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

General RCC page
Histology-specific:
- Clear cell renal cell carcinoma (this page)
- Non-clear cell renal cell carcinoma
  - Papillary renal cell carcinoma
  - Sarcomatoid renal cell carcinoma
Biomarker-specific:
- RCC, VHL-associated

34 regimens on this page 48 variants on this page

Guidelines

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

ASCO

2023: Singer et al. Management of Metastatic Renal Clear Cell Cancer: ASCO Guideline Rapid Recommendation Update PubMed
- 2022: Rathmell et al. Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline PubMed

2017: Finelli et al. Management of Small Renal Masses: American Society of Clinical Oncology Clinical Practice Guideline PubMed

EAU

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

ESMO

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

NCCN

NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Kidney Cancer.

Adjuvant therapy

Pembrolizumab monotherapy

Regimen variant #1, 200 mg q3wk

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Choueiri et al. 2021 (KEYNOTE-564)	2017-2019	Phase 3 (E-RT-esc)	Placebo	Superior DFS¹ (primary endpoint) Median DFS: NYR vs NYR (HR 0.63, 95% CI 0.50-0.80) Superior OS² (secondary endpoint) OS48: 91.2% vs 86% (HR 0.62, 95% CI 0.44-0.87)

¹Reported efficacy is based on the 2022 update.
²Reported efficacy is based on the 2024 update.

Preceding treatment

Complete resection, within 1 year

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

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

Regimen variant #2, 400 mg q6wk

FDA-recommended dose

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

Preceding treatment

Complete resection

Immunotherapy

Pembrolizumab (Keytruda) 400 mg IV once on day 1

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

References

KEYNOTE-564: Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Chang YH, Hajek J, Symeonides SN, Lee JL, Sarwar N, Thiery-Vuillemin A, Gross-Goupil M, Mahave M, Haas NB, Sawrycki P, Gurney H, Chevreau C, Melichar B, Kopyltsov E, Alva A, Burke JM, Doshi G, Topart D, Oudard S, Hammers H, Kitamura H, Bedke J, Perini RF, Zhang P, Imai K, Willemann-Rogerio J, Quinn DI, Powles T; KEYNOTE-564 Investigators. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med. 2021 Aug 19;385(8):683-694. link to original article link to free full text via University of Zurich contains dosing details in manuscript PubMed NCT03142334
1. Update: Powles T, Tomczak P, Park SH, Venugopal B, Ferguson T, Symeonides SN, Hajek J, Gurney H, Chang YH, Lee JL, Sarwar N, Thiery-Vuillemin A, Gross-Goupil M, Mahave M, Haas NB, Sawrycki P, Burgents JE, Xu L, Imai K, Quinn DI, Choueiri TK; KEYNOTE-564 Investigators. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022 Sep;23(9):1133-1144. link to original article PubMed
2. Update: Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Symeonides SN, Hajek J, Chang YH, Lee JL, Sarwar N, Haas NB, Gurney H, Sawrycki P, Mahave M, Gross-Goupil M, Zhang T, Burke JM, Doshi G, Melichar B, Kopyltsov E, Alva A, Oudard S, Topart D, Hammers H, Kitamura H, McDermott DF, Silva A, Winquist E, Cornell J, Elfiky A, Burgents JE, Perini RF, Powles T; KEYNOTE-564 Investigators. Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma. N Engl J Med. 2024 Apr 18;390(15):1359-1371. link to original article PubMed

Sunitinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Ravaud et al. 2016 (S-TRAC)	2007-2011	Phase 3 (E-RT-esc)	Placebo	Seems to have superior DFS (primary endpoint) Median DFS: 6.8 vs 5.6 yr (HR 0.76, 95% CI 0.59-0.98)	More toxicity

Preceding treatment

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

S-TRAC: Ravaud A, Motzer RJ, Pandha HS, George DJ, Pantuck AJ, Patel A, Chang YH, Escudier B, Donskov F, Magheli A, Carteni G, Laguerre B, Tomczak P, Breza J, Gerletti P, Lechuga M, Lin X, Martini JF, Ramaswamy K, Casey M, Staehler M, Patard JJ; S-TRAC Investigators. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016 Dec 8;375(23):2246-2254. Epub 2016 Oct 9. link to original article contains dosing details in manuscript PubMed NCT00375674
1. Update: Motzer RJ, Ravaud A, Patard JJ, Pandha HS, George DJ, Patel A, Chang YH, Escudier B, Donskov F, Magheli A, Carteni G, Laguerre B, Tomczak P, Breza J, Gerletti P, Lechuga M, Lin X, Casey M, Serfass L, Pantuck AJ, Staehler M. Adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy: subgroup analyses and updated overall survival results. Eur Urol. 2018 Jan;73(1):62-68. Epub 2017 Sep 26. link to original article link to PMC article PubMed

Metastatic disease, first-line

Axitinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hutson et al. 2013 (A4061051)	2010-06-14 to 2011-04-21	Phase 3 (E-switch-ic)	Sorafenib	Might have superior PFS (primary endpoint) Median PFS: 10.1 vs 6.5 mo (HR 0.77, 95% CI 0.56-1.05) Did not meet secondary endpoint of OS¹ Median OS: 21.7 vs 23.3 mo (HR 0.995, 95% CI 0.73-1.36)

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

Targeted therapy

Axitinib (Inlyta) 5 mg PO twice per day

Continued indefinitely

Dose and schedule modifications

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

References

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

Axitinib & Avelumab

Regimen variant #1, weight-based dosing

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2019 (JAVELIN Renal 101)	2016-03-29 to 2017-12-19	Phase 3 (E-RT-esc)	Sunitinib	Superior overall PFS¹ (secondary endpoint) Median PFS: 13.3 vs 8 mo (HR 0.69, 95% CI 0.57-0.83) Superior PFS² (primary endpoint) Median PFS: 13.8 vs 7.2 mo (HR 0.61, 95% CI 0.47-0.79)

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

Targeted therapy

Axitinib (Inlyta) 5 mg PO twice per day

Immunotherapy

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

14-day cycles

Regimen variant #2, flat dosing

FDA-recommended dose

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

Targeted therapy

Axitinib (Inlyta) 5 mg PO twice per day

Immunotherapy

Avelumab (Bavencio) 800 mg IV once on day 1

14-day cycles

References

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

Axitinib & Pembrolizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rini et al. 2019 (KEYNOTE-426)	2016-10-24 to 2018-01-24	Phase 3 (E-RT-esc)	Sunitinib	Superior OS¹ (co-primary endpoint) Median OS: NYR vs 36 mo (HR 0.68, 95% CI 0.55-0.85) Superior PFS (co-primary endpoint) Median PFS: 15.1 vs 11.1 mo (HR 0.69, 95% CI 0.57-0.84)

¹Reported efficacy is based on the 2020 update.

Targeted therapy

Axitinib (Inlyta) 5 mg PO twice per day

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycles

References

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

Axitinib & Toripalimab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yan et al. 2023 (RENOTORCH)	2020-08-23 to 2022-09-23	Phase 3 (E-RT-esc)	Sunitinib	Superior OS (secondary endpoint) Median OS: NYR vs 26.8 mo (HR 0.61, 95% CI 0.40-0.92) Superior PFS (primary endpoint) Median PFS: 18 vs 9.8 mo (HR 0.65, 95% CI 0.49-0.86)

Targeted therapy

Axitinib (Inlyta) 5 mg PO twice per day

Immunotherapy

Toripalimab (Loqtorzi) as follows:
- Cycles 1 to 35: 240 mg IV once on day 1

21-day cycles

References

RENOTORCH: Yan XQ, Ye MJ, Zou Q, Chen P, He ZS, Wu B, He DL, He CH, Xue XY, Ji ZG, Chen H, Zhang S, Liu YP, Zhang XD, Fu C, Xu DF, Qiu MX, Lv JJ, Huang J, Ren XB, Cheng Y, Qin WJ, Zhang X, Zhou FJ, Ma LL, Guo JM, Ding DG, Wei SZ, He Y, Guo HQ, Shi BK, Liu L, Liu F, Hu ZQ, Jin XM, Yang L, Zhu SX, Liu JH, Huang YH, Xu T, Liu B, Sun T, Wang ZJ, Jiang HW, Yu DX, Zhou AP, Jiang J, Luan GD, Jin CL, Xu J, Hu JX, Huang YR, Guo J, Zhai W, Sheng XN. Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study. Ann Oncol. 2024 Feb;35(2):190-199. Epub 2023 Oct 21. link to original article contains dosing details in manuscript PubMed [NCT04394975

Bevacizumab monotherapy

Regimen

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

Targeted therapy

Bevacizumab (Avastin) 10 mg/kg IV over 90 minutes once on day 1

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

Dose and schedule modifications

Bevacizumab infusion time can subsequently be reduced to 60 and 30 minute infusions as tolerated

References

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

Bevacizumab & Interferon alfa-2a

Regimen variant #1, 1 year of interferon

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Escudier et al. 2007 (AVOREN)	2004-06 to 2005-10	Phase 3 (E-RT-esc)	Interferon alfa-2a	Did not meet primary endpoint of OS¹ Median OS: 23.3 vs 21.3 mo (HR 0.91, 95% CI 0.76-1.10) Superior PFS² (secondary endpoint) Median PFS: 10.2 vs 5.4 mo (HR 0.63, 95% CI 0.52-0.75)

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

Targeted therapy

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

Immunotherapy

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

14-day cycles

Dose and schedule modifications

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

Regimen variant #2, indefinite

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

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

Targeted therapy

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

Immunotherapy

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

14-day cycles

Dose and schedule modifications

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

References

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

Cabozantinib monotherapy

Regimen

FDA-recommended dose

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

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

Targeted therapy

Cabozantinib (Cabometyx) 60 mg PO once per day on days 1 to 28

28-day cycles

References

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

Cabozantinib & Nivolumab

Regimen variant #1, bi-weekly nivolumab

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Choueiri et al. 2021 (CheckMate 9ER)	2017-2019	Phase 3 (E-RT-esc)	Sunitinib	Superior PFS¹ (primary endpoint) Median PFS: 16.6 vs 8.4 mo (HR 0.59, 95% CI 0.49-0.71) Superior OS¹ (secondary endpoint) Median OS: 49.5 vs 35.5 mo (HR 0.70, 95% CI 0.56-0.87)

¹Reported efficacy is based on the 2024 update.

Targeted therapy

Cabozantinib (Cabometyx) 40 mg PO once per day on days 1 to 14

Immunotherapy

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

14-day cycles

Regimen variant #2, monthly nivolumab

FDA-recommended dose

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

Targeted therapy

Cabozantinib (Cabometyx) 40 mg PO once per day on days 1 to 28

Immunotherapy

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

28-day cycles

References

CheckMate 9ER: Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, Oyervides Juárez VM, Hsieh JJ, Basso U, Shah AY, Suárez C, Hamzaj A, Goh JC, Barrios C, Richardet M, Porta C, Kowalyszyn R, Feregrino JP, Żołnierek J, Pook D, Kessler ER, Tomita Y, Mizuno R, Bedke J, Zhang J, Maurer MA, Simsek B, Ejzykowicz F, Schwab GM, Apolo AB, Motzer RJ; CheckMate 9ER Investigators. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03141177
1. Update: Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, Suárez C, Hamzaj A, Porta C, Hocking CM, Kessler ER, Gurney H, Tomita Y, Bedke J, Zhang J, Simsek B, Scheffold C, Apolo AB, Choueiri TK. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Jul;23(7):888-898. Epub 2022 Jun 7. link to original article PubMed
2. Update: Powles T, Burotto M, Escudier B, Apolo AB, Bourlon MT, Shah AY, Suárez C, Porta C, Barrios CH, Richardet M, Gurney H, Kessler ER, Tomita Y, Bedke J, George S, Scheffold C, Wang P, Fedorov V, Motzer RJ, Choueiri TK. Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial. ESMO Open. 2024 May;9(5):102994. Epub 2024 Apr 20. link to original article link to PMC article PubMed

Cabozantinib, Ipilimumab, Nivolumab

Regimen

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

Targeted therapy

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

Immunotherapy

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

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

References

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

Erlotinib & Bevacizumab

Regimen

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

Targeted therapy

Erlotinib (Tarceva) 150 mg PO once per day
Bevacizumab (Avastin) 10 mg/kg IV over 90 minutes once on day 1

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

Dose and schedule modifications

Bevacizumab infusion time can subsequently be reduced to 60 and 30 minute infusions as tolerated

References

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

Everolimus & 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
Motzer et al. 2021 (CLEAR)	2016-10-13 to 2019-07-24	Phase 3 (E-RT-esc)	2. Sunitinib	Superior PFS (primary endpoint) Median PFS: 14.7 vs 9.2 mo (HR 0.65, 95% CI 0.53-0.80)

Targeted therapy

Everolimus (Afinitor) 5 mg PO once per day on days 1 to 21
Lenvatinib (Lenvima) 18 mg PO once per day on days 1 to 21

21-day cycles

References

CLEAR: Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. link to original article contains dosing details in manuscript PubMed NCT02811861
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. Update: Motzer RJ, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Alekseev B, Rha SY, Merchan J, Goh JC, Lalani AA, De Giorgi U, Melichar B, Hong SH, Gurney H, Méndez-Vidal MJ, Kopyltsov E, Tjulandin S, Gordoa TA, Kozlov V, Alyasova A, Winquist E, Maroto P, Kim M, Peer A, Procopio G, Takagi T, Wong S, Bedke J, Schmidinger M, Rodriguez-Lopez K, Burgents J, He C, Okpara CE, McKenzie J, Choueiri TK; CLEAR Trial Investigators. Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study. J Clin Oncol. 2024 Apr 10;42(11):1222-1228. Epub 2024 Jan 16. link to original article PubMed

Gemcitabine & Sunitinib

Regimen

Study	Evidence
Pandya et al. 2011	Retrospective

Chemotherapy

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

Targeted therapy

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

21-day cycles

References

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

Interferon alfa-2a monotherapy

Regimen variant #1, 9 MU TIW

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rini et al. 2008 (CALGB 90206)	2003-2005	Phase 3 (C)	Bevacizumab & Interferon alfa-2a	Might have inferior OS¹
Escudier et al. 2007 (AVOREN)	2004-06 to 2005-10	Phase 3 (C)	Bevacizumab & Interferon alfa-2a	Did not meet primary endpoint of OS²
Escudier et al. 2009 (Bayer 11848)	2005-06-28 to 2005-09-30	Randomized Phase 2 (C)	Sorafenib	Did not meet primary endpoint of PFS

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

Immunotherapy

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

7-day cycles

Dose and schedule modifications

Some protocols: Dose can be reduced to 3,000,000 or 6,000,000 units SC 3 times per week based on tolerability

Regimen variant #2, 9 MU TIW, with lead-in

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

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

Immunotherapy

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

7-day cycles

References

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 NCT00083889
1. Update: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Aug 1;27(22):3584-90. Epub 2009 Jun 1. link to original article contains dosing details in manuscript link to PMC article PubMed content property of HemOnc.org
2. HRQoL analysis: Cella D, Michaelson MD, Bushmakin AG, Cappelleri JC, Charbonneau C, Kim ST, Li JZ, Motzer RJ. Health-related quality of life in patients with metastatic renal cell carcinoma treated with sunitinib vs interferon-alpha in a phase III trial: final results and geographical analysis. Br J Cancer. 2010 Feb 16;102(4):658-64. Epub 2010 Jan 26. link to original article link to PMC article PubMed
AVOREN: Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007 Dec 22;370(9605):2103-11. link to original article PubMed NCT00738530
1. Update: Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, Sneller V. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010 May 1;28(13):2144-50. Epub 2010 Apr 5. link to original article contains dosing details in manuscript PubMed
CALGB 90206: Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008 Nov 20;26(33):5422-8. Epub 2008 Oct 20. link to original article link to PMC article PubMed NCT00072046
1. Update: Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010 May 1;28(13):2137-43. Epub 2010 Apr 5. link to original article link to PMC article PubMed
Bayer 11848: Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, Negrier S, Laferriere N, Scheuring UJ, Cella D, Shah S, Bukowski RM. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Mar 10;27(8):1280-9. Epub 2009 Jan 26. Erratum in: J Clin Oncol. 2009 May 1; 27(13):2305. link to original article PubMed NCT00117637

High-dose Interleukin-2

HD IL-2: High-Dose InterLeukin-2

Example orders

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

Regimen

Study	Evidence
Klapper et al. 2008	Retrospective

Immunotherapy

IL-2 - Aldesleukin (Proleukin) 720,000 units/kg IV every 8 hours for up to 12 doses (reduced from originally up to 15 doses due to few patients tolerating 15 doses)

Supportive therapy

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

14- to 19-day cycle for 2 cycles

Subsequent treatment

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

References

Retrospective: Klapper JA, Downey SG, Smith FO, Yang JC, Hughes MS, Kammula US, Sherry RM, Royal RE, Steinberg SM, Rosenberg S. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma : a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008 Jul 15;113(2):293-301. link to original article contains dosing details in manuscript link to PMC article PubMed

Ipilimumab & Nivolumab

Regimen variant #1

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

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

Immunotherapy

Ipilimumab (Yervoy) as follows:
- Cycles 1 to 4: 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, then 14-day cycles

Regimen variant #2

FDA-recommended dose

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

Immunotherapy

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

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

Regimen variant #3

FDA-recommended dose

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

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

Immunotherapy

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

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

References

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

Lenvatinib & Pembrolizumab

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2021 (CLEAR)	2016-10-13 to 2019-07-24	Phase 3 (E-RT-esc)	1. Everolimus & Lenvatinib	Not reported
Motzer et al. 2021 (CLEAR)	2016-10-13 to 2019-07-24	Phase 3 (E-RT-esc)	2. Sunitinib	Superior PFS¹ (primary endpoint) Median PFS: 23.9 vs 9.2 mo (HR 0.47, 95% CI 0.38-0.57) Seems to have superior OS¹ (secondary endpoint) Median OS: 53.7 vs 54.3 (HR 0.79, 95% CI 0.63-0.99)

¹Reported efficacy is based on the 2024 update.

Targeted therapy

Lenvatinib (Lenvima) 20 mg PO once per day on days 1 to 21

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

21-day cycles

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (MK-6482-012)	2021-ongoing	Phase 3 (C)	1. Belzutifan, Lenvatinib, Pembrolizumab 2. Lenvatinib, Pembrolizumab, Quavonlimab	TBD if different co-primary endpoints of PFS/OS

Targeted therapy

Lenvatinib (Lenvima) 20 mg PO once per day on days 1 to 42

Immunotherapy

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

42-day cycles

References

CLEAR: Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. link to original article contains dosing details in manuscript PubMed NCT02811861
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. Update: Motzer RJ, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Alekseev B, Rha SY, Merchan J, Goh JC, Lalani AA, De Giorgi U, Melichar B, Hong SH, Gurney H, Méndez-Vidal MJ, Kopyltsov E, Tjulandin S, Gordoa TA, Kozlov V, Alyasova A, Winquist E, Maroto P, Kim M, Peer A, Procopio G, Takagi T, Wong S, Bedke J, Schmidinger M, Rodriguez-Lopez K, Burgents J, He C, Okpara CE, McKenzie J, Choueiri TK; CLEAR Trial Investigators. Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study. J Clin Oncol. 2024 Apr 10;42(11):1222-1228. Epub 2024 Jan 16. link to original article PubMed
MK-6482-012: NCT04736706

Pazopanib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hutson et al. 2009 (VEG102616)	2005-10 to 2006-09	Phase 2
Sternberg et al. 2010 (VEG105192)	2006-04 to 2007-04	Phase 3 (E-RT-esc)	Placebo	Superior PFS (primary endpoint) Median PFS: 9.2 vs 4.2 mo (HR 0.46, 95% CI 0.34-0.62) Did not meet secondary endpoint of OS¹ Median OS: 22.9 vs 20.5 mo (HR 0.91, 95% CI 0.71-1.16)
Motzer et al. 2013 (COMPARZ)	2008-2011	Phase 3 (E-switch-ic)	Sunitinib	Non-inferior PFS (primary endpoint) Median PFS: 8.4 vs 9.5 mo (HR 1.05, 95% CI 0.90-1.22)
Cirkel et al. 2017 (ROPETAR)	2012-2014	Randomized (C)	Pazopanib/Everolimus	Did not meet primary endpoint of PFS
Brown et al. 2023 (STAR)	2012-01-13 to 2017-09-12	Phase 2/3 (C)	1a. Pazopanib x 2 y, then treatment-free interval 1b. Sunitinib x 2 y, then treatment-free interval	Inconclusive whether non-inferior OS (co-primary endpoint)

Targeted therapy

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

28-day cycles

Dose and schedule modifications

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

References

VEG102616: Hutson TE, Davis ID, Machiels JP, De Souza PL, Rottey S, Hong BF, Epstein RJ, Baker KL, McCann L, Crofts T, Pandite L, Figlin RA. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2010 Jan 20;28(3):475-80. Epub 2009 Dec 14. link to original article contains dosing details in manuscript PubMed NCT00244764
VEG105192: Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarbá JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010 Feb 20;28(6):1061-8. Epub 2010 Jan 25. link to original article contains dosing details in manuscript PubMed NCT00334282
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
COMPARZ: Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, Jin J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R, Pandite LN, Choueiri TK. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013 Aug 22;369(8):722-31. link to original article contains dosing details in manuscript PubMed NCT00720941
1. Update: Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med. 2014 May 1;370(18):1769-70. link to letter PubMed
PISCES: Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U, Parikh O, Hawkins R, Sevin E, Négrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol. 2014 May 10;32(14):1412-8. Epub 2014 Mar 31. link to original article PubMed NCT01064310
ROPETAR: Cirkel GA, Hamberg P, Sleijfer S, Loosveld OJL, Dercksen MW, Los M, Polee MB, van den Berkmortel F, Aarts MJ, Beerepoot LV, Groenewegen G, Lolkema MP, Tascilar M, Portielje JEA, Peters FPJ, Klümpen HJ, van der Noort V, Haanen JBAG, Voest EE; Dutch WIN-O Consortium. Alternating treatment with pazopanib and everolimus vs continuous pazopanib to delay disease progression in patients with metastatic clear cell renal cell cancer: the ROPETAR randomized clinical trial. JAMA Oncol. 2017 Apr 1;3(4):501-508. link to original article contains dosing details in abstract PubMed NCT01408004
STAR: Brown JE, Royle KL, Gregory W, Ralph C, Maraveyas A, Din O, Eisen T, Nathan P, Powles T, Griffiths R, Jones R, Vasudev N, Wheater M, Hamid A, Waddell T, McMenemin R, Patel P, Larkin J, Faust G, Martin A, Swain J, Bestall J, McCabe C, Meads D, Goh V, Min Wah T, Brown J, Hewison J, Selby P, Collinson F; STAR Investigators. Temporary treatment cessation versus continuation of first-line tyrosine kinase inhibitor in patients with advanced clear cell renal cell carcinoma (STAR): an open-label, non-inferiority, randomised, controlled, phase 2/3 trial. Lancet Oncol. 2023 Mar;24(3):213-227. Epub 2023 Feb 13. link to original article PubMed ISRCTN06473203

