Renal cell carcinoma

Section editor
	Eddy J. Chen, MD Massachusetts General Hospital Boston, MA

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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

• 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

Adjuvant therapy

Observation

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Messing et al. 2003 (INT-0079)	Phase III (C)	Interferon alfa-NL	Might have superior OS
Clark et al. 2003	Phase III (C)	High-dose IL-2	Seems not superior
Jocham et al. 2004	Phase III (C)	Renal tumor cell vaccine	Seems to have inferior TTP
Wood et al. 2008	Phase III (C)	Vitespen	Seems not superior
Aitchison et al. 2013 (EORTC 30955)	Phase III (C)	5-FU, IFN, IL-2	Seems not superior
Passalacqua et al. 2014 (POLAR-01)	Phase III (C)	IFN & IL-2	Seems not superior

No treatment after surgery.

Preceding treatment

• Surgery

References

1. INT-0079: Messing EM, Manola J, Wilding G, Propert K, Fleischmann J, Crawford ED, Pontes JE, Hahn R, Trump D; Eastern Cooperative Oncology Group/Intergroup trial. Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: an Eastern Cooperative Oncology Group/Intergroup trial. J Clin Oncol. 2003 Apr 1;21(7):1214-22. link to original article PubMed
2. Clark JI, Atkins MB, Urba WJ, Creech S, Figlin RA, Dutcher JP, Flaherty L, Sosman JA, Logan TF, White R, Weiss GR, Redman BG, Tretter CP, McDermott D, Smith JW, Gordon MS, Margolin KA. Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine working group randomized trial. J Clin Oncol. 2003 Aug 15;21(16):3133-40. Epub 2003 Jun 16. link to original article PubMed
3. Jocham D, Richter A, Hoffmann L, Iwig K, Fahlenkamp D, Zakrzewski G, Schmitt E, Dannenberg T, Lehmacher W, von Wietersheim J, Doehn C. Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial. Lancet. 2004 Feb 21;363(9409):594-9. link to original article PubMed
4. Wood C, Srivastava P, Bukowski R, Lacombe L, Gorelov AI, Gorelov S, Mulders P, Zielinski H, Hoos A, Teofilovici F, Isakov L, Flanigan R, Figlin R, Gupta R, Escudier B; C-100-12 RCC Study Group. An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial. Lancet. 2008 Jul 12;372(9633):145-54. Epub 2008 Jul 3. link to original article PubMed
5. EORTC 30955: Aitchison M, Bray CA, Van Poppel H, Sylvester R, Graham J, Innes C, McMahon L, Vasey PA. Adjuvant 5-flurouracil, alpha-interferon and interleukin-2 versus observation in patients at high risk of recurrence after nephrectomy for renal cell carcinoma: results of a phase III randomised European Organisation for Research and Treatment of Cancer (Genito-Urinary Cancers Group)/National Cancer Research Institute trial. Eur J Cancer. 2014 Jan;50(1):70-7. Epub 2013 Sep 25. link to original article PubMed
6. POLAR-01: Passalacqua R, Caminiti C, Buti S, Porta C, Camisa R, Braglia L, Tomasello G, Vaglio A, Labianca R, Rondini E, Sabbatini R, Nastasi G, Artioli F, Prati A, Potenzoni M, Pezzuolo D, Oliva E, Alberici F, Buzio C; POLAR-01 Trial Investigators. Adjuvant low-dose interleukin-2 (IL-2) plus interferon-α (IFN-α) in operable renal cell carcinoma (RCC): a phase III, randomized, multicentre trial of the Italian Oncology Group for Clinical Research (GOIRC). J Immunother. 2014 Nov-Dec;37(9):440-7. Erratum in: J Immunother. 2015 Jun;38(5):216. link to original article PubMed

Placebo

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Regimen

Study	Evidence	Comparator	Efficacy	Toxicity
Haas et al. 2016 (ECOG-ACRIN E2805)	Phase III (C)	1. Sorafenib	Seems not superior
		2. Sunitinib	Seems not superior
Ravaud et al. 2016 (S-TRAC)	Phase III (C)	Sunitinib	Seems to have inferior DFS	Less toxicity
Chamie et al. 2017 (ARISER)	Phase III (C)	Girentuximab	Seems not superior
Motzer et al. 2017 (PROTECT)	Phase III (C)	Pazopanib	Seems not superior
Gross-Goupil et al. 2018 (ATLAS-RCC)	Phase III (C)	Axitinib	Seems not superior

