Renal cell carcinoma
Page editor | Section editor | ||
---|---|---|---|
Teja Ganta, MD Icahn School of Medicine at Mount Sinai New York, NY, USA |
Ali Raza Khaki, MD Stanford University Palo Alto, CA, USA |
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 or to a histology- or biomarker-specific 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:
- Histology-specific:
- Biomarker-specific:
26 regimens on this page
43 variants on this page
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Living Interactive Systematic Reviews
Guidelines
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any article published 5+ years ago to be for historical purposes, only.
ESMO
- 2021: Kanesveran et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with renal cell carcinoma PubMed
- 2021: Powles et al. ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma PubMed
- 2019: Escudier et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2016: Escudier et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2014: Escudier et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2012: Escudier et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2010: Escudier & Kataja. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2009: Escudier & Kataja. Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
NCCN
- NCCN Guidelines - Kidney Cancer
- 2022: Motzer et al. Kidney Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. PubMed
- 2017: Motzer et al. Kidney Cancer, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology PubMed
- 2015: Motzer et al. Kidney Cancer, Version 3.2015 PubMed
- 2014: Motzer et al. Kidney cancer, version 2.2014 PubMed
- 2011: Motzer et al. Kidney cancer. PubMed
- 2009: Motzer et al. NCCN clinical practice guidelines in oncology: kidney cancer. PubMed
- 2006: Motzer et al. Kidney cancer. Clinical practice guidelines in oncology. PubMed
- 2005: Motzer et al. Kidney cancer. Clinical practice guidelines. PubMed
SIOG
- 2018: Kanesvaran et al. Elderly patients with metastatic renal cell carcinoma: position paper from the International Society of Geriatric Oncology PubMed
SITC
- 2019: Rini et al. The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC) PubMed
Risk Stratification Calculators
- 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. link to PMC article PubMed
- 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. link to original article PubMed
- Mortality and complication risk calculator for a patients with clinical T1 renal cortical mass up to 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. PubMed
- Leibovich prognostic model
- ref: Leibovich BC, Lohse CM, Cheville JC, Zaid HB, Boorjian SA, Frank I, Thompson RH, Parker WP. Predicting Oncologic Outcomes in Renal Cell Carcinoma After Surgery. Eur Urol. 2018 May;73(5):772-780. Epub 2018 Feb 3. PubMed
Adjuvant therapy
Sunitinib monotherapy
Regimen
Study | Dates 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 (primary endpoint) Median DFS: 6.8 vs 5.6 yr (HR 0.76, 95% CI 0.59-0.98) |
More toxicity |
Preceding treatment
Targeted therapy
- Sunitinib (Sutent) 50 mg PO once per day on days 1 to 28
42-day cycle for up to 9 cycles (1 year)
References
- ECOG-ACRIN E2805: Haas NB, Manola J, Uzzo RG, Flaherty KT, Wood CG, Kane C, Jewett M, Dutcher JP, Atkins MB, Pins M, Wilding G, Cella D, Wagner L, Matin S, Kuzel TM, Sexton WJ, Wong YN, Choueiri TK, Pili R, Puzanov I, Kohli M, Stadler W, Carducci M, Coomes R, DiPaola RS. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016 May 14;387(10032):2008-16. Epub 2016 Mar 9. Erratum in: Lancet. 2016 May 14;387(10032):1998. link to original article link to PMC article 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. link to original article contains dosing details in manuscript 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. link to original article link to PMC article PubMed
Metastatic disease, first-line
Atezolizumab & Bevacizumab
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Rini et al. 2019 (IMmotion151) | 2015-05-20 to 2016-10-12 | Phase 3 (E-esc) | Sunitinib | Seems to have superior PFS1 (co-primary endpoint) 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.
Note: patients could have clear cell or sarcomatoid histology.
Immunotherapy
- Atezolizumab (Tecentriq) 1200 mg IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- IMmotion151: Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. link to original article contains dosing details in abstract PubMed NCT02420821
- Update: Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Alekseev BY, Lee JL, Suarez C, Stroyakovskiy D, De Giorgi U, Donskov F, Mellado B, Banchereau R, Hamidi H, Khan O, Craine V, Huseni M, Flinn N, Dubey S, Rini BI. Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol. 2022 Feb 1;8(2):275-280. link to original article [link to PMC article PubMed
Bevacizumab monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bukowski et al. 2007 | 2004 | Randomized Phase 2 (C) | Erlotinib & Bevacizumab | Did not meet co-primary endpoints of ORR/PFS |
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV over 90 minutes once on day 1
14-day cycle for up to 52 cycles (2 years)
Dose and schedule modifications
- Bevacizumab infusion time can subsequently be reduced to 60 and 30 minute infusions as tolerated
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. link to original article contains dosing details in manuscript PubMed
Bevacizumab & Interferon alfa-2a
Regimen variant #1, 1 year of interferon
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Escudier et al. 2007 (AVOREN) | 2004-06 to 2005-10 | 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) Superior PFS2 (secondary endpoint) Median PFS: 10.2 vs 5.4 mo (HR 0.63, 95% CI 0.52-0.75) |
1Reported efficacy for AVOREN is based on the 2010 update.
2The secondary endpoint of PFS was used in the FDA regulatory decision; please see paper for details.
Note: Timing below reflects starting treatment on a Monday.
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once on day 1
Immunotherapy
- Interferon alfa-2a (Roferon-A) as follows:
- Cycles 1 to 26: 9,000,000 units SC once per day on days 1, 3, 5, 8, 10, 12 (3 times per week)
14-day cycles
Dose and schedule modifications
- Interferon alfa-2a (Roferon-A) dose can be reduced to 3,000,000 or 6,000,000 units SC 3 times per week based on tolerability
Regimen variant #2, indefinite
Study | Dates 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 (primary endpoint) Median OS: 18.3 vs 17.4 mo (HR 0.86, 95% CI 0.73-1.01) |
Rini et al. 2013 (INTORACT) | 2008-2010 | Phase 3 (C) | Temsirolimus & Bevacizumab | Did not meet primary endpoint of PFS |
1Reported efficacy for CALGB 90206 is based on the 2010 update and is based on a stratified analysis.
