Renal cell carcinoma

Section editor
	Ali Raza Khaki, MD Stanford University Palo Alto, CA arkhaki

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!.
There are several related dedicated pages:

• Histology-specific:
  • Papillary renal cell carcinoma
  • Sarcomatoid renal cell carcinoma

14 regimens on this page 22 variants on this page

Guidelines

EAU

• 2016: Powles et al. Updated EAU guidelines for clear cell renal cancer patients who fail VEGF targeted therapy PubMed

ESMO

• 2021: Powles Recent eUpdate to the ESMO Clinical Practice Guidelines on renal cell carcinoma on cabozantinib and nivolumab for first-line clear cell renal cancer: Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
• 2019: Escudier et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Older

• 2016: Escudier et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
• 2014: Escudier et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
• 2012: Escudier et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
• 2010: Escudier et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

NCCN

• NCCN Guidelines - Kidney Cancer

SIOG

• 2018: Kanesvaran et al. Elderly patients with metastatic renal cell carcinoma: position paper from the International Society of Geriatric Oncology

Risk Stratification Calculators

• International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) calculator
  • ref: Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, Mackenzie M, Wood L, Donskov F, Tan MH, Rha SY, Agarwal N, Kollmannsberger C, Rini BI, Choueiri TK; External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013 Feb;14(2):141-8. Epub 2013 Jan 9. link to original article PubMed

• Memorial Sloan Kettering Cancer Center (MSKCC) calculator
  • ref: Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002 Jan 1;20(1):289-96. link to original article PubMed

• Mortality and complication risk calculator for a patients with clinical T1 renal cortical mass ≤ 7 cm (Dr. Sarah P. Psutka)
  • ref: Psutka SP et al., A clinical decision aid to support personalized treatment selection for patients with stage T1 renal masses: Results from a multi-institutional competing risks analysis including performance status and comorbidity. Working paper. link to news article

Adjuvant therapy

Sunitinib monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Haas et al. 2016 (ECOG-ACRIN E2805)	2006-2010	Phase III (E-esc)	Placebo	Did not meet primary endpoint of DFS
Ravaud et al. 2016 (S-TRAC)	2007-2011	Phase III (E-RT-esc)	Placebo	Seems to have superior DFS	More toxicity

Preceding treatment

• Surgery

Targeted therapy

• Sunitinib (Sutent) 50 mg PO once per day on days 1 to 28

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

References

1. ECOG-ACRIN E2805: Haas NB, Manola J, Uzzo RG, Flaherty KT, Wood CG, Kane C, Jewett M, Dutcher JP, Atkins MB, Pins M, Wilding G, Cella D, Wagner L, Matin S, Kuzel TM, Sexton WJ, Wong YN, Choueiri TK, Pili R, Puzanov I, Kohli M, Stadler W, Carducci M, Coomes R, DiPaola RS. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016 May 14;387(10032):2008-16. Epub 2016 Mar 9. Erratum in: Lancet. 2016 May 14;387(10032):1998. link to original article link to PMC article PubMed NCT00326898
2. S-TRAC: Ravaud A, Motzer RJ, Pandha HS, George DJ, Pantuck AJ, Patel A, Chang YH, Escudier B, Donskov F, Magheli A, Carteni G, Laguerre B, Tomczak P, Breza J, Gerletti P, Lechuga M, Lin X, Martini JF, Ramaswamy K, Casey M, Staehler M, Patard JJ; S-TRAC Investigators. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016 Dec 8;375(23):2246-2254. Epub 2016 Oct 9. link to original article contains verified protocol PubMed
   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 PubMed

Metastatic disease, first-line

Atezolizumab & Bevacizumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rini et al. 2019 (IMmotion151)	2015-2016	Phase III (E-esc)	Sunitinib	Seems to have superior PFS

Immunotherapy

• Atezolizumab (Tecentriq) 1200 mg IV once on day 1

Targeted therapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycles

References

1. IMmotion151: Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. link to original article contains protocol PubMed NCT02420821

Axitinib monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR	Comparator ORR
Hutson et al. 2013 (A4061051)	2010-2011	Phase III (E-switch-ic)	Sorafenib	Might have superior PFS (*)	32%	15%

Note: in the 2016 update, there is no difference in OS.

Targeted therapy

• Axitinib (Inlyta) as follows:
  • 5 mg PO twice per day for at least 2 weeks
  • Then if tolerated and BP not greater than 150/90, increased to 7 mg PO twice per day
  • Then if tolerated and BP not greater than 150/90, 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

Continued indefinitely

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 protocol PubMed
   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

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Regimen variant #1, weight-based dosing

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2019 (JAVELIN Renal 101)	2016-2017	Phase III (E-RT-esc)	Sunitinib	Seems to have superior OS (*)

Note: this is not the FDA-recommended dose. Reported efficacy is based on the 2020 update, although the authors state that OS data remains immature.

Targeted therapy

• Axitinib (Inlyta) 5 mg PO twice per day

Immunotherapy

• Avelumab (Bavencio) 10 mg/kg IV once on day 1

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

• Axitinib (Inlyta) 5 mg PO twice per day

Immunotherapy

• Avelumab (Bavencio) 800 mg IV once on day 1

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 protocol 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 PubMed

Axitinib & Pembrolizumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rini et al. 2019 (KEYNOTE-426)	2016-2018	Phase III (E-RT-esc)	Sunitinib	Superior OS

Targeted therapy

• Axitinib (Inlyta) 5 mg PO twice per day

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

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 protocol 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

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR	Comparator ORR
Bukowski et al. 2007	2004	Randomized Phase II (C)	Erlotinib & Bevacizumab	Did not meet primary endpoints of ORR/PFS	13%	14%

Targeted therapy

• Bevacizumab (Avastin) 10 mg/kg IV over 90 minutes once on day 1
  • Can subsequently be reduced to 60 and 30 minute infusions as tolerated

14-day cycle for up to 52 cycles (2 years)

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 verified protocol PubMed

Bevacizumab & Interferon alfa-2a

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Regimen variant #1, 1 year

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Escudier et al. 2007 (AVOREN)	2004-2005	Phase III (E-RT-esc)	Interferon alfa-2a	Did not meet primary endpoint of OS (*)

Note: Reported efficacy for AVOREN is based on the 2010 update.