Pembrolizumab monotherapy

Regimen

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

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

Immunotherapy

Pembrolizumab (Keytruda) 200 mg IV once on day 1

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

References

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

Regorafenib monotherapy

Regimen

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

Targeted therapy

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

28-day cycles

References

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

Sorafenib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Escudier et al. 2009 (Bayer 11848)	2005-06-28 to 2005-09-30	Randomized Phase 2 (E-switch-ooc)	Interferon alfa-2a	Did not meet primary endpoint of PFS
Motzer et al. 2013 (TIVO-1)	2010-02 to 2010-08	Phase 3 (C)	Tivozanib	Seems to have inferior PFS
Hutson et al. 2013 (A4061051)	2010-06-14 to 2011-04-21	Phase 3 (C)	Axitinib	Might have inferior PFS¹
Tomita et al. 2020 (CROSS-J-RCC)	2010-2012	Phase 3 (E-switch-ic)	Sunitinib	Did not meet primary endpoint of PFS

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

Targeted therapy

Sorafenib (Nexavar) 400 mg PO twice per day

Continued indefinitely

Dose and schedule modifications

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

References

Bayer 11848: Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, Negrier S, Laferriere N, Scheuring UJ, Cella D, Shah S, Bukowski RM. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Mar 10;27(8):1280-9. Epub 2009 Jan 26. Erratum in: J Clin Oncol. 2009 May 1; 27(13):2305. link to original article PubMed NCT00117637
TIVO-1: Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, Tomczak P, Lyulko O, Alyasova A, Harza M, Kogan M, Alekseev BY, Sternberg CN, Szczylik C, Cella D, Ivanescu C, Krivoshik A, Strahs A, Esteves B, Berkenblit A, Hutson TE. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013 Oct 20;31(30):3791-9. Epub 2013 Sep 9. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01030783
A4061051: Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, Rosbrook B, Chen C, Kim S, Vogelzang NJ. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1287-94. Epub 2013 Oct 25. link to original article contains dosing details in abstract PubMed NCT00920816
1. Update: Hutson TE, Al-Shukri S, Stus VP, Lipatov ON, Shparyk Y, Bair AH, Rosbrook B, Andrews GI, Vogelzang NJ. Axitinib versus sorafenib in first-line metastatic renal cell carcinoma: Overall survival from a randomized phase III trial. Clin Genitourin Cancer. 2017 Feb;15(1):72-76. Epub 2016 May 27. link to original article PubMed
CROSS-J-RCC: Tomita Y, Naito S, Sassa N, Takahashi A, Kondo T, Koie T, Obara W, Kobayashi Y, Teishima J, Takahashi M, Matsuyama H, Ueda T, Yamaguchi K, Kishida T, Shiroki R, Saika T, Shinohara N, Oya M, Kanayama HO. Sunitinib Versus Sorafenib as Initial Targeted Therapy for mCC-RCC With Favorable/Intermediate Risk: Multicenter Randomized Trial CROSS-J-RCC. Clin Genitourin Cancer. 2020 Aug;18(4):e374-e385. Epub 2020 Mar 6. link to original article PubMed NCT01481870

Sunitinib monotherapy

Regimen variant #1, 4 out of 6 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2007 (A618-1034)	2004-08 to 2005-10	Phase 3 (E-RT-switch-ooc)	Interferon alfa-2a	Superior PFS (primary endpoint) Median PFS: 11 vs 5 mo (HR 0.42, 95% CI 0.32-0.54) Might have superior OS¹ (secondary endpoint) Median OS: 26.4 vs 21.8 mo (HR 0.82, 95% CI 0.67-1.001)
Amato et al. 2010 (TroVax Renal Immunotherapy Survival Trial)	2006-2008	Phase 3 (C)	Sunitinib & MVA-5T4	Did not meet primary endpoint of OS Median OS: 19.2 vs 20.1 mo (HR 0.93, 95% CI 0.76-1.16)
Motzer et al. 2013 (COMPARZ)	2008-2011	Phase 3 (C)	Pazopanib	Non-inferior PFS
Méjean et al. 2018 (CARMENA)	2009-2017	Phase 3 (E-de-esc)	Nephrectomy, then Sunitinib	Non-inferior OS (primary endpoint) Median OS: 18.4 vs 13.9 mo (HR 0.89, 95% CI 0.71-1.10)
Rini et al. 2016 (IMPRINT)	2010-2012	Phase 3 (C)	Sunitinib & IMA-901	Might have superior OS Median OS: NYR vs 33.2 mo (HR 0.75, 95% CI 0.54-1.04)
Tomita et al. 2020 (CROSS-J-RCC)	2010-2012	Phase 3 (E-switch-ic)	Sorafenib	Did not meet primary endpoint of PFS
Brown et al. 2023 (STAR)	2012-01-13 to 2017-09-12	Phase 2/3 (C)	1a. Pazopanib x 2 y, then treatment-free interval 1b. Sunitinib x 2 y, then treatment-free interval	Inconclusive whether non-inferior OS (co-primary endpoint)
Choueiri et al. 2016 (CABOSUN)	2013-2015	Phase 3 (C)	Cabozantinib	Inferior PFS²
Figlin et al. 2020 (ADAPT)	2013-2016	Phase 3 (C)	Rocapuldencel-T & Sunitinib	Did not meet primary endpoint of OS Median OS: 32.4 vs 27.7 mo (HR 0.91, 95% CI 0.71-1.20)
Motzer et al. 2018 (CheckMate 214)	2014-2016	Phase 3 (C)	Ipilimumab & Nivolumab	Inferior OS
Motzer et al. 2019 (JAVELIN Renal 101)	2016-03-29 to 2017-12-19	Phase 3 (C)	Axitinib & Avelumab	Seems to have inferior OS³
Motzer et al. 2021 (CLEAR)	2016-10-13 to 2019-07-24	Phase 3 (C)	1. Everolimus & Lenvatinib	Inferior PFS
Motzer et al. 2021 (CLEAR)	2016-10-13 to 2019-07-24	Phase 3 (C)	2. Lenvatinib & Pembrolizumab	Inferior OS
Rini et al. 2019 (KEYNOTE-426)	2016-10-24 to 2018-01-24	Phase 3 (C)	Axitinib & Pembrolizumab	Inferior OS
Choueiri et al. 2021 (CheckMate 9ER)	2017-2019	Phase 3 (C)	Cabozantinib & Nivolumab	Inferior OS
Yan et al. 2023 (RENOTORCH)	2020-08-23 to 2022-09-23	Phase 3 (C)	Axitinib & Toripalimab	Inferior OS

¹Reported efficacy for A618-1034 is based on the 2009 update.
²Reported efficacy for CABOSUN is based on the 2018 update.
³Reported efficacy for JAVELIN Renal 101 is based on the 2020 update, although the authors state that OS data remains immature.

Targeted therapy

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

42-day cycles

Dose and schedule modifications

Per some references, dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability

Regimen variant #2, 2 out of 3 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yan et al. 2023 (RENOTORCH)	2020-08-23 to 2022-09-23	Phase 3 (C)	Axitinib & Toripalimab	Inferior OS

Targeted therapy

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

21-day cycles

Regimen variant #3, 2 out of 4 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (TQB2450-III-07)	2020-ongoing	Phase 3 (C)	Anlotinib & TQB-2450	TBD if different primary endpoint of PFS

Targeted therapy

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

28-day cycles

References

A618-1034: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. link to original article contains dosing details in manuscript PubMed NCT00083889
1. Update: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Aug 1;27(22):3584-90. Epub 2009 Jun 1. link to original article contains dosing details in manuscript link to PMC article PubMed
2. HRQoL analysis: Cella D, Michaelson MD, Bushmakin AG, Cappelleri JC, Charbonneau C, Kim ST, Li JZ, Motzer RJ. Health-related quality of life in patients with metastatic renal cell carcinoma treated with sunitinib vs interferon-alpha in a phase III trial: final results and geographical analysis. Br J Cancer. 2010 Feb 16;102(4):658-64. Epub 2010 Jan 26. link to original article link to PMC article PubMed
TroVax Renal Immunotherapy Survival Trial: Amato RJ, Hawkins RE, Kaufman HL, Thompson JA, Tomczak P, Szczylik C, McDonald M, Eastty S, Shingler WH, de Belin J, Goonewardena M, Naylor S, Harrop R. Vaccination of metastatic renal cancer patients with MVA-5T4: a randomized, double-blind, placebo-controlled phase III study. Clin Cancer Res. 2010 Nov 15;16(22):5539-47. Epub 2010 Sep 29. link to original article contains dosing details in manuscript PubMed NCT00397345
COMPARZ: Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, Jin J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R, Pandite LN, Choueiri TK. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013 Aug 22;369(8):722-31. link to original article contains dosing details in manuscript PubMed NCT00720941
1. Update: Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med. 2014 May 1;370(18):1769-70. link to letter PubMed
CABOSUN: Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, Feldman DR, Olencki T, Picus J, Small EJ, Dakhil S, George DJ, Morris MJ. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol. 2017 Feb 20;35(6):591-597. Epub 2016 Nov 14. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01835158
1. Update: Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, Walsh M, Olencki T, Picus J, Small EJ, Dakhil S, Feldman DR, Mangeshkar M, Scheffold C, George D, Morris MJ. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer. 2018 May;94:115-125. Epub 2018 Mar 20. link to original article contains dosing details in manuscript link to PMC article PubMed
IMPRINT: Rini BI, Stenzl A, Zdrojowy R, Kogan M, Shkolnik M, Oudard S, Weikert S, Bracarda S, Crabb SJ, Bedke J, Ludwig J, Maurer D, Mendrzyk R, Wagner C, Mahr A, Fritsche J, Weinschenk T, Walter S, Kirner A, Singh-Jasuja H, Reinhardt C, Eisen T. IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2016 Nov;17(11):1599-1611. Epub 2016 Oct 3. link to original article contains dosing details in abstract PubMed NCT01265901
CheckMate 214: Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. Epub 2018 Mar 21. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02231749
1. PRO analysis: Cella D, Grünwald V, Escudier B, Hammers HJ, George S, Nathan P, Grimm MO, Rini BI, Doan J, Ivanescu C, Paty J, Mekan S, Motzer RJ. Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial. Lancet Oncol. 2019 Feb;20(2):297-310. Epub 2019 Jan 15. Erratum in: Lancet Oncol. 2019 Jun;20(6):e293. link to original article link to PMC article PubMed
2. Update: Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, Salman P, Escudier B, Beuselinck B, Amin A, Porta C, George S, Neiman V, Bracarda S, Tykodi SS, Barthélémy P, Leibowitz-Amit R, Plimack ER, Oosting SF, Redman B, Melichar B, Powles T, Nathan P, Oudard S, Pook D, Choueiri TK, Donskov F, Grimm MO, Gurney H, Heng DYC, Kollmannsberger CK, Harrison MR, Tomita Y, Duran I, Grünwald V, McHenry MB, Mekan S, Tannir NM; CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019 Oct;20(10):1370-1385. Epub 2019 Aug 16. Erratum in: Lancet Oncol. 2019 Aug 21. link to original article link to PMC article PubMed
3. Update: Motzer RJ, Escudier B, McDermott DF, Arén Frontera O, Melichar B, Powles T, Donskov F, Plimack ER, Barthélémy P, Hammers HJ, George S, Grünwald V, Porta C, Neiman V, Ravaud A, Choueiri TK, Rini BI, Salman P, Kollmannsberger CK, Tykodi SS, Grimm MO, Gurney H, Leibowitz-Amit R, Geertsen PF, Amin A, Tomita Y, McHenry MB, Saggi SS, Tannir NM. Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer. 2020 Jul;8(2):e000891. Erratum in: J Immunother Cancer. 2021 May;9(5). link to original article link to PMC article PubMed
4. Update: Albiges L, Tannir NM, Burotto M, McDermott D, Plimack ER, Barthélémy P, Porta C, Powles T, Donskov F, George S, Kollmannsberger CK, Gurney H, Grimm MO, Tomita Y, Castellano D, Rini BI, Choueiri TK, Saggi SS, McHenry MB, Motzer RJ. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020 Nov;5(6):e001079. link to original article link to PMC article PubMed
CARMENA: Méjean A, Ravaud A, Thezenas S, Colas S, Beauval JB, Bensalah K, Geoffrois L, Thiery-Vuillemin A, Cormier L, Lang H, Guy L, Gravis G, Rolland F, Linassier C, Lechevallier E, Beisland C, Aitchison M, Oudard S, Patard JJ, Theodore C, Chevreau C, Laguerre B, Hubert J, Gross-Goupil M, Bernhard JC, Albiges L, Timsit MO, Lebret T, Escudier B. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018 Aug 2;379(5):417-427. Epub 2018 Jun 3. link to original article contains dosing details in abstract PubMed NCT00930033
KEYNOTE-426: Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, Vynnychenko I, Kryzhanivska A, Bondarenko I, Azevedo SJ, Borchiellini D, Szczylik C, Markus M, McDermott RS, Bedke J, Tartas S, Chang YH, Tamada S, Shou Q, Perini RF, Chen M, Atkins MB, Powles T; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116-1127. Epub 2019 Feb 16. link to original article contains dosing details in abstract PubMed NCT02853331
1. Update: Powles T, Plimack ER, Soulières D, Waddell T, Stus V, Gafanov R, Nosov D, Pouliot F, Melichar B, Vynnychenko I, Azevedo SJ, Borchiellini D, McDermott RS, Bedke J, Tamada S, Yin L, Chen M, Molife LR, Atkins MB, Rini BI. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1563-1573. Epub 2020 Oct 23. Erratum in: Lancet Oncol. 2020 Dec;21(12):e553. link to original article PubMed
JAVELIN Renal 101: Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M, Lee JL, Vasiliev A, Miller WH Jr, Gurney H, Schmidinger M, Larkin J, Atkins MB, Bedke J, Alekseev B, Wang J, Mariani M, Robbins PB, Chudnovsky A, Fowst C, Hariharan S, Huang B, di Pietro A, Choueiri TK. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1103-1115. Epub 2019 Feb 16. link to original article contains dosing details in abstract link to PMC article PubMed NCT02684006
1. Update: Choueiri TK, Motzer RJ, Rini BI, Haanen J, Campbell MT, Venugopal B, Kollmannsberger C, Gravis-Mescam G, Uemura M, Lee JL, Grimm MO, Gurney H, Schmidinger M, Larkin J, Atkins MB, Pal SK, Wang J, Mariani M, Krishnaswami S, Cislo P, Chudnovsky A, Fowst C, Huang B, di Pietro A, Albiges L. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020 Aug;31(8):1030-1039. Epub 2020 Apr 25. link to original article link to PMC article PubMed
ADAPT: Figlin RA, Tannir NM, Uzzo RG, Tykodi SS, Chen DYT, Master V, Kapoor A, Vaena D, Lowrance W, Bratslavsky G, DeBenedette M, Gamble A, Plachco A, Norris MS, Horvatinovich J, Tcherepanova IY, Nicolette CA, Wood CG; ADAPT study group. Results of the ADAPT Phase 3 Study of Rocapuldencel-T in Combination with Sunitinib as First-Line Therapy in Patients with Metastatic Renal Cell Carcinoma. Clin Cancer Res. 2020 May 15;26(10):2327-2336. Epub 2020 Feb 7. link to original article PubMed NCT01582672
CROSS-J-RCC: Tomita Y, Naito S, Sassa N, Takahashi A, Kondo T, Koie T, Obara W, Kobayashi Y, Teishima J, Takahashi M, Matsuyama H, Ueda T, Yamaguchi K, Kishida T, Shiroki R, Saika T, Shinohara N, Oya M, Kanayama HO. Sunitinib Versus Sorafenib as Initial Targeted Therapy for mCC-RCC With Favorable/Intermediate Risk: Multicenter Randomized Trial CROSS-J-RCC. Clin Genitourin Cancer. 2020 Aug;18(4):e374-e385. Epub 2020 Mar 6. link to original article PubMed NCT01481870
CLEAR: Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. link to original article contains dosing details in abstract PubMed NCT02811861
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. Update: Motzer RJ, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Alekseev B, Rha SY, Merchan J, Goh JC, Lalani AA, De Giorgi U, Melichar B, Hong SH, Gurney H, Méndez-Vidal MJ, Kopyltsov E, Tjulandin S, Gordoa TA, Kozlov V, Alyasova A, Winquist E, Maroto P, Kim M, Peer A, Procopio G, Takagi T, Wong S, Bedke J, Schmidinger M, Rodriguez-Lopez K, Burgents J, He C, Okpara CE, McKenzie J, Choueiri TK; CLEAR Trial Investigators. Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study. J Clin Oncol. 2024 Apr 10;42(11):1222-1228. Epub 2024 Jan 16. link to original article PubMed
CheckMate 9ER: Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, Oyervides Juárez VM, Hsieh JJ, Basso U, Shah AY, Suárez C, Hamzaj A, Goh JC, Barrios C, Richardet M, Porta C, Kowalyszyn R, Feregrino JP, Żołnierek J, Pook D, Kessler ER, Tomita Y, Mizuno R, Bedke J, Zhang J, Maurer MA, Simsek B, Ejzykowicz F, Schwab GM, Apolo AB, Motzer RJ; CheckMate 9ER Investigators. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03141177
1. Update: Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, Suárez C, Hamzaj A, Porta C, Hocking CM, Kessler ER, Gurney H, Tomita Y, Bedke J, Zhang J, Simsek B, Scheffold C, Apolo AB, Choueiri TK. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Jul;23(7):888-898. Epub 2022 Jun 7. link to original article PubMed
2. Update: Powles T, Burotto M, Escudier B, Apolo AB, Bourlon MT, Shah AY, Suárez C, Porta C, Barrios CH, Richardet M, Gurney H, Kessler ER, Tomita Y, Bedke J, George S, Scheffold C, Wang P, Fedorov V, Motzer RJ, Choueiri TK. Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial. ESMO Open. 2024 May;9(5):102994. Epub 2024 Apr 20. link to original article link to PMC article PubMed
STAR: Brown JE, Royle KL, Gregory W, Ralph C, Maraveyas A, Din O, Eisen T, Nathan P, Powles T, Griffiths R, Jones R, Vasudev N, Wheater M, Hamid A, Waddell T, McMenemin R, Patel P, Larkin J, Faust G, Martin A, Swain J, Bestall J, McCabe C, Meads D, Goh V, Min Wah T, Brown J, Hewison J, Selby P, Collinson F; STAR Investigators. Temporary treatment cessation versus continuation of first-line tyrosine kinase inhibitor in patients with advanced clear cell renal cell carcinoma (STAR): an open-label, non-inferiority, randomised, controlled, phase 2/3 trial. Lancet Oncol. 2023 Mar;24(3):213-227. Epub 2023 Feb 13. link to original article PubMed ISRCTN06473203
RENOTORCH: Yan XQ, Ye MJ, Zou Q, Chen P, He ZS, Wu B, He DL, He CH, Xue XY, Ji ZG, Chen H, Zhang S, Liu YP, Zhang XD, Fu C, Xu DF, Qiu MX, Lv JJ, Huang J, Ren XB, Cheng Y, Qin WJ, Zhang X, Zhou FJ, Ma LL, Guo JM, Ding DG, Wei SZ, He Y, Guo HQ, Shi BK, Liu L, Liu F, Hu ZQ, Jin XM, Yang L, Zhu SX, Liu JH, Huang YH, Xu T, Liu B, Sun T, Wang ZJ, Jiang HW, Yu DX, Zhou AP, Jiang J, Luan GD, Jin CL, Xu J, Hu JX, Huang YR, Guo J, Zhai W, Sheng XN. Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study. Ann Oncol. 2024 Feb;35(2):190-199. Epub 2023 Oct 21. link to original article contains dosing details in manuscript PubMed [NCT04394975
KEYNOTE-679: NCT03260894
PIVOT-09: NCT03729245
TQB2450-III-07: NCT04523272

Tivozanib monotherapy

Regimen

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

Targeted therapy

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

28-day cycles

References

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

Metastatic disease, second-line

Axitinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rini et al. 2011 (AXIS)	2008-2010	Phase 3 (E-RT-switch-ic)	Sorafenib	Superior PFS¹ (primary endpoint) Median PFS: 8.3 vs 5.7 mo (HR 0.66, 95% CI 0.55-0.78) Did not meet secondary endpoint of OS¹ Median OS: 20.1 vs 19.2 mo (HR 0.97, 95% CI 0.80-1.17)

¹Reported efficacy is based on the 2013 update.

Prior treatment criteria

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

Targeted therapy

Axitinib (Inlyta) 5 mg PO twice per day

Continued indefinitely

Dose and schedule modifications

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

References

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

Belzutifan monotherapy

Regimen

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

¹Reported efficacy is based on the FDA announcement; hazards were non-proportional.
Note: Dosing details are from CT.gov.

Targeted therapy

Belzutifan (Welireg) 120 mg PO once per day

Continued indefinitely

References

LITESPARK-005: NCT04195750

Bevacizumab monotherapy

Regimen

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

Prior treatment criteria

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

Targeted therapy

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

14-day cycles

References

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

Cabozantinib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Choueiri et al. 2015 (METEOR)	2013-08 to 2014-11	Phase 3 (E-RT-switch-ic)	Everolimus	Superior PFS (primary endpoint) Median PFS: 7.4 vs 3.8 mo (HR 0.58, 95% CI 0.45-0.75) Superior OS¹ (secondary endpoint) Median OS: 21.4 vs 17.1 mo (HR 0.70, 95% CI 0.58-0.85)
Tannir et al. 2022 (CANTATA)	2018-11-27 to 2019-09-30	Phase 3 (C)	Cabozantinib & Telaglenastat	Did not meet primary endpoint of PFS

¹Reported efficacy is based on the 2018 update.