Note: Timing below reflects starting treatment on a Monday.
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once on day 1
Immunotherapy
- Interferon alfa-2a (Roferon-A) 9,000,000 units SC once per day on days 1, 3, 5, 8, 10, 12 (3 times per week)
14-day cycles
Dose and schedule modifications
- Interferon alfa-2a (Roferon-A) dose can be reduced to 3,000,000 or 6,000,000 units SC 3 times per week based on tolerability
References
- AVOREN: Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007 Dec 22;370(9605):2103-11. link to original article 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. link to original article contains dosing details in manuscript PubMed
- CALGB 90206: Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008 Nov 20;26(33):5422-8. Epub 2008 Oct 20. link to original article link to PMC article PubMed NCT00072046
- Update: Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010 May 1;28(13):2137-43. Epub 2010 Apr 5. link to original article link to PMC article 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. link to original article contains dosing details in abstract PubMed NCT00631371
Erlotinib & Bevacizumab
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bukowski et al. 2007 | 2004 | Randomized Phase 2 (E-esc) | Bevacizumab | Did not meet co-primary endpoints of ORR/PFS |
Targeted therapy
- Erlotinib (Tarceva) 150 mg PO once per day
- Bevacizumab (Avastin) 10 mg/kg IV over 90 minutes once on day 1
14-day cycle for up to 52 cycles (2 years)
Dose and schedule modifications
- Bevacizumab infusion time can subsequently be reduced to 60 and 30 minute infusions as tolerated
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. link to original article contains dosing details in manuscript PubMed
Everolimus monotherapy
Regimen
Study | Dates 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 (primary endpoint) |
Subsequent treatment
- RECORD-3, upon progression: Sunitinib
Dose and schedule modifications
- Everolimus dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability
References
- RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article link to PMC article PubMed NCT00903175
Everolimus & Lenvatinib
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Motzer et al. 2021 (CLEAR) | 2016-10-13 to 2019-07-24 | Phase 3 (E-RT-esc) | 1. Lenvatinib & Pembrolizumab | Not reported |
2. Sunitinib | Superior PFS (primary endpoint) Median PFS: 14.7 vs 9.2 mo (HR 0.65, 95% CI 0.53-0.80) |
Targeted therapy
- Everolimus (Afinitor) 5 mg PO once per day on days 1 to 21
- Lenvatinib (Lenvima) 18 mg PO once per day on days 1 to 21
21-day cycles
References
- CLEAR: Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. link to original article contains dosing details in manuscript PubMed NCT02811861
- Update: Choueiri TK, Eto M, Motzer R, De Giorgi U, Buchler T, Basappa NS, Méndez-Vidal MJ, Tjulandin S, Hoon Park S, Melichar B, Hutson T, Alemany C, McGregor B, Powles T, Grünwald V, Alekseev B, Rha SY, Kopyltsov E, Kapoor A, Alonso Gordoa T, Goh JC, Staehler M, Merchan JR, Xie R, Perini RF, Mody K, McKenzie J, Porta CG. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol. 2023 Mar;24(3):228-238. Erratum in: Lancet Oncol. 2023 Apr;24(4):e146. link to original article PubMed
Gemcitabine & Sunitinib
Regimen variant #1
Study | Dates of enrollment | Evidence |
---|---|---|
Michaelson et al. 2015 (MGH 07-212) | 2007-2013 | Phase 2 |
Chemotherapy
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
Targeted therapy
- Sunitinib (Sutent) 37.5 mg PO once per day on days 1 to 14
21-day cycles
Regimen variant #2
Study | Evidence |
---|---|
Pandya et al. 2011 | Retrospective |
Chemotherapy
- Gemcitabine (Gemzar) 750 mg/m2 IV over 90 minutes once per day on days 1 & 8
Targeted therapy
- Sunitinib (Sutent) 37.5 mg PO once per day on days 2 to 15
21-day cycles
References
- Retrospective: Pandya SS, Mier JW, McDermott DF, Cho DC. Addition of gemcitabine at the time of sunitinib resistance in metastatic renal cell cancer. BJU Int. 2011 Oct;108(8 Pt 2):E245-9. Epub 2011 Feb 14. link to original article contains dosing details in manuscript PubMed
- MGH 07-212: Michaelson MD, McKay RR, Werner L, Atkins MB, Van Allen EM, Olivier KM, Song J, Signoretti S, McDermott DF, Choueiri TK. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer. 2015 Oct 1;121(19):3435-43. Epub 2015 Jun 8. link to original article PubMed NCT00556049
High-dose Interleukin-2
HD IL-2: High-Dose InterLeukin-2
Example orders
Regimen variant #1, 1.8 MU/kg/day, intermittent
Study | Dates 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
- IL-2 - Aldesleukin (Proleukin) 600,000 units/kg IV every 8 hours for up to 14 doses per week, on days 1 to 5, 15 to 19
Supportive therapy
- Ciprofloxacin (Cipro) 250 mg PO twice per day on days 1 to 10, 15 to 24
- All antihypertensive therapy discontinued at least 24 hours before each cycle
- Acetaminophen (Tylenol) 650 mg PO every 4 hours
- Indomethacin (Indocin) 25 mg PO every 6 hours
- Ranitidine (Zantac) 150 mg PO or Famotidine (Pepcid) 20 mg PO every 12 hours
- Hydroxyzine (Atarax) 25 to 50 mg PO every 6 hours or Diphenhydramine (Benadryl) 25 mg PO every (note: frequency was blank in reference) hours for pruritis
- Meperidine (Demerol) 25 to 50 mg PO every 6 hours for chills and rigors
- "An antidiarrheal agent, antiemetics, anxiolytics, diuretics, and vasopressors as needed"
28-day cycle for up to 3 cycles
Regimen variant #2, 2.16 MU/kg/day, intermittent, goal 10.8 MU
Study | Dates 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
- 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, IL-2 - Aldesleukin (Proleukin) 720,000 units/kg IV every 8 hours for up to 15 doses is given again
8-week cycle for up to 2 cycles
Regimen variant #3, 2.16 MU/kg/day, intermittent, goal 8.64 MU
Study | Evidence |
---|---|
Klapper et al. 2008 | Retrospective |
Immunotherapy
- 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, IL-2 - Aldesleukin (Proleukin) 720,000 units/kg IV every 8 hours for up to 12 doses is given again
Supportive therapy
- "Routine administration of antipyretics, anti-inflammatories, antiemetics, antidiarrheals, and H2 antagonists."
