Clear cell renal cell carcinoma

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Teja Ganta, MD
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Ali Raza Khaki, MD
Stanford University
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Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
Note: This page contains regimens that were tested specifically in the population of patients with clear cell renal cell carcinoma; regimens tested in the more general RCC population can be found on the general RCC page.
There are several related dedicated pages:

33 regimens on this page
46 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASCO

EAU

ESMO

NCCN

Adjuvant therapy

Pembrolizumab monotherapy

Regimen variant #1, 200 mg q3wk

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Choueiri et al. 2021 (KEYNOTE-564) 2017-2019 Phase 3 (E-RT-esc) Placebo Superior DFS1 (primary endpoint)
Median DFS: NYR vs NYR
(HR 0.63, 95% CI 0.50-0.80)

1Reported efficacy is based on the 2022 update.

Preceding treatment

Immunotherapy

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


Regimen variant #2, 400 mg q6wk

FDA-recommended dose

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

Preceding treatment

Immunotherapy

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

References

  1. KEYNOTE-564: Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Chang YH, Hajek J, Symeonides SN, Lee JL, Sarwar N, Thiery-Vuillemin A, Gross-Goupil M, Mahave M, Haas NB, Sawrycki P, Gurney H, Chevreau C, Melichar B, Kopyltsov E, Alva A, Burke JM, Doshi G, Topart D, Oudard S, Hammers H, Kitamura H, Bedke J, Perini RF, Zhang P, Imai K, Willemann-Rogerio J, Quinn DI, Powles T; KEYNOTE-564 Investigators. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med. 2021 Aug 19;385(8):683-694. link to original article link to free full text via University of Zurich contains dosing details in manuscript PubMed NCT03142334
    1. Update: Powles T, Tomczak P, Park SH, Venugopal B, Ferguson T, Symeonides SN, Hajek J, Gurney H, Chang YH, Lee JL, Sarwar N, Thiery-Vuillemin A, Gross-Goupil M, Mahave M, Haas NB, Sawrycki P, Burgents JE, Xu L, Imai K, Quinn DI, Choueiri TK; KEYNOTE-564 Investigators. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022 Sep;23(9):1133-1144. link to original article PubMed

Sunitinib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
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

42-day cycle for up to 9 cycles (1 year)

References

  1. 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
    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

Metastatic disease, first-line

Axitinib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hutson et al. 2013 (A4061051) 2010-06-14 to 2011-04-21 Phase 3 (E-switch-ic) Sorafenib Might have superior PFS (primary endpoint)
Median PFS: 10.1 vs 6.5 mo
(HR 0.77, 95% CI 0.56-1.05)

Did not meet secondary endpoint of OS1
Median OS: 21.7 vs 23.3 mo
(HR 0.995, 95% CI 0.73-1.36)

1Reported efficacy for OS is based on the 2016 update.

Targeted therapy

Continued indefinitely

Dose and schedule modifications

  • After at least 2 weeks, if tolerated and BP not greater than 150/90, dose can be increased to 7 mg PO twice per day
  • After at least another 2 weeks, if tolerated and BP not greater than 150/90, dose can be increased to 10 mg PO twice per day
  • Dose can be reduced to 2 to 3 mg PO twice per day if needed based on tolerability

References

  1. A4061051: Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, Rosbrook B, Chen C, Kim S, Vogelzang NJ. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1287-94. Epub 2013 Oct 25. link to original article contains dosing details in abstract PubMed NCT00920816
    1. Update: Hutson TE, Al-Shukri S, Stus VP, Lipatov ON, Shparyk Y, Bair AH, Rosbrook B, Andrews GI, Vogelzang NJ. Axitinib versus sorafenib in first-line metastatic renal cell carcinoma: Overall survival from a randomized phase III trial. Clin Genitourin Cancer. 2017 Feb;15(1):72-76. Epub 2016 May 27. link to original article PubMed

Axitinib & Avelumab

Regimen variant #1, weight-based dosing

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2019 (JAVELIN Renal 101) 2016-03-29 to 2017-12-19 Phase 3 (E-RT-esc) Sunitinib Superior overall PFS1 (secondary endpoint)
Median PFS: 13.3 vs 8 mo
(HR 0.69, 95% CI 0.57-0.83)

Superior PFS2 (primary endpoint)
Median PFS: 13.8 vs 7.2 mo
(HR 0.61, 95% CI 0.47-0.79)

1Reported efficacy is for the overall population (secondary endpoint) and is based on the 2020 update.
2Reported efficacy is for the patients with PD-L1-positive tumors (primary endpoint).
Note: this is not the FDA-recommended dose.

Targeted therapy

Immunotherapy

14-day cycles


Regimen variant #2, flat dosing

FDA-recommended dose

Note: this is not the dose described in Motzer et al. 2019.

Targeted therapy

Immunotherapy

14-day cycles

References

  1. JAVELIN Renal 101: Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M, Lee JL, Vasiliev A, Miller WH Jr, Gurney H, Schmidinger M, Larkin J, Atkins MB, Bedke J, Alekseev B, Wang J, Mariani M, Robbins PB, Chudnovsky A, Fowst C, Hariharan S, Huang B, di Pietro A, Choueiri TK. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1103-1115. Epub 2019 Feb 16. link to original article contains dosing details in abstract link to PMC article PubMed NCT02684006
    1. Update: Choueiri TK, Motzer RJ, Rini BI, Haanen J, Campbell MT, Venugopal B, Kollmannsberger C, Gravis-Mescam G, Uemura M, Lee JL, Grimm MO, Gurney H, Schmidinger M, Larkin J, Atkins MB, Pal SK, Wang J, Mariani M, Krishnaswami S, Cislo P, Chudnovsky A, Fowst C, Huang B, di Pietro A, Albiges L. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020 Aug;31(8):1030-1039. Epub 2020 Apr 25. link to original article link to PMC article PubMed

Axitinib & Pembrolizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rini et al. 2019 (KEYNOTE-426) 2016-10-24 to 2018-01-24 Phase 3 (E-RT-esc) Sunitinib Superior OS1 (co-primary endpoint)
Median OS: NYR vs 36 mo
(HR 0.68, 95% CI 0.55-0.85)

Superior PFS (co-primary endpoint)
Median PFS: 15.1 vs 11.1 mo
(HR 0.69, 95% CI 0.57-0.84)

1Reported efficacy is based on the 2020 update.

