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 RCC page for regimens that include active anticancer treatment.
=Adjuvant therapy=
==Observation==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Messing et al. 2003 (INT-0079) 	1987-1992 	Phase 3 (C)	Interferon alfa-NL 	Might have longer OS
Passalacqua et al. 2014 (POLAR-01) 	1994-2006 	Phase 3 (C)	IFN & IL-2 	Did not meet primary endpoint of RFS
Clark et al. 2003 	1997-2002 	Phase 3 (C)	High-dose IL-2 	Did not meet primary endpoint of DFS24
Jocham et al. 2004 	1997-01 to 1998-09 	Phase 3 (C)	Renal tumor cell vaccine 	Seems to have shorter TTP
Wood et al. 2008 (C-100-12 Part I) 	Not reported 	Phase 3 (C)	Vitespen 	Did not meet primary endpoint of RFS
Aitchison et al. 2013 (EORTC 30955)	1998-2007 	Phase 3 (C)	5-FU, IFN, IL-2 	Did not meet primary endpoint of DFS36
Allaf et al. 2024 (PROSPER EA8143) 	2017-02-02 to 2021-06-02	Phase 3 (C)	Perioperative Nivolumab 	Did not meet primary endpoint of RFS
Awaiting publication (RAMPART) 	2018-ongoing 	Phase 3 (C)	1. Durvalumab2. Durvalumab & Tremelimumab	TBD if different co-primary endpoints of DFS/OS
No treatment after surgery.
====Preceding treatment====
*Surgery
===References===
# INT-0079: Messing EM, Manola J, Wilding G, Propert K, Fleischmann J, Crawford ED, Pontes JE, Hahn R, Trump D; Eastern Cooperative Oncology Group. Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: an Eastern Cooperative Oncology Group/Intergroup trial. J Clin Oncol. 2003 Apr 1;21(7):1214-22. link to original article EuroPMC
# Clark JI, Atkins MB, Urba WJ, Creech S, Figlin RA, Dutcher JP, Flaherty L, Sosman JA, Logan TF, White R, Weiss GR, Redman BG, Tretter CP, McDermott D, Smith JW, Gordon MS, Margolin KA. Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine working group randomized trial. J Clin Oncol. 2003 Aug 15;21(16):3133-40. Epub 2003 Jun 16. link to original article EuroPMC
# Jocham D, Richter A, Hoffmann L, Iwig K, Fahlenkamp D, Zakrzewski G, Schmitt E, Dannenberg T, Lehmacher W, von Wietersheim J, Doehn C. Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial. Lancet. 2004 Feb 21;363(9409):594-9. link to original article EuroPMC
# C-100-12 Part I: Wood C, Srivastava P, Bukowski R, Lacombe L, Gorelov AI, Gorelov S, Mulders P, Zielinski H, Hoos A, Teofilovici F, Isakov L, Flanigan R, Figlin R, Gupta R, Escudier B; C-100-12 RCC Study Group. An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial. Lancet. 2008 Jul 12;372(9633):145-54. Epub 2008 Jul 3. link to original article EuroPMC NCT00033904
# EORTC 30955: Aitchison M, Bray CA, Van Poppel H, Sylvester R, Graham J, Innes C, McMahon L, Vasey PA. Adjuvant 5-flurouracil, alpha-interferon and interleukin-2 versus observation in patients at high risk of recurrence after nephrectomy for renal cell carcinoma: results of a phase III randomised European Organisation for Research and Treatment of Cancer (Genito-Urinary Cancers Group)/National Cancer Research Institute trial. Eur J Cancer. 