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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 or to a histology- or biomarker-specific page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
Note: This page contains trials that did not specify histology or allowed patients with multiple histologies. Trials limited to a specific histology including those that required a clear-cell component are on dedicated pages:

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

14 regimens on this page 22 variants on this page

Living Interactive Systematic Reviews

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.

ESMO

2021: Kanesveran et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with renal cell carcinoma PubMed
2021: Powles et al. ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma PubMed
2019: Escudier et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2016: Escudier et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2014: Escudier et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2012: Escudier et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2010: Escudier & Kataja. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2009: Escudier & Kataja. Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed

ISRS

2024: Siva et al. Stereotactic body radiotherapy for primary renal cell carcinoma: a systematic review and practice guideline from the International Society of Stereotactic Radiosurgery (ISRS) PubMed

NCCN

NCCN Guidelines - Kidney Cancer
2022: Motzer et al. Kidney Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. PubMed
2017: Motzer et al. Kidney Cancer, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology PubMed
2015: Motzer et al. Kidney Cancer, Version 3.2015 PubMed
2014: Motzer et al. Kidney cancer, version 2.2014 PubMed
2011: Motzer et al. Kidney cancer. PubMed
2009: Motzer et al. NCCN clinical practice guidelines in oncology: kidney cancer. PubMed
2006: Motzer et al. Kidney cancer. Clinical practice guidelines in oncology. PubMed
2005: Motzer et al. Kidney cancer. Clinical practice guidelines. PubMed

SIOG

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

SITC

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

Risk Stratification Calculators

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

Adjuvant therapy

Sunitinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Haas et al. 2016 (ECOG-ACRIN E2805)	2006-2010	Phase 3 (E-esc)	1. Placebo 2. Sorafenib	Did not meet primary endpoint of DFS

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

ECOG-ACRIN E2805: Haas NB, Manola J, Uzzo RG, Flaherty KT, Wood CG, Kane C, Jewett M, Dutcher JP, Atkins MB, Pins M, Wilding G, Cella D, Wagner L, Matin S, Kuzel TM, Sexton WJ, Wong YN, Choueiri TK, Pili R, Puzanov I, Kohli M, Stadler W, Carducci M, Coomes R, DiPaola RS. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016 May 14;387(10032):2008-16. Epub 2016 Mar 9. Erratum in: Lancet. 2016 May 14;387(10032):1998. link to original article link to PMC article PubMed NCT00326898

Metastatic disease, first-line

Atezolizumab & Bevacizumab

Regimen

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

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

Immunotherapy

Atezolizumab (Tecentriq) 1200 mg IV once on day 1

Targeted therapy

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

21-day cycles

References

IMmotion151: Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. link to original article contains dosing details in abstract PubMed NCT02420821
1. Update: Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Alekseev BY, Lee JL, Suarez C, Stroyakovskiy D, De Giorgi U, Donskov F, Mellado B, Banchereau R, Hamidi H, Khan O, Craine V, Huseni M, Flinn N, Dubey S, Rini BI. Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol. 2022 Feb 1;8(2):275-280. link to original article [link to PMC article PubMed

Everolimus monotherapy

Regimen

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

Targeted therapy

Everolimus (Afinitor) 10 mg PO once per day

Continued indefinitely

Subsequent treatment

RECORD-3, upon progression: Second-line Sunitinib

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

Gemcitabine & Sunitinib

Regimen

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

Chemotherapy

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

Targeted therapy

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

21-day cycles

References

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

High-dose Interleukin-2

HD IL-2: High-Dose InterLeukin-2

Example orders

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

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

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

Immunotherapy

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

Supportive therapy

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

28-day cycle for up to 3 cycles

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

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

Note: reported efficacy is based on the 2003 update.

Immunotherapy

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

8-week cycle for up to 2 cycles

Regimen variant #3, 5 MU/m²/day, CI

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

Immunotherapy

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

8-week cycles

References

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

Low-dose Interleukin-2

LD IL-2: Low-Dose InterLeukin-2

Regimen variant #1, Intravenous

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

Note: efficacy is based on the 2003 update.

Immunotherapy

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

8-week cycle for up to 2 cycles

Regimen variant #2, Subcutaneous

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

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

Immunotherapy

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

8-week cycle for up to 2 cycles

References

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

Interferon alfa-2a monotherapy

Regimen variant #1, 5 MU 5x per week

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

Immunotherapy

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

7-day cycles

Regimen variant #2, 9 MU TIW

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gore et al. 2010 (MRC RE04/EORTC GU 30012)	2001-2006	Phase 3 (C)	5-FU, Interferon alfa-2a, IL-2	Did not meet primary endpoint of OS
Hawkins et al. 2016 (Active Biotech 06762004)	2007-2010	Phase 2/3 (C)	Naptumomab estafenatox + IFNα	Did not meet primary endpoint of OS

Immunotherapy

Interferon alfa-2a (Roferon-A) 9,000,000 units SC 3 times per week

Given for varying lengths of time; see individual trials

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 #3, 9 MU daily, with lead-in

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

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 to 7
- Cycle 2: 6,000,000 units SC once per day on days 1 to 7
- Cycle 3 onwards: 9,000,000 units SC once per day on days 1 to 7

7-day cycles

Regimen variant #4, 10 MU TIW, with lead-in

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ritchie et al. 1999 (MRC RE01)	1992-1997	Phase 3 (E-switch-ooc)	MPA	Superior OS (primary endpoint) Median OS: 8.5 vs 6 mo (HR 0.72, 95% CI 0.55-0.94)

Immunotherapy

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

7-day cycle for 12 cycles

Regimen variant #5, 10 MU TIW

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gore et al. 2010 (MRC RE04/EORTC GU 30012)	2001-2006	Phase 3 (C)	5-FU, Interferon alfa-2a, IL-2	Did not meet primary endpoint of OS

Immunotherapy

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

7-day cycles

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

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

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: 9,000,000 units SC once per day on days 1, 3, 5
- Cycle 3 onwards: 18,000,000 units SC once per day on days 1, 3, 5

7-day cycles

Dose and schedule modifications

If higher doses cannot be tolerated, highest tolerable doses of 3,000,000, 4,500,500, or 6,000,000 units can be used

References

Fosså SD, Martinelli G, Otto U, Schneider G, Wander H, Oberling F, Bauer HW, Achtnicht U, Holdener EE. Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: results of a European multi-center phase III study. Ann Oncol. 1992 Apr;3(4):301-5. link to original article PubMed
Sagaster P, Micksche M, Flamm J, Ludwig H. Randomised study using IFN-alpha versus IFN-alpha plus coumarin and cimetidine for treatment of advanced renal cell cancer. Ann Oncol. 1995 Dec;6(10):999-1003. link to original article contains dosing details in abstract PubMed
MRC RE01: Ritchie A, Griffiths G, Parmar M; Medical Research Council Renal Cancer Collaborators. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet. 1999 Jan 2;353(9146):14-7. link to original article contains dosing details in abstract PubMed
Motzer RJ, Murphy BA, Bacik J, Schwartz LH, Nanus DM, Mariani T, Loehrer P, Wilding G, Fairclough DL, Cella D, Mazumdar M. Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol. 2000 Aug;18(16):2972-80. link to original article PubMed
ARCC: Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. link to original article contains dosing details in manuscript PubMed NCT00065468
MRC RE04/EORTC GU 30012: Gore ME, Griffin CL, Hancock B, Patel PM, Pyle L, Aitchison M, James N, Oliver RT, Mardiak J, Hussain T, Sylvester R, Parmar MK, Royston P, Mulders PF. Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial. Lancet. 2010 Feb 20;375(9715):641-8. Epub 2010 Feb 10. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00053820
Active Biotech 06762004: Hawkins RE, Gore M, Shparyk Y, Bondar V, Gladkov O, Ganev T, Harza M, Polenkov S, Bondarenko I, Karlov P, Karyakin O, Khasanov R, Hedlund G, Forsberg G, Nordle Ö, Eisen T. A randomized phase II/III study of naptumomab estafenatox + IFNα versus IFNα in renal cell carcinoma: final analysis with baseline biomarker subgroup and trend analysis. Clin Cancer Res. 2016 Jul 1;22(13):3172-81. Epub 2016 Feb 5. link to original article contains dosing details in manuscript PubMed NCT00420888

Sorafenib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Stadler et al. 2010 (ARCCS)	2005-06 to 2006-07	Non-randomized
Retz et al. 2018 (SWITCH-II)	2012-06-14 to 2016-11-14	Phase 3 (C)	Pazopanib	Inconclusive whether non-inferior tPFS

Targeted therapy

Sorafenib (Nexavar) 400 mg PO twice per day

Continued indefinitely

Dose and schedule modifications

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

Subsequent treatment

SWITCH-II, upon progression: Pazopanib

References

ARCCS: Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010 Mar 1;116(5):1272-80. link to original article PubMed NCT00111020
SWITCH-II: Retz M, Bedke J, Bögemann M, Grimm MO, Zimmermann U, Müller L, Leiber C, Teber D, Wirth M, Bolenz C, van Alphen R, De Santis M, Beeker A, Lehmann J, Indorf M, Frank M, Bokemeyer C, Gschwend JE. SWITCH II: Phase III randomized, sequential, open-label study to evaluate the efficacy and safety of sorafenib-pazopanib versus pazopanib-sorafenib in the treatment of advanced or metastatic renal cell carcinoma (AUO AN 33/11). Eur J Cancer. 2019 Jan;107:37-45. Epub 2018 Dec 7. link to original article contains dosing details in abstract PubMed NCT01613846

Sunitinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gore et al. 2009 (A618-1037)	2005-2007	Non-randomized
Motzer et al. 2014 (RECORD-3)	2009-2011	Randomized Phase 2 (E-switch-ic)	Everolimus	Inconclusive whether non-inferior PFS (primary endpoint)
Eichelberg et al. 2015 (SWITCH)	2009-2011	Phase 3 (C)	Sorafenib	Did not meet primary endpoint of PFS
Rini et al. 2019 (IMmotion151)	2015-05-20 to 2016-10-12	Phase 3 (C)	Atezolizumab & Bevacizumab	Seems to have inferior PFS

Targeted therapy

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

42-day cycles

Subsequent treatment

SWITCH, upon progression: Second-line Sorafenib

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

References

A618-1037: Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009 Aug;10(8):757-63. Epub 2009 Jul 15. link to original article contains dosing details in manuscript PubMed NCT00130897
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
RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article link to PMC article PubMed NCT00903175
SWITCH: Eichelberg C, Vervenne WL, De Santis M, Fischer von Weikersthal L, Goebell PJ, Lerchenmüller C, Zimmermann U, Bos MM, Freier W, Schirrmacher-Memmel S, Staehler M, Pahernik S, Los M, Schenck M, Flörcken A, van Arkel C, Hauswald K, Indorf M, Gottstein D, Michel MS. SWITCH: A Randomised, Sequential, Open-label Study to Evaluate the Efficacy and Safety of Sorafenib-sunitinib Versus Sunitinib-sorafenib in the Treatment of Metastatic Renal Cell Cancer. Eur Urol. 2015 Nov;68(5):837-47. Epub 2015 May 4. link to original article contains dosing details in abstract PubMed NCT00732914
IMmotion151: Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. link to original article contains dosing details in abstract PubMed NCT02420821
1. Update: Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Alekseev BY, Lee JL, Suarez C, Stroyakovskiy D, De Giorgi U, Donskov F, Mellado B, Banchereau R, Hamidi H, Khan O, Craine V, Huseni M, Flinn N, Dubey S, Rini BI. Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol. 2022 Feb 1;8(2):275-280. link to original article [link to PMC article PubMed

Temsirolimus monotherapy

Regimen

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

Targeted therapy

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

Supportive therapy

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

7-day cycles

References

ARCC: Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. link to original article contains dosing details in manuscript PubMed NCT00065468

Metastatic disease, second-line

Cabozantinib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Pal et al. 2023 (CONTACT-03)	2020-07-28 to 2021-12-27	Phase 3 (C)	Cabozantinib & Atezolizumab	Did not meet co-primary endpoints of PFS/OS

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

CONTACT-03: Pal SK, Albiges L, Tomczak P, Suárez C, Voss MH, de Velasco G, Chahoud J, Mochalova A, Procopio G, Mahammedi H, Zengerling F, Kim C, Osawa T, Angel M, Gupta S, Khan O, Bergthold G, Liu B, Kalaitzidou M, Huseni M, Scheffold C, Powles T, Choueiri TK. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2023 Jul 15;402(10397):185-195. Epub 2023 Jun 5. link to original article contains dosing details in abstract PubMed NCT04338269