Targeted therapy

Immunotherapy

21-day cycles

References

  1. KEYNOTE-426: Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, Vynnychenko I, Kryzhanivska A, Bondarenko I, Azevedo SJ, Borchiellini D, Szczylik C, Markus M, McDermott RS, Bedke J, Tartas S, Chang YH, Tamada S, Shou Q, Perini RF, Chen M, Atkins MB, Powles T; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116-1127. Epub 2019 Feb 16. link to original article contains dosing details in abstract PubMed NCT02853331
    1. Update: Powles T, Plimack ER, Soulières D, Waddell T, Stus V, Gafanov R, Nosov D, Pouliot F, Melichar B, Vynnychenko I, Azevedo SJ, Borchiellini D, McDermott RS, Bedke J, Tamada S, Yin L, Chen M, Molife LR, Atkins MB, Rini BI. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1563-1573. Epub 2020 Oct 23. Erratum in: Lancet Oncol. 2020 Dec;21(12):e553. link to original article PubMed

Bevacizumab monotherapy

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

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

  1. Bukowski RM, Kabbinavar FF, Figlin RA, Flaherty K, Srinivas S, Vaishampayan U, Drabkin HA, Dutcher J, Ryba S, Xia Q, Scappaticci FA, McDermott D. Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol. 2007 Oct 10;25(29):4536-41. Epub 2007 Sep 17. link to original article contains 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

Immunotherapy

14-day cycles

Dose and schedule modifications


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

Immunotherapy

14-day cycles

Dose and schedule modifications

References

  1. AVOREN: Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007 Dec 22;370(9605):2103-11. link to original article PubMed NCT00738530
    1. Update: Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, Sneller V. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010 May 1;28(13):2144-50. Epub 2010 Apr 5. link to original article contains dosing details in manuscript PubMed
  2. CALGB 90206: Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008 Nov 20;26(33):5422-8. Epub 2008 Oct 20. link to original article link to PMC article PubMed NCT00072046
    1. Update: Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010 May 1;28(13):2137-43. Epub 2010 Apr 5. link to original article link to PMC article PubMed
  3. INTORACT: Rini BI, Bellmunt J, Clancy J, Wang K, Niethammer AG, Hariharan S, Escudier B. Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol. 2014 Mar 10;32(8):752-9. Epub 2013 Dec 2. link to original article contains dosing details in abstract PubMed NCT00631371

Cabozantinib monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Choueiri et al. 2016 (CABOSUN) 2013-2015 Phase 3 (E-RT-switch-ic) Sunitinib Superior PFS1 (primary endpoint)
Median PFS: 8.6 vs 5.3 mo
(HR 0.48, 95% CI 0.31-0.74)

1Reported efficacy is based on the 2018 update; in this update, independent review gave an ORR of 20% (95% CI 12-31%) in the experimental arm and 9% (95% CI 4-18%) in the control arm.

Targeted therapy

28-day cycles

References

  1. CABOSUN: Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, Feldman DR, Olencki T, Picus J, Small EJ, Dakhil S, George DJ, Morris MJ; Alliance. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol. 2017 Feb 20;35(6):591-597. Epub 2016 Nov 14. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01835158
    1. Update: Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, Walsh M, Olencki T, Picus J, Small EJ, Dakhil S, Feldman DR, Mangeshkar M, Scheffold C, George D, Morris MJ. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer. 2018 May;94:115-125. Epub 2018 Mar 20. link to original article contains dosing details in manuscript link to PMC article PubMed
  2. PIVOT-09: NCT03729245

Cabozantinib & Nivolumab

Regimen variant #1, bi-weekly nivolumab

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Choueiri et al. 2021 (CheckMate 9ER) 2017-2019 Phase 3 (E-RT-esc) Sunitinib Superior PFS (primary endpoint)
Median PFS: 16.6 vs 8.3 mo
(HR 0.51, 95% CI 0.41-0.64)

Superior OS1 (secondary endpoint)
Median OS: 37.7 vs 34.3 mo
(HR 0.70, 95% CI 0.55-0.90)

1Reported efficacy is based on the 2022 update.

Targeted therapy

Immunotherapy

14-day cycles


Regimen variant #2, monthly nivolumab

FDA-recommended dose

Note: this dosing does not appear to have been used in a trial, but is recommended by the FDA.

Targeted therapy

Immunotherapy

28-day cycles

References

  1. CheckMate 9ER: Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, Oyervides Juárez VM, Hsieh JJ, Basso U, Shah AY, Suárez C, Hamzaj A, Goh JC, Barrios C, Richardet M, Porta C, Kowalyszyn R, Feregrino JP, Żołnierek J, Pook D, Kessler ER, Tomita Y, Mizuno R, Bedke J, Zhang J, Maurer MA, Simsek B, Ejzykowicz F, Schwab GM, Apolo AB, Motzer RJ; CheckMate 9ER Investigators. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03141177
    1. Update: Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, Suárez C, Hamzaj A, Porta C, Hocking CM, Kessler ER, Gurney H, Tomita Y, Bedke J, Zhang J, Simsek B, Scheffold C, Apolo AB, Choueiri TK. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Jul;23(7):888-898. Epub 2022 Jun 7. link to original article PubMed

Cabozantinib, Ipilimumab, Nivolumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Choueiri et al. 2023 (COSMIC-313) 2019-2022 Phase 3 (E-esc) Ipilimumab & Nivolumab Superior PFS (primary endpoint)
PFS12: 57% vs 49%
(HR 0.73, 95% CI 0.57-0.94)

Targeted therapy

  • Cabozantinib (Cabometyx) as follows:
    • Cycles 1 to 4: 40 mg PO once per day on days 1 to 21
    • Cycle 5 onwards: 40 mg PO once per day on days 1 to 28

Immunotherapy

  • Ipilimumab (Yervoy) as follows:
    • Cycles 1 to 4: 1 mg/kg IV over 30 minutes once on day 1
  • Nivolumab (Opdivo) as follows:
    • Cycles 1 to 4: 3 mg/kg IV over 60 minutes once on day 1
    • Cycles 5 up to 30: 480 mg IV once on day 1

21-day cycle for 4 cycles, then 28-day cycles

References

  1. COSMIC-313: Choueiri TK, Powles T, Albiges L, Burotto M, Szczylik C, Zurawski B, Yanez Ruiz E, Maruzzo M, Suarez Zaizar A, Fein LE, Schutz FA, Heng DYC, Wang F, Mataveli F, Chang YL, van Kooten Losio M, Suarez C, Motzer RJ; COSMIC-313 Investigators. Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. N Engl J Med. 2023 May 11;388(19):1767-1778. link to original article contains dosing details in abstract link to PMC article PubMed NCT03937219

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

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

  1. Bukowski RM, Kabbinavar FF, Figlin RA, Flaherty K, Srinivas S, Vaishampayan U, Drabkin HA, Dutcher J, Ryba S, Xia Q, Scappaticci FA, McDermott D. Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol. 2007 Oct 10;25(29):4536-41. Epub 2007 Sep 17. link to original article contains dosing details in manuscript PubMed

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

21-day cycles

References

  1. CLEAR: Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. link to original article contains dosing details in manuscript PubMed NCT02811861
    1. 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

Study Evidence
Pandya et al. 2011 Retrospective

Chemotherapy

Targeted therapy

21-day cycles

References

  1. Retrospective: Pandya SS, Mier JW, McDermott DF, Cho DC. Addition of gemcitabine at the time of sunitinib resistance in metastatic renal cell cancer. BJU Int. 2011 Oct;108(8 Pt 2):E245-9. Epub 2011 Feb 14. link to original article contains dosing details in manuscript PubMed [move]

Interferon alfa-2a monotherapy

Regimen variant #1, 9 MU TIW

Study Dates of enrollment Evidence Comparator Comparative Efficacy
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

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

7-day cycles

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 #2, 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

Note: Interferon alfa-2a dose was increased only if the prior dose was tolerated.