Subsequent treatment
- After this one course of treatments--defined by the paper as "two cycles"--patients with stable to improved disease would receive additional courses of treatments every 2 months (no maximum number of courses listed)
Regimen variant #4, 5 MU/m2/day, CI
Study | Dates 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
- 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
- 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
- Update: Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. link to original article link to PMC article contains dosing details in manuscript PubMed
- 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
- Figlin RA, Thompson JA, Bukowski RM, Vogelzang NJ, Novick AC, Lange P, Steinberg GD, Belldegrun AS. Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol. 1999 Aug;17(8):2521-9. link to original article contains dosing details in manuscript PubMed
- McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, Kirkwood JM, Gordon MS, Sosman JA, Ernstoff MS, Tretter CP, Urba WJ, Smith JW, Margolin KA, Mier JW, Gollob JA, Dutcher JP, Atkins MB. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005 Jan 1;23(1):133-41. link to original article contains dosing details in manuscript PubMed
- Retrospective: Klapper JA, Downey SG, Smith FO, Yang JC, Hughes MS, Kammula US, Sherry RM, Royal RE, Steinberg SM, Rosenberg S. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma : a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008 Jul 15;113(2):293-301. link to original article contains dosing details in manuscript link to PMC article PubMed
Low-dose Interleukin-2
LD IL-2: Low-Dose InterLeukin-2
Regimen variant #1, Intravenous
Study | Dates 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 | Dates 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
- 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
- Update: Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. link to original article link to PMC article contains dosing details in manuscript PubMed
Interferon alfa-2a monotherapy
Regimen variant #1, 5 MU 5x per week
Study | Dates 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
- Interferon alfa-2a (Roferon-A) 5,000,000 units SC 5 times per week
Continued indefinitely
Regimen variant #2, 9 MU TIW
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
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 |
Rini et al. 2008 (CALGB 90206) | 2003-2005 | Phase 3 (C) | Bevacizumab & Interferon alfa-2a | Might have inferior OS1 |
Escudier et al. 2007 (AVOREN) | 2004-06 to 2005-10 | Phase 3 (C) | Bevacizumab & Interferon alfa-2a | Did not meet primary endpoint of OS2 |
Escudier et al. 2009 (Bayer 11848) | 2005-06-28 to 2005-09-30 | Randomized Phase 2 (C) | Sorafenib | Did not meet primary endpoint of PFS |
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 CALGB 90206 is based on the 2010 update and is based on a stratified analysis.
2Reported efficacy for AVOREN is based on the 2010 update.
Immunotherapy
- Interferon alfa-2a (Roferon-A) 9,000,000 units SC 3 times per week
Given for varying lengths of time; see individual trials
Dose and schedule modifications
- Some protocols: Dose can be reduced to 3,000,000 or 6,000,000 units SC 3 times per week based on tolerability
Regimen variant #3, 9 MU daily, with lead-in
Study | Dates 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 | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Motzer et al. 2007 (A618-1034) | 2004-08 to 2005-10 | 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 | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ritchie et al. 1999 (MRC RE01) | 1992-1997 | Phase 3 (E-switch-ooc) | MPA | Superior OS (primary endpoint) Median OS: 8.5 vs 6 mo (HR 0.72, 95% CI 0.55-0.94) |
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
- 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
12-week course (MRC RE01) or continued indefinitely (MRC RE04/EORTC GU 30012)
Regimen variant #6, 18 MU TIW, with lead-in
Study | Dates 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
- 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
- Sagaster P, Micksche M, Flamm J, Ludwig H. Randomised study using IFN-alpha versus IFN-alpha plus coumarin and cimetidine for treatment of advanced renal cell cancer. Ann Oncol. 1995 Dec;6(10):999-1003. link to original article contains dosing details in abstract PubMed
- MRC RE01: Ritchie A, Griffiths G, Parmar M; Medical Research Council Renal Cancer Collaborators. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet. 1999 Jan 2;353(9146):14-7. link to original article contains dosing details in abstract PubMed
- 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
- A618-1034: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. link to original article contains dosing details in manuscript PubMed NCT00098657
- Update: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Aug 1;27(22):3584-90. Epub 2009 Jun 1. link to original article contains dosing details in manuscript link to PMC article PubMed content property of HemOnc.org
- ARCC: Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. link to original article contains dosing details in manuscript PubMed NCT00065468
- 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
- Update: Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, Sneller V. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010 May 1;28(13):2144-50. Epub 2010 Apr 5. link to original article contains dosing details in manuscript PubMed
- 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
- 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
- Bayer 11848: 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
- MRC RE04/EORTC GU 30012: Gore ME, Griffin CL, Hancock B, Patel PM, Pyle L, Aitchison M, James N, Oliver RT, Mardiak J, Hussain T, Sylvester R, Parmar MK, Royston P, Mulders PF. Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial. Lancet. 2010 Feb 20;375(9715):641-8. Epub 2010 Feb 10. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00053820
- Active Biotech 06762004: Hawkins RE, Gore M, Shparyk Y, Bondar V, Gladkov O, Ganev T, Harza M, Polenkov S, Bondarenko I, Karlov P, Karyakin O, Khasanov R, Hedlund G, Forsberg G, Nordle Ö, Eisen T. A randomized phase II/III study of naptumomab estafenatox + IFNα versus IFNα in renal cell carcinoma: final analysis with baseline biomarker subgroup and trend analysis. Clin Cancer Res. 2016 Jul 1;22(13):3172-81. Epub 2016 Feb 5. link to original article contains dosing details in manuscript PubMed NCT00420888
Lenvatinib & Pembrolizumab
Regimen variant #1
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Motzer et al. 2021 (CLEAR) | 2016-10-13 to 2019-07-24 | Phase 3 (E-RT-esc) | 1. Everolimus & Lenvatinib | Not reported |
2. Sunitinib | Superior OS1 (secondary endpoint) Median OS: NYR vs NYR (HR 0.72, 95% CI 0.55-0.93) |
1Reported efficacy is based on the 2023 update.
