Renal cell carcinoma

Page editor		Section editor
	Teja Ganta, MD Icahn School of Medicine at Mount Sinai New York, NY LinkedIn		Ali Raza Khaki, MD Stanford University Palo Alto, CA LinkedIn

Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page or to a histology- or biomarker-specific page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
There are several related dedicated pages:

• Histology-specific:
  • Clear cell renal cell carcinoma
  • Non-clear cell renal cell carcinoma
    • Papillary renal cell carcinoma
    • Sarcomatoid renal cell carcinoma
• Biomarker-specific:
  • RCC, VHL-associated

26 regimens on this page 43 variants on this page

Living Interactive Systematic Reviews

• Adjuvant treatment options in renal cell carcinoma
• Metastatic renal cell carcinoma (mRCC)

Guidelines

ESMO

• 2021: Powles et al. ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma
• 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

Older

• 2017: Motzer et al. Kidney Cancer, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology PubMed
• 2015: Motzer et al. Kidney Cancer, Version 3.2015 PubMed
• 2014: Motzer et al. Kidney cancer, version 2.2014 PubMed

SIOG

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

SITC

• 2019: Rini et al. The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC)

Risk Stratification Calculators

• International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) calculator
  • ref: Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, Mackenzie M, Wood L, Donskov F, Tan MH, Rha SY, Agarwal N, Kollmannsberger C, Rini BI, Choueiri TK; External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013 Feb;14(2):141-8. Epub 2013 Jan 9. link to PMC article PubMed
• Memorial Sloan Kettering Cancer Center (MSKCC) calculator
  • ref: Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002 Jan 1;20(1):289-96. link to original article PubMed
• Mortality and complication risk calculator for a patients with clinical T1 renal cortical mass ≤ 7 cm (Dr. Sarah P. Psutka)
  • ref: Psutka SP et al., A clinical decision aid to support personalized treatment selection for patients with stage T1 renal masses: Results from a multi-institutional competing risks analysis including performance status and comorbidity. Working paper. link to news article
• UCLA Integrated Staging System (UISS) for Renal Cell Carcinoma (RCC)
  • ref: Zisman A, Pantuck AJ, Dorey F, Said JW, Shvarts O, Quintana D, Gitlitz BJ, deKernion JB, Figlin RA, Belldegrun AS. Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol. 2001 Mar 15;19(6):1649-57. PubMed
• Leibovich prognostic model
  • ref: Leibovich BC, Lohse CM, Cheville JC, Zaid HB, Boorjian SA, Frank I, Thompson RH, Parker WP. Predicting Oncologic Outcomes in Renal Cell Carcinoma After Surgery. Eur Urol. 2018 May;73(5):772-780. Epub 2018 Feb 3. PubMed

Adjuvant therapy

Sunitinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Haas et al. 2016 (ECOG-ACRIN E2805)	2006-2010	Phase 3 (E-esc)	1. Placebo 2. Sorafenib	Did not meet primary endpoint of DFS
Ravaud et al. 2016 (S-TRAC)	2007-2011	Phase 3 (E-RT-esc)	Placebo	Seems to have superior DFS Median DFS: 6.8 vs 5.6 yr (HR 0.76, 95% CI 0.59-0.98)	More toxicity

Preceding treatment

• Surgery

Targeted therapy

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

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

References

1. ECOG-ACRIN E2805: Haas NB, Manola J, Uzzo RG, Flaherty KT, Wood CG, Kane C, Jewett M, Dutcher JP, Atkins MB, Pins M, Wilding G, Cella D, Wagner L, Matin S, Kuzel TM, Sexton WJ, Wong YN, Choueiri TK, Pili R, Puzanov I, Kohli M, Stadler W, Carducci M, Coomes R, DiPaola RS. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016 May 14;387(10032):2008-16. Epub 2016 Mar 9. Erratum in: Lancet. 2016 May 14;387(10032):1998. link to original article link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT00326898
2. S-TRAC: Ravaud A, Motzer RJ, Pandha HS, George DJ, Pantuck AJ, Patel A, Chang YH, Escudier B, Donskov F, Magheli A, Carteni G, Laguerre B, Tomczak P, Breza J, Gerletti P, Lechuga M, Lin X, Martini JF, Ramaswamy K, Casey M, Staehler M, Patard JJ; S-TRAC Investigators. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016 Dec 8;375(23):2246-2254. Epub 2016 Oct 9. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00375674
   1. Update: Motzer RJ, Ravaud A, Patard JJ, Pandha HS, George DJ, Patel A, Chang YH, Escudier B, Donskov F, Magheli A, Carteni G, Laguerre B, Tomczak P, Breza J, Gerletti P, Lechuga M, Lin X, Casey M, Serfass L, Pantuck AJ, Staehler M. Adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy: subgroup analyses and updated overall survival results. Eur Urol. 2018 Jan;73(1):62-68. Epub 2017 Sep 26. link to original article link to PMC article PubMed

Metastatic disease, first-line

Atezolizumab & Bevacizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rini et al. 2019 (IMmotion151)	2015-05-20 to 2016-10-12	Phase 3 (E-esc)	Sunitinib	Seems to have superior PFS1 Median PFS: 11.2 vs 7.7 mo (HR 0.74, 95% CI 0.57-0.96)

¹Reported efficacy is for the PD-L1-positive subgroup, which was the predefined co-primary endpoint.
Note: patients could have clear cell or sarcomatoid histology.

Immunotherapy

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

Targeted therapy

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

21-day cycles

References

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 dosing details in abstract PubMed https://clinicaltrials.gov/ct2/show/NCT02420821
   1. Update: Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Alekseev BY, Lee JL, Suarez C, Stroyakovskiy D, De Giorgi U, Donskov F, Mellado B, Banchereau R, Hamidi H, Khan O, Craine V, Huseni M, Flinn N, Dubey S, Rini BI. Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol. 2022 Feb 1;8(2):275-280. link to original article [link to PMC article PubMed

Bevacizumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bukowski et al. 2007	2004	Randomized Phase 2 (C)	Erlotinib & Bevacizumab	Did not meet co-primary endpoints of ORR/PFS

Targeted therapy

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

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

References

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

Bevacizumab & Interferon alfa-2a

Regimen variant #1, 1 year of interferon

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Escudier et al. 2007 (AVOREN) ESMO-MCBS (3)	2004-2005	Phase 3 (E-RT-esc)	Interferon alfa-2a	Did not meet primary endpoint of OS1 Median OS: 23.3 vs 21.3 mo (HR 0.91, 95% CI 0.76-1.10) Superior PFS2 (secondary endpoint) Median PFS: 10.2 vs 5.4 mo (HR 0.63, 95% CI 0.52-0.75)

¹Reported efficacy for AVOREN is based on the 2010 update.
²The secondary endpoint of PFS was used in the FDA regulatory decision; please see paper for details.
Note: Timing below reflects starting treatment on a Monday.

Targeted therapy

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

Immunotherapy

• Interferon alfa-2a (Roferon-A) as follows:
  • Cycles 1 to 26: 9,000,000 units SC once per day on days 1, 3, 5, 8, 10, 12 (3 times per week)

14-day cycles

Dose modifications

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

Regimen variant #2, indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rini et al. 2008 (CALGB 90206)	2003-2005	Phase 3 (E-esc)	Interferon alfa-2a	Might have superior OS1 Median OS: 18.3 vs 17.4 mo (HR 0.86, 95% CI 0.73-1.01)
Rini et al. 2013 (INTORACT)	2008-2010	Phase 3 (C)	Temsirolimus & Bevacizumab	Did not meet primary endpoint of PFS

¹Reported efficacy for CALGB 90206 is based on the 2010 update and is based on a stratified analysis.
Note: Timing below reflects starting treatment on a Monday.