Immunotherapy

  • Interferon alfa-2a (Roferon-A) as follows:
    • Cycle 1: 3,000,000 units SC once per day on days 1, 3, 5
    • Cycle 2: 6,000,000 units SC once per day on days 1, 3, 5
    • Cycle 3 onwards: 9,000,000 units SC once per day on days 1, 3, 5

7-day cycles

References

  1. A618-1034: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. link to original article contains dosing details in manuscript PubMed NCT00098657
    1. Update: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Aug 1;27(22):3584-90. Epub 2009 Jun 1. link to original article contains dosing details in manuscript link to PMC article PubMed content property of HemOnc.org
    2. HRQoL analysis: Cella D, Michaelson MD, Bushmakin AG, Cappelleri JC, Charbonneau C, Kim ST, Li JZ, Motzer RJ. Health-related quality of life in patients with metastatic renal cell carcinoma treated with sunitinib vs interferon-alpha in a phase III trial: final results and geographical analysis. Br J Cancer. 2010 Feb 16;102(4):658-64. Epub 2010 Jan 26. link to original article link to PMC article PubMed
  2. AVOREN: Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007 Dec 22;370(9605):2103-11. link to original article PubMed NCT00738530
    1. Update: Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, Sneller V. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010 May 1;28(13):2144-50. Epub 2010 Apr 5. link to original article contains dosing details in manuscript PubMed
  3. CALGB 90206: Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008 Nov 20;26(33):5422-8. Epub 2008 Oct 20. link to original article link to PMC article PubMed NCT00072046
    1. Update: Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010 May 1;28(13):2137-43. Epub 2010 Apr 5. link to original article link to PMC article PubMed
  4. 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

High-dose Interleukin-2

HD IL-2: High-Dose InterLeukin-2

Example orders

Regimen

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)

Supportive therapy

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

14- to 19-day cycle for 2 cycles

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)

References

  1. 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

Ipilimumab & Nivolumab

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2018 (CheckMate 214) 2014-2016 Phase 3 (E-RT-switch-ooc) Sunitinib Superior OS1 (co-primary endpoint)
OS42: 56% vs 47%
(HR 0.72, 95% CI 0.61-0.86)

1Reported efficacy is for the ITT population per the 2020 update.
Note: while this is the dosing studied in CheckMate 214, it is not the FDA-recommended dosing.

Immunotherapy

21-day cycle for 4 cycles, then 14-day cycles


Regimen variant #2

FDA-recommended dose

Note: while this one of two FDA-recommended dosing options, we are not aware of any particular published trial using this dosing.

Immunotherapy

  • Ipilimumab (Yervoy) as follows:
    • Cycles 1 to 4: 1 mg/kg IV once on day 1, given second
  • Nivolumab (Opdivo) as follows:
    • Cycles 1 to 4: 3 mg/kg IV once on day 1, given first
    • Cycle 5 onwards: 240 mg IV once on day 1

21-day cycle for 4 cycles, then 14-day cycles


Regimen variant #3

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Choueiri et al. 2023 (COSMIC-313) 2019-2022 Phase 3 (C) Cabozantinib, Ipilimumab, Nivolumab Inferior PFS (primary endpoint)

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Immunotherapy

  • Ipilimumab (Yervoy) as follows:
    • Cycles 1 to 4: 1 mg/kg IV once on day 1, given second
  • Nivolumab (Opdivo) as follows:
    • Cycles 1 to 4: 3 mg/kg IV once on day 1, given first
    • Cycles 5 up to 30: 480 mg IV once on day 1

21-day cycle for 4 cycles, then 28-day cycle for up to 26 cycles (2 years)

References

  1. CheckMate 214: Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. Epub 2018 Mar 21. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02231749
    1. PRO analysis: Cella D, Grünwald V, Escudier B, Hammers HJ, George S, Nathan P, Grimm MO, Rini BI, Doan J, Ivanescu C, Paty J, Mekan S, Motzer RJ. Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial. Lancet Oncol. 2019 Feb;20(2):297-310. Epub 2019 Jan 15. Erratum in: Lancet Oncol. 2019 Jun;20(6):e293. link to original article link to PMC article PubMed
    2. Update: Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, Salman P, Escudier B, Beuselinck B, Amin A, Porta C, George S, Neiman V, Bracarda S, Tykodi SS, Barthélémy P, Leibowitz-Amit R, Plimack ER, Oosting SF, Redman B, Melichar B, Powles T, Nathan P, Oudard S, Pook D, Choueiri TK, Donskov F, Grimm MO, Gurney H, Heng DYC, Kollmannsberger CK, Harrison MR, Tomita Y, Duran I, Grünwald V, McHenry MB, Mekan S, Tannir NM; CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019 Oct;20(10):1370-1385. Epub 2019 Aug 16. Erratum in: Lancet Oncol. 2019 Aug 21. link to original article link to PMC article PubMed
    3. Update: Motzer RJ, Escudier B, McDermott DF, Arén Frontera O, Melichar B, Powles T, Donskov F, Plimack ER, Barthélémy P, Hammers HJ, George S, Grünwald V, Porta C, Neiman V, Ravaud A, Choueiri TK, Rini BI, Salman P, Kollmannsberger CK, Tykodi SS, Grimm MO, Gurney H, Leibowitz-Amit R, Geertsen PF, Amin A, Tomita Y, McHenry MB, Saggi SS, Tannir NM. Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer. 2020 Jul;8(2):e000891. Erratum in: J Immunother Cancer. 2021 May;9(5). link to original article link to PMC article PubMed
    4. Update: Albiges L, Tannir NM, Burotto M, McDermott D, Plimack ER, Barthélémy P, Porta C, Powles T, Donskov F, George S, Kollmannsberger CK, Gurney H, Grimm MO, Tomita Y, Castellano D, Rini BI, Choueiri TK, Saggi SS, McHenry MB, Motzer RJ. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020 Nov;5(6):e001079. link to original article link to PMC article PubMed
  2. COSMIC-313: Choueiri TK, Powles T, Albiges L, Burotto M, Szczylik C, Zurawski B, Yanez Ruiz E, Maruzzo M, Suarez Zaizar A, Fein LE, Schutz FA, Heng DYC, Wang F, Mataveli F, Chang YL, van Kooten Losio M, Suarez C, Motzer RJ; COSMIC-313 Investigators. Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. N Engl J Med. 2023 May 11;388(19):1767-1778. link to original article contains dosing details in abstract link to PMC article PubMed NCT03937219
  3. PDIGREE: NCT03793166

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

Immunotherapy

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

Immunotherapy

42-day cycles

References

  1. CLEAR: Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. link to original article contains dosing details in manuscript PubMed NCT02811861
    1. 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
  2. MK-6482-012: NCT04736706