Targeted therapy
- Lenvatinib (Lenvima) 20 mg PO once per day on days 1 to 21
Immunotherapy
- Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycles
Regimen variant #2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Awaiting publication (MK-6482-012) | 2021-ongoing | Phase 3 (C) | 1. Belzutifan, Lenvatinib, Pembrolizumab 2. Lenvatinib, Pembrolizumab, Quavonlimab |
TBD if different co-primary endpoints of PFS/OS |
Targeted therapy
- Lenvatinib (Lenvima) 20 mg PO once per day on days 1 to 42
Immunotherapy
- Pembrolizumab (Keytruda) as follows:
- Cycles 1 to 18: 400 mg IV once on day 1
42-day cycles
References
- CLEAR: Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. link to original article contains dosing details in manuscript PubMed NCT02811861
- Update: Choueiri TK, Eto M, Motzer R, De Giorgi U, Buchler T, Basappa NS, Méndez-Vidal MJ, Tjulandin S, Hoon Park S, Melichar B, Hutson T, Alemany C, McGregor B, Powles T, Grünwald V, Alekseev B, Rha SY, Kopyltsov E, Kapoor A, Alonso Gordoa T, Goh JC, Staehler M, Merchan JR, Xie R, Perini RF, Mody K, McKenzie J, Porta CG. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol. 2023 Mar;24(3):228-238. Erratum in: Lancet Oncol. 2023 Apr;24(4):e146. link to original article PubMed
- MK-6482-012: NCT04736706
Regorafenib monotherapy
Regimen
Study | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Eisen et al. 2012 (Bayer 11726) | 2008-2011 | Phase 2 | ORR: 40% (90% CI 28-53%) |
Targeted therapy
- Regorafenib (Stivarga) 160 mg PO once per day on days 1 to 21, given while fasting or after a light meal
28-day cycles
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. link to original article contains dosing details in manuscript PubMed NCT00664326
Sorafenib monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Escudier et al. 2009 (Bayer 11848) | 2005-06-28 to 2005-09-30 | Randomized Phase 2 (E-switch-ooc) | Interferon alfa-2a | Did not meet primary endpoint of PFS |
Stadler et al. 2010 (ARCCS) | 2005-06 to 2006-07 | Non-randomized | ||
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) | 2012-06-14 to 2016-11-14 | Phase 3 (C) | Pazopanib | Inconclusive whether non-inferior tPFS |
Dose and schedule modifications
- Sorafenib can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity
Subsequent treatment
- SWITCH-II, upon progression: Pazopanib
References
- Bayer 11848: 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
- 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
- SWITCH-II: Retz M, Bedke J, Bögemann M, Grimm MO, Zimmermann U, Müller L, Leiber C, Teber D, Wirth M, Bolenz C, van Alphen R, De Santis M, Beeker A, Lehmann J, Indorf M, Frank M, Bokemeyer C, Gschwend JE. SWITCH II: Phase III randomized, sequential, open-label study to evaluate the efficacy and safety of sorafenib-pazopanib versus pazopanib-sorafenib in the treatment of advanced or metastatic renal cell carcinoma (AUO AN 33/11). Eur J Cancer. 2019 Jan;107:37-45. Epub 2018 Dec 7. link to original article contains dosing details in abstract PubMed NCT01613846
- CROSS-J-RCC: Tomita Y, Naito S, Sassa N, Takahashi A, Kondo T, Koie T, Obara W, Kobayashi Y, Teishima J, Takahashi M, Matsuyama H, Ueda T, Yamaguchi K, Kishida T, Shiroki R, Saika T, Shinohara N, Oya M, Kanayama HO. Sunitinib Versus Sorafenib as Initial Targeted Therapy for mCC-RCC With Favorable/Intermediate Risk: Multicenter Randomized Trial CROSS-J-RCC. Clin Genitourin Cancer. 2020 Aug;18(4):e374-e385. Epub 2020 Mar 6. link to original article PubMed NCT01481870
Sunitinib monotherapy
Regimen variant #1, 4 out of 6 weeks
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Motzer et al. 2007 (A618-1034) | 2004-08 to 2005-10 | Phase 3 (E-RT-switch-ooc) | Interferon alfa-2a | Superior PFS (primary endpoint) Median PFS: 11 vs 5 mo (HR 0.42, 95% CI 0.32-0.54) Might have superior OS1 (secondary endpoint) Median OS: 26.4 vs 21.8 mo (HR 0.82, 95% CI 0.67-1.001) |
Gore et al. 2009 (A618-1037) | 2005-2007 | Non-randomized | ||
Amato et al. 2010 (TroVax Renal Immunotherapy Survival Trial) | 2006-2008 | Phase 3 (C) | Sunitinib & MVA-5T4 | Did not meet primary endpoint of OS Median OS: 19.2 vs 20.1 mo (HR 0.93, 95% CI 0.76-1.16) |
Motzer et al. 2014 (RECORD-3) | 2009-2011 | Randomized Phase 2 (E-switch-ic) | Everolimus | Inconclusive whether non-inferior PFS (primary endpoint) |
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 (primary endpoint) Median OS: 18.4 vs 13.9 mo (HR 0.89, 95% CI 0.71-1.10) |
Rini et al. 2016 (IMPRINT) | 2010-2012 | Phase 3 (C) | Sunitinib & IMA-901 | Might have superior OS Median OS: NYR vs 33.2 mo (HR 0.75, 95% CI 0.54-1.04) |
Tomita et al. 2020 (CROSS-J-RCC) | 2010-2012 | Phase 3 (E-switch-ic) | Sorafenib | Did not meet primary endpoint of PFS |
Figlin et al. 2020 (ADAPT) | 2013-2016 | Phase 3 (C) | Rocapuldencel-T & Sunitinib | Did not meet primary endpoint of OS Median OS: 32.4 vs 27.7 mo (HR 0.91, 95% CI 0.71-1.20) |