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

Preceding treatment

• Surgery

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
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
3. ARISER: Chamie K, Donin NM, Klöpfer P, Bevan P, Fall B, Wilhelm O, Störkel S, Said J, Gambla M, Hawkins RE, Jankilevich G, Kapoor A, Kopyltsov E, Staehler M, Taari K, Wainstein AJA, Pantuck AJ, Belldegrun AS. Adjuvant weekly girentuximab following nephrectomy for high-risk renal cell carcinoma: The ARISER randomized clinical trial. JAMA Oncol. 2017 Jul 1;3(7):913-920. link to original article PubMed
4. PROTECT: Motzer RJ, Haas NB, Donskov F, Gross-Goupil M, Varlamov S, Kopyltsov E, Lee JL, Melichar B, Rini BI, Choueiri TK, Zemanova M, Wood LA, Reaume MN, Stenzl A, Chowdhury S, Lim HY, McDermott R, Michael A, Bao W, Carrasco-Alfonso MJ, Aimone P, Voi M, Doehn C, Russo P, Sternberg CN; PROTECT investigators. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. J Clin Oncol. 2017 Dec 10;35(35):3916-3923. Epub 2017 Sep 13. link to original article PubMed
5. ATLAS: Gross-Goupil M, Kwon TG, Eto M, Ye D, Miyake H, Seo SI, Byun SS, Lee JL, Master V, Jin J, DeBenedetto R, Linke R, Casey M, Rosbrook B, Lechuga M, Valota O, Grande E, Quinn DI. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial. Ann Oncol. 2018 Dec 1;29(12):2371-2378. Epub 2018 Oct 20. link to original article link to PMC article PubMed

Sunitinib monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy	Toxicity
Haas et al. 2016 (ECOG-ACRIN E2805)	Phase III (E)	1. Placebo	Seems not superior
		2. Sorafenib	Seems not superior
Ravaud et al. 2016 (S-TRAC)	Phase III (E)	Placebo	Seems to have superior DFS	More toxicity

Preceding treatment

• Surgery

Chemotherapy

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

42-day cycles, given for up to 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
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	Evidence	Comparator	Comparative Efficacy
Rini et al. 2019 (IMmotion151)	Phase III (E)	Sunitinib	Seems to have superior PFS

Immunotherapy

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

Chemotherapy

• 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

Axitinib monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy	ORR	Comparator ORR
Hutson et al. 2013 (A4061051)	Phase III (E)	Sorafenib	Might have superior PFS (*)	32%	15%

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

Chemotherapy

• 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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Variant #1, weight-based dosing

Study	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2019 (JAVELIN Renal 101)	Phase III (E)	Sunitinib	Superior PFS

Note: this is not the FDA-recommended dose.

Chemotherapy

• Axitinib (Inlyta) 5 mg PO twice per day

Immunotherapy

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

14-day cycles

Variant #2, flat dosing

FDA-recommended dose

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

Chemotherapy

• 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 PubMed

Axitinib & Pembrolizumab

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Rini et al. 2019 (KEYNOTE-426)	Phase III (E)	Sunitinib	Superior OS

Chemotherapy

• Axitinib (Inlyta) 5 mg PO twice per day

Immunotherapy

• Pembrolizumab (Keytruda) 300 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

Bevacizumab monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy	ORR	Comparator ORR
Bukowski et al. 2007	Randomized Phase II (C)	Erlotinib & Bevacizumab	Seems not superior	13%	14%

Chemotherapy

• 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 104 weeks

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

Study	Evidence	Comparator	Efficacy
Escudier et al. 2007 (AVOREN)	Phase III (E)	Interferon alfa-2a	Seems not superior (*)
Rini et al. 2008 (CALGB 90206)	Phase III (E)	Interferon alfa-2a	Might have superior OS (*)
Rini et al. 2013 (INTORACT)	Phase III (C)	Temsirolimus & Bevacizumab	Seems not superior

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

Chemotherapy

• 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 52 week course (AVOREN) or indefinitely (CALGB 90206 & INTORACT)

Subsequent treatment

• AVOREN: Bevacizumab maintenance

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
   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

Cabozantinib monotherapy

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Regimen

FDA-recommended dose

Study	Evidence	Comparator	Efficacy	ORR	Comparator ORR
Choueiri et al. 2016 (CABOSUN)	Phase III (E)	Sunitinib	Superior PFS (*)	33% (95% CI 23-44%)	12% (95% CI 5-21%)

Note: 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.