Targeted therapy

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

Immunotherapy

• Interferon alfa-2a (Roferon-A) 9,000,000 units SC once per day on days 1, 3, 5, 8, 10, 12 (3 times per week)

14-day cycles

Dose modifications

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

References

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 https://clinicaltrials.gov/ct2/show/NCT00738530
   1. Update: Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, Sneller V. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010 May 1;28(13):2144-50. Epub 2010 Apr 5. link to original article contains dosing details in manuscript PubMed
2. CALGB 90206: Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008 Nov 20;26(33):5422-8. Epub 2008 Oct 20. link to original article link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT00072046
   1. Update: Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010 May 1;28(13):2137-43. Epub 2010 Apr 5. link to original article link to PMC article PubMed
3. INTORACT: Rini BI, Bellmunt J, Clancy J, Wang K, Niethammer AG, Hariharan S, Escudier B. Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol. 2014 Mar 10;32(8):752-9. Epub 2013 Dec 2. link to original article contains dosing details in abstract PubMed https://clinicaltrials.gov/ct2/show/NCT00631371

Erlotinib & Bevacizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bukowski et al. 2007	2004	Randomized Phase 2 (E-esc)	Bevacizumab	Did not meet primary endpoints of ORR/PFS

Targeted therapy

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

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

References

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

Everolimus monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2014 (RECORD-3)	2009-2011	Randomized Phase 2 (E-switch-ic)	Sunitinib	Inconclusive whether non-inferior PFS

Targeted therapy

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

Continued indefinitely

Subsequent treatment

• RECORD-3, upon progression: Sunitinib

References

1. RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT00903175

Everolimus & Lenvatinib

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2021 (CLEAR)	2016-10-13 to 2019-07-24	Phase 3 (E-RT-esc)	1. Lenvatinib & Pembrolizumab	Not reported
			2. Sunitinib	Superior PFS (primary endpoint) Median PFS: 14.7 vs 9.2 mo (HR 0.65, 95% CI 0.53-0.80)

Targeted therapy

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

21-day cycles

References

1. CLEAR: Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT02811861
   1. Update: Choueiri TK, Eto M, Motzer R, De Giorgi U, Buchler T, Basappa NS, Méndez-Vidal MJ, Tjulandin S, Hoon Park S, Melichar B, Hutson T, Alemany C, McGregor B, Powles T, Grünwald V, Alekseev B, Rha SY, Kopyltsov E, Kapoor A, Alonso Gordoa T, Goh JC, Staehler M, Merchan JR, Xie R, Perini RF, Mody K, McKenzie J, Porta CG. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol. 2023 Mar;24(3):228-238. Erratum in: Lancet Oncol. 2023 Apr;24(4):e146. link to original article PubMed

Gemcitabine & Sunitinib

Regimen variant #1

Study	Dates of enrollment	Evidence
Michaelson et al. 2015 (MGH 07-212)	2007-2013	Phase 2

Chemotherapy

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

Targeted therapy

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

21-day cycles

Regimen variant #2

Study	Evidence
Pandya et al. 2011	Retrospective

Chemotherapy

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

Targeted therapy

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

21-day cycles

References

1. Retrospective: Pandya SS, Mier JW, McDermott DF, Cho DC. Addition of gemcitabine at the time of sunitinib resistance in metastatic renal cell cancer. BJU Int. 2011 Oct;108(8 Pt 2):E245-9. Epub 2011 Feb 14. link to original article contains dosing details in manuscript PubMed
2. MGH 07-212: Michaelson MD, McKay RR, Werner L, Atkins MB, Van Allen EM, Olivier KM, Song J, Signoretti S, McDermott DF, Choueiri TK. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer. 2015 Oct 1;121(19):3435-43. Epub 2015 Jun 8. link to original article PubMed https://clinicaltrials.gov/ct2/show/NCT00556049

High-dose Interleukin-2

HD IL-2: High-Dose InterLeukin-2

Example orders

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

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rosenberg et al. 1994	1985-1992	Non-randomized
Fyfe et al. 1995	NR	Phase 2 (RT)
McDermott et al. 2005	1997-2000	Phase 3 (C)	Subcutaneous IL-2 & Interferon	Might have superior PFS

Immunotherapy

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

Supportive therapy

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

28-day cycle for up to 3 cycles

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yang et al. 1994	1991-1993	Phase 3 (C)	1. LD IL-2 (IV)	Seems to have superior ORR
			2. LD IL-2 (SC)	Seems to have superior ORR

Note: reported efficacy is based on the 2003 update.

Immunotherapy

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

8-week cycle for up to 2 cycles

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

Study	Evidence
Klapper et al. 2008	Retrospective

Immunotherapy

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

Supportive therapy

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

Subsequent treatment

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

Regimen variant #4, 5 MU/m²/day, CI

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Figlin et al. 1999	1994-1997	Phase 3 (C)	IL-2 & CD8+ TILs	Did not meet primary endpoint of ORR

Immunotherapy

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

8-week cycles

References

1. Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994 Mar 23-30;271(12):907-13. link to original article PubMed
2. Yang JC, Topalian SL, Parkinson D, Schwartzentruber DJ, Weber JS, Ettinghausen SE, White DE, Steinberg SM, Cole DJ, Kim HI, Levin R, Guleria A, MacFarlane MP, White RL, Einhorn JH, Seipp CA, Rosenberg SA. Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol. 1994 Aug;12(8):1572-6. link to original article PubMed
   1. Update: Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. link to original article link to PMC article contains dosing details in manuscript PubMed
3. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995 Mar;13(3):688-96. link to original article PubMed
4. Figlin RA, Thompson JA, Bukowski RM, Vogelzang NJ, Novick AC, Lange P, Steinberg GD, Belldegrun AS. Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol. 1999 Aug;17(8):2521-9. link to original article contains dosing details in manuscript PubMed
5. McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, Kirkwood JM, Gordon MS, Sosman JA, Ernstoff MS, Tretter CP, Urba WJ, Smith JW, Margolin KA, Mier JW, Gollob JA, Dutcher JP, Atkins MB. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005 Jan 1;23(1):133-41. link to original article contains dosing details in manuscript PubMed
6. Retrospective: Klapper JA, Downey SG, Smith FO, Yang JC, Hughes MS, Kammula US, Sherry RM, Royal RE, Steinberg SM, Rosenberg S. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma : a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008 Jul 15;113(2):293-301. link to original article contains dosing details in manuscript link to PMC article PubMed

Low-dose Interleukin-2

LD IL-2: Low-Dose InterLeukin-2

Regimen variant #1, Intravenous

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yang et al. 1994	1991-1993	Phase 3 (E-de-esc)	1. High-dose IL-2	Seems to have inferior ORR
			2. LD IL-2; SC	Not reported

Note: efficacy is based on the 2003 update.