Rini et al. 2019 (IMmotion151) | 2015-05-20 to 2016-10-12 | Phase 3 (C) | Atezolizumab & Bevacizumab | Seems to have inferior PFS |
Motzer et al. 2021 (CLEAR) | 2016-10-13 to 2019-07-24 | Phase 3 (C) | 1. Everolimus & Lenvatinib | Inferior PFS |
2. Lenvatinib & Pembrolizumab | Inferior OS | |||
Awaiting publication (JS001-036-III-RCC) | 2020-ongoing | Phase 3 (C) | Axitinib & Toripalimab | TBD if different primary endpoint of PFS |
1Reported efficacy for A618-1034 is based on the 2009 update.
Subsequent treatment
- SWITCH, upon progression: Sorafenib
Dose and schedule modifications
- Per some references, dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability
Regimen variant #2, 2 out of 4 weeks
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Awaiting publication (TQB2450-III-07) | 2020-ongoing | Phase 3 (C) | Anlotinib & TQB-2450 | TBD if different primary endpoint of PFS |
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. link to original article contains dosing details in manuscript 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. link to original article contains dosing details in manuscript link to PMC article 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. link to original article contains dosing details in manuscript PubMed NCT00130897
- TroVax Renal Immunotherapy Survival Trial: Amato RJ, Hawkins RE, Kaufman HL, Thompson JA, Tomczak P, Szczylik C, McDonald M, Eastty S, Shingler WH, de Belin J, Goonewardena M, Naylor S, Harrop R. Vaccination of metastatic renal cancer patients with MVA-5T4: a randomized, double-blind, placebo-controlled phase III study. Clin Cancer Res. 2010 Nov 15;16(22):5539-47. Epub 2010 Sep 29. link to original article contains dosing details in manuscript PubMed NCT00397345
- PISCES: 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
- 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
- SWITCH: Eichelberg C, Vervenne WL, De Santis M, Fischer von Weikersthal L, Goebell PJ, Lerchenmüller C, Zimmermann U, Bos MM, Freier W, Schirrmacher-Memmel S, Staehler M, Pahernik S, Los M, Schenck M, Flörcken A, van Arkel C, Hauswald K, Indorf M, Gottstein D, Michel MS. SWITCH: A Randomised, Sequential, Open-label Study to Evaluate the Efficacy and Safety of Sorafenib-sunitinib Versus Sunitinib-sorafenib in the Treatment of Metastatic Renal Cell Cancer. Eur Urol. 2015 Nov;68(5):837-47. Epub 2015 May 4. link to original article contains dosing details in abstract PubMed NCT00732914
- IMPRINT: Rini BI, Stenzl A, Zdrojowy R, Kogan M, Shkolnik M, Oudard S, Weikert S, Bracarda S, Crabb SJ, Bedke J, Ludwig J, Maurer D, Mendrzyk R, Wagner C, Mahr A, Fritsche J, Weinschenk T, Walter S, Kirner A, Singh-Jasuja H, Reinhardt C, Eisen T. IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2016 Nov;17(11):1599-1611. link to original article contains dosing details in abstract PubMed NCT01265901
- CARMENA: Méjean A, Ravaud A, Thezenas S, Colas S, Beauval JB, Bensalah K, Geoffrois L, Thiery-Vuillemin A, Cormier L, Lang H, Guy L, Gravis G, Rolland F, Linassier C, Lechevallier E, Beisland C, Aitchison M, Oudard S, Patard JJ, Theodore C, Chevreau C, Laguerre B, Hubert J, Gross-Goupil M, Bernhard JC, Albiges L, Timsit MO, Lebret T, Escudier B. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018 Aug 2;379(5):417-427. Epub 2018 Jun 3. link to original article contains dosing details in abstract PubMed NCT00930033
- IMmotion151: Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. link to original article contains dosing details in abstract PubMed NCT02420821
- Update: Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Alekseev BY, Lee JL, Suarez C, Stroyakovskiy D, De Giorgi U, Donskov F, Mellado B, Banchereau R, Hamidi H, Khan O, Craine V, Huseni M, Flinn N, Dubey S, Rini BI. Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol. 2022 Feb 1;8(2):275-280. link to original article [link to PMC article PubMed
- 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
- 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
- CLEAR: Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. link to original article contains dosing details in abstract PubMed NCT02811861
- Update: Choueiri TK, Eto M, Motzer R, De Giorgi U, Buchler T, Basappa NS, Méndez-Vidal MJ, Tjulandin S, Hoon Park S, Melichar B, Hutson T, Alemany C, McGregor B, Powles T, Grünwald V, Alekseev B, Rha SY, Kopyltsov E, Kapoor A, Alonso Gordoa T, Goh JC, Staehler M, Merchan JR, Xie R, Perini RF, Mody K, McKenzie J, Porta CG. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol. 2023 Mar;24(3):228-238. Erratum in: Lancet Oncol. 2023 Apr;24(4):e146. link to original article PubMed
- KEYNOTE-679: NCT03260894
- JS001-036-III-RCC: NCT04394975
- PIVOT-09: NCT03729245
- TQB2450-III-07: NCT04523272
Temsirolimus monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hudes et al. 2007 (ARCC) | 2003-2005 | Phase 3 (E-RT-switch-ooc) | 1. Interferon alfa-2a | Superior OS (primary endpoint) Median OS: 10.9 vs 7.3 mo (HR 0.73, 95% CI 0.58-0.92) |