2014 Jan;50(1):70-7. Epub 2013 Sep 25. link to original article EuroPMC NCT00053807
# POLAR-01: Passalacqua R, Caminiti C, Buti S, Porta C, Camisa R, Braglia L, Tomasello G, Vaglio A, Labianca R, Rondini E, Sabbatini R, Nastasi G, Artioli F, Prati A, Potenzoni M, Pezzuolo D, Oliva E, Alberici F, Buzio C; POLAR-01 Trial Investigators; GOIRC. Adjuvant low-dose interleukin-2 (IL-2) plus interferon-α (IFN-α) in operable renal cell carcinoma (RCC): a phase III, randomized, multicentre trial of the Italian Oncology Group for Clinical Research (GOIRC). J Immunother. 2014 Nov-Dec;37(9):440-7. Erratum in: J Immunother. 2015 Jun;38(5):216. link to original article EuroPMC NCT00502034
# PROSPER EA8143: Allaf ME, Kim SE, Master V, McDermott DF, Harshman LC, Cole SM, Drake CG, Signoretti S, Akgul M, Baniak N, Li-Ning E, Palmer MB, Emamekhoo H, Adra N, Kaimakliotis H, Ged Y, Pierorazio PM, Abel EJ, Bilen MA, Ogan K, Moon HH, Ramaswamy KA, Singer EA, Mayer TM, Lohrey J, Margulis V, Gills J, Delacroix SE, Waples MJ, James AC, Wang P, Choueiri T, Michaelson MD, Kapoor A, Heng DY, Shuch B, Leibovich BC, Lara PN, Manola J, Maskens D, Battle D, Uzzo R, Bratslavsky G, Haas NB, Carducci MA. Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study. Lancet Oncol. 2024 Aug;25(8):1038-1052. Epub 2024 Jun 25. link to original article EuroPMC NCT03055013
# RAMPART: NCT03288532
==Placebo==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Chamie et al. 2017 (ARISER) 	2004-2013 	Phase 3 (C)	Girentuximab	Did not meet co-primary endpoints of DFS/OS
Haas et al. 2016 (ECOG-ACRIN E2805) 	2006-2010 	Phase 3 (C)	1. Sorafenib	Did not meet primary endpoint of DFS
Haas et al. 2016 (ECOG-ACRIN E2805) 	2006-2010 	Phase 3 (C)	2. Sunitinib	Did not meet primary endpoint of DFS
Eisen et al. 2020 (SORCE) 	2007-2013 	Phase 3 (C)	Sorafenib 	Did not meet primary endpoint of DFS
Motzer et al. 2017 (PROTECT) 	2010-2013 	Phase 3 (C)	Pazopanib 	Did not meet primary endpoint of DFS
Ryan et al. 2023 (EVERESTRCC) 	2011-04-01 to 2016-09-15	Phase 3 (C)	Everolimus 	Might have shorter RFSRFS60: 63% vs 67%(sHR 1.18, 95% CI 1.00-1.39)
Gross-Goupil et al. 2018 (ATLAS-RCC) 	2012-2016 	Phase 3 (C)	Axitinib 	Did not meet primary endpoint of DFS
Appleman et al. 2024 (ECOG-ACRIN E2810)	2012-08 to 2017-07 	Phase 3 (C)	Pazopanib 	Did not meet primary endpoint of DFSDFS36: 21.9% vs 27.4%(HR 1.11, 95% CI 0.75-1.67)
Pal et al. 2022 (IMmotion010) 	2017-2019 	Phase 3 (C)	Atezolizumab	Did not meet primary endpoint of DFSMedian DFS: 49.5 vs 57.2 mo(HR 1.08, 95% CI 0.87-1.33)
No active antineoplastic treatment. Note that ATLAS has been labeled ATLAS-RCC to avoid confusion with the trials with the same name in breast cancer and in NSCLC. Note that EVEREST has been labeled EVERESTRCC to avoid confusion with a trial of the same name.