Prior treatment criteria

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

Targeted therapy

Cabozantinib (Cabometyx) 60 mg PO once per day on days 1 to 28, taken at least 2 hours before or 1 hour after meals

28-day cycles

References

METEOR: Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1814-23. Epub 2015 Sep 25. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01865747
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
CANTATA: Tannir NM, Agarwal N, Porta C, Lawrence NJ, Motzer R, McGregor B, Lee RJ, Jain RK, Davis N, Appleman LJ, Goodman O Jr, Stadler WM, Gandhi S, Geynisman DM, Iacovelli R, Mellado B, Sepúlveda Sánchez JM, Figlin R, Powles T, Akella L, Orford K, Escudier B. Efficacy and Safety of Telaglenastat Plus Cabozantinib vs Placebo Plus Cabozantinib in Patients With Advanced Renal Cell Carcinoma: The CANTATA Randomized Clinical Trial. JAMA Oncol. 2022 Oct 1;8(10):1411-1418. link to orginal article link to PMC article PubMed NCT03428217
MK-6482-011: NCT04586231

Everolimus monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2008 (RECORD-1)	2006-04 to 2007-04	Phase 3 (E-RT-esc)	Placebo	Superior PFS¹ (primary endpoint) Median PFS: 4.9 vs 1.9 mo (HR 0.33, 95% CI 0.25-0.43) Did not meet secondary endpoint of OS¹ Median OS: 14.8 vs 14.4 mo (HR 0.87, 95% CI 0.65-1.15)
Motzer et al. 2015 (RECORD-4)	2011-2013	Phase 2
Motzer et al. 2015 (CheckMate 025)	2012-2014	Phase 3 (C)	Nivolumab	Inferior OS
Motzer et al. 2015 (E7080-G000-205)	2012-03-16 to 2013-06-19	Randomized Phase 2 (C)	1. Everolimus & Lenvatinib	Inferior PFS
Motzer et al. 2015 (E7080-G000-205)	2012-03-16 to 2013-06-19	Randomized Phase 2 (C)	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 (CONCEPT_RCC)	2017-2019	Phase 3 (C)	1. Everolimus & Vorolanib	Inferior PFS
Sheng et al. 2022 (CONCEPT_RCC)	2017-2019	Phase 3 (C)	2. Vorolanib	Might have inferior PFS
Awaiting publication (LITESPARK-005)	2020-ongoing	Phase 3 (C)	Belzutifan	Inferior PFS

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

Prior treatment criteria

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

Targeted therapy

Everolimus (Afinitor) 10 mg PO once per day

Continued indefinitely

Dose and schedule modifications

Everolimus dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability

References

RECORD-1: Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008 Aug 9;372(9637):449-56. Epub 2008 Jul 22. link to original article contains dosing details in manuscript PubMed NCT00410124 [move]
1. Update: Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A; RECORD-1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010 Sep 15;116(18):4256-65. link to original article contains dosing details in manuscript PubMed
CheckMate 025: Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803-13. Epub 2015 Sep 25. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01668784
1. HRQoL analysis: Cella D, Grünwald V, Nathan P, Doan J, Dastani H, Taylor F, Bennett B, DeRosa M, Berry S, Broglio K, Berghorn E, Motzer RJ. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):994-1003. Epub 2016 Jun 6. Erratum in: Lancet Oncol. 2016 Jul;17 (7):e270. link to original article link to PMC article PubMed
2. Subgroup analysis: Escudier B, Sharma P, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Gurney H, Donskov F, Peltola K, Wagstaff J, Gauler TC, Ueda T, Zhao H, Waxman IM, Motzer RJ; CheckMate 025 investigators. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol. 2017 Dec;72(6):962-971. Epub 2017 Mar 3. Erratum in: Eur Urol. 2018 Jan 3. link to original article PubMed
3. Subgroup analysis: Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Saito M, Kimura G, Yonese J, Yao M, Uemura H. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the phase III CheckMate 025 study. Jpn J Clin Oncol. 2019 Jun 1;49(6):506-514. link to original article PubMed
4. Update: Motzer RJ, Escudier B, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Plimack ER, Procopio G, McDermott DF, Castellano D, Choueiri TK, Donskov F, Gurney H, Oudard S, Richardet M, Peltola K, Alva AS, Carducci M, Wagstaff J, Chevreau C, Fukasawa S, Tomita Y, Gauler TC, Kollmannsberger CK, Schutz FA, Larkin J, Cella D, McHenry MB, Saggi SS, Tannir NM. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer. 2020 Sep 15;126(18):4156-4167. Epub 2020 Jul 16. link to original article link to PMC article PubMed
METEOR: Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1814-23. Epub 2015 Sep 25. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01865747
1. Update: Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, Hammers HJ, Donskov F, Roth BJ, Peltola K, Lee JL, Heng DY, Schmidinger M, Agarwal N, Sternberg CN, McDermott DF, Aftab DT, Hessel C, Scheffold C, Schwab G, Hutson TE, Pal S, Motzer RJ; METEOR investigators. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):917-27. Epub 2016 Jun 5. link to original article PubMed
2. HRQoL analysis: Cella D, Escudier B, Tannir NM, Powles T, Donskov F, Peltola K, Schmidinger M, Heng DYC, Mainwaring PN, Hammers HJ, Lee JL, Roth BJ, Marteau F, Williams P, Baer J, Mangeshkar M, Scheffold C, Hutson TE, Pal S, Motzer RJ, Choueiri TK. Quality of life outcomes for cabozantinib versus everolimus in patients with metastatic renal cell carcinoma: METEOR phase III randomized trial. J Clin Oncol. 2018 Mar 10;36(8):757-764. Epub 2018 Jan 29. link to original article link to PMC article PubMed
3. Update: Motzer RJ, Escudier B, Powles T, Scheffold C, Choueiri TK. Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer. 2018 May;118(9):1176-1178. Epub 2018 Mar 26. link to original article link to PMC article PubMed
E7080-G000-205: Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. link to original article contains dosing details in manuscript PubMed NCT01136733
1. Update: Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 Jan;17(1):e4-5. Epub 2015 Dec 23. link to original article PubMed
RECORD-4: Motzer RJ, Alyasova A, Ye D, Karpenko A, Li H, Alekseev B, Xie L, Kurteva G, Kowalyszyn R, Karyakin O, Neron Y, Cosgriff T, Collins L, Brechenmacher T, Lin C, Morgan L, Yang L. Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4). Ann Oncol. 2016 Mar;27(3):441-8. Epub 2015 Dec 17. link to original article link to PMC article contains dosing details in abstract PubMed NCT01491672
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 NCT03095040
LITESPARK-005: NCT04195750

Everolimus & Lenvatinib

Regimen

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

Prior treatment criteria

VEGFR TKI treatment, with progression

Targeted therapy

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

Continued indefinitely

References

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

Lenvatinib monotherapy

Regimen

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

Targeted therapy

Lenvatinib (Lenvima) 24 mg PO once per day on days 1 to 28

28-day cycles

References

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

Nivolumab monotherapy

Regimen variant #1, 0.3 mg/kg q3wk

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

Immunotherapy

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)	2012-2014	Phase 3 (E-RT-switch-ooc)	Everolimus	Superior OS (primary endpoint) Median OS: 25 vs 19.6 mo (HR 0.73, 98.5% CI 0.57-0.93)

Note: On 2016-09-13 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

Immunotherapy

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

14-day cycles

Regimen variant #4, 10 mg/kg q3wk

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

Immunotherapy

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

21-day cycles

Regimen variant #5, flat dose

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

Immunotherapy

Nivolumab (Opdivo) 240 mg IV once on day 1

14-day cycles

References

CheckMate 010: Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, Vaishampayan UN, Drabkin HA, George S, Logan TF, Margolin KA, Plimack ER, Lambert AM, Waxman IM, Hammers HJ. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. 2015 May 1;33(13):1430-7. Epub 2014 Dec 1. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01354431
CheckMate 025: Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803-13. Epub 2015 Sep 25. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01668784
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
CheckMate 374: McFarlane JJ, Kochenderfer MD, Olsen MR, Bauer TM, Molina A, Hauke RJ, Reeves JA, Babu S, Van Veldhuizen P, Somer B, Gunuganti V, Schnadig I, George S, Page RD, Arrowsmith E, Jain RK, Zhang J, McHenry MB, Johansen JL, Vogelzang NJ. Safety and Efficacy of Nivolumab in Patients With Advanced Clear Cell Renal Cell Carcinoma: Results From the Phase IIIb/IV CheckMate 374 Study. Clin Genitourin Cancer. 2020 Dec;18(6):469-476.e4. Epub 2020 Jun 14. link to original article contains dosing details in abstract PubMed NCT02596035

Pazopanib monotherapy

Regimen

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

Prior treatment criteria

VEG105192: Progression on 1 prior cytokine-based systemic therapy

Targeted therapy

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

28-day cycles

Dose and schedule modifications

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

References

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

Sorafenib monotherapy

Regimen

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

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

Prior treatment criteria

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

Targeted therapy

Sorafenib (Nexavar) 400 mg PO twice per day

Continued indefinitely

Dose and schedule modifications

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

References

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

Sunitinib monotherapy

Regimen

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

Targeted therapy

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

42-day cycles

Dose and schedule modifications

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

References

A618-1006: Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, Redman BG, Margolin KA, Merchan JR, Wilding G, Ginsberg MS, Bacik J, Kim ST, Baum CM, Michaelson MD. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006 Jun 7;295(21):2516-24. link to original article contains dosing details in abstract PubMed NCT00077974

Metastatic disease, third-line

Sorafenib monotherapy

Regimen

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

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

Targeted therapy

Sorafenib (Nexavar) 400 mg PO twice per day on days 1 to 28

28-day cycles

References

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

Tivozanib monotherapy

Regimen variant #1, 1.34 mg/day

FDA-recommended dose

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

Targeted therapy

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)	2016-05-24 to 2017-08-14	Phase 3 (E-RT-switch-ic)	Sorafenib	Seems to have superior PFS (primary endpoint) Median PFS: 5.6 vs 3.9 mo (HR 0.73, 95% CI 0.56-0.94)

Targeted therapy

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

28-day cycles

References

TIVO-3: Rini BI, Pal SK, Escudier BJ, Atkins MB, Hutson TE, Porta C, Verzoni E, Needle MN, McDermott DF. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020 Jan;21(1):95-104. Epub 2019 Dec 3. link to original article contains dosing details in manuscript PubMed NCT02627963
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