Immunotherapy

• IL-2 - Aldesleukin (Proleukin) as follows:
  • Week 1: 72,000 units/kg IV every 8 hours for up to 15 doses
  • Then after 7 to 10 days of rest: 72,000 units/kg IV every 8 hours for up to 15 doses is given again

8-week cycle for up to 2 cycles

Regimen variant #2, Subcutaneous

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yang et al. 1994	1991-1993	Phase 3 (E-de-esc)	1. High-dose IL-2	Seems to have inferior ORR
			2. LD IL-2; IV	Not reported

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

Immunotherapy

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

8-week cycle for up to 2 cycles

References

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 dosing details in manuscript PubMed

Interferon alfa-2a monotherapy

Regimen variant #1, 5 MU 5x per week

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sagaster et al. 1995	NR-1992	Phase 3 (C)	Cimetidine, Coumarin, IFN alfa-2a	Did not meet primary endpoint of ORR

Immunotherapy

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

Continued indefinitely

Regimen variant #2, 9 MU TIW

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gore et al. 2010 (MRC RE04/EORTC GU 30012)	2001-2006	Phase 3 (C)	5-FU, Interferon alfa-2a, IL-2	Did not meet primary endpoint of OS
Rini et al. 2008 (CALGB 90206)	2003-2005	Phase 3 (C)	Bevacizumab & Interferon alfa-2a	Might have inferior OS1
Escudier et al. 2007 (AVOREN)	2004-2005	Phase 3 (C)	Bevacizumab & Interferon alfa-2a	Did not meet primary endpoint of OS2
Escudier et al. 2009 (Bayer 11848)	2005-06-28 to 2005-09-30	Randomized Phase 2 (C)	Sorafenib	Did not meet primary endpoint of PFS
Hawkins et al. 2016 (Active Biotech 06762004)	2007-2010	Phase 2/3 (C)	Naptumomab estafenatox + IFNα	Did not meet primary endpoint of OS

¹Reported efficacy for CALGB 90206 is based on the 2010 update and is based on a stratified analysis.
²Reported efficacy for AVOREN is based on the 2010 update.

Immunotherapy

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

Given for varying lengths of time; see individual trials

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2000	1994-1996	Phase 3 (C)	IFN alfa & 13-CRA	Did not meet primary endpoint of ORR

Immunotherapy

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

Continued indefinitely

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2007 (A618-1034)	2004-08 to 2005-10	Phase 3 (C)	Sunitinib	Inferior PFS

Immunotherapy

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

Continued indefinitely

Regimen variant #5, 10 MU TIW

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ritchie et al. 1999 (MRC RE01)	1992-1997	Phase 3 (E-switch-ooc)	MPA	Seems to have superior OS
Gore et al. 2010 (MRC RE04/EORTC GU 30012)	2001-2006	Phase 3 (C)	5-FU, Interferon alfa-2a, IL-2	Did not meet primary endpoint of OS

Immunotherapy

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

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

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fosså et al. 1992	1985-1986	Phase 3 (C)	IFN alfa-2a & Vinblastine	Did not meet efficacy endpoints
Hudes et al. 2007 (ARCC)	2003-2005	Phase 3 (C)	1. Interferon alfa-2a & Temsirolimus	Did not meet primary endpoint of OS
			2. Temsirolimus	Inferior OS

Immunotherapy

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

Continued indefinitely

References

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 dosing details in abstract 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 contains dosing details in abstract 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 dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00098657
   1. Update: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Aug 1;27(22):3584-90. Epub 2009 Jun 1. link to original article contains dosing details in manuscript link to PMC article PubMed content property of HemOnc.org
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 dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00065468
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 https://clinicaltrials.gov/ct2/show/NCT00738530
   1. Update: Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, Sneller V. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010 May 1;28(13):2144-50. Epub 2010 Apr 5. link to original article contains dosing details in manuscript PubMed
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 https://clinicaltrials.gov/ct2/show/NCT00072046
   1. Update: Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010 May 1;28(13):2137-43. Epub 2010 Apr 5. link to original article link to PMC article PubMed
9. Bayer 11848: Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, Negrier S, Laferriere N, Scheuring UJ, Cella D, Shah S, Bukowski RM. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Mar 10;27(8):1280-9. Epub 2009 Jan 26. Erratum in: J Clin Oncol. 2009 May 1; 27(13):2305. link to original article PubMed https://clinicaltrials.gov/ct2/show/NCT00117637
10. MRC RE04/EORTC GU 30012: Gore ME, Griffin CL, Hancock B, Patel PM, Pyle L, Aitchison M, James N, Oliver RT, Mardiak J, Hussain T, Sylvester R, Parmar MK, Royston P, Mulders PF. Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial. Lancet. 2010 Feb 20;375(9715):641-8. Epub 2010 Feb 10. link to original article link to PMC article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00053820
11. Active Biotech 06762004: Hawkins RE, Gore M, Shparyk Y, Bondar V, Gladkov O, Ganev T, Harza M, Polenkov S, Bondarenko I, Karlov P, Karyakin O, Khasanov R, Hedlund G, Forsberg G, Nordle Ö, Eisen T. A randomized phase II/III study of naptumomab estafenatox + IFNα versus IFNα in renal cell carcinoma: final analysis with baseline biomarker subgroup and trend analysis. Clin Cancer Res. 2016 Jul 1;22(13):3172-81. Epub 2016 Feb 5. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00420888

Lenvatinib & Pembrolizumab

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2021 (CLEAR) ESMO-MCBS (4)	2016-10-13 to 2019-07-24	Phase 3 (E-RT-esc)	1. Everolimus & Lenvatinib	Not reported
			2. Sunitinib	Superior OS1 (secondary endpoint) Median OS: NYR vs NYR (HR 0.72, 95% CI 0.55-0.93)

¹Reported efficacy is based on the 2023 update.

Targeted therapy

• Lenvatinib (Lenvima) 20 mg PO once per day

Immunotherapy

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

21-day cycles

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (MK-6482-012)	2021-ongoing	Phase 3 (C)	1. Belzutifan, Lenvatinib, Pembrolizumab 2. Lenvatinib, Quavonlimab, Pembrolizumab	TBD

Targeted therapy

• Lenvatinib (Lenvima) 20 mg PO once per day

Immunotherapy

• Pembrolizumab (Keytruda) as follows:
  • Cycles 1 to 18: 400 mg IV once on day 1

42-day cycles

References

1. CLEAR: Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT02811861
   1. Update: Choueiri TK, Eto M, Motzer R, De Giorgi U, Buchler T, Basappa NS, Méndez-Vidal MJ, Tjulandin S, Hoon Park S, Melichar B, Hutson T, Alemany C, McGregor B, Powles T, Grünwald V, Alekseev B, Rha SY, Kopyltsov E, Kapoor A, Alonso Gordoa T, Goh JC, Staehler M, Merchan JR, Xie R, Perini RF, Mody K, McKenzie J, Porta CG. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol. 2023 Mar;24(3):228-238. Erratum in: Lancet Oncol. 2023 Apr;24(4):e146. link to original article PubMed
2. MK-6482-012: https://clinicaltrials.gov/ct2/show/NCT04736706

Pazopanib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hutson et al. 2009 (VEG102616)	2005-10 to 2006-09	Phase 2
Sternberg et al. 2010 (VEG105192) ESMO-MCBS (3)	2006-04 to 2007-04	Phase 3 (E-RT-esc)	Placebo	Superior PFS (primary endpoint) Median PFS: 9.2 vs 4.2 mo (HR 0.46, 95% CI 0.34-0.62) Did not meet secondary endpoint of OS1 Median OS: 22.9 vs 20.5 mo (HR 0.91, 95% CI 0.71-1.16)
Motzer et al. 2013 (COMPARZ) ESMO-MCBS (4)	2008-2011	Phase 3 (E-switch-ic)	Sunitinib	Non-inferior PFS (primary endpoint) Median PFS: 8.4 vs 9.5 mo (HR 1.05, 95% CI 0.90-1.22)
Cirkel et al. 2017 (ROPETAR)	2012-2014	Randomized (C)	Pazopanib/Everolimus	Did not meet primary endpoint of PFS