Targeted therapy

• Bevacizumab (Avastin) 10 mg/kg IV once on day 1

Immunotherapy

• Interferon alfa-2a (Roferon-A) 9,000,000 units SC 3 times per week
  • Dose can be reduced to 3,000,000 or 6,000,000 units SC 3 times per week based on tolerability

14-day cycle for up to 26 cycles (1 year)

Subsequent treatment

• Bevacizumab maintenance

Regimen variant #2, indefinite

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rini et al. 2008 (CALGB 90206)	2003-2005	Phase III (E-esc)	Interferon alfa-2a	Might have superior OS (*)
Rini et al. 2013 (INTORACT)	2008-2010	Phase III (C)	Temsirolimus & Bevacizumab	Did not meet primary endpoint of PFS

Note: Reported efficacy for CALGB 90206 is based on the 2010 update.

Targeted therapy

• Bevacizumab (Avastin) 10 mg/kg IV once on day 1

Immunotherapy

• Interferon alfa-2a (Roferon-A) 9,000,000 units SC 3 times per week
  • Dose can be reduced to 3,000,000 or 6,000,000 units SC 3 times per week based on tolerability

14-day cycles

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
   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 verified protocol 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 protocol PubMed NCT00631371

Cabozantinib monotherapy

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Choueiri et al. 2016 (CABOSUN)	2013-2015	Phase III (E-RT-switch-ic)	Sunitinib	Superior PFS (*)

Note: reported 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

• Cabozantinib (Cabometyx) 60 mg PO once per day

Continued indefinitely

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. 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 verified protocol link to PMC article PubMed
   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 verified protocol link to PMC article PubMed

Cabozantinib & Nivolumab

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Regimen variant #1, bi-weekly nivolumab

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Choueiri et al. 2021 (CheckMate 9ER)	2017-2019	Phase III (E-RT-esc)	Sunitinib	Superior OS

Targeted therapy

• Cabozantinib (Cabometyx) 40 mg PO once per day

Immunotherapy

• Nivolumab (Opdivo) as follows:
  • Cycles 1 to 52: 240 mg IV over 30 minutes once on day 1

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

• Cabozantinib (Cabometyx) 40 mg PO once per day

Immunotherapy

• Nivolumab (Opdivo) as follows:
  • Cycles 1 to 26: 480 mg IV over 30 minutes once on day 1

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 verified protocol PubMed NCT03141177

Erlotinib & Bevacizumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bukowski et al. 2007	2004	Randomized Phase II (E-esc)	Bevacizumab	Did not meet primary endpoints of ORR/PFS

Targeted therapy

• Erlotinib (Tarceva) 150 mg PO once per day
• Bevacizumab (Avastin) 10 mg/kg IV over 90 minutes once on day 1
  • Can subsequently be reduced to 60 and 30 minute infusions as tolerated

14-day cycle for up to 52 cycles (2 years)

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 verified protocol PubMed

Everolimus monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2014 (RECORD-3)	2009-2011	Randomized Phase II (E-switch-ic)	Sunitinib	Inconclusive whether non-inferior PFS
Tannir et al. 2015 (ESPN)	2010-2013	Randomized Phase II (E-switch-ic)	Sunitinib	Did not meet primary endpoint of PFS
Armstrong et al. 2016 (ASPEN)	2010-2013	Randomized Phase II (E-switch-ic)	Sunitinib	Might have inferior PFS

Targeted therapy

• Everolimus (Afinitor) 10 mg PO once per day
  • Dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability

Continued indefinitely

Subsequent treatment

• RECORD-3, upon progression: Sunitinib

References

1. RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article link to PMC article PubMed NCT00903175
2. ESPN: Tannir NM, Jonasch E, Albiges L, Altinmakas E, Ng CS, Matin SF, Wang X, Qiao W, Dubauskas Lim Z, Tamboli P, Rao P, Sircar K, Karam JA, McDermott DF, Wood CG, Choueiri TK. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol. 2016 May;69(5):866-74. Epub 2015 Nov 26. link to original article link to PMC article contains verified protocol PubMed NCT01185366
3. ASPEN: Armstrong AJ, Halabi S, Eisen T, Broderick S, Stadler WM, Jones RJ, Garcia JA, Vaishampayan UN, Picus J, Hawkins RE, Hainsworth JD, Kollmannsberger CK, Logan TF, Puzanov I, Pickering LM, Ryan CW, Protheroe A, Lusk CM, Oberg S, George DJ. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016 Mar;17(3):378-88. Epub 2016 Jan 13. link to original article PubMed NCT01108445

Everolimus & Lenvatinib

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2021 (CLEAR)	2016-2019	Phase III (E-RT-esc)	Sunitinib	Superior PFS (primary) and OS (secondary)

Targeted therapy

• Everolimus (Afinitor) 5 mg PO once per day
• Lenvatinib (Lenvima) 18 mg PO once per day

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 Feb 13. Online ahead of print. link to original article contains protocol PubMed NCT02811861

Gemcitabine & Sunitinib

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Regimen variant #1

Study	Years of enrollment	Evidence
Michaelson et al. 2015 (MGH 07-212)	2007-2013	Phase II

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Sunitinib (Sutent) 37.5 mg PO once per day on days 1 to 14

21-day cycles

Regimen variant #2

Study	Evidence
Pandya et al. 2011	Retrospective

Chemotherapy

• Gemcitabine (Gemzar) 750 mg/m² IV over 90 minutes once per day on days 1 & 8

Targeted therapy

• Sunitinib (Sutent) 37.5 mg PO once per day on days 2 to 15

21-day cycles

References

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 verified protocol PubMed
2. MGH 07-212: Michaelson MD, McKay RR, Werner L, Atkins MB, Van Allen EM, Olivier KM, Song J, Signoretti S, McDermott DF, Choueiri TK. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer. 2015 Oct 1;121(19):3435-43. Epub 2015 Jun 8. link to original article PubMed NCT00556049

High-dose Interleukin-2

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HD IL-2: High-Dose InterLeukin-2

