Clear cell renal cell carcinoma - null regimens

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The purpose of this page is to provide references to "null therapy" such as placebo and observation. These references provide further insight into the historical development of the treatment landscape. See the main clear cell RCC page for regimens that include active anticancer treatment.
=Adjuvant therapy=
==Placebo==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Ravaud et al. 2016 (S-TRAC) 	2007-2011 	Phase 3 (C)	Sunitinib 	Seems to have shorter DFSMedian DFS: 5.6 vs 6.8 years(HR 1.32, 95% CI 1.02-1.69) 	Less toxicity
Choueiri et al. 2021 (KEYNOTE-564) 	2017-2019 	Phase 3 (C)	Pembrolizumab 	Shorter OS1 	
Motzer et al. 2023 (CheckMate 914 part A)	2017-08-28 to 2021-03-16	Phase 3 (C)	Ipilimumab & Nivolumab	Did not meet primary endpoint of DFSMedian DFS: 50.7 mo vs NYR(HR 1.09, 95% CI 0.84-1.41)	
Motzer et al. 2024 (CheckMate 914 part B)	2020-03 to 2022-03 	Phase 3 (C)	Nivolumab 	Did not meet primary endpoint of DFSMedian DFS: NYR vs NYR(HR 1.15, 95% CI 0.83-1.61) 	
1Reported efficacy for KEYNOTE-564 is based on the 2024 update.
No active antineoplastic treatment.
====Preceding treatment====
*Surgery
===References===
# 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 EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 EuroPMC NCT03142334
##Update: Powles T, Tomczak P, Park SH, Venugopal B, Ferguson T, Symeonides SN, Hajek J, Gurney H, Chang YH, Lee JL, Sarwar N, Thiery-Vuillemin A, Gross-Goupil M, Mahave M, Haas NB, Sawrycki P, Burgents JE, Xu L, Imai K, Quinn DI, Choueiri TK; KEYNOTE-564 Investigators. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022 Sep;23(9):1133-1144. link to original article EuroPMC
##PRO analysis: Choueiri TK, Tomczak P, Park SH, Venugopal B, Symeonides S, Hajek J, Ferguson T, Chang YH, Lee JL, Haas N, Sawrycki P, Sarwar N, Gross-Goupil M, Thiery-Vuillemin A, Mahave M, Kimura G, Perini RF, Saretsky TL, Bhattacharya R, Xu L, Powles T. Patient-Reported Outcomes in KEYNOTE-564: Adjuvant Pembrolizumab Versus Placebo for Renal Cell Carcinoma. Oncologist. 2024 Feb 2;29(2):142-150. link to original article link to PMC article EuroPMC
##Update: Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Symeonides SN, Hajek J, Chang YH, Lee JL, Sarwar N, Haas NB, Gurney H, Sawrycki P, Mahave M, Gross-Goupil M, Zhang T, Burke JM, Doshi G, Melichar B, Kopyltsov E, Alva A, Oudard S, Topart D, Hammers H, Kitamura H, McDermott DF, Silva A, Winquist E, Cornell J, Elfiky A, Burgents JE, Perini RF, Powles T; KEYNOTE-564 Investigators. Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma. N Engl J Med. 2024 Apr 18;390(15):1359-1371. link to original article EuroPMC
#CheckMate 914 part A: Motzer RJ, Russo P, Gruenwald V, Tomita Y, Zurawski B, Parikh O, Buti S, Barthelemy P, Goh JC, Ye D, Lingua A, Lattouf JB, Albiges L, George S, Shuch B, Sosman J, Staehler M, Vazquez Estevez S, Simsek B, Spiridigliozzi J, Chudnovsky A, Bex A. Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial. Lancet. 2023 Mar 11;401(10379):821-832. Epub 2023 Feb 9. link to original article link to PMC article EuroPMC NCT03138512
#CheckMate 914 part B: Motzer RJ, Bex A, Russo P, Tomita Y, Cutuli HJ, Rojas C, Gross-Goupil M, Schinzari G, Melichar B, Barthélémy P, Ruiz Garcia A, Sosman J, Grimm MO, Goh JC, Suarez C, Kollmannsberger CK, Nair SG, Shuch BM, Huang J, Simsek B, Spiridigliozzi J, Lee CW, van Kooten Losio M, Grünwald V. Adjuvant Nivolumab for Localized Renal Cell Carcinoma at High Risk of Recurrence After Nephrectomy: Part B of the Randomized, Placebo-Controlled, Phase III CheckMate 914 Trial. J Clin Oncol. 2025 Jan 10;43(2):189-200. Epub 2024 Sep 20. link to original article link to PMC article EuroPMC NCT03138512
=Metastatic disease, first-line=
==Placebo==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Sternberg et al. 2010 (VEG105192)	2006-04 to 2007-04 	Phase 3 (C)	Pazopanib 	Shorter PFS
No active antineoplastic treatment.
===References===
# 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 EuroPMC 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. link to original article EuroPMC
=Metastatic disease, second-line=
==Placebo==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Yang et al. 2003 	1998-2001 	Randomized Phase 2 (C)	Bevacizumab	Shorter TTP
Escudier et al. 2007 (TARGETRCC)	2003-2005 	Phase 3 (C) 	Sorafenib 	Might have shorter OS1Median OS: 15.2 vs 17.8 mo(HR 1.14, 95% CI 0.96-1.35)
Motzer et al. 2008 (RECORD-1) 	2006-04 to 2007-04 	Phase 3 (C) 	Everolimus 	Shorter PFS
1Reported efficacy for TARGET is based on the 2009 update.
No active antineoplastic treatment. Note that TARGET should not be confused with the study by the same name in breast cancer.
====Prior treatment criteria====
*Yang et al. 2003: Previous therapy with IL-2 or contraindication to IL-2
*RECORD-1: Progression on sunitinib, sorafenib, or both
*TARGETRCC: Progression after 1 systemic treatment within the previous 8 months
===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. link to original article link to PMC article EuroPMC
# 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 EuroPMC 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. link to original article EuroPMC
# TARGETRCC: Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):125-34. Erratum in: N Engl J Med. 2007 Jul 12;357(2):203. link to original article EuroPMC 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. link to original article EuroPMC
## 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 EuroPMC
Category:Clear cell renal cell carcinoma regimens
Category:Histology-specific pages
Category:Renal cell carcinomas
Category:Null regimens