@@ Line 25: / Line 25: @@
 '''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.'''
 ==[http://www.asco.org/ ASCO]==
-*'''2022:''' Rathmell et al. [https://doi.org/10.1200/jco.22.00868 Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/35728020 PubMed]
+*'''2023:''' Singer et al. [https://doi.org/10.1200/jco.23.01977 Management of Metastatic Renal Clear Cell Cancer: ASCO Guideline Rapid Recommendation Update] [https://pubmed.ncbi.nlm.nih.gov/37812756/ PubMed]
+**'''2022:''' Rathmell et al. [https://doi.org/10.1200/jco.22.00868 Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/35728020 PubMed]
 *'''2017:''' Finelli et al. [https://doi.org/10.1200/jco.2016.69.9645 Management of Small Renal Masses: American Society of Clinical Oncology Clinical Practice Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/28095147 PubMed]
@@ Line 31: / Line 32: @@
 ==EAU==
 *'''2016:''' Powles et al. [https://doi.org/10.1016/j.eururo.2015.10.017 Updated EAU guidelines for clear cell renal cancer patients who fail VEGF targeted therapy] [https://www.ncbi.nlm.nih.gov/pubmed/26508312 PubMed]
-==[http://www.esmo.org/ ESMO]==
+==[https://www.esmo.org/ ESMO]==
 *'''2021:''' Powles [https://doi.org/10.1016/j.annonc.2020.11.016 Recent eUpdate to the ESMO Clinical Practice Guidelines on renal cell carcinoma on cabozantinib and nivolumab for first-line clear cell renal cancer: Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/33271289/ PubMed]
-==[https://www.nccn.org/ NCCN]==
+==NCCN==
-*''NCCN does not currently have guidelines at this granular level; please see [https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf NCCN Guidelines - Kidney Cancer].''
+*''NCCN does not currently have guidelines at this granular level; please see [https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1440 NCCN Guidelines - Kidney Cancer].''
 =Adjuvant therapy=
@@ Line 59: / Line 60: @@
 | style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 |[[Clear_cell_renal_cell_carcinoma_-_null_regimens#Placebo|Placebo]]
-| style="background-color:#1a9850" |Superior DFS<sup>1</sup> (primary endpoint)<br>Median DFS: NYR vs NYR<br>(HR 0.63, 95% CI 0.50-0.80)
+| style="background-color:#1a9850" |Superior DFS<sup>1</sup> (primary endpoint)<br>Median DFS: NYR vs NYR<br>(HR 0.63, 95% CI 0.50-0.80)<br><br>Superior OS<sup>2</sup> (secondary endpoint)<br>OS48: 91.2% vs 86%<br>(HR 0.62, 95% CI 0.44-0.87)
 |-
 |}
-''<sup>1</sup>Reported efficacy is based on the 2022 update.''
+''<sup>1</sup>Reported efficacy is based on the 2022 update.''<br>
+''<sup>2</sup>Reported efficacy is based on the 2024 update.''
 <div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
@@ Line 91: / Line 93: @@
 # '''KEYNOTE-564:''' Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Chang YH, Hajek J, Symeonides SN, Lee JL, Sarwar N, Thiery-Vuillemin A, Gross-Goupil M, Mahave M, Haas NB, Sawrycki P, Gurney H, Chevreau C, Melichar B, Kopyltsov E, Alva A, Burke JM, Doshi G, Topart D, Oudard S, Hammers H, Kitamura H, Bedke J, Perini RF, Zhang P, Imai K, Willemann-Rogerio J, Quinn DI, Powles T; KEYNOTE-564 Investigators. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med. 2021 Aug 19;385(8):683-694. [https://doi.org/10.1056/nejmoa2106391 link to original article] [https://www.zora.uzh.ch/id/eprint/207435/ link to free full text via University of Zurich] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/34407342/ PubMed] [https://clinicaltrials.gov/study/NCT03142334 NCT03142334]
 ##'''Update:''' Powles T, Tomczak P, Park SH, Venugopal B, Ferguson T, Symeonides SN, Hajek J, Gurney H, Chang YH, Lee JL, Sarwar N, Thiery-Vuillemin A, Gross-Goupil M, Mahave M, Haas NB, Sawrycki P, Burgents JE, Xu L, Imai K, Quinn DI, Choueiri TK; KEYNOTE-564 Investigators. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022 Sep;23(9):1133-1144. [https://doi.org/10.1016/s1470-2045(22)00487-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36055304/ PubMed]
+##'''Update:''' Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Symeonides SN, Hajek J, Chang YH, Lee JL, Sarwar N, Haas NB, Gurney H, Sawrycki P, Mahave M, Gross-Goupil M, Zhang T, Burke JM, Doshi G, Melichar B, Kopyltsov E, Alva A, Oudard S, Topart D, Hammers H, Kitamura H, McDermott DF, Silva A, Winquist E, Cornell J, Elfiky A, Burgents JE, Perini RF, Powles T; KEYNOTE-564 Investigators. Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma. N Engl J Med. 2024 Apr 18;390(15):1359-1371. [https://doi.org/10.1056/nejmoa2312695 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38631003/ PubMed]
+==Sunitinib monotherapy {{#subobject:cf6852|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:3c0a01|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 17%" |Study
+! style="width: 15%" |Dates of enrollment
+! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 17%" |Comparator
+! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
+|-
+|[https://doi.org/10.1056/NEJMoa1611406 Ravaud et al. 2016 (S-TRAC)]
+|2007-2011
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[Renal_cell_carcinoma_-_null_regimens#Placebo|Placebo]]
+| style="background-color:#91cf60" |Seems to have superior DFS (primary endpoint)<br>Median DFS: 6.8 vs 5.6 yr<br>(HR 0.76, 95% CI 0.59-0.98)
+| style="background-color:#d73027" |More toxicity
+|-
+|}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#Renal_cell_carcinoma_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====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)'''
+</div></div>
+===References===
+#'''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. [https://doi.org/10.1056/NEJMoa1611406 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27718781/ PubMed] [https://clinicaltrials.gov/study/NCT00375674 NCT00375674]
+##'''Update:''' Motzer RJ, Ravaud A, Patard JJ, Pandha HS, George DJ, Patel A, Chang YH, Escudier B, Donskov F, Magheli A, Carteni G, Laguerre B, Tomczak P, Breza J, Gerletti P, Lechuga M, Lin X, Casey M, Serfass L, Pantuck AJ, Staehler M. Adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy: subgroup analyses and updated overall survival results. Eur Urol. 2018 Jan;73(1):62-68. Epub 2017 Sep 26. [https://doi.org/10.1016/j.eururo.2017.09.008 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6684251/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28967554/ PubMed]
 =Metastatic disease, first-line=
@@ Line 143: / Line 177: @@
 |2016-03-29 to 2017-12-19
 | style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-|[[#Sunitinib_monotherapy|Sunitinib]]
+|[[#Sunitinib_monotherapy_2|Sunitinib]]
 | style="background-color:#1a9850" |Superior overall PFS<sup>1</sup> (secondary endpoint)<br>Median PFS: 13.3 vs 8 mo<br>(HR 0.69, 95% CI 0.57-0.83)<br><br>Superior PFS<sup>2</sup> (primary endpoint)<br>Median PFS: 13.8 vs 7.2 mo<br>(HR 0.61, 95% CI 0.47-0.79)
 |-
@@ Line 194: / Line 228: @@
 | style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 |[[#Sunitinib_monotherapy_2|Sunitinib]]
-| style="background-color:#1a9850" |Superior OS<sup>1</sup> (co-primary endpoint)<br>Median OS: NYR vs 36 mo<br>(HR 0.68, 95% CI 0.55-0.85)
+| style="background-color:#1a9850" |Superior OS<sup>1</sup> (co-primary endpoint)<br>Median OS: NYR vs 36 mo<br>(HR 0.68, 95% CI 0.55-0.85)<br><br>Superior PFS (co-primary endpoint)<br>Median PFS: 15.1 vs 11.1 mo<br>(HR 0.69, 95% CI 0.57-0.84)
 |-
 |}
@@ Line 208: / Line 242: @@
 #'''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. [https://doi.org/10.1056/NEJMoa1816714 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30779529/ PubMed] [https://clinicaltrials.gov/study/NCT02853331 NCT02853331]
 ##'''Update:''' Powles T, Plimack ER, Soulières D, Waddell T, Stus V, Gafanov R, Nosov D, Pouliot F, Melichar B, Vynnychenko I, Azevedo SJ, Borchiellini D, McDermott RS, Bedke J, Tamada S, Yin L, Chen M, Molife LR, Atkins MB, Rini BI. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1563-1573. Epub 2020 Oct 23. Erratum in: Lancet Oncol. 2020 Dec;21(12):e553. [https://doi.org/10.1016/S1470-2045(20)30436-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33284113/ PubMed]
-==Bevacizumab monotherapy {{#subobject:29beb2|Regimen=1}}==
+==Axitinib & Toripalimab {{#subobject:torgac|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:433717|Variant=1}}===
+===Regimen {{#subobject:tora4d|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
 ! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
+! style="width: 20%" | Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2007.11.5154 Bukowski et al. 2007]
+|[https://doi.org/10.1016/j.annonc.2023.09.3108 Yan et al. 2023 (RENOTORCH)]
-|2004
+|2020-08-23 to 2022-09-23
-| style="background-color:#1a9851" |Randomized Phase 2 (C)
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-|[[#Erlotinib_.26_Bevacizumab|Erlotinib & Bevacizumab]]
+|[[#Sunitinib_monotherapy_2|Sunitinib]]
-| style="background-color:#ffffbf" |Did not meet co-primary endpoints of ORR/PFS
+| style="background-color:#1a9850" |Superior OS (secondary endpoint)<br>Median OS: NYR vs 26.8 mo<br>(HR 0.61, 95% CI 0.40-0.92)<br><br>Superior PFS (primary endpoint)<br>Median PFS: 18 vs 9.8 mo<br>(HR 0.65, 95% CI 0.49-0.86)
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
+*[[Axitinib (Inlyta)]] 5 mg PO twice per day
+====Immunotherapy====
+*[[Toripalimab (Loqtorzi)]] as follows:
+**Cycles 1 to 35: 240 mg IV once on day 1
+'''21-day cycles'''
+</div></div>
+===References===
+#'''RENOTORCH:''' Yan XQ, Ye MJ, Zou Q, Chen P, He ZS, Wu B, He DL, He CH, Xue XY, Ji ZG, Chen H, Zhang S, Liu YP, Zhang XD, Fu C, Xu DF, Qiu MX, Lv JJ, Huang J, Ren XB, Cheng Y, Qin WJ, Zhang X, Zhou FJ, Ma LL, Guo JM, Ding DG, Wei SZ, He Y, Guo HQ, Shi BK, Liu L, Liu F, Hu ZQ, Jin XM, Yang L, Zhu SX, Liu JH, Huang YH, Xu T, Liu B, Sun T, Wang ZJ, Jiang HW, Yu DX, Zhou AP, Jiang J, Luan GD, Jin CL, Xu J, Hu JX, Huang YR, Guo J, Zhai W, Sheng XN. Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study. Ann Oncol. 2024 Feb;35(2):190-199. Epub 2023 Oct 21. [https://doi.org/10.1016/j.annonc.2023.09.3108 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37872020/ PubMed] [[https://clinicaltrials.gov/study/NCT04394975 NCT04394975]
+==Bevacizumab monotherapy {{#subobject:29beb2|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:433717|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/jco.2007.11.5154 Bukowski et al. 2007]
+|2004
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
+|[[#Erlotinib_.26_Bevacizumab|Erlotinib & Bevacizumab]]
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of ORR/PFS
 |-
 |}
@@ Line 336: / Line 399: @@
 |2013-2015
 | style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
-|[[#Sunitinib_monotherapy|Sunitinib]]
+|[[#Sunitinib_monotherapy_2|Sunitinib]]
 | style="background-color:#1a9850" |Superior PFS<sup>1</sup> (primary endpoint)<br>Median PFS: 8.6 vs 5.3 mo<br>(HR 0.48, 95% CI 0.31-0.74)
 |-
@@ Line 372: / Line 435: @@
 |2017-2019
 | style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-|[[#Sunitinib_monotherapy|Sunitinib]]
+|[[#Sunitinib_monotherapy_2|Sunitinib]]
-| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 16.6 vs 8.3 mo<br>(HR 0.51, 95% CI 0.41-0.64)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: 37.7 vs 34.3 mo<br>(HR 0.70, 95% CI 0.55-0.90)
+| style="background-color:#1a9850" |Superior PFS<sup>1</sup> (primary endpoint)<br>Median PFS: 16.6 vs 8.4 mo<br>(HR 0.59, 95% CI 0.49-0.71)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: 49.5 vs 35.5 mo<br>(HR 0.70, 95% CI 0.56-0.87)
 |-
 |}
-''<sup>1</sup>Reported efficacy is based on the 2022 update.''
+''<sup>1</sup>Reported efficacy is based on the 2024 update.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ==== Targeted therapy====
@@ Line 382: / Line 445: @@
 ====Immunotherapy====
 *[[Nivolumab (Opdivo)]] as follows:
-** Cycles 1 to 52: 240 mg IV over 30 minutes once on day 1
+**Cycles 1 to 52: 240 mg IV over 30 minutes once on day 1
 '''14-day cycles'''
 </div></div><br>
@@ Line 403: / Line 466: @@
 #'''CheckMate 9ER:''' Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, Oyervides Juárez VM, Hsieh JJ, Basso U, Shah AY, Suárez C, Hamzaj A, Goh JC, Barrios C, Richardet M, Porta C, Kowalyszyn R, Feregrino JP, Żołnierek J, Pook D, Kessler ER, Tomita Y, Mizuno R, Bedke J, Zhang J, Maurer MA, Simsek B, Ejzykowicz F, Schwab GM, Apolo AB, Motzer RJ; CheckMate 9ER Investigators. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841. [https://doi.org/10.1056/nejmoa2026982 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8436591/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33657295/ PubMed] [https://clinicaltrials.gov/study/NCT03141177 NCT03141177]
 ##'''Update:''' Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, Suárez C, Hamzaj A, Porta C, Hocking CM, Kessler ER, Gurney H, Tomita Y, Bedke J, Zhang J, Simsek B, Scheffold C, Apolo AB, Choueiri TK. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Jul;23(7):888-898. Epub 2022 Jun 7. [https://doi.org/10.1016/s1470-2045(22)00290-x link to original article] [https://pubmed.ncbi.nlm.nih.gov/35688173/ PubMed]
+##'''Update:''' Powles T, Burotto M, Escudier B, Apolo AB, Bourlon MT, Shah AY, Suárez C, Porta C, Barrios CH, Richardet M, Gurney H, Kessler ER, Tomita Y, Bedke J, George S, Scheffold C, Wang P, Fedorov V, Motzer RJ, Choueiri TK. Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial. ESMO Open. 2024 May;9(5):102994. Epub 2024 Apr 20. [https://doi.org/10.1016/j.esmoop.2024.102994 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc11046044/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/38642472/ PubMed]
 ==Cabozantinib, Ipilimumab, Nivolumab {{#subobject:tsrnqw|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
@@ Line 413: / Line 478: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc102578986/ Choueiri et al. 2023 (COSMIC-313)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc102578986/ Choueiri et al. 2023 (COSMIC-313)]
 |2019-2022
 | style="background-color:#1a9851" |Phase 3 (E-esc)
@@ Line 435: / Line 500: @@
 </div></div>
 ===References===
-#'''COSMIC-313:''' Choueiri TK, Powles T, Albiges L, Burotto M, Szczylik C, Zurawski B, Yanez Ruiz E, Maruzzo M, Suarez Zaizar A, Fein LE, Schutz FA, Heng DYC, Wang F, Mataveli F, Chang YL, van Kooten Losio M, Suarez C, Motzer RJ; COSMIC-313 Investigators. Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. N Engl J Med. 2023 May 11;388(19):1767-1778. [https://doi.org/10.1056/nejmoa2212851 link to original article] '''contains dosing details in abstract''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc102578986/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37163623/ PubMed] [https://clinicaltrials.gov/study/NCT03937219 NCT03937219]
+#'''COSMIC-313:''' Choueiri TK, Powles T, Albiges L, Burotto M, Szczylik C, Zurawski B, Yanez Ruiz E, Maruzzo M, Suarez Zaizar A, Fein LE, Schutz FA, Heng DYC, Wang F, Mataveli F, Chang YL, van Kooten Losio M, Suarez C, Motzer RJ; COSMIC-313 Investigators. Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. N Engl J Med. 2023 May 11;388(19):1767-1778. [https://doi.org/10.1056/nejmoa2212851 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc102578986/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37163623/ PubMed] [https://clinicaltrials.gov/study/NCT03937219 NCT03937219]
 ==Erlotinib & Bevacizumab {{#subobject:1a1b7b|Regimen=1}}==
@@ Line 495: / Line 560: @@
 #'''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. [https://doi.org/10.1056/NEJMoa2035716 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33616314/ PubMed] [https://clinicaltrials.gov/study/NCT02811861 NCT02811861]
 ##'''Update:''' Choueiri TK, Eto M, Motzer R, De Giorgi U, Buchler T, Basappa NS, Méndez-Vidal MJ, Tjulandin S, Hoon Park S, Melichar B, Hutson T, Alemany C, McGregor B, Powles T, Grünwald V, Alekseev B, Rha SY, Kopyltsov E, Kapoor A, Alonso Gordoa T, Goh JC, Staehler M, Merchan JR, Xie R, Perini RF, Mody K, McKenzie J, Porta CG. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol. 2023 Mar;24(3):228-238. Erratum in: Lancet Oncol. 2023 Apr;24(4):e146. [https://doi.org/10.1016/s1470-2045(23)00049-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36858721/ PubMed]
-==Ipilimumab & Nivolumab {{#subobject:7bc416|Regimen=1}}==
+##'''Update:''' Motzer RJ, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Alekseev B, Rha SY, Merchan J, Goh JC, Lalani AA, De Giorgi U, Melichar B, Hong SH, Gurney H, Méndez-Vidal MJ, Kopyltsov E, Tjulandin S, Gordoa TA, Kozlov V, Alyasova A, Winquist E, Maroto P, Kim M, Peer A, Procopio G, Takagi T, Wong S, Bedke J, Schmidinger M, Rodriguez-Lopez K, Burgents J, He C, Okpara CE, McKenzie J, Choueiri TK; CLEAR Trial Investigators. Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study. J Clin Oncol. 2024 Apr 10;42(11):1222-1228. Epub 2024 Jan 16. [https://doi.org/10.1200/jco.23.01569 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38227898/ PubMed]
+==Gemcitabine & Sunitinib {{#subobject:ec76af|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:e9a6b9|Variant=1}}===
+{| class="wikitable" style="width: 40%; text-align:center;"
+! style="width: 50%" |Study
+! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1111/j.1464-410X.2011.10096.x Pandya et al. 2011]
+| style="background-color:#ffffbe" |Retrospective
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Gemcitabine (Gemzar)]] 750 mg/m<sup>2</sup> 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'''
+</div></div>
+===References===
+#'''Retrospective:''' Pandya SS, Mier JW, McDermott DF, Cho DC. Addition of gemcitabine at the time of sunitinib resistance in metastatic renal cell cancer. BJU Int. 2011 Oct;108(8 Pt 2):E245-9. Epub 2011 Feb 14. [https://doi.org/10.1111/j.1464-410X.2011.10096.x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21320274/ PubMed] [move]
+==Interferon alfa-2a monotherapy {{#subobject:8f04d6|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1 {{#subobject:aa43c1|Variant=1}}===
+===Regimen variant #1, 9 MU TIW {{#subobject:524ccc|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 505: / Line 593: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5972549/ Motzer et al. 2018 (CheckMate 214)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651074/ Rini et al. 2008 (CALGB 90206)]
-<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|2003-2005
-|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-117-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Bevacizumab_.26_Interferon_alfa-2a|Bevacizumab & Interferon alfa-2a]]
+| style="background-color:#fee08b" |Might have inferior OS<sup>1</sup>
+|-
+|[https://doi.org/10.1016/S0140-6736(07)61904-7 Escudier et al. 2007 (AVOREN)]
+|2004-06 to 2005-10
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Bevacizumab_.26_Interferon_alfa-2a|Bevacizumab & Interferon alfa-2a]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<sup>2</sup>
 |-
-|} -->
+|[https://doi.org/10.1200/jco.2008.19.3342 Escudier et al. 2009 (Bayer 11848)]
-|2014-2016
+|2005-06-28 to 2005-09-30
-| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
-|[[#Sunitinib_monotherapy_2|Sunitinib]]
+|[[#Sorafenib_monotherapy|Sorafenib]]
-| style="background-color:#1a9850" |Superior OS<sup>1</sup> (co-primary endpoint)<br>OS42: 56% vs 47%<br>(HR 0.72, 95% CI 0.61-0.86)
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
 |}
-''<sup>1</sup>Reported efficacy is for the ITT population per the 2020 update.''<br>
+''<sup>1</sup>Reported efficacy for CALGB 90206 is based on the 2010 update and is based on a stratified analysis.''<br>
-''Note: while this is the dosing studied in CheckMate 214, it is not the FDA-recommended dosing.''
+''<sup>2</sup>Reported efficacy for AVOREN is based on the 2010 update.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
-*[[Ipilimumab (Yervoy)]] as follows:
+*[[Interferon alfa-2a (Roferon-A)]] 9,000,000 units SC once per day on days 1, 3, 5 (3 times per week)
-**Cycles 1 to 4: 1 mg/kg IV over 30 minutes once on day 1
+'''7-day cycles'''
-*[[Nivolumab (Opdivo)]] 3 mg/kg IV over 60 minutes once on day 1
+</div>
-'''21-day cycle for 4 cycles, then 14-day cycles'''
+<div class="toccolours" style="background-color:#fff2ae">
+====Dose and schedule modifications====
+*Some protocols: Dose can be reduced to 3,000,000 or 6,000,000 units SC 3 times per week based on tolerability
 </div></div><br>
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2 {{#subobject:2fc613|Variant=1}}===
+===Regimen variant #2, 9 MU TIW, with lead-in {{#subobject:2c65a4|Variant=1}}===
-{| class="wikitable" style="color:white; background-color:#404040"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-|<small>'''FDA-recommended dose'''</small>
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|}
+|[https://doi.org/10.1056/NEJMoa065044 Motzer et al. 2007 (A618-1034)]
-''Note: while this one of two FDA-recommended dosing options, we are not aware of any particular published trial using this dosing.''
+|2004-08 to 2005-10
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Sunitinib_monotherapy_2|Sunitinib]]
+| style="background-color:#d73027" |Inferior PFS
+|-
+|}
+''Note: Interferon alfa-2a dose was increased only if the prior dose was tolerated.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
-*[[Ipilimumab (Yervoy)]] as follows:
+*[[Interferon alfa-2a (Roferon-A)]] as follows:
-** Cycles 1 to 4: 1 mg/kg IV once on day 1, '''given second'''
+**Cycle 1: 3,000,000 units SC once per day on days 1, 3, 5
-*[[Nivolumab (Opdivo)]] as follows:
+**Cycle 2: 6,000,000 units SC once per day on days 1, 3, 5
-**Cycles 1 to 4: 3 mg/kg IV once on day 1, '''given first'''
+**Cycle 3 onwards: 9,000,000 units SC once per day on days 1, 3, 5
-**Cycle 5 onwards: 240 mg IV once on day 1
+'''7-day cycles'''
-'''21-day cycle for 4 cycles, then 14-day cycles'''
+</div></div>
-</div></div><br>
+===References===
+#'''A618-1034:''' Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. [https://doi.org/10.1056/NEJMoa065044 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17215529/ PubMed] [https://clinicaltrials.gov/study/NCT00083889 NCT00083889]
+##'''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. [https://doi.org/10.1200/jco.2008.20.1293 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646307/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19487381/ PubMed] content property of [https://hemonc.org HemOnc.org]
+##'''HRQoL analysis:''' Cella D, Michaelson MD, Bushmakin AG, Cappelleri JC, Charbonneau C, Kim ST, Li JZ, Motzer RJ. Health-related quality of life in patients with metastatic renal cell carcinoma treated with sunitinib vs interferon-alpha in a phase III trial: final results and geographical analysis. Br J Cancer. 2010 Feb 16;102(4):658-64. Epub 2010 Jan 26. [https://doi.org/10.1038/sj.bjc.6605552 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2837567/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20104222/ PubMed]
+#'''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. [https://doi.org/10.1016/S0140-6736(07)61904-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18156031/ PubMed] [https://clinicaltrials.gov/study/NCT00738530 NCT00738530]
+##'''Update:''' Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, Sneller V. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010 May 1;28(13):2144-50. Epub 2010 Apr 5. [https://doi.org/10.1200/jco.2009.26.7849 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20368553/ PubMed]
+#'''CALGB 90206:''' Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008 Nov 20;26(33):5422-8. Epub 2008 Oct 20. [https://doi.org/10.1200/jco.2008.16.9847 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651074/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18936475/ PubMed] [https://clinicaltrials.gov/study/NCT00072046 NCT00072046]
+##'''Update:''' Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010 May 1;28(13):2137-43. Epub 2010 Apr 5. [https://doi.org/10.1200/jco.2009.26.5561 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860433/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20368558/ PubMed]
+#'''Bayer 11848:''' Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, Negrier S, Laferriere N, Scheuring UJ, Cella D, Shah S, Bukowski RM. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Mar 10;27(8):1280-9. Epub 2009 Jan 26. Erratum in: J Clin Oncol. 2009 May 1; 27(13):2305. [https://doi.org/10.1200/jco.2008.19.3342 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19171708/ PubMed] [https://clinicaltrials.gov/study/NCT00117637 NCT00117637]
+==High-dose Interleukin-2 {{#subobject:d95f4e|Regimen=1}}==
+HD IL-2: '''<u>H</u>'''igh-'''<u>D</u>'''ose '''<u>I</u>'''nter'''<u>L</u>'''eukin-'''<u>2</u>'''
+===Example orders===
+*[[Example orders for High-dose (HD) IL-2 in renal cancer]]
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #3 {{#subobject:1d722d|Variant=1}}===
+===Regimen {{#subobject:9a662|Variant=1}}===
-{| class="wikitable" style="color:white; background-color:#404040"
+{| class="wikitable" style="width: 40%; text-align:center;"
-|<small>'''FDA-recommended dose'''</small>
+! style="width: 50%" |Study
+! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486432/ Klapper et al. 2008]
+| style="background-color:#ffffbe" |Retrospective
 |-
 |}
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
+<div class="toccolours" style="background-color:#b3e2cd">
-! style="width: 20%" |Study
+====Immunotherapy====
+*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours for up to 12 doses (reduced from originally up to 15 doses due to few patients tolerating 15 doses)
+====Supportive therapy====
+*"Routine administration of antipyretics, anti-inflammatories, antiemetics, antidiarrheals, and H2 antagonists."
+'''14- to 19-day cycle for 2 cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====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)
+</div></div>
+===References===
+#'''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. [https://doi.org/10.1002/cncr.23552 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486432/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18457330/ PubMed]
+==Ipilimumab & Nivolumab {{#subobject:7bc416|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1 {{#subobject:aa43c1|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
 ! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
@@ Line 554: / Line 696: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc102578986/ Choueiri et al. 2023 (COSMIC-313)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5972549/ Motzer et al. 2018 (CheckMate 214)]
-|2019-2022
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-| style="background-color:#1a9851" |Phase 3 (C)
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-117-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
-|[[#Cabozantinib.2C_Ipilimumab.2C_Nivolumab|Cabozantinib, Ipilimumab, Nivolumab]]
+|-
-| style="background-color:#d73027" |Inferior PFS (primary endpoint)
+|} -->
+|2014-2016
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+|[[#Sunitinib_monotherapy_2|Sunitinib]]
+| style="background-color:#1a9850" |Superior OS<sup>1</sup> (co-primary endpoint)<br>OS42: 56% vs 47%<br>(HR 0.72, 95% CI 0.61-0.86)
 |-
 |}
-''Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
+''<sup>1</sup>Reported efficacy is for the ITT population per the 2020 update.''<br>
+''Note: while this is the dosing studied in CheckMate 214, it is not the FDA-recommended dosing.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
 *[[Ipilimumab (Yervoy)]] as follows:
-**Cycles 1 to 4: 1 mg/kg IV once on day 1, '''given second'''
+**Cycles 1 to 4: 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, then 14-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2 {{#subobject:2fc613|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
+|-
+|}
+''Note: while this one of two FDA-recommended dosing options, we are not aware of any particular published trial using this dosing.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Ipilimumab (Yervoy)]] as follows:
+** Cycles 1 to 4: 1 mg/kg IV once on day 1, '''given second'''
 *[[Nivolumab (Opdivo)]] as follows:
 **Cycles 1 to 4: 3 mg/kg IV once on day 1, '''given first'''
-**Cycles 5 up to 30: 480 mg IV once on day 1
+**Cycle 5 onwards: 240 mg IV once on day 1
-'''21-day cycle for 4 cycles, then 28-day cycle for up to 26 cycles (2 years)'''
+'''21-day cycle for 4 cycles, then 14-day cycles'''
-</div></div>
+</div></div><br>
-===References===
+<div class="toccolours" style="background-color:#eeeeee">
-#'''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. [https://doi.org/10.1056/NEJMoa1712126 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5972549/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29562145/ PubMed] [https://clinicaltrials.gov/study/NCT02231749 NCT02231749]
+===Regimen variant #3 {{#subobject:1d722d|Variant=1}}===
-##'''PRO analysis:''' Cella D, Grünwald V, Escudier B, Hammers HJ, George S, Nathan P, Grimm MO, Rini BI, Doan J, Ivanescu C, Paty J, Mekan S, Motzer RJ. Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial. Lancet Oncol. 2019 Feb;20(2):297-310. Epub 2019 Jan 15. Erratum in: Lancet Oncol. 2019 Jun;20(6):e293. [https://doi.org/10.1016/s1470-2045(18)30778-2 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6701190/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30658932/ PubMed]
+{| class="wikitable" style="color:white; background-color:#404040"
-##'''Update:''' Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, Salman P, Escudier B, Beuselinck B, Amin A, Porta C, George S, Neiman V, Bracarda S, Tykodi SS, Barthélémy P, Leibowitz-Amit R, Plimack ER, Oosting SF, Redman B, Melichar B, Powles T, Nathan P, Oudard S, Pook D, Choueiri TK, Donskov F, Grimm MO, Gurney H, Heng DYC, Kollmannsberger CK, Harrison MR, Tomita Y, Duran I, Grünwald V, McHenry MB, Mekan S, Tannir NM; CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019 Oct;20(10):1370-1385. Epub 2019 Aug 16. Erratum in: Lancet Oncol. 2019 Aug 21. [https://doi.org/10.1016/S1470-2045(19)30413-9 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7497870/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31427204/ PubMed]
+|<small>'''FDA-recommended dose'''</small>
-##'''Update:''' Motzer RJ, Escudier B, McDermott DF, Arén Frontera O, Melichar B, Powles T, Donskov F, Plimack ER, Barthélémy P, Hammers HJ, George S, Grünwald V, Porta C, Neiman V, Ravaud A, Choueiri TK, Rini BI, Salman P, Kollmannsberger CK, Tykodi SS, Grimm MO, Gurney H, Leibowitz-Amit R, Geertsen PF, Amin A, Tomita Y, McHenry MB, Saggi SS, Tannir NM. Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer. 2020 Jul;8(2):e000891. Erratum in: J Immunother Cancer. 2021 May;9(5). [https://doi.org/10.1136/jitc-2020-000891 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7359377/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32661118/ PubMed]
+|-
-##'''Update:''' Albiges L, Tannir NM, Burotto M, McDermott D, Plimack ER, Barthélémy P, Porta C, Powles T, Donskov F, George S, Kollmannsberger CK, Gurney H, Grimm MO, Tomita Y, Castellano D, Rini BI, Choueiri TK, Saggi SS, McHenry MB, Motzer RJ. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020 Nov;5(6):e001079. [https://doi.org/10.1136/esmoopen-2020-001079 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7703447/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33246931/ PubMed]
+|}
