell carcinoma: Overall survival from a randomized phase III trial. Clin Genitourin Cancer. 2017 Feb;15(1):72-76. Epub 2016 May 27. [http://www.clinical-genitourinary-cancer.com/article/S1558-7673(16)30134-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/27498023 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 protocol''' [https://pubmed.ncbi.nlm.nih.gov/30529901/ PubMed] NCT01613846
 
#'''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 protocol''' [https://pubmed.ncbi.nlm.nih.gov/30529901/ PubMed] NCT01613846
−
#'''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
+
#'''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}}==
 
==Sunitinib monotherapy {{#subobject:b4a97a|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
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|}
 
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===Regimen {{#subobject:92e618|Variant=1}}===
 
===Regimen {{#subobject:92e618|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
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|31% (95% CI 27-34%)
 
|31% (95% CI 27-34%)
 
|-
 
|-
−
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
 
|2009-2011
 
|2009-2011
 
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
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''ASPEN should not be confused with the trial by the same name in Waldenström macroglobulinemia.''
 
''ASPEN should not be confused with the trial by the same name in Waldenström macroglobulinemia.''
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Sunitinib (Sutent)]] 50 mg PO once per day on days 1 to 28
 
*[[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
 
**Per some references, dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability
−
 
 
'''42-day cycles'''
 
'''42-day cycles'''
 
====Subsequent treatment====
 
====Subsequent treatment====
−
 
 
*SWITCH, upon progression: [[#Sorafenib_monotherapy_2|Sorafenib]]
 
*SWITCH, upon progression: [[#Sorafenib_monotherapy_2|Sorafenib]]
−
 
 
===References===
 
===References===
−
 
+
#'''A618-1034:''' Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. [https://www.nejm.org/doi/full/10.1056/NEJMoa065044 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17215529 PubMed] NCT00098657
−
#'''A618-1034:''' Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. [https://www.nejm.org/doi/full/10.1056/NEJMoa065044 link to original article] '''contains verified protocol''' [https://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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646307/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19487381 PubMed]
 
##'''Update:''' Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Aug 1;27(22):3584-90. Epub 2009 Jun 1. [https://doi.org/10.1200/jco.2008.20.1293 link to original article] '''contains verified protocol''' [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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970162-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19615940 PubMed] NCT00130897
 
#'''A618-1037:''' Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009 Aug;10(8):757-63. Epub 2009 Jul 15. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970162-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19615940 PubMed] NCT00130897
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##'''Update:''' Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med. 2014 May 1;370(18):1769-70. [https://www.nejm.org/doi/full/10.1056/NEJMc1400731 link to letter] [https://pubmed.ncbi.nlm.nih.gov/24785224 PubMed]
 
##'''Update:''' Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med. 2014 May 1;370(18):1769-70. [https://www.nejm.org/doi/full/10.1056/NEJMc1400731 link to letter] [https://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
 
#'''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
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<!-- # '''Abstract:''' Robert John Motzer, Carlos H. Barrios, Tae Min Kim, Silvia Falcon, Thomas Cosgriff, W. Graydon Harker, Kenneth B. Pittman, Roberto Sabbatini, Sun Young Rha, Thomas W. Flaig, Ray D. Page, Sevil E. Bavbek, J. Thaddeus Beck, Poulam M Patel, Edward Schiff, Alexandra Vaury, Julie Niolat, Sven Gogov, Ozlem Anak, Jennifer Knox. Record-3: Phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC). 2013 ASCO Annual Meeting abstract 4504. [http://meetinglibrary.asco.org/content/113103-132 link to abstract] -->
+
#'''RECORD-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [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
−
#'''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] [http://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/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/25952317 PubMed] NCT00732914
 
#'''SWITCH:''' Eichelberg C, Vervenne WL, De Santis M, Fischer von Weikersthal L, Goebell PJ, Lerchenmüller C, Zimmermann U, Bos MM, Freier W, Schirrmacher-Memmel S, Staehler M, Pahernik S, Los M, Schenck M, Flörcken A, van Arkel C, Hauswald K, Indorf M, Gottstein D, Michel MS. SWITCH: A Randomised, Sequential, Open-label Study to Evaluate the Efficacy and Safety of Sorafenib-sunitinib Versus Sunitinib-sorafenib in the Treatment of Metastatic Renal Cell Cancer. Eur Urol. 2015 Nov;68(5):837-47. Epub 2015 May 4. [https://www.europeanurology.com/article/S0302-2838(15)00319-X/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/25952317 PubMed] NCT00732914
 
#'''ESPN:''' Tannir NM, Jonasch E, Albiges L, Altinmakas E, Ng CS, Matin SF, Wang X, Qiao W, Dubauskas Lim Z, Tamboli P, Rao P, Sircar K, Karam JA, McDermott DF, Wood CG, Choueiri TK. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol. 2016 May;69(5):866-74. Epub 2015 Nov 26. [http://www.europeanurology.com/article/S0302-2838(15)01083-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879109/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26626617 PubMed] NCT01185366
 
#'''ESPN:''' Tannir NM, Jonasch E, Albiges L, Altinmakas E, Ng CS, Matin SF, Wang X, Qiao W, Dubauskas Lim Z, Tamboli P, Rao P, Sircar K, Karam JA, McDermott DF, Wood CG, Choueiri TK. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol. 2016 May;69(5):866-74. Epub 2015 Nov 26. [http://www.europeanurology.com/article/S0302-2838(15)01083-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879109/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26626617 PubMed] NCT01185366
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#'''CheckMate 214:''' Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. Epub 2018 Mar 21. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712126 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29562145 PubMed] NCT02231749
 
#'''CheckMate 214:''' Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. Epub 2018 Mar 21. [https://www.nejm.org/doi/full/10.1056/NEJMoa1712126 link to original article] '''contains verified protocol''' [https://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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30413-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/31427204 PubMed]
 
##'''Update:''' Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, Salman P, Escudier B, Beuselinck B, Amin A, Porta C, George S, Neiman V, Bracarda S, Tykodi SS, Barthélémy P, Leibowitz-Amit R, Plimack ER, Oosting SF, Redman B, Melichar B, Powles T, Nathan P, Oudard S, Pook D, Choueiri TK, Donskov F, Grimm MO, Gurney H, Heng DYC, Kollmannsberger CK, Harrison MR, Tomita Y, Duran I, Grünwald V, McHenry MB, Mekan S, Tannir NM; CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019 Oct;20(10):1370-1385. Epub 2019 Aug 16. Erratum in: Lancet Oncol. 2019 Aug 21. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30413-9/fulltext link to original article] [https://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] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7359377/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32661118/ 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] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7703447/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33246931/ 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://www.nejm.org/doi/10.1056/NEJMoa1803675 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/29860937 PubMed] NCT00930033
 
#'''CARMENA:''' Méjean A, Ravaud A, Thezenas S, Colas S, Beauval JB, Bensalah K, Geoffrois L, Thiery-Vuillemin A, Cormier L, Lang H, Guy L, Gravis G, Rolland F, Linassier C, Lechevallier E, Beisland C, Aitchison M, Oudard S, Patard JJ, Theodore C, Chevreau C, Laguerre B, Hubert J, Gross-Goupil M, Bernhard JC, Albiges L, Timsit MO, Lebret T, Escudier B. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018 Aug 2;379(5):417-427. Epub 2018 Jun 3. [https://www.nejm.org/doi/10.1056/NEJMoa1803675 link to original article] '''contains protocol''' [https://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://www.nejm.org/doi/full/10.1056/NEJMoa1816047 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716603/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30779531/ PubMed] NCT02684006
 