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-RT-esc) Placebo Superior PFS (primary endpoint)
Median PFS: 9.2 vs 4.2 mo
(HR 0.46, 95% CI 0.34-0.62)

Did not meet secondary endpoint of OS1
Median OS: 22.9 vs 20.5 mo
(HR 0.91, 95% CI 0.71-1.16)
Motzer et al. 2013 (COMPARZ) 2008-2011 Phase 3 (E-switch-ic) Sunitinib Non-inferior PFS (primary endpoint)
Median PFS: 8.4 vs 9.5 mo
(HR 1.05, 95% CI 0.90-1.22)
Cirkel et al. 2017 (ROPETAR) 2012-2014 Randomized (C) Pazopanib/Everolimus Did not meet primary endpoint of PFS
Brown et al. 2023 (STAR) 2012-01-13 to 2017-09-12 Phase 2/3 (C) 1a. Pazopanib x 2 y, then treatment-free interval
1b. Sunitinib x 2 y, then treatment-free interval
Inconclusive whether non-inferior OS (co-primary endpoint)

Targeted therapy

  • Pazopanib (Votrient) 800 mg PO once per day on days 1 to 28, taken at least 1 hour before or 2 hours after meals

28-day cycles

Dose and schedule modifications

  • Dose may be decreased to 600 mg or 400 mg PO once per day depending on tolerability

References

  1. VEG102616: Hutson TE, Davis ID, Machiels JP, De Souza PL, Rottey S, Hong BF, Epstein RJ, Baker KL, McCann L, Crofts T, Pandite L, Figlin RA. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2010 Jan 20;28(3):475-80. Epub 2009 Dec 14. link to original article contains dosing details in manuscript PubMed NCT00244764
  2. VEG105192: Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarbá JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010 Feb 20;28(6):1061-8. Epub 2010 Jan 25. link to original article contains dosing details in manuscript PubMed NCT00334282
    1. Update: Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, Zarba JJ, Gladkov OA, Lee E, Szczylik C, McCann L, Rubin SD, Chen M, Davis ID. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013 Apr;49(6):1287-96. Epub 2013 Jan 12. link to original article contains dosing details in manuscript PubMed
  3. COMPARZ: Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, Jin J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R, Pandite LN, Choueiri TK. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013 Aug 22;369(8):722-31. link to original article contains dosing details in manuscript PubMed NCT00720941
    1. Update: Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med. 2014 May 1;370(18):1769-70. link to letter PubMed
  4. 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
  5. ROPETAR: Cirkel GA, Hamberg P, Sleijfer S, Loosveld OJL, Dercksen MW, Los M, Polee MB, van den Berkmortel F, Aarts MJ, Beerepoot LV, Groenewegen G, Lolkema MP, Tascilar M, Portielje JEA, Peters FPJ, Klümpen HJ, van der Noort V, Haanen JBAG, Voest EE; Dutch WIN-O Consortium. Alternating treatment with pazopanib and everolimus vs continuous pazopanib to delay disease progression in patients with metastatic clear cell renal cell cancer: the ROPETAR randomized clinical trial. JAMA Oncol. 2017 Apr 1;3(4):501-508. link to original article contains dosing details in abstract PubMed NCT01408004
  6. STAR: Brown JE, Royle KL, Gregory W, Ralph C, Maraveyas A, Din O, Eisen T, Nathan P, Powles T, Griffiths R, Jones R, Vasudev N, Wheater M, Hamid A, Waddell T, McMenemin R, Patel P, Larkin J, Faust G, Martin A, Swain J, Bestall J, McCabe C, Meads D, Goh V, Min Wah T, Brown J, Hewison J, Selby P, Collinson F; STAR Investigators. Temporary treatment cessation versus continuation of first-line tyrosine kinase inhibitor in patients with advanced clear cell renal cell carcinoma (STAR): an open-label, non-inferiority, randomised, controlled, phase 2/3 trial. Lancet Oncol. 2023 Mar;24(3):213-227. Epub 2023 Feb 13. link to original article PubMed ISRCTN06473203

Pembrolizumab monotherapy

Regimen

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

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

Immunotherapy

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

References

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

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

28-day cycles

References

  1. Bayer 11726: Eisen T, Joensuu H, Nathan PD, Harper PG, Wojtukiewicz MZ, Nicholson S, Bahl A, Tomczak P, Pyrhonen S, Fife K, Bono P, Boxall J, Wagner A, Jeffers M, Lin T, Quinn DI. Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial. Lancet Oncol. 2012 Oct;13(10):1055-62. Epub 2012 Sep 6. link to original article contains 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
Motzer et al. 2013 (TIVO-1) 2010-02 to 2010-08 Phase 3 (C) Tivozanib Seems to have inferior PFS
Hutson et al. 2013 (A4061051) 2010-06-14 to 2011-04-21 Phase 3 (C) Axitinib Might have inferior PFS1
Tomita et al. 2020 (CROSS-J-RCC) 2010-2012 Phase 3 (E-switch-ic) Sunitinib Did not meet primary endpoint of PFS

1In the 2016 update to A4061051, there was no difference in OS, which was a secondary endpoint. Reported efficacy here is from the primary (2013) analysis.

Targeted therapy

Continued indefinitely

Dose and schedule modifications

  • Can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity

References

  1. 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
  2. TIVO-1: Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, Tomczak P, Lyulko O, Alyasova A, Harza M, Kogan M, Alekseev BY, Sternberg CN, Szczylik C, Cella D, Ivanescu C, Krivoshik A, Strahs A, Esteves B, Berkenblit A, Hutson TE. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013 Oct 20;31(30):3791-9. Epub 2013 Sep 9. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01030783
  3. A4061051: Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, Rosbrook B, Chen C, Kim S, Vogelzang NJ. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1287-94. Epub 2013 Oct 25. link to original article contains dosing details in abstract PubMed NCT00920816
    1. Update: Hutson TE, Al-Shukri S, Stus VP, Lipatov ON, Shparyk Y, Bair AH, Rosbrook B, Andrews GI, Vogelzang NJ. Axitinib versus sorafenib in first-line metastatic renal cell carcinoma: Overall survival from a randomized phase III trial. Clin Genitourin Cancer. 2017 Feb;15(1):72-76. Epub 2016 May 27. link to original article PubMed
  4. 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)
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. 2013 (COMPARZ) 2008-2011 Phase 3 (C) Pazopanib Non-inferior 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
Brown et al. 2023 (STAR) 2012-01-13 to 2017-09-12 Phase 2/3 (C) 1a. Pazopanib x 2 y, then treatment-free interval
1b. Sunitinib x 2 y, then treatment-free interval
Inconclusive whether non-inferior OS (co-primary endpoint)
Choueiri et al. 2016 (CABOSUN) 2013-2015 Phase 3 (C) Cabozantinib Inferior PFS2
Figlin et al. 2020 (ADAPT) 2013-2016 Phase 3 (C) Rocapuldencel-T & Sunitinib Did not meet primary endpoint of OS
Median OS: 32.4 vs 27.7 mo
(HR 0.91, 95% CI 0.71-1.20)
Motzer et al. 2018 (CheckMate 214) 2014-2016 Phase 3 (C) Ipilimumab & Nivolumab Inferior OS
Motzer et al. 2019 (JAVELIN Renal 101) 2016-03-29 to 2017-12-19 Phase 3 (C) Axitinib & Avelumab Seems to have inferior OS3
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
Rini et al. 2019 (KEYNOTE-426) 2016-10-24 to 2018-01-24 Phase 3 (C) Axitinib & Pembrolizumab Inferior OS
Choueiri et al. 2021 (CheckMate 9ER) 2017-2019 Phase 3 (C) Cabozantinib & Nivolumab 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.
2Reported efficacy for CABOSUN is based on the 2018 update.
3Reported efficacy for JAVELIN Renal 101 is based on the 2020 update, although the authors state that OS data remains immature.

