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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:ChenEddy Sept2016.jpg|frameless|upright=0.3|center]]
+</div>
-|<big>[[User:Eddychen|Eddy J. Chen, MD]]<br>Boston, MA</big>
+{{#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:'''
+*'''Histology-specific:'''
+**'''[[Clear cell 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 12: / 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.'''
-*'''2016:''' [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]
+==[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]
-==[http://www.esmo.org/ ESMO]==
+==ISRS==
-*'''2016:''' [http://annonc.oxfordjournals.org/content/27/suppl_5/v58.full.pdf+html Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/27664262 PubMed]
+*'''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]
-==[https://www.nccn.org/ NCCN]==
+==NCCN==
-*[https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf NCCN Guidelines - Kidney Cancer]
+*[https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1440 NCCN Guidelines - Kidney Cancer]
+*'''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]
+*'''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]
+*'''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]
+*'''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]
+*'''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]
+*'''2005:''' Motzer et al. Kidney cancer. Clinical practice guidelines. [https://pubmed.ncbi.nlm.nih.gov/19813325/ PubMed]
-= Risk Stratification Calculators =
+==[http://www.siog.org/ SIOG]==
-* [https://www.mdcalc.com/heng-score-metastatic-renal-cell-carcinoma-rcc-prognosis International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) calculator]
+*'''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]
-** 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]
+==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]
-* [https://www.mdcalc.com/memorial-sloan-kettering-cancer-center-mskcc-motzer-score-metastatic-renal-cell-carcinoma-rcc Memorial Sloan Kettering Cancer Center (MSKCC) calculator]
+=Risk Stratification Calculators=
-** 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. [http://ascopubs.org/doi/abs/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://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]
+*[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://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: 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=
-==Observation==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!Study
-![[Levels_of_Evidence#Evidence|Evidence]]
-!Comparator
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2003.02.005 Messing et al. 2003 (INT-0079)]
-| style="background-color:#1a9851" |Phase III (C)
-|Interferon alfa-NL
-| style="background-color:#d9ef8b" |Might have superior OS
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2003.02.014 Clark et al. 2003]
-| style="background-color:#1a9851" |Phase III (C)
-|High-dose IL-2
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60697-2/fulltext Wood et al. 2008]
-| style="background-color:#1a9851" |Phase III (C)
-|Vitespen
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|}
-''No treatment after surgery.''
-====Preceding treatment====
-*Surgery
-===References===
-# '''INT-0079:''' Messing EM, Manola J, Wilding G, Propert K, Fleischmann J, Crawford ED, Pontes JE, Hahn R, Trump D; Eastern Cooperative Oncology Group/Intergroup trial. Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: an Eastern Cooperative Oncology Group/Intergroup trial. J Clin Oncol. 2003 Apr 1;21(7):1214-22. [http://ascopubs.org/doi/full/10.1200/JCO.2003.02.005 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12663707 PubMed]
-# Clark JI, Atkins MB, Urba WJ, Creech S, Figlin RA, Dutcher JP, Flaherty L, Sosman JA, Logan TF, White R, Weiss GR, Redman BG, Tretter CP, McDermott D, Smith JW, Gordon MS, Margolin KA. Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine working group randomized trial. J Clin Oncol. 2003 Aug 15;21(16):3133-40. Epub 2003 Jun 16. [http://ascopubs.org/doi/full/10.1200/JCO.2003.02.014 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12810695 PubMed]
-# Wood C, Srivastava P, Bukowski R, Lacombe L, Gorelov AI, Gorelov S, Mulders P, Zielinski H, Hoos A, Teofilovici F, Isakov L, Flanigan R, Figlin R, Gupta R, Escudier B; C-100-12 RCC Study Group. An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial. Lancet. 2008 Jul 12;372(9633):145-54. Epub 2008 Jul 3. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60697-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18602688 PubMed]
-==Placebo==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 20%" |Study
-! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]
-|-
-| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878938/ Haas et al. 2016 (ECOG-ACRIN E2805)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|Sorafenib
-| style="background-color:#ffffbf" |Seems not superior
-|
-|-
-|[[#Sunitinib_monotherapy|Sunitinib]]
-| style="background-color:#ffffbf" |Seems not superior
-|
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1611406 Ravaud et al. 2016 (S-TRAC)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Sunitinib_monotherapy|Sunitinib]]
-| style="background-color:#fc8d59" |Seems to have inferior DFS
-| style="background-color:#1a9850" |Less toxicity
-|-
-|[https://jamanetwork.com/journals/jamaoncology/fullarticle/2575469 Chamie et al. 2017 (ARISER)]
-| style="background-color:#1a9851" |Phase III (C)
-|Girentuximab
-| style="background-color:#ffffbf" |Seems not superior
-|
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2017.73.5324 Motzer et al. 2017 (PROTECT)]
-| style="background-color:#1a9851" |Phase III (C)
-|Pazopanib
-| style="background-color:#ffffbf" |Seems not superior
-|
-|-
-|}
-''No active antineoplastic treatment.''