Everolimus monotherapy

Regimen

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

Prior treatment criteria

RECORD-3: Sunitinib, with progression

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

Sorafenib monotherapy

Regimen

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

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

Prior treatment criteria

INTORSECT: Sunitinib, with progression

Targeted therapy

Sorafenib (Nexavar) 400 mg PO twice per day

Continued indefinitely

Dose and schedule modifications

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

References

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

Sunitinib monotherapy

Regimen

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

Preceding treatment

RECORD-3: First-line Everolimus

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

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

@@ Line 1: / Line 1: @@
-{| class="wikitable" style="text-align:center; width:50%;"
+<span id="BackToTop"></span>
-! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''
+<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
-|-
+[[#top|Back to Top]]
-| style="background-color:#F0F0F0" |[[File:Alikhaki.jpg|frameless|upright=0.3|center]]
+</div>
-|<big>[[User:Alikhaki|Ali Raza Khaki, MD]]<br>Stanford University<br>Palo Alto, CA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/arkhaki arkhaki]
+{{#lst:Editorial board transclusions|rcc}}
-|-
+''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Renal_cell_carcinoma_-_historical|historical regimens page]] or to a histology- or biomarker-specific page. For placebo or observational studies in this condition, please visit [[Renal cell carcinoma - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''<br>
-|}
+'''Note: This page contains trials that did not specify histology or allowed patients with multiple histologies. Trials limited to a specific histology including those that required a clear-cell component are on dedicated pages:'''
-''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Renal_cell_carcinoma_-_historical|historical regimens page]]. For placebo or observational studies in this condition, please visit [[Renal cell carcinoma - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''.
-<br>There are several related dedicated pages:
 *'''Histology-specific:'''
-**'''[[Papillary renal cell carcinoma]]'''
+**'''[[Clear cell renal cell carcinoma]]'''
-**'''[[Sarcomatoid renal cell carcinoma]]'''
+**'''[[Non-clear cell renal cell carcinoma]]'''
+***'''[[Papillary renal cell carcinoma]]'''
+***'''[[Sarcomatoid renal cell carcinoma]]'''
+*'''Biomarker-specific:'''
+**'''[[Renal_cell_carcinoma,_VHL-associated|RCC, VHL-associated]]'''
 {| class="wikitable" style="float:right; margin-right: 5px;"
 |-
@@ Line 19: / Line 19: @@
 |}
 {{TOC limit|limit=3}}
+=Living Interactive Systematic Reviews=
+*[https://adjrcc.network-meta-analysis.com/ Adjuvant treatment options in renal cell carcinoma]
+*[https://rcc.network-meta-analysis.com/RCC.html Metastatic renal cell carcinoma (mRCC)]
 =Guidelines=
-==EAU==
+'''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.'''
+==[https://www.esmo.org/ ESMO]==
+*'''2021:''' Kanesveran et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8645910/ Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with renal cell carcinoma] [https://pubmed.ncbi.nlm.nih.gov/34864348/ PubMed]
+*'''2021:''' Powles et al. [https://doi.org/10.1016/j.annonc.2021.09.014 ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma] [https://pubmed.ncbi.nlm.nih.gov/34597799/ PubMed]
+*'''2019:''' Escudier et al. [https://doi.org/10.1093/annonc/mdz056 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/30788497/ PubMed]
+**'''2016:''' Escudier et al. [https://doi.org/10.1093/annonc/mdw328 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/27664262/ PubMed]
+**'''2014:''' Escudier et al. [https://doi.org/10.1093/annonc/mdu259 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/25210086/ PubMed]
+**'''2012:''' Escudier et al. [https://doi.org/10.1093/annonc/mds227 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/22997456/ PubMed]
+**'''2010:''' Escudier & Kataja. [https://doi.org/10.1093/annonc/mdq206 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/20555064/ PubMed]
+**'''2009:''' Escudier & Kataja. [https://doi.org/10.1093/annonc/mdp137 Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454473/ PubMed]
-*'''2016:''' Powles et al. [http://www.europeanurology.com/article/S0302-2838(15)00998-7/fulltext Updated EAU guidelines for clear cell renal cancer patients who fail VEGF targeted therapy] [https://www.ncbi.nlm.nih.gov/pubmed/26508312 PubMed]
+==ISRS==
+*'''2024:''' Siva et al. [https://doi.org/10.1016/s1470-2045(23)00513-2 Stereotactic body radiotherapy for primary renal cell carcinoma: a systematic review and practice guideline from the International Society of Stereotactic Radiosurgery (ISRS)] [https://pubmed.ncbi.nlm.nih.gov/38181809/ PubMed]
-==[http://www.esmo.org/ ESMO]==
+==NCCN==
+*[https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1440 NCCN Guidelines - Kidney Cancer]
-*'''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]
+*'''2022:''' Motzer et al. [https://doi.org/10.6004/Jnccn.2022.0001 Kidney Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/34991070/ PubMed]
-*'''2019:''' Escudier et al. [https://doi.org/10.1093/annonc/mdz056 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
+*'''2017:''' Motzer et al. [https://doi.org/10.6004/jnccn.2017.0100 Kidney Cancer, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology] [https://pubmed.ncbi.nlm.nih.gov/28596261/ PubMed]
+*'''2015:''' Motzer et al. [https://doi.org/10.6004/jnccn.2015.0022 Kidney Cancer, Version 3.2015] [https://pubmed.ncbi.nlm.nih.gov/25691606/ PubMed]
-===Older===
+*'''2014:''' Motzer et al. [https://doi.org/10.6004/jnccn.2014.0018 Kidney cancer, version 2.2014] [https://pubmed.ncbi.nlm.nih.gov/24586079/ PubMed]
+*'''2011:''' Motzer et al. [https://doi.org/10.6004/Jnccn.2011.0082 Kidney cancer.] [https://pubmed.ncbi.nlm.nih.gov/21917622/ PubMed]
-*'''2016:''' Escudier et al. [https://doi.org/10.1093/annonc/mdw328 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/27664262 PubMed]
+*'''2009:''' Motzer et al. [https://doi.org/10.6004/Jnccn.2009.0043 NCCN clinical practice guidelines in oncology: kidney cancer.] [https://pubmed.ncbi.nlm.nih.gov/19555584/ PubMed]
-*'''2014:''' Escudier et al. [https://doi.org/10.1093/annonc/mdu259 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
+*'''2006:''' Motzer et al. [https://doi.org/10.6004/Jnccn.2006.0089 Kidney cancer. Clinical practice guidelines in oncology.] [https://pubmed.ncbi.nlm.nih.gov/17112454/ PubMed]
-*'''2012:''' Escudier et al. [https://doi.org/10.1093/annonc/mds227 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
+*'''2005:''' Motzer et al. Kidney cancer. Clinical practice guidelines. [https://pubmed.ncbi.nlm.nih.gov/19813325/ PubMed]
-*'''2010:''' Escudier et al. [https://doi.org/10.1093/annonc/mdq206 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
-==[https://www.nccn.org/ NCCN]==
-*[https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf NCCN Guidelines - Kidney Cancer]
 ==[http://www.siog.org/ SIOG]==
+*'''2018:''' Kanesvaran et al. [https://doi.org/10.1016/S1470-2045(18)30125-6 Elderly patients with metastatic renal cell carcinoma: position paper from the International Society of Geriatric Oncology] [https://pubmed.ncbi.nlm.nih.gov/29893263/ PubMed]
-*'''2018:''' Kanesvaran et al. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30125-6/fulltext Elderly patients with metastatic renal cell carcinoma: position paper from the International Society of Geriatric Oncology]
+==SITC==
+*'''2019:''' Rini et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6924043/ The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC)] [https://pubmed.ncbi.nlm.nih.gov/31856918/ PubMed]
 =Risk Stratification Calculators=
+*[https://www.mdcalc.com/heng-score-metastatic-renal-cell-carcinoma-rcc-prognosis International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) calculator]
-*[https://www.mdcalc.com/heng-score-metastatic-renal-cell-carcinoma-rcc-prognosis International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) calculator]
+**ref: Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, Mackenzie M, Wood L, Donskov F, Tan MH, Rha SY, Agarwal N, Kollmannsberger C, Rini BI, Choueiri TK; External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013 Feb;14(2):141-8. Epub 2013 Jan 9. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144042/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23312463/ PubMed]
-**ref: Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, Mackenzie M, Wood L, Donskov F, Tan MH, Rha SY, Agarwal N, Kollmannsberger C, Rini BI, Choueiri TK; External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013 Feb;14(2):141-8. Epub 2013 Jan 9. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144042/ link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23312463 PubMed]
+*[https://www.mdcalc.com/memorial-sloan-kettering-cancer-center-mskcc-motzer-score-metastatic-renal-cell-carcinoma-rcc Memorial Sloan Kettering Cancer Center (MSKCC) calculator]
+**ref: Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002 Jan 1;20(1):289-96. [https://doi.org/10.1200/JCO.2002.20.1.289?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed link to original article] [https://pubmed.ncbi.nlm.nih.gov/11773181/ PubMed]
-*[https://www.mdcalc.com/memorial-sloan-kettering-cancer-center-mskcc-motzer-score-metastatic-renal-cell-carcinoma-rcc Memorial Sloan Kettering Cancer Center (MSKCC) calculator]
+*[https://rgulati.shinyapps.io/rcc-risk-calculator/ Mortality and complication risk calculator for a patients with clinical T1 renal cortical mass up to 7 cm] (Dr. Sarah P. Psutka)
-**ref: Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002 Jan 1;20(1):289-96. [https://doi.org/10.1200/JCO.2002.20.1.289?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11773181 PubMed]
-*[https://rgulati.shinyapps.io/rcc-risk-calculator/ Mortality and complication risk calculator for a patients with clinical T1 renal cortical mass ≤ 7 cm] (Dr. Sarah P. Psutka)
 **ref: Psutka SP et al., A clinical decision aid to support personalized treatment selection for patients with stage T1 renal masses: Results from a multi-institutional competing risks analysis including performance status and comorbidity. Working paper. [https://www.urotoday.com/conference-highlights/asco-gu-2020/asco-gu-2020-kidney-cancer/119296-asco-gu-2020-a-novel-clinical-decision-aid-to-support-personalized-treatment-selection-for-patients-with-ct1-renal-cortical-masses-results-from-a-multi-institutional-competing-risks-analysis-including-performance-status-and-comorbidity.html link to news article]
+*[https://www.mdcalc.com/ucla-integrated-staging-system-uiss-renal-cell-carcinoma-rcc UCLA Integrated Staging System (UISS) for Renal Cell Carcinoma (RCC)]
+**ref: Zisman A, Pantuck AJ, Dorey F, Said JW, Shvarts O, Quintana D, Gitlitz BJ, deKernion JB, Figlin RA, Belldegrun AS. Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol. 2001 Mar 15;19(6):1649-57. [https://pubmed.ncbi.nlm.nih.gov/11250993/ PubMed]
+*Leibovich prognostic model
+**ref: Leibovich BC, Lohse CM, Cheville JC, Zaid HB, Boorjian SA, Frank I, Thompson RH, Parker WP. Predicting Oncologic Outcomes in Renal Cell Carcinoma After Surgery. Eur Urol. 2018 May;73(5):772-780. Epub 2018 Feb 3. [https://pubmed.ncbi.nlm.nih.gov/29398265/ PubMed]
 =Adjuvant therapy=
 ==Sunitinib monotherapy {{#subobject:cf6852|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:3c0a01|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 17%" |Study
+! style="width: 20%" |Study
-! style="width: 15%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
-! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 17%" |Comparator
+! style="width: 20%" |Comparator
-! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878938/ Haas et al. 2016 (ECOG-ACRIN E2805)]
 |2006-2010
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-|[[Renal_cell_carcinoma_-_null_regimens#Placebo|Placebo]]
+|1. [[Renal_cell_carcinoma_-_null_regimens#Placebo|Placebo]]<br>2. [[#Sorafenib_monotherapy_999|Sorafenib]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
-|
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1611406 Ravaud et al. 2016 (S-TRAC)]
-|2007-2011
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[Renal_cell_carcinoma_-_null_regimens#Placebo|Placebo]]
-| style="background-color:#91cf60" |Seems to have superior DFS
-| 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===
+#'''ECOG-ACRIN E2805:''' Haas NB, Manola J, Uzzo RG, Flaherty KT, Wood CG, Kane C, Jewett M, Dutcher JP, Atkins MB, Pins M, Wilding G, Cella D, Wagner L, Matin S, Kuzel TM, Sexton WJ, Wong YN, Choueiri TK, Pili R, Puzanov I, Kohli M, Stadler W, Carducci M, Coomes R, DiPaola RS. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016 May 14;387(10032):2008-16. Epub 2016 Mar 9. Erratum in: Lancet. 2016 May 14;387(10032):1998. [https://doi.org/10.1016/S0140-6736(16)00559-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878938/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26969090/ PubMed] [https://clinicaltrials.gov/study/NCT00326898 NCT00326898]
-#'''ECOG-ACRIN E2805:''' Haas NB, Manola J, Uzzo RG, Flaherty KT, Wood CG, Kane C, Jewett M, Dutcher JP, Atkins MB, Pins M, Wilding G, Cella D, Wagner L, Matin S, Kuzel TM, Sexton WJ, Wong YN, Choueiri TK, Pili R, Puzanov I, Kohli M, Stadler W, Carducci M, Coomes R, DiPaola RS. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016 May 14;387(10032):2008-16. Epub 2016 Mar 9. Erratum in: Lancet. 2016 May 14;387(10032):1998. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00559-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878938/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26969090 PubMed] NCT00326898
-#'''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://www.nejm.org/doi/full/10.1056/NEJMoa1611406 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27718781 PubMed]
-##'''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. [http://www.europeanurology.com/article/S0302-2838(17)30772-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28967554 PubMed]
 =Metastatic disease, first-line=
 ==Atezolizumab & Bevacizumab {{#subobject:af0d04|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:34c462|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! 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://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30723-8/fulltext Rini et al. 2019 (IMmotion151)]
+|[https://doi.org/10.1016/S0140-6736(19)30723-8 Rini et al. 2019 (IMmotion151)]
-|2015-2016
+|2015-05-20 to 2016-10-12
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#1a9851" |Phase 3 (E-esc)
 |[[#Sunitinib_monotherapy_2|Sunitinib]]
-| style="background-color:#91cf60" |Seems to have superior PFS
+| style="background-color:#91cf60" |Seems to have superior PFS<sup>1</sup> (co-primary endpoint)<br>Median PFS: 11.2 vs 7.7 mo<br>(HR 0.74, 95% CI 0.57-0.96)
 |-
 |}
+''<sup>1</sup>Reported efficacy is for the PD-L1-positive subgroup, which was the predefined co-primary endpoint.''<br>
+''Note: patients could have clear cell or sarcomatoid histology.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
 *[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1
 ====Targeted therapy====
 *[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
-'''21-day cycles'''
-===References===
-#'''IMmotion151:''' Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30723-8/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/31079938 PubMed] NCT02420821
-==Axitinib monotherapy {{#subobject:e83fa|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:90ba4d|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-![[Overall response rate|ORR]]
-!Comparator [[Overall response rate|ORR]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70465-0/fulltext Hutson et al. 2013 (A4061051)]
-|2010-2011
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#Sorafenib_monotherapy|Sorafenib]]
-| style="background-color:#d9ef8b" |Might have superior PFS (*)
-|32%
-|15%
-|-
-|}
-''Note: in the 2016 update, there is no difference in OS.''
-====Targeted therapy====
-*[[Axitinib (Inlyta)]] as follows:
-**5 mg PO twice per day for at least 2 weeks
-**Then if tolerated and BP not greater than 150/90, increased to 7 mg PO twice per day
-**Then if tolerated and BP not greater than 150/90, increased to 10 mg PO twice per day
-**Dose can be reduced to 2 to 3 mg PO twice per day if needed based on tolerability
-'''Continued indefinitely'''
-===References===
-#'''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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70465-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24206640 PubMed]
-##'''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. [http://www.clinical-genitourinary-cancer.com/article/S1558-7673(16)30134-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27498023 PubMed]
-==Axitinib & Avelumab {{#subobject:e83faz|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen variant #1, weight-based dosing {{#subobject:88ca4d|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716603/ Motzer et al. 2019 (JAVELIN Renal 101)]
-|2016-2017
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[#Sunitinib_monotherapy_2|Sunitinib]]
-| style="background-color:#91cf60" |Seems to have superior OS (*)
-|-
-|}
-''Note: this is not the FDA-recommended dose. Reported efficacy is based on the 2020 update, although the authors state that OS data remains immature.''
-====Targeted therapy====
-*[[Axitinib (Inlyta)]] 5 mg PO twice per day
-====Immunotherapy====
-*[[Avelumab (Bavencio)]] 10 mg/kg IV once on day 1
-'''14-day cycles'''
-===Regimen variant #2, flat dosing {{#subobject:33ca4d|Variant=1}}===
-{| class="wikitable" style="color:white; background-color:#404040"
-|<small>'''FDA-recommended dose'''</small>
-|-
-|}
-''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1816047 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716603/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30779531 PubMed] 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://pubmed.ncbi.nlm.nih.gov/32339648/ PubMed]
-==Axitinib & Pembrolizumab {{#subobject:e83gac|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:22bc4d|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years 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://www.nejm.org/doi/full/10.1056/NEJMoa1816714 Rini et al. 2019 (KEYNOTE-426)]
-|2016-2018
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[#Sunitinib_monotherapy_2|Sunitinib]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|}
-====Targeted therapy====
-*[[Axitinib (Inlyta)]] 5 mg PO twice per day
-====Immunotherapy====
-*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
 '''21-day cycles'''
+</div></div>
-===References===
+===References ===
+#'''IMmotion151:''' Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. [https://doi.org/10.1016/S0140-6736(19)30723-8 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31079938/ PubMed] [https://clinicaltrials.gov/study/NCT02420821 NCT02420821]
-#'''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://www.nejm.org/doi/full/10.1056/NEJMoa1816714 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30779529 PubMed] NCT02853331
+##'''Update:''' Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Alekseev BY, Lee JL, Suarez C, Stroyakovskiy D, De Giorgi U, Donskov F, Mellado B, Banchereau R, Hamidi H, Khan O, Craine V, Huseni M, Flinn N, Dubey S, Rini BI. Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol. 2022 Feb 1;8(2):275-280. [https://doi.org/10.1001/jamaoncol.2021.5981 link to original article] [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8855230/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34940781/ PubMed]
-##'''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://www.ncbi.nlm.nih.gov/pubmed/33284113 PubMed]