====Preceding treatment====
*ECOG-ACRIN E2810: Metastasectomy
*All others: Nephrectomy
===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. link to original article link to PMC article EuroPMC NCT00326898
# ARISER: Chamie K, Donin NM, Klöpfer P, Bevan P, Fall B, Wilhelm O, Störkel S, Said J, Gambla M, Hawkins RE, Jankilevich G, Kapoor A, Kopyltsov E, Staehler M, Taari K, Wainstein AJA, Pantuck AJ, Belldegrun AS. Adjuvant weekly girentuximab following nephrectomy for high-risk renal cell carcinoma: The ARISER randomized clinical trial. JAMA Oncol. 2017 Jul 1;3(7):913-920. link to original article link to PMC article EuroPMC NCT00087022
# PROTECT: Motzer RJ, Haas NB, Donskov F, Gross-Goupil M, Varlamov S, Kopyltsov E, Lee JL, Melichar B, Rini BI, Choueiri TK, Zemanova M, Wood LA, Reaume MN, Stenzl A, Chowdhury S, Lim HY, McDermott R, Michael A, Bao W, Carrasco-Alfonso MJ, Aimone P, Voi M, Doehn C, Russo P, Sternberg CN; PROTECT investigators. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. J Clin Oncol. 2017 Dec 10;35(35):3916-3923. Epub 2017 Sep 13. link to original article link to PMC article EuroPMC NCT01235962
##Update: Motzer RJ, Russo P, Haas N, Doehn C, Donskov F, Gross-Goupil M, Varlamov S, Kopyltsov E, Lee JL, Lim HY, Melichar B, Zemanova M, Rini B, Choueiri TK, Wood L, Reaume MN, Stenzl A, Chowdhury S, McDermott R, Michael A, Izquierdo M, Aimone P, Zhang H, Sternberg CN; PROTECT study investigators. Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma: Final Overall Survival Analysis of the Phase 3 PROTECT Trial. Eur Urol. 2021 Mar;79(3):334-338. Epub 2021 Jan 15. link to original article link to PMC article EuroPMC
# ATLAS: Gross-Goupil M, Kwon TG, Eto M, Ye D, Miyake H, Seo SI, Byun SS, Lee JL, Master V, Jin J, DeBenedetto R, Linke R, Casey M, Rosbrook B, Lechuga M, Valota O, Grande E, Quinn DI. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial. Ann Oncol. 2018 Dec 1;29(12):2371-2378. Epub 2018 Oct 20. link to original article link to PMC article EuroPMC NCT01599754
# SORCE: Eisen T, Frangou E, Oza B, Ritchie AWS, Smith B, Kaplan R, Davis ID, Stockler MR, Albiges L, Escudier B, Larkin J, Bex A, Joniau S, Hancock B, Hermann GG, Bellmunt J, Hodgkinson E, Stewart GD, Barber J, Brown J, McMenemin R, Nathan P, Pickering LM, Parmar MKB, Meade A. Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial. J Clin Oncol. 2020 Dec 1;38(34):4064-4075. Epub 2020 Oct 14. link to original article link to PMC article EuroPMC NCT00492258
# IMmotion010: Pal SK, Uzzo R, Karam JA, Master VA, Donskov F, Suarez C, Albiges L, Rini B, Tomita Y, Kann AG, Procopio G, Massari F, Zibelman M, Antonyan I, Huseni M, Basu D, Ci B, Leung W, Khan O, Dubey S, Bex A. Adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2022 Oct 1;400(10358):1103-1116. Epub 2022 Sep 10. link to original article EuroPMC NCT03024996
#EVERESTRCC: Ryan CW, Tangen CM, Heath EI, Stein MN, Meng MV, Alva AS, Pal SK, Puzanov I, Clark JI, Choueiri TK, Agarwal N, Uzzo RG, Haas NB, Synold TW, Plets M, Vaishampayan UN, Shuch BM, Thompson IM Jr, Lara PN Jr. Adjuvant everolimus after surgery for renal cell carcinoma (EVEREST): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2023 Sep 23;402(10407):1043-1051. Epub 2023 Jul 28. link to original article link to PMC article EuroPMC NCT01120249
#ECOG-ACRIN E2810: Appleman LJ, Kim SE, Harris WB, Pal SK, Pins MR, Kolesar J, Agarwal N, Parikh RA, Vaena DA, Ryan CW, Hashmi M, Costello BA, Cella D, Dutcher JP, DiPaola RS, Haas NB, Wagner LI, Carducci MA. Randomized, Double-Blind Phase III Study of Pazopanib Versus Placebo in Patients With Metastatic Renal Cell Carcinoma Who Have No Evidence of Disease After Metastasectomy: ECOG-ACRIN E2810. J Clin Oncol. 2024 Jun 10;42(17):2061-2070. Epub 2024 Mar 26. link to original article EuroPMC NCT01575548
# SWOG S0931: NCT01120249
=Metastatic disease, first-line=
==Placebo==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Gleave et al. 1998	1993-1995 	Phase 3 (C)	Interferon gamma-1b	Did not meet primary endpoint of ORR
No active antineoplastic treatment.
===References===
# Gleave ME, Elhilali M, Fradet Y, Davis I, Venner P, Saad F, Klotz LH, Moore MJ, Paton V, Bajamonde A; Canadian Urologic Oncology Group. Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma. N Engl J Med. 1998 Apr 30;338(18):1265-71. link to original article EuroPMC
Category:Renal_cell_carcinoma regimens
Category:Disease-specific pages
Category:Genitourinary cancers
Category:Null regimens