#'''JAVELIN Renal 101:''' Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M, Lee JL, Vasiliev A, Miller WH Jr, Gurney H, Schmidinger M, Larkin J, Atkins MB, Bedke J, Alekseev B, Wang J, Mariani M, Robbins PB, Chudnovsky A, Fowst C, Hariharan S, Huang B, di Pietro A, Choueiri TK. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1103-1115. Epub 2019 Feb 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1816047 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716603/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30779531/ PubMed] NCT02684006
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#'''IMmotion151:''' Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30723-8/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/31079938 PubMed] NCT02420821
 
#'''IMmotion151:''' Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30723-8/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/31079938 PubMed] NCT02420821
 
#'''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
 
#'''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
+
#'''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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33657295/ PubMed] NCT03141177
 
#'''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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33657295/ PubMed] NCT03141177
 
#'''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://www.nejm.org/doi/full/10.1056/NEJMoa2035716 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/33616314/ PubMed] NCT02811861
 
#'''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://www.nejm.org/doi/full/10.1056/NEJMoa2035716 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/33616314/ PubMed] NCT02811861
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#'''JS001-036-Ⅲ-RCC:''' NCT04394975
 
#'''JS001-036-Ⅲ-RCC:''' NCT04394975
 
#'''TQB2450-III-07:''' NCT04523272
 
#'''TQB2450-III-07:''' NCT04523272
−
 
 
==Temsirolimus monotherapy {{#subobject:8160ec|Regimen=1}}==
 
==Temsirolimus monotherapy {{#subobject:8160ec|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
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|}
 
|}
 
===Regimen {{#subobject:f56815|Variant=1}}===
 
===Regimen {{#subobject:f56815|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
Line 1,682: Line 1,468:
 
|}
 
|}
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Temsirolimus (Torisel)]] 25 mg IV over 30 minutes once on day 1
 
*[[Temsirolimus (Torisel)]] 25 mg IV over 30 minutes once on day 1
−
 
 
====Supportive medications====
 
====Supportive medications====
−
 
 
*[[Diphenhydramine (Benadryl)]] (or similar H1 blocker) 25 to 50 mg IV once on day 1; 30 minutes prior to [[Temsirolimus (Torisel)]]
 
*[[Diphenhydramine (Benadryl)]] (or similar H1 blocker) 25 to 50 mg IV once on day 1; 30 minutes prior to [[Temsirolimus (Torisel)]]
−
 
 
'''7-day cycles'''
 
'''7-day cycles'''
−
 
 
===References===
 
===References===
−
 
 
#'''ARCC:''' Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. [https://www.nejm.org/doi/full/10.1056/NEJMoa066838 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17538086 PubMed] NCT00065468
 
#'''ARCC:''' Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. [https://www.nejm.org/doi/full/10.1056/NEJMoa066838 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17538086 PubMed] NCT00065468
−
 
 
==Tivozanib monotherapy {{#subobject:f8qut0|Regimen=1}}==
 
==Tivozanib monotherapy {{#subobject:f8qut0|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
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|}
 
|}
 
===Regimen {{#subobject:1yga4d|Variant=1}}===
 
===Regimen {{#subobject:1yga4d|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
Line 1,716: Line 1,495:
 
|}
 
|}
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Tivozanib (Fotivda)]] 1.5 mg PO once per day on days 1 to 21
 
*[[Tivozanib (Fotivda)]] 1.5 mg PO once per day on days 1 to 21
−
 
 
'''28-day cycles'''
 
'''28-day cycles'''
−
 
 
===References===
 
===References===
−
 
 
#'''AV-951-09-902:''' Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, Tomczak P, Lyulko O, Alyasova A, Harza M, Kogan M, Alekseev BY, Sternberg CN, Szczylik C, Cella D, Ivanescu C, Krivoshik A, Strahs A, Esteves B, Berkenblit A, Hutson TE. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013 Oct 20;31(30):3791-9. Epub 2013 Sep 9. [https://doi.org/10.1200/JCO.2012.47.4940 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569677/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24019545 PubMed] NCT01030783
 
#'''AV-951-09-902:''' Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, Tomczak P, Lyulko O, Alyasova A, Harza M, Kogan M, Alekseev BY, Sternberg CN, Szczylik C, Cella D, Ivanescu C, Krivoshik A, Strahs A, Esteves B, Berkenblit A, Hutson TE. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013 Oct 20;31(30):3791-9. Epub 2013 Sep 9. [https://doi.org/10.1200/JCO.2012.47.4940 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569677/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24019545 PubMed] NCT01030783
−
 
 
=Metastatic disease, second-line=
 
=Metastatic disease, second-line=
 
==Axitinib monotherapy {{#subobject:832684|Regimen=1}}==
 
==Axitinib monotherapy {{#subobject:832684|Regimen=1}}==
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|[[#top|back to top]]
 
|[[#top|back to top]]
 
|}
 
|}
−
 
 
===Regimen {{#subobject:a48a96|Variant=1}}===
 
===Regimen {{#subobject:a48a96|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
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''<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.''
 
''<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.''
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Axitinib (Inlyta)]] as follows:
 
*[[Axitinib (Inlyta)]] as follows:
 
**Starting dose: 5 mg PO twice per day for at least 2 weeks
 
**Starting dose: 5 mg PO twice per day for at least 2 weeks
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**Then if tolerated and BP not greater than 150/90: 10 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
 
**Dose can be reduced to 2 to 3 mg PO twice per day if needed based on tolerability
−
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
−
 
 
===References===
 
===References===
−
 
 
#'''AXIS:''' Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011 Dec 3;378(9807):1931-9. Epub 2011 Nov 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961613-9/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22056247 PubMed] NCT00678392
 
#'''AXIS:''' Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011 Dec 3;378(9807):1931-9. Epub 2011 Nov 4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961613-9/fulltext link to original article] '''contains verified protocol''' [https://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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70093-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23598172 PubMed]
 
##'''Update:''' Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, Oudard S, Gore ME, Tarazi J, Hariharan S, Chen C, Rosbrook B, Kim S, Rini BI. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013 May;14(6):552-62. Epub 2013 Apr 15. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70093-7/fulltext link to original article] '''contains verified protocol''' [https://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]
 
##'''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}}==
 
==Bevacizumab monotherapy {{#subobject:dc7874|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
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|}
 
|}
 
===Regimen {{#subobject:24489f|Variant=1}}===
 
===Regimen {{#subobject:24489f|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
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|}
 
|}
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
 
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
−
 
 
'''14-day cycles'''
 
'''14-day cycles'''
−
 
 
===References===
 
===References===
−
 
 
#Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003 Jul 31;349(5):427-34. [https://www.nejm.org/doi/full/10.1056/NEJMoa021491 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275324/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/12890841 PubMed]
 
#Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003 Jul 31;349(5):427-34. [https://www.nejm.org/doi/full/10.1056/NEJMoa021491 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275324/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/12890841 PubMed]
−
 