Example orders

• Example orders for High-dose (HD) IL-2 in renal cancer

Regimen variant #1, 1.8 MU/kg/day, intermittent

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rosenberg et al. 1994	1985-1992	Non-randomized
Fyfe et al. 1995	NR	Phase II (RT)
McDermott et al. 2005	1997-2000	Phase III (C)	Subcutaneous IL-2 & Interferon	Might have superior PFS

Immunotherapy

• IL-2 - Aldesleukin (Proleukin) 600,000 units/kg IV every 8 hours for up to 14 doses per week, on days 1 to 5, 15 to 19

Supportive medications

• Ciprofloxacin (Cipro) 250 mg PO twice per day on days 1 to 10, 15 to 24
• All antihypertensive therapy discontinued at least 24 hours before each cycle
• Acetaminophen (Tylenol) 650 mg PO every 4 hours
• Indomethacin (Indocin) 25 mg PO every 6 hours
• Ranitidine (Zantac) 150 mg PO or Famotidine (Pepcid) 20 mg PO every 12 hours
• Hydroxyzine (Atarax) 25 to 50 mg PO every 6 hours or Diphenhydramine (Benadryl) 25 mg PO every (note: frequency was blank in reference) hours for pruritis
• Meperidine (Demerol) 25 to 50 mg PO every 6 hours for chills and rigors
• "An antidiarrheal agent, antiemetics, anxiolytics, diuretics, and vasopressors as needed"

28-day cycle for up to 3 cycles

Regimen variant #2, 2.16 MU/kg/day, intermittent, goal 10.8 MU

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Yang et al. 1994	1991-1993	Phase III (C)	1. LD IL-2 (IV)	Seems to have superior ORR
			2. LD IL-2 (SC)	Seems to have superior ORR

Note: reported efficacy is based on the 2003 update.

Immunotherapy

• IL-2 - Aldesleukin (Proleukin) 720,000 units/kg IV every 8 hours for up to 15 doses
  • Then after 7 to 10 days of rest, IL-2 - Aldesleukin (Proleukin) 720,000 units/kg IV every 8 hours for up to 15 doses is given again

8-week cycle for up to 2 cycles

Regimen variant #3, 2.16 MU/kg/day, intermittent, goal 8.64 MU

Study	Evidence
Klapper et al. 2008	Retrospective

Immunotherapy

• IL-2 - Aldesleukin (Proleukin) 720,000 units/kg IV every 8 hours for up to 12 doses (reduced from originally up to 15 doses due to few patients tolerating 15 doses)
  • Then after 10 to 15 days of rest, IL-2 - Aldesleukin (Proleukin) 720,000 units/kg IV every 8 hours for up to 12 doses is given again

Supportive medications

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

Subsequent treatment

• After this one course of treatments--defined by the paper as "two cycles"--patients with stable to improved disease would receive additional courses of treatments every 2 months (no maximum number of courses listed)

Regimen variant #4, 5 MU/m²/day, CI

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Figlin et al. 1999	1994-1997	Phase III (C)	IL-2 & CD8+ TILs	Did not meet primary endpoint of ORR

Immunotherapy

• IL-2 - Aldesleukin (Proleukin) 5,000,000 units/m²/day IV continuous infusion over 96 hours, started on days 1, 8, 15, 22 (total dose per cycle: 80 MU/m²)

8-week cycles

References

1. Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994 Mar 23-30;271(12):907-13. link to original article PubMed
2. Yang JC, Topalian SL, Parkinson D, Schwartzentruber DJ, Weber JS, Ettinghausen SE, White DE, Steinberg SM, Cole DJ, Kim HI, Levin R, Guleria A, MacFarlane MP, White RL, Einhorn JH, Seipp CA, Rosenberg SA. Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol. 1994 Aug;12(8):1572-6. link to original article PubMed
   1. Update: Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. link to original article link to PMC article contains verified protocol PubMed
3. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995 Mar;13(3):688-96. link to original article PubMed
4. Figlin RA, Thompson JA, Bukowski RM, Vogelzang NJ, Novick AC, Lange P, Steinberg GD, Belldegrun AS. Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol. 1999 Aug;17(8):2521-9. link to original article contains verified protocol PubMed
5. McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, Kirkwood JM, Gordon MS, Sosman JA, Ernstoff MS, Tretter CP, Urba WJ, Smith JW, Margolin KA, Mier JW, Gollob JA, Dutcher JP, Atkins MB. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005 Jan 1;23(1):133-41. link to original article contains verified protocol PubMed
6. 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 verified protocol link to PMC article PubMed

Low-dose Interleukin-2

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LD IL-2: Low-Dose InterLeukin-2

Regimen variant #1, Intravenous

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Yang et al. 1994	1991-1993	Phase III (E-de-esc)	1. High-dose IL-2	Seems to have inferior ORR
			2. LD IL-2; SC	Not reported

Note: efficacy is based on the 2003 update.

Immunotherapy

• IL-2 - Aldesleukin (Proleukin) as follows:
  • 72,000 units/kg IV every 8 hours for up to 15 doses
  • Then after 7 to 10 days of rest: 72,000 units/kg IV every 8 hours for up to 15 doses is given again

8-week cycle for up to 2 cycles

Regimen variant #2, Subcutaneous

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Yang et al. 1994	1991-1993	Phase III (E-de-esc)	1. High-dose IL-2	Seems to have inferior ORR
			2. LD IL-2; IV	Not reported

Note: this arm was added to the trial after the interim results were announced in 1994.