-==Bevacizumab monotherapy {{#subobject:29beb2|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:433717|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-![[Overall response rate|ORR]]
-!Comparator [[Overall response rate|ORR]]
-|-
-|[https://doi.org/10.1200/jco.2007.11.5154 Bukowski et al. 2007]
-|2004
-| style="background-color:#1a9851" |Randomized Phase II (C)
-|[[#Erlotinib_.26_Bevacizumab|Erlotinib & Bevacizumab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoints of ORR/PFS
-|13%
-|14%
-|-
-|}
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV over 90 minutes once on day 1
-**Can subsequently be reduced to 60 and 30 minute infusions as tolerated
-'''14-day cycle for up to 52 cycles (2 years)'''
-===References===
-#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. [https://doi.org/10.1200/jco.2007.11.5154 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17876014 PubMed]
-==Bevacizumab & Interferon alfa-2a {{#subobject:808d58|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen variant #1, 1 year {{#subobject:dbebac|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years 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://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61904-7/fulltext Escudier et al. 2007 (AVOREN)]
-|2004-2005
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (*)
-|-
-|}
-''Note: Reported efficacy for AVOREN is based on the 2010 update.''
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
-====Immunotherapy====
-*[[Interferon alfa-2a (Roferon-A)]] 9,000,000 units SC 3 times per week
-**Dose can be reduced to 3,000,000 or 6,000,000 units SC 3 times per week based on tolerability
-'''14-day cycle for up to 26 cycles (1 year)'''
-====Subsequent treatment====
-*[[#Bevacizumab_monotherapy_2|Bevacizumab maintenance]]
-===Regimen variant #2, indefinite {{#subobject:d136cc|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651074/ Rini et al. 2008 (CALGB 90206)]
-|2003-2005
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
-| style="background-color:#d9ef8b" |Might have superior OS (*)
-|-
-|[https://doi.org/10.1200/JCO.2013.50.5305 Rini et al. 2013 (INTORACT)]
-|2008-2010
-| style="background-color:#1a9851" |Phase III (C)
-|Temsirolimus & Bevacizumab
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-''Note: Reported efficacy for CALGB 90206 is based on the 2010 update.''
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
-====Immunotherapy====
-*[[Interferon alfa-2a (Roferon-A)]] 9,000,000 units SC 3 times per week
-**Dose can be reduced to 3,000,000 or 6,000,000 units SC 3 times per week based on tolerability
-'''14-day cycles'''
-===References===
-#'''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://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61904-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18156031 PubMed]
-##'''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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/18936475 PubMed] 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://www.ncbi.nlm.nih.gov/pubmed/20368558 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. [https://doi.org/10.1200/JCO.2013.50.5305 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24297945 PubMed] NCT00631371
-==Cabozantinib monotherapy {{#subobject:e3ff16|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:a0ee63|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%" |Years 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455807/ Choueiri et al. 2016 (CABOSUN)]
-|2013-2015
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
-|[[#Sunitinib_monotherapy_2|Sunitinib]]
-| style="background-color:#1a9850" |Superior PFS (*)
-|-
-|}
-''Note: reported efficacy is based on the 2018 update; in this update, independent review gave an ORR of 20% (95% CI 12-31%) in the experimental arm and 9% (95% CI 4-18%) in the control arm.''
-====Targeted therapy====
-*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 60 mg PO once per day
-'''Continued indefinitely'''
-===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. 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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455807/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28199818 PubMed]
-##'''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://www.ejcancer.com/article/S0959-8049(18)30181-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057479/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29550566 PubMed]
-==Cabozantinib & Nivolumab {{#subobject:e3igp6|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen variant #1, bi-weekly nivolumab {{#subobject:ajg89a|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%" |Years 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/nejmoa2026982 Choueiri et al. 2021 (CheckMate 9ER)]
-|2017-2019
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[#Sunitinib_monotherapy_2|Sunitinib]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|}
-====Targeted therapy====
-*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 40 mg PO once per day
-====Immunotherapy====
-*[[Nivolumab (Opdivo)]] as follows:
-**Cycles 1 to 52: 240 mg IV over 30 minutes once on day 1
-'''14-day cycles'''
-===Regimen variant #2, monthly nivolumab {{#subobject:aj9iya|Variant=1}}===
-{| class="wikitable" style="color:white; background-color:#404040"
-|<small>'''FDA-recommended dose'''</small>
-|-
-|}
-''Note: this dosing does not appear to have been used in a trial, but is recommended by the FDA.''
-====Targeted therapy====
-*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 40 mg PO once per day
-====Immunotherapy====
-*[[Nivolumab (Opdivo)]] as follows:
-**Cycles 1 to 26: 480 mg IV over 30 minutes once on day 1
-'''28-day cycles'''
-===References===
-#'''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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33657295/ PubMed] NCT03141177
-==Erlotinib & Bevacizumab {{#subobject:1a1b7b|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:1e7b71|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years 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 II (E-esc)
-|[[#Bevacizumab_monotherapy|Bevacizumab]]
-| style="background-color:#ffffbf" |Did not meet primary endpoints of ORR/PFS
-|-
-|}
-====Targeted therapy====
-*[[Erlotinib (Tarceva)]] 150 mg PO once per day
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV over 90 minutes once on day 1
-**Can subsequently be reduced to 60 and 30 minute infusions as tolerated
-'''14-day cycle for up to 52 cycles (2 years)'''
-===References===
-#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. [https://doi.org/10.1200/jco.2007.11.5154 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17876014 PubMed]
 ==Everolimus monotherapy {{#subobject:b3af63|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:474ade|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! 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]]
 |-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
 |2009-2011
-| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
+| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 |[[#Sunitinib_monotherapy_2|Sunitinib]]
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS (primary endpoint)
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879109/ Tannir et al. 2015 (ESPN)]
-|2010-2013
-| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
-|[[#Sunitinib_monotherapy_2|Sunitinib]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00515-X/fulltext Armstrong et al. 2016 (ASPEN)]
-|2010-2013
-| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
-|[[#Sunitinib_monotherapy_2|Sunitinib]]
-| style="background-color:#fee08b" |Might have inferior PFS
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
 *[[Everolimus (Afinitor)]] 10 mg PO once per day
-**Dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability
 '''Continued indefinitely'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
+*RECORD-3, upon progression: Second-line [[#Sunitinib_monotherapy_3|Sunitinib]]
-*RECORD-3, upon progression: [[#Sunitinib_monotherapy_3|Sunitinib]]
+</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===
-<!-- # '''Abstract:''' Robert John Motzer, Carlos H. Barrios, Tae Min Kim, Silvia Falcon, Thomas Cosgriff, W. Graydon Harker, Kenneth B. Pittman, Roberto Sabbatini, Sun Young Rha, Thomas W. Flaig, Ray D. Page, Sevil E. Bavbek, J. Thaddeus Beck, Poulam M Patel, Edward Schiff, Alexandra Vaury, Julie Niolat, Sven Gogov, Ozlem Anak, Jennifer Knox. Record-3: Phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC). 2013 ASCO Annual Meeting abstract 4504. [http://meetinglibrary.asco.org/content/113103-132 link to abstract] -->
+#'''RECORD-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [https://doi.org/10.1200/jco.2013.54.6911 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25049330/ PubMed] [https://clinicaltrials.gov/study/NCT00903175 NCT00903175]
-#'''RECORD-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [https://doi.org/10.1200/jco.2013.54.6911 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25049330 PubMed] NCT00903175
-#'''ESPN:''' Tannir NM, Jonasch E, Albiges L, Altinmakas E, Ng CS, Matin SF, Wang X, Qiao W, Dubauskas Lim Z, Tamboli P, Rao P, Sircar K, Karam JA, McDermott DF, Wood CG, Choueiri TK. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol. 2016 May;69(5):866-74. Epub 2015 Nov 26. [http://www.europeanurology.com/article/S0302-2838(15)01083-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879109/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26626617 PubMed] NCT01185366
-#'''ASPEN:''' Armstrong AJ, Halabi S, Eisen T, Broderick S, Stadler WM, Jones RJ, Garcia JA, Vaishampayan UN, Picus J, Hawkins RE, Hainsworth JD, Kollmannsberger CK, Logan TF, Puzanov I, Pickering LM, Ryan CW, Protheroe A, Lusk CM, Oberg S, George DJ. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016 Mar;17(3):378-88. Epub 2016 Jan 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00515-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26794930 PubMed] NCT01108445
-<br />
-==Everolimus & Lenvatinib {{#subobject:e83gac|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:22bc4d|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years 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://www.nejm.org/doi/full/10.1056/NEJMoa2035716 Motzer et al. 2021 (CLEAR)]
-|2016-2019
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[#Sunitinib_monotherapy_2|Sunitinib]]
-| style="background-color:#1a9850" |Superior PFS (primary) and OS (secondary)
-|-
-|}
-====Targeted therapy====
-*[[Everolimus (Afinitor)]] 5 mg PO once per day
-*[[Lenvatinib (Lenvima)]] 18 mg PO once per day
-'''21-day cycles'''
-===References===
-#'''CLEAR:''' Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Feb 13. Online ahead of print. [https://www.nejm.org/doi/full/10.1056/NEJMoa2035716 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/33616314/ PubMed] NCT02811861
 ==Gemcitabine & Sunitinib {{#subobject:ec76af|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
+===Regimen {{#subobject:py1|Variant=1}}===
-|[[#top|back to top]]
+{| class="wikitable" style="width: 60%; text-align:center;"
-|}
-===Regimen variant #1 {{#subobject:py1|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
 ! style="width: 33%" |Study
-! style="width: 33%" |Years of enrollment
+! style="width: 33%" |Dates of enrollment
 ! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.29503/abstract Michaelson et al. 2015 (MGH 07-212)]
+|[https://doi.org/10.1002/cncr.29503 Michaelson et al. 2015 (MGH 07-212)]
 |2007-2013
-| style="background-color:#91cf61" |Phase II
+| style="background-color:#91cf61" |Phase 2
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
 ====Targeted therapy====
 *[[Sunitinib (Sutent)]] 37.5 mg PO once per day on days 1 to 14
 '''21-day cycles'''
+</div></div>
-===Regimen variant #2 {{#subobject:e9a6b9|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2011.10096.x/full Pandya et al. 2011]
-| style="background-color:#ffffbe" |Retrospective
-|-
-|}
-====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'''
 ===References===
+#'''MGH 07-212:''' Michaelson MD, McKay RR, Werner L, Atkins MB, Van Allen EM, Olivier KM, Song J, Signoretti S, McDermott DF, Choueiri TK. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer. 2015 Oct 1;121(19):3435-43. Epub 2015 Jun 8. [https://doi.org/10.1002/cncr.29503 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26058385/ PubMed] [https://clinicaltrials.gov/study/NCT00556049 NCT00556049]
-#'''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://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2011.10096.x/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21320274 PubMed]
-#'''MGH 07-212:''' Michaelson MD, McKay RR, Werner L, Atkins MB, Van Allen EM, Olivier KM, Song J, Signoretti S, McDermott DF, Choueiri TK. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer. 2015 Oct 1;121(19):3435-43. Epub 2015 Jun 8. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.29503/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26058385 PubMed] NCT00556049
 ==High-dose Interleukin-2 {{#subobject:d95f4e|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 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 #1, 1.8 MU/kg/day, intermittent {{#subobject:ca472e|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! 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]]
 |-
-|[http://jamanetwork.com/journals/jama/article-abstract/368156 Rosenberg et al. 1994]
+|[https://doi.org/10.1001/jama.1994.03510360033032 Rosenberg et al. 1994]
 |1985-1992
 | style="background-color:#91cf61" |Non-randomized
@@ Line 655: / Line 202: @@
 |[https://doi.org/10.1200/JCO.1995.13.3.688 Fyfe et al. 1995]
 |NR
-| style="background-color:#91cf61" |Phase II (RT)
+| style="background-color:#91cf61" |Phase 2 (RT)
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 |-
 |[https://doi.org/10.1200/jco.2005.03.206 McDermott et al. 2005]
-|1997-2000
+| 1997-2000
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|Subcutaneous IL-2 & Interferon
+|[[#Interferon_alfa-2a_.26_Interleukin-2_999|Subcutaneous IL-2 & Interferon]]
 | style="background-color:#d9ef8b" |Might have superior PFS
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
 *[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 600,000 units/kg IV every 8 hours for up to 14 doses per week, on days 1 to 5, 15 to 19
+====Supportive therapy====
-====Supportive medications====
 *[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10, 15 to 24
 *All antihypertensive therapy discontinued at least 24 hours before each cycle
@@ Line 680: / Line 225: @@
 *[[Meperidine (Demerol)]] 25 to 50 mg PO every 6 hours for chills and rigors
 *"An antidiarrheal agent, antiemetics, anxiolytics, diuretics, and vasopressors as needed"
 '''28-day cycle for up to 3 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #2, 2.16 MU/kg/day, intermittent, goal 10.8 MU {{#subobject:9867a|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
@@ Line 693: / Line 238: @@
 | rowspan="2" |[https://doi.org/10.1200/JCO.1994.12.8.1572 Yang et al. 1994]
 | rowspan="2" |1991-1993
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 |1. [[#Low-dose_Interleukin-2|LD IL-2 (IV)]]
 | style="background-color:#91cf60" |Seems to have superior ORR
@@ Line 702: / Line 247: @@
 |}
 ''Note: reported efficacy is based on the 2003 update.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
 *[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours for up to 15 doses
 **Then after 7 to 10 days of rest, [[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours for up to 15 doses is given again
 '''8-week cycle for up to 2 cycles'''
+</div></div><br>
-===Regimen variant #3, 2.16 MU/kg/day, intermittent, goal 8.64 MU {{#subobject:9a662|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="width: 50%; text-align:center;"
+===Regimen variant #3, 5 MU/m<sup>2</sup>/day, CI {{#subobject:bd04b6|Variant=1}}===
-! style="width: 50%" |Study
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! 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
-|-
-|}
-====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)
-**Then after 10 to 15 days of rest, [[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours for up to 12 doses is given again
-====Supportive medications====
-*"Routine administration of antipyretics, anti-inflammatories, antiemetics, antidiarrheals, and H2 antagonists."
-====Subsequent treatment====
-*After this one course of treatments--defined by the paper as "two cycles"--patients with stable to improved disease would receive additional courses of treatments every 2 months (no maximum number of courses listed)
-===Regimen variant #4, 5 MU/m<sup>2</sup>/day, CI {{#subobject:bd04b6|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
@@ Line 741: / Line 264: @@
 |[https://doi.org/10.1200/JCO.1999.17.8.2521 Figlin et al. 1999]
 |1994-1997
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|IL-2 & CD8+ TILs
+|[[#Interleukin-2_.26_TILs_999|IL-2 & CD8+ TILs]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
 *[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 5,000,000 units/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on days 1, 8, 15, 22 (total dose per cycle: 80 MU/m<sup>2</sup>)
 '''8-week cycles'''
+</div></div>
 ===References===
+#Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994 Mar 23-30;271(12):907-13. [https://doi.org/10.1001/jama.1994.03510360033032 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8120958/ PubMed]
-#Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994 Mar 23-30;271(12):907-13. [http://jamanetwork.com/journals/jama/article-abstract/368156 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8120958 PubMed]
+#Yang JC, Topalian SL, Parkinson D, Schwartzentruber DJ, Weber JS, Ettinghausen SE, White DE, Steinberg SM, Cole DJ, Kim HI, Levin R, Guleria A, MacFarlane MP, White RL, Einhorn JH, Seipp CA, Rosenberg SA. Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol. 1994 Aug;12(8):1572-6. [https://doi.org/10.1200/JCO.1994.12.8.1572 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8040669/ PubMed]
-#Yang JC, Topalian SL, Parkinson D, Schwartzentruber DJ, Weber JS, Ettinghausen SE, White DE, Steinberg SM, Cole DJ, Kim HI, Levin R, Guleria A, MacFarlane MP, White RL, Einhorn JH, Seipp CA, Rosenberg SA. Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol. 1994 Aug;12(8):1572-6. [https://doi.org/10.1200/JCO.1994.12.8.1572 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8040669 PubMed]
+##'''Update:''' Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. [https://doi.org/10.1200/jco.2003.02.122 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275327/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12915604/ PubMed]
-##'''Update:''' Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. [https://doi.org/10.1200/jco.2003.02.122 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275327/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12915604 PubMed]
+#Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995 Mar;13(3):688-96. [https://doi.org/10.1200/JCO.1995.13.3.688 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7884429/ PubMed]
-#Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995 Mar;13(3):688-96. [https://doi.org/10.1200/JCO.1995.13.3.688 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7884429 PubMed]
+#Figlin RA, Thompson JA, Bukowski RM, Vogelzang NJ, Novick AC, Lange P, Steinberg GD, Belldegrun AS. Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol. 1999 Aug;17(8):2521-9. [https://doi.org/10.1200/JCO.1999.17.8.2521 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10561318/ PubMed]
-#Figlin RA, Thompson JA, Bukowski RM, Vogelzang NJ, Novick AC, Lange P, Steinberg GD, Belldegrun AS. Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol. 1999 Aug;17(8):2521-9. [https://doi.org/10.1200/JCO.1999.17.8.2521 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10561318 PubMed]