Targeted therapy

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

Continued indefinitely

References

1. VEG102616: Hutson TE, Davis ID, Machiels JP, De Souza PL, Rottey S, Hong BF, Epstein RJ, Baker KL, McCann L, Crofts T, Pandite L, Figlin RA. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2010 Jan 20;28(3):475-80. Epub 2009 Dec 14. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00244764
2. VEG105192: Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarbá JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010 Feb 20;28(6):1061-8. Epub 2010 Jan 25. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00334282
   1. Update: Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, Zarba JJ, Gladkov OA, Lee E, Szczylik C, McCann L, Rubin SD, Chen M, Davis ID. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013 Apr;49(6):1287-96. Epub 2013 Jan 12. link to original article contains dosing details in manuscript PubMed
3. COMPARZ: Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, Jin J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R, Pandite LN, Choueiri TK. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013 Aug 22;369(8):722-31. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00720941
   1. Update: Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med. 2014 May 1;370(18):1769-70. link to letter PubMed
4. HRQoL analysis: Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U, Parikh O, Hawkins R, Sevin E, Négrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol. 2014 May 10;32(14):1412-8. Epub 2014 Mar 31. link to original article PubMed https://clinicaltrials.gov/ct2/show/NCT01064310
5. ROPETAR: Cirkel GA, Hamberg P, Sleijfer S, Loosveld OJL, Dercksen MW, Los M, Polee MB, van den Berkmortel F, Aarts MJ, Beerepoot LV, Groenewegen G, Lolkema MP, Tascilar M, Portielje JEA, Peters FPJ, Klümpen HJ, van der Noort V, Haanen JBAG, Voest EE; Dutch WIN-O Consortium. Alternating treatment with pazopanib and everolimus vs continuous pazopanib to delay disease progression in patients with metastatic clear cell renal cell cancer: the ROPETAR randomized clinical trial. JAMA Oncol. 2017 Apr 1;3(4):501-508. link to original article contains dosing details in abstract PubMed https://clinicaltrials.gov/ct2/show/NCT01408004

Regorafenib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Efficacy
Eisen et al. 2012 (Bayer 11726)	2008-2011	Phase 2	ORR: 40% (90% CI 28-53%)

Targeted therapy

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

28-day cycles

References

1. Bayer 11726: Eisen T, Joensuu H, Nathan PD, Harper PG, Wojtukiewicz MZ, Nicholson S, Bahl A, Tomczak P, Pyrhonen S, Fife K, Bono P, Boxall J, Wagner A, Jeffers M, Lin T, Quinn DI. Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial. Lancet Oncol. 2012 Oct;13(10):1055-62. Epub 2012 Sep 6. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00664326

Sorafenib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Escudier et al. 2009 (Bayer 11848)	2005-06-28 to 2005-09-30	Randomized Phase 2 (E-switch-ooc)	Interferon alfa-2a	Did not meet primary endpoint of PFS
Stadler et al. 2010 (ARCCS)	2005-06 to 2006-07	Non-randomized
Tomita et al. 2020 (CROSS-J-RCC)	2010-2012	Phase 3 (E-switch-ic)	Sunitinib	Did not meet primary endpoint of PFS
Retz et al. 2018 (SWITCH-II)	2012-06-14 to 2016-11-14	Phase 3 (C)	Pazopanib	Inconclusive whether non-inferior tPFS

Targeted therapy

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

Continued indefinitely

Subsequent treatment

• SWITCH-II, upon progression: Pazopanib

References

1. Bayer 11848: Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, Negrier S, Laferriere N, Scheuring UJ, Cella D, Shah S, Bukowski RM. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Mar 10;27(8):1280-9. Epub 2009 Jan 26. Erratum in: J Clin Oncol. 2009 May 1; 27(13):2305. link to original article PubMed https://clinicaltrials.gov/ct2/show/NCT00117637
2. ARCCS: Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010 Mar 1;116(5):1272-80. link to original article PubMed https://clinicaltrials.gov/ct2/show/NCT00111020
3. SWITCH-II: Retz M, Bedke J, Bögemann M, Grimm MO, Zimmermann U, Müller L, Leiber C, Teber D, Wirth M, Bolenz C, van Alphen R, De Santis M, Beeker A, Lehmann J, Indorf M, Frank M, Bokemeyer C, Gschwend JE. SWITCH II: Phase III randomized, sequential, open-label study to evaluate the efficacy and safety of sorafenib-pazopanib versus pazopanib-sorafenib in the treatment of advanced or metastatic renal cell carcinoma (AUO AN 33/11). Eur J Cancer. 2019 Jan;107:37-45. Epub 2018 Dec 7. link to original article contains dosing details in abstract PubMed https://clinicaltrials.gov/ct2/show/NCT01613846
4. CROSS-J-RCC: Tomita Y, Naito S, Sassa N, Takahashi A, Kondo T, Koie T, Obara W, Kobayashi Y, Teishima J, Takahashi M, Matsuyama H, Ueda T, Yamaguchi K, Kishida T, Shiroki R, Saika T, Shinohara N, Oya M, Kanayama HO. Sunitinib Versus Sorafenib as Initial Targeted Therapy for mCC-RCC With Favorable/Intermediate Risk: Multicenter Randomized Trial CROSS-J-RCC. Clin Genitourin Cancer. 2020 Aug;18(4):e374-e385. Epub 2020 Mar 6. link to original article PubMed https://clinicaltrials.gov/ct2/show/NCT01481870

Sunitinib monotherapy

Regimen variant #1, 4 out of 6 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2007 (A618-1034) ESMO-MCBS (4)	2004-08 to 2005-10	Phase 3 (E-RT-switch-ooc)	Interferon alfa-2a	Superior PFS (primary endpoint) Median PFS: 11 vs 5 mo (HR 0.42, 95% CI 0.32-0.54) Might have superior OS1 (secondary endpoint) Median OS: 26.4 vs 21.8 mo (HR 0.82, 95% CI 0.67-1.001)
Gore et al. 2009 (A618-1037)	2005-2007	Non-randomized
Amato et al. 2010 (TroVax Renal Immunotherapy Survival Trial)	2006-2008	Phase 3 (C)	Sunitinib & MVA-5T4	Did not meet primary endpoint of OS Median OS: 19.2 vs 20.1 mo (HR 0.93, 95% CI 0.76-1.16)
Motzer et al. 2013 (COMPARZ)	2008-2011	Phase 3 (C)	Pazopanib	Non-inferior PFS
Motzer et al. 2014 (RECORD-3)	2009-2011	Randomized Phase 2 (E-switch-ic)	Everolimus	Inconclusive whether non-inferior PFS
Eichelberg et al. 2015 (SWITCH)	2009-2011	Phase 3 (C)	Sorafenib	Did not meet primary endpoint of PFS
Méjean et al. 2018 (CARMENA)	2009-2017	Phase 3 (E-de-esc)	Nephrectomy, then Sunitinib	Non-inferior OS Median OS: 18.4 vs 13.9 mo (HR 0.89, 95% CI 0.71-1.10)
Rini et al. 2016 (IMPRINT)	2010-2012	Phase 3 (C)	Sunitinib & IMA901	Might have superior OS Median OS: NYR vs 33.2 mo (HR 0.75, 95% CI 0.54-1.04)
Tomita et al. 2020 (CROSS-J-RCC)	2010-2012	Phase 3 (E-switch-ic)	Sorafenib	Did not meet primary endpoint of PFS
Figlin et al. 2020 (ADAPT)	2013-2016	Phase 3 (C)	Rocapuldencel-T & Sunitinib	Did not meet primary endpoint of OS Median OS: 32.4 vs 27.7 mo (HR 0.91, 95% CI 0.71-1.20)
Rini et al. 2019 (IMmotion151)	2015-05-20 to 2016-10-12	Phase 3 (C)	Atezolizumab & Bevacizumab	Seems to have inferior PFS
Motzer et al. 2021 (CLEAR)	2016-10-13 to 2019-07-24	Phase 3 (C)	1. Everolimus & Lenvatinib	Inferior PFS
			2. Lenvatinib & Pembrolizumab	Inferior OS
Awaiting publication (JS001-036-III-RCC)	2020-ongoing	Phase 3 (C)	Axitinib & Toripalimab	TBD