-====Preceding treatment====
-*Surgery
-===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://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]
-# '''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. [http://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]
-# '''ARISER:''' Chamie K, Donin NM, Klöpfer P, Bevan P, Fall B, Wilhelm O, Störkel S, Said J, Gambla M, Hawkins RE, Jankilevich G, Kapoor A, Kopyltsov E, Staehler M, Taari K, Wainstein AJA, Pantuck AJ, Belldegrun AS. Adjuvant weekly girentuximab following nephrectomy for high-risk renal cell carcinoma: The ARISER randomized clinical trial. JAMA Oncol. 2017 Jul 1;3(7):913-920. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2575469 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27787547 PubMed]
-# '''PROTECT:''' Motzer RJ, Haas NB, Donskov F, Gross-Goupil M, Varlamov S, Kopyltsov E, Lee JL, Melichar B, Rini BI, Choueiri TK, Zemanova M, Wood LA, Reaume MN, Stenzl A, Chowdhury S, Lim HY, McDermott R, Michael A, Bao W, Carrasco-Alfonso MJ, Aimone P, Voi M, Doehn C, Russo P, Sternberg CN; PROTECT investigators. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. J Clin Oncol. 2017 Dec 10;35(35):3916-3923. Epub 2017 Sep 13. [http://ascopubs.org/doi/full/10.1200/JCO.2017.73.5324 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28902533 PubMed]
 ==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" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
 ! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
 ! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 ! style="width: 20%" |Comparator
-! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-! style="width: 20%" |[[Levels_of_Evidence#Toxicity|Toxicity]]
-|-
-| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878938/ Haas et al. 2016 (ECOG-ACRIN E2805)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (E)
-|[[#Placebo|Placebo]]
-| style="background-color:#ffffbf" |Seems not superior
-|
-|-
-|Sorafenib
-| style="background-color:#ffffbf" |Seems not superior
-|
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1611406 Ravaud et al. 2016 (S-TRAC)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878938/ Haas et al. 2016 (ECOG-ACRIN E2805)]
-| style="background-color:#1a9851" |Phase III (E)
+|2006-2010
-|[[#Placebo|Placebo]]
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-| style="background-color:#91cf60" |Seems to have superior DFS
+|1. [[Renal_cell_carcinoma_-_null_regimens#Placebo|Placebo]]<br>2. [[#Sorafenib_monotherapy_999|Sorafenib]]
-| style="background-color:#d73027" |More toxicity
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*Surgery
+*[[Surgery#Renal_cell_carcinoma_surgery|Surgery]]
-====Chemotherapy====
+</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)'''
-'''42-day cycles, given for up to 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://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]
+#'''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]
-# '''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. [http://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=
-==Axitinib monotherapy {{#subobject:e83fa|Regimen=1}}==
+==Atezolizumab & Bevacizumab {{#subobject:af0d04|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
+===Regimen {{#subobject:34c462|Variant=1}}===
-|[[#top|back to top]]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-|}
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
-===Regimen {{#subobject:90ba4d|Variant=1}}===
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-{| class="wikitable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Comparator
-!Study
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-![[Levels_of_Evidence#Evidence|Evidence]]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-!Comparator
-!Comparator [[Overall response rate|'''ORR''']]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70465-0/abstract Hutson et al. 2013 (A4061051)]
-| style="background-color:#1a9851" |Phase III (E)
-|32%
-|[[#Sorafenib_monotherapy|Sorafenib]]
-|15%
-| style="background-color:#d9ef8b" |Might have superior PFS (*)
-|-
-|}
-''Note: in the 2016 update, there is no difference in OS.''