Immunotherapy

• IL-2 - Aldesleukin (Proleukin) as follows:
  • Week 1: 250,000 units/kg SC once per day for 5 days
  • Weeks 2 to 6: 125,000 units/kg SC once per day for 5 days per week

8-week cycle for up to 2 cycles

References

1. Yang JC, Topalian SL, Parkinson D, Schwartzentruber DJ, Weber JS, Ettinghausen SE, White DE, Steinberg SM, Cole DJ, Kim HI, Levin R, Guleria A, MacFarlane MP, White RL, Einhorn JH, Seipp CA, Rosenberg SA. Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol. 1994 Aug;12(8):1572-6. link to original article PubMed
   1. Update: Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. link to original article link to PMC article contains verified protocol PubMed

Interferon alfa-2a monotherapy

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Regimen variant #1, 5 MU 5x per week

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Sagaster et al. 1995	NR-1992	Phase III (C)	Cimetidine, Coumarin, IFN alfa-2a	Did not meet primary endpoint of ORR

Immunotherapy

• Interferon alfa-2a (Roferon-A) 5,000,000 units SC 5 times per week

Continued indefinitely

Regimen variant #2, 9 MU TIW

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Escudier et al. 2007 (AVOREN)	2004-2005	Phase III (C)	Bevacizumab & Interferon alfa-2a	Did not meet primary endpoint of OS (*)
Rini et al. 2008 (CALGB 90206)	2003-2005	Phase III (C)	Bevacizumab & Interferon alfa-2a	Might have inferior OS (*)
Escudier et al. 2009	2005	Randomized Phase II (C)	Sorafenib	Did not meet primary endpoint of PFS
Gore et al. 2010 (MRC RE04/EORTC GU 30012)	2001-2006	Phase III (C)	5-FU, Interferon alfa-2a, IL-2	Did not meet primary endpoint of OS
Hawkins et al. 2016	2007-2010	Phase II/III (C)	Naptumomab estafenatox + IFNα	Did not meet primary endpoint of OS

Note: reported efficacy for AVOREN is based on the 2010 update. Reported efficacy for CALGB 90206 is based on the 2010 update.

Immunotherapy

• Interferon alfa-2a (Roferon-A) 9,000,000 units SC 3 times per week
  • Some protocols: Dose can be reduced to 3 or 6,000,000 units SC 3 times per week based on tolerability

Given for varying lengths of time; see individual trials

Regimen variant #3, 9 MU daily, with lead-in

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2000	1994-1996	Phase III (C)	IFN alfa & 13-CRA	Did not meet primary endpoint of ORR

Immunotherapy

• Interferon alfa-2a (Roferon-A) as follows:
  • Week 1: 3,000,000 units SC once per day
  • Week 2 (if prior dose tolerated): 6,000,000 units SC once per day
  • Week 3 onwards (if prior dose tolerated): 9,000,000 units SC once per day

Continued indefinitely

Regimen variant #4, 9 MU TIW, with lead-in

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2007 (A618-1034)	2004-2005	Phase III (C)	Sunitinib	Inferior PFS

Immunotherapy

• Interferon alfa-2a (Roferon-A) as follows:
  • Week 1: 3,000,000 units SC 3 times per week
  • Week 2 (if prior dose tolerated): 6,000,000 units SC 3 times per week
  • Week 3 onwards (if prior dose tolerated): 9,000,000 units SC 3 times per week

Continued indefinitely

Regimen variant #5, 10 MU TIW

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ritchie et al. 1999 (MRC RE01)	1992-1997	Phase III (E-switch-ooc)	MPA	Seems to have superior OS
Gore et al. 2010 (MRC RE04/EORTC GU 30012)	2001-2006	Phase III (C)	Chemoimmunotherapy	Did not meet primary endpoint of OS

Immunotherapy

• Interferon alfa-2a (Roferon-A) 10,000,000 units SC 3 times per week
  • In MRC RE01, the first two doses were 5,000,000 units

12-week course (MRC RE01) or continued indefinitely (MRC RE04/EORTC GU 30012)

Regimen variant #6, 18 MU TIW, with lead-in

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fosså et al. 1992	1985-1986	Phase III (C)	IFN alfa-2a & Vinblastine	Did not meet efficacy endpoints
Hudes et al. 2007 (ARCC)	2003-2005	Phase III (C)	1. Interferon alfa-2a & Temsirolimus	Did not meet primary endpoint of OS
			2. Temsirolimus	Inferior OS

Immunotherapy

• Interferon alfa-2a (Roferon-A) as follows:
  • Week 1: 3,000,000 units SC 3 times per week
  • Week 2 (if prior dose tolerated): 9,000,000 units SC 3 times per week
  • Week 3 onwards (if prior dose tolerated): 18,000,000 units SC 3 times per week
    • If higher doses cannot be tolerated, highest tolerable doses of 3,000,000, 4,500,500, or 6,000,000 units can be used

Continued indefinitely

References

1. Fosså SD, Martinelli G, Otto U, Schneider G, Wander H, Oberling F, Bauer HW, Achtnicht U, Holdener EE. Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: results of a European multi-center phase III study. Ann Oncol. 1992 Apr;3(4):301-5. link to original article PubMed
2. Sagaster P, Micksche M, Flamm J, Ludwig H. Randomised study using IFN-alpha versus IFN-alpha plus coumarin and cimetidine for treatment of advanced renal cell cancer. Ann Oncol. 1995 Dec;6(10):999-1003. link to original article contains protocol PubMed
3. MRC RE01: Ritchie A, Griffiths G, Parmar M; Medical Research Council Renal Cancer Collaborators. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet. 1999 Jan 2;353(9146):14-7. link to original article contans protocol PubMed
4. Motzer RJ, Murphy BA, Bacik J, Schwartz LH, Nanus DM, Mariani T, Loehrer P, Wilding G, Fairclough DL, Cella D, Mazumdar M. Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol. 2000 Aug;18(16):2972-80. link to original article PubMed
5. 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 verified protocol PubMed
   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 verified protocol link to PMC article PubMed content property of HemOnc.org
6. ARCC: Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. link to original article contains verified protocol PubMed
7. 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
   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 verified protocol PubMed
8. 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
9. 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
10. MRC RE04/EORTC GU 30012: Gore ME, Griffin CL, Hancock B, Patel PM, Pyle L, Aitchison M, James N, Oliver RT, Mardiak J, Hussain T, Sylvester R, Parmar MK, Royston P, Mulders PF. Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial. Lancet. 2010 Feb 20;375(9715):641-8. Epub 2010 Feb 10. link to original article link to PMC article contains verified protocol PubMed ISRCTN46518965
11. Hawkins RE, Gore M, Shparyk Y, Bondar V, Gladkov O, Ganev T, Harza M, Polenkov S, Bondarenko I, Karlov P, Karyakin O, Khasanov R, Hedlund G, Forsberg G, Nordle Ö, Eisen T. A randomized phase II/III study of naptumomab estafenatox + IFNα versus IFNα in renal cell carcinoma: final analysis with baseline biomarker subgroup and trend analysis. Clin Cancer Res. 2016 Jul 1;22(13):3172-81. Epub 2016 Feb 5. link to original article contains verified protocol PubMed

Interferon alfa-2a & Interleukin-2

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Negrier et al. 1998	1992-1995	Phase III (E-esc)	1. HD IL-2 2. Interferon alfa-2a	Superior EFS
Passalacqua et al. 2009	1998-2003	Phase III (C)	Maintenance IFN & IL-2	Did not meet primary endpoint of OS

Of historic interest.