 
==Cabozantinib monotherapy {{#subobject:pyr1|Regimen=1}}==
 
==Cabozantinib monotherapy {{#subobject:pyr1|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
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|-
 
|-
 
|}
 
|}
−
{| 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
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|}
 
|}
 
====Preceding treatment====
 
====Preceding treatment====
−
 
 
*VEGFR TKI, with progression
 
*VEGFR TKI, with progression
−
 
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 60 mg PO once per day
 
*[[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]
 
**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'''
 
'''Continued indefinitely'''
−
 
 
===References===
 
===References===
−
 
 
#'''METEOR:''' Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1814-23. Epub 2015 Sep 25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1510016 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26406150 PubMed] NCT01865747
 
#'''METEOR:''' Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1814-23. Epub 2015 Sep 25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1510016 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ link to PMC article] [https://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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30107-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/27279544 PubMed]
 
##'''Update:''' Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, Hammers HJ, Donskov F, Roth BJ, Peltola K, Lee JL, Heng DY, Schmidinger M, Agarwal N, Sternberg CN, McDermott DF, Aftab DT, Hessel C, Scheffold C, Schwab G, Hutson TE, Pal S, Motzer RJ; METEOR investigators. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):917-27. Epub 2016 Jun 5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30107-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/27279544 PubMed]
Line 1,841: Line 1,598:
 
#'''CONTACT-03:''' NCT04338269
 
#'''CONTACT-03:''' NCT04338269
 
#'''MK-6482-011:''' NCT04586231
 
#'''MK-6482-011:''' NCT04586231
−
 
 
==Everolimus monotherapy {{#subobject:893557|Regimen=1}}==
 
==Everolimus monotherapy {{#subobject:893557|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
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|}
 
|}
 
===Regimen {{#subobject:9d436d|Variant=1}}===
 
===Regimen {{#subobject:9d436d|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
Line 1,865: Line 1,621:
 
|0%
 
|0%
 
|-
 
|-
−
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
 
|2009-2011
 
|2009-2011
 
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
Line 1,926: Line 1,682:
 
''Note: 72% of patients in Checkmate 025 had anti-angiogenic therapy prior to progression.''
 
''Note: 72% of patients in Checkmate 025 had anti-angiogenic therapy prior to progression.''
 
====Preceding treatment====
 
====Preceding treatment====
−
 
 
*RECORD-1 & METEOR: VEGFR TKI, with progression
 
*RECORD-1 & METEOR: VEGFR TKI, with progression
 
*RECORD-3: [[#Sunitinib_monotherapy_2|Sunitinib]], with progression
 
*RECORD-3: [[#Sunitinib_monotherapy_2|Sunitinib]], with progression
−
 
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Everolimus (Afinitor)]] 10 mg PO once per day
 
*[[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
 
**Dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability
−
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
−
 
 
===References===
 
===References===
−
 
 
#'''RECORD-1:''' Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008 Aug 9;372(9637):449-56. Epub 2008 Jul 22. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2808%2961039-9/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/18653228 PubMed] NCT00410124
 
#'''RECORD-1:''' Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008 Aug 9;372(9637):449-56. Epub 2008 Jul 22. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2808%2961039-9/fulltext link to original article] '''contains verified protocol''' [https://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://onlinelibrary.wiley.com/doi/10.1002/cncr.25219/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20549832 PubMed]
 
##'''Update:''' Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A; RECORD-1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010 Sep 15;116(18):4256-65. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.25219/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20549832 PubMed]
−
<!-- # '''Abstract:''' Robert John Motzer, Carlos H. Barrios, Tae Min Kim, Silvia Falcon, Thomas Cosgriff, W. Graydon Harker, Kenneth B. Pittman, Roberto Sabbatini, Sun Young Rha, Thomas W. Flaig, Ray D. Page, Sevil E. Bavbek, J. Thaddeus Beck, Poulam M Patel, Edward Schiff, Alexandra Vaury, Julie Niolat, Sven Gogov, Ozlem Anak, Jennifer Knox. Record-3: Phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC). 2013 ASCO Annual Meeting abstract 4504. [http://meetinglibrary.asco.org/content/113103-132 link to abstract] -->
+
#'''RECORD-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [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
−
#'''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] [http://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://www.nejm.org/doi/full/10.1056/NEJMoa1510665 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26406148 PubMed] NCT01668784
 
#'''CheckMate 025:''' Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803-13. Epub 2015 Sep 25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1510665 link to original article] '''contains verified protocol''' [https://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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30125-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521044/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27283863 PubMed]
 
##'''HRQoL analysis:''' Cella D, Grünwald V, Nathan P, Doan J, Dastani H, Taylor F, Bennett B, DeRosa M, Berry S, Broglio K, Berghorn E, Motzer RJ. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):994-1003. Epub 2016 Jun 6. Erratum in: Lancet Oncol. 2016 Jul;17 (7):e270. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30125-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521044/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27283863 PubMed]
Line 1,956: Line 1,705:
 
#'''RECORD-4:''' Motzer RJ, Alyasova A, Ye D, Karpenko A, Li H, Alekseev B, Xie L, Kurteva G, Kowalyszyn R, Karyakin O, Neron Y, Cosgriff T, Collins L, Brechenmacher T, Lin C, Morgan L, Yang L. Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4). Ann Oncol. 2016 Mar;27(3):441-8. Epub 2015 Dec 17. [https://doi.org/10.1093/annonc/mdv612 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006123/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/26681676 PubMed] NCT01491672
 
#'''RECORD-4:''' Motzer RJ, Alyasova A, Ye D, Karpenko A, Li H, Alekseev B, Xie L, Kurteva G, Kowalyszyn R, Karyakin O, Neron Y, Cosgriff T, Collins L, Brechenmacher T, Lin C, Morgan L, Yang L. Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4). Ann Oncol. 2016 Mar;27(3):441-8. Epub 2015 Dec 17. [https://doi.org/10.1093/annonc/mdv612 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006123/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/26681676 PubMed] NCT01491672
 
#'''CONCEPT:''' NCT03095040
 
#'''CONCEPT:''' NCT03095040
−
 
 
==Everolimus & Lenvatinib {{#subobject:21039d|Regimen=1}}==
 
==Everolimus & Lenvatinib {{#subobject:21039d|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 1,963: Line 1,711:
 
|}
 
|}
 
===Regimen {{#subobject:71ef67|Variant=1}}===
 
===Regimen {{#subobject:71ef67|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
Line 1,982: Line 1,730:
 
''Patients had progressed after [[:Category:VEGFR_inhibitors|VEGFR TKI]] treatment.''
 