-#'''COSMIC-313:''' Choueiri TK, Powles T, Albiges L, Burotto M, Szczylik C, Zurawski B, Yanez Ruiz E, Maruzzo M, Suarez Zaizar A, Fein LE, Schutz FA, Heng DYC, Wang F, Mataveli F, Chang YL, van Kooten Losio M, Suarez C, Motzer RJ; COSMIC-313 Investigators. Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. N Engl J Med. 2023 May 11;388(19):1767-1778. [https://doi.org/10.1056/nejmoa2212851 link to original article] '''contains dosing details in abstract''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc102578986/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37163623/ PubMed] [https://clinicaltrials.gov/study/NCT03937219 NCT03937219]
-#'''PDIGREE:''' [https://clinicaltrials.gov/study/NCT03793166 NCT03793166]
-==Lenvatinib & Pembrolizumab {{#subobject:e83gac|Regimen=1}}==
-<div class="toccolours" style="background-color:#eeeeee">
-=== Regimen variant #1 {{#subobject:22bc4d|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 590: / Line 745: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-| rowspan="2" |[https://doi.org/10.1056/NEJMoa2035716 Motzer et al. 2021 (CLEAR)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc102578986/ Choueiri et al. 2023 (COSMIC-313)]
-<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|2019-2022
-|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-284-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
+| style="background-color:#1a9851" |Phase 3 (C)
-|-
+|[[#Cabozantinib.2C_Ipilimumab.2C_Nivolumab|Cabozantinib, Ipilimumab, Nivolumab]]
-|} -->
+| style="background-color:#d73027" |Inferior PFS (primary endpoint)
-| rowspan="2" |2016-10-13 to 2019-07-24
-| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-| 1. [[#Everolimus_.26_Lenvatinib|Everolimus & Lenvatinib]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-|2. [[#Sunitinib_monotherapy_2|Sunitinib]]
-| style="background-color:#1a9850" |Superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: NYR vs NYR<br>(HR 0.72, 95% CI 0.55-0.93)
 |-
 |}
-''<sup>1</sup>Reported efficacy is based on the 2023 update.''
+''Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 <div class="toccolours" style="background-color:#b3e2cd">
-==== Targeted therapy====
-*[[Lenvatinib (Lenvima)]] 20 mg PO once per day on days 1 to 21
 ====Immunotherapy====
-*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
+*[[Ipilimumab (Yervoy)]] as follows:
-'''21-day cycles'''
+**Cycles 1 to 4: 1 mg/kg IV once on day 1, '''given second'''
-</div></div><br>
+*[[Nivolumab (Opdivo)]] as follows:
+**Cycles 1 to 4: 3 mg/kg IV once on day 1, '''given first'''
+**Cycles 5 up to 30: 480 mg IV once on day 1
+'''21-day cycle for 4 cycles, then 28-day cycle for up to 26 cycles (2 years)'''
+</div></div>
+===References===
+#'''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. [https://doi.org/10.1056/NEJMoa1712126 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5972549/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29562145/ PubMed] [https://clinicaltrials.gov/study/NCT02231749 NCT02231749]
+##'''PRO analysis:''' Cella D, Grünwald V, Escudier B, Hammers HJ, George S, Nathan P, Grimm MO, Rini BI, Doan J, Ivanescu C, Paty J, Mekan S, Motzer RJ. Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial. Lancet Oncol. 2019 Feb;20(2):297-310. Epub 2019 Jan 15. Erratum in: Lancet Oncol. 2019 Jun;20(6):e293. [https://doi.org/10.1016/s1470-2045(18)30778-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6701190/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30658932/ PubMed]
+##'''Update:''' Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, Salman P, Escudier B, Beuselinck B, Amin A, Porta C, George S, Neiman V, Bracarda S, Tykodi SS, Barthélémy P, Leibowitz-Amit R, Plimack ER, Oosting SF, Redman B, Melichar B, Powles T, Nathan P, Oudard S, Pook D, Choueiri TK, Donskov F, Grimm MO, Gurney H, Heng DYC, Kollmannsberger CK, Harrison MR, Tomita Y, Duran I, Grünwald V, McHenry MB, Mekan S, Tannir NM; CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019 Oct;20(10):1370-1385. Epub 2019 Aug 16. Erratum in: Lancet Oncol. 2019 Aug 21. [https://doi.org/10.1016/S1470-2045(19)30413-9 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7497870/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31427204/ PubMed]
+##'''Update:''' Motzer RJ, Escudier B, McDermott DF, Arén Frontera O, Melichar B, Powles T, Donskov F, Plimack ER, Barthélémy P, Hammers HJ, George S, Grünwald V, Porta C, Neiman V, Ravaud A, Choueiri TK, Rini BI, Salman P, Kollmannsberger CK, Tykodi SS, Grimm MO, Gurney H, Leibowitz-Amit R, Geertsen PF, Amin A, Tomita Y, McHenry MB, Saggi SS, Tannir NM. Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer. 2020 Jul;8(2):e000891. Erratum in: J Immunother Cancer. 2021 May;9(5). [https://doi.org/10.1136/jitc-2020-000891 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7359377/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32661118/ PubMed]
+##'''Update:''' Albiges L, Tannir NM, Burotto M, McDermott D, Plimack ER, Barthélémy P, Porta C, Powles T, Donskov F, George S, Kollmannsberger CK, Gurney H, Grimm MO, Tomita Y, Castellano D, Rini BI, Choueiri TK, Saggi SS, McHenry MB, Motzer RJ. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020 Nov;5(6):e001079. [https://doi.org/10.1136/esmoopen-2020-001079 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7703447/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33246931/ PubMed]
+#'''COSMIC-313:''' Choueiri TK, Powles T, Albiges L, Burotto M, Szczylik C, Zurawski B, Yanez Ruiz E, Maruzzo M, Suarez Zaizar A, Fein LE, Schutz FA, Heng DYC, Wang F, Mataveli F, Chang YL, van Kooten Losio M, Suarez C, Motzer RJ; COSMIC-313 Investigators. Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. N Engl J Med. 2023 May 11;388(19):1767-1778. [https://doi.org/10.1056/nejmoa2212851 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc102578986/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37163623/ PubMed] [https://clinicaltrials.gov/study/NCT03937219 NCT03937219]
+#'''PDIGREE:''' [https://clinicaltrials.gov/study/NCT03793166 NCT03793166]
+==Lenvatinib & Pembrolizumab {{#subobject:e83gac|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2 {{#subobject:22bug8|Variant=1}}===
+=== Regimen variant #1 {{#subobject:22bc4d|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 621: / Line 781: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.clinicaltrials.gov/study/NCT04736706 Awaiting publication (MK-6482-012)]
+| rowspan="2" |[https://doi.org/10.1056/NEJMoa2035716 Motzer et al. 2021 (CLEAR)]
-|2021-ongoing
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-| style="background-color:#1a9851" |Phase 3 (C)
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-284-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
-|1. [[#Belzutifan.2C_Lenvatinib.2C_Pembrolizumab_666|Belzutifan, Lenvatinib, Pembrolizumab]]<br>2. [[#Lenvatinib.2C_Pembrolizumab.2C_Quavonlimab_777|Lenvatinib, Pembrolizumab, Quavonlimab]]
+|-
-| style="background-color:#d3d3d3" |TBD if different co-primary endpoints of PFS/OS
+|} -->
+| rowspan="2" |2016-10-13 to 2019-07-24
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+| 1. [[#Everolimus_.26_Lenvatinib|Everolimus & Lenvatinib]]
+| style="background-color:#d3d3d3" |Not reported
+|-
+|2. [[#Sunitinib_monotherapy_2|Sunitinib]]
+| style="background-color:#1a9850" |Superior PFS<sup>1</sup> (primary endpoint)<br>Median PFS: 23.9 vs 9.2 mo<br>(HR 0.47, 95% CI 0.38-0.57)<br><br>Seems to have superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: 53.7 vs 54.3<br>(HR 0.79, 95% CI 0.63-0.99)
 |-
 |}
+''<sup>1</sup>Reported efficacy is based on the 2024 update.''
 <div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+==== Targeted therapy====
-*[[Lenvatinib (Lenvima)]] 20 mg PO once per day on days 1 to 42
+*[[Lenvatinib (Lenvima)]] 20 mg PO once per day on days 1 to 21
 ====Immunotherapy====
-*[[Pembrolizumab (Keytruda)]] as follows:
+*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
-**Cycles 1 to 18: 400 mg IV once on day 1
+'''21-day cycles'''
-'''42-day cycles'''
+</div></div><br>
-</div></div>
-===References===
-#'''CLEAR:''' Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. [https://doi.org/10.1056/NEJMoa2035716 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33616314/ PubMed] [https://clinicaltrials.gov/study/NCT02811861 NCT02811861]
-##'''Update:''' Choueiri TK, Eto M, Motzer R, De Giorgi U, Buchler T, Basappa NS, Méndez-Vidal MJ, Tjulandin S, Hoon Park S, Melichar B, Hutson T, Alemany C, McGregor B, Powles T, Grünwald V, Alekseev B, Rha SY, Kopyltsov E, Kapoor A, Alonso Gordoa T, Goh JC, Staehler M, Merchan JR, Xie R, Perini RF, Mody K, McKenzie J, Porta CG. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol. 2023 Mar;24(3):228-238. Erratum in: Lancet Oncol. 2023 Apr;24(4):e146. [https://doi.org/10.1016/s1470-2045(23)00049-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36858721/ PubMed]
-#'''MK-6482-012:''' [https://clinicaltrials.gov/study/NCT04736706 NCT04736706]
-==Pazopanib monotherapy {{#subobject:443024|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:d6c07c|Variant=1}}===
+===Regimen variant #2 {{#subobject:22bug8|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
 ! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" | Comparator
+! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/jco.2008.21.6994 Hutson et al. 2009 (VEG102616)]
+|[https://www.clinicaltrials.gov/study/NCT04736706 Awaiting publication (MK-6482-012)]
-|2005-10 to 2006-09
+|2021-ongoing
-| style="background-color:#91cf61" |Phase 2
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#d3d3d3" |
+|1. [[#Belzutifan.2C_Lenvatinib.2C_Pembrolizumab_666|Belzutifan, Lenvatinib, Pembrolizumab]]<br>2. [[#Lenvatinib.2C_Pembrolizumab.2C_Quavonlimab_777|Lenvatinib, Pembrolizumab, Quavonlimab]]
-| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |TBD if different co-primary endpoints of PFS/OS
 |-
-|[https://doi.org/10.1200/jco.2009.23.9764 Sternberg et al. 2010 (VEG105192)]
+|}
-<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+<div class="toccolours" style="background-color:#b3e2cd">
-|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-109-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
+====Targeted therapy====
-|-
+*[[Lenvatinib (Lenvima)]] 20 mg PO once per day on days 1 to 42
-|} -->
+====Immunotherapy====
-|2006-04 to 2007-04
+*[[Pembrolizumab (Keytruda)]] as follows:
-| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+**Cycles 1 to 18: 400 mg IV once on day 1
-|[[Clear_cell_renal_cell_carcinoma_-_null_regimens#Placebo_2|Placebo]]
+'''42-day cycles'''
-| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 9.2 vs 4.2 mo<br>(HR 0.46, 95% CI 0.34-0.62)<br><br>Did not meet secondary endpoint of OS<sup>1</sup><br>Median OS: 22.9 vs 20.5 mo<br>(HR 0.91, 95% CI 0.71-1.16)
+</div></div>
+===References===
+#'''CLEAR:''' Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. [https://doi.org/10.1056/NEJMoa2035716 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33616314/ PubMed] [https://clinicaltrials.gov/study/NCT02811861 NCT02811861]
+##'''Update:''' Choueiri TK, Eto M, Motzer R, De Giorgi U, Buchler T, Basappa NS, Méndez-Vidal MJ, Tjulandin S, Hoon Park S, Melichar B, Hutson T, Alemany C, McGregor B, Powles T, Grünwald V, Alekseev B, Rha SY, Kopyltsov E, Kapoor A, Alonso Gordoa T, Goh JC, Staehler M, Merchan JR, Xie R, Perini RF, Mody K, McKenzie J, Porta CG. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol. 2023 Mar;24(3):228-238. Erratum in: Lancet Oncol. 2023 Apr;24(4):e146. [https://doi.org/10.1016/s1470-2045(23)00049-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36858721/ PubMed]
+##'''Update:''' Motzer RJ, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Alekseev B, Rha SY, Merchan J, Goh JC, Lalani AA, De Giorgi U, Melichar B, Hong SH, Gurney H, Méndez-Vidal MJ, Kopyltsov E, Tjulandin S, Gordoa TA, Kozlov V, Alyasova A, Winquist E, Maroto P, Kim M, Peer A, Procopio G, Takagi T, Wong S, Bedke J, Schmidinger M, Rodriguez-Lopez K, Burgents J, He C, Okpara CE, McKenzie J, Choueiri TK; CLEAR Trial Investigators. Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study. J Clin Oncol. 2024 Apr 10;42(11):1222-1228. Epub 2024 Jan 16. [https://doi.org/10.1200/jco.23.01569 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38227898/ PubMed]
+#'''MK-6482-012:''' [https://clinicaltrials.gov/study/NCT04736706 NCT04736706]
+==Pazopanib monotherapy {{#subobject:443024|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:d6c07c|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" | Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/jco.2008.21.6994 Hutson et al. 2009 (VEG102616)]
+|2005-10 to 2006-09
+| style="background-color:#91cf61" |Phase 2
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
 |-
-|[https://doi.org/10.1056/NEJMoa1303989 Motzer et al. 2013 (COMPARZ)]
+|[https://doi.org/10.1200/jco.2009.23.9764 Sternberg et al. 2010 (VEG105192)]
 <!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-105-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-109-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
+|-
+|} -->
+|2006-04 to 2007-04
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[Clear_cell_renal_cell_carcinoma_-_null_regimens#Placebo_2|Placebo]]
+| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 9.2 vs 4.2 mo<br>(HR 0.46, 95% CI 0.34-0.62)<br><br>Did not meet secondary endpoint of OS<sup>1</sup><br>Median OS: 22.9 vs 20.5 mo<br>(HR 0.91, 95% CI 0.71-1.16)
+|-
+|[https://doi.org/10.1056/NEJMoa1303989 Motzer et al. 2013 (COMPARZ)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-105-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
 |-
 |} -->
 |2008-2011
 | style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|[[#Sunitinib_monotherapy|Sunitinib]]
+|[[#Sunitinib_monotherapy_2|Sunitinib]]
 | style="background-color:#eeee01" |Non-inferior PFS (primary endpoint)<br>Median PFS: 8.4 vs 9.5 mo<br>(HR 1.05, 95% CI 0.90-1.22)
 |-
@@ Line 686: / Line 878: @@
 |2012-01-13 to 2017-09-12
 | style="background-color:#1a9851" |Phase 2/3 (C)
-|1a. [[#Pazopanib_monotherapy|Pazopanib]] x 2 y, then treatment-free interval<br>1b. [[#Sunitinib_monotherapy|Sunitinib]] x 2 y, then treatment-free interval
+|1a. [[#Pazopanib_monotherapy|Pazopanib]] x 2 y, then treatment-free interval<br>1b. [[#Sunitinib_monotherapy_2|Sunitinib]] x 2 y, then treatment-free interval
 | style="background-color:#ffffbf" |Inconclusive whether non-inferior OS (co-primary endpoint)
 |-
@@ Line 706: / Line 898: @@
 #'''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. [https://doi.org/10.1056/NEJMoa1303989 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23964934/ PubMed] [https://clinicaltrials.gov/study/NCT00720941 NCT00720941]
 ##'''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. [https://doi.org/10.1056/NEJMc1400731 link to letter] [https://pubmed.ncbi.nlm.nih.gov/24785224/ PubMed]
-#'''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. [https://doi.org/10.1200/JCO.2013.50.8267 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24687826/ PubMed] [https://clinicaltrials.gov/study/NCT01064310 NCT01064310]
+#'''PISCES:''' Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U, Parikh O, Hawkins R, Sevin E, Négrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol. 2014 May 10;32(14):1412-8. Epub 2014 Mar 31. [https://doi.org/10.1200/JCO.2013.50.8267 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24687826/ PubMed] [https://clinicaltrials.gov/study/NCT01064310 NCT01064310]
 #'''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. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2588465 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27918762/ PubMed] [https://clinicaltrials.gov/study/NCT01408004 NCT01408004]
 #'''STAR:''' Brown JE, Royle KL, Gregory W, Ralph C, Maraveyas A, Din O, Eisen T, Nathan P, Powles T, Griffiths R, Jones R, Vasudev N, Wheater M, Hamid A, Waddell T, McMenemin R, Patel P, Larkin J, Faust G, Martin A, Swain J, Bestall J, McCabe C, Meads D, Goh V, Min Wah T, Brown J, Hewison J, Selby P, Collinson F; STAR Investigators. Temporary treatment cessation versus continuation of first-line tyrosine kinase inhibitor in patients with advanced clear cell renal cell carcinoma (STAR): an open-label, non-inferiority, randomised, controlled, phase 2/3 trial. Lancet Oncol. 2023 Mar;24(3):213-227. Epub 2023 Feb 13. [https://doi.org/10.1016/s1470-2045(22)00793-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36796394/ PubMed] ISRCTN06473203
@@ Line 719: / Line 911: @@
 !style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8078336/ McDermott et al. 2021 (KEYNOTE-427)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8078336/ McDermott et al. 2021 (KEYNOTE-427<sub>ccRCC</sub>)]
 |2016-NR
 | style="background-color:#91cf61" |Phase 2
@@ Line 725: / Line 917: @@
 |-
 |}
-''Note: this reference describes the clear cell cohort of KEYNOTE-427.''
+''Note: this reference described the clear cell cohort of KEYNOTE-427.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
@@ Line 732: / Line 924: @@
 </div></div>
 ===References===
-#'''KEYNOTE-427:''' McDermott DF, Lee JL, Bjarnason GA, Larkin JMG, Gafanov RA, Kochenderfer MD, Jensen NV, Donskov F, Malik J, Poprach A, Tykodi SS, Alonso-Gordoa T, Cho DC, Geertsen PF, Climent Duran MA, DiSimone C, Silverman RK, Perini RF, Schloss C, Atkins MB. Open-Label, Single-Arm Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Clear Cell Renal Cell Carcinoma. J Clin Oncol. 2021 Mar 20;39(9):1020-1028. Epub 2021 Feb 2. [https://doi.org/10.1200/jco.20.02363 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8078336/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33529051/ PubMed] [https://clinicaltrials.gov/study/NCT02853344 NCT02853344]
+#'''KEYNOTE-427<sub>ccRCC</sub>:''' McDermott DF, Lee JL, Bjarnason GA, Larkin JMG, Gafanov RA, Kochenderfer MD, Jensen NV, Donskov F, Malik J, Poprach A, Tykodi SS, Alonso-Gordoa T, Cho DC, Geertsen PF, Climent Duran MA, DiSimone C, Silverman RK, Perini RF, Schloss C, Atkins MB. Open-Label, Single-Arm Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Clear Cell Renal Cell Carcinoma. J Clin Oncol. 2021 Mar 20;39(9):1020-1028. Epub 2021 Feb 2. [https://doi.org/10.1200/jco.20.02363 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8078336/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33529051/ PubMed] [https://clinicaltrials.gov/study/NCT02853344 NCT02853344]
 ==Regorafenib monotherapy {{#subobject:183793|Regimen=1}}==
@@ Line 765: / Line 957: @@
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/jco.2008.19.3342 Escudier et al. 2009 (Bayer 11848)]
+|2005-06-28 to 2005-09-30
+| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ooc)
+|[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569677/ Motzer et al. 2013 (TIVO-1)]
@@ Line 777: / Line 975: @@
 |[[#Axitinib_monotherapy|Axitinib]]
 | style="background-color:#fee08b" |Might have inferior PFS<sup>1</sup>
+|-
+|[https://doi.org/10.1016/j.clgc.2020.01.001 Tomita et al. 2020 (CROSS-J-RCC)]
+|2010-2012
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[#Sunitinib_monotherapy_2|Sunitinib]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
 |}
@@ Line 790: / Line 994: @@
 </div></div>
 ===References===
+#'''Bayer 11848:''' Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, Negrier S, Laferriere N, Scheuring UJ, Cella D, Shah S, Bukowski RM. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Mar 10;27(8):1280-9. Epub 2009 Jan 26. Erratum in: J Clin Oncol. 2009 May 1; 27(13):2305. [https://doi.org/10.1200/jco.2008.19.3342 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19171708/ PubMed] [https://clinicaltrials.gov/study/NCT00117637 NCT00117637]
 #'''TIVO-1:''' Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, Tomczak P, Lyulko O, Alyasova A, Harza M, Kogan M, Alekseev BY, Sternberg CN, Szczylik C, Cella D, Ivanescu C, Krivoshik A, Strahs A, Esteves B, Berkenblit A, Hutson TE. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013 Oct 20;31(30):3791-9. Epub 2013 Sep 9. [https://doi.org/10.1200/JCO.2012.47.4940 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569677/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24019545/ PubMed] [https://clinicaltrials.gov/study/NCT01030783 NCT01030783]
 #'''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. [https://doi.org/10.1016/S1470-2045(13)70465-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24206640/ PubMed] [https://clinicaltrials.gov/study/NCT00920816 NCT00920816]
 ##'''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. [https://doi.org/10.1016/j.clgc.2016.05.008 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27498023/ PubMed]
+#'''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. [https://doi.org/10.1016/j.clgc.2020.01.001 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32466961/ PubMed] [https://clinicaltrials.gov/study/NCT01481870 NCT01481870]
 ==Sunitinib monotherapy {{#subobject:b4a97a|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:92e618|Variant=1}}===
+===Regimen variant #1, 4 out of 6 weeks {{#subobject:92e618|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 803: / Line 1,009: @@
 ! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1056/NEJMoa065044 Motzer et al. 2007 (A618-1034)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-106-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
+|-
+|} -->
+|2004-08 to 2005-10
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+|[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
+| style="background-color:#d9ef8b" |Superior PFS (primary endpoint)<br>Median PFS: 11 vs 5 mo<br>(HR 0.42, 95% CI 0.32-0.54)<br><br>Might have superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: 26.4 vs 21.8 mo<br>(HR 0.82, 95% CI 0.67-1.001)
+|-
+|[https://doi.org/10.1158/1078-0432.CCR-10-2082 Amato et al. 2010 (TroVax Renal Immunotherapy Survival Trial)]
+|2006-2008
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#MVA-5T4_.26_Sunitinib_999|Sunitinib & MVA-5T4]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br>Median OS: 19.2 vs 20.1 mo<br>(HR 0.93, 95% CI 0.76-1.16)
 |-
 |[https://doi.org/10.1056/NEJMoa1303989 Motzer et al. 2013 (COMPARZ)]
@@ Line 809: / Line 1,031: @@
 |[[#Pazopanib_monotherapy|Pazopanib]]
 | style="background-color:#eeee01" |Non-inferior PFS
+|-
+|[https://doi.org/10.1056/NEJMoa1803675 Méjean et al. 2018 (CARMENA)]
+|2009-2017
+| style="background-color:#1a9851" | Phase 3 (E-de-esc)
+|Nephrectomy, then [[#Sunitinib_monotherapy_2|Sunitinib]]
+| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)<br>Median OS: 18.4 vs 13.9 mo<br>(HR 0.89, 95% CI 0.71-1.10)
+|-
+|[https://doi.org/10.1016/S1470-2045(16)30408-9 Rini et al. 2016 (IMPRINT)]
+|2010-2012
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#IMA-901_.26_Sunitinib_777|Sunitinib & IMA-901]]
+| style="background-color:#d9ef8b" |Might have superior OS<br>Median OS: NYR vs 33.2 mo<br>(HR 0.75, 95% CI 0.54-1.04)
+|-
+|[https://doi.org/10.1016/j.clgc.2020.01.001 Tomita et al. 2020 (CROSS-J-RCC)]
+|2010-2012
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[#Sorafenib_monotherapy|Sorafenib]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
 |[https://doi.org/10.1016/s1470-2045(22)00793-8 Brown et al. 2023 (STAR)]
 |2012-01-13 to 2017-09-12
 | style="background-color:#1a9851" |Phase 2/3 (C)
-|1a. [[#Pazopanib_monotherapy|Pazopanib]] x 2 y, then treatment-free interval<br>1b. [[#Sunitinib_monotherapy|Sunitinib]] x 2 y, then treatment-free interval
+|1a. [[#Pazopanib_monotherapy|Pazopanib]] x 2 y, then treatment-free interval<br>1b. [[#Sunitinib_monotherapy_2|Sunitinib]] x 2 y, then treatment-free interval
 | style="background-color:#ffffbf" |Inconclusive whether non-inferior OS (co-primary endpoint)
 |-
@@ Line 820: / Line 1,060: @@
 | style="background-color:#1a9851" |Phase 3 (C)
 |[[#Cabozantinib_monotherapy|Cabozantinib]]
-| style="background-color:#d73027" |Inferior PFS<sup>1</sup>
+| style="background-color:#d73027" |Inferior PFS<sup>2</sup>
+|-
+|[https://doi.org/10.1158/1078-0432.ccr-19-2427 Figlin et al. 2020 (ADAPT)]
+|2013-2016
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Rocapuldencel-T_.26_Sunitinib_999|Rocapuldencel-T & Sunitinib]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br>Median OS: 32.4 vs 27.7 mo<br>(HR 0.91, 95% CI 0.71-1.20)
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5972549/ Motzer et al. 2018 (CheckMate 214)]
@@ Line 832: / Line 1,078: @@
 | style="background-color:#1a9851" |Phase 3 (C)
 |[[#Axitinib_.26_Avelumab|Axitinib & Avelumab]]
-| style="background-color:#fc8d59" |Seems to have inferior OS<sup>2</sup>
+| style="background-color:#fc8d59" |Seems to have inferior OS<sup>3</sup>
+|-
+| rowspan="2" |[https://doi.org/10.1056/NEJMoa2035716 Motzer et al. 2021 (CLEAR)]
+| rowspan="2" |2016-10-13 to 2019-07-24
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#Everolimus_.26_Lenvatinib|Everolimus & Lenvatinib]]
+| style="background-color:#d73027" |Inferior PFS
+|-
+|2. [[#Lenvatinib_.26_Pembrolizumab|Lenvatinib & Pembrolizumab]]
+| style="background-color:#d73027" |Inferior OS
 |-
 |[https://doi.org/10.1056/NEJMoa1816714 Rini et al. 2019 (KEYNOTE-426)]
@@ Line 844: / Line 1,099: @@
 | style="background-color:#1a9851" |Phase 3 (C)
 |[[#Cabozantinib_.26_Nivolumab|Cabozantinib & Nivolumab]]
+| style="background-color:#d73027" |Inferior OS
+|-
+|[https://doi.org/10.1016/j.annonc.2023.09.3108 Yan et al. 2023 (RENOTORCH)]
+|2020-08-23 to 2022-09-23
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Axitinb_.26_Toripalimab|Axitinib & Toripalimab]]
 | style="background-color:#d73027" |Inferior OS
 |-
 |}
-''<sup>1</sup>Reported efficacy for CABOSUN is based on the 2018 update.''<br>
+''<sup>1</sup>Reported efficacy for A618-1034 is based on the 2009 update.''<br>
-''<sup>2</sup>Reported efficacy for JAVELIN Renal 101 is based on the 2020 update, although the authors state that OS data remains immature.''
+''<sup>2</sup>Reported efficacy for CABOSUN is based on the 2018 update.''<br>
+''<sup>3</sup>Reported efficacy for JAVELIN Renal 101 is based on the 2020 update, although the authors state that OS data remains immature.''
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
@@ Line 857: / Line 1,119: @@
 ====Dose and schedule modifications====
 *Per some references, dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability
-</div></div>
+</div></div><br>
-===References===
+<div class="toccolours" style="background-color:#eeeeee">
-#'''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. [https://doi.org/10.1056/NEJMoa1303989 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23964934/ PubMed] [https://clinicaltrials.gov/study/NCT00720941 NCT00720941]
+===Regimen variant #2, 2 out of 3 weeks {{#subobject:92e328|Variant=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. [https://doi.org/10.1056/NEJMc1400731 link to letter] [https://pubmed.ncbi.nlm.nih.gov/24785224/ PubMed]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-#'''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. [https://doi.org/10.1200/JCO.2016.70.7398 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455807/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28199818/ PubMed] [https://clinicaltrials.gov/study/NCT01835158 NCT01835158]
+! style="width: 20%" |Study
-##'''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. [https://doi.org/10.1016/j.ejca.2018.02.012 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057479/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29550566/ PubMed]
-#'''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. [https://doi.org/10.1056/NEJMoa1712126 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5972549/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29562145/ PubMed] [https://clinicaltrials.gov/study/NCT02231749 NCT02231749]
-##'''PRO analysis:''' Cella D, Grünwald V, Escudier B, Hammers HJ, George S, Nathan P, Grimm MO, Rini BI, Doan J, Ivanescu C, Paty J, Mekan S, Motzer RJ. Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial. Lancet Oncol. 2019 Feb;20(2):297-310. Epub 2019 Jan 15. Erratum in: Lancet Oncol. 2019 Jun;20(6):e293. [https://doi.org/10.1016/s1470-2045(18)30778-2 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6701190/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30658932/ PubMed]
-##'''Update:''' Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, Salman P, Escudier B, Beuselinck B, Amin A, Porta C, George S, Neiman V, Bracarda S, Tykodi SS, Barthélémy P, Leibowitz-Amit R, Plimack ER, Oosting SF, Redman B, Melichar B, Powles T, Nathan P, Oudard S, Pook D, Choueiri TK, Donskov F, Grimm MO, Gurney H, Heng DYC, Kollmannsberger CK, Harrison MR, Tomita Y, Duran I, Grünwald V, McHenry MB, Mekan S, Tannir NM; CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019 Oct;20(10):1370-1385. Epub 2019 Aug 16. Erratum in: Lancet Oncol. 2019 Aug 21. [https://doi.org/10.1016/S1470-2045(19)30413-9 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7497870/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31427204/ PubMed]
-##'''Update:''' Motzer RJ, Escudier B, McDermott DF, Arén Frontera O, Melichar B, Powles T, Donskov F, Plimack ER, Barthélémy P, Hammers HJ, George S, Grünwald V, Porta C, Neiman V, Ravaud A, Choueiri TK, Rini BI, Salman P, Kollmannsberger CK, Tykodi SS, Grimm MO, Gurney H, Leibowitz-Amit R, Geertsen PF, Amin A, Tomita Y, McHenry MB, Saggi SS, Tannir NM. Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer. 2020 Jul;8(2):e000891. Erratum in: J Immunother Cancer. 2021 May;9(5). [https://doi.org/10.1136/jitc-2020-000891 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7359377/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32661118/ PubMed]
-##'''Update:''' Albiges L, Tannir NM, Burotto M, McDermott D, Plimack ER, Barthélémy P, Porta C, Powles T, Donskov F, George S, Kollmannsberger CK, Gurney H, Grimm MO, Tomita Y, Castellano D, Rini BI, Choueiri TK, Saggi SS, McHenry MB, Motzer RJ. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020 Nov;5(6):e001079. [https://doi.org/10.1136/esmoopen-2020-001079 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7703447/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33246931/ PubMed]
-#'''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. [https://doi.org/10.1056/NEJMoa1816714 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30779529/ PubMed] [https://clinicaltrials.gov/study/NCT02853331 NCT02853331]
-##'''Update:''' Powles T, Plimack ER, Soulières D, Waddell T, Stus V, Gafanov R, Nosov D, Pouliot F, Melichar B, Vynnychenko I, Azevedo SJ, Borchiellini D, McDermott RS, Bedke J, Tamada S, Yin L, Chen M, Molife LR, Atkins MB, Rini BI. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1563-1573. Epub 2020 Oct 23. Erratum in: Lancet Oncol. 2020 Dec;21(12):e553. [https://doi.org/10.1016/S1470-2045(20)30436-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33284113/ PubMed]
-#'''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. [https://doi.org/10.1056/NEJMoa1816047 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716603/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30779531/ PubMed] [https://clinicaltrials.gov/study/NCT02684006 NCT02684006]
-##'''Update:''' Choueiri TK, Motzer RJ, Rini BI, Haanen J, Campbell MT, Venugopal B, Kollmannsberger C, Gravis-Mescam G, Uemura M, Lee JL, Grimm MO, Gurney H, Schmidinger M, Larkin J, Atkins MB, Pal SK, Wang J, Mariani M, Krishnaswami S, Cislo P, Chudnovsky A, Fowst C, Huang B, di Pietro A, Albiges L. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020 Aug;31(8):1030-1039. Epub 2020 Apr 25. [https://doi.org/10.1016/j.annonc.2020.04.010 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8436592/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32339648/ PubMed]