Immunotherapy

• Interferon alfa-2a (Roferon-A)
• Aldesleukin (Proleukin)

References

1. Negrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C, Ravaud A, Mercatello A, Peny J, Mousseau M, Philip T, Tursz T; Groupe Français d'Immunothérapie. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. N Engl J Med. 1998 Apr 30;338(18):1272-8. link to original article PubMed
2. Passalacqua R, Buzio C, Buti S, Porta C, Labianca R, Pezzuolo D, Camisa R, Sabbatini R, Benecchi L, Messina C, Cengarle R, Vaglio A, Dalla Chiesa M, Tomasello G, Caminiti C. Phase III, randomised, multicentre trial of maintenance immunotherapy with low-dose interleukin-2 and interferon-alpha for metastatic renal cell cancer. Cancer Immunol Immunother. 2010 Apr;59(4):553-61. Epub 2009 Sep 25. link to original article PubMed

Interferon alfa-2b monotherapy

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Regimen

Study	Evidence
Mickisch et al. 2001 (EORTC 30947)	Non-randomized portion of RCT
Flanigan et al. 2001 (SWOG 8949)	Non-randomized portion of RCT

Of historic interest.

Preceding treatment

• Nephrectomy versus no preceding treatment

Immunotherapy

• Interferon alfa-2b (Intron-A)

References

1. EORTC 30947: Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R; EORTC Genitourinary Group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001 Sep 22;358(9286):966-70. link to original article PubMed
2. SWOG 8949: Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, Caton JR Jr, Munshi N, Crawford ED. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001 Dec 6;345(23):1655-9. link to original article PubMed

Ipilimumab & Nivolumab

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Regimen variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2018 (CheckMate 214)	2014-2016	Phase III (E-RT-switch-ooc)	Sunitinib	Superior OS

Note: while this is the dosing studied in CheckMate 214, it is not the FDA-recommended dosing.

Immunotherapy, part 1

• Ipilimumab (Yervoy) 1 mg/kg IV over 30 minutes once on day 1
• Nivolumab (Opdivo) 3 mg/kg IV over 60 minutes once on day 1

21-day cycle for 4 cycles, followed by:

Immunotherapy, part 2

• Nivolumab (Opdivo) 3 mg/kg IV over 60 minutes once on day 1

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, part 1

• Ipilimumab (Yervoy) 1 mg/kg IV once on day 1, given second
• Nivolumab (Opdivo) 3 mg/kg IV once on day 1, given first

21-day cycle for 4 cycles, followed by:

Immunotherapy, part 2

• Nivolumab (Opdivo) 240 mg IV once on day 1

14-day cycles

Regimen variant #3

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, part 1

• Ipilimumab (Yervoy) 1 mg/kg IV once on day 1, given second
• Nivolumab (Opdivo) 3 mg/kg IV once on day 1, given first

21-day cycle for 4 cycles, followed by:

Immunotherapy, part 2

• Nivolumab (Opdivo) 480 mg IV once on day 1

28-day cycles

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 verified protocol PubMed
   1. 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 PubMed

Lenvatinib & Pembrolizumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2021 (CLEAR)	2016-2019	Phase III (E-RT-esc)	Sunitinib	Superior PFS (primary) and OS (secondary)

Targeted therapy

• Lenvatinib (Lenvima) 20 mg PO once per day

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

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 Feb 13. Online ahead of print. link to original article contains protocol PubMed NCT02811861

Pazopanib monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR	Comparator ORR
Hutson et al. 2009 (VEG102616)	2005-2006	Phase II
Sternberg et al. 2010 (VEG105192)	2006-2007	Phase III (E-RT-esc)	Placebo	Superior PFS	30% (95% CI 25-36%)	3% (95% CI 0-6%)
Motzer et al. 2013 (COMPARZ)	2008-2011	Phase III (E-switch-ic)	Sunitinib	Non-inferior PFS	31% (95% CI 27-34%)	25% (95% CI 21-28%)
Cirkel et al. 2017 (ROPETAR)	2012-2014	Randomized (C)	Pazopanib/Everolimus	Did not meet primary endpoint of PFS

Targeted therapy

• Pazopanib (Votrient) 800 mg PO once per day, given 1 hour before or 2 hours after meals
  • Dose may be decreased to 600 mg or 400 mg PO once per day depending on tolerability

Continued indefinitely

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 verified protocol 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 verified protocol 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 verified protocol 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 verified protocol 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. HRQoL analysis: 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
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 protocol PubMed NCT01408004

Regorafenib monotherapy

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Regimen

Study	Evidence	Efficacy
Eisen et al. 2012 (Bayer 11726)	Phase II	40% (90% CI 28-53%)

Targeted therapy

• Regorafenib (Stivarga) 160 mg PO once per day on days 1 to 21, given while fasting or after a light meal

28-day cycles

References

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 verified protocol PubMed

Sorafenib monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR	Comparator ORR
Escudier et al. 2009	2005	Randomized Phase II (E-switch-ooc)	Interferon alfa-2a	Did not meet primary endpoint of PFS	5%	9%
Stadler et al. 2010 (ARCCS)	2005-2006	Non-randomized
Motzer et al. 2013 (AV-951-09-902)	2010	Phase III (C)	Tivozanib	Seems to have inferior PFS
Hutson et al. 2013 (A4061051)	2010-2011	Phase III (C)	Axitinib	Might have inferior PFS (*)	15%	32%

Note: in the 2016 update to A4061051, there is no difference in OS.