''Patients had progressed after [[:Category:VEGFR_inhibitors|VEGFR TKI]] treatment.''
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Everolimus (Afinitor)]] 5 mg PO once per day
 
*[[Everolimus (Afinitor)]] 5 mg PO once per day
 
*[[Lenvatinib (Lenvima)]] 18 mg PO once per day
 
*[[Lenvatinib (Lenvima)]] 18 mg PO once per day
−
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
−
 
 
===References===
 
===References===
−
 
 
#'''E7080-G000-205:''' Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26482279 PubMed] NCT01136733
 
#'''E7080-G000-205:''' Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext link to original article] '''contains verified protocol''' [https://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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00543-4/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/26758760 PubMed]
 
##'''Update:''' Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 Jan;17(1):e4-5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00543-4/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/26758760 PubMed]
−
 
 
==Lenvatinib monotherapy {{#subobject:PYR3|Regimen=1}}==
 
==Lenvatinib monotherapy {{#subobject:PYR3|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 1,999: Line 1,742:
 
|}
 
|}
 
===Regimen {{#subobject:PYV3|Variant=1}}===
 
===Regimen {{#subobject:PYV3|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
Line 2,017: Line 1,760:
 
|}
 
|}
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Lenvatinib (Lenvima)]] 24 mg PO once per day
 
*[[Lenvatinib (Lenvima)]] 24 mg PO once per day
−
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
−
 
 
===References===
 
===References===
−
 
 
#'''E7080-G000-205:''' Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26482279 PubMed] NCT01136733
 
#'''E7080-G000-205:''' Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext link to original article] '''contains verified protocol''' [https://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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00543-4/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/26758760 PubMed]
 
##'''Update:''' Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 Jan;17(1):e4-5. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00543-4/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/26758760 PubMed]
−
 
 
==Nivolumab monotherapy {{#subobject:pyr2|Regimen=1}}==
 
==Nivolumab monotherapy {{#subobject:pyr2|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 2,033: Line 1,771:
 
|}
 
|}
 
===Regimen variant #1, 0.3 mg/kg q3wk {{#subobject:6d0807|Variant=1}}===
 
===Regimen variant #1, 0.3 mg/kg q3wk {{#subobject:6d0807|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
Line 2,048: Line 1,786:
 
|}
 
|}
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Nivolumab (Opdivo)]] 0.3 mg/kg IV once on day 1
 
*[[Nivolumab (Opdivo)]] 0.3 mg/kg IV once on day 1
−
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
 
===Regimen variant #2, 2 mg/kg q3wk {{#subobject:e0b43a|Variant=1}}===
 
===Regimen variant #2, 2 mg/kg q3wk {{#subobject:e0b43a|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
Line 2,069: Line 1,804:
 
|}
 
|}
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Nivolumab (Opdivo)]] 2 mg/kg IV once on day 1
 
*[[Nivolumab (Opdivo)]] 2 mg/kg IV once on day 1
−
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
 
===Regimen variant #3, 3 mg/kg q2wk {{#subobject:pyv2|Variant=1}}===
 
===Regimen variant #3, 3 mg/kg q2wk {{#subobject:pyv2|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
Line 2,094: Line 1,826:
 
|}
 
|}
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Nivolumab (Opdivo)]] 3 mg/kg IV over 60 minutes once on day 1
 
*[[Nivolumab (Opdivo)]] 3 mg/kg IV over 60 minutes once on day 1
 
**Notably, on 9/13/16 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
 
**Notably, on 9/13/16 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
−
 
 
'''14-day cycles'''
 
'''14-day cycles'''
−
 
 
===Regimen variant #4, 10 mg/kg q3wk {{#subobject:6f2515|Variant=1}}===
 
===Regimen variant #4, 10 mg/kg q3wk {{#subobject:6f2515|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
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|}
 
|}
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Nivolumab (Opdivo)]] 10 mg/kg IV once on day 1
 
*[[Nivolumab (Opdivo)]] 10 mg/kg IV once on day 1
−
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
 
===Regimen variant #5, 240 mg q2wk {{#subobject:6fagc5|Variant=1}}===
 
===Regimen variant #5, 240 mg q2wk {{#subobject:6fagc5|Variant=1}}===
−
{| class="wikitable sortable" 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
Line 2,133: Line 1,859:
 
|}
 
|}
 
====Immunotherapy====
 
====Immunotherapy====
−
 
 
*[[Nivolumab (Opdivo)]] 240 mg IV once on day 1
 
*[[Nivolumab (Opdivo)]] 240 mg IV once on day 1
−
 
 
'''14-day cycles'''
 
'''14-day cycles'''
−
 
 
===References===
 
===References===
−
 
 
#'''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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25452452 PubMed] NCT01354431
 
#'''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 verified protocol''' [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://www.nejm.org/doi/full/10.1056/NEJMoa1510665 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26406148 PubMed] NCT01668784
 
#'''CheckMate 025:''' Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803-13. Epub 2015 Sep 25. [https://www.nejm.org/doi/full/10.1056/NEJMoa1510665 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26406148 PubMed] NCT01668784
Line 2,147: Line 1,869:
 
##'''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]
 
##'''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]
 
#'''CheckMate 374:''' McFarlane JJ, Kochenderfer MD, Olsen MR, Bauer TM, Molina A, Hauke RJ, Reeves JA, Babu S, Van Veldhuizen P, Somer B, Gunuganti V, Schnadig I, George S, Page RD, Arrowsmith E, Jain RK, Zhang J, McHenry MB, Johansen JL, Vogelzang NJ. Safety and Efficacy of Nivolumab in Patients With Advanced Clear Cell Renal Cell Carcinoma: Results From the Phase IIIb/IV CheckMate 374 Study. Clin Genitourin Cancer. 2020 Dec;18(6):469-476.e4. Epub 2020 Jun 14. [https://doi.org/10.1016/j.clgc.2020.06.002 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/32641261/ PubMed] NCT02596035
 
#'''CheckMate 374:''' McFarlane JJ, Kochenderfer MD, Olsen MR, Bauer TM, Molina A, Hauke RJ, Reeves JA, Babu S, Van Veldhuizen P, Somer B, Gunuganti V, Schnadig I, George S, Page RD, Arrowsmith E, Jain RK, Zhang J, McHenry MB, Johansen JL, Vogelzang NJ. Safety and Efficacy of Nivolumab in Patients With Advanced Clear Cell Renal Cell Carcinoma: Results From the Phase IIIb/IV CheckMate 374 Study. Clin Genitourin Cancer. 2020 Dec;18(6):469-476.e4. Epub 2020 Jun 14. [https://doi.org/10.1016/j.clgc.2020.06.002 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/32641261/ PubMed] NCT02596035
−
 
 
==Pazopanib monotherapy {{#subobject:443024|Regimen=1}}==
 
==Pazopanib monotherapy {{#subobject:443024|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 2,154: Line 1,875:
 
|}
 
|}
 
===Regimen {{#subobject:d6c07c|Variant=1}}===
 
===Regimen {{#subobject:d6c07c|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
Line 2,189: Line 1,910:
 
|}
 
|}
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Pazopanib (Votrient)]] 800 mg PO once per day, given 1 hour before or 2 hours after meals
 
*[[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
 
**Dose may be decreased to 600 mg or 400 mg PO once per day depending on tolerability
−
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
−
 
 
===References===
 
===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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20008644 PubMed] NCT00244764
 
#'''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 verified protocol''' [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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20100962 PubMed] NCT00334282
 
#'''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 verified protocol''' [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/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23321547 PubMed]
 
##'''Update:''' Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, Zarba JJ, Gladkov OA, Lee E, Szczylik C, McCann L, Rubin SD, Chen M, Davis ID. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013 Apr;49(6):1287-96. Epub 2013 Jan 12. [https://www.ejcancer.com/article/S0959-8049(12)00980-X/fulltext link to original article] '''contains verified protocol''' [https://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/abstract link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23665131 PubMed]
 
#Hainsworth JD, Rubin MS, Arrowsmith ER, Khatcheressian J, Crane EJ, Franco LA. Pazopanib as second-line treatment after sunitinib or bevacizumab in patients with advanced renal cell carcinoma: a Sarah Cannon Oncology Research Consortium phase II trial. Clin Genitourin Cancer. 2013 Sep;11(3):270-5. Epub 2013 May 9. [http://www.clinical-genitourinary-cancer.com/article/S1558-7673(13)00052-9/abstract link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23665131 PubMed]
−
 
 
==Sorafenib monotherapy {{#subobject:6e18d8|Regimen=1}}==
 
==Sorafenib monotherapy {{#subobject:6e18d8|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 2,208: Line 1,924:
 
|}
 
|}
 
===Regimen {{#subobject:a50d71|Variant=1}}===
 
===Regimen {{#subobject:a50d71|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
Line 2,262: Line 1,978:
 
''Note that TARGET should not be confused with the study by the same name in breast cancer.''
 