-#'''CheckMate 9ER:''' Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, Oyervides Juárez VM, Hsieh JJ, Basso U, Shah AY, Suárez C, Hamzaj A, Goh JC, Barrios C, Richardet M, Porta C, Kowalyszyn R, Feregrino JP, Żołnierek J, Pook D, Kessler ER, Tomita Y, Mizuno R, Bedke J, Zhang J, Maurer MA, Simsek B, Ejzykowicz F, Schwab GM, Apolo AB, Motzer RJ; CheckMate 9ER Investigators. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841. [https://doi.org/10.1056/nejmoa2026982 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8436591/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33657295/ PubMed] [https://clinicaltrials.gov/study/NCT03141177 NCT03141177]
-##'''Update:''' Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, Suárez C, Hamzaj A, Porta C, Hocking CM, Kessler ER, Gurney H, Tomita Y, Bedke J, Zhang J, Simsek B, Scheffold C, Apolo AB, Choueiri TK. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Jul;23(7):888-898. Epub 2022 Jun 7. [https://doi.org/10.1016/s1470-2045(22)00290-x link to original article] [https://pubmed.ncbi.nlm.nih.gov/35688173/ PubMed]
-#'''STAR:''' Brown JE, Royle KL, Gregory W, Ralph C, Maraveyas A, Din O, Eisen T, Nathan P, Powles T, Griffiths R, Jones R, Vasudev N, Wheater M, Hamid A, Waddell T, McMenemin R, Patel P, Larkin J, Faust G, Martin A, Swain J, Bestall J, McCabe C, Meads D, Goh V, Min Wah T, Brown J, Hewison J, Selby P, Collinson F; STAR Investigators. Temporary treatment cessation versus continuation of first-line tyrosine kinase inhibitor in patients with advanced clear cell renal cell carcinoma (STAR): an open-label, non-inferiority, randomised, controlled, phase 2/3 trial. Lancet Oncol. 2023 Mar;24(3):213-227. Epub 2023 Feb 13. [https://doi.org/10.1016/s1470-2045(22)00793-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36796394/ PubMed] ISRCTN06473203
-==Tivozanib monotherapy {{#subobject:f8qut0|Regimen=1}}==
-<div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:1yga4d|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
 ! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
@@ Line 885: / Line 1,129: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569677/ Motzer et al. 2013 (TIVO-1)]
+|[https://doi.org/10.1016/j.annonc.2023.09.3108 Yan et al. 2023 (RENOTORCH)]
-<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|2020-08-23 to 2022-09-23
-|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-118-1 <span style="color:white;">ESMO-MCBS (1)</span>]'''
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Axitinb_.26_Toripalimab|Axitinib & Toripalimab]]
+| style="background-color:#d73027" |Inferior OS
 |-
-|} -->
+|}
-|2010-02 to 2010-08
+<div class="toccolours" style="background-color:#b3e2cd">
-| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
-|[[#Sorafenib_monotherapy|Sorafenib]]
-| style="background-color:#91cf60" |Seems to have superior PFS (primary endpoint)<br>Median PFS: 11.9 vs 9.1 mo<br>(HR 0.80, 95% CI 0.64-0.993)
-|-
-|}
-<div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
-*[[Tivozanib (Fotivda)]] 1.5 mg PO once per day on days 1 to 21
+*[[Sunitinib (Sutent)]] 50 mg PO once per day on days 1 to 14
-'''28-day cycles'''
+'''21-day cycles'''
-</div></div>
+</div></div><br>
-===References===
-#'''TIVO-1:''' Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, Tomczak P, Lyulko O, Alyasova A, Harza M, Kogan M, Alekseev BY, Sternberg CN, Szczylik C, Cella D, Ivanescu C, Krivoshik A, Strahs A, Esteves B, Berkenblit A, Hutson TE. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013 Oct 20;31(30):3791-9. Epub 2013 Sep 9. [https://doi.org/10.1200/JCO.2012.47.4940 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569677/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24019545/ PubMed] [https://clinicaltrials.gov/study/NCT01030783 NCT01030783]
-=Metastatic disease, second-line=
-==Axitinib monotherapy {{#subobject:832684|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:a48a96|Variant=1}}===
+===Regimen variant #3, 2 out of 4 weeks {{#subobject:92ejg8|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 915: / Line 1,150: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1016/S0140-6736(11)61613-9 Rini et al. 2011 (AXIS)]
+|[https://www.clinicaltrials.gov/study/NCT04523272 Awaiting publication (TQB2450-III-07)]
-<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+| 2020-ongoing
-|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-104-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
+| style="background-color:#1a9851" |Phase 3 (C)
-|-
+|[[#Anlotinib_.26_TQB-2450_777|Anlotinib & TQB-2450]]
-|} -->
+| style="background-color:#d3d3d3" |TBD if different primary endpoint of PFS
-| 2008-2010
-| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
-|[[#Sorafenib_monotherapy_2|Sorafenib]]
-| style="background-color:#1a9850" |Superior PFS<sup>1</sup> (primary endpoint)<br>Median PFS: 8.3 vs 5.7 mo<br>(HR 0.66, 95% CI 0.55-0.78)<br><br>Did not meet secondary endpoint of OS<sup>1</sup><br>Median OS: 20.1 vs 19.2 mo<br>(HR 0.97, 95% CI 0.80-1.17)
 |-
 |}
-''<sup>1</sup>Reported efficacy is based on the 2013 update.''
-<div class="toccolours" style="background-color:#fdcdac">
-====Prior treatment criteria====
-*AXIS: Progression on first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines
-</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
-*[[Axitinib (Inlyta)]] 5 mg PO twice per day
+*[[Sunitinib (Sutent)]] 50 mg PO once per day on days 1 to 14
-'''Continued indefinitely'''
+'''28-day cycles'''
-</div>
-<div class="toccolours" style="background-color:#fff2ae">
-====Dose and schedule modifications====
-*After at least 2 weeks, if tolerated and BP not greater than 150/90, dose can be increased to 7 mg PO twice per day
-*After at least another 2 weeks, if tolerated and BP not greater than 150/90, dose can be increased to 10 mg PO twice per day
-*Dose can be reduced to 2 to 3 mg PO twice per day if needed based on tolerability
 </div></div>
 ===References===
-#'''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. [https://doi.org/10.1016/S0140-6736(11)61613-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22056247/ PubMed] [https://clinicaltrials.gov/study/NCT00678392 NCT00678392]
+#'''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. [https://doi.org/10.1056/NEJMoa065044 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17215529/ PubMed] [https://clinicaltrials.gov/study/NCT00083889 NCT00083889]
-##'''PRO analysis:''' Cella D, Escudier B, Rini B, Chen C, Bhattacharyya H, Tarazi J, Rosbrook B, Kim S, Motzer R. Patient-reported outcomes for axitinib vs sorafenib in metastatic renal cell carcinoma: phase III (AXIS) trial. Br J Cancer. 2013 Apr 30;108(8):1571-8. Epub 2013 Apr 11. [https://doi.org/10.1038/bjc.2013.145 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3668468/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23579211/ PubMed]
+##'''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. [https://doi.org/10.1200/jco.2008.20.1293 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646307/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19487381/ PubMed]
-##'''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. [https://doi.org/10.1016/S1470-2045(13)70093-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23598172/ PubMed]
+##'''HRQoL analysis:''' Cella D, Michaelson MD, Bushmakin AG, Cappelleri JC, Charbonneau C, Kim ST, Li JZ, Motzer RJ. Health-related quality of life in patients with metastatic renal cell carcinoma treated with sunitinib vs interferon-alpha in a phase III trial: final results and geographical analysis. Br J Cancer. 2010 Feb 16;102(4):658-64. Epub 2010 Jan 26. [https://doi.org/10.1038/sj.bjc.6605552 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2837567/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20104222/ PubMed]
-##'''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. [https://www.nature.com/articles/bjc2014244 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056058/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24823696/ PubMed]
+#'''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. [https://doi.org/10.1158/1078-0432.CCR-10-2082 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20881001/ PubMed] [https://clinicaltrials.gov/study/NCT00397345 NCT00397345]
-==Belzutifan monotherapy {{#subobject:anc684|Regimen=1}}==
+#'''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. [https://doi.org/10.1056/NEJMoa1303989 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23964934/ PubMed] [https://clinicaltrials.gov/study/NCT00720941 NCT00720941]
-<div class="toccolours" style="background-color:#eeeeee">
+##'''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. [https://doi.org/10.1056/NEJMc1400731 link to letter] [https://pubmed.ncbi.nlm.nih.gov/24785224/ PubMed]
-===Regimen {{#subobject:aigj26|Variant=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. [https://doi.org/10.1200/JCO.2016.70.7398 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455807/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28199818/ PubMed] [https://clinicaltrials.gov/study/NCT01835158 NCT01835158]
+##'''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. [https://doi.org/10.1016/j.ejca.2018.02.012 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057479/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29550566/ PubMed]
+#'''IMPRINT:''' Rini BI, Stenzl A, Zdrojowy R, Kogan M, Shkolnik M, Oudard S, Weikert S, Bracarda S, Crabb SJ, Bedke J, Ludwig J, Maurer D, Mendrzyk R, Wagner C, Mahr A, Fritsche J, Weinschenk T, Walter S, Kirner A, Singh-Jasuja H, Reinhardt C, Eisen T. IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2016 Nov;17(11):1599-1611. Epub 2016 Oct 3. [https://doi.org/10.1016/S1470-2045(16)30408-9 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27720136/ PubMed] [https://clinicaltrials.gov/study/NCT01265901 NCT01265901]
+#'''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. [https://doi.org/10.1056/NEJMoa1712126 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5972549/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29562145/ PubMed] [https://clinicaltrials.gov/study/NCT02231749 NCT02231749]
+##'''PRO analysis:''' Cella D, Grünwald V, Escudier B, Hammers HJ, George S, Nathan P, Grimm MO, Rini BI, Doan J, Ivanescu C, Paty J, Mekan S, Motzer RJ. Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial. Lancet Oncol. 2019 Feb;20(2):297-310. Epub 2019 Jan 15. Erratum in: Lancet Oncol. 2019 Jun;20(6):e293. [https://doi.org/10.1016/s1470-2045(18)30778-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6701190/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30658932/ PubMed]
+##'''Update:''' Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, Salman P, Escudier B, Beuselinck B, Amin A, Porta C, George S, Neiman V, Bracarda S, Tykodi SS, Barthélémy P, Leibowitz-Amit R, Plimack ER, Oosting SF, Redman B, Melichar B, Powles T, Nathan P, Oudard S, Pook D, Choueiri TK, Donskov F, Grimm MO, Gurney H, Heng DYC, Kollmannsberger CK, Harrison MR, Tomita Y, Duran I, Grünwald V, McHenry MB, Mekan S, Tannir NM; CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019 Oct;20(10):1370-1385. Epub 2019 Aug 16. Erratum in: Lancet Oncol. 2019 Aug 21. [https://doi.org/10.1016/S1470-2045(19)30413-9 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7497870/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31427204/ PubMed]
+##'''Update:''' Motzer RJ, Escudier B, McDermott DF, Arén Frontera O, Melichar B, Powles T, Donskov F, Plimack ER, Barthélémy P, Hammers HJ, George S, Grünwald V, Porta C, Neiman V, Ravaud A, Choueiri TK, Rini BI, Salman P, Kollmannsberger CK, Tykodi SS, Grimm MO, Gurney H, Leibowitz-Amit R, Geertsen PF, Amin A, Tomita Y, McHenry MB, Saggi SS, Tannir NM. Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer. 2020 Jul;8(2):e000891. Erratum in: J Immunother Cancer. 2021 May;9(5). [https://doi.org/10.1136/jitc-2020-000891 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7359377/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32661118/ PubMed]
+##'''Update:''' Albiges L, Tannir NM, Burotto M, McDermott D, Plimack ER, Barthélémy P, Porta C, Powles T, Donskov F, George S, Kollmannsberger CK, Gurney H, Grimm MO, Tomita Y, Castellano D, Rini BI, Choueiri TK, Saggi SS, McHenry MB, Motzer RJ. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020 Nov;5(6):e001079. [https://doi.org/10.1136/esmoopen-2020-001079 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7703447/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33246931/ PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa1803675 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29860937/ PubMed] [https://clinicaltrials.gov/study/NCT00930033 NCT00930033]
+#'''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. [https://doi.org/10.1056/NEJMoa1816714 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30779529/ PubMed] [https://clinicaltrials.gov/study/NCT02853331 NCT02853331]
+##'''Update:''' Powles T, Plimack ER, Soulières D, Waddell T, Stus V, Gafanov R, Nosov D, Pouliot F, Melichar B, Vynnychenko I, Azevedo SJ, Borchiellini D, McDermott RS, Bedke J, Tamada S, Yin L, Chen M, Molife LR, Atkins MB, Rini BI. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1563-1573. Epub 2020 Oct 23. Erratum in: Lancet Oncol. 2020 Dec;21(12):e553. [https://doi.org/10.1016/S1470-2045(20)30436-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33284113/ PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa1816047 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716603/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30779531/ PubMed] [https://clinicaltrials.gov/study/NCT02684006 NCT02684006]
+##'''Update:''' Choueiri TK, Motzer RJ, Rini BI, Haanen J, Campbell MT, Venugopal B, Kollmannsberger C, Gravis-Mescam G, Uemura M, Lee JL, Grimm MO, Gurney H, Schmidinger M, Larkin J, Atkins MB, Pal SK, Wang J, Mariani M, Krishnaswami S, Cislo P, Chudnovsky A, Fowst C, Huang B, di Pietro A, Albiges L. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020 Aug;31(8):1030-1039. Epub 2020 Apr 25. [https://doi.org/10.1016/j.annonc.2020.04.010 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8436592/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32339648/ PubMed]
+#'''ADAPT:''' Figlin RA, Tannir NM, Uzzo RG, Tykodi SS, Chen DYT, Master V, Kapoor A, Vaena D, Lowrance W, Bratslavsky G, DeBenedette M, Gamble A, Plachco A, Norris MS, Horvatinovich J, Tcherepanova IY, Nicolette CA, Wood CG; ADAPT study group. Results of the ADAPT Phase 3 Study of Rocapuldencel-T in Combination with Sunitinib as First-Line Therapy in Patients with Metastatic Renal Cell Carcinoma. Clin Cancer Res. 2020 May 15;26(10):2327-2336. Epub 2020 Feb 7. [https://doi.org/10.1158/1078-0432.ccr-19-2427 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32034074/ PubMed] [https://clinicaltrials.gov/study/NCT01582672 NCT01582672]
+#'''CROSS-J-RCC:''' Tomita Y, Naito S, Sassa N, Takahashi A, Kondo T, Koie T, Obara W, Kobayashi Y, Teishima J, Takahashi M, Matsuyama H, Ueda T, Yamaguchi K, Kishida T, Shiroki R, Saika T, Shinohara N, Oya M, Kanayama HO. Sunitinib Versus Sorafenib as Initial Targeted Therapy for mCC-RCC With Favorable/Intermediate Risk: Multicenter Randomized Trial CROSS-J-RCC. Clin Genitourin Cancer. 2020 Aug;18(4):e374-e385. Epub 2020 Mar 6. [https://doi.org/10.1016/j.clgc.2020.01.001 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32466961/ PubMed] [https://clinicaltrials.gov/study/NCT01481870 NCT01481870]
+#'''CLEAR:''' Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. Epub 2021 Feb 13. [https://doi.org/10.1056/NEJMoa2035716 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/33616314/ PubMed] [https://clinicaltrials.gov/study/NCT02811861 NCT02811861]
+##'''Update:''' Choueiri TK, Eto M, Motzer R, De Giorgi U, Buchler T, Basappa NS, Méndez-Vidal MJ, Tjulandin S, Hoon Park S, Melichar B, Hutson T, Alemany C, McGregor B, Powles T, Grünwald V, Alekseev B, Rha SY, Kopyltsov E, Kapoor A, Alonso Gordoa T, Goh JC, Staehler M, Merchan JR, Xie R, Perini RF, Mody K, McKenzie J, Porta CG. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol. 2023 Mar;24(3):228-238. Erratum in: Lancet Oncol. 2023 Apr;24(4):e146. [https://doi.org/10.1016/s1470-2045(23)00049-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36858721/ PubMed]
+##'''Update:''' Motzer RJ, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Alekseev B, Rha SY, Merchan J, Goh JC, Lalani AA, De Giorgi U, Melichar B, Hong SH, Gurney H, Méndez-Vidal MJ, Kopyltsov E, Tjulandin S, Gordoa TA, Kozlov V, Alyasova A, Winquist E, Maroto P, Kim M, Peer A, Procopio G, Takagi T, Wong S, Bedke J, Schmidinger M, Rodriguez-Lopez K, Burgents J, He C, Okpara CE, McKenzie J, Choueiri TK; CLEAR Trial Investigators. Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study. J Clin Oncol. 2024 Apr 10;42(11):1222-1228. Epub 2024 Jan 16. [https://doi.org/10.1200/jco.23.01569 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38227898/ PubMed]
+#'''CheckMate 9ER:''' Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, Oyervides Juárez VM, Hsieh JJ, Basso U, Shah AY, Suárez C, Hamzaj A, Goh JC, Barrios C, Richardet M, Porta C, Kowalyszyn R, Feregrino JP, Żołnierek J, Pook D, Kessler ER, Tomita Y, Mizuno R, Bedke J, Zhang J, Maurer MA, Simsek B, Ejzykowicz F, Schwab GM, Apolo AB, Motzer RJ; CheckMate 9ER Investigators. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841. [https://doi.org/10.1056/nejmoa2026982 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8436591/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33657295/ PubMed] [https://clinicaltrials.gov/study/NCT03141177 NCT03141177]
+##'''Update:''' Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, Suárez C, Hamzaj A, Porta C, Hocking CM, Kessler ER, Gurney H, Tomita Y, Bedke J, Zhang J, Simsek B, Scheffold C, Apolo AB, Choueiri TK. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Jul;23(7):888-898. Epub 2022 Jun 7. [https://doi.org/10.1016/s1470-2045(22)00290-x link to original article] [https://pubmed.ncbi.nlm.nih.gov/35688173/ PubMed]
+##'''Update:''' Powles T, Burotto M, Escudier B, Apolo AB, Bourlon MT, Shah AY, Suárez C, Porta C, Barrios CH, Richardet M, Gurney H, Kessler ER, Tomita Y, Bedke J, George S, Scheffold C, Wang P, Fedorov V, Motzer RJ, Choueiri TK. Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial. ESMO Open. 2024 May;9(5):102994. Epub 2024 Apr 20. [https://doi.org/10.1016/j.esmoop.2024.102994 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc11046044/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/38642472/ PubMed]
+#'''STAR:''' Brown JE, Royle KL, Gregory W, Ralph C, Maraveyas A, Din O, Eisen T, Nathan P, Powles T, Griffiths R, Jones R, Vasudev N, Wheater M, Hamid A, Waddell T, McMenemin R, Patel P, Larkin J, Faust G, Martin A, Swain J, Bestall J, McCabe C, Meads D, Goh V, Min Wah T, Brown J, Hewison J, Selby P, Collinson F; STAR Investigators. Temporary treatment cessation versus continuation of first-line tyrosine kinase inhibitor in patients with advanced clear cell renal cell carcinoma (STAR): an open-label, non-inferiority, randomised, controlled, phase 2/3 trial. Lancet Oncol. 2023 Mar;24(3):213-227. Epub 2023 Feb 13. [https://doi.org/10.1016/s1470-2045(22)00793-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36796394/ PubMed] ISRCTN06473203
+#'''RENOTORCH:''' Yan XQ, Ye MJ, Zou Q, Chen P, He ZS, Wu B, He DL, He CH, Xue XY, Ji ZG, Chen H, Zhang S, Liu YP, Zhang XD, Fu C, Xu DF, Qiu MX, Lv JJ, Huang J, Ren XB, Cheng Y, Qin WJ, Zhang X, Zhou FJ, Ma LL, Guo JM, Ding DG, Wei SZ, He Y, Guo HQ, Shi BK, Liu L, Liu F, Hu ZQ, Jin XM, Yang L, Zhu SX, Liu JH, Huang YH, Xu T, Liu B, Sun T, Wang ZJ, Jiang HW, Yu DX, Zhou AP, Jiang J, Luan GD, Jin CL, Xu J, Hu JX, Huang YR, Guo J, Zhai W, Sheng XN. Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study. Ann Oncol. 2024 Feb;35(2):190-199. Epub 2023 Oct 21. [https://doi.org/10.1016/j.annonc.2023.09.3108 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37872020/ PubMed] [[https://clinicaltrials.gov/study/NCT04394975 NCT04394975]
+#'''KEYNOTE-679:''' [https://clinicaltrials.gov/study/NCT03260894 NCT03260894]
+#'''PIVOT-09:''' [https://clinicaltrials.gov/study/NCT03729245 NCT03729245]
+#'''TQB2450-III-07:''' [https://clinicaltrials.gov/study/NCT04523272 NCT04523272]
+==Tivozanib monotherapy {{#subobject:f8qut0|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:1yga4d|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 957: / Line 1,206: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://clinicaltrials.gov/study/NCT03095040 Awaiting publication (LITESPARK-005)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569677/ Motzer et al. 2013 (TIVO-1)]
-|2020-ongoing
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-118-1 <span style="color:white;">ESMO-MCBS (1)</span>]'''
-|[[#Everolimus_monotherapy|Everolimus]]
-| style="background-color:#1a9850" |Superior PFS<sup>1</sup> (primary endpoint)<br>Median PFS: 5.6 vs 5.6 mo<br>(HR 0.75, 95% CI 0.63-0.90)
 |-
-|}
+|} -->
-''<sup>1</sup>Reported efficacy is based on the FDA announcement; hazards were non-proportional.''
+|2010-02 to 2010-08
-<div class="toccolours" style="background-color:#b3e2cd">
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[#Sorafenib_monotherapy|Sorafenib]]
+| style="background-color:#91cf60" |Seems to have superior PFS (primary endpoint)<br>Median PFS: 11.9 vs 9.1 mo<br>(HR 0.80, 95% CI 0.64-0.993)
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
-*[[Belzutifan (Welireg)]] 120 mg PO twice per day
+*[[Tivozanib (Fotivda)]] 1.5 mg PO once per day on days 1 to 21
-'''Continued indefinitely'''
+'''28-day cycles'''
 </div></div>
 ===References===
-#'''LITESPARK-005:''' [https://clinicaltrials.gov/study/NCT04195750 NCT04195750]
+#'''TIVO-1:''' Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, Tomczak P, Lyulko O, Alyasova A, Harza M, Kogan M, Alekseev BY, Sternberg CN, Szczylik C, Cella D, Ivanescu C, Krivoshik A, Strahs A, Esteves B, Berkenblit A, Hutson TE. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013 Oct 20;31(30):3791-9. Epub 2013 Sep 9. [https://doi.org/10.1200/JCO.2012.47.4940 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569677/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24019545/ PubMed] [https://clinicaltrials.gov/study/NCT01030783 NCT01030783]
-==Bevacizumab monotherapy {{#subobject:dc7874|Regimen=1}}==
+=Metastatic disease, second-line=
+==Axitinib monotherapy {{#subobject:832684|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-=== Regimen {{#subobject:24489f|Variant=1}}===
+===Regimen {{#subobject:a48a96|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 983: / Line 1,236: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275324/ Yang et al. 2003]
+|[https://doi.org/10.1016/S0140-6736(11)61613-9 Rini et al. 2011 (AXIS)]
-|1998-2001
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-104-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
-|[[Renal_cell_carcinoma_-_null_regimens#Placebo_3|Placebo]]
-| style="background-color:#1a9850" |Superior TTP (primary endpoint)
 |-
-|}
+|} -->
-<div class="toccolours" style="background-color:#fdcdac">
+| 2008-2010
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
+|[[#Sorafenib_monotherapy_2|Sorafenib]]
+| style="background-color:#1a9850" |Superior PFS<sup>1</sup> (primary endpoint)<br>Median PFS: 8.3 vs 5.7 mo<br>(HR 0.66, 95% CI 0.55-0.78)<br><br>Did not meet secondary endpoint of OS<sup>1</sup><br>Median OS: 20.1 vs 19.2 mo<br>(HR 0.97, 95% CI 0.80-1.17)
+|-
+|}
+''<sup>1</sup>Reported efficacy is based on the 2013 update.''
+<div class="toccolours" style="background-color:#fdcdac">
 ====Prior treatment criteria====
-*Previous therapy with IL-2 or contraindication to IL-2
+*AXIS: Progression on first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
+*[[Axitinib (Inlyta)]] 5 mg PO twice per day
-'''14-day cycles'''
+'''Continued indefinitely'''
+</div>
+<div class="toccolours" style="background-color:#fff2ae">
+====Dose and schedule modifications====
+*After at least 2 weeks, if tolerated and BP not greater than 150/90, dose can be increased to 7 mg PO twice per day
+*After at least another 2 weeks, if tolerated and BP not greater than 150/90, dose can be increased to 10 mg PO twice per day
+*Dose can be reduced to 2 to 3 mg PO twice per day if needed based on tolerability
 </div></div>
 ===References===
-#Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003 Jul 31;349(5):427-34. [https://doi.org/10.1056/NEJMoa021491 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275324/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/12890841/ PubMed]
+#'''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. [https://doi.org/10.1016/S0140-6736(11)61613-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22056247/ PubMed] [https://clinicaltrials.gov/study/NCT00678392 NCT00678392]
-==Cabozantinib monotherapy {{#subobject:pyr1|Regimen=1}}==
+##'''PRO analysis:''' Cella D, Escudier B, Rini B, Chen C, Bhattacharyya H, Tarazi J, Rosbrook B, Kim S, Motzer R. Patient-reported outcomes for axitinib vs sorafenib in metastatic renal cell carcinoma: phase III (AXIS) trial. Br J Cancer. 2013 Apr 30;108(8):1571-8. Epub 2013 Apr 11. [https://doi.org/10.1038/bjc.2013.145 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc3668468/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23579211/ PubMed]
+##'''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. [https://doi.org/10.1016/S1470-2045(13)70093-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23598172/ PubMed]
+##'''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. [https://www.nature.com/articles/bjc2014244 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056058/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24823696/ PubMed]
+==Belzutifan monotherapy {{#subobject:anc684|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:pyv1|Variant=1}}===
+===Regimen {{#subobject:aigj26|Variant=1}}===
-{| class="wikitable" style="color:white; background-color:#404040"
-|<small>'''FDA-recommended dose'''</small>
-|-
-|}
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
 ! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" | Comparator
+! style="width: 20%" |Comparator
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ Choueiri et al. 2015 (METEOR)]
+|[https://clinicaltrials.gov/study/NCT03095040 Awaiting publication (LITESPARK-005)]
-<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|2020-ongoing
-|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-111-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
-|-
+|[[#Everolimus_monotherapy|Everolimus]]
-|} -->
+| style="background-color:#1a9850" |Superior PFS<sup>1</sup> (primary endpoint)<br>Median PFS: 5.6 vs 5.6 mo<br>(HR 0.75, 95% CI 0.63-0.90)
-|2013-08 to 2014-11
-| style="background-color:#1a9851" | Phase 3 (E-RT-switch-ic)
-|[[#Everolimus_monotherapy_2|Everolimus]]
-| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 7.4 vs 3.8 mo<br>(HR 0.58, 95% CI 0.45-0.75)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: 21.4 vs 17.1 mo<br>(HR 0.70, 95% CI 0.58-0.85)
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9437824/ Tannir et al. 2022 (CANTATA)]
-|2018-11-27 to 2019-09-30
-| style="background-color:#1a9851" | Phase 3 (C)
-|[[#Cabozantinib_.26_Telaglenastat_777|Cabozantinib & Telaglenastat]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
 |}
-''<sup>1</sup>Reported efficacy is based on the 2018 update.''
+''<sup>1</sup>Reported efficacy is based on the FDA announcement; hazards were non-proportional.''<br>
-<div class="toccolours" style="background-color:#fdcdac">
+''Note: Dosing details are from CT.gov.''
-====Prior treatment criteria====
+<div class="toccolours" style="background-color:#b3e2cd">
-*METEOR: [[Regimen_classes#VEGFR_inhibitor_therapy|VEGFR TKI]], with progression
+====Targeted therapy====
-*CANTATA: 1 to 2 prior lines of therapy, including 1 or more antiangiogenic therapies or Ipilimumab & Nivolumab
+*[[Belzutifan (Welireg)]] 120 mg PO once per day
-</div>
+'''Continued indefinitely'''
-<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
-*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 60 mg PO once per day on days 1 to 28, taken at least 2 hours before or 1 hour after meals
-'''28-day cycles'''
 </div></div>
 ===References===
-#'''METEOR:''' Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1814-23. Epub 2015 Sep 25. [https://doi.org/10.1056/NEJMoa1510016 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26406150/ PubMed] [https://clinicaltrials.gov/study/NCT01865747 NCT01865747]
+#'''LITESPARK-005:''' [https://clinicaltrials.gov/study/NCT04195750 NCT04195750]
-##'''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. [https://doi.org/10.1016/S1470-2045(16)30107-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27279544/ PubMed]
-##'''HRQoL analysis:''' Cella D, Escudier B, Tannir NM, Powles T, Donskov F, Peltola K, Schmidinger M, Heng DYC, Mainwaring PN, Hammers HJ, Lee JL, Roth BJ, Marteau F, Williams P, Baer J, Mangeshkar M, Scheffold C, Hutson TE, Pal S, Motzer RJ, Choueiri TK. Quality of life outcomes for cabozantinib versus everolimus in patients with metastatic renal cell carcinoma: METEOR phase III randomized trial. J Clin Oncol. 2018 Mar 10;36(8):757-764. Epub 2018 Jan 29. [https://doi.org/10.1200/JCO.2017.75.2170 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6804841/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29377755/ PubMed]
-##'''Update:''' Motzer RJ, Escudier B, Powles T, Scheffold C, Choueiri TK. Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer. 2018 May;118(9):1176-1178. Epub 2018 Mar 26. [https://doi.org/10.1038/s41416-018-0061-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943250/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29576624/ PubMed]
-#'''CANTATA:''' Tannir NM, Agarwal N, Porta C, Lawrence NJ, Motzer R, McGregor B, Lee RJ, Jain RK, Davis N, Appleman LJ, Goodman O Jr, Stadler WM, Gandhi S, Geynisman DM, Iacovelli R, Mellado B, Sepúlveda Sánchez JM, Figlin R, Powles T, Akella L, Orford K, Escudier B. Efficacy and Safety of Telaglenastat Plus Cabozantinib vs Placebo Plus Cabozantinib in Patients With Advanced Renal Cell Carcinoma: The CANTATA Randomized Clinical Trial. JAMA Oncol. 2022 Oct 1;8(10):1411-1418. [https://doi.org/10.1001/jamaoncol.2022.3511 link to orginal article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9437824/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/36048457/ PubMed] [https://clinicaltrials.gov/study/NCT03428217 NCT03428217]
-==Everolimus monotherapy {{#subobject:893557|Regimen=1}}==
+==Bevacizumab monotherapy {{#subobject:dc7874|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-=== Regimen {{#subobject:9d436d|Variant=1}}===
+=== Regimen {{#subobject:24489f|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 1,061: / Line 1,305: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006123/ Motzer et al. 2015 (RECORD-4)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275324/ Yang et al. 2003]
-|2011-2013
+|1998-2001
-| style="background-color:#91cf61" |Phase 2
+| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
-| style="background-color:#d3d3d3" |