2. Interferon alfa-2a & Temsirolimus | Not reported |
Targeted therapy
- Temsirolimus (Torisel) 25 mg IV over 30 minutes once on day 1
Supportive therapy
- Diphenhydramine (Benadryl) (or similar H1 blocker) 25 to 50 mg IV once on day 1; 30 minutes prior to temsirolimus
7-day cycles
References
- ARCC: Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. link to original article contains dosing details in manuscript PubMed NCT00065468
Metastatic disease, second-line
Bevacizumab monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Yang et al. 2003 | 1998-2001 | Randomized Phase 2 (E-esc) | Placebo | Superior TTP (primary endpoint) |
Prior treatment criteria
- Previous therapy with IL-2 or contraindication to IL-2
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 contains dosing details in abstract link to PMC article PubMed
Cabozantinib monotherapy
Regimen
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Choueiri et al. 2015 (METEOR) | 2013-08 to 2014-11 | Phase 3 (E-RT-switch-ic) | Everolimus | Superior PFS (primary endpoint) Median PFS: 7.4 vs 3.8 mo (HR 0.58, 95% CI 0.45-0.75) Superior OS1 (secondary endpoint) Median OS: 21.4 vs 17.1 mo (HR 0.70, 95% CI 0.58-0.85) |
Tannir et al. 2022 (CANTATA) | 2018-11-27 to 2019-09-30 | Phase 3 (C) | Cabozantinib & Telaglenastat | Did not meet primary endpoint of PFS |
Pal et al. 2023 (CONTACT-03) | 2020-07-28 to 2021-12-27 | Phase 3 (C) | Cabozantinib & Atezolizumab | Did not meet co-primary endpoints of PFS/OS |
1Reported efficacy is based on the 2018 update.
Prior treatment criteria
- METEOR: VEGFR TKI, with progression
- CANTATA: 1 to 2 prior lines of therapy, including 1 or more antiangiogenic therapies or Ipilimumab & Nivolumab
Targeted therapy
- Cabozantinib (Cabometyx) 60 mg PO once per day on days 1 to 28
- At least 2 hours before or 1 hour after meals according to the Cabozantinib (Cabometyx) package insert
28-day cycles
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. link to original article contains dosing details in manuscript link to PMC article 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. link to original article PubMed
- HRQoL analysis: Cella D, Escudier B, Tannir NM, Powles T, Donskov F, Peltola K, Schmidinger M, Heng DYC, Mainwaring PN, Hammers HJ, Lee JL, Roth BJ, Marteau F, Williams P, Baer J, Mangeshkar M, Scheffold C, Hutson TE, Pal S, Motzer RJ, Choueiri TK. Quality of life outcomes for cabozantinib versus everolimus in patients with metastatic renal cell carcinoma: METEOR phase III randomized trial. J Clin Oncol. 2018 Mar 10;36(8):757-764. Epub 2018 Jan 29. link to original article link to PMC article PubMed
- Update: Motzer RJ, Escudier B, Powles T, Scheffold C, Choueiri TK. Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer. 2018 May;118(9):1176-1178. Epub 2018 Mar 26. link to original article link to PMC article PubMed
- CANTATA: Tannir NM, Agarwal N, Porta C, Lawrence NJ, Motzer R, McGregor B, Lee RJ, Jain RK, Davis N, Appleman LJ, Goodman O Jr, Stadler WM, Gandhi S, Geynisman DM, Iacovelli R, Mellado B, Sepúlveda Sánchez JM, Figlin R, Powles T, Akella L, Orford K, Escudier B. Efficacy and Safety of Telaglenastat Plus Cabozantinib vs Placebo Plus Cabozantinib in Patients With Advanced Renal Cell Carcinoma: The CANTATA Randomized Clinical Trial. JAMA Oncol. 2022 Oct 1;8(10):1411-1418. link to orginal article link to PMC article PubMed NCT03428217
- CONTACT-03: Pal SK, Albiges L, Tomczak P, Suárez C, Voss MH, de Velasco G, Chahoud J, Mochalova A, Procopio G, Mahammedi H, Zengerling F, Kim C, Osawa T, Angel M, Gupta S, Khan O, Bergthold G, Liu B, Kalaitzidou M, Huseni M, Scheffold C, Powles T, Choueiri TK. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2023 Jul 15;402(10397):185-195. Epub 2023 Jun 5. link to original article contains dosing details in abstract PubMed NCT04338269
- MK-6482-011: NCT04586231
Everolimus monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Motzer et al. 2008 (RECORD-1) | 2006-04 to 2007-04 | Phase 3 (E-RT-esc) | Placebo | Superior PFS1 (primary endpoint) Median PFS: 4.9 vs 1.9 mo (HR 0.33, 95% CI 0.25-0.43) Did not meet secondary endpoint of OS1 Median OS: 14.8 vs 14.4 mo (HR 0.87, 95% CI 0.65-1.15) |
Motzer et al. 2014 (RECORD-3) | 2009-2011 | Randomized Phase 2 (E-switch-ic) | Sunitinib | Inconclusive whether non-inferior PFS (primary endpoint) |
Motzer et al. 2015 (RECORD-4) | 2011-2013 | Phase 2 | ||
Motzer et al. 2015 (CheckMate 025) | 2012-2014 | Phase 3 (C) | Nivolumab | Inferior OS |
Motzer et al. 2015 (E7080-G000-205) | 2012-03-16 to 2013-06-19 | Randomized Phase 2 (C) | 1. Everolimus & Lenvatinib | Inferior PFS |
2. Lenvatinib | Seems to have inferior PFS | |||
Choueiri et al. 2015 (METEOR) | 2013-08 to 2014-11 | Phase 3 (C) | Cabozantinib | Inferior OS |
Sheng et al. 2022 (CONCEPTRCC) | 2017-2019 | Phase 3 (C) | 1. Everolimus & Vorolanib | Inferior PFS |
2. Vorolanib | Might have inferior PFS |
1Reported efficacy for RECORD-1 is based on the 2010 update.