''Note that TARGET should not be confused with the study by the same name in breast cancer.''
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Sorafenib (Nexavar)]] 400 mg PO twice per day
 
*[[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
 
**Can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity
−
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
−
 
 
===References===
 
===References===
−
 
 
#'''TARGET:''' Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):125-34. Erratum in: N Engl J Med. 2007 Jul 12;357(2):203. [https://www.nejm.org/doi/full/10.1056/NEJMoa060655 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17215530 PubMed] NCT00073307
 
#'''TARGET:''' Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):125-34. Erratum in: N Engl J Med. 2007 Jul 12;357(2):203. [https://www.nejm.org/doi/full/10.1056/NEJMoa060655 link to original article] '''contains verified protocol''' [https://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]
 
##'''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]
Line 2,279: Line 1,991:
 
##'''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]
 
##'''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 protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569683/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24297950 PubMed] NCT00474786
 
#'''INTORSECT:''' Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, Senico P, Niethammer A, Lu DR, Hariharan S, Motzer RJ. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Mar 10;32(8):760-7. Epub 2013 Dec 2. [https://doi.org/10.1200/JCO.2013.50.3961 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569683/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24297950 PubMed] NCT00474786
−
 
 
==Sunitinib monotherapy {{#subobject:f929da|Regimen=1}}==
 
==Sunitinib monotherapy {{#subobject:f929da|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
{| class="wikitable" style="float:right; margin-left: 5px;"
Line 2,286: Line 1,997:
 
|}
 
|}
 
===Regimen {{#subobject:955949|Variant=1}}===
 
===Regimen {{#subobject:955949|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
Line 2,311: Line 2,022:
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
 
|2009-2011
 
|2009-2011
 
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
Line 2,319: Line 2,030:
 
|}
 
|}
 
====Preceding treatment====
 
====Preceding treatment====
−
 
 
*RECORD-3: [[#Everolimus_monotherapy|Everolimus]]
 
*RECORD-3: [[#Everolimus_monotherapy|Everolimus]]
−
 
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Sunitinib (Sutent)]] 50 mg PO once per day on days 1 to 28
 
*[[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
 
**Dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability
−
 
 
'''42-day cycles'''
 
'''42-day cycles'''
−
 
 
===References===
 
===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]
 
#'''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 protocol''' [https://pubmed.ncbi.nlm.nih.gov/16757724 PubMed] NCT00077974
 
#'''A618-1006:''' Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, Redman BG, Margolin KA, Merchan JR, Wilding G, Ginsberg MS, Bacik J, Kim ST, Baum CM, Michaelson MD. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006 Jun 7;295(21):2516-24. [https://jamanetwork.com/journals/jama/fullarticle/202955 link to original article] '''contains protocol''' [https://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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970162-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19615940 PubMed] NCT00130897
 
#'''A618-1037:''' Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009 Aug;10(8):757-63. Epub 2009 Jul 15. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970162-7/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19615940 PubMed] NCT00130897
−
<!-- # '''Abstract:''' Robert John Motzer, Carlos H. Barrios, Tae Min Kim, Silvia Falcon, Thomas Cosgriff, W. Graydon Harker, Kenneth B. Pittman, Roberto Sabbatini, Sun Young Rha, Thomas W. Flaig, Ray D. Page, Sevil E. Bavbek, J. Thaddeus Beck, Poulam M Patel, Edward Schiff, Alexandra Vaury, Julie Niolat, Sven Gogov, Ozlem Anak, Jennifer Knox. Record-3: Phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC). 2013 ASCO Annual Meeting abstract 4504. [http://meetinglibrary.asco.org/content/113103-132 link to abstract] -->
+
#'''RECORD-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [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
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#'''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] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25049330 PubMed] NCT00903175
 
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=Metastatic disease, third-line=
 
=Metastatic disease, third-line=
−
 
 
==Sorafenib monotherapy {{#subobject:7b51ba|Regimen=1}}==
 
==Sorafenib monotherapy {{#subobject:7b51ba|Regimen=1}}==
 
{| class="wikitable" style="float:right; margin-left: 5px;"
 
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===Regimen {{#subobject:87cb7d|Variant=1}}===
 
===Regimen {{#subobject:87cb7d|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
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''Note: GOLD should not be confused for the one with the same name in gastric cancer.''
 
''Note: GOLD should not be confused for the one with the same name in gastric cancer.''
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Sorafenib (Nexavar)]] 400 mg PO twice per day
 
*[[Sorafenib (Nexavar)]] 400 mg PO twice per day
−
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
 
===References===
 
===References===
−
 
 
#'''GOLD:''' Motzer RJ, Porta C, Vogelzang NJ, Sternberg CN, Szczylik C, Zolnierek J, Kollmannsberger C, Rha SY, Bjarnason GA, Melichar B, De Giorgi U, Grünwald V, Davis ID, Lee JL, Esteban E, Urbanowitz G, Cai C, Squires M, Marker M, Shi MM, Escudier B. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Mar;15(3):286-96. Epub 2014 Feb 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70030-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719485/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24556040 PubMed] NCT01223027
 
#'''GOLD:''' Motzer RJ, Porta C, Vogelzang NJ, Sternberg CN, Szczylik C, Zolnierek J, Kollmannsberger C, Rha SY, Bjarnason GA, Melichar B, De Giorgi U, Grünwald V, Davis ID, Lee JL, Esteban E, Urbanowitz G, Cai C, Squires M, Marker M, Shi MM, Escudier B. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Mar;15(3):286-96. Epub 2014 Feb 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70030-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719485/ link to PMC article] [https://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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30735-1/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/31810797 PubMed] NCT02627963
 
#'''TIVO-3:''' Rini BI, Pal SK, Escudier BJ, Atkins MB, Hutson TE, Porta C, Verzoni E, Needle MN, McDermott DF. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020 Jan;21(1):95-104. Epub 2019 Dec 3. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30735-1/fulltext link to original article] [https://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]
 
##'''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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==Tivozanib monotherapy {{#subobject:h7qut0|Regimen=1}}==
 
==Tivozanib monotherapy {{#subobject:h7qut0|Regimen=1}}==
 
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''Note: this is not the dose reported in the manuscript.''
 
''Note: this is not the dose reported in the manuscript.''
 