Targeted therapy

42-day cycles

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

Targeted therapy

28-day cycles

References

  1. A618-1034: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. link to original article contains dosing details in manuscript PubMed NCT00098657
    1. Update: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Aug 1;27(22):3584-90. Epub 2009 Jun 1. link to original article contains dosing details in manuscript link to PMC article PubMed
    2. HRQoL analysis: Cella D, Michaelson MD, Bushmakin AG, Cappelleri JC, Charbonneau C, Kim ST, Li JZ, Motzer RJ. Health-related quality of life in patients with metastatic renal cell carcinoma treated with sunitinib vs interferon-alpha in a phase III trial: final results and geographical analysis. Br J Cancer. 2010 Feb 16;102(4):658-64. Epub 2010 Jan 26. link to original article link to PMC article PubMed
  2. 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
  3. COMPARZ: Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, Jin J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R, Pandite LN, Choueiri TK. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013 Aug 22;369(8):722-31. link to original article contains dosing details in manuscript PubMed NCT00720941
    1. Update: Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med. 2014 May 1;370(18):1769-70. link to letter PubMed
  4. CABOSUN: Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, Feldman DR, Olencki T, Picus J, Small EJ, Dakhil S, George DJ, Morris MJ. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol. 2017 Feb 20;35(6):591-597. Epub 2016 Nov 14. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01835158
    1. Update: Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, Walsh M, Olencki T, Picus J, Small EJ, Dakhil S, Feldman DR, Mangeshkar M, Scheffold C, George D, Morris MJ. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer. 2018 May;94:115-125. Epub 2018 Mar 20. link to original article contains dosing details in manuscript link to PMC article PubMed
  5. 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. Epub 2016 Oct 3. link to original article contains dosing details in abstract PubMed NCT01265901
  6. CheckMate 214: Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. Epub 2018 Mar 21. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02231749
    1. PRO analysis: Cella D, Grünwald V, Escudier B, Hammers HJ, George S, Nathan P, Grimm MO, Rini BI, Doan J, Ivanescu C, Paty J, Mekan S, Motzer RJ. Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial. Lancet Oncol. 2019 Feb;20(2):297-310. Epub 2019 Jan 15. Erratum in: Lancet Oncol. 2019 Jun;20(6):e293. link to original article link to PMC article PubMed
    2. Update: Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, Salman P, Escudier B, Beuselinck B, Amin A, Porta C, George S, Neiman V, Bracarda S, Tykodi SS, Barthélémy P, Leibowitz-Amit R, Plimack ER, Oosting SF, Redman B, Melichar B, Powles T, Nathan P, Oudard S, Pook D, Choueiri TK, Donskov F, Grimm MO, Gurney H, Heng DYC, Kollmannsberger CK, Harrison MR, Tomita Y, Duran I, Grünwald V, McHenry MB, Mekan S, Tannir NM; CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019 Oct;20(10):1370-1385. Epub 2019 Aug 16. Erratum in: Lancet Oncol. 2019 Aug 21. link to original article link to PMC article PubMed
    3. Update: Motzer RJ, Escudier B, McDermott DF, Arén Frontera O, Melichar B, Powles T, Donskov F, Plimack ER, Barthélémy P, Hammers HJ, George S, Grünwald V, Porta C, Neiman V, Ravaud A, Choueiri TK, Rini BI, Salman P, Kollmannsberger CK, Tykodi SS, Grimm MO, Gurney H, Leibowitz-Amit R, Geertsen PF, Amin A, Tomita Y, McHenry MB, Saggi SS, Tannir NM. Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer. 2020 Jul;8(2):e000891. Erratum in: J Immunother Cancer. 2021 May;9(5). link to original article link to PMC article PubMed
    4. Update: Albiges L, Tannir NM, Burotto M, McDermott D, Plimack ER, Barthélémy P, Porta C, Powles T, Donskov F, George S, Kollmannsberger CK, Gurney H, Grimm MO, Tomita Y, Castellano D, Rini BI, Choueiri TK, Saggi SS, McHenry MB, Motzer RJ. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020 Nov;5(6):e001079. link to original article link to PMC article PubMed
  7. 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
  8. KEYNOTE-426: Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, Vynnychenko I, Kryzhanivska A, Bondarenko I, Azevedo SJ, Borchiellini D, Szczylik C, Markus M, McDermott RS, Bedke J, Tartas S, Chang YH, Tamada S, Shou Q, Perini RF, Chen M, Atkins MB, Powles T; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116-1127. Epub 2019 Feb 16. link to original article contains dosing details in abstract PubMed NCT02853331
    1. Update: Powles T, Plimack ER, Soulières D, Waddell T, Stus V, Gafanov R, Nosov D, Pouliot F, Melichar B, Vynnychenko I, Azevedo SJ, Borchiellini D, McDermott RS, Bedke J, Tamada S, Yin L, Chen M, Molife LR, Atkins MB, Rini BI. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1563-1573. Epub 2020 Oct 23. Erratum in: Lancet Oncol. 2020 Dec;21(12):e553. link to original article PubMed
  9. JAVELIN Renal 101: Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M, Lee JL, Vasiliev A, Miller WH Jr, Gurney H, Schmidinger M, Larkin J, Atkins MB, Bedke J, Alekseev B, Wang J, Mariani M, Robbins PB, Chudnovsky A, Fowst C, Hariharan S, Huang B, di Pietro A, Choueiri TK. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1103-1115. Epub 2019 Feb 16. link to original article contains dosing details in abstract link to PMC article PubMed NCT02684006
    1. Update: Choueiri TK, Motzer RJ, Rini BI, Haanen J, Campbell MT, Venugopal B, Kollmannsberger C, Gravis-Mescam G, Uemura M, Lee JL, Grimm MO, Gurney H, Schmidinger M, Larkin J, Atkins MB, Pal SK, Wang J, Mariani M, Krishnaswami S, Cislo P, Chudnovsky A, Fowst C, Huang B, di Pietro A, Albiges L. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020 Aug;31(8):1030-1039. Epub 2020 Apr 25. link to original article link to PMC article PubMed
  10. 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
  11. 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
  12. 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
    1. 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
  13. CheckMate 9ER: Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, Oyervides Juárez VM, Hsieh JJ, Basso U, Shah AY, Suárez C, Hamzaj A, Goh JC, Barrios C, Richardet M, Porta C, Kowalyszyn R, Feregrino JP, Żołnierek J, Pook D, Kessler ER, Tomita Y, Mizuno R, Bedke J, Zhang J, Maurer MA, Simsek B, Ejzykowicz F, Schwab GM, Apolo AB, Motzer RJ; CheckMate 9ER Investigators. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03141177
    1. Update: Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, Suárez C, Hamzaj A, Porta C, Hocking CM, Kessler ER, Gurney H, Tomita Y, Bedke J, Zhang J, Simsek B, Scheffold C, Apolo AB, Choueiri TK. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Jul;23(7):888-898. Epub 2022 Jun 7. link to original article PubMed
  14. STAR: Brown JE, Royle KL, Gregory W, Ralph C, Maraveyas A, Din O, Eisen T, Nathan P, Powles T, Griffiths R, Jones R, Vasudev N, Wheater M, Hamid A, Waddell T, McMenemin R, Patel P, Larkin J, Faust G, Martin A, Swain J, Bestall J, McCabe C, Meads D, Goh V, Min Wah T, Brown J, Hewison J, Selby P, Collinson F; STAR Investigators. Temporary treatment cessation versus continuation of first-line tyrosine kinase inhibitor in patients with advanced clear cell renal cell carcinoma (STAR): an open-label, non-inferiority, randomised, controlled, phase 2/3 trial. Lancet Oncol. 2023 Mar;24(3):213-227. Epub 2023 Feb 13. link to original article PubMed ISRCTN06473203
  15. KEYNOTE-679: NCT03260894
  16. JS001-036-III-RCC: NCT04394975
  17. PIVOT-09: NCT03729245
  18. TQB2450-III-07: NCT04523272