-====Chemotherapy====
-*[[Axitinib (Inlyta)]] as follows:
-**5 mg PO BID for at least 2 weeks
-**Then if tolerated and BP not greater than 150/90, increased to 7 mg PO BID
-**Then if tolerated and BP not greater than 150/90, increased to 10 mg PO BID
-**Dose can be reduced to 2 to 3 mg PO BID if needed based on tolerability
-===References===
-# '''A4061051:''' Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, Rosbrook B, Chen C, Kim S, Vogelzang NJ. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1287-94. Epub 2013 Oct 25. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70465-0/abstract 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]
-==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" style="width: 100%; text-align:center;"
-!Study
-![[Levels_of_Evidence#Evidence|Evidence]]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-!Comparator
-!Comparator [[Overall response rate|'''ORR''']]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/25/29/4536.full Bukowski et al. 2007]
-| style="background-color:#1a9851" |Randomized Phase II (C)
-|13%
-|[[#Erlotinib_.26_Bevacizumab|Erlotinib & Bevacizumab]]
-|14%
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|}
-====Chemotherapy====
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV over 90 minutes once every 2 weeks
-**Can subsequently be reduced to 60 and 30 minute infusions as tolerated
-'''Given for up to 104 weeks, until progression of disease, or unacceptable toxicity'''
-===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. [http://jco.ascopubs.org/content/25/29/4536.full 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 {{#subobject:dbebac|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61904-7/abstract Escudier et al. 2007 (AVOREN)]
-| style="background-color:#1a9851" |Phase III (E)
-|[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651074/ Rini et al. 2008 (CALGB 90206)]
-| style="background-color:#1a9851" |Phase III (E)
-|[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2013.50.5305 Rini et al. 2013 (INTORACT)]
-| style="background-color:#1a9851" |Phase III (C)
-|Temsirolimus & Bevacizumab
-| style="background-color:#ffffbf" |Seems not superior
 |-
-|}
+|[https://doi.org/10.1016/S0140-6736(19)30723-8 Rini et al. 2019 (IMmotion151)]
-====Chemoimmunotherapy====
+|2015-05-20 to 2016-10-12
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV once every 2 weeks
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-*[[Interferon alfa-2a (Roferon-A)]] 9 million units SC 3 times per week
-**Dose can be reduced to 3 or 6 million units SC 3 times per week based on tolerability
-'''Interferon alfa-2a given for up to 52 weeks, until progression of disease, or unacceptable toxicity; bevacizumab given until progression of disease or unacceptable toxicity'''
-===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/abstract 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. [http://jco.ascopubs.org/content/28/13/2144.long 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. [http://jco.ascopubs.org/content/26/33/5422.long 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]
-## '''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. [http://jco.ascopubs.org/content/28/13/2137.long 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. [http://ascopubs.org/doi/full/10.1200/JCO.2013.50.5305 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24297945 PubMed]
-==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" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 15%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 15%" |Efficacy
-! style="width: 10%" |Comparator
-! style="width: 15%" |Comparator ORR
-! style="width: 20%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455807/ Choueiri et al. 2016 (CABOSUN)]
-| style="background-color:#1a9851" |Phase III (E)
-|33% (95% CI 23-44%)
 |[[#Sunitinib_monotherapy_2|Sunitinib]]
-|12% (95% CI 5-21%)
+| 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)
-| style="background-color:#91cf60" |Seems to have superior PFS
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057479/ Choueiri et al. 2018 (CABOSUN)]
-|
-|20% (95% CI 12-31%)
-|
-|9% (95% CI 4-18%)
-|
 |}
-====Chemotherapy====
+''<sup>1</sup>Reported efficacy is for the PD-L1-positive subgroup, which was the predefined co-primary endpoint.''<br>
-*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 60 mg PO once per day
+''Note: patients could have clear cell or sarcomatoid histology.''
+<div class="toccolours" style="background-color:#b3e2cd">
-'''Continued indefinitely'''
+====Immunotherapy====
+*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1
-===References===
+====Targeted therapy====
-# '''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. [http://ascopubs.org/doi/full/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]
+*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
-## '''Update:''' Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, Walsh M, Olencki T, Picus J, Small EJ, Dakhil S, Feldman DR, Mangeshkar M, Scheffold C, George D, Morris MJ. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free survival by independent review and overall survival update. Eur J Cancer. 2018 May;94:115-125. Epub 2018 Mar 20. [https://www.sciencedirect.com/science/article/pii/S0959804918301813?via%3Dihub 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]
+'''21-day cycles'''
+</div></div>
-==Doxorubicin & Gemcitabine {{#subobject:bad0b3|Regimen=1}}==
+===References ===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+#'''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]
-|-
+##'''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]
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:bdc472|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[http://www.springerlink.com/content/dnk52234n2567m5h/?MUD=MP Haas et al. 2012 (ECOG 8802)]
-| style="background-color:#91cf61" |Phase II
-|-
-|}
-''Patients had disease with sarcomatoid features.''