====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Tivozanib (Fotivda)]] 1.34 mg PO once per day on days 1 to 21
 
*[[Tivozanib (Fotivda)]] 1.34 mg PO once per day on days 1 to 21
−
 
 
'''28-day cycles'''
 
'''28-day cycles'''
−
 
 
===Regimen variant #2, 1.5 mg/day {{#subobject:1yq32d|Variant=1}}===
 
===Regimen variant #2, 1.5 mg/day {{#subobject:1yq32d|Variant=1}}===
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====Targeted therapy====
 
====Targeted therapy====
−
 
 
*[[Tivozanib (Fotivda)]] 1.5 mg PO once per day on days 1 to 21
 
*[[Tivozanib (Fotivda)]] 1.5 mg PO once per day on days 1 to 21
−
 
 
'''28-day cycles'''
 
'''28-day cycles'''
−
 
 
===References===
 
===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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30735-1/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/31810797 PubMed] NCT02627963
 
#'''TIVO-3:''' Rini BI, Pal SK, Escudier BJ, Atkins MB, Hutson TE, Porta C, Verzoni E, Needle MN, McDermott DF. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020 Jan;21(1):95-104. Epub 2019 Dec 3. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30735-1/fulltext link to original article] '''contains verified protocol''' [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]
 
##'''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:Renal_cell_carcinoma regimens]]
 
[[Category:Disease-specific pages]]
 
[[Category:Disease-specific pages]]
 
[[Category:Genitourinary cancers]]
 
[[Category:Genitourinary cancers]]

Revision as of 23:40, 17 March 2022

Section editor
Alikhaki.jpg
 Ali Raza Khaki, MD
Stanford University
Palo Alto, CA
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Are you looking for a regimen but can't find it here? It is possible that we've moved it to the 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!
There are several related dedicated pages:

14 regimens on this page
22 variants on this page


Guidelines

EAU

ESMO

Older

NCCN

SIOG

Risk Stratification Calculators

  • 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. link to news article
  • 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. doi: 10.1200/JCO.2001.19.6.1649. PMID: 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. doi: 10.1016/j.eururo.2018.01.005. Epub 2018 Feb 3. PMID: 29398265. PubMed

Adjuvant therapy

Pembrolizumab monotherapy

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Regimen variant #1, 200 mg q3wk

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Choueiri et al. 2021 (KEYNOTE-564) 2017-2019 Phase 3 (E-RT-esc) Placebo Superior DFS
DFS24: 77.3% vs 68.1%
(HR 0.68, 95% CI 0.53-0.87)

Preceding treatment

Immunotherapy

21-day cycle for up to 17 cycles (1 year)

Regimen variant #2, 400 mg q6wk

FDA-recommended dose

Note: this dose was not used in the prospective RCT.

Preceding treatment

Immunotherapy

42-day cycle for up to 8 cycles (1 year)

References

  1. KEYNOTE-564: Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Chang YH, Hajek J, Symeonides SN, Lee JL, Sarwar N, Thiery-Vuillemin A, Gross-Goupil M, Mahave M, Haas NB, Sawrycki P, Gurney H, Chevreau C, Melichar B, Kopyltsov E, Alva A, Burke JM, Doshi G, Topart D, Oudard S, Hammers H, Kitamura H, Bedke J, Perini RF, Zhang P, Imai K, Willemann-Rogerio J, Quinn DI, Powles T; KEYNOTE-564 Investigators. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med. 2021 Aug 19;385(8):683-694. link to original article contains verified protocol PubMed NCT03142334

Sunitinib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Haas et al. 2016 (ECOG-ACRIN E2805) 2006-2010 Phase 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 verified protocol 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

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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 protocol PubMed NCT02420821

Axitinib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Hutson et al. 2013 (A4061051) 2010-2011 Phase 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 protocol 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

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Regimen variant #1, weight-based dosing

Study Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2019 (JAVELIN Renal 101) 2016-2017 Phase 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 protocol 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

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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: NR 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 protocol 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

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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 verified protocol PubMed

Bevacizumab & Interferon alfa-2a

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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
(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 verified protocol PubMed
  2. CALGB 90206: Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008 Nov 20;26(33):5422-8. Epub 2008 Oct 20. link to original article link to PMC article PubMed 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 protocol PubMed NCT00631371

Cabozantinib monotherapy

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Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Choueiri et al. 2016 (CABOSUN) 2013-2015 Phase 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 verified protocol 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 verified protocol link to PMC article PubMed

Cabozantinib & Nivolumab

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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 OS
OS12: 85.7% vs 75.6%
(HR 0.60, 98.89% CI 0.40-0.89)

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 verified protocol PubMed NCT03141177

Erlotinib & Bevacizumab

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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 verified protocol PubMed

Everolimus monotherapy

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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
Tannir et al. 2015 (ESPN) 2010-2013 Randomized Phase 2 (E-switch-ic) Sunitinib Did not meet primary endpoint of PFS
Armstrong et al. 2016 (ASPENRCC) 2010-2013 Randomized Phase 2 (E-switch-ic) Sunitinib Might have inferior PFS

Note: ASPEN should not be confused with the trial by the same name in Waldenström macroglobulinemia.

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
  2. ESPN: Tannir NM, Jonasch E, Albiges L, Altinmakas E, Ng CS, Matin SF, Wang X, Qiao W, Dubauskas Lim Z, Tamboli P, Rao P, Sircar K, Karam JA, McDermott DF, Wood CG, Choueiri TK. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol. 2016 May;69(5):866-74. Epub 2015 Nov 26. link to original article link to PMC article contains verified protocol PubMed NCT01185366
  3. ASPEN: Armstrong AJ, Halabi S, Eisen T, Broderick S, Stadler WM, Jones RJ, Garcia JA, Vaishampayan UN, Picus J, Hawkins RE, Hainsworth JD, Kollmannsberger CK, Logan TF, Puzanov I, Pickering LM, Ryan CW, Protheroe A, Lusk CM, Oberg S, George DJ. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016 Mar;17(3):378-88. Epub 2016 Jan 13. link to original article PubMed NCT01108445

Everolimus & Lenvatinib

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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 verified protocol PubMed NCT02811861

Gemcitabine & Sunitinib

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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 verified protocol PubMed
  2. MGH 07-212: Michaelson MD, McKay RR, Werner L, Atkins MB, Van Allen EM, Olivier KM, Song J, Signoretti S, McDermott DF, Choueiri TK. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer. 2015 Oct 1;121(19):3435-43. Epub 2015 Jun 8. link to original article PubMed NCT00556049

High-dose Interleukin-2

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HD IL-2: High-Dose InterLeukin-2

Example orders

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

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rosenberg et al. 1994 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 medications

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 medications

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

Subsequent treatment

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

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

Study 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 verified protocol PubMed
  3. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995 Mar;13(3):688-96. link to original article PubMed
  4. Figlin RA, Thompson JA, Bukowski RM, Vogelzang NJ, Novick AC, Lange P, Steinberg GD, Belldegrun AS. Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol. 1999 Aug;17(8):2521-9. link to original article contains verified protocol PubMed
  5. McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, Kirkwood JM, Gordon MS, Sosman JA, Ernstoff MS, Tretter CP, Urba WJ, Smith JW, Margolin KA, Mier JW, Gollob JA, Dutcher JP, Atkins MB. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005 Jan 1;23(1):133-41. link to original article contains verified protocol PubMed
  6. Retrospective: Klapper JA, Downey SG, Smith FO, Yang JC, Hughes MS, Kammula US, Sherry RM, Royal RE, Steinberg SM, Rosenberg S. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma : a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008 Jul 15;113(2):293-301. link to original article contains verified protocol link to PMC article PubMed