¹Reported efficacy for A618-1034 is based on the 2009 update.

Targeted therapy

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

42-day cycles

Subsequent treatment

• SWITCH, upon progression: Sorafenib

Regimen variant #2, 2 out of 4 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (TQB2450-III-07)	2020-ongoing	Phase 3 (C)	Anlotinib & TQB2450	TBD

Targeted therapy

• Sunitinib (Sutent) 50 mg PO once per day on days 1 to 14

28-day cycles

References

1. A618-1034: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00098657
   1. Update: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Aug 1;27(22):3584-90. Epub 2009 Jun 1. link to original article contains dosing details in manuscript link to PMC article PubMed
2. A618-1037: Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009 Aug;10(8):757-63. Epub 2009 Jul 15. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00130897
3. TroVax Renal Immunotherapy Survival Trial: Amato RJ, Hawkins RE, Kaufman HL, Thompson JA, Tomczak P, Szczylik C, McDonald M, Eastty S, Shingler WH, de Belin J, Goonewardena M, Naylor S, Harrop R. Vaccination of metastatic renal cancer patients with MVA-5T4: a randomized, double-blind, placebo-controlled phase III study. Clin Cancer Res. 2010 Nov 15;16(22):5539-47. Epub 2010 Sep 29. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00397345
4. COMPARZ: Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, Jin J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R, Pandite LN, Choueiri TK. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013 Aug 22;369(8):722-31. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00720941
   1. Update: Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med. 2014 May 1;370(18):1769-70. link to letter PubMed
5. HRQoL analysis: Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U, Parikh O, Hawkins R, Sevin E, Négrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol. 2014 May 10;32(14):1412-8. Epub 2014 Mar 31. link to original article PubMed https://clinicaltrials.gov/ct2/show/NCT01064310
6. RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT00903175
7. SWITCH: Eichelberg C, Vervenne WL, De Santis M, Fischer von Weikersthal L, Goebell PJ, Lerchenmüller C, Zimmermann U, Bos MM, Freier W, Schirrmacher-Memmel S, Staehler M, Pahernik S, Los M, Schenck M, Flörcken A, van Arkel C, Hauswald K, Indorf M, Gottstein D, Michel MS. SWITCH: A Randomised, Sequential, Open-label Study to Evaluate the Efficacy and Safety of Sorafenib-sunitinib Versus Sunitinib-sorafenib in the Treatment of Metastatic Renal Cell Cancer. Eur Urol. 2015 Nov;68(5):837-47. Epub 2015 May 4. link to original article contains dosing details in abstract PubMed https://clinicaltrials.gov/ct2/show/NCT00732914
8. IMPRINT: Rini BI, Stenzl A, Zdrojowy R, Kogan M, Shkolnik M, Oudard S, Weikert S, Bracarda S, Crabb SJ, Bedke J, Ludwig J, Maurer D, Mendrzyk R, Wagner C, Mahr A, Fritsche J, Weinschenk T, Walter S, Kirner A, Singh-Jasuja H, Reinhardt C, Eisen T. IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2016 Nov;17(11):1599-1611. link to original article contains dosing details in abstract PubMed https://clinicaltrials.gov/ct2/show/NCT01265901
9. CARMENA: Méjean A, Ravaud A, Thezenas S, Colas S, Beauval JB, Bensalah K, Geoffrois L, Thiery-Vuillemin A, Cormier L, Lang H, Guy L, Gravis G, Rolland F, Linassier C, Lechevallier E, Beisland C, Aitchison M, Oudard S, Patard JJ, Theodore C, Chevreau C, Laguerre B, Hubert J, Gross-Goupil M, Bernhard JC, Albiges L, Timsit MO, Lebret T, Escudier B. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018 Aug 2;379(5):417-427. Epub 2018 Jun 3. link to original article contains dosing details in abstract PubMed https://clinicaltrials.gov/ct2/show/NCT00930033
10. IMmotion151: Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. link to original article contains dosing details in abstract PubMed https://clinicaltrials.gov/ct2/show/NCT02420821
    1. Update: Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Alekseev BY, Lee JL, Suarez C, Stroyakovskiy D, De Giorgi U, Donskov F, Mellado B, Banchereau R, Hamidi H, Khan O, Craine V, Huseni M, Flinn N, Dubey S, Rini BI. Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol. 2022 Feb 1;8(2):275-280. link to original article [link to PMC article PubMed
11. ADAPT: Figlin RA, Tannir NM, Uzzo RG, Tykodi SS, Chen DYT, Master V, Kapoor A, Vaena D, Lowrance W, Bratslavsky G, DeBenedette M, Gamble A, Plachco A, Norris MS, Horvatinovich J, Tcherepanova IY, Nicolette CA, Wood CG; ADAPT study group. Results of the ADAPT Phase 3 Study of Rocapuldencel-T in Combination with Sunitinib as First-Line Therapy in Patients with Metastatic Renal Cell Carcinoma. Clin Cancer Res. 2020 May 15;26(10):2327-2336. Epub 2020 Feb 7. link to original article PubMed https://clinicaltrials.gov/ct2/show/NCT01582672
12. CROSS-J-RCC: Tomita Y, Naito S, Sassa N, Takahashi A, Kondo T, Koie T, Obara W, Kobayashi Y, Teishima J, Takahashi M, Matsuyama H, Ueda T, Yamaguchi K, Kishida T, Shiroki R, Saika T, Shinohara N, Oya M, Kanayama HO. Sunitinib Versus Sorafenib as Initial Targeted Therapy for mCC-RCC With Favorable/Intermediate Risk: Multicenter Randomized Trial CROSS-J-RCC. Clin Genitourin Cancer. 2020 Aug;18(4):e374-e385. Epub 2020 Mar 6. link to original article PubMed https://clinicaltrials.gov/ct2/show/NCT01481870
13. CLEAR: Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. link to original article contains dosing details in abstract PubMed https://clinicaltrials.gov/ct2/show/NCT02811861
    1. Update: Choueiri TK, Eto M, Motzer R, De Giorgi U, Buchler T, Basappa NS, Méndez-Vidal MJ, Tjulandin S, Hoon Park S, Melichar B, Hutson T, Alemany C, McGregor B, Powles T, Grünwald V, Alekseev B, Rha SY, Kopyltsov E, Kapoor A, Alonso Gordoa T, Goh JC, Staehler M, Merchan JR, Xie R, Perini RF, Mody K, McKenzie J, Porta CG. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol. 2023 Mar;24(3):228-238. Erratum in: Lancet Oncol. 2023 Apr;24(4):e146. link to original article PubMed
14. KEYNOTE-679: https://clinicaltrials.gov/ct2/show/NCT03260894
15. JS001-036-III-RCC: https://clinicaltrials.gov/ct2/show/NCT04394975
16. PIVOT-09: https://clinicaltrials.gov/ct2/show/NCT03729245
17. TQB2450-III-07: https://clinicaltrials.gov/ct2/show/NCT04523272