Chemotherapy

• 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

Doxorubicin & Gemcitabine

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Regimen

Study	Evidence
Haas et al. 2012 (ECOG 8802)	Phase II

Patients had disease with sarcomatoid features.

Chemotherapy

• Doxorubicin (Adriamycin) 50 mg/m² IV push once on day 1
• Gemcitabine (Gemzar) 1500 mg/m² IV over 30 minutes once on day 1

Supportive medications

• One of the following:
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 2 or 3, given until day 10
  • Pegfilgrastim (Neulasta) 6 mg SC once on day 2

14-day cycles, given up to cumulative doxorubicin dose of 300 to 450 mg/m² (depending on cardiac function)

References

1. ECOG 8802: Haas NB, Lin X, Manola J, Pins M, Liu G, McDermott D, Nanus D, Heath E, Wilding G, Dutcher J. A phase II trial of doxorubicin and gemcitabine in renal cell carcinoma with sarcomatoid features: ECOG 8802. Med Oncol. 2012 Jun;29(2):761-7. Epub 2011 Feb 6. link to original article contains verified protocol link to PMC article PubMed

Erlotinib monotherapy

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Regimen

Study	Evidence	Efficacy
Gordon et al. 2009 (SWOG S0317)	Phase II	11% (95% CI 3-24%)

Chemotherapy

• Erlotinib (Tarceva) 150 mg PO once per day, given 1 hour before or 2 hours after meals

Continued indefinitely

References

1. SWOG S0317: Gordon MS, Hussey M, Nagle RB, Lara PN Jr, Mack PC, Dutcher J, Samlowski W, Clark JI, Quinn DI, Pan CX, Crawford D. Phase II study of erlotinib in patients with locally advanced or metastatic papillary histology renal cell cancer: SWOG S0317. J Clin Oncol. 2009 Dec 1;27(34):5788-93. Epub 2009 Nov 2. link to original article contains verified protocol link to PMC article PubMed

Erlotinib & Bevacizumab

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Regimen

Study	Evidence	Comparator	Efficacy
Bukowski et al. 2007	Randomized Phase II (E)	Bevacizumab	Seems not superior

Chemotherapy

• 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 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	Evidence	Comparator	Efficacy
Motzer et al. 2014 (RECORD-3)	Randomized Phase II (E)	Sunitinib	Inconclusive whether non-inferior
Tannir et al. 2015 (ESPN)	Randomized Phase II (E)	Sunitinib	Seems not superior
Armstrong et al. 2016 (ASPEN)	Randomized Phase II (E)	Sunitinib	Might have inferior PFS

Chemotherapy

• 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: Sunitinib at the time of progression

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 PubMed
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 PubMed
3. 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

Gemcitabine & Sunitinib

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Variant #1

Study	Evidence
Michaelson et al. 2015	Phase II

Patients had disease with sarcomatoid features.

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Sunitinib (Sutent) 37.5 mg PO once per day on days 1 to 14

21-day cycles

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
• 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. 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

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

Variant #1, 1.8 MU/kg/day, intermittent

Study	Evidence	Comparator	Efficacy
McDermott et al. 2005	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

Variant #2, 2.16 MU/kg/day, intermittent, goal 10.8 MU

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

Note: 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

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)

Variant #4, 5 MU/m²/day, CI

Study	Evidence	Comparator	Efficacy
Figlin et al. 1999	Phase III (C)	IL-2 & CD8+ TILs	Seems not superior

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. Case series: 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 link to PMC article PubMed
3. 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
4. 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
5. 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

Variant #1, Intravenous

Study	Evidence	Comparator	Efficacy
Yang et al. 1994	Phase III (E)	1. High-dose IL-2	Seems to have inferior ORR
		2. Subcutaneous LD IL-2	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

Variant #2, Subcutaneous

Study	Evidence	Comparator	Efficacy
Yang et al. 1994	Phase III (E)	1. High-dose IL-2	Seems to have inferior ORR
		2. Intravenous LD IL-2	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 link to PMC article PubMed

Interferon alfa-2a monotherapy

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Variant #1, 5 MU 5x per week