Tivozanib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Motzer et al. 2013 (TIVO-1) 2010-02 to 2010-08 Phase 3 (E-switch-ic) Sorafenib Seems to have superior PFS (primary endpoint)
Median PFS: 11.9 vs 9.1 mo
(HR 0.80, 95% CI 0.64-0.993)

Targeted therapy

28-day cycles

References

  1. TIVO-1: Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, Tomczak P, Lyulko O, Alyasova A, Harza M, Kogan M, Alekseev BY, Sternberg CN, Szczylik C, Cella D, Ivanescu C, Krivoshik A, Strahs A, Esteves B, Berkenblit A, Hutson TE. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013 Oct 20;31(30):3791-9. Epub 2013 Sep 9. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01030783

Metastatic disease, second-line

Axitinib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rini et al. 2011 (AXIS) 2008-2010 Phase 3 (E-RT-switch-ic) Sorafenib Superior PFS1 (primary endpoint)
Median PFS: 8.3 vs 5.7 mo
(HR 0.66, 95% CI 0.55-0.78)

Did not meet secondary endpoint of OS1
Median OS: 20.1 vs 19.2 mo
(HR 0.97, 95% CI 0.80-1.17)

1Reported efficacy is based on the 2013 update.

Prior treatment criteria

  • AXIS: Progression on first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines

Targeted therapy

Continued indefinitely

Dose and schedule modifications

  • After at least 2 weeks, if tolerated and BP not greater than 150/90, dose can be increased to 7 mg PO twice per day
  • After at least another 2 weeks, if tolerated and BP not greater than 150/90, dose can be increased to 10 mg PO twice per day
  • Dose can be reduced to 2 to 3 mg PO twice per day if needed based on tolerability

References

  1. AXIS: Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011 Dec 3;378(9807):1931-9. Epub 2011 Nov 4. link to original article contains dosing details in manuscript PubMed NCT00678392
    1. PRO analysis: Cella D, Escudier B, Rini B, Chen C, Bhattacharyya H, Tarazi J, Rosbrook B, Kim S, Motzer R. Patient-reported outcomes for axitinib vs sorafenib in metastatic renal cell carcinoma: phase III (AXIS) trial. Br J Cancer. 2013 Apr 30;108(8):1571-8. Epub 2013 Apr 11. link to original article link to PMC article PubMed
    2. Update: Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, Oudard S, Gore ME, Tarazi J, Hariharan S, Chen C, Rosbrook B, Kim S, Rini BI. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013 May;14(6):552-62. Epub 2013 Apr 15. link to original article contains dosing details in manuscript PubMed
    3. Subgroup analysis: Escudier B, Michaelson MD, Motzer RJ, Hutson TE, Clark JI, Lim HY, Porfiri E, Zalewski P, Kannourakis G, Staehler M, Tarazi J, Rosbrook B, Cisar L, Hariharan S, Kim S, Rini BI. Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial. Br J Cancer. 2014 Jun 10;110(12):2821-8. Epub 2014 May 13. link to original article link to PMC article PubMed

Belzutifan monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (LITESPARK-005) 2020-ongoing Phase 3 (E-RT-switch-ooc) Everolimus Superior PFS1 (primary endpoint)
Median PFS: 5.6 vs 5.6 mo
(HR 0.75, 95% CI 0.63-0.90)

1Reported efficacy is based on the FDA announcement; hazards were non-proportional.

Targeted therapy

Continued indefinitely

References

  1. LITESPARK-005: NCT04195750

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

Targeted therapy

14-day cycles

References

  1. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003 Jul 31;349(5):427-34. link to original article contains 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

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

28-day cycles

References

  1. METEOR: Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1814-23. Epub 2015 Sep 25. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01865747
    1. Update: Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, Hammers HJ, Donskov F, Roth BJ, Peltola K, Lee JL, Heng DY, Schmidinger M, Agarwal N, Sternberg CN, McDermott DF, Aftab DT, Hessel C, Scheffold C, Schwab G, Hutson TE, Pal S, Motzer RJ; METEOR investigators. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):917-27. Epub 2016 Jun 5. link to original article PubMed
    2. HRQoL analysis: Cella D, Escudier B, Tannir NM, Powles T, Donskov F, Peltola K, Schmidinger M, Heng DYC, Mainwaring PN, Hammers HJ, Lee JL, Roth BJ, Marteau F, Williams P, Baer J, Mangeshkar M, Scheffold C, Hutson TE, Pal S, Motzer RJ, Choueiri TK. Quality of life outcomes for cabozantinib versus everolimus in patients with metastatic renal cell carcinoma: METEOR phase III randomized trial. J Clin Oncol. 2018 Mar 10;36(8):757-764. Epub 2018 Jan 29. link to original article link to PMC article PubMed
    3. Update: Motzer RJ, Escudier B, Powles T, Scheffold C, Choueiri TK. Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer. 2018 May;118(9):1176-1178. Epub 2018 Mar 26. link to original article link to PMC article PubMed
  2. 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
  3. 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. 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
Awaiting publication (LITESPARK-005) 2020-ongoing Phase 3 (C) Belzutifan 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