-====Chemotherapy====
-*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV push once on day 1
-*[[Gemcitabine (Gemzar)]] 1500 mg/m<sup>2</sup> IV over 30 minutes once on day 1
-'''14-day cycles, given until cumulative doxorubicin dose of 300 to 450 mg/m<sup>2</sup> (depending on cardiac function), progression of disease, or unacceptable toxicity'''
-====Supportive medications====
-*One of the following:
-**[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day on starting on day 2 or 3, given until day 10
-**[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 2
-===References===
-# '''ECOG 8802:''' Haas NB, Lin X, Manola J, Pins M, Liu G, McDermott D, Nanus D, Heath E, Wilding G, Dutcher J. A phase II trial of doxorubicin and gemcitabine in renal cell carcinoma with sarcomatoid features: ECOG 8802. Med Oncol. 2012 Jun;29(2):761-7. Epub 2011 Feb 6. [http://www.springerlink.com/content/dnk52234n2567m5h/?MUD=MP link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566570/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21298497 PubMed]
-==Erlotinib monotherapy {{#subobject:862d0a|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen {{#subobject:79bb24|Variant=1}}===
-{| class="wikitable" style="width: 100%; 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.ncbi.nlm.nih.gov/pmc/articles/PMC2793000/ Gordon et al. 2009 (SWOG S0317)]
-| style="background-color:#91cf61" |Phase II
-|11% (95% CI 3-24%)
-|-
-|}
-====Chemotherapy====
-*[[Erlotinib (Tarceva)]] 150 mg PO once per day, given 1 hour before or 2 hours after meals
-'''Given until progression of disease or unacceptable toxicity'''
-===References===
-# Gordon MS, Hussey M, Nagle RB, Lara PN Jr, Mack PC, Dutcher J, Samlowski W, Clark JI, Quinn DI, Pan CX, Crawford D. Phase II study of erlotinib in patients with locally advanced or metastatic papillary histology renal cell cancer: SWOG S0317. J Clin Oncol. 2009 Dec 1;27(34):5788-93. Epub 2009 Nov 2. [http://jco.ascopubs.org/content/27/34/5788.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2793000/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19884559 PubMed]
-==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" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/25/29/4536.full Bukowski et al. 2007]
-| style="background-color:#1a9851" |Randomized Phase II (E)
-|[[#Bevacizumab_monotherapy|Bevacizumab]]
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|}
-====Chemotherapy====
-*[[Erlotinib (Tarceva)]] 150 mg PO once per day
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV over 90 minutes once every 2 weeks
-**Can subsequently be reduced to 60 and 30 minute infusions as tolerated
-'''Given for up to 104 weeks, until progression of disease, or unacceptable toxicity'''
-===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. [http://jco.ascopubs.org/content/25/29/4536.full 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" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 20%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+! style="width: 20%" |Comparator
-|-
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|[http://jco.ascopubs.org/content/32/25/2765.long Motzer et al. 2014 (RECORD-3)]
-| style="background-color:#1a9851" |Randomized Phase II (E)
-|[[#Sunitinib_monotherapy_2|Sunitinib]]
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879109/ Tannir et al. 2015 (ESPN)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
-| style="background-color:#1a9851" |Randomized Phase II (E)
+|2009-2011
+| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 |[[#Sunitinib_monotherapy_2|Sunitinib]]
-| style="background-color:#ffffbf" |Seems not superior
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS (primary endpoint)
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00515-X/abstract Armstrong et al. 2016 (ASPEN)]
-| style="background-color:#1a9851" |Randomized Phase II (E)
-|[[#Sunitinib_monotherapy_2|Sunitinib]]
-| style="background-color:#fee08b" |Might have inferior PFS
 |-
 |}
-====Chemotherapy====
+<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>
-'''Given until progression of disease or unacceptable toxicity'''
+<div class="toccolours" style="background-color:#cbd5e7">
 ====Subsequent treatment====
-*RECORD-3: [[#Sunitinib_monotherapy_3|Sunitinib]] at the time of progression
+*RECORD-3, upon progression: Second-line [[#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. [http://jco.ascopubs.org/content/32/25/2765.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25049330 PubMed]
-# '''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] [https://www.ncbi.nlm.nih.gov/pubmed/26626617 PubMed]
-# 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/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26794930 PubMed]
 ==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;"
-|}
+! style="width: 33%" |Study
-===Variant #1 {{#subobject:py1|Variant=1}}===
+! style="width: 33%" |Dates of enrollment
-{| class="wikitable" style="width: 100%; text-align:center;"
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 |-
-|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.29503/abstract Michaelson et al. 2015]
+|[https://doi.org/10.1002/cncr.29503 Michaelson et al. 2015 (MGH 07-212)]
-| style="background-color:#91cf61" |Phase II
+|2007-2013
+| style="background-color:#91cf61" |Phase 2
 |-
 |}
-''Patients had disease with sarcomatoid features.''