Low-dose Interleukin-2

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LD IL-2: Low-Dose InterLeukin-2

Regimen variant #1, Intravenous

Study 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 verified protocol PubMed

Interferon alfa-2a monotherapy

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Regimen variant #1, 5 MU 5x per week

Study Years of enrollment Evidence Comparator Comparative Efficacy
Sagaster et al. 1995 NR-1992 Phase 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 protocol PubMed
  3. MRC RE01: Ritchie A, Griffiths G, Parmar M; Medical Research Council Renal Cancer Collaborators. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet. 1999 Jan 2;353(9146):14-7. link to original article contains protocol PubMed
  4. Motzer RJ, Murphy BA, Bacik J, Schwartz LH, Nanus DM, Mariani T, Loehrer P, Wilding G, Fairclough DL, Cella D, Mazumdar M. Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol. 2000 Aug;18(16):2972-80. link to original article PubMed
  5. A618-1034: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. link to original article contains verified protocol PubMed 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 verified protocol link to PMC article PubMed content property of HemOnc.org
  6. ARCC: Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. link to original article contains verified protocol PubMed 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 verified protocol PubMed
  8. CALGB 90206: Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008 Nov 20;26(33):5422-8. Epub 2008 Oct 20. link to original article link to PMC article PubMed 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 verified protocol 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 verified protocol PubMed NCT00420888

Interferon alfa-2b monotherapy

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Regimen

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

Of historic interest.

Preceding treatment

Immunotherapy

References

  1. EORTC 30947: Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R; EORTC Genitourinary Group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001 Sep 22;358(9286):966-70. link to original article PubMed
  2. SWOG 8949: Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, Caton JR Jr, Munshi N, Crawford ED. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001 Dec 6;345(23):1655-9. link to original article PubMed
  3. ECOG E2898: NCT00005966

Ipilimumab & Nivolumab

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Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2018 (CheckMate 214) 2014-2016 Phase 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 verified protocol 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

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Regimen

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: NR vs NR
(HR 0.66, 95% CI 0.49-0.88)

Targeted therapy

Immunotherapy

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 verified protocol PubMed NCT02811861

Pazopanib monotherapy

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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 verified protocol 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 verified protocol 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 verified protocol PubMed
  3. COMPARZ: Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, Jin J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R, Pandite LN, Choueiri TK. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013 Aug 22;369(8):722-31. link to original article contains verified protocol PubMed 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 protocol PubMed NCT01408004

Pembrolizumab monotherapy

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Regimen

Study Years of enrollment Evidence Efficacy
McDermott et al. 2021 (KEYNOTE-427) 2016-NR Phase 2 ORR: 36%

Note: this reference describes the clear cell cohort of KEYNOTE-427.

Immunotherapy

21-day cycle for up to 36 cycles (2 years)

References

  1. KEYNOTE-427: McDermott DF, Lee JL, Bjarnason GA, Larkin JMG, Gafanov RA, Kochenderfer MD, Jensen NV, Donskov F, Malik J, Poprach A, Tykodi SS, Alonso-Gordoa T, Cho DC, Geertsen PF, Climent Duran MA, DiSimone C, Silverman RK, Perini RF, Schloss C, Atkins MB. Open-Label, Single-Arm Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Clear Cell Renal Cell Carcinoma. J Clin Oncol. 2021 Mar 20;39(9):1020-1028. Epub 2021 Feb 2. link to original article contains protocol PubMed NCT02853344

Regorafenib monotherapy

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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 verified protocol PubMed NCT00664326

Sorafenib monotherapy

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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 verified protocol 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 protocol 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 protocol 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

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Motzer et al. 2007 (A618-1034) 2004-2005 Phase 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
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
Rini et al. 2016 (IMPRINT) 2010-2012 Phase 3 (C) Sunitinib & IMA901 Might have superior OS
Tomita et al. 2020 (CROSS-J-RCC) 2010-2012 Phase 3 (E-switch-ic) Sorafenib Did not meet primary endpoint of PFS
Tannir et al. 2015 (ESPN) 2010-2013 Randomized Phase 2 (E-switch-ic) Everolimus Did not meet primary endpoint of PFS
Armstrong et al. 2016 (ASPENRCC) 2010-2013 Randomized Phase 2 (E-switch-ic) Everolimus Might have superior 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
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%

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.
ASPEN should not be confused with the trial by the same name in Waldenström macroglobulinemia.

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

References

  1. A618-1034: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. link to original article contains verified protocol PubMed 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 verified protocol 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 verified protocol 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 verified protocol 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 verified protocol 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 protocol PubMed NCT00732914
  8. ESPN: Tannir NM, Jonasch E, Albiges L, Altinmakas E, Ng CS, Matin SF, Wang X, Qiao W, Dubauskas Lim Z, Tamboli P, Rao P, Sircar K, Karam JA, McDermott DF, Wood CG, Choueiri TK. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol. 2016 May;69(5):866-74. Epub 2015 Nov 26. link to original article link to PMC article contains verified protocol PubMed NCT01185366
  9. ASPEN: Armstrong AJ, Halabi S, Eisen T, Broderick S, Stadler WM, Jones RJ, Garcia JA, Vaishampayan UN, Picus J, Hawkins RE, Hainsworth JD, Kollmannsberger CK, Logan TF, Puzanov I, Pickering LM, Ryan CW, Protheroe A, Lusk CM, Oberg S, George DJ. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016 Mar;17(3):378-88. Epub 2016 Jan 13. link to original article PubMed NCT01108445
  10. IMPRINT: Rini BI, Stenzl A, Zdrojowy R, Kogan M, Shkolnik M, Oudard S, Weikert S, Bracarda S, Crabb SJ, Bedke J, Ludwig J, Maurer D, Mendrzyk R, Wagner C, Mahr A, Fritsche J, Weinschenk T, Walter S, Kirner A, Singh-Jasuja H, Reinhardt C, Eisen T. IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2016 Nov;17(11):1599-1611. link to original article contains protocol PubMed NCT01265901
  11. CABOSUN: Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, Feldman DR, Olencki T, Picus J, Small EJ, Dakhil S, George DJ, Morris MJ. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol. 2017 Feb 20;35(6):591-597. Epub 2016 Nov 14. link to original article contains verified protocol link to PMC article PubMed 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 verified protocol link to PMC article PubMed
  12. CheckMate 214: Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. Epub 2018 Mar 21. link to original article contains verified protocol PubMed 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
  13. CARMENA: Méjean A, Ravaud A, Thezenas S, Colas S, Beauval JB, Bensalah K, Geoffrois L, Thiery-Vuillemin A, Cormier L, Lang H, Guy L, Gravis G, Rolland F, Linassier C, Lechevallier E, Beisland C, Aitchison M, Oudard S, Patard JJ, Theodore C, Chevreau C, Laguerre B, Hubert J, Gross-Goupil M, Bernhard JC, Albiges L, Timsit MO, Lebret T, Escudier B. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018 Aug 2;379(5):417-427. Epub 2018 Jun 3. link to original article contains protocol PubMed NCT00930033
  14. JAVELIN Renal 101: Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M, Lee JL, Vasiliev A, Miller WH Jr, Gurney H, Schmidinger M, Larkin J, Atkins MB, Bedke J, Alekseev B, Wang J, Mariani M, Robbins PB, Chudnovsky A, Fowst C, Hariharan S, Huang B, di Pietro A, Choueiri TK. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1103-1115. Epub 2019 Feb 16. link to original article contains protocol link to PMC article PubMed 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
  15. KEYNOTE-426: Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, Vynnychenko I, Kryzhanivska A, Bondarenko I, Azevedo SJ, Borchiellini D, Szczylik C, Markus M, McDermott RS, Bedke J, Tartas S, Chang YH, Tamada S, Shou Q, Perini RF, Chen M, Atkins MB, Powles T; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116-1127. Epub 2019 Feb 16. link to original article contains protocol PubMed 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
  16. IMmotion151: Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. link to original article contains protocol PubMed NCT02420821
  17. 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
  18. 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
  19. 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 verified protocol PubMed NCT03141177
  20. 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 protocol PubMed NCT02811861
  21. KEYNOTE-679: NCT03260894
  22. CA045002: NCT03729245
  23. JS001-036-Ⅲ-RCC: NCT04394975
  24. TQB2450-III-07: NCT04523272