Note: 72% of patients in Checkmate 025 had anti-angiogenic therapy prior to progression.
Prior treatment criteria
Dose and schedule modifications
- Everolimus dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability
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. link to original article contains dosing details in manuscript 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. link to original article contains dosing details in manuscript PubMed
- RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article link to PMC article 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. link to original article contains dosing details in manuscript link to PMC article 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. link to original article link to PMC article PubMed
- Subgroup analysis: Escudier B, Sharma P, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Gurney H, Donskov F, Peltola K, Wagstaff J, Gauler TC, Ueda T, Zhao H, Waxman IM, Motzer RJ; CheckMate 025 investigators. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol. 2017 Dec;72(6):962-971. Epub 2017 Mar 3. Erratum in: Eur Urol. 2018 Jan 3. link to original article PubMed
- Subgroup analysis: Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Saito M, Kimura G, Yonese J, Yao M, Uemura H. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the phase III CheckMate 025 study. Jpn J Clin Oncol. 2019 Jun 1;49(6):506-514. link to original article 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. link to original article link to PMC article PubMed
- METEOR: Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1814-23. Epub 2015 Sep 25. link to original article contains dosing details in manuscript link to PMC article 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. link to original article PubMed
- HRQoL analysis: Cella D, Escudier B, Tannir NM, Powles T, Donskov F, Peltola K, Schmidinger M, Heng DYC, Mainwaring PN, Hammers HJ, Lee JL, Roth BJ, Marteau F, Williams P, Baer J, Mangeshkar M, Scheffold C, Hutson TE, Pal S, Motzer RJ, Choueiri TK. Quality of life outcomes for cabozantinib versus everolimus in patients with metastatic renal cell carcinoma: METEOR phase III randomized trial. J Clin Oncol. 2018 Mar 10;36(8):757-764. Epub 2018 Jan 29. link to original article link to PMC article PubMed
- Update: Motzer RJ, Escudier B, Powles T, Scheffold C, Choueiri TK. Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer. 2018 May;118(9):1176-1178. Epub 2018 Mar 26. link to original article link to PMC article PubMed
- E7080-G000-205: Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. link to original article contains dosing details in manuscript 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. link to original article PubMed
- RECORD-4: Motzer RJ, Alyasova A, Ye D, Karpenko A, Li H, Alekseev B, Xie L, Kurteva G, Kowalyszyn R, Karyakin O, Neron Y, Cosgriff T, Collins L, Brechenmacher T, Lin C, Morgan L, Yang L. Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4). Ann Oncol. 2016 Mar;27(3):441-8. Epub 2015 Dec 17. link to original article link to PMC article contains dosing details in abstract PubMed NCT01491672
- CONCEPTRCC: Sheng X, Ye D, Zhou A, Yao X, Luo H, He Z, Wang Z, Zhao Y, Ji Z, Zou Q, He C, Guo J, Tu X, Liu Z, Shi B, Liu B, Chen P, Wei Q, Hu Z, Zhang Y, Jiang K, Zhou F, Wu D, Fu C, Li X, Wu B, Wang L, Qin S, Li G, Liu Y, Guo H, Chen K, Zhang D, Wang G, Ding L, Wang Y, Yuan X, Guo J. Efficacy and safety of vorolanib plus everolimus in metastatic renal cell carcinoma: A three-arm, randomised, double-blind, multicentre phase III study (CONCEPT). Eur J Cancer. 2023 Jan;178:205-215. Epub 2022 Nov 1. link to original article PubMed NCT03095040
Everolimus & Lenvatinib
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Motzer et al. 2015 (E7080-G000-205) | 2012-03-16 to 2013-06-19 | Randomized Phase 2 (E-RT-esc) | 1. Everolimus | Superior PFS (primary endpoint) Median PFS: 14.6 vs 5.5 mo (HR 0.40, 95% CI 0.24-0.68) |
2. Lenvatinib | Did not meet primary endpoint of PFS Median PFS: 14.6 vs 7.4 mo (HR 0.66, 95% CI 0.30-1.10) |
Prior treatment criteria
- VEGFR TKI treatment, with progression
Targeted therapy
- Everolimus (Afinitor) 5 mg PO once per day
- Lenvatinib (Lenvima) 18 mg PO once per day
Continued indefinitely
References
- E7080-G000-205: Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. link to original article contains dosing details in manuscript 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. link to original article PubMed
Lenvatinib monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Motzer et al. 2015 (E7080-G000-205) | 2012-03-16 to 2013-06-19 | Randomized Phase 2 (E-RT-switch-ic) | 1. Everolimus | Seems to have superior PFS (primary endpoint) Median PFS: 7.4 vs 5.5 mo (HR 0.61, 95% CI 0.38-0.98) |
2. Everolimus & Lenvatinib | Did not meet primary endpoint of PFS |
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. link to original article contains dosing details in manuscript 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. link to original article PubMed
Nivolumab monotherapy
Regimen variant #1, 0.3 mg/kg q3wk
Study | Dates 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 |
Regimen variant #2, 2 mg/kg q3wk
Study | Dates 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 |
Regimen variant #3, 3 mg/kg q2wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Motzer et al. 2015 (CheckMate 025) | 2012-2014 | Phase 3 (E-RT-switch-ooc) | Everolimus | Superior OS (primary endpoint) Median OS: 25 vs 19.6 mo (HR 0.73, 98.5% CI 0.57-0.93) |
Note: On 2016-09-13 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
Immunotherapy
- Nivolumab (Opdivo) 3 mg/kg IV over 60 minutes once on day 1
14-day cycles
Regimen variant #4, 10 mg/kg q3wk