+<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>
-===Variant #2 {{#subobject:e9a6b9|Variant=1}}===
-{| class="wikitable" style="width: 100%; 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
-*[[Sunitinib (Sutent)]] 37.5 mg PO once per day on days 2 to 15
-'''21-day cycles'''
 ===References===
-# '''Retrospective:''' Pandya SS, Mier JW, McDermott DF, Cho DC. Addition of gemcitabine at the time of sunitinib resistance in metastatic renal cell cancer. BJU Int. 2011 Oct;108(8 Pt 2):E245-9. Epub 2011 Feb 14. [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://doi.org/10.1002/cncr.29503 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26058385/ PubMed] [https://clinicaltrials.gov/study/NCT00556049 NCT00556049]
-# 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]
 ==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">
-===Variant #1 {{#subobject:ca472e|Variant=1}}===
+===Regimen variant #1, 1.8 MU/kg/day, intermittent {{#subobject:ca472e|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 20%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1001/jama.1994.03510360033032 Rosenberg et al. 1994]
+|1985-1992
+| style="background-color:#91cf61" |Non-randomized
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+|-
+|[https://doi.org/10.1200/JCO.1995.13.3.688 Fyfe et al. 1995]
+|NR
+| style="background-color:#91cf61" |Phase 2 (RT)
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
 |-
-|[http://jco.ascopubs.org/content/23/1/133.long McDermott et al. 2005]
+|[https://doi.org/10.1200/jco.2005.03.206 McDermott et al. 2005]
-| style="background-color:#1a9851" |Phase III (C)
+| 1997-2000
-|Subcutaneous IL-2 & Interferon
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#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====
-'''28-day cycle for up to 3 cycles'''
+*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10, 15 to 24
-====Supportive medications====
-*[[Ciprofloxacin (Cipro)]] 250 mg PO BID 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
@@ Line 512: / 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'''
-===Variant #2 {{#subobject:9867a|Variant=1}}===
+</div></div><br>
-{| class="wikitable" style="width: 100%; text-align:center;"
+<div class="toccolours" style="background-color:#eeeeee">
-! style="width: 25%" |Study
+===Regimen variant #2, 2.16 MU/kg/day, intermittent, goal 10.8 MU {{#subobject:9867a|Variant=1}}===
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Comparator
+! style="width: 20%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+! 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]]
 |-
-| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275327/ Yang et al. 2003]
+| rowspan="2" |[https://doi.org/10.1200/JCO.1994.12.8.1572 Yang et al. 1994]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
+| rowspan="2" |1991-1993
-|[[#Low-dose_Interleukin-2|LD IL-2 (IV)]]
+| 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
 |-
-|[[#Low-dose_Interleukin-2|LD IL-2 (SC)]]
+|2. [[#Low-dose_Interleukin-2|LD IL-2 (SC)]]
 | style="background-color:#91cf60" |Seems to have superior ORR
 |-
 |}
+''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>
-===Variant #3 {{#subobject:9a662|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="width: 100%; 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]]
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486432/ Klapper et al. 2008]
+|[https://doi.org/10.1200/JCO.1999.17.8.2521 Figlin et al. 1999]
-| style="background-color:#ffffbe" |Retrospective
+|1994-1997
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#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)]] 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)
+*[[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>)
-**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
+'''8-week cycles'''
+</div></div>
-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)
-====Supportive medications====
-*"Routine administration of antipyretics, anti-inflammatories, antiemetics, antidiarrheals, and H2 antagonists."
