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 superior 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 inferior TTP
Wood et al. 2008 (C-100-12 Part I) NR 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
Awaiting publication (PROSPERRCC) 2017-ongoing Phase 3 (C) Nivolumab TBD if different primary endpoint of EFS
Awaiting publication (RAMPART) 2018-ongoing Phase 3 (C) 1. Durvalumab
2. Durvalumab & Tremelimumab 		TBD if different co-primary endpoints of DFS/OS

No treatment after surgery.

Preceding treatment

References

  1. 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 PubMed
  2. 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 PubMed
  3. 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 PubMed
  4. 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 PubMed NCT00033904
  5. 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 PubMed NCT00053807
  6. 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 PubMed NCT00502034
  7. PROSPERRCC: NCT03055013
  8. RAMPART: NCT03288532

Placebo

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
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
2. Sunitinib Did not meet primary endpoint of DFS
Ravaud et al. 2016 (S-TRAC) 2007-2011 Phase 3 (C) Sunitinib Seems to have inferior DFS Less toxicity
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 inferior RFS
RFS60: 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
Pal et al. 2022 (IMmotion010) 2017-2019 Phase 3 (C) Atezolizumab Did not meet primary endpoint of DFS
Median DFS: 49.5 vs 57.2 mo
(HR 1.08, 95% CI 0.87-1.33)

No active antineoplastic treatment. Note that ATLAS should not be confused with the trials with the same name in breast cancer and in NSCLC.

Preceding treatment

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 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 link to PMC article PubMed
  3. 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 PubMed NCT00087022
  4. 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 PubMed NCT01235962
  5. 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 PubMed NCT01599754
  6. 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 PubMed NCT00492258
  7. 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 PubMed NCT03024996
  8. 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 PubMed NCT01120249
  9. 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

  1. 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 PubMed
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