+|[[Renal_cell_carcinoma_-_null_regimens#Placebo_3|Placebo]]
-| style="background-color:#d3d3d3" |
+| style="background-color:#1a9850" |Superior TTP (primary endpoint)
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5719487/ Motzer et al. 2015 (CheckMate 025)]
+|}
-|2012-2014
+<div class="toccolours" style="background-color:#fdcdac">
-| style="background-color:#1a9851" |Phase 3 (C)
+====Prior treatment criteria====
-|[[#Nivolumab_monotherapy|Nivolumab]]
+*Previous therapy with IL-2 or contraindication to IL-2
-| style="background-color:#d73027" |Inferior OS
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
+*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
+'''14-day cycles'''
+</div></div>
+===References===
+#Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003 Jul 31;349(5):427-34. [https://doi.org/10.1056/NEJMoa021491 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275324/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/12890841/ PubMed]
+==Cabozantinib monotherapy {{#subobject:pyr1|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:pyv1|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
 |-
-| rowspan="2" |[https://doi.org/10.1016/S1470-2045(15)00290-9 Motzer et al. 2015 (E7080-G000-205)]
+|}
-| rowspan="2" |2012-03-16 to 2013-06-19
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (C)
+! style="width: 20%" |Study
-|1. [[#Everolimus_.26_Lenvatinib | Everolimus & Lenvatinib]]
+! style="width: 20%" |Dates of enrollment
-| style="background-color:#d73027" |Inferior PFS
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" | Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|2. [[#Lenvatinib_monotherapy|Lenvatinib]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ Choueiri et al. 2015 (METEOR)]
-| style="background-color:#fc8d59" |Seems to have inferior PFS
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-111-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ Choueiri et al. 2015 (METEOR)]
+|} -->
 |2013-08 to 2014-11
-| style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#1a9851" | Phase 3 (E-RT-switch-ic)
-|[[#Cabozantinib_monotherapy_2|Cabozantinib]]
+|[[#Everolimus_monotherapy_2|Everolimus]]
-| style="background-color:#d73027" |Inferior OS
+| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 7.4 vs 3.8 mo<br>(HR 0.58, 95% CI 0.45-0.75)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: 21.4 vs 17.1 mo<br>(HR 0.70, 95% CI 0.58-0.85)
 |-
-| rowspan="2" |[https://doi.org/10.1016/j.ejca.2022.10.025 Sheng et al. 2022 (CONCEPT<sub>RCC</sub>)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9437824/ Tannir et al. 2022 (CANTATA)]
-| rowspan="2" | 2017-2019
+|2018-11-27 to 2019-09-30
-| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+| style="background-color:#1a9851" | Phase 3 (C)
-| 1. [[#Everolimus_.26_Vorolanib_777|Everolimus & Vorolanib]]
+|[[#Cabozantinib_.26_Telaglenastat_999|Cabozantinib & Telaglenastat]]
-| style="background-color:#d73027" |Inferior PFS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|2. [[#Vorolanib_monotherapy_777|Vorolanib]]
-| style="background-color:#fee08b" |Might have inferior PFS
-|-
-|[https://clinicaltrials.gov/study/NCT03095040 Awaiting publication (LITESPARK-005)]
-|2020-ongoing
-| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Belzutifan_monotherapy|Belzutifan]]
-| style="background-color:#d73027" |Inferior PFS
 |-
 |}
-''Note: 72% of patients in Checkmate 025 had anti-angiogenic therapy prior to progression.''
+''<sup>1</sup>Reported efficacy is based on the 2018 update.''
 <div class="toccolours" style="background-color:#fdcdac">
 ====Prior treatment criteria====
 *METEOR: [[Regimen_classes#VEGFR_inhibitor_therapy|VEGFR TKI]], with progression
-*CONCEPT<sub>RCC</sub>: One prior [[Regimen_classes#VEGFR_inhibitor_therapy|VEGFR TKI]]
+*CANTATA: 1 to 2 prior lines of therapy, including 1 or more antiangiogenic therapies or Ipilimumab & Nivolumab
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
-*[[Everolimus (Afinitor)]] 10 mg PO once per day
+*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 60 mg PO once per day on days 1 to 28, taken at least 2 hours before or 1 hour after meals
-'''Continued indefinitely'''
+'''28-day cycles'''
-</div>
+</div></div>
-<div class="toccolours" style="background-color:#fff2ae">
-====Dose and schedule modifications====
-*Everolimus dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability
-</div></div>
 ===References===
-#'''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. [https://doi.org/10.1056/NEJMoa1510665 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5719487/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26406148/ PubMed] [https://clinicaltrials.gov/study/NCT01668784 NCT01668784]
-##'''HRQoL analysis:''' Cella D, Grünwald V, Nathan P, Doan J, Dastani H, Taylor F, Bennett B, DeRosa M, Berry S, Broglio K, Berghorn E, Motzer RJ. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):994-1003. Epub 2016 Jun 6. Erratum in: Lancet Oncol. 2016 Jul;17 (7):e270. [https://doi.org/10.1016/S1470-2045(16)30125-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521044/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27283863/ PubMed]
-##'''Subgroup analysis:''' Escudier B, Sharma P, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Gurney H, Donskov F, Peltola K, Wagstaff J, Gauler TC, Ueda T, Zhao H, Waxman IM, Motzer RJ; CheckMate 025 investigators. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol. 2017 Dec;72(6):962-971. Epub 2017 Mar 3. Erratum in: Eur Urol. 2018 Jan 3. [https://doi.org/10.1016/j.eururo.2017.02.010 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28262413/ PubMed]
-##'''Subgroup analysis:''' Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Saito M, Kimura G, Yonese J, Yao M, Uemura H. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the phase III CheckMate 025 study. Jpn J Clin Oncol. 2019 Jun 1;49(6):506-514. [https://academic.oup.com/jjco/article-abstract/49/6/506/5426435 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30941424/ PubMed]
-##'''Update:''' Motzer RJ, Escudier B, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Plimack ER, Procopio G, McDermott DF, Castellano D, Choueiri TK, Donskov F, Gurney H, Oudard S, Richardet M, Peltola K, Alva AS, Carducci M, Wagstaff J, Chevreau C, Fukasawa S, Tomita Y, Gauler TC, Kollmannsberger CK, Schutz FA, Larkin J, Cella D, McHenry MB, Saggi SS, Tannir NM. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer. 2020 Sep 15;126(18):4156-4167. Epub 2020 Jul 16. [https://doi.org/10.1002/cncr.33033 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8415096/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32673417/ PubMed]
 #'''METEOR:''' Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1814-23. Epub 2015 Sep 25. [https://doi.org/10.1056/NEJMoa1510016 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26406150/ PubMed] [https://clinicaltrials.gov/study/NCT01865747 NCT01865747]
 ##'''Update:''' Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, Hammers HJ, Donskov F, Roth BJ, Peltola K, Lee JL, Heng DY, Schmidinger M, Agarwal N, Sternberg CN, McDermott DF, Aftab DT, Hessel C, Scheffold C, Schwab G, Hutson TE, Pal S, Motzer RJ; METEOR investigators. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):917-27. Epub 2016 Jun 5. [https://doi.org/10.1016/S1470-2045(16)30107-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27279544/ PubMed]
 ##'''HRQoL analysis:''' Cella D, Escudier B, Tannir NM, Powles T, Donskov F, Peltola K, Schmidinger M, Heng DYC, Mainwaring PN, Hammers HJ, Lee JL, Roth BJ, Marteau F, Williams P, Baer J, Mangeshkar M, Scheffold C, Hutson TE, Pal S, Motzer RJ, Choueiri TK. Quality of life outcomes for cabozantinib versus everolimus in patients with metastatic renal cell carcinoma: METEOR phase III randomized trial. J Clin Oncol. 2018 Mar 10;36(8):757-764. Epub 2018 Jan 29. [https://doi.org/10.1200/JCO.2017.75.2170 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6804841/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29377755/ PubMed]
 ##'''Update:''' Motzer RJ, Escudier B, Powles T, Scheffold C, Choueiri TK. Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer. 2018 May;118(9):1176-1178. Epub 2018 Mar 26. [https://doi.org/10.1038/s41416-018-0061-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943250/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29576624/ PubMed]
-#'''E7080-G000-205:''' Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. [https://doi.org/10.1016/S1470-2045(15)00290-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26482279/ PubMed] [https://clinicaltrials.gov/study/NCT01136733 NCT01136733]
+#'''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. [https://doi.org/10.1001/jamaoncol.2022.3511 link to orginal article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9437824/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/36048457/ PubMed] [https://clinicaltrials.gov/study/NCT03428217 NCT03428217]
-##'''Update:''' Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 Jan;17(1):e4-5. Epub 2015 Dec 23. [https://doi.org/10.1016/S1470-2045(15)00543-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26758760/ PubMed]
+#'''MK-6482-011:''' [https://clinicaltrials.gov/study/NCT04586231 NCT04586231]
-#'''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. [https://doi.org/10.1093/annonc/mdv612 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006123/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26681676/ PubMed] [https://clinicaltrials.gov/study/NCT01491672 NCT01491672]
-#'''CONCEPT<sub>RCC</sub>:''' 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. [https://doi.org/10.1016/j.ejca.2022.10.025 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36459768/ PubMed] [https://clinicaltrials.gov/study/NCT03095040 NCT03095040]
+==Everolimus monotherapy {{#subobject:893557|Regimen=1}}==
-#'''LITESPARK-005:''' [https://clinicaltrials.gov/study/NCT04195750 NCT04195750]
-==Everolimus & Lenvatinib {{#subobject:21039d|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:71ef67|Variant=1}}===
+=== Regimen {{#subobject:9d436d|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 1,144: / Line 1,384: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-| rowspan="2" |[https://doi.org/10.1016/S1470-2045(15)00290-9 Motzer et al. 2015 (E7080-G000-205)]
+|[https://doi.org/10.1016/S0140-6736(08)61039-9 Motzer et al. 2008 (RECORD-1)]
 <!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-112-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-108-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 |-
 |} -->
-| rowspan="2" |2012-03-16 to 2013-06-19
+|2006-04 to 2007-04
-| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (E-RT-esc)
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
-|1. [[#Everolimus_monotherapy|Everolimus]]
+|[[Renal_cell_carcinoma_-_null_regimens#Placebo_2|Placebo]]
-| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 14.6 vs 5.5 mo<br>(HR 0.40, 95% CI 0.24-0.68)
+| style="background-color:#1a9850" |Superior PFS<sup>1</sup> (primary endpoint)<br>Median PFS: 4.9 vs 1.9 mo<br>(HR 0.33, 95% CI 0.25-0.43)<br><br>Did not meet secondary endpoint of OS<sup>1</sup><br>Median OS: 14.8 vs 14.4 mo<br>(HR 0.87, 95% CI 0.65-1.15)
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006123/ Motzer et al. 2015 (RECORD-4)]
+|2011-2013
+| style="background-color:#91cf61" |Phase 2
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5719487/ Motzer et al. 2015 (CheckMate 025)]
+|2012-2014
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Nivolumab_monotherapy|Nivolumab]]
+| style="background-color:#d73027" |Inferior OS
+|-
+| rowspan="2" |[https://doi.org/10.1016/S1470-2045(15)00290-9 Motzer et al. 2015 (E7080-G000-205)]
+| rowspan="2" |2012-03-16 to 2013-06-19
+| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (C)
+|1. [[#Everolimus_.26_Lenvatinib | Everolimus & Lenvatinib]]
+| style="background-color:#d73027" |Inferior PFS
 |-
 |2. [[#Lenvatinib_monotherapy|Lenvatinib]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br>Median PFS: 14.6 vs 7.4 mo<br>(HR 0.66, 95% CI 0.30-1.10)
+| style="background-color:#fc8d59" |Seems to have inferior PFS
 |-
-|}
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ Choueiri et al. 2015 (METEOR)]
-<div class="toccolours" style="background-color:#fdcdac">
+|2013-08 to 2014-11
-====Prior treatment criteria====
+| style="background-color:#1a9851" |Phase 3 (C)
-*[[:Category:VEGFR_inhibitors|VEGFR TKI]] treatment, with progression
+|[[#Cabozantinib_monotherapy_2|Cabozantinib]]
+| style="background-color:#d73027" |Inferior OS
+|-
+| rowspan="2" |[https://doi.org/10.1016/j.ejca.2022.10.025 Sheng et al. 2022 (CONCEPT<sub>RCC</sub>)]
+| rowspan="2" | 2017-2019
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+| 1. [[#Everolimus_.26_Vorolanib_777|Everolimus & Vorolanib]]
+| style="background-color:#d73027" |Inferior PFS
+|-
+|2. [[#Vorolanib_monotherapy_777|Vorolanib]]
+| style="background-color:#fee08b" |Might have inferior PFS
+|-
+|[https://clinicaltrials.gov/study/NCT03095040 Awaiting publication (LITESPARK-005)]
+|2020-ongoing
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Belzutifan_monotherapy|Belzutifan]]
+| style="background-color:#d73027" |Inferior PFS
+|-
+|}
+''<sup>1</sup>Reported efficacy for RECORD-1 is based on the 2010 update.''<br>
+''Note: 72% of patients in Checkmate 025 had anti-angiogenic therapy prior to progression.''
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*RECORD-1 & METEOR: [[Regimen_classes#VEGFR_inhibitor_therapy|VEGFR TKI]], with progression
+*CONCEPT<sub>RCC</sub>: One prior [[Regimen_classes#VEGFR_inhibitor_therapy|VEGFR TKI]]
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
-*[[Everolimus (Afinitor)]] 5 mg PO once per day
+*[[Everolimus (Afinitor)]] 10 mg PO once per day
-*[[Lenvatinib (Lenvima)]] 18 mg PO once per day
 '''Continued indefinitely'''
+</div>
+<div class="toccolours" style="background-color:#fff2ae">
+====Dose and schedule modifications====
+*Everolimus dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability
 </div></div>
 ===References===
+#'''RECORD-1:''' Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008 Aug 9;372(9637):449-56. Epub 2008 Jul 22. [https://doi.org/10.1016/S0140-6736(08)61039-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18653228/ PubMed] [https://clinicaltrials.gov/study/NCT00410124 NCT00410124] [move]
+##'''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. [https://doi.org/10.1002/cncr.25219 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20549832/ PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa1510665 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5719487/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26406148/ PubMed] [https://clinicaltrials.gov/study/NCT01668784 NCT01668784]
+##'''HRQoL analysis:''' Cella D, Grünwald V, Nathan P, Doan J, Dastani H, Taylor F, Bennett B, DeRosa M, Berry S, Broglio K, Berghorn E, Motzer RJ. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):994-1003. Epub 2016 Jun 6. Erratum in: Lancet Oncol. 2016 Jul;17 (7):e270. [https://doi.org/10.1016/S1470-2045(16)30125-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521044/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27283863/ PubMed]
+##'''Subgroup analysis:''' Escudier B, Sharma P, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Gurney H, Donskov F, Peltola K, Wagstaff J, Gauler TC, Ueda T, Zhao H, Waxman IM, Motzer RJ; CheckMate 025 investigators. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol. 2017 Dec;72(6):962-971. Epub 2017 Mar 3. Erratum in: Eur Urol. 2018 Jan 3. [https://doi.org/10.1016/j.eururo.2017.02.010 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28262413/ PubMed]
+##'''Subgroup analysis:''' Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Saito M, Kimura G, Yonese J, Yao M, Uemura H. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the phase III CheckMate 025 study. Jpn J Clin Oncol. 2019 Jun 1;49(6):506-514. [https://academic.oup.com/jjco/article-abstract/49/6/506/5426435 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30941424/ PubMed]
+##'''Update:''' Motzer RJ, Escudier B, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Plimack ER, Procopio G, McDermott DF, Castellano D, Choueiri TK, Donskov F, Gurney H, Oudard S, Richardet M, Peltola K, Alva AS, Carducci M, Wagstaff J, Chevreau C, Fukasawa S, Tomita Y, Gauler TC, Kollmannsberger CK, Schutz FA, Larkin J, Cella D, McHenry MB, Saggi SS, Tannir NM. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer. 2020 Sep 15;126(18):4156-4167. Epub 2020 Jul 16. [https://doi.org/10.1002/cncr.33033 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8415096/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32673417/ PubMed]
+#'''METEOR:''' Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1814-23. Epub 2015 Sep 25. [https://doi.org/10.1056/NEJMoa1510016 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26406150/ PubMed] [https://clinicaltrials.gov/study/NCT01865747 NCT01865747]
+##'''Update:''' Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, Hammers HJ, Donskov F, Roth BJ, Peltola K, Lee JL, Heng DY, Schmidinger M, Agarwal N, Sternberg CN, McDermott DF, Aftab DT, Hessel C, Scheffold C, Schwab G, Hutson TE, Pal S, Motzer RJ; METEOR investigators. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016 Jul;17(7):917-27. Epub 2016 Jun 5. [https://doi.org/10.1016/S1470-2045(16)30107-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27279544/ PubMed]
+##'''HRQoL analysis:''' Cella D, Escudier B, Tannir NM, Powles T, Donskov F, Peltola K, Schmidinger M, Heng DYC, Mainwaring PN, Hammers HJ, Lee JL, Roth BJ, Marteau F, Williams P, Baer J, Mangeshkar M, Scheffold C, Hutson TE, Pal S, Motzer RJ, Choueiri TK. Quality of life outcomes for cabozantinib versus everolimus in patients with metastatic renal cell carcinoma: METEOR phase III randomized trial. J Clin Oncol. 2018 Mar 10;36(8):757-764. Epub 2018 Jan 29. [https://doi.org/10.1200/JCO.2017.75.2170 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6804841/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29377755/ PubMed]
+##'''Update:''' Motzer RJ, Escudier B, Powles T, Scheffold C, Choueiri TK. Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer. 2018 May;118(9):1176-1178. Epub 2018 Mar 26. [https://doi.org/10.1038/s41416-018-0061-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943250/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29576624/ PubMed]
 #'''E7080-G000-205:''' Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. [https://doi.org/10.1016/S1470-2045(15)00290-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26482279/ PubMed] [https://clinicaltrials.gov/study/NCT01136733 NCT01136733]
 ##'''Update:''' Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 Jan;17(1):e4-5. Epub 2015 Dec 23. [https://doi.org/10.1016/S1470-2045(15)00543-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26758760/ PubMed]
+#'''RECORD-4:''' Motzer RJ, Alyasova A, Ye D, Karpenko A, Li H, Alekseev B, Xie L, Kurteva G, Kowalyszyn R, Karyakin O, Neron Y, Cosgriff T, Collins L, Brechenmacher T, Lin C, Morgan L, Yang L. Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4). Ann Oncol. 2016 Mar;27(3):441-8. Epub 2015 Dec 17. [https://doi.org/10.1093/annonc/mdv612 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006123/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26681676/ PubMed] [https://clinicaltrials.gov/study/NCT01491672 NCT01491672]
+#'''CONCEPT<sub>RCC</sub>:''' 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. [https://doi.org/10.1016/j.ejca.2022.10.025 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36459768/ PubMed] [https://clinicaltrials.gov/study/NCT03095040 NCT03095040]
+#'''LITESPARK-005:''' [https://clinicaltrials.gov/study/NCT04195750 NCT04195750]
-==Lenvatinib monotherapy {{#subobject:PYR3|Regimen=1}}==
+==Everolimus & Lenvatinib {{#subobject:21039d|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen {{#subobject:PYV3|Variant=1}}===
+===Regimen {{#subobject:71ef67|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 1,185: / Line 1,483: @@
 | rowspan="2" |[https://doi.org/10.1016/S1470-2045(15)00290-9 Motzer et al. 2015 (E7080-G000-205)]
 <!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-113-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-112-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
 |-
 |} -->
 | rowspan="2" |2012-03-16 to 2013-06-19
-| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (E-RT-switch-ic)
+| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (E-RT-esc)
 |1. [[#Everolimus_monotherapy|Everolimus]]
-| style="background-color:#91cf60" |Seems to have superior PFS (primary endpoint)<br>Median PFS: 7.4 vs 5.5 mo<br>(HR 0.61, 95% CI 0.38-0.98)
+| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 14.6 vs 5.5 mo<br>(HR 0.40, 95% CI 0.24-0.68)
 |-
-|2. [[#Everolimus_.26_Lenvatinib | Everolimus & Lenvatinib]]
+|2. [[#Lenvatinib_monotherapy|Lenvatinib]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br>Median PFS: 14.6 vs 7.4 mo<br>(HR 0.66, 95% CI 0.30-1.10)
 |-
 |}
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*[[:Category:VEGFR_inhibitors|VEGFR TKI]] treatment, with progression
+</div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
-*[[Lenvatinib (Lenvima)]] 24 mg PO once per day on days 1 to 28
+*[[Everolimus (Afinitor)]] 5 mg PO once per day
-'''28-day cycles'''
+*[[Lenvatinib (Lenvima)]] 18 mg PO once per day
+'''Continued indefinitely'''
 </div></div>
 ===References===
@@ Line 1,206: / Line 1,510: @@
 ##'''Update:''' Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 Jan;17(1):e4-5. Epub 2015 Dec 23. [https://doi.org/10.1016/S1470-2045(15)00543-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26758760/ PubMed]
-==Nivolumab monotherapy {{#subobject:pyr2|Regimen=1}}==
+==Lenvatinib monotherapy {{#subobject:PYR3|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #1, 0.3 mg/kg q3wk {{#subobject:6d0807|Variant=1}}===
+===Regimen {{#subobject:PYV3|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 1,216: / Line 1,520: @@
 ! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://doi.org/10.1200/JCO.2014.59.0703 Motzer et al. 2015 (CheckMate 010)]
+| rowspan="2" |[https://doi.org/10.1016/S1470-2045(15)00290-9 Motzer et al. 2015 (E7080-G000-205)]
-|2011-2012
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-| style="background-color:#1a9851" |Randomized Phase 2 (E-de-esc)
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-113-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
-|1. [[#Nivolumab_monotherapy|Nivolumab]]; 2 mg/kg<br>2. [[#Nivolumab_monotherapy|Nivolumab]]; 10 mg/kg
+|-
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
+|} -->
+| rowspan="2" |2012-03-16 to 2013-06-19
+| rowspan="2" style="background-color:#1a9851" |Randomized Phase 2 (E-RT-switch-ic)
+|1. [[#Everolimus_monotherapy|Everolimus]]
+| style="background-color:#91cf60" |Seems to have superior PFS (primary endpoint)<br>Median PFS: 7.4 vs 5.5 mo<br>(HR 0.61, 95% CI 0.38-0.98)
+|-
+|2. [[#Everolimus_.26_Lenvatinib | Everolimus & Lenvatinib]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
 |}
 <div class="toccolours" style="background-color:#b3e2cd">
-====Immunotherapy====
+====Targeted therapy====
-*[[Nivolumab (Opdivo)]] 0.3 mg/kg IV once on day 1
+*[[Lenvatinib (Lenvima)]] 24 mg PO once per day on days 1 to 28
-'''21-day cycles'''
+'''28-day cycles'''
-</div></div><br>
+</div></div>
+===References===
+#'''E7080-G000-205:''' Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-82. Epub 2015 Oct 22. [https://doi.org/10.1016/S1470-2045(15)00290-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26482279/ PubMed] [https://clinicaltrials.gov/study/NCT01136733 NCT01136733]
+##'''Update:''' Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016 Jan;17(1):e4-5. Epub 2015 Dec 23. [https://doi.org/10.1016/S1470-2045(15)00543-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26758760/ PubMed]
+==Nivolumab monotherapy {{#subobject:pyr2|Regimen=1}}==
 <div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #2, 2 mg/kg q3wk {{#subobject:e0b43a|Variant=1}}===
+===Regimen variant #1, 0.3 mg/kg q3wk {{#subobject:6d0807|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
@@ Line 1,239: / Line 1,555: @@
 |[https://doi.org/10.1200/JCO.2014.59.0703 Motzer et al. 2015 (CheckMate 010)]
 |2011-2012
-| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
+| style="background-color:#1a9851" |Randomized Phase 2 (E-de-esc)
-|1. [[#Nivolumab_monotherapy|Nivolumab]]; 0.3 mg/kg<br>2. [[#Nivolumab_monotherapy|Nivolumab]]; 10 mg/kg
+|1. [[#Nivolumab_monotherapy|Nivolumab]]; 2 mg/kg<br>2. [[#Nivolumab_monotherapy|Nivolumab]]; 10 mg/kg
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Nivolumab (Opdivo)]] 0.3 mg/kg IV once on day 1
+'''21-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, 2 mg/kg q3wk {{#subobject:e0b43a|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/JCO.2014.59.0703 Motzer et al. 2015 (CheckMate 010)]
+|2011-2012
+| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
+|1. [[#Nivolumab_monotherapy|Nivolumab]]; 0.3 mg/kg<br>2. [[#Nivolumab_monotherapy|Nivolumab]]; 10 mg/kg
 | style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
@@ Line 1,389: / Line 1,726: @@
 |2003-2005
 | style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 |[[Clear_cell_renal_cell_carcinoma_-_null_regimens#Placebo_3|Placebo]]
 | style="background-color:#d9ef8b" |Might have superior OS<sup>1</sup> (primary endpoint)<br>Median OS: 17.8 vs 15.2 mo<br>(HR 0.88, 95% CI 0.74-1.04)
 |-
 |[https://doi.org/10.1016/S0140-6736(11)61613-9 Rini et al. 2011 (AXIS)]
 |2008-2010
 | style="background-color:#1a9851" |Phase 3 (C)
 |[[#Axitinib_monotherapy|Axitinib]]
 | style="background-color:#d73027" |Inferior PFS
 |-
 |}
 ''Note: TARGET should not be confused with the study by the same name in breast cancer.''
 <div class="toccolours" style="background-color:#fdcdac">
 ====Prior treatment criteria====
 *TARGET<sub>RCC</sub>: 1 systemic treatment within the previous 8 months, with progression
 *AXIS: Progression on first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines
 </div>
 <div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
 *[[Sorafenib (Nexavar)]] 400 mg PO twice per day
 '''Continued indefinitely'''
+</div>
+<div class="toccolours" style="background-color:#fff2ae">
+====Dose and schedule modifications====
+*[[Sorafenib (Nexavar)]] can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity
+</div></div>
+===References===
+#'''TARGET<sub>RCC</sub>:''' 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. [https://doi.org/10.1056/NEJMoa060655 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17215530/ PubMed] [https://clinicaltrials.gov/study/NCT00073307 NCT00073307]
+##'''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. [https://doi.org/10.1200/JCO.2008.19.5511 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19451442/ PubMed]
+##'''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. [https://doi.org/10.1016/j.ejca.2010.06.121 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20656473/ PubMed]
+#'''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. [https://doi.org/10.1016/S0140-6736(11)61613-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22056247/ PubMed] [https://clinicaltrials.gov/study/NCT00678392 NCT00678392]
+##'''PRO analysis:''' Cella D, Escudier B, Rini B, Chen C, Bhattacharyya H, Tarazi J, Rosbrook B, Kim S, Motzer R. Patient-reported outcomes for axitinib vs sorafenib in metastatic renal cell carcinoma: phase III (AXIS) trial. Br J Cancer. 2013 Apr 30;108(8):1571-8. Epub 2013 Apr 11. [https://doi.org/10.1038/bjc.2013.145 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc3668468/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23579211/ PubMed]
+##'''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. [https://doi.org/10.1016/S1470-2045(13)70093-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23598172/ PubMed]
+##'''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. [https://www.nature.com/articles/bjc2014244 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056058/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24823696/ PubMed]
+==Sunitinib monotherapy {{#subobject:f929da|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:955949|Variant=1}}===
+{| class="wikitable sortable" style="width: 60%; text-align:center;"
+!style="width: 33%"|Study
+!style="width: 33%"|Dates of enrollment
+!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1001/jama.295.21.2516 Motzer et al. 2006 (A618-1006)]
+|2004
+| style="background-color:#91cf61" |Phase 2 (RT)
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
+*[[Sunitinib (Sutent)]] 50 mg PO once per day on days 1 to 28
+'''42-day cycles'''
 </div>
 <div class="toccolours" style="background-color:#fff2ae">
 ====Dose and schedule modifications====
-*[[Sorafenib (Nexavar)]] can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity
+*Dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability
 </div></div>
 ===References===
-#'''TARGET<sub>RCC</sub>:''' 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. [https://doi.org/10.1056/NEJMoa060655 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17215530/ PubMed] [https://clinicaltrials.gov/study/NCT00073307 NCT00073307]
+#'''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. [https://doi.org/10.1001/jama.295.21.2516 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16757724/ PubMed] [https://clinicaltrials.gov/study/NCT00077974 NCT00077974]
-##'''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. [https://doi.org/10.1200/JCO.2008.19.5511 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19451442/ PubMed]
-##'''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. [https://doi.org/10.1016/j.ejca.2010.06.121 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20656473/ PubMed]
-#'''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. [https://doi.org/10.1016/S0140-6736(11)61613-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22056247/ PubMed] [https://clinicaltrials.gov/study/NCT00678392 NCT00678392]
-##'''PRO analysis:''' Cella D, Escudier B, Rini B, Chen C, Bhattacharyya H, Tarazi J, Rosbrook B, Kim S, Motzer R. Patient-reported outcomes for axitinib vs sorafenib in metastatic renal cell carcinoma: phase III (AXIS) trial. Br J Cancer. 2013 Apr 30;108(8):1571-8. Epub 2013 Apr 11. [https://doi.org/10.1038/bjc.2013.145 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3668468/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23579211/ PubMed]
-##'''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. [https://doi.org/10.1016/S1470-2045(13)70093-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23598172/ PubMed]
-##'''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. [https://www.nature.com/articles/bjc2014244 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056058/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24823696/ PubMed]
 =Metastatic disease, third-line=
@@ Line 1,500: / Line 1,861: @@
 ##'''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. [https://doi.org/10.1016/j.eururo.2020.08.007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32938569/ PubMed]
 [[Category:Clear cell renal cell carcinoma regimens]]
-[[Category:Disease-specific pages]]
 [[Category:Histology-specific pages]]
 [[Category:Renal cell carcinomas]]