Temsirolimus monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hudes et al. 2007 (ARCC)	2003-2005	Phase 3 (E-RT-switch-ooc)	1. Interferon alfa-2a	Superior OS Median OS: 10.9 vs 7.3 mo (HR 0.73, 95% CI 0.58-0.92)
			2. Interferon alfa-2a & Temsirolimus	Not reported

Targeted therapy

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

Supportive therapy

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

7-day cycles

References

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 dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00065468

Metastatic disease, second-line

Bevacizumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yang et al. 2003	1998-2001	Randomized Phase 2 (E-esc)	Placebo	Superior TTP

Prior treatment criteria

• Previous therapy with IL-2 or contraindication to IL-2

Targeted therapy

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

14-day cycles

References

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

Cabozantinib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Choueiri et al. 2015 (METEOR) ESMO-MCBS (3)	2013-08 to 2014-11	Phase 3 (E-RT-switch-ic)	Everolimus	Superior PFS (primary endpoint) Median PFS: 7.4 vs 3.8 mo (HR 0.58, 95% CI 0.45-0.75) Superior OS1 (secondary endpoint) Median OS: 21.4 vs 17.1 mo (HR 0.70, 95% CI 0.58-0.85)
Tannir et al. 2022 (CANTATA)	2018-2019	Phase 3 (C)	Cabozantinib & Telaglenastat	Did not meet primary endpoint of PFS

¹Reported efficacy is based on the 2018 update.

Prior treatment criteria

• METEOR: VEGFR TKI, with progression
• CANTATA: 1 to 2 prior lines of therapy, including 1 or more antiangiogenic therapies or Ipilimumab & Nivolumab

Targeted therapy

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

Continued indefinitely

References

1. METEOR: Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1814-23. Epub 2015 Sep 25. link to original article contains dosing details in manuscript link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT01865747
   1. Update: Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, Hammers HJ, Donskov F, Roth BJ, Peltola K, Lee JL, Heng DY, Schmidinger M, Agarwal N, Sternberg CN, McDermott DF, Aftab DT, Hessel C, Scheffold C, Schwab G, Hutson TE, Pal S, Motzer RJ; METEOR investigators. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):917-27. Epub 2016 Jun 5. link to original article PubMed
   2. HRQoL analysis: Cella D, Escudier B, Tannir NM, Powles T, Donskov F, Peltola K, Schmidinger M, Heng DYC, Mainwaring PN, Hammers HJ, Lee JL, Roth BJ, Marteau F, Williams P, Baer J, Mangeshkar M, Scheffold C, Hutson TE, Pal S, Motzer RJ, Choueiri TK. Quality of life outcomes for cabozantinib versus everolimus in patients with metastatic renal cell carcinoma: METEOR phase III randomized trial. J Clin Oncol. 2018 Mar 10;36(8):757-764. Epub 2018 Jan 29. link to original article link to PMC article PubMed
   3. Update: Motzer RJ, Escudier B, Powles T, Scheffold C, Choueiri TK. Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer. 2018 May;118(9):1176-1178. Epub 2018 Mar 26. link to original article link to PMC article PubMed
2. CANTATA: Tannir NM, Agarwal N, Porta C, Lawrence NJ, Motzer R, McGregor B, Lee RJ, Jain RK, Davis N, Appleman LJ, Goodman O Jr, Stadler WM, Gandhi S, Geynisman DM, Iacovelli R, Mellado B, Sepúlveda Sánchez JM, Figlin R, Powles T, Akella L, Orford K, Escudier B. Efficacy and Safety of Telaglenastat Plus Cabozantinib vs Placebo Plus Cabozantinib in Patients With Advanced Renal Cell Carcinoma: The CANTATA Randomized Clinical Trial. JAMA Oncol. 2022 Oct 1;8(10):1411-1418. link to orginal article link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT03428217
3. CONTACT-03: https://clinicaltrials.gov/ct2/show/NCT04338269
4. MK-6482-011: https://clinicaltrials.gov/ct2/show/NCT04586231

Everolimus monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2008 (RECORD-1) ESMO-MCBS (3)	2006-04 to 2007-04	Phase 3 (E-RT-esc)	Placebo	Superior PFS1 (primary endpoint) Median PFS: 4.9 vs 1.9 mo (HR 0.33, 95% CI 0.25-0.43) Did not meet secondary endpoint of OS1 Median OS: 14.8 vs 14.4 mo (HR 0.87, 95% CI 0.65-1.15)
Motzer et al. 2014 (RECORD-3)	2009-2011	Randomized Phase 2 (E-switch-ic)	Sunitinib	Inconclusive whether non-inferior PFS
Motzer et al. 2015 (RECORD-4)	2011-2013	Phase 2
Motzer et al. 2015 (CheckMate 025)	2012-2014	Phase 3 (C)	Nivolumab	Inferior OS
Motzer et al. 2015 (E7080-G000-205)	2012-03-16 to 2013-06-19	Randomized Phase 2 (C)	1. Everolimus & Lenvatinib	Inferior PFS
			2. Lenvatinib	Seems to have inferior PFS
Choueiri et al. 2015 (METEOR)	2013-08 to 2014-11	Phase 3 (C)	Cabozantinib	Inferior OS
Sheng et al. 2022 (CONCEPTRCC)	2017-2019	Phase 3 (C)	1. Everolimus & Vorolanib	Inferior PFS
			2. Vorolanib	Might have inferior PFS

¹Reported efficacy for RECORD-1 is based on the 2010 update.
Note: 72% of patients in Checkmate 025 had anti-angiogenic therapy prior to progression.