Temsirolimus monotherapy

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Regimen

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

Targeted therapy

Supportive medications

7-day cycles

References

  1. ARCC: Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. link to original article contains verified protocol PubMed NCT00065468

Tivozanib monotherapy

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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

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 verified protocol PubMed NCT01030783

Metastatic disease, second-line

Axitinib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rini et al. 2011 (AXIS) 2008-2010 Phase 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.

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 verified protocol 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 verified protocol PubMed
    2. Subgroup analysis: Escudier B, Michaelson MD, Motzer RJ, Hutson TE, Clark JI, Lim HY, Porfiri E, Zalewski P, Kannourakis G, Staehler M, Tarazi J, Rosbrook B, Cisar L, Hariharan S, Kim S, Rini BI. Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial. Br J Cancer. 2014 Jun 10;110(12):2821-8. Epub 2014 May 13. link to original article link to PMC article PubMed

Bevacizumab monotherapy

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Regimen

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

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 protocol link to PMC article PubMed

Cabozantinib monotherapy

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Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Choueiri et al. 2015 (METEOR) 2013-2014 Phase 3 (E-RT-switch-ic) Everolimus Superior OS 21% (95% CI 16-28%) 5% (95% CI 2-9%)

Preceding treatment

  • VEGFR TKI, with progression

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 verified protocol 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

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Motzer et al. 2008 (RECORD-1) 2006-2007 Phase 3 (E-RT-esc) Placebo Superior PFS 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 (CONCEPT) 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

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

  1. RECORD-1: Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008 Aug 9;372(9637):449-56. Epub 2008 Jul 22. link to original article contains verified protocol PubMed 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 verified protocol PubMed
  2. RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article 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 verified protocol 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 and update: Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Saito M, Kimura G, Yonese J, Yao M, Uemura H. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the phase III CheckMate 025 study. Jpn J Clin Oncol. 2019 Jun 1;49(6):506-514. link to original article PubMed
    4. 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 verified protocol 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 verified protocol 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 protocol PubMed NCT01491672
  7. CONCEPT: NCT03095040

Everolimus & Lenvatinib

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2015 (E7080-G000-205) 2012-2013 Randomized Phase 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 verified protocol 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

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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 verified protocol 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

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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 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

Regimen variant #5, 240 mg q2wk

Study Years of enrollment Evidence
McFarlane et al. 2020 (CheckMate 374) 2015-2016 Phase 3b/4

Immunotherapy

14-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 verified protocol 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 verified protocol 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 and update: Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Saito M, Kimura G, Yonese J, Yao M, Uemura H. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the phase III CheckMate 025 study. Jpn J Clin Oncol. 2019 Jun 1;49(6):506-514. link to original article PubMed
    4. 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
  3. CheckMate 374: McFarlane JJ, Kochenderfer MD, Olsen MR, Bauer TM, Molina A, Hauke RJ, Reeves JA, Babu S, Van Veldhuizen P, Somer B, Gunuganti V, Schnadig I, George S, Page RD, Arrowsmith E, Jain RK, Zhang J, McHenry MB, Johansen JL, Vogelzang NJ. Safety and Efficacy of Nivolumab in Patients With Advanced Clear Cell Renal Cell Carcinoma: Results From the Phase IIIb/IV CheckMate 374 Study. Clin Genitourin Cancer. 2020 Dec;18(6):469-476.e4. Epub 2020 Jun 14. link to original article contains protocol PubMed NCT02596035

Pazopanib monotherapy

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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 30% (95% CI 25-36%) 3% (95% CI 0-6%)
Hainsworth et al. 2013 2008-2011 Phase 2

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 verified protocol 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 verified protocol 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 verified protocol PubMed
  3. Hainsworth JD, Rubin MS, Arrowsmith ER, Khatcheressian J, Crane EJ, Franco LA. Pazopanib as second-line treatment after sunitinib or bevacizumab in patients with advanced renal cell carcinoma: a Sarah Cannon Oncology Research Consortium phase II trial. Clin Genitourin Cancer. 2013 Sep;11(3):270-5. Epub 2013 May 9. link to original article contains protocol PubMed

Sorafenib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy ORR Comparator ORR
Escudier et al. 2007 (TARGETRCC) 2003-2005 Phase 3 (E-RT-esc) Placebo Did not meet primary endpoint of OS1 10% 2%
Stadler et al. 2010 (ARCCS) 2005-2006 Non-randomized
Beck et al. 2011 (EU-ARCCS) 2005-2007 Non-randomized
Hutson et al. 2013 (INTORSECT) 2007-2011 Phase 3 (C) Temsirolimus Did not meet primary endpoint of PFS2
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.
Note that TARGET should not be confused with the study by the same name in breast cancer.

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. TARGET: Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):125-34. Erratum in: N Engl J Med. 2007 Jul 12;357(2):203. link to original article contains verified protocol PubMed 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 verified protocol PubMed
  2. ARCCS: Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010 Mar 1;116(5):1272-80. link to original article PubMed 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 verified protocol PubMed
  4. AXIS: Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011 Dec 3;378(9807):1931-9. Epub 2011 Nov 4. link to original article contains verified protocol PubMed 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 verified protocol PubMed
    2. Subgroup analysis: Escudier B, Michaelson MD, Motzer RJ, Hutson TE, Clark JI, Lim HY, Porfiri E, Zalewski P, Kannourakis G, Staehler M, Tarazi J, Rosbrook B, Cisar L, Hariharan S, Kim S, Rini BI. Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial. Br J Cancer. 2014 Jun 10;110(12):2821-8. Epub 2014 May 13. link to original article link to PMC article PubMed
  5. INTORSECT: Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, Senico P, Niethammer A, Lu DR, Hariharan S, Motzer RJ. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Mar 10;32(8):760-7. Epub 2013 Dec 2. link to original article contains protocol link to PMC article PubMed NCT00474786

Sunitinib monotherapy

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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 protocol 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 verified protocol 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

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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 protocol 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

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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 verified protocol 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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