Study | Dates 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 |
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. link to original article link to PMC article contains dosing details in manuscript 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. link to original article contains dosing details in manuscript link to PMC article 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. link to original article link to PMC article PubMed
- Subgroup analysis: Escudier B, Sharma P, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Gurney H, Donskov F, Peltola K, Wagstaff J, Gauler TC, Ueda T, Zhao H, Waxman IM, Motzer RJ; CheckMate 025 investigators. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol. 2017 Dec;72(6):962-971. Epub 2017 Mar 3. Erratum in: Eur Urol. 2018 Jan 3. link to original article PubMed
- Subgroup analysis: Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Saito M, Kimura G, Yonese J, Yao M, Uemura H. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the phase III CheckMate 025 study. Jpn J Clin Oncol. 2019 Jun 1;49(6):506-514. link to original article 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. link to original article link to PMC article PubMed
Pazopanib monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hutson et al. 2009 (VEG102616) | 2005-10 to 2006-09 | Phase 2 | ||
Sternberg et al. 2010 (VEG105192) | 2006-04 to 2007-04 | Phase 3 (E-esc) | Placebo | Superior PFS (primary endpoint) Median PFS: 9.2 vs 4.2 mo (HR 0.46, 95% CI 0.34-0.62) |
Hainsworth et al. 2013 | 2008-2011 | Phase 2 |
Prior treatment criteria
- VEG105192: Progression on 1 prior cytokine-based systemic therapy
Targeted therapy
- Pazopanib (Votrient) 800 mg PO once per day, given 1 hour before or 2 hours after meals
Continued indefinitely
Dose and schedule modifications
- Dose may be decreased to 600 mg or 400 mg PO once per day depending on tolerability
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. link to original article contains dosing details in manuscript 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. link to original article contains dosing details in manuscript 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. link to original article contains dosing details in manuscript 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. link to original article contains dosing details in abstract PubMed
Sorafenib monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Stadler et al. 2010 (ARCCS) | 2005-06 to 2006-07 | Non-randomized expanded access study | ||
Beck et al. 2011 (EU-ARCCS) | 2005-2007 | Non-randomized expanded access study | ||
Hutson et al. 2013 (INTORSECT) | 2007-2011 | Phase 3 (C) | Temsirolimus | Did not meet primary endpoint of PFS2 Median PFS: 3.9 vs 4.3 mo (HR 1.15, 95% CI 0.93-1.41) |
1Reported efficacy for TARGET is based on the 2009 update.
2While the primary endpoint (PFS) was not met in INTORSECT, the control arm actually had superior OS compared to the experimental arm.
Prior treatment criteria
- INTORSECT: Sunitinib, with progression
Dose and schedule modifications
- Sorafenib can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity
References
- 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
- EU-ARCCS: Beck J, Procopio G, Bajetta E, Keilholz U, Negrier S, Szczylik C, Bokemeyer C, Bracarda S, Richel DJ, Staehler M, Strauss UP, Mersmann S, Burock K, Escudier B. Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings. Ann Oncol. 2011 Aug;22(8):1812-23. Epub 2011 Feb 15. link to original article contains dosing details in manuscript PubMed
- INTORSECT: Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, Senico P, Niethammer A, Lu DR, Hariharan S, Motzer RJ. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Mar 10;32(8):760-7. Epub 2013 Dec 2. link to original article contains dosing details in abstract link to PMC article PubMed NCT00474786
Sunitinib monotherapy
Regimen
Study | Dates 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 (primary endpoint) |
Preceding treatment
- RECORD-3: Everolimus
Dose and schedule modifications
- Dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability
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. link to original article 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. link to original article contains dosing details in abstract 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. link to original article contains dosing details in manuscript PubMed NCT00130897
- RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article link to PMC article PubMed NCT00903175
Metastatic disease, third-line
Sorafenib monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Motzer et al. 2014 (GOLD-RCC) | 2011-03 to 2012-09 | Phase 3 (C) | Dovitinib | Might have inferior PFS |
Rini et al. 2019 (TIVO-3) | 2016-05-24 to 2017-08-14 | 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.
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. link to original article contains dosing details in abstract link to PMC article 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. link to original article 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. link to original article PubMed
Tivozanib monotherapy
Regimen variant #1, 1.34 mg/day
FDA-recommended dose |
Note: this is not the dose reported in the manuscript.
Regimen variant #2, 1.5 mg/day
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Rini et al. 2019 (TIVO-3) | 2016-05-24 to 2017-08-14 | Phase 3 (E-RT-switch-ic) | Sorafenib | Seems to have superior PFS (primary endpoint) Median PFS: 5.6 vs 3.9 mo (HR 0.73, 95% CI 0.56-0.94) |
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. link to original article contains dosing details in manuscript 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. link to original article PubMed