Study	Evidence	Comparator	Efficacy
Sagaster et al. 1995	Phase III (C)	Cimetidine, Coumarin, IFN alfa-2a	Seems not superior

Immunotherapy

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

Continued indefinitely

Variant #2, 9 MU TIW

Study	Evidence	Comparator	Efficacy
Escudier et al. 2007 (AVOREN)	Phase III (C)	Bevacizumab & Interferon alfa-2a	Seems not superior (*)
Rini et al. 2008 (CALGB 90206)	Phase III (C)	Bevacizumab & Interferon alfa-2a	Might have inferior OS (*)
Escudier et al. 2009	Randomized Phase II (C)	Sorafenib	Seems not superior
Gore et al. 2010 (MRC RE04/EORTC GU 30012)	Phase III (C)	Chemoimmunotherapy	Seems not superior
Hawkins et al. 2016	Phase II/III (C)	Naptumomab estafenatox + IFNα	Seems not superior

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

Variant #3, 9 MU daily, with lead-in

Study	Evidence	Comparator	Efficacy
Motzer et al. 2000	Phase III (C)	IFN alfa & 13-CRA	Seems not superior

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

Variant #4, 9 MU TIW, with lead-in

Study	Evidence	Comparator	Efficacy
Motzer et al. 2007 (A618-1034)	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

Variant #5, 10 MU TIW

Study	Evidence	Comparator	Efficacy
Ritchie et al. 1999 (MRC RE01)	Phase III (E)	MPA	Seems to have superior OS
Gore et al. 2010 (MRC RE04/EORTC GU 30012)	Phase III (C)	Chemoimmunotherapy	Seems not superior

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

Continued for 12 weeks (MRC RE01) or indefinitely (MRC RE04/EORTC GU 30012)

Variant #6, 18 MU TIW, with lead-in

Study	Evidence	Comparator	Efficacy
Fosså et al. 1992	Phase III (C)	IFN alfa-2a & Vinblastine	Seems not superior
Hudes et al. 2007 (ARCC)	Phase III (C)	1. Interferon alfa-2a & Temsirolimus	Seems not superior
		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
   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
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
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	Evidence	Comparator	Efficacy
Negrier et al. 1998	Phase III (E)	1. HD IL-2 2. Interferon alfa-2a	Superior EFS
Passalacqua et al. 2009	Phase III (C)	Maintenance IFN & IL-2	Seems not superior

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; European Organisation for Research and Treatment of Cancer (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 SD 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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Variant #1

Study	Evidence	Comparator	Efficacy
Motzer et al. 2018 (CheckMate 214)	Phase III (E)	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

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

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

Pazopanib monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy	ORR	Comparator ORR
Hutson et al. 2010	Phase II
Sternberg et al. 2010 (VEG105192)	Phase III (E)	Placebo	Superior PFS	30% (95% CI 25-36%)	3% (95% CI 0-6%)
Motzer et al. 2013 (COMPARZ)	Phase III (E)	Sunitinib	Non-inferior PFS	31% (95% CI 27-34%)	25% (95% CI 21-28%)
Cirkel et al. 2017 (ROPETAR)	Randomized (C)	Pazopanib/Everolimus	Seems not superior

Chemotherapy

• 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. 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
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
   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
   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

Placebo

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Regimen

Study	Evidence	Comparator	Efficacy
Gleave et al. 1998	Phase III (C)	Interferon gamma-1b	Seems not superior
Sternberg et al. 2010 (VEG105192)	Phase III (C)	Pazopanib	Inferior PFS

No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.

References

1. Gleave ME, Elhilali M, Fradet Y, Davis I, Venner P, Saad F, Klotz LH, Moore MJ, Paton V, Bajamonde A; Canadian Urologic Oncology Group. Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma. N Engl J Med. 1998 Apr 30;338(18):1265-71. link to original article PubMed
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
   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

Regorafenib monotherapy

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Regimen

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

Chemotherapy

• 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. 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	Evidence	Comparator	Efficacy	ORR	Comparator ORR
Escudier et al. 2009	Randomized Phase II (E)	Interferon alfa-2a	Seems not superior	5%	9%
Stadler et al. 2010 (ARCCS)	Non-randomized
Motzer et al. 2013 (AV-951-09-902)	Phase III (C)	Tivozanib	Seems to have inferior PFS
Hutson et al. 2013 (A4061051)	Phase III (C)	Axitinib	Might have inferior PFS (*)	15%	32%