+#McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, Kirkwood JM, Gordon MS, Sosman JA, Ernstoff MS, Tretter CP, Urba WJ, Smith JW, Margolin KA, Mier JW, Gollob JA, Dutcher JP, Atkins MB. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005 Jan 1;23(1):133-41. [https://doi.org/10.1200/jco.2005.03.206 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15625368/ PubMed]
-#McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, Kirkwood JM, Gordon MS, Sosman JA, Ernstoff MS, Tretter CP, Urba WJ, Smith JW, Margolin KA, Mier JW, Gollob JA, Dutcher JP, Atkins MB. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005 Jan 1;23(1):133-41. [https://doi.org/10.1200/jco.2005.03.206 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15625368 PubMed]
-#'''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://onlinelibrary.wiley.com/doi/10.1002/cncr.23552/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486432/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18457330 PubMed]
 ==Low-dose Interleukin-2 {{#subobject:a2e938|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
 LD IL-2: '''<u>L</u>'''ow-'''<u>D</u>'''ose '''<u>I</u>'''nter'''<u>L</u>'''eukin-'''<u>2</u>'''
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #1, Intravenous {{#subobject:445b6c|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! 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]]
 |-
 | rowspan="2" |[https://doi.org/10.1200/JCO.1994.12.8.1572 Yang et al. 1994]
-| rowspan="2" |1991-1993
+| rowspan="2" | 1991-1993
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-de-esc)
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-de-esc)
 |1. [[#High-dose_Interleukin-2|High-dose IL-2]]
 | style="background-color:#fc8d59" |Seems to have inferior ORR
@@ Line 787: / Line 303: @@
 |}
 ''Note: efficacy is based on the 2003 update.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
 *[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] as follows:
-**72,000 units/kg IV every 8 hours for up to 15 doses
+**Week 1: 72,000 units/kg IV every 8 hours for up to 15 doses
 **Then after 7 to 10 days of rest: 72,000 units/kg IV every 8 hours for up to 15 doses is given again
 '''8-week cycle for up to 2 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #2, Subcutaneous {{#subobject:cbb5b2|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
@@ Line 805: / Line 321: @@
 | rowspan="2" |[https://doi.org/10.1200/JCO.1994.12.8.1572 Yang et al. 1994]
 | rowspan="2" |1991-1993
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-de-esc)
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-de-esc)
 |1. [[#High-dose_Interleukin-2|High-dose IL-2]]
 | style="background-color:#fc8d59" |Seems to have inferior ORR
@@ Line 814: / Line 330: @@
 |}
 ''Note: this arm was added to the trial after the interim results were announced in 1994.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
 *[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] as follows:
 **Week 1: 250,000 units/kg SC once per day for 5 days
 **Weeks 2 to 6: 125,000 units/kg SC once per day for 5 days per week
 '''8-week cycle for up to 2 cycles'''
+</div></div>
 ===References===
+#Yang JC, Topalian SL, Parkinson D, Schwartzentruber DJ, Weber JS, Ettinghausen SE, White DE, Steinberg SM, Cole DJ, Kim HI, Levin R, Guleria A, MacFarlane MP, White RL, Einhorn JH, Seipp CA, Rosenberg SA. Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol. 1994 Aug;12(8):1572-6. [https://doi.org/10.1200/JCO.1994.12.8.1572 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8040669/ PubMed]
-#Yang JC, Topalian SL, Parkinson D, Schwartzentruber DJ, Weber JS, Ettinghausen SE, White DE, Steinberg SM, Cole DJ, Kim HI, Levin R, Guleria A, MacFarlane MP, White RL, Einhorn JH, Seipp CA, Rosenberg SA. Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol. 1994 Aug;12(8):1572-6. [https://doi.org/10.1200/JCO.1994.12.8.1572 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8040669 PubMed]
+##'''Update:''' Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. [https://doi.org/10.1200/jco.2003.02.122 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275327/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12915604/ PubMed]
-##'''Update:''' Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. [https://doi.org/10.1200/jco.2003.02.122 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275327/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12915604 PubMed]
 ==Interferon alfa-2a monotherapy {{#subobject:8f04d6|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen variant #1, 5 MU 5x per week {{#subobject:f49d4e|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
+! style="width: 20%" | Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
@@ Line 842: / Line 352: @@
 |[https://doi.org/10.1093/oxfordjournals.annonc.a059097 Sagaster et al. 1995]
 |NR-1992
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|Cimetidine, Coumarin, IFN alfa-2a
+|[[#Cimetidine.2C_Coumarin.2C_Interferon_alfa-2a_999|Cimetidine, Coumarin, IFN alfa-2a]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
+*[[Interferon alfa-2a (Roferon-A)]] 5,000,000 units SC once per day on days 1 to 5 (5 times per week)
-*[[Interferon alfa-2a (Roferon-A)]] 5,000,000 units SC 5 times per week
+'''7-day cycles'''
+</div></div><br>
-'''Continued indefinitely'''
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #2, 9 MU TIW {{#subobject:524ccc|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! 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://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61904-7/fulltext Escudier et al. 2007 (AVOREN)]
-|2004-2005
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Bevacizumab_.26_Interferon_alfa-2a|Bevacizumab & Interferon alfa-2a]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (*)
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651074/ Rini et al. 2008 (CALGB 90206)]
-|2003-2005
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Bevacizumab_.26_Interferon_alfa-2a|Bevacizumab & Interferon alfa-2a]]
-| style="background-color:#fee08b" |Might have inferior OS (*)
-|-
-|[https://doi.org/10.1200/jco.2008.19.3342 Escudier et al. 2009]
-|2005
-| style="background-color:#1a9851" |Randomized Phase II (C)
-|[[#Sorafenib_monotherapy|Sorafenib]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835851/ Gore et al. 2010 (MRC RE04/EORTC GU 30012)]
 |2001-2006
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|5-FU, Interferon alfa-2a, IL-2
+|[[#Fluorouracil.2C_Interferon_alfa-2a.2C_Interleukin-2_999|5-FU, Interferon alfa-2a, IL-2]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[http://clincancerres.aacrjournals.org/content/22/13/3172.long Hawkins et al. 2016]
+|[https://doi.org/10.1158/1078-0432.ccr-15-0580 Hawkins et al. 2016 (Active Biotech 06762004)]
 |2007-2010
-| style="background-color:#1a9851" |Phase II/III (C)
+| style="background-color:#1a9851" |Phase 2/3 (C)
-|Naptumomab estafenatox + IFNα
+|[[#Naptumomab estafenatox_.26_Interferon_alfa_999|Naptumomab estafenatox + IFNα]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-''Note: reported efficacy for AVOREN is based on the 2010 update. Reported efficacy for CALGB 90206 is based on the 2010 update.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
+*[[Interferon alfa-2a (Roferon-A)]] 9,000,000 units SC 3 times per week
-*[[Interferon alfa-2a (Roferon-A)]] 9,000,000 units SC 3 times per week
-**Some protocols: Dose can be reduced to 3 or 6,000,000 units SC 3 times per week based on tolerability
 '''Given for varying lengths of time; see individual trials'''
+</div>
+<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 #3, 9 MU daily, with lead-in {{#subobject:5f04fc|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
+! style="width: 20%" | Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
@@ Line 910: / Line 406: @@
 |[https://doi.org/10.1200/JCO.2000.18.16.2972 Motzer et al. 2000]
 |1994-1996
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|IFN alfa & 13-CRA
+|[[#Interferon_alfa_.26_13-CRA_999|IFN alfa & 13-CRA]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
+| style="background-color:#ffffbf" | Did not meet primary endpoint of ORR
 |-
 |}
+''Note: Interferon alfa-2a dose was increased only if the prior dose was tolerated.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
 *[[Interferon alfa-2a (Roferon-A)]] as follows:
-**Week 1: 3,000,000 units SC once per day
+**Cycle 1: 3,000,000 units SC once per day on days 1 to 7
-**Week 2 (if prior dose tolerated): 6,000,000 units SC once per day
+**Cycle 2: 6,000,000 units SC once per day on days 1 to 7
-**Week 3 onwards (if prior dose tolerated): 9,000,000 units SC once per day
+**Cycle 3 onwards: 9,000,000 units SC once per day on days 1 to 7
+'''7-day cycles'''
-'''Continued indefinitely'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-===Regimen variant #4, 9 MU TIW, with lead-in {{#subobject:2c65a4|Variant=1}}===
+===Regimen variant #4, 10 MU TIW, with lead-in {{#subobject:leadd5|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! 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://www.nejm.org/doi/full/10.1056/NEJMoa065044 Motzer et al. 2007 (A618-1034)]
+|[https://doi.org/10.1016/S0140-6736(98)03544-2 Ritchie et al. 1999 (MRC RE01)]
-|2004-2005
+|1992-1997
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
-|[[#Sunitinib_monotherapy_2|Sunitinib]]
+|[[Renal_cell_carcinoma_-_historical#Medroxyprogesterone_acetate_monotherapy|MPA]]
-| style="background-color:#d73027" |Inferior PFS
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 8.5 vs 6 mo<br>(HR 0.72, 95% CI 0.55-0.94)
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
 *[[Interferon alfa-2a (Roferon-A)]] as follows:
-**Week 1: 3,000,000 units SC 3 times per week
+**Cycle 1: 5,000,000 units SC once per day on days 1 & 3, then 10,000,000 units SC once on day 5
-**Week 2 (if prior dose tolerated): 6,000,000 units SC 3 times per week
+**Cycles 2 to 12: 10,000,000 units SC once per day on days 1, 3, 5 (3 times per week)
-**Week 3 onwards (if prior dose tolerated): 9,000,000 units SC 3 times per week
+'''7-day cycle for 12 cycles'''
+</div></div><br>
-'''Continued indefinitely'''
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen variant #5, 10 MU TIW {{#subobject:800dd5|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! 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://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03544-2/fulltext Ritchie et al. 1999 (MRC RE01)]
-|1992-1997
-| style="background-color:#1a9851" |Phase III (E-switch-ooc)
-|MPA
-| style="background-color:#91cf60" |Seems to have superior OS
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835851/ Gore et al. 2010 (MRC RE04/EORTC GU 30012)]
 |2001-2006
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|Chemoimmunotherapy
+|[[#Fluorouracil.2C_Interferon_alfa-2a.2C_Interleukin-2_999|5-FU, Interferon alfa-2a, IL-2]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
+*[[Interferon alfa-2a (Roferon-A)]] 10,000,000 units SC once per day on days 1, 3, 5 (3 times per week)
-*[[Interferon alfa-2a (Roferon-A)]] 10,000,000 units SC 3 times per week
+'''7-day cycles'''
-**In MRC RE01, the first two doses were 5,000,000 units
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-'''12-week course (MRC RE01) or continued indefinitely (MRC RE04/EORTC GU 30012)'''
 ===Regimen variant #6, 18 MU TIW, with lead-in {{#subobject:b28245|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
@@ Line 986: / Line 476: @@
 |[https://doi.org/10.1093/oxfordjournals.annonc.a058185 Fosså et al. 1992]
 |1985-1986
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|IFN alfa-2a & Vinblastine
+|[[#Interferon_alfa-2a_.26_Vinblastine_999|IFN alfa-2a & Vinblastine]]
 | style="background-color:#ffffbf" |Did not meet efficacy endpoints
 |-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa066838 Hudes et al. 2007 (ARCC)]
+| rowspan="2" |[https://doi.org/10.1056/NEJMoa066838 Hudes et al. 2007 (ARCC)]
 | rowspan="2" |2003-2005
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
-|1. Interferon alfa-2a & Temsirolimus
+|1. [[#Interferon_alfa-2a_.26_Temsirolimus_999|Interferon alfa-2a & Temsirolimus]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
@@ Line 1,000: / Line 490: @@
 |-
 |}
+''Note: Interferon alfa-2a dose was increased only if the prior dose was tolerated.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
 *[[Interferon alfa-2a (Roferon-A)]] as follows:
-**Week 1: 3,000,000 units SC 3 times per week
+**Cycle 1: 3,000,000 units SC once per day on days 1, 3, 5
-**Week 2 (if prior dose tolerated): 9,000,000 units SC 3 times per week
+**Cycle 2: 9,000,000 units SC once per day on days 1, 3, 5
-**Week 3 onwards (if prior dose tolerated): 18,000,000 units SC 3 times per week
+**Cycle 3 onwards: 18,000,000 units SC once per day on days 1, 3, 5
-***If higher doses cannot be tolerated, highest tolerable doses of 3,000,000, 4,500,500, or 6,000,000 units can be used
+'''7-day cycles'''
+</div>
-'''Continued indefinitely'''
+<div class="toccolours" style="background-color:#fff2ae">
+====Dose and schedule modifications====
-===References===
+*If higher doses cannot be tolerated, highest tolerable doses of 3,000,000, 4,500,500, or 6,000,000 units can be used
+</div></div>
-#Fosså SD, Martinelli G, Otto U, Schneider G, Wander H, Oberling F, Bauer HW, Achtnicht U, Holdener EE. Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: results of a European multi-center phase III study. Ann Oncol. 1992 Apr;3(4):301-5. [https://doi.org/10.1093/oxfordjournals.annonc.a058185 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/1390305 PubMed]
+=== References===
-#Sagaster P, Micksche M, Flamm J, Ludwig H. Randomised study using IFN-alpha versus IFN-alpha plus coumarin and cimetidine for treatment of advanced renal cell cancer. Ann Oncol. 1995 Dec;6(10):999-1003. [https://doi.org/10.1093/oxfordjournals.annonc.a059097 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8750152 PubMed]
+# Fosså SD, Martinelli G, Otto U, Schneider G, Wander H, Oberling F, Bauer HW, Achtnicht U, Holdener EE. Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: results of a European multi-center phase III study. Ann Oncol. 1992 Apr;3(4):301-5. [https://doi.org/10.1093/oxfordjournals.annonc.a058185 link to original article] [https://pubmed.ncbi.nlm.nih.gov/1390305/ PubMed]
-#'''MRC RE01:''' Ritchie A, Griffiths G, Parmar M; Medical Research Council Renal Cancer Collaborators. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet. 1999 Jan 2;353(9146):14-7. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)03544-2/fulltext link to original article] '''contans protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10023944 PubMed]
+# Sagaster P, Micksche M, Flamm J, Ludwig H. Randomised study using IFN-alpha versus IFN-alpha plus coumarin and cimetidine for treatment of advanced renal cell cancer. Ann Oncol. 1995 Dec;6(10):999-1003. [https://doi.org/10.1093/oxfordjournals.annonc.a059097 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/8750152/ PubMed]
-#Motzer RJ, Murphy BA, Bacik J, Schwartz LH, Nanus DM, Mariani T, Loehrer P, Wilding G, Fairclough DL, Cella D, Mazumdar M. Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol. 2000 Aug;18(16):2972-80. [https://doi.org/10.1200/JCO.2000.18.16.2972 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10944130 PubMed]
+#'''MRC RE01:''' Ritchie A, Griffiths G, Parmar M; Medical Research Council Renal Cancer Collaborators. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet. 1999 Jan 2;353(9146):14-7. [https://doi.org/10.1016/S0140-6736(98)03544-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10023944/ PubMed]
-#'''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://www.nejm.org/doi/full/10.1056/NEJMoa065044 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17215529 PubMed]
+#Motzer RJ, Murphy BA, Bacik J, Schwartz LH, Nanus DM, Mariani T, Loehrer P, Wilding G, Fairclough DL, Cella D, Mazumdar M. Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol. 2000 Aug;18(16):2972-80. [https://doi.org/10.1200/JCO.2000.18.16.2972 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10944130/ 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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646307/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19487381 PubMed] content property of [http://hemonc.org HemOnc.org]
+#'''ARCC:''' Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. [https://doi.org/10.1056/NEJMoa066838 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17538086/ PubMed] [https://clinicaltrials.gov/study/NCT00065468 NCT00065468]
-#'''ARCC:''' Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. [https://www.nejm.org/doi/full/10.1056/NEJMoa066838 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538086 PubMed]
+#'''MRC RE04/EORTC GU 30012:''' Gore ME, Griffin CL, Hancock B, Patel PM, Pyle L, Aitchison M, James N, Oliver RT, Mardiak J, Hussain T, Sylvester R, Parmar MK, Royston P, Mulders PF. Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial. Lancet. 2010 Feb 20;375(9715):641-8. Epub 2010 Feb 10. [https://doi.org/10.1016/S0140-6736(09)61921-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835851/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20153039/ PubMed] [https://clinicaltrials.gov/study/NCT00053820 NCT00053820]
-#'''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://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61904-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18156031 PubMed]
+#'''Active Biotech 06762004:''' Hawkins RE, Gore M, Shparyk Y, Bondar V, Gladkov O, Ganev T, Harza M, Polenkov S, Bondarenko I, Karlov P, Karyakin O, Khasanov R, Hedlund G, Forsberg G, Nordle Ö, Eisen T. A randomized phase II/III study of naptumomab estafenatox + IFNα versus IFNα in renal cell carcinoma: final analysis with baseline biomarker subgroup and trend analysis. Clin Cancer Res. 2016 Jul 1;22(13):3172-81. Epub 2016 Feb 5. [https://doi.org/10.1158/1078-0432.ccr-15-0580 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26851187/ PubMed] [https://clinicaltrials.gov/study/NCT00420888 NCT00420888]
-##'''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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/18936475 PubMed] 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://www.ncbi.nlm.nih.gov/pubmed/20368558 PubMed]
-#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://www.ncbi.nlm.nih.gov/pubmed/19171708 PubMed] NCT00117637
-#'''MRC RE04/EORTC GU 30012:''' Gore ME, Griffin CL, Hancock B, Patel PM, Pyle L, Aitchison M, James N, Oliver RT, Mardiak J, Hussain T, Sylvester R, Parmar MK, Royston P, Mulders PF. Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial. Lancet. 2010 Feb 20;375(9715):641-8. Epub 2010 Feb 10. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61921-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835851/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20153039 PubMed] ISRCTN46518965
-#Hawkins RE, Gore M, Shparyk Y, Bondar V, Gladkov O, Ganev T, Harza M, Polenkov S, Bondarenko I, Karlov P, Karyakin O, Khasanov R, Hedlund G, Forsberg G, Nordle Ö, Eisen T. A randomized phase II/III study of naptumomab estafenatox + IFNα versus IFNα in renal cell carcinoma: final analysis with baseline biomarker subgroup and trend analysis. Clin Cancer Res. 2016 Jul 1;22(13):3172-81. Epub 2016 Feb 5. [http://clincancerres.aacrjournals.org/content/22/13/3172.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26851187 PubMed]
-==Interferon alfa-2a & Interleukin-2 {{#subobject:77d26e|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:89bca8|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years 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://www.nejm.org/doi/full/10.1056/NEJM199804303381805 Negrier et al. 1998]
-|1992-1995
-| style="background-color:#1a9851" |Phase III (E-esc)
-|1. [[#High-dose_Interleukin-2|HD IL-2]]<br> 2. [[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
-| style="background-color:#1a9850" |Superior EFS
-|-
-|[https://link.springer.com/article/10.1007%2Fs00262-009-0773-9 Passalacqua et al. 2009]
-|1998-2003
-| style="background-color:#1a9851" |Phase III (C)
-|Maintenance IFN & IL-2
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|}
-''Of historic interest.''
-====Immunotherapy====