Targeted therapy

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

Continued indefinitely

References

1. 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. ARCCS: Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010 Mar 1;116(5):1272-80. link to original article PubMed NCT00111020
3. AV-951-09-902: 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 verified protocol PubMed NCT01030783
4. 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 protocol 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

Sunitinib monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR	Comparator ORR
Motzer et al. 2007 (A618-1034)	2004-2005	Phase III (E-RT-switch-ooc)	Interferon alfa-2a	Superior PFS	31%	6%
Gore et al. 2009 (A618-1037)	2005-2007	Non-randomized			17%
Amato et al. 2010 (TroVax Renal Immunotherapy Survival Trial)	2006-2008	Phase III (C)	Sunitinib & MVA-5T4	Did not meet primary endpoint of OS
Motzer et al. 2013 (COMPARZ)	2008-2011	Phase III (C)	Pazopanib	Non-inferior PFS	25% (95% CI 21-28%)	31% (95% CI 27-34%)
Motzer et al. 2014 (RECORD-3)	2009-2011	Randomized Phase II (E-switch-ic)	Everolimus	Inconclusive whether non-inferior PFS
Eichelberg et al. 2015 (SWITCH)	2009-2011	Phase III (C)	Sorafenib	Did not meet primary endpoint of PFS
Méjean et al. 2018 (CARMENA)	2009-2017	Phase III (E-de-esc)	Nephrectomy & Sunitinib	Non-inferior OS
Rini et al. 2016 (IMPRINT)	2010-2012	Phase III (C)	Sunitinib & IMA901	Might have superior OS
Tannir et al. 2015 (ESPN)	2010-2013	Randomized Phase II (E-switch-ic)	Everolimus	Did not meet primary endpoint of PFS
Armstrong et al. 2016 (ASPEN)	2010-2013	Randomized Phase II (E-switch-ic)	Everolimus	Might have superior PFS
Choueiri et al. 2016 (CABOSUN)	2013-2015	Phase III (C)	Cabozantinib	Inferior PFS
Motzer et al. 2018 (CheckMate 214)	2014-2016	Phase III (C)	Ipilimumab & Nivolumab	Inferior OS
Rini et al. 2019 (IMmotion151)	2015-2016	Phase III (C)	Atezolizumab & Bevacizumab	Seems to have inferior PFS
Motzer et al. 2019 (JAVELIN Renal 101)	2016-2017	Phase III (C)	Axitinib & Avelumab	Seems to have inferior OS (*)
Rini et al. 2019 (KEYNOTE-426)	2016-2018	Phase III (C)	Axitinib & Pembrolizumab	Inferior OS
Choueiri et al. 2021 (CheckMate 9ER)	2017-2019	Phase III (C)	Cabozantinib & Nivolumab	Inferior OS
Motzer et al. 2021 (CLEAR)	2016-209	Phase III (C)	Everolimus & Lenvatinib	Inferior PFS (primary) and OS (secondary)	36.1%	53.5%
Motzer et al. 2021 (CLEAR)	2016-209	Phase III (C)	Lenvatinib & Pembrolizumab	Inferior PFS (primary) and OS (secondary)	36.1%	71.0%

Note: reported efficacy for CABOSUN is based on the 2018 update. Reported efficacy for Javelin Renal 101 is based on the 2020 update, although the authors state that OS data remains immature.

Targeted therapy

• Sunitinib (Sutent) 50 mg PO once per day on days 1 to 28
  • Per some references, dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability

42-day cycles

Subsequent treatment

• SWITCH, upon progression: Sorafenib

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 verified protocol PubMed
   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 verified protocol link to PMC article PubMed
2. A618-1037: Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009 Aug;10(8):757-63. Epub 2009 Jul 15. link to original article contains verified protocol PubMed NCT00130897
3. 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 verified protocol PubMed NCT00397345
4. 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 verified protocol 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
5. HRQoL analysis: 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
6. RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article link to PMC article PubMed NCT00903175
7. SWITCH: Eichelberg C, Vervenne WL, De Santis M, Fischer von Weikersthal L, Goebell PJ, Lerchenmüller C, Zimmermann U, Bos MM, Freier W, Schirrmacher-Memmel S, Staehler M, Pahernik S, Los M, Schenck M, Flörcken A, van Arkel C, Hauswald K, Indorf M, Gottstein D, Michel MS. SWITCH: A Randomised, Sequential, Open-label Study to Evaluate the Efficacy and Safety of Sorafenib-sunitinib Versus Sunitinib-sorafenib in the Treatment of Metastatic Renal Cell Cancer. Eur Urol. 2015 Nov;68(5):837-47. Epub 2015 May 4. link to original article contains protocol PubMed NCT00732914
8. ESPN: Tannir NM, Jonasch E, Albiges L, Altinmakas E, Ng CS, Matin SF, Wang X, Qiao W, Dubauskas Lim Z, Tamboli P, Rao P, Sircar K, Karam JA, McDermott DF, Wood CG, Choueiri TK. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol. 2016 May;69(5):866-74. Epub 2015 Nov 26. link to original article link to PMC article contains verified protocol PubMed NCT01185366
9. ASPEN: Armstrong AJ, Halabi S, Eisen T, Broderick S, Stadler WM, Jones RJ, Garcia JA, Vaishampayan UN, Picus J, Hawkins RE, Hainsworth JD, Kollmannsberger CK, Logan TF, Puzanov I, Pickering LM, Ryan CW, Protheroe A, Lusk CM, Oberg S, George DJ. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016 Mar;17(3):378-88. Epub 2016 Jan 13. link to original article PubMed NCT01108445
10. IMPRINT: Rini BI, Stenzl A, Zdrojowy R, Kogan M, Shkolnik M, Oudard S, Weikert S, Bracarda S, Crabb SJ, Bedke J, Ludwig J, Maurer D, Mendrzyk R, Wagner C, Mahr A, Fritsche J, Weinschenk T, Walter S, Kirner A, Singh-Jasuja H, Reinhardt C, Eisen T. IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2016 Nov;17(11):1599-1611. link to original article contains protocol PubMed NCT01265901
11. 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 verified protocol link to PMC article PubMed
    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 verified protocol link to PMC article PubMed
12. 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 verified protocol PubMed
    1. 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 PubMed
13. 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 protocol PubMed NCT00930033
14. 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 protocol 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 PubMed
15. 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 protocol 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
16. IMmotion151: Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. link to original article contains protocol PubMed NCT02420821
17. 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 verified protocol PubMed NCT03141177
18. 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 Feb 13. Online ahead of print. link to original article contains protocol PubMed NCT02811861