Targeted therapy

Continued indefinitely

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

  1. RECORD-1: Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008 Aug 9;372(9637):449-56. Epub 2008 Jul 22. link to original article contains dosing details in manuscript PubMed NCT00410124 [move]
    1. Update: Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A; RECORD-1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010 Sep 15;116(18):4256-65. link to original article contains dosing details in manuscript PubMed
  2. CheckMate 025: Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803-13. Epub 2015 Sep 25. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01668784
    1. HRQoL analysis: Cella D, Grünwald V, Nathan P, Doan J, Dastani H, Taylor F, Bennett B, DeRosa M, Berry S, Broglio K, Berghorn E, Motzer RJ. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):994-1003. Epub 2016 Jun 6. Erratum in: Lancet Oncol. 2016 Jul;17 (7):e270. link to original article link to PMC article PubMed
    2. Subgroup analysis: Escudier B, Sharma P, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Gurney H, Donskov F, Peltola K, Wagstaff J, Gauler TC, Ueda T, Zhao H, Waxman IM, Motzer RJ; CheckMate 025 investigators. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol. 2017 Dec;72(6):962-971. Epub 2017 Mar 3. Erratum in: Eur Urol. 2018 Jan 3. link to original article PubMed
    3. Subgroup analysis: Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Saito M, Kimura G, Yonese J, Yao M, Uemura H. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the phase III CheckMate 025 study. Jpn J Clin Oncol. 2019 Jun 1;49(6):506-514. link to original article PubMed
    4. Update: Motzer RJ, Escudier B, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Plimack ER, Procopio G, McDermott DF, Castellano D, Choueiri TK, Donskov F, Gurney H, Oudard S, Richardet M, Peltola K, Alva AS, Carducci M, Wagstaff J, Chevreau C, Fukasawa S, Tomita Y, Gauler TC, Kollmannsberger CK, Schutz FA, Larkin J, Cella D, McHenry MB, Saggi SS, Tannir NM. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer. 2020 Sep 15;126(18):4156-4167. Epub 2020 Jul 16. link to original article link to PMC article PubMed
  3. 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
    1. Update: Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, Hammers HJ, Donskov F, Roth BJ, Peltola K, Lee JL, Heng DY, Schmidinger M, Agarwal N, Sternberg CN, McDermott DF, Aftab DT, Hessel C, Scheffold C, Schwab G, Hutson TE, Pal S, Motzer RJ; METEOR investigators. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):917-27. Epub 2016 Jun 5. link to original article PubMed
    2. HRQoL analysis: Cella D, Escudier B, Tannir NM, Powles T, Donskov F, Peltola K, Schmidinger M, Heng DYC, Mainwaring PN, Hammers HJ, Lee JL, Roth BJ, Marteau F, Williams P, Baer J, Mangeshkar M, Scheffold C, Hutson TE, Pal S, Motzer RJ, Choueiri TK. Quality of life outcomes for cabozantinib versus everolimus in patients with metastatic renal cell carcinoma: METEOR phase III randomized trial. J Clin Oncol. 2018 Mar 10;36(8):757-764. Epub 2018 Jan 29. link to original article link to PMC article PubMed
    3. Update: Motzer RJ, Escudier B, Powles T, Scheffold C, Choueiri TK. Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer. 2018 May;118(9):1176-1178. Epub 2018 Mar 26. link to original article link to PMC article PubMed
  4. 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
    1. Update: Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 Jan;17(1):e4-5. Epub 2015 Dec 23. link to original article PubMed
  5. 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
  6. 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
  7. LITESPARK-005: NCT04195750

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

Targeted therapy

Continued indefinitely

References

  1. E7080-G000-205: Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. link to original article contains dosing details in manuscript PubMed NCT01136733
    1. Update: Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 Jan;17(1):e4-5. Epub 2015 Dec 23. 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

Targeted therapy

28-day cycles

References

  1. E7080-G000-205: Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. link to original article contains dosing details in manuscript PubMed NCT01136733
    1. Update: Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 Jan;17(1):e4-5. Epub 2015 Dec 23. 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

Immunotherapy

21-day cycles


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

Immunotherapy

21-day cycles


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

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

Immunotherapy

21-day cycles


Regimen variant #5, flat dose

Study Dates of enrollment Evidence
McFarlane et al. 2020 (CheckMate 374) 2015-12 to 2016-12 Phase 3b/4

Immunotherapy

14-day cycles

References

  1. CheckMate 010: Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, Vaishampayan UN, Drabkin HA, George S, Logan TF, Margolin KA, Plimack ER, Lambert AM, Waxman IM, Hammers HJ. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. 2015 May 1;33(13):1430-7. Epub 2014 Dec 1. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01354431
  2. CheckMate 025: Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803-13. Epub 2015 Sep 25. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01668784
    1. HRQoL analysis: Cella D, Grünwald V, Nathan P, Doan J, Dastani H, Taylor F, Bennett B, DeRosa M, Berry S, Broglio K, Berghorn E, Motzer RJ. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):994-1003. Epub 2016 Jun 6. Erratum in: Lancet Oncol. 2016 Jul;17 (7):e270. link to original article link to PMC article PubMed
    2. Subgroup analysis: Escudier B, Sharma P, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Gurney H, Donskov F, Peltola K, Wagstaff J, Gauler TC, Ueda T, Zhao H, Waxman IM, Motzer RJ; CheckMate 025 investigators. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol. 2017 Dec;72(6):962-971. Epub 2017 Mar 3. Erratum in: Eur Urol. 2018 Jan 3. link to original article PubMed
    3. Subgroup analysis: Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Saito M, Kimura G, Yonese J, Yao M, Uemura H. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the phase III CheckMate 025 study. Jpn J Clin Oncol. 2019 Jun 1;49(6):506-514. link to original article PubMed
    4. Update: Motzer RJ, Escudier B, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Plimack ER, Procopio G, McDermott DF, Castellano D, Choueiri TK, Donskov F, Gurney H, Oudard S, Richardet M, Peltola K, Alva AS, Carducci M, Wagstaff J, Chevreau C, Fukasawa S, Tomita Y, Gauler TC, Kollmannsberger CK, Schutz FA, Larkin J, Cella D, McHenry MB, Saggi SS, Tannir NM. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer. 2020 Sep 15;126(18):4156-4167. Epub 2020 Jul 16. link to original article link to PMC article PubMed
  3. CheckMate 374: McFarlane JJ, Kochenderfer MD, Olsen MR, Bauer TM, Molina A, Hauke RJ, Reeves JA, Babu S, Van Veldhuizen P, Somer B, Gunuganti V, Schnadig I, George S, Page RD, Arrowsmith E, Jain RK, Zhang J, McHenry MB, Johansen JL, Vogelzang NJ. Safety and Efficacy of Nivolumab in Patients With Advanced Clear Cell Renal Cell Carcinoma: Results From the Phase IIIb/IV CheckMate 374 Study. Clin Genitourin Cancer. 2020 Dec;18(6):469-476.e4. Epub 2020 Jun 14. link to original article contains dosing details in abstract PubMed NCT02596035

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 on days 1 to 28, taken at least 1 hour before or 2 hours after meals