-*[[Interferon alfa-2a (Roferon-A)]]
-*[[Aldesleukin (Proleukin)]]
-===References===
-#Negrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C, Ravaud A, Mercatello A, Peny J, Mousseau M, Philip T, Tursz T; Groupe Français d'Immunothérapie. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. N Engl J Med. 1998 Apr 30;338(18):1272-8. [https://www.nejm.org/doi/full/10.1056/NEJM199804303381805 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9562581 PubMed]
-#Passalacqua R, Buzio C, Buti S, Porta C, Labianca R, Pezzuolo D, Camisa R, Sabbatini R, Benecchi L, Messina C, Cengarle R, Vaglio A, Dalla Chiesa M, Tomasello G, Caminiti C. Phase III, randomised, multicentre trial of maintenance immunotherapy with low-dose interleukin-2 and interferon-alpha for metastatic renal cell cancer. Cancer Immunol Immunother. 2010 Apr;59(4):553-61. Epub 2009 Sep 25. [https://link.springer.com/article/10.1007%2Fs00262-009-0773-9 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19779715 PubMed]
-==Interferon alfa-2b monotherapy {{#subobject:6b5be6|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:39f1ab|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06103-7/fulltext Mickisch et al. 2001 (EORTC 30947)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa003013 Flanigan et al. 2001 (SWOG 8949)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-''Of historic interest.''
-====Preceding treatment====
-*[[Surgery#Renal_cell_carcinoma_surgery|Nephrectomy]] versus no preceding treatment
-====Immunotherapy====
-*[[Interferon alfa-2b (Intron-A)]]
-===References===
-#'''EORTC 30947:''' Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R; [[Study_Groups#EORTC|EORTC]] Genitourinary Group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001 Sep 22;358(9286):966-70. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06103-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11583750 PubMed]
-#'''SWOG 8949:''' Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, Caton JR Jr, Munshi N, Crawford ED. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001 Dec 6;345(23):1655-9. [https://www.nejm.org/doi/full/10.1056/NEJMoa003013 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11759643 PubMed]
-==Ipilimumab & Nivolumab {{#subobject:7bc416|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen variant #1 {{#subobject:aa43c1|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years 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://www.nejm.org/doi/full/10.1056/NEJMoa1712126 Motzer et al. 2018 (CheckMate 214)]
-|2014-2016
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)
-|[[#Sunitinib_monotherapy_2|Sunitinib]]
-| style="background-color:#1a9850" |Superior OS
-|-
-|}
-''Note: while this is the dosing studied in CheckMate 214, it is not the FDA-recommended dosing.''
-====Immunotherapy, part 1====
-*[[Ipilimumab (Yervoy)]] 1 mg/kg IV over 30 minutes once on day 1
-*[[Nivolumab (Opdivo)]] 3 mg/kg IV over 60 minutes once on day 1
-'''21-day cycle for 4 cycles, followed by:'''
-====Immunotherapy, part 2====
-*[[Nivolumab (Opdivo)]] 3 mg/kg IV over 60 minutes once on day 1
-'''14-day cycles'''
-===Regimen variant #2 {{#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.''
-====Immunotherapy, part 1====
-*[[Ipilimumab (Yervoy)]] 1 mg/kg IV once on day 1, '''given second'''
-*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1, '''given first'''
-'''21-day cycle for 4 cycles, followed by:'''
-====Immunotherapy, part 2====
-*[[Nivolumab (Opdivo)]] 240 mg IV once on day 1
-'''14-day cycles'''
-===Regimen variant #3 {{#subobject:1d722d|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.''
-====Immunotherapy, part 1====
-*[[Ipilimumab (Yervoy)]] 1 mg/kg IV once on day 1, '''given second'''
-*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1, '''given first'''
-'''21-day cycle for 4 cycles, followed by:'''
-====Immunotherapy, part 2====
-*[[Nivolumab (Opdivo)]] 480 mg IV once on day 1
-'''28-day cycles'''
-===References===
-#'''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://www.nejm.org/doi/full/10.1056/NEJMoa1712126 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29562145 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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30413-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31427204 PubMed]
-==Lenvatinib & Pembrolizumab {{#subobject:e83gac|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:22bc4d|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years 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://www.nejm.org/doi/full/10.1056/NEJMoa2035716 Motzer et al. 2021 (CLEAR)]
-|2016-2019
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[#Sunitinib_monotherapy_2|Sunitinib]]
-| style="background-color:#1a9850" |Superior PFS (primary) and OS (secondary)
-|-
-|}
-====Targeted therapy====
-*[[Lenvatinib (Lenvima)]] 20 mg PO once per day
-====Immunotherapy====
-*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
-'''21-day cycles'''
-===References===
-#'''CLEAR:''' Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Feb 13. Online ahead of print. [https://www.nejm.org/doi/full/10.1056/NEJMoa2035716 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/33616314/ PubMed] NCT02811861
-==Pazopanib monotherapy {{#subobject:443024|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:d6c07c|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-![[Overall response rate|ORR]]
-!Comparator [[Overall response rate|ORR]]
-|-
-|[https://doi.org/10.1200/jco.2008.21.6994 Hutson et al. 2009 (VEG102616)]
-|2005-2006
-| style="background-color:#91cf61" |Phase II
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|
-|
-|-
-|[https://doi.org/10.1200/jco.2009.23.9764 Sternberg et al. 2010 (VEG105192)]
-|2006-2007
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[Renal_cell_carcinoma_-_null_regimens#Placebo_2|Placebo]]
-| style="background-color:#1a9850" |Superior PFS
-|30% (95% CI 25-36%)
-|3% (95% CI 0-6%)
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1303989 Motzer et al. 2013 (COMPARZ)]
-|2008-2011
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#Sunitinib_monotherapy_2|Sunitinib]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|31% (95% CI 27-34%)
-|25% (95% CI 21-28%)
-|-
-|[https://jamanetwork.com/journals/jamaoncology/fullarticle/2588465 Cirkel et al. 2017 (ROPETAR)]
-|2012-2014
-| style="background-color:#1a9851" |Randomized (C)
-|Pazopanib/Everolimus
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|
-|
-|-
-|}
-====Targeted therapy====
-*[[Pazopanib (Votrient)]] 800 mg PO once per day, given 1 hour before or 2 hours after meals
-**Dose may be decreased to 600 mg or 400 mg PO once per day depending on tolerability
-'''Continued indefinitely'''
-===References===
-#'''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. [https://doi.org/10.1200/jco.2008.21.6994 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20008644 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. [https://doi.org/10.1200/jco.2009.23.9764 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20100962 PubMed] NCT00334282
-##'''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. [https://www.ejcancer.com/article/S0959-8049(12)00980-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23321547 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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1303989 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23964934 PubMed] 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://www.nejm.org/doi/full/10.1056/NEJMc1400731 link to letter] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/24687826 PubMed]
-#'''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 protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27918762 PubMed] NCT01408004
-==Regorafenib monotherapy {{#subobject:183793|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:a55057|Variant=1}}===
-{| class="wikitable" style="width: 75%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70364-9/fulltext Eisen et al. 2012 (Bayer 11726)]
-| style="background-color:#91cf61" |Phase II
-|40% (90% CI 28-53%)
-|-
-|}
-====Targeted therapy====
-*[[Regorafenib (Stivarga)]] 160 mg PO once per day on days 1 to 21, given while fasting or after a light meal
-'''28-day cycles'''
-===References===
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70364-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22959186 PubMed]
 ==Sorafenib monotherapy {{#subobject:fe45b0|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:90ba4d|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! 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]]
-![[Overall response rate|ORR]]
-!Comparator [[Overall response rate|ORR]]
-|-
-|[https://doi.org/10.1200/jco.2008.19.3342 Escudier et al. 2009]
-|2005
-| style="background-color:#1a9851" |Randomized Phase II (E-switch-ooc)
-|[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|5%
-|9%
 |-
-|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.24864/abstract Stadler et al. 2010 (ARCCS)]
+|[https://doi.org/10.1002/cncr.24864 Stadler et al. 2010 (ARCCS)]
-|2005-2006
+|2005-06 to 2006-07
 | style="background-color:#91cf61" |Non-randomized
 | style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|
 | style="background-color:#d3d3d3" |
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569677/ Motzer et al. 2013 (AV-951-09-902)]
+|[https://doi.org/10.1016/j.ejca.2018.11.001 Retz et al. 2018 (SWITCH-II)]
-|2010
+|2012-06-14 to 2016-11-14
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Tivozanib_monotherapy|Tivozanib]]
+|[[#Pazopanib_monotherapy|Pazopanib]]
-| style="background-color:#fc8d59" |Seems to have inferior PFS
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior tPFS
-|
-|
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70465-0/fulltext Hutson et al. 2013 (A4061051)]
-|2010-2011
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Axitinib_monotherapy|Axitinib]]
-| style="background-color:#fee08b" |Might have inferior PFS (*)
-|15%
-|32%
 |-
 |}
-''Note: in the 2016 update to A4061051, there is no difference in OS.''
+<div class="toccolours" style="background-color:#b3e2cd">
-====Targeted therapy====
+====Targeted therapy ====
 *[[Sorafenib (Nexavar)]] 400 mg PO twice per day
-**Can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity
 '''Continued indefinitely'''
+</div>
+<div class="toccolours" style="background-color:#fff2ae">
+====Dose and schedule modifications====
+*Sorafenib can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment ====
+*SWITCH-II, upon progression: [[#Pazopanib_monotherapy_2|Pazopanib]]
+</div></div>
 ===References===
+#'''ARCCS:''' Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010 Mar 1;116(5):1272-80. [https://doi.org/10.1002/cncr.24864 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20082451/ PubMed] [https://clinicaltrials.gov/study/NCT00111020 NCT00111020]
-#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://www.ncbi.nlm.nih.gov/pubmed/19171708 PubMed] NCT00117637
+#'''SWITCH-II:''' Retz M, Bedke J, Bögemann M, Grimm MO, Zimmermann U, Müller L, Leiber C, Teber D, Wirth M, Bolenz C, van Alphen R, De Santis M, Beeker A, Lehmann J, Indorf M, Frank M, Bokemeyer C, Gschwend JE. SWITCH II: Phase III randomized, sequential, open-label study to evaluate the efficacy and safety of sorafenib-pazopanib versus pazopanib-sorafenib in the treatment of advanced or metastatic renal cell carcinoma (AUO AN 33/11). Eur J Cancer. 2019 Jan;107:37-45. Epub 2018 Dec 7. [https://doi.org/10.1016/j.ejca.2018.11.001 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30529901/ PubMed] [https://clinicaltrials.gov/study/NCT01613846 NCT01613846]
-#'''ARCCS:''' Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010 Mar 1;116(5):1272-80. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.24864/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20082451 PubMed] NCT00111020
-#'''AV-951-09-902:''' Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, Tomczak P, Lyulko O, Alyasova A, Harza M, Kogan M, Alekseev BY, Sternberg CN, Szczylik C, Cella D, Ivanescu C, Krivoshik A, Strahs A, Esteves B, Berkenblit A, Hutson TE. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013 Oct 20;31(30):3791-9. Epub 2013 Sep 9. [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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24019545 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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70465-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24206640 PubMed] 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. [http://www.clinical-genitourinary-cancer.com/article/S1558-7673(16)30134-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27498023 PubMed]
 ==Sunitinib monotherapy {{#subobject:b4a97a|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:92e618|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! 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]]
-![[Overall response rate|ORR]]
-!Comparator [[Overall response rate|ORR]]
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa065044 Motzer et al. 2007 (A618-1034)]
-|2004-2005
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)
-|[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
-| style="background-color:#1a9850" |Superior PFS
-|31%
-|6%
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970162-7/fulltext Gore et al. 2009 (A618-1037)]
+|[https://doi.org/10.1016/S1470-2045%2809%2970162-7 Gore et al. 2009 (A618-1037)]
 |2005-2007
-| style="background-color:#91cf61" |Non-randomized
+| style="background-color:#91cf61" | Non-randomized
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
-|17%
-| style="background-color:#d3d3d3" |
-|-
-|[http://clincancerres.aacrjournals.org/content/16/22/5539 Amato et al. 2010 (TroVax Renal Immunotherapy Survival Trial)]
-|2006-2008
-| style="background-color:#1a9851" |Phase III (C)
-|Sunitinib & MVA-5T4
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|
-|
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1303989 Motzer et al. 2013 (COMPARZ)]
-|2008-2011
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Pazopanib_monotherapy|Pazopanib]]
-| style="background-color:#eeee01" |Non-inferior PFS
-|25% (95% CI 21-28%)
-|31% (95% CI 27-34%)
 |-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
 |2009-2011
-| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
+| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 |[[#Everolimus_monotherapy|Everolimus]]
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS (primary endpoint)
-|
-|
 |-
-|[https://www.europeanurology.com/article/S0302-2838(15)00319-X/fulltext Eichelberg et al. 2015 (SWITCH)]
+|[https://doi.org/10.1016/j.eururo.2015.04.017 Eichelberg et al. 2015 (SWITCH)]
 |2009-2011
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" | Phase 3 (C)
 |[[#Sorafenib_monotherapy|Sorafenib]]
 | style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|
-|
-|-
-|[https://www.nejm.org/doi/10.1056/NEJMoa1803675 Méjean et al. 2018 (CARMENA)]
-|2009-2017
-| style="background-color:#1a9851" |Phase III (E-de-esc)
-|Nephrectomy & Sunitinib
-| style="background-color:#eeee01" |Non-inferior OS
-|
-|
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30408-9/fulltext Rini et al. 2016 (IMPRINT)]
-|2010-2012
-| style="background-color:#1a9851" |Phase III (C)
-|Sunitinib & IMA901
-| style="background-color:#d9ef8b" |Might have superior OS
-|
-|
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879109/ Tannir et al. 2015 (ESPN)]
-|2010-2013
-| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
-|[[#Everolimus_monotherapy|Everolimus]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|
-|
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00515-X/fulltext Armstrong et al. 2016 (ASPEN)]
-|2010-2013
-| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
-|[[#Everolimus_monotherapy|Everolimus]]
-| style="background-color:#d9ef8b" |Might have superior PFS
-|
-|
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455807/ Choueiri et al. 2016 (CABOSUN)]
-|2013-2015
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Cabozantinib_monotherapy|Cabozantinib]]
-| style="background-color:#d73027" |Inferior PFS
-|
-|
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1712126 Motzer et al. 2018 (CheckMate 214)]
-|2014-2016
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Ipilimumab_.26_Nivolumab|Ipilimumab & Nivolumab]]
-| style="background-color:#d73027" |Inferior OS
-|
-|
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30723-8/fulltext Rini et al. 2019 (IMmotion151)]
+|[https://doi.org/10.1016/S0140-6736(19)30723-8 Rini et al. 2019 (IMmotion151)]
-|2015-2016
+|2015-05-20 to 2016-10-12
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#Atezolizumab_.26_Bevacizumab|Atezolizumab & Bevacizumab]]
 | style="background-color:#fc8d59" |Seems to have inferior PFS
-|
-|
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716603/ Motzer et al. 2019 (JAVELIN Renal 101)]
-|2016-2017
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Axitinib_.26_Avelumab|Axitinib & Avelumab]]
-| style="background-color:#fc8d59" |Seems to have inferior OS (*)
-|
-|
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1816714 Rini et al. 2019 (KEYNOTE-426)]
-|2016-2018
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Axitinib_.26_Pembrolizumab|Axitinib & Pembrolizumab]]
-| style="background-color:#d73027" |Inferior OS
-|
-|
-|-
-|[https://doi.org/10.1056/nejmoa2026982 Choueiri et al. 2021 (CheckMate 9ER)]
-|2017-2019
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Cabozantinib_.26_Nivolumab|Cabozantinib & Nivolumab]]
-| style="background-color:#d73027" |Inferior OS
-|
-|
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa2035716 Motzer et al. 2021 (CLEAR)]
-|2016-209
-|Phase III (C)
-|Everolimus & Lenvatinib
-|Inferior PFS (primary) and OS (secondary)
-|36.1%
-|53.5%
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa2035716 Motzer et al. 2021 (CLEAR)]
-|2016-209
-|Phase III (C)
-|Lenvatinib & Pembrolizumab
-|Inferior PFS (primary) and OS (secondary)
-|36.1%
-|71.0%
 |-
 |}
-''Note: reported efficacy for CABOSUN is based on the 2018 update. Reported efficacy for Javelin Renal 101 is based on the 2020 update, although the authors state that OS data remains immature.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
 *[[Sunitinib (Sutent)]] 50 mg PO once per day on days 1 to 28
-**Per some references, dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability
 '''42-day cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
+*SWITCH, upon progression: Second-line [[#Sorafenib_monotherapy_2|Sorafenib]]
-*SWITCH, upon progression: [[#Sorafenib_monotherapy_2|Sorafenib]]
+</div>
+<div class="toccolours" style="background-color:#fff2ae">
+====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>
 ===References===
+#'''A618-1037:''' Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009 Aug;10(8):757-63. Epub 2009 Jul 15. [https://doi.org/10.1016/S1470-2045%2809%2970162-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19615940/ PubMed] [https://clinicaltrials.gov/study/NCT00130897 NCT00130897]
-#'''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://www.nejm.org/doi/full/10.1056/NEJMoa065044 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17215529 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. [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]
-##'''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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646307/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19487381 PubMed]
+#'''RECORD-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [https://doi.org/10.1200/jco.2013.54.6911 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25049330/ PubMed] [https://clinicaltrials.gov/study/NCT00903175 NCT00903175]
-#'''A618-1037:''' Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009 Aug;10(8):757-63. Epub 2009 Jul 15. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970162-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19615940 PubMed] NCT00130897