Temsirolimus monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR	Comparator ORR
Hudes et al. 2007 (ARCC)	2003-2005	Phase III (E-RT-switch-ooc)	1. Interferon alfa-2a	Superior OS	9% (95% CI 5-12%)	5% (95% CI 2-8%)
			2. Interferon alfa-2a & Temsirolimus	Not reported	8% (95% CI 4-12%)

Targeted therapy

• Temsirolimus (Torisel) 25 mg IV over 30 minutes once on day 1

Supportive medications

• Diphenhydramine (Benadryl) (or similar H1 blocker) 25 to 50 mg IV once on day 1; 30 minutes prior to Temsirolimus (Torisel)

7-day cycles

References

1. ARCC: Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. link to original article contains verified protocol PubMed

Tivozanib monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2013 (AV-951-09-902)	2010	Phase III (E-switch-ic)	Sorafenib	Seems to have superior PFS

Targeted therapy

• Tivozanib (Fotivda) 1.5 mg PO once per day on days 1 to 21

28-day cycles

References

1. AV-951-09-902: 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 verified protocol PubMed NCT01030783

Maintenance after first-line therapy

Bevacizumab monotherapy

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Regimen

Study	Evidence
Escudier et al. 2007 (AVOREN)	Non-randomized portion of RCT

Preceding treatment

• Bevacizumab & IFN alfa-2a x 12 mo

Targeted therapy

• Bevacizumab (Avastin) 10 mg/kg IV once on day 1

14-day cycles

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
   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 verified protocol PubMed

Metastatic disease, second-line

Axitinib monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rini et al. 2011 (AXIS)	2008-2010	Phase III (E-RT-switch-ic)	Sorafenib	Superior PFS

In the 2013 update, ORR was 23% in this arm, and 12% in the control arm.

Targeted therapy

• Axitinib (Inlyta) as follows:
  • 5 mg PO twice per day for at least 2 weeks
  • Then if tolerated and BP not greater than 150/90, increased to 7 mg PO twice per day
  • Then if tolerated and BP not greater than 150/90, 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

Continued indefinitely

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 verified protocol PubMed
   1. 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 verified protocol PubMed
   2. 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

Bevacizumab monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Yang et al. 2003	1998-2001	Randomized Phase II (E-esc)	Placebo	Superior TTP

Targeted therapy

• Bevacizumab (Avastin) 10 mg/kg IV once on day 1

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 protocol link to PMC article PubMed

Cabozantinib monotherapy

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR	Comparator ORR
Choueiri et al. 2015 (METEOR)	2013-2014	Phase III (E-RT-switch-ic)	Everolimus	Superior OS	21% (95% CI 16-28%)	5% (95% CI 2-9%)

Preceding treatment

• VEGFR TKI, with progression

Targeted therapy

• Cabozantinib (Cabometyx) 60 mg PO once per day
  • At least 2 hours before or 1 hour after meals according to the Cabozantinib (Cabometyx) package insert

Continued indefinitely

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 verified protocol link to PMC article PubMed
   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 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

Everolimus monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR	Comparator ORR
Motzer et al. 2008 (RECORD-1)	2006-2007	Phase III (E-RT-esc)	Placebo	Superior PFS	1%	0%
Motzer et al. 2014 (RECORD-3)	2009-2011	Randomized Phase II (E-switch-ic)	Sunitinib	Inconclusive whether non-inferior PFS
Motzer et al. 2015 (RECORD-4)	2011-2013	Phase II
Motzer et al. 2015 (CheckMate 025)	2012-2014	Phase III (C)	Nivolumab	Inferior OS	5%	25%
Motzer et al. 2015 (E7080-G000-205)	2012-2013	Randomized Phase II (C)	1. Everolimus & Lenvatinib	Inferior PFS
			2. Lenvatinib	Seems to have inferior PFS
Choueiri et al. 2015 (METEOR)	2013-2014	Phase III (C)	Cabozantinib	Inferior OS	5% (95% CI 2-9%)	21% (95% CI 16-28%)

Note: 72% of patients in Checkmate 025 had anti-angiogenic therapy prior to progression.

Preceding treatment

• RECORD-1 & METEOR: VEGFR TKI, with progression
• RECORD-3: Sunitinib, with progression

Targeted therapy

• Everolimus (Afinitor) 10 mg PO once per day
  • Dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability

Continued indefinitely

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 verified protocol PubMed
   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 verified protocol PubMed
2. RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article link to PMC article PubMed NCT00903175
3. 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 verified protocol 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 and update: 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 Jul 16. Epub ahead of print. link to original article PubMed
4. 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 verified protocol link to PMC article PubMed
   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 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
5. 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 verified protocol PubMed
   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. link to original article PubMed
6. 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 protocol PubMed NCT01491672

Everolimus & Lenvatinib

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2015 (E7080-G000-205)	2012-2013	Randomized Phase II (E-RT-esc)	1. Everolimus	Superior PFS
			2. Lenvatinib	Did not meet primary endpoint of PFS

Patients had progressed after VEGFR TKI treatment.