Prior treatment criteria

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

Targeted therapy

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

Continued indefinitely

References

1. RECORD-1: Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008 Aug 9;372(9637):449-56. Epub 2008 Jul 22. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00410124
   1. Update: Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A; RECORD-1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010 Sep 15;116(18):4256-65. link to original article contains dosing details in manuscript PubMed
2. RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT00903175
3. CheckMate 025: Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803-13. Epub 2015 Sep 25. link to original article contains dosing details in manuscript link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT01668784
   1. HRQoL analysis: Cella D, Grünwald V, Nathan P, Doan J, Dastani H, Taylor F, Bennett B, DeRosa M, Berry S, Broglio K, Berghorn E, Motzer RJ. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):994-1003. Epub 2016 Jun 6. Erratum in: Lancet Oncol. 2016 Jul;17 (7):e270. link to original article link to PMC article PubMed
   2. Subgroup analysis: Escudier B, Sharma P, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Gurney H, Donskov F, Peltola K, Wagstaff J, Gauler TC, Ueda T, Zhao H, Waxman IM, Motzer RJ; CheckMate 025 investigators. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol. 2017 Dec;72(6):962-971. Epub 2017 Mar 3. Erratum in: Eur Urol. 2018 Jan 3. link to original article PubMed
   3. Subgroup analysis: Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Saito M, Kimura G, Yonese J, Yao M, Uemura H. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the phase III CheckMate 025 study. Jpn J Clin Oncol. 2019 Jun 1;49(6):506-514. link to original article PubMed
   4. Update: Motzer RJ, Escudier B, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Plimack ER, Procopio G, McDermott DF, Castellano D, Choueiri TK, Donskov F, Gurney H, Oudard S, Richardet M, Peltola K, Alva AS, Carducci M, Wagstaff J, Chevreau C, Fukasawa S, Tomita Y, Gauler TC, Kollmannsberger CK, Schutz FA, Larkin J, Cella D, McHenry MB, Saggi SS, Tannir NM. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer. 2020 Sep 15;126(18):4156-4167. Epub 2020 Jul 16. link to original article link to PMC article PubMed
4. METEOR: Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1814-23. Epub 2015 Sep 25. link to original article contains dosing details in manuscript link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT01865747
   1. Update: Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, Hammers HJ, Donskov F, Roth BJ, Peltola K, Lee JL, Heng DY, Schmidinger M, Agarwal N, Sternberg CN, McDermott DF, Aftab DT, Hessel C, Scheffold C, Schwab G, Hutson TE, Pal S, Motzer RJ; METEOR investigators. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):917-27. Epub 2016 Jun 5. link to original article PubMed
   2. HRQoL analysis: Cella D, Escudier B, Tannir NM, Powles T, Donskov F, Peltola K, Schmidinger M, Heng DYC, Mainwaring PN, Hammers HJ, Lee JL, Roth BJ, Marteau F, Williams P, Baer J, Mangeshkar M, Scheffold C, Hutson TE, Pal S, Motzer RJ, Choueiri TK. Quality of life outcomes for cabozantinib versus everolimus in patients with metastatic renal cell carcinoma: METEOR phase III randomized trial. J Clin Oncol. 2018 Mar 10;36(8):757-764. Epub 2018 Jan 29. link to original article link to PMC article PubMed
   3. Update: Motzer RJ, Escudier B, Powles T, Scheffold C, Choueiri TK. Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer. 2018 May;118(9):1176-1178. Epub 2018 Mar 26. link to original article link to PMC article PubMed
5. E7080-G000-205: Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT01136733
   1. Update: Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 Jan;17(1):e4-5. 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 dosing details in abstract PubMed https://clinicaltrials.gov/ct2/show/NCT01491672
7. CONCEPT_RCC: Sheng X, Ye D, Zhou A, Yao X, Luo H, He Z, Wang Z, Zhao Y, Ji Z, Zou Q, He C, Guo J, Tu X, Liu Z, Shi B, Liu B, Chen P, Wei Q, Hu Z, Zhang Y, Jiang K, Zhou F, Wu D, Fu C, Li X, Wu B, Wang L, Qin S, Li G, Liu Y, Guo H, Chen K, Zhang D, Wang G, Ding L, Wang Y, Yuan X, Guo J. Efficacy and safety of vorolanib plus everolimus in metastatic renal cell carcinoma: A three-arm, randomised, double-blind, multicentre phase III study (CONCEPT). Eur J Cancer. 2023 Jan;178:205-215. Epub 2022 Nov 1. link to original article PubMed https://clinicaltrials.gov/ct2/show/NCT03095040

Everolimus & Lenvatinib

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2015 (E7080-G000-205) ESMO-MCBS (4)	2012-03-16 to 2013-06-19	Randomized Phase 2 (E-RT-esc)	1. Everolimus	Superior PFS Median PFS: 14.6 vs 5.5 mo (HR 0.40, 95% CI 0.24-0.68)
			2. Lenvatinib	Did not meet primary endpoint of PFS Median PFS: 14.6 vs 7.4 mo (HR 0.66, 95% CI 0.30-1.10)

Prior treatment criteria

• VEGFR TKI treatment, with progression

Targeted therapy

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

Continued indefinitely

References

1. E7080-G000-205: Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT01136733
   1. Update: Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 Jan;17(1):e4-5. link to original article PubMed

Lenvatinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2015 (E7080-G000-205) ESMO-MCBS (3)	2012-03-16 to 2013-06-19	Randomized Phase 2 (E-RT-switch-ic)	1. Everolimus	Seems to have superior PFS Median PFS: 7.4 vs 5.5 mo (HR 0.61, 95% CI 0.38-0.98)
			2. Everolimus & Lenvatinib	Did not meet primary endpoint of PFS

Targeted therapy

• Lenvatinib (Lenvima) 24 mg PO once per day

Continued indefinitely

References

1. E7080-G000-205: Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT01136733
   1. Update: Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 Jan;17(1):e4-5. link to original article PubMed

Nivolumab monotherapy

Regimen variant #1, 0.3 mg/kg q3wk

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

Immunotherapy

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

21-day cycles

Regimen variant #2, 2 mg/kg q3wk

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

Immunotherapy

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

21-day cycles

Regimen variant #3, 3 mg/kg q2wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2015 (CheckMate 025) ESMO-MCBS (5)	2012-2014	Phase 3 (E-RT-switch-ooc)	Everolimus	Superior OS (primary endpoint) Median OS: 25 vs 19.6 mo (HR 0.73, 98.5% CI 0.57-0.93)

Immunotherapy

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

14-day cycles

Regimen variant #4, 10 mg/kg q3wk

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

Immunotherapy

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

21-day cycles

References

1. CheckMate 010: Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, Vaishampayan UN, Drabkin HA, George S, Logan TF, Margolin KA, Plimack ER, Lambert AM, Waxman IM, Hammers HJ. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. 2015 May 1;33(13):1430-7. Epub 2014 Dec 1. link to original article link to PMC article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT01354431
2. CheckMate 025: Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803-13. Epub 2015 Sep 25. link to original article contains dosing details in manuscript link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT01668784
   1. HRQoL analysis: Cella D, Grünwald V, Nathan P, Doan J, Dastani H, Taylor F, Bennett B, DeRosa M, Berry S, Broglio K, Berghorn E, Motzer RJ. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):994-1003. Epub 2016 Jun 6. Erratum in: Lancet Oncol. 2016 Jul;17 (7):e270. link to original article link to PMC article PubMed
   2. Subgroup analysis: Escudier B, Sharma P, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Gurney H, Donskov F, Peltola K, Wagstaff J, Gauler TC, Ueda T, Zhao H, Waxman IM, Motzer RJ; CheckMate 025 investigators. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol. 2017 Dec;72(6):962-971. Epub 2017 Mar 3. Erratum in: Eur Urol. 2018 Jan 3. link to original article PubMed
   3. Subgroup analysis: Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Saito M, Kimura G, Yonese J, Yao M, Uemura H. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the phase III CheckMate 025 study. Jpn J Clin Oncol. 2019 Jun 1;49(6):506-514. link to original article PubMed
   4. Update: Motzer RJ, Escudier B, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Plimack ER, Procopio G, McDermott DF, Castellano D, Choueiri TK, Donskov F, Gurney H, Oudard S, Richardet M, Peltola K, Alva AS, Carducci M, Wagstaff J, Chevreau C, Fukasawa S, Tomita Y, Gauler TC, Kollmannsberger CK, Schutz FA, Larkin J, Cella D, McHenry MB, Saggi SS, Tannir NM. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer. 2020 Sep 15;126(18):4156-4167. Epub 2020 Jul 16. link to original article link to PMC article PubMed