+#'''SWITCH:''' Eichelberg C, Vervenne WL, De Santis M, Fischer von Weikersthal L, Goebell PJ, Lerchenmüller C, Zimmermann U, Bos MM, Freier W, Schirrmacher-Memmel S, Staehler M, Pahernik S, Los M, Schenck M, Flörcken A, van Arkel C, Hauswald K, Indorf M, Gottstein D, Michel MS. SWITCH: A Randomised, Sequential, Open-label Study to Evaluate the Efficacy and Safety of Sorafenib-sunitinib Versus Sunitinib-sorafenib in the Treatment of Metastatic Renal Cell Cancer. Eur Urol. 2015 Nov;68(5):837-47. Epub 2015 May 4. [https://doi.org/10.1016/j.eururo.2015.04.017 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25952317/ PubMed] [https://clinicaltrials.gov/study/NCT00732914 NCT00732914]
-#'''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. [http://clincancerres.aacrjournals.org/content/16/22/5539 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20881001 PubMed] NCT00397345
+#'''IMmotion151:''' Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. [https://doi.org/10.1016/S0140-6736(19)30723-8 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31079938/ PubMed] [https://clinicaltrials.gov/study/NCT02420821 NCT02420821]
-#'''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://www.nejm.org/doi/full/10.1056/NEJMoa1303989 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23964934 PubMed] NCT00720941
+##'''Update:''' Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Alekseev BY, Lee JL, Suarez C, Stroyakovskiy D, De Giorgi U, Donskov F, Mellado B, Banchereau R, Hamidi H, Khan O, Craine V, Huseni M, Flinn N, Dubey S, Rini BI. Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol. 2022 Feb 1;8(2):275-280. [https://doi.org/10.1001/jamaoncol.2021.5981 link to original article] [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8855230/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34940781/ PubMed]
-##'''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://www.nejm.org/doi/full/10.1056/NEJMc1400731 link to letter] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/24687826 PubMed]
-<!-- # '''Abstract:''' Robert John Motzer, Carlos H. Barrios, Tae Min Kim, Silvia Falcon, Thomas Cosgriff, W. Graydon Harker, Kenneth B. Pittman, Roberto Sabbatini, Sun Young Rha, Thomas W. Flaig, Ray D. Page, Sevil E. Bavbek, J. Thaddeus Beck, Poulam M Patel, Edward Schiff, Alexandra Vaury, Julie Niolat, Sven Gogov, Ozlem Anak, Jennifer Knox. Record-3: Phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC). 2013 ASCO Annual Meeting abstract 4504. [http://meetinglibrary.asco.org/content/113103-132 link to abstract] -->
-#'''RECORD-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [https://doi.org/10.1200/jco.2013.54.6911 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25049330 PubMed] NCT00903175
-#'''SWITCH:''' Eichelberg C, Vervenne WL, De Santis M, Fischer von Weikersthal L, Goebell PJ, Lerchenmüller C, Zimmermann U, Bos MM, Freier W, Schirrmacher-Memmel S, Staehler M, Pahernik S, Los M, Schenck M, Flörcken A, van Arkel C, Hauswald K, Indorf M, Gottstein D, Michel MS. SWITCH: A Randomised, Sequential, Open-label Study to Evaluate the Efficacy and Safety of Sorafenib-sunitinib Versus Sunitinib-sorafenib in the Treatment of Metastatic Renal Cell Cancer. Eur Urol. 2015 Nov;68(5):837-47. Epub 2015 May 4. [https://www.europeanurology.com/article/S0302-2838(15)00319-X/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25952317 PubMed] NCT00732914
-#'''ESPN:''' Tannir NM, Jonasch E, Albiges L, Altinmakas E, Ng CS, Matin SF, Wang X, Qiao W, Dubauskas Lim Z, Tamboli P, Rao P, Sircar K, Karam JA, McDermott DF, Wood CG, Choueiri TK. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol. 2016 May;69(5):866-74. Epub 2015 Nov 26. [http://www.europeanurology.com/article/S0302-2838(15)01083-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879109/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26626617 PubMed] NCT01185366
-#'''ASPEN:''' Armstrong AJ, Halabi S, Eisen T, Broderick S, Stadler WM, Jones RJ, Garcia JA, Vaishampayan UN, Picus J, Hawkins RE, Hainsworth JD, Kollmannsberger CK, Logan TF, Puzanov I, Pickering LM, Ryan CW, Protheroe A, Lusk CM, Oberg S, George DJ. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016 Mar;17(3):378-88. Epub 2016 Jan 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00515-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26794930 PubMed] NCT01108445
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30408-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27720136 PubMed] NCT01265901
-#'''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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455807/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28199818 PubMed]
-##'''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://www.ejcancer.com/article/S0959-8049(18)30181-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057479/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.nejm.org/doi/full/10.1056/NEJMoa1712126 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29562145 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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30413-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31427204 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://www.nejm.org/doi/10.1056/NEJMoa1803675 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29860937 PubMed] NCT00930033
-#'''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://www.nejm.org/doi/full/10.1056/NEJMoa1816047 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716603/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30779531 PubMed] 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://pubmed.ncbi.nlm.nih.gov/32339648/ 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://www.nejm.org/doi/full/10.1056/NEJMoa1816714 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30779529 PubMed] 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://www.ncbi.nlm.nih.gov/pubmed/33284113 PubMed]
-#'''IMmotion151:''' Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30723-8/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/31079938 PubMed] NCT02420821
-#'''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 verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/33657295/ PubMed] NCT03141177
-#'''CLEAR:''' Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021 Feb 13. Online ahead of print. [https://www.nejm.org/doi/full/10.1056/NEJMoa2035716 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/33616314/ PubMed] NCT02811861
 ==Temsirolimus monotherapy {{#subobject:8160ec|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
+=== Regimen {{#subobject:f56815|Variant=1}}===
-|[[#top|back to top]]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-|}
-===Regimen {{#subobject:f56815|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! 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]]
-![[Overall response rate|ORR]]
-!Comparator [[Overall response rate|ORR]]
 |-
-| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJMoa066838 Hudes et al. 2007 (ARCC)]
+| rowspan="2" |[https://doi.org/10.1056/NEJMoa066838 Hudes et al. 2007 (ARCC)]
 | rowspan="2" |2003-2005
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
 |1. [[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
-| style="background-color:#1a9850" |Superior OS
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 10.9 vs 7.3 mo<br>(HR 0.73, 95% CI 0.58-0.92)
-|9% (95% CI 5-12%)
-|5% (95% CI 2-8%)
 |-
-|2. Interferon alfa-2a & Temsirolimus
+|2. [[#Interferon_alfa-2a_.26_Temsirolimus_999|Interferon alfa-2a & Temsirolimus]]
 | style="background-color:#d3d3d3" |Not reported
-|8% (95% CI 4-12%)
-|
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
 *[[Temsirolimus (Torisel)]] 25 mg IV over 30 minutes once on day 1
+====Supportive therapy====
-====Supportive medications====
+*[[Diphenhydramine (Benadryl)]] (or similar H1 blocker) 25 to 50 mg IV once on day 1; 30 minutes prior to temsirolimus
-*[[Diphenhydramine (Benadryl)]] (or similar H1 blocker) 25 to 50 mg IV once on day 1; 30 minutes prior to [[Temsirolimus (Torisel)]]
 '''7-day cycles'''
+</div></div>
-===References===
-#'''ARCC:''' Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. [https://www.nejm.org/doi/full/10.1056/NEJMoa066838 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538086 PubMed]
-==Tivozanib monotherapy {{#subobject:f8qut0|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:1yga4d|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569677/ Motzer et al. 2013 (AV-951-09-902)]
-|2010
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#Sorafenib_monotherapy|Sorafenib]]
-| style="background-color:#91cf60" |Seems to have superior PFS
-|-
-|}
-====Targeted therapy====
-*[[Tivozanib (Fotivda)]] 1.5 mg PO once per day on days 1 to 21
-'''28-day cycles'''
 ===References===
+#'''ARCC:''' Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. [https://doi.org/10.1056/NEJMoa066838 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17538086/ PubMed] [https://clinicaltrials.gov/study/NCT00065468 NCT00065468]
-#'''AV-951-09-902:''' Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, Tomczak P, Lyulko O, Alyasova A, Harza M, Kogan M, Alekseev BY, Sternberg CN, Szczylik C, Cella D, Ivanescu C, Krivoshik A, Strahs A, Esteves B, Berkenblit A, Hutson TE. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013 Oct 20;31(30):3791-9. Epub 2013 Sep 9. [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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24019545 PubMed] NCT01030783
-=Maintenance after first-line therapy=
-==Bevacizumab monotherapy {{#subobject:6aea81|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:a2085a|Variant=1}}===
-{| class="wikitable" style="width: 50%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61904-7/fulltext Escudier et al. 2007 (AVOREN)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
-|-
-|}
-====Preceding treatment====
-*[[#Bevacizumab_.26_Interferon_alfa-2a|Bevacizumab & IFN alfa-2a]] x 12 mo
-====Targeted therapy====
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
-'''14-day cycles'''
-===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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61904-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18156031 PubMed]
-##'''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 verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20368553 PubMed]
 =Metastatic disease, second-line=
-==Axitinib monotherapy {{#subobject:832684|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:a48a96|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years 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://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961613-9/fulltext Rini et al. 2011 (AXIS)]
-|2008-2010
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
-|[[#Sorafenib_monotherapy_2|Sorafenib]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|}
-''In the 2013 update, ORR was 23% in this arm, and 12% in the control arm.''
-====Targeted therapy====
-*[[Axitinib (Inlyta)]] as follows:
-**5 mg PO twice per day for at least 2 weeks
-**Then if tolerated and BP not greater than 150/90, increased to 7 mg PO twice per day
-**Then if tolerated and BP not greater than 150/90, increased to 10 mg PO twice per day
-**Dose can be reduced to 2 to 3 mg PO twice per day if needed based on tolerability
-'''Continued indefinitely'''
-===References===
-#'''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://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961613-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22056247 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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70093-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/24823696 PubMed]
-==Bevacizumab monotherapy {{#subobject:dc7874|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:24489f|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275324/ Yang et al. 2003]
-|1998-2001
-| style="background-color:#1a9851" |Randomized Phase II (E-esc)
-|[[Renal_cell_carcinoma_-_null_regimens#Placebo_3|Placebo]]
-| style="background-color:#1a9850" |Superior TTP
-|-
-|}
-====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. [https://www.nejm.org/doi/full/10.1056/NEJMoa021491 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275324/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/12890841 PubMed]
 ==Cabozantinib monotherapy {{#subobject:pyr1|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:pyv1|Variant=1}}===
 {| class="wikitable" style="color:white; background-color:#404040"
@@ Line 1,742: / Line 647: @@
 |-
 |}
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! 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]]
-![[Overall response rate|ORR]]
-!Comparator [[Overall response rate|ORR]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ Choueiri et al. 2015 (METEOR)]
+|[https://doi.org/10.1016/s0140-6736(23)00922-4 Pal et al. 2023 (CONTACT-03)]
-|2013-2014
+|2020-07-28 to 2021-12-27
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ic)
+| style="background-color:#1a9851" | Phase 3 (C)
-|[[#Everolimus_monotherapy_2|Everolimus]]
+|[[#Cabozantinib_.26_Atezolizumab_999|Cabozantinib & Atezolizumab]]
-| style="background-color:#1a9850" |Superior OS
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of PFS/OS
-| style="background-color:#88419d; color:white " |21% (95% CI 16-28%)
-| style="background-color:#6e016b; color:white " |5% (95% CI 2-9%)
 |-
 |}
-====Preceding treatment====
+<div class="toccolours" style="background-color:#b3e2cd">
-*VEGFR TKI, with progression
 ====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
-*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 60 mg PO once per day
+'''28-day cycles'''
-**At least 2 hours before or 1 hour after meals according to the [https://www.cabometyx.com/downloads/CABOMETYXUSPI.pdf Cabozantinib (Cabometyx) package insert]
+</div></div>
-'''Continued indefinitely'''
 ===References===
+#'''CONTACT-03:''' Pal SK, Albiges L, Tomczak P, Suárez C, Voss MH, de Velasco G, Chahoud J, Mochalova A, Procopio G, Mahammedi H, Zengerling F, Kim C, Osawa T, Angel M, Gupta S, Khan O, Bergthold G, Liu B, Kalaitzidou M, Huseni M, Scheffold C, Powles T, Choueiri TK. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2023 Jul 15;402(10397):185-195. Epub 2023 Jun 5. [https://doi.org/10.1016/s0140-6736(23)00922-4 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/37290461/ PubMed] [https://clinicaltrials.gov/study/NCT04338269 NCT04338269]
-#'''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://www.nejm.org/doi/full/10.1056/NEJMoa1510016 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26406150 PubMed]
-##'''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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30107-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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/pubmed/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://www.nature.com/articles/s41416-018-0061-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943250/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29576624 PubMed]
 ==Everolimus monotherapy {{#subobject:893557|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
+=== Regimen {{#subobject:9d436d|Variant=1}}===
-|[[#top|back to top]]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-|}
-===Regimen {{#subobject:9d436d|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! 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]]
-![[Overall response rate|ORR]]
-!Comparator [[Overall response rate|ORR]]
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2808%2961039-9/fulltext Motzer et al. 2008 (RECORD-1)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
-|2006-2007
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
-|[[Renal_cell_carcinoma_-_null_regimens#Placebo_2|Placebo]]
-| style="background-color:#1a9850" |Superior PFS
-|1%
-|0%
-|-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
 |2009-2011
-| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
+| style="background-color:#1a9851" | Randomized Phase 2 (E-switch-ic)
 |[[#Sunitinib_monotherapy_3|Sunitinib]]
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS (primary endpoint)
-|
-|
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006123/ Motzer et al. 2015 (RECORD-4)]
-|2011-2013
-| style="background-color:#91cf61" |Phase II
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|
-|
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1510665 Motzer et al. 2015 (CheckMate 025)]
-|2012-2014
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Nivolumab_monotherapy|Nivolumab]]
-| style="background-color:#d73027" |Inferior OS
-|5%
-|25%
-|-
-| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext Motzer et al. 2015 (E7080-G000-205)]
-| rowspan="2" |2012-2013
-| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (C)
-|1. [[#Everolimus_.26_Lenvatinib | Everolimus & Lenvatinib]]
-| style="background-color:#d73027" |Inferior PFS
-|
-|
-|-
-|2. [[#Lenvatinib_monotherapy|Lenvatinib]]
-| style="background-color:#fc8d59" |Seems to have inferior PFS
-|
-|
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ Choueiri et al. 2015 (METEOR)]
-|2013-2014
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Cabozantinib_monotherapy_2|Cabozantinib]]
-| style="background-color:#d73027" |Inferior OS
-|5% (95% CI 2-9%)
-|21% (95% CI 16-28%)
 |-
 |}
-''Note: 72% of patients in Checkmate 025 had anti-angiogenic therapy prior to progression.''
+<div class="toccolours" style="background-color:#fdcdac">
-====Preceding treatment====
+====Prior treatment criteria====
-*RECORD-1 & METEOR: VEGFR TKI, with progression
 *RECORD-3: [[#Sunitinib_monotherapy_2|Sunitinib]], with progression
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
 *[[Everolimus (Afinitor)]] 10 mg PO once per day
-**Dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability
-'''Continued indefinitely'''
-===References===
-#'''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://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2808%2961039-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18653228 PubMed]
-##'''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://onlinelibrary.wiley.com/doi/10.1002/cncr.25219/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20549832 PubMed]
-<!-- # '''Abstract:''' Robert John Motzer, Carlos H. Barrios, Tae Min Kim, Silvia Falcon, Thomas Cosgriff, W. Graydon Harker, Kenneth B. Pittman, Roberto Sabbatini, Sun Young Rha, Thomas W. Flaig, Ray D. Page, Sevil E. Bavbek, J. Thaddeus Beck, Poulam M Patel, Edward Schiff, Alexandra Vaury, Julie Niolat, Sven Gogov, Ozlem Anak, Jennifer Knox. Record-3: Phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC). 2013 ASCO Annual Meeting abstract 4504. [http://meetinglibrary.asco.org/content/113103-132 link to abstract] -->
-#'''RECORD-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [https://doi.org/10.1200/jco.2013.54.6911 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25049330 PubMed] NCT00903175
-#'''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://www.nejm.org/doi/full/10.1056/NEJMoa1510665 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26406148 PubMed] 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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30125-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521044/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.europeanurology.com/article/S0302-2838(17)30099-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28262413 PubMed]
-##'''Subgroup analysis and update:''' Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Saito M, Kimura G, Yonese J, Yao M, Uemura H. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the phase III CheckMate 025 study. Jpn J Clin Oncol. 2019 Jun 1;49(6):506-514. [https://academic.oup.com/jjco/article-abstract/49/6/506/5426435 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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 Jul 16. Epub ahead of print. [https://doi.org/10.1002/cncr.33033 link to original 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://www.nejm.org/doi/full/10.1056/NEJMoa1510016 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26406150 PubMed]