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

Chemotherapy

• 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
2. 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
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
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
   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	Evidence	Comparator	Efficacy	ORR	Comparator ORR
Motzer et al. 2007 (A618-1034)	Phase III (E)	Interferon alfa-2a	Superior PFS	31%	6%
Gore et al. 2009 (A618-1037)	Non-randomized			17%
Amato et al. 2010	Phase III (C)	Sunitinib & MVA-5T4	Seems not superior
Motzer et al. 2013 (COMPARZ)	Phase III (C)	Pazopanib	Non-inferior PFS	25% (95% CI 21-28%)	31% (95% CI 27-34%)
Motzer et al. 2014 (RECORD-3)	Randomized Phase II (E)	Everolimus	Inconclusive whether non-inferior
Eichelberg et al. 2015 (SWITCH)	Phase III (C)	Sorafenib	Seems not superior
Tannir et al. 2015 (ESPN)	Randomized Phase II (E)	Everolimus	Seems not superior
Armstrong et al. 2016 (ASPEN)	Randomized Phase II (E)	Everolimus	Might have superior PFS
Rini et al. 2016 (IMPRINT)	Phase III (C)	Sunitinib & IMA901	Might have superior OS
Choueiri et al. 2016 (CABOSUN)	Phase III (C)	Cabozantinib	Inferior PFS
Motzer et al. 2018 (CheckMate 214)	Phase III (C)	Ipilimumab & Nivolumab	Inferior OS
Méjean et al. 2018 (CARMENA)	Phase III (E)	Nephrectomy & Sunitinib	Non-inferior OS
Motzer et al. 2019 (JAVELIN Renal 101)	Phase III (C)	Axitinib & Avelumab	Inferior PFS
Rini et al. 2019 (KEYNOTE-426)	Phase III (C)	Axitinib & Pembrolizumab	Inferior OS
Rini et al. 2019 (IMmotion151)	Phase III (C)	Atezolizumab & Bevacizumab	Seems to have inferior PFS

Note: efficacy for CABOSUN is based on the 2018 update.

Chemotherapy

• 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. Retrospective: Choueiri TK, Plantade A, Elson P, Negrier S, Ravaud A, Oudard S, Zhou M, Rini BI, Bukowski RM, Escudier B. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol. 2008 Jan 1;26(1):127-31. link to original article 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
4. 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
5. 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
   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
6. 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
7. 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 PubMed
8. 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
9. 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 PubMed
10. 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
11. 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
12. 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
13. 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
14. 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
15. 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 PubMed
16. 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
17. 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

Temsirolimus monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy	ORR	Comparator ORR
Hudes et al. 2007 (ARCC)	Phase III (E)	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%)

Chemotherapy

• 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, 30 minutes prior to temsirolimus

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

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

Chemotherapy

• 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	Evidence	Comparator	Efficacy	ORR	Comparator ORR
Rini et al. 2011 (AXIS)	Phase III (E)	Sorafenib	Superior PFS	19% (95% CI 15-24%)	9% (95% CI 7-13%)

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

Chemotherapy

• 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	Evidence	Comparator	Efficacy
Yang et al. 2003	Randomized Phase II (E)	Placebo	Superior TTP

Chemotherapy

• 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	Evidence	Comparator	Efficacy	ORR	Comparator ORR
Choueiri et al. 2015 (METEOR)	Phase III (E)	Everolimus	Superior OS	21% (95% CI 16-28%)	5% (95% CI 2-9%)

Preceding treatment

• VEGFR TKI, with progression

Chemotherapy

• 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. 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	Evidence	Comparator	Efficacy	ORR	Comparator ORR
Motzer et al. 2008 (RECORD-1)	Phase III (E)	Placebo	Superior PFS	1%	0%
Motzer et al. 2014 (RECORD-3)	Randomized Phase II (E)	Sunitinib	Inconclusive whether non-inferior
Motzer et al. 2015 (CheckMate 025)	Phase III (C)	Nivolumab	Inferior OS	5%	25%
Choueiri et al. 2015 (METEOR)	Phase III (C)	Cabozantinib	Inferior OS	5% (95% CI 2-9%)	21% (95% CI 16-28%)
Motzer et al. 2015	Randomized Phase II (C)	1. Everolimus & Lenvatinib	Inferior PFS
		2. Lenvatinib	Seems to have inferior PFS
Motzer et al. 2015 (RECORD-4)	Phase II

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

Chemotherapy

• 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 PubMed
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
   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
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. 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. 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

Everolimus & Lenvatinib

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Regimen

Study	Evidence	Comparator	Efficacy
Motzer et al. 2015	Randomized Phase II (E)	1. Everolimus	Superior PFS
		2. Lenvatinib	Seems not superior

Patients had progressed after VEGFR TKI treatment.