Pazopanib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hutson et al. 2009 (VEG102616)	2005-10 to 2006-09	Phase 2
Sternberg et al. 2010 (VEG105192)	2006-04 to 2007-04	Phase 3 (E-esc)	Placebo	Superior PFS Median PFS: 9.2 vs 4.2 mo (HR 0.46, 95% CI 0.34-0.62)
Hainsworth et al. 2013	2008-2011	Phase 2

Prior treatment criteria

• VEG105192: Progression on 1 prior cytokine-based systemic therapy

Targeted therapy

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

Continued indefinitely

References

1. VEG102616: Hutson TE, Davis ID, Machiels JP, De Souza PL, Rottey S, Hong BF, Epstein RJ, Baker KL, McCann L, Crofts T, Pandite L, Figlin RA. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2010 Jan 20;28(3):475-80. Epub 2009 Dec 14. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00244764
2. VEG105192: Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarbá JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010 Feb 20;28(6):1061-8. Epub 2010 Jan 25. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00334282
   1. Update: Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, Zarba JJ, Gladkov OA, Lee E, Szczylik C, McCann L, Rubin SD, Chen M, Davis ID. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013 Apr;49(6):1287-96. Epub 2013 Jan 12. link to original article contains dosing details in manuscript PubMed
3. Hainsworth JD, Rubin MS, Arrowsmith ER, Khatcheressian J, Crane EJ, Franco LA. Pazopanib as second-line treatment after sunitinib or bevacizumab in patients with advanced renal cell carcinoma: a Sarah Cannon Oncology Research Consortium phase II trial. Clin Genitourin Cancer. 2013 Sep;11(3):270-5. Epub 2013 May 9. link to original article contains dosing details in abstract PubMed

Sorafenib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Stadler et al. 2010 (ARCCS)	2005-06 to 2006-07	Non-randomized expanded access study
Beck et al. 2011 (EU-ARCCS)	2005-2007	Non-randomized expanded access study
Hutson et al. 2013 (INTORSECT)	2007-2011	Phase 3 (C)	Temsirolimus	Did not meet primary endpoint of PFS2 Median PFS: 3.9 vs 4.3 mo (HR 1.15, 95% CI 0.93-1.41)

¹Reported efficacy for TARGET is based on the 2009 update.
²While the primary endpoint (PFS) was not met in INTORSECT, the control arm actually had superior OS compared to the experimental arm.

Prior treatment criteria

• INTORSECT: Sunitinib, with progression

Targeted therapy

• Sorafenib (Nexavar) 400 mg PO twice per day

Continued indefinitely

Dose modifications

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

References

1. 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 https://clinicaltrials.gov/ct2/show/NCT00111020
2. EU-ARCCS: Beck J, Procopio G, Bajetta E, Keilholz U, Negrier S, Szczylik C, Bokemeyer C, Bracarda S, Richel DJ, Staehler M, Strauss UP, Mersmann S, Burock K, Escudier B. Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings. Ann Oncol. 2011 Aug;22(8):1812-23. Epub 2011 Feb 15. link to original article contains dosing details in manuscript PubMed
3. INTORSECT: Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, Senico P, Niethammer A, Lu DR, Hariharan S, Motzer RJ. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Mar 10;32(8):760-7. Epub 2013 Dec 2. link to original article contains dosing details in abstract link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT00474786

Sunitinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2005 (RTKC-0511-014)	2003	Phase 2 (RT)
Motzer et al. 2006 (A618-1006)	2004	Phase 2 (RT)
Gore et al. 2009 (A618-1037)	2005-2007	Non-randomized
Motzer et al. 2014 (RECORD-3)	2009-2011	Randomized Phase 2 (E-switch-ic)	Everolimus	Inconclusive whether non-inferior PFS

Preceding treatment

• RECORD-3: Everolimus

Targeted therapy

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

42-day cycles

References

1. RTKC-0511-014: Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006 Jan 1;24(1):16-24. Epub 2005 Dec 5. link to original article PubMed
2. A618-1006: Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, Redman BG, Margolin KA, Merchan JR, Wilding G, Ginsberg MS, Bacik J, Kim ST, Baum CM, Michaelson MD. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006 Jun 7;295(21):2516-24. link to original article contains dosing details in abstract PubMed https://clinicaltrials.gov/ct2/show/NCT00077974
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 dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT00130897
4. RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT00903175

Metastatic disease, third-line

Sorafenib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2014 (GOLD-RCC)	2011-03 to 2012-09	Phase 3 (C)	Dovitinib	Might have inferior PFS
Rini et al. 2019 (TIVO-3)	2016-05-24 to 2017-08-14	Phase 3 (C)	Tivozanib	Seems to have inferior PFS

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

Targeted therapy

• Sorafenib (Nexavar) 400 mg PO twice per day

Continued indefinitely

References

1. GOLD: Motzer RJ, Porta C, Vogelzang NJ, Sternberg CN, Szczylik C, Zolnierek J, Kollmannsberger C, Rha SY, Bjarnason GA, Melichar B, De Giorgi U, Grünwald V, Davis ID, Lee JL, Esteban E, Urbanowitz G, Cai C, Squires M, Marker M, Shi MM, Escudier B. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Mar;15(3):286-96. Epub 2014 Feb 17. link to original article contains dosing details in abstract link to PMC article PubMed https://clinicaltrials.gov/ct2/show/NCT01223027
2. TIVO-3: Rini BI, Pal SK, Escudier BJ, Atkins MB, Hutson TE, Porta C, Verzoni E, Needle MN, McDermott DF. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020 Jan;21(1):95-104. Epub 2019 Dec 3. link to original article PubMed https://clinicaltrials.gov/ct2/show/NCT02627963
   1. Update: Pal SK, Escudier BJ, Atkins MB, Hutson TE, Porta C, Verzoni E, Needle MN, Powers D, McDermott DF, Rini BI. Final Overall Survival Results from a Phase 3 Study to Compare Tivozanib to Sorafenib as Third- or Fourth-line Therapy in Subjects with Metastatic Renal Cell Carcinoma. Eur Urol. 2020 Dec;78(6):783-785. Epub 2020 Sep 13. link to original article PubMed

Tivozanib monotherapy

Regimen variant #1, 1.34 mg/day

FDA-recommended dose

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

Targeted therapy

• Tivozanib (Fotivda) 1.34 mg PO once per day on days 1 to 21

28-day cycles

Regimen variant #2, 1.5 mg/day

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rini et al. 2019 (TIVO-3) ESMO-MCBS (3)	2016-05-24 to 2017-08-14	Phase 3 (E-RT-switch-ic)	Sorafenib	Seems to have superior PFS Median PFS: 5.6 vs 3.9 mo (HR 0.73, 95% CI 0.56-0.94)

Targeted therapy

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

28-day cycles

References

1. TIVO-3: Rini BI, Pal SK, Escudier BJ, Atkins MB, Hutson TE, Porta C, Verzoni E, Needle MN, McDermott DF. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020 Jan;21(1):95-104. Epub 2019 Dec 3. link to original article contains dosing details in manuscript PubMed https://clinicaltrials.gov/ct2/show/NCT02627963
   1. Update: Pal SK, Escudier BJ, Atkins MB, Hutson TE, Porta C, Verzoni E, Needle MN, Powers D, McDermott DF, Rini BI. Final Overall Survival Results from a Phase 3 Study to Compare Tivozanib to Sorafenib as Third- or Fourth-line Therapy in Subjects with Metastatic Renal Cell Carcinoma. Eur Urol. 2020 Dec;78(6):783-785. Epub 2020 Sep 13. link to original article PubMed