-##'''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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30107-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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/pubmed/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://www.nature.com/articles/s41416-018-0061-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943250/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26482279 PubMed]
-##'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00543-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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 protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26681676 PubMed] NCT01491672
-==Everolimus & Lenvatinib {{#subobject:21039d|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:71ef67|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext Motzer et al. 2015 (E7080-G000-205)]
-| rowspan="2" |2012-2013
-| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-RT-esc)
-|1. [[#Everolimus_monotherapy|Everolimus]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|2. [[#Lenvatinib_monotherapy|Lenvatinib]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-''Patients had progressed after [[:Category:VEGFR_inhibitors|VEGFR TKI]] treatment.''
-====Targeted therapy====
-*[[Everolimus (Afinitor)]] 5 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-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [https://doi.org/10.1200/jco.2013.54.6911 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25049330/ PubMed] [https://clinicaltrials.gov/study/NCT00903175 NCT00903175]
-#'''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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26482279 PubMed]
-##'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00543-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26758760 PubMed]
-==Lenvatinib monotherapy {{#subobject:PYR3|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:PYV3|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext Motzer et al. 2015 (E7080-G000-205)]
-| rowspan="2" |2012-2013
-| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E-RT-switch-ic)
-|1. [[#Everolimus_monotherapy|Everolimus]]
-| style="background-color:#91cf60" |Seems to have superior PFS
-|-
-|2. [[#Everolimus_.26_Lenvatinib | Everolimus & Lenvatinib]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-====Targeted therapy====
-*[[Lenvatinib (Lenvima)]] 24 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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26482279 PubMed]
-##'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00543-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26758760 PubMed]
-==Nivolumab monotherapy {{#subobject:pyr2|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===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
-! style="width: 20%" |Years 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 II (E-de-esc)
-|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
-|-
-|}
-====Immunotherapy====
-*[[Nivolumab (Opdivo)]] 0.3 mg/kg IV once on day 1
-'''21-day cycles'''
-===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%" |Years 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 II (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
-|-
-|}
-====Immunotherapy====
-*[[Nivolumab (Opdivo)]] 2 mg/kg IV once on day 1
-'''21-day cycles'''
-===Regimen variant #3, 3 mg/kg q2wk {{#subobject:pyv2|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-![[Overall response rate|ORR]]
-!Comparator [[Overall response rate|ORR]]
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1510665 Motzer et al. 2015 (CheckMate 025)]
-|2012-2014
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)
-|[[#Everolimus_monotherapy_2|Everolimus]]
-| style="background-color:#1a9850" |Superior OS
-|25%
-|5%
-|-
-|}
-====Immunotherapy====
-*[[Nivolumab (Opdivo)]] 3 mg/kg IV over 60 minutes once on day 1
-**Notably, on 9/13/16 the [http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm FDA recommended] that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.
-'''14-day cycles'''
-===Regimen variant #4, 10 mg/kg q3wk {{#subobject:6f2515|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years 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 II (E-esc)
-|1.[[#Nivolumab_monotherapy|Nivolumab]]; 0.3 mg/kg<br> 2. [[#Nivolumab_monotherapy|Nivolumab]]; 2 mg/kg
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-|-
-|}
-====Immunotherapy====
-*[[Nivolumab (Opdivo)]] 10 mg/kg IV once on day 1
-'''21-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. [https://doi.org/10.1200/JCO.2014.59.0703 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806782/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25452452 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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1510665 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26406148 PubMed] 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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30125-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521044/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/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://www.europeanurology.com/article/S0302-2838(17)30099-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28262413 PubMed]
-##'''Subgroup analysis and update:''' Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, Tanabe K, Saito M, Kimura G, Yonese J, Yao M, Uemura H. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the phase III CheckMate 025 study. Jpn J Clin Oncol. 2019 Jun 1;49(6):506-514. [https://academic.oup.com/jjco/article-abstract/49/6/506/5426435 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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 Jul 16. Epub ahead of print. [https://doi.org/10.1002/cncr.33033 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32673417 PubMed]
-==Pazopanib monotherapy {{#subobject:443024|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:d6c07c|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-![[Overall response rate|ORR]]
-!Comparator [[Overall response rate|ORR]]
-|-
-|[https://doi.org/10.1200/jco.2008.21.6994 Hutson et al. 2009 (VEG102616)]
-|2005-2006
-| style="background-color:#91cf61" |Phase II
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|
-| style="background-color:#d3d3d3" |
-|-
-|[https://doi.org/10.1200/jco.2009.23.9764 Sternberg et al. 2010 (VEG105192)]
-|2006-2007
-| style="background-color:#1a9851" |Phase III (E-esc)
-|[[Renal_cell_carcinoma_-_null_regimens#Placebo_3|Placebo]]
-| style="background-color:#1a9850" |Superior PFS
-|30% (95% CI 25-36%)
-|3% (95% CI 0-6%)
-|-
-|[http://www.clinical-genitourinary-cancer.com/article/S1558-7673(13)00052-9/abstract Hainsworth et al. 2013]
-|2008-2011
-| style="background-color:#91cf61" |Phase II
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|
-| style="background-color:#d3d3d3" |
-|-
-|}
-====Targeted therapy====
-*[[Pazopanib (Votrient)]] 800 mg PO once per day, given 1 hour before or 2 hours after meals
-**Dose may be decreased to 600 mg or 400 mg PO once per day depending on tolerability
-'''Continued indefinitely'''
-===References===
-#'''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. [https://doi.org/10.1200/jco.2008.21.6994 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20008644 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. [https://doi.org/10.1200/jco.2009.23.9764 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20100962 PubMed] NCT00334282
-##'''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. [https://www.ejcancer.com/article/S0959-8049(12)00980-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23321547 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. [http://www.clinical-genitourinary-cancer.com/article/S1558-7673(13)00052-9/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23665131 PubMed]
 ==Sorafenib monotherapy {{#subobject:6e18d8|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:a50d71|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! 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]]
-![[Overall response rate|ORR]]
-!Comparator [[Overall response rate|ORR]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa060655 Escudier et al. 2007 (TARGET<sub>RCC</sub>)]
+|[https://doi.org/10.1002/cncr.24864 Stadler et al. 2010 (ARCCS)]
-|2003-2005
+|2005-06 to 2006-07
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
+| style="background-color:#91cf61" |Non-randomized expanded access study
-|[[Renal_cell_carcinoma_-_null_regimens#Placebo_2|Placebo]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS (*)
-|10%
-|2%
-|-
-|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.24864/abstract Stadler et al. 2010 (ARCCS)]
-|2005-2006
-| style="background-color:#91cf61" |Non-randomized
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
-|
-|
 |-
 |[https://doi.org/10.1093/annonc/mdq651 Beck et al. 2011 (EU-ARCCS)]
 |2005-2007
-| style="background-color:#91cf61" |Non-randomized
+| style="background-color:#91cf61" |Non-randomized expanded access study
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
-|
-|
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569683/ Hutson et al. 2013 (INTORSECT)]
 |2007-2011
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9851" |Phase 3 (C)
-|Temsirolimus
+|[[#Temsirolimus_monotherapy_999|Temsirolimus]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS (*)
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<sup>2</sup><br>Median PFS: 3.9 vs 4.3 mo<br>(HR 1.15, 95% CI 0.93-1.41)
-|
-|
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961613-9/fulltext Rini et al. 2011 (AXIS)]
-|2008-2010
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Axitinib_monotherapy|Axitinib]]
-| style="background-color:#d73027" |Inferior PFS
-|9% (95% CI 7-13%)
-|19% (95% CI 15-24%)
 |-
 |}
-''Note that TARGET should not be confused with the study by the same name in breast cancer. Reported efficacy for TARGET is based on the 2009 update. While the primary endpoint (PFS) was not met in INTORSECT, the control arm actually had superior OS compared to the experimental arm.''
+''<sup>1</sup>Reported efficacy for TARGET is based on the 2009 update.''<br>
+''<sup>2</sup>While the primary endpoint (PFS) was not met in INTORSECT, the control arm actually had superior OS compared to the experimental arm.''<br>
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*INTORSECT: Sunitinib, with progression
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
 *[[Sorafenib (Nexavar)]] 400 mg PO twice per day
-**Can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity
 '''Continued indefinitely'''
+</div>
+<div class="toccolours" style="background-color:#fff2ae">
+====Dose and schedule modifications====
+*Sorafenib 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===
+#'''ARCCS:''' Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010 Mar 1;116(5):1272-80. [https://doi.org/10.1002/cncr.24864 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20082451/ PubMed] [https://clinicaltrials.gov/study/NCT00111020 NCT00111020]
-#'''TARGET:''' Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):125-34. Erratum in: N Engl J Med. 2007 Jul 12;357(2):203. [https://www.nejm.org/doi/full/10.1056/NEJMoa060655 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17215530 PubMed]
+#'''EU-ARCCS:''' Beck J, Procopio G, Bajetta E, Keilholz U, Negrier S, Szczylik C, Bokemeyer C, Bracarda S, Richel DJ, Staehler M, Strauss UP, Mersmann S, Burock K, Escudier B. Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings. Ann Oncol. 2011 Aug;22(8):1812-23. Epub 2011 Feb 15. [https://doi.org/10.1093/annonc/mdq651 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21324953/ PubMed]
-##'''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://www.ncbi.nlm.nih.gov/pubmed/19451442 PubMed]
+#'''INTORSECT:''' Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, Senico P, Niethammer A, Lu DR, Hariharan S, Motzer RJ. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Mar 10;32(8):760-7. Epub 2013 Dec 2. [https://doi.org/10.1200/JCO.2013.50.3961 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569683/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24297950/ PubMed] [https://clinicaltrials.gov/study/NCT00474786 NCT00474786]
-##'''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://www.ejcancer.com/article/S0959-8049(10)00637-4/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20656473 PubMed]
-#'''ARCCS:''' Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010 Mar 1;116(5):1272-80. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.24864/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20082451 PubMed] NCT00111020
-#'''EU-ARCCS:''' Beck J, Procopio G, Bajetta E, Keilholz U, Negrier S, Szczylik C, Bokemeyer C, Bracarda S, Richel DJ, Staehler M, Strauss UP, Mersmann S, Burock K, Escudier B. Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings. Ann Oncol. 2011 Aug;22(8):1812-23. Epub 2011 Feb 15. [https://doi.org/10.1093/annonc/mdq651 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21324953 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://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961613-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22056247 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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70093-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/24823696 PubMed]
-#'''INTORSECT:''' Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, Senico P, Niethammer A, Lu DR, Hariharan S, Motzer RJ. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Mar 10;32(8):760-7. Epub 2013 Dec 2. [https://doi.org/10.1200/JCO.2013.50.3961 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569683/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24297950 PubMed] NCT00474786
 ==Sunitinib monotherapy {{#subobject:f929da|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:955949|Variant=1}}===
 {| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
-! style="width: 20%" |Years of enrollment
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
@@ Line 2,196: / Line 763: @@
 |[https://doi.org/10.1200/JCO.2005.02.2574 Motzer et al. 2005 (RTKC-0511-014)]
 |2003
-| style="background-color:#91cf61" |Phase II (RT)
+| style="background-color:#91cf61" |Phase 2 (RT)
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 |-
-|[https://jamanetwork.com/journals/jama/fullarticle/202955 Motzer et al. 2006 (A618-1006)]
+|[https://doi.org/10.1016/S1470-2045%2809%2970162-7 Gore et al. 2009 (A618-1037)]
-|2004
-| style="background-color:#91cf61" |Phase II (RT)
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970162-7/fulltext Gore et al. 2009 (A618-1037)]
 |2005-2007
 | style="background-color:#91cf61" |Non-randomized
@@ Line 2,212: / Line 773: @@
 | style="background-color:#d3d3d3" |
 |-
-|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
 |2009-2011
-| style="background-color:#1a9851" |Randomized Phase II (E-switch-ic)
+| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 |[[#Everolimus_monotherapy|Everolimus]]
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS (primary endpoint)
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
+*RECORD-3: First-line [[#Everolimus_monotherapy|Everolimus]]
-*RECORD-3: [[#Everolimus_monotherapy|Everolimus]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Targeted therapy====
 *[[Sunitinib (Sutent)]] 50 mg PO once per day on days 1 to 28
-**Dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability
 '''42-day cycles'''
+</div>
+<div class="toccolours" style="background-color:#fff2ae">
+====Dose and schedule modifications====
+*Dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability
+</div></div>
 ===References===
+#'''RTKC-0511-014:''' Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006 Jan 1;24(1):16-24. Epub 2005 Dec 5. [https://doi.org/10.1200/JCO.2005.02.2574 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16330672/ PubMed]
+#'''A618-1037:''' Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009 Aug;10(8):757-63. Epub 2009 Jul 15. [https://doi.org/10.1016/S1470-2045%2809%2970162-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19615940/ PubMed] [https://clinicaltrials.gov/study/NCT00130897 NCT00130897]
+#'''RECORD-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [https://doi.org/10.1200/jco.2013.54.6911 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25049330/ PubMed] [https://clinicaltrials.gov/study/NCT00903175 NCT00903175]
-#'''RTKC-0511-014:''' Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006 Jan 1;24(1):16-24. Epub 2005 Dec 5. [https://doi.org/10.1200/JCO.2005.02.2574 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16330672 PubMed]
+[[Category:Renal cell carcinoma regimens]]
-#'''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://jamanetwork.com/journals/jama/fullarticle/202955 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16757724 PubMed]
-#'''A618-1037:''' Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009 Aug;10(8):757-63. Epub 2009 Jul 15. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970162-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19615940 PubMed] NCT00130897
-<!-- # '''Abstract:''' Robert John Motzer, Carlos H. Barrios, Tae Min Kim, Silvia Falcon, Thomas Cosgriff, W. Graydon Harker, Kenneth B. Pittman, Roberto Sabbatini, Sun Young Rha, Thomas W. Flaig, Ray D. Page, Sevil E. Bavbek, J. Thaddeus Beck, Poulam M Patel, Edward Schiff, Alexandra Vaury, Julie Niolat, Sven Gogov, Ozlem Anak, Jennifer Knox. Record-3: Phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC). 2013 ASCO Annual Meeting abstract 4504. [http://meetinglibrary.asco.org/content/113103-132 link to abstract] -->
-#'''RECORD-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [https://doi.org/10.1200/jco.2013.54.6911 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25049330 PubMed] NCT00903175
-=Metastatic disease, third-line=
-==Sorafenib monotherapy {{#subobject:7b51ba|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:87cb7d|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719485/ Motzer et al. 2014 (GOLD-RCC)]
-|2011-2012
-| style="background-color:#1a9851" |Phase III (C)
-|Dovitinib
-| style="background-color:#fee08b" |Might have inferior PFS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70030-0/fulltext Rini et al. 2019 (TIVO-3)]
-|2016-2017
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Tivozanib_monotherapy_2|Tivozanib]]
-| style="background-color:#fc8d59" |Seems to have inferior PFS
-|-
-|}
-''Note: GOLD should not be confused for the one with the same name in gastric cancer.''
-====Targeted therapy====
-*[[Sorafenib (Nexavar)]] 400 mg PO twice per day
-'''Continued indefinitely'''
-===References===
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70030-0/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719485/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24556040 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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30735-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31810797 PubMed] NCT02627963
-==Tivozanib monotherapy {{#subobject:h7qut0|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:1yq32d|Variant=1}}===
-{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |Years 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://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70030-0/fulltext Rini et al. 2019 (TIVO-3)]
-|2016-2017
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#Sorafenib_monotherapy_3|Sorafenib]]
-| style="background-color:#91cf60" |Seems to have superior PFS
-|-
-|}
-====Targeted therapy====
-*[[Tivozanib (Fotivda)]] 1.5 mg PO once per day on days 1 to 21
-'''28-day cycles'''
-===References===
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30735-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/31810797 PubMed] NCT02627963
-[[Category:Renal_cell_carcinoma regimens]]
 [[Category:Disease-specific pages]]
 [[Category:Genitourinary cancers]]