Chemotherapy

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

Continued indefinitely

References

1. 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	Evidence	Comparator	Efficacy
Motzer et al. 2015	Randomized Phase II (E)	1. Everolimus	Seems to have superior PFS
		2. Everolimus & Lenvatinib	Seems not superior

Chemotherapy

• Lenvatinib (Lenvima) 24 mg PO once per day

Continued indefinitely

References

1. 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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Variant #1, 0.3 mg/kg q3wk

Study	Evidence	Comparator	Efficacy
Motzer et al. 2015 (CA209-010)	Randomized Phase II (E)	1. Nivo 2 mg/kg 2. Nivo 10 mg/kg	Seems not superior

Immunotherapy

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

21-day cycles

Variant #2, 2 mg/kg q3wk

Study	Evidence	Comparator	Efficacy
Motzer et al. 2015 (CA209-010)	Randomized Phase II (E)	1. Nivo 0.3 mg/kg 2. Nivo 10 mg/kg	Seems not superior

Immunotherapy

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

21-day cycles

Variant #3, 3 mg/kg q2wk

Study	Evidence	Comparator	Efficacy	ORR	Comparator ORR
Motzer et al. 2015 (CheckMate 025)	Phase III (E)	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

Variant #4, 10 mg/kg q3wk

Study	Evidence	Comparator	Efficacy
Motzer et al. 2015 (CA209-010)	Randomized Phase II (E)	1. Nivo 0.3 mg/kg 2. Nivo 2 mg/kg	Seems not superior

Immunotherapy

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

21-day cycles

References

1. CA209-010: 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
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
   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

Pazopanib monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy	ORR	Comparator ORR
Hutson et al. 2010	Phase II
Sternberg et al. 2010 (VEG105192)	Phase III (E)	Placebo	Superior PFS	30% (95% CI 25-36%)	3% (95% CI 0-6%)
Hainsworth et al. 2013	Phase II

Chemotherapy

• 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. 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
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
   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

Placebo

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Regimen

Study	Evidence	Comparator	Efficacy
Yang et al. 2003	Randomized Phase II (C)	Bevacizumab	Inferior TTP
Escudier et al. 2007 (TARGETRCC)	Phase III (C)	Sorafenib	Seems not superior (*)
Motzer et al. 2008 (RECORD-1)	Phase III (C)	Everolimus	Inferior PFS
Sternberg et al. 2010 (VEG105192)	Phase III (C)	Pazopanib	Inferior PFS

No active antineoplastic treatment. 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.

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
2. 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
3. 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
4. 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
   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

Sorafenib monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy	ORR	Comparator ORR
Escudier et al. 2007 (TARGETRCC)	Phase III (E)	Placebo	Seems not superior (*)	10%	2%
Stadler et al. 2010 (ARCCS)	Non-randomized
Beck et al. 2011 (EU-ARCCS)	Non-randomized
Rini et al. 2011 (AXIS)	Phase III (C)	Axitinib	Inferior PFS	9% (95% CI 7-13%)	19% (95% CI 15-24%)
Hutson et al. 2013 (INTORSECT)	Phase III (C)	Temsirolimus	Seems not superior (*)

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.

Chemotherapy

• 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
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

Sunitinib monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2006 (A618-1006)	Phase II
Gore et al. 2009 (A618-1037)	Non-randomized		ORR: 17%
Motzer et al. 2014 (RECORD-3)	Randomized Phase II (E)	Everolimus	Inconclusive whether non-inferior

Preceding treatment

• RECORD-3: Everolimus

Chemotherapy

• 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. 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
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
3. 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 PubMed

Metastatic disease, third-line

Sorafenib monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Motzer et al. 2014 (GOLD-RCC)	Phase III (C)	Dovitinib	Might have inferior PFS

Note: this trial should not be confused for the one with the same name in gastric cancer.

Chemotherapy

• 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 PubMed