Difference between revisions of "Clear cell renal cell carcinoma"

Revision as of 17:50, 23 June 2024

Guidelines

ASCO

EAU

ESMO

NCCN

Adjuvant therapy

Pembrolizumab monotherapy

Regimen variant #1, 200 mg q3wk

Preceding treatment

Immunotherapy

Regimen variant #2, 400 mg q6wk

Preceding treatment

Immunotherapy

References

Sunitinib monotherapy

Regimen

Preceding treatment

Targeted therapy

References

Metastatic disease, first-line

Axitinib monotherapy

Regimen

Targeted therapy

Dose and schedule modifications

References

Axitinib & Avelumab

Regimen variant #1, weight-based dosing

Targeted therapy

Immunotherapy

Regimen variant #2, flat dosing

Targeted therapy

Immunotherapy

References

Axitinib & Pembrolizumab

Regimen

Targeted therapy

Immunotherapy

References

Axitinib & Toripalimab

Regimen

Targeted therapy

Immunotherapy

References

Bevacizumab monotherapy

Regimen

Targeted therapy

Dose and schedule modifications

References

Bevacizumab & Interferon alfa-2a

Regimen variant #1, 1 year of interferon

Targeted therapy

Immunotherapy

Dose and schedule modifications

Regimen variant #2, indefinite

Targeted therapy

Immunotherapy

Dose and schedule modifications

References

Cabozantinib monotherapy

Regimen

Targeted therapy

References

Cabozantinib & Nivolumab

Regimen variant #1, bi-weekly nivolumab

Targeted therapy

Immunotherapy

Regimen variant #2, monthly nivolumab

Targeted therapy

Immunotherapy

References

Cabozantinib, Ipilimumab, Nivolumab

Regimen

Targeted therapy

Immunotherapy

References

Erlotinib & Bevacizumab

Regimen

Targeted therapy