Difference between revisions of "Renal cell carcinoma"

Latest revision as of 17:53, 23 June 2024

Living Interactive Systematic Reviews

Guidelines

ESMO

ISRS

NCCN

SIOG

SITC

Risk Stratification Calculators

Adjuvant therapy

Sunitinib monotherapy

Regimen

Preceding treatment

Targeted therapy

References

Metastatic disease, first-line

Atezolizumab & Bevacizumab

Regimen

Immunotherapy

Targeted therapy

References

Everolimus monotherapy

Regimen

Targeted therapy

Subsequent treatment

Dose and schedule modifications

References

Gemcitabine & Sunitinib

Regimen

Chemotherapy

Targeted therapy

References

High-dose Interleukin-2

Example orders

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

Immunotherapy

Supportive therapy

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

Immunotherapy

Regimen variant #3, 5 MU/m2/day, CI

Immunotherapy

References

Low-dose Interleukin-2

Regimen variant #1, Intravenous

Immunotherapy

Regimen variant #2, Subcutaneous

Immunotherapy

References

Interferon alfa-2a monotherapy

Regimen variant #1, 5 MU 5x per week

Immunotherapy

Regimen variant #2, 9 MU TIW

Immunotherapy

Dose and schedule modifications

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

Immunotherapy

Regimen variant #4, 10 MU TIW, with lead-in

Immunotherapy

Regimen variant #5, 10 MU TIW

Immunotherapy

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

Immunotherapy

Dose and schedule modifications

References

Sorafenib monotherapy

Regimen

Targeted therapy

Dose and schedule modifications

Subsequent treatment

References

Sunitinib monotherapy

Regimen

Targeted therapy

Subsequent treatment

Dose and schedule modifications

References

Temsirolimus monotherapy

Regimen

Targeted therapy

Regimen variant #3, 5 MU/m²/day, CI