Targeted therapy

• Everolimus (Afinitor) 5 mg PO once per day
• Lenvatinib (Lenvima) 18 mg PO once per day

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 verified protocol PubMed
   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. link to original article PubMed

Lenvatinib monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2015 (E7080-G000-205)	2012-2013	Randomized Phase II (E-RT-switch-ic)	1. Everolimus	Seems to have superior PFS
			2. Everolimus & Lenvatinib	Did not meet primary endpoint of PFS

Targeted therapy

• Lenvatinib (Lenvima) 24 mg PO once per day

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 verified protocol PubMed
   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. link to original article PubMed

Nivolumab monotherapy

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Regimen variant #1, 0.3 mg/kg q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2015 (CheckMate-010)	2011-2012	Randomized Phase II (E-de-esc)	1. Nivolumab; 2 mg/kg 2. Nivolumab; 10 mg/kg	Did not meet primary endpoint of PFS

Immunotherapy

• Nivolumab (Opdivo) 0.3 mg/kg IV once on day 1

21-day cycles

Regimen variant #2, 2 mg/kg q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2015 (CheckMate-010)	2011-2012	Randomized Phase II (E-esc)	1. Nivolumab; 0.3 mg/kg 2. Nivolumab; 10 mg/kg	Did not meet primary endpoint of PFS

Immunotherapy

• Nivolumab (Opdivo) 2 mg/kg IV once on day 1

21-day cycles

Regimen variant #3, 3 mg/kg q2wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR	Comparator ORR
Motzer et al. 2015 (CheckMate 025)	2012-2014	Phase III (E-RT-switch-ooc)	Everolimus	Superior OS	25%	5%

Immunotherapy

• Nivolumab (Opdivo) 3 mg/kg IV over 60 minutes once on day 1
  • Notably, on 9/13/16 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

14-day cycles

Regimen variant #4, 10 mg/kg q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2015 (CheckMate-010)	2011-2012	Randomized Phase II (E-esc)	1.Nivolumab; 0.3 mg/kg 2. Nivolumab; 2 mg/kg	Did not meet primary endpoint of PFS

Immunotherapy

• Nivolumab (Opdivo) 10 mg/kg IV once on day 1

21-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 verified protocol 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 verified protocol 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 and update: 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 Jul 16. Epub ahead of print. link to original article PubMed

Pazopanib monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR	Comparator ORR
Hutson et al. 2009 (VEG102616)	2005-2006	Phase II
Sternberg et al. 2010 (VEG105192)	2006-2007	Phase III (E-esc)	Placebo	Superior PFS	30% (95% CI 25-36%)	3% (95% CI 0-6%)
Hainsworth et al. 2013	2008-2011	Phase II

Targeted therapy

• Pazopanib (Votrient) 800 mg PO once per day, given 1 hour before or 2 hours after meals
  • Dose may be decreased to 600 mg or 400 mg PO once per day depending on tolerability

Continued indefinitely

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 verified protocol 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 verified protocol 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 verified protocol 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 protocol PubMed

Sorafenib monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	ORR	Comparator ORR
Escudier et al. 2007 (TARGETRCC)	2003-2005	Phase III (E-RT-esc)	Placebo	Did not meet primary endpoint of OS (*)	10%	2%
Stadler et al. 2010 (ARCCS)	2005-2006	Non-randomized
Beck et al. 2011 (EU-ARCCS)	2005-2007	Non-randomized
Hutson et al. 2013 (INTORSECT)	2007-2011	Phase III (C)	Temsirolimus	Did not meet primary endpoint of PFS (*)
Rini et al. 2011 (AXIS)	2008-2010	Phase III (C)	Axitinib	Inferior PFS	9% (95% CI 7-13%)	19% (95% CI 15-24%)

Note that TARGET should not be confused with the study by the same name in breast cancer. Reported efficacy for TARGET is based on the 2009 update. While the primary endpoint (PFS) was not met in INTORSECT, the control arm actually had superior OS compared to the experimental arm.

Targeted therapy

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

Continued indefinitely

References

1. TARGET: 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 verified protocol PubMed
   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 verified protocol PubMed
2. ARCCS: Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010 Mar 1;116(5):1272-80. link to original article PubMed NCT00111020
3. EU-ARCCS: Beck J, Procopio G, Bajetta E, Keilholz U, Negrier S, Szczylik C, Bokemeyer C, Bracarda S, Richel DJ, Staehler M, Strauss UP, Mersmann S, Burock K, Escudier B. Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings. Ann Oncol. 2011 Aug;22(8):1812-23. Epub 2011 Feb 15. link to original article contains verified protocol PubMed
4. 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 verified protocol PubMed
   1. 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 verified protocol PubMed
   2. 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
5. INTORSECT: Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, Senico P, Niethammer A, Lu DR, Hariharan S, Motzer RJ. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Mar 10;32(8):760-7. Epub 2013 Dec 2. link to original article contains protocol link to PMC article PubMed NCT00474786

Sunitinib monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2005 (RTKC-0511-014)	2003	Phase II (RT)
Motzer et al. 2006 (A618-1006)	2004	Phase II (RT)
Gore et al. 2009 (A618-1037)	2005-2007	Non-randomized
Motzer et al. 2014 (RECORD-3)	2009-2011	Randomized Phase II (E-switch-ic)	Everolimus	Inconclusive whether non-inferior PFS

Preceding treatment

• RECORD-3: Everolimus

Targeted therapy

• Sunitinib (Sutent) 50 mg PO once per day on days 1 to 28
  • Dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability

42-day cycles

References

1. RTKC-0511-014: Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006 Jan 1;24(1):16-24. Epub 2005 Dec 5. link to original article PubMed
2. 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 protocol PubMed
3. A618-1037: Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009 Aug;10(8):757-63. Epub 2009 Jul 15. link to original article contains verified protocol PubMed NCT00130897
4. RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article link to PMC article PubMed NCT00903175

Metastatic disease, third-line

Sorafenib monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2014 (GOLD-RCC)	2011-2012	Phase III (C)	Dovitinib	Might have inferior PFS
Rini et al. 2019 (TIVO-3)	2016-2017	Phase III (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

• Sorafenib (Nexavar) 400 mg PO twice per day

Continued indefinitely

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 protocol 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 PubMed NCT02627963

Tivozanib monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rini et al. 2019 (TIVO-3)	2016-2017	Phase III (E-switch-ic)	Sorafenib	Seems to have superior PFS

Targeted therapy

• Tivozanib (Fotivda) 1.5 mg PO once per day on days 1 to 21

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 verified protocol PubMed NCT02627963