28-day cycles

Dose and schedule modifications

  • Dose may be decreased to 600 mg or 400 mg PO once per day depending on tolerability

References

  1. VEG102616: Hutson TE, Davis ID, Machiels JP, De Souza PL, Rottey S, Hong BF, Epstein RJ, Baker KL, McCann L, Crofts T, Pandite L, Figlin RA. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2010 Jan 20;28(3):475-80. Epub 2009 Dec 14. link to original article contains dosing details in manuscript PubMed NCT00244764
  2. VEG105192: Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarbá JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010 Feb 20;28(6):1061-8. Epub 2010 Jan 25. link to original article contains dosing details in manuscript PubMed NCT00334282
    1. Update: Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, Zarba JJ, Gladkov OA, Lee E, Szczylik C, McCann L, Rubin SD, Chen M, Davis ID. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013 Apr;49(6):1287-96. Epub 2013 Jan 12. link to original article contains dosing details in manuscript PubMed
  3. Hainsworth JD, Rubin MS, Arrowsmith ER, Khatcheressian J, Crane EJ, Franco LA. Pazopanib as second-line treatment after sunitinib or bevacizumab in patients with advanced renal cell carcinoma: a Sarah Cannon Oncology Research Consortium phase II trial. Clin Genitourin Cancer. 2013 Sep;11(3):270-5. Epub 2013 May 9. link to original article contains dosing details in abstract PubMed

Sorafenib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Escudier et al. 2007 (TARGETRCC) 2003-2005 Phase 3 (E-RT-esc) Placebo Might have superior OS1 (primary endpoint)
Median OS: 17.8 vs 15.2 mo
(HR 0.88, 95% CI 0.74-1.04)
Rini et al. 2011 (AXIS) 2008-2010 Phase 3 (C) Axitinib Inferior PFS

Note: TARGET should not be confused with the study by the same name in breast cancer.

Prior treatment criteria

  • TARGETRCC: 1 systemic treatment within the previous 8 months, with progression
  • AXIS: Progression on first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines

Targeted therapy

Continued indefinitely

Dose and schedule modifications

  • Sorafenib (Nexavar) can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity

References

  1. TARGETRCC: Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):125-34. Erratum in: N Engl J Med. 2007 Jul 12;357(2):203. link to original article contains dosing details in manuscript PubMed NCT00073307
    1. Update: Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, Negrier S, Chevreau C, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Anderson S, Hofilena G, Shan M, Pena C, Lathia C, Bukowski RM. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009 Jul 10;27(20):3312-8. Epub 2009 May 18. link to original article PubMed
    2. Subgroup analysis: Hutson TE, Bellmunt J, Porta C, Szczylik C, Staehler M, Nadel A, Anderson S, Bukowski R, Eisen T, Escudier B; Sorafenib TARGET Clinical Trial Group. Long-term safety of sorafenib in advanced renal cell carcinoma: follow-up of patients from phase III TARGET. Eur J Cancer. 2010 Sep;46(13):2432-40. Epub 2010 Jul 23. link to original article contains dosing details in manuscript PubMed
  2. AXIS: Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011 Dec 3;378(9807):1931-9. Epub 2011 Nov 4. link to original article contains dosing details in manuscript PubMed NCT00678392
    1. PRO analysis: Cella D, Escudier B, Rini B, Chen C, Bhattacharyya H, Tarazi J, Rosbrook B, Kim S, Motzer R. Patient-reported outcomes for axitinib vs sorafenib in metastatic renal cell carcinoma: phase III (AXIS) trial. Br J Cancer. 2013 Apr 30;108(8):1571-8. Epub 2013 Apr 11. link to original article link to PMC article PubMed
    2. Update: Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, Oudard S, Gore ME, Tarazi J, Hariharan S, Chen C, Rosbrook B, Kim S, Rini BI. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013 May;14(6):552-62. Epub 2013 Apr 15. link to original article contains dosing details in manuscript PubMed
    3. Subgroup analysis: Escudier B, Michaelson MD, Motzer RJ, Hutson TE, Clark JI, Lim HY, Porfiri E, Zalewski P, Kannourakis G, Staehler M, Tarazi J, Rosbrook B, Cisar L, Hariharan S, Kim S, Rini BI. Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial. Br J Cancer. 2014 Jun 10;110(12):2821-8. Epub 2014 May 13. link to original article link to PMC article PubMed

Sunitinib monotherapy

Regimen

Study Dates of enrollment Evidence
Motzer et al. 2006 (A618-1006) 2004 Phase 2 (RT)

Targeted therapy

42-day cycles

Dose and schedule modifications

  • Dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability

References

  1. 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

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.

Targeted therapy

28-day cycles

References

  1. GOLD: Motzer RJ, Porta C, Vogelzang NJ, Sternberg CN, Szczylik C, Zolnierek J, Kollmannsberger C, Rha SY, Bjarnason GA, Melichar B, De Giorgi U, Grünwald V, Davis ID, Lee JL, Esteban E, Urbanowitz G, Cai C, Squires M, Marker M, Shi MM, Escudier B. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Mar;15(3):286-96. Epub 2014 Feb 17. link to original article contains dosing details in abstract link to PMC article PubMed NCT01223027
  2. TIVO-3: Rini BI, Pal SK, Escudier BJ, Atkins MB, Hutson TE, Porta C, Verzoni E, Needle MN, McDermott DF. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020 Jan;21(1):95-104. Epub 2019 Dec 3. link to original article contains dosing details in manuscript' PubMed NCT02627963
    1. Update: Pal SK, Escudier BJ, Atkins MB, Hutson TE, Porta C, Verzoni E, Needle MN, Powers D, McDermott DF, Rini BI. Final Overall Survival Results from a Phase 3 Study to Compare Tivozanib to Sorafenib as Third- or Fourth-line Therapy in Subjects with Metastatic Renal Cell Carcinoma. Eur Urol. 2020 Dec;78(6):783-785. Epub 2020 Sep 13. link to original article PubMed

Tivozanib monotherapy

Regimen variant #1, 1.34 mg/day

FDA-recommended dose

Note: this is not the dose reported in the manuscript.

Targeted therapy

28-day cycles


Regimen variant #2, 1.5 mg/day

Study 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)

Targeted therapy

28-day cycles

References

  1. TIVO-3: Rini BI, Pal SK, Escudier BJ, Atkins MB, Hutson TE, Porta C, Verzoni E, Needle MN, McDermott DF. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020 Jan;21(1):95-104. Epub 2019 Dec 3. link to original article contains dosing details in manuscript PubMed NCT02627963
    1. Update: Pal SK, Escudier BJ, Atkins MB, Hutson TE, Porta C, Verzoni E, Needle MN, Powers D, McDermott DF, Rini BI. Final Overall Survival Results from a Phase 3 Study to Compare Tivozanib to Sorafenib as Third- or Fourth-line Therapy in Subjects with Metastatic Renal Cell Carcinoma. Eur Urol. 2020 Dec;78(6):783-785. Epub 2020 Sep 13. link to original article PubMed