 ===References===
-# '''Case series:''' Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994 Mar 23-30;271(12):907-13. [http://jamanetwork.com/journals/jama/article-abstract/368156 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/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. [https://doi.org/10.1001/jama.1994.03510360033032 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8120958/ PubMed]
-# 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. [http://jco.ascopubs.org/content/21/16/3127.long 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/pmc/articles/PMC2275327/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/12915604 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]
-# 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. [http://jco.ascopubs.org/content/23/1/133.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15625368 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]
-# '''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]
+#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]
+#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]
+#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]
 ==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>'''
-===Variant #1, Intravenous {{#subobject:445b6c|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Regimen variant #1, Intravenous {{#subobject:445b6c|Variant=1}}===
-! style="width: 25%" |Study
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Study
-! style="width: 25%" |Comparator
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+! 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.ncbi.nlm.nih.gov/pmc/articles/PMC2275327/ Yang et al. 2003]
+| rowspan="2" |[https://doi.org/10.1200/JCO.1994.12.8.1572 Yang et al. 1994]
-| rowspan="2" style="background-color:#1a9851" |Phase III (E)
+| rowspan="2" | 1991-1993
-|[[#High-dose_Interleukin-2|High-dose IL-2]]
+| 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
 |-
-|Subcutaneous LD IL-2
+|2. [[#Low-dose_Interleukin-2|LD IL-2]]; SC
 | style="background-color:#d3d3d3" |Not reported
 |-
 |}
+''Note: efficacy is based on the 2003 update.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
-*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 72,000 units/kg IV every 8 hours for up to 15 doses
+*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] as follows:
-**Then after 7 to 10 days of rest, [[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 72,000 units/kg IV every 8 hours for up to 15 doses is given again
+**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>
-===Variant #2, Subcutaneous {{#subobject:cbb5b2|Variant=1}}===
+<div class="toccolours" style="background-color:#eeeeee">
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Regimen variant #2, Subcutaneous {{#subobject:cbb5b2|Variant=1}}===
-! style="width: 25%" |Study
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Study
-! style="width: 25%" |Comparator
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+! 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.ncbi.nlm.nih.gov/pmc/articles/PMC2275327/ Yang et al. 2003]
+| rowspan="2" |[https://doi.org/10.1200/JCO.1994.12.8.1572 Yang et al. 1994]
-| rowspan="2" style="background-color:#1a9851" |Phase III (E)
+| rowspan="2" |1991-1993
-|[[#High-dose_Interleukin-2|High-dose IL-2]]
+| 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
 |-
-|Intravenous LD IL-2
+|2. [[#Low-dose_Interleukin-2|LD IL-2]]; IV
 | style="background-color:#d3d3d3" |Not reported
 |-
 |}
+''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)]] 250,000 units/kg SC once per day for 5 days on week 1
+*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] as follows:
-**Then [[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 125,000 units/kg SC once per day for 5 days per week during weeks 2 to 6
+**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, 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. [http://jco.ascopubs.org/content/21/16/3127.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275327/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/12915604 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]
+##'''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]
 ==Interferon alfa-2a monotherapy {{#subobject:8f04d6|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===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%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1093/oxfordjournals.annonc.a059097 Sagaster et al. 1995]
+|NR-1992
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Cimetidine.2C_Coumarin.2C_Interferon_alfa-2a_999|Cimetidine, Coumarin, IFN alfa-2a]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
-|[[#top|back to top]]
 |}
-===Variant #1, 9 MU TIW {{#subobject:524ccc|Variant=1}}===
+<div class="toccolours" style="background-color:#b3e2cd">
-{| class="wikitable" style="width: 100%; text-align:center;"
+====Immunotherapy====
-! style="width: 25%" |Study
+*[[Interferon alfa-2a (Roferon-A)]] 5,000,000 units SC once per day on days 1 to 5 (5 times per week)
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+'''7-day cycles'''
-! style="width: 25%" |Comparator
+</div></div><br>
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61904-7/abstract Escudier et al. 2007 (AVOREN)]
+===Regimen variant #2, 9 MU TIW {{#subobject:524ccc|Variant=1}}===
-| style="background-color:#1a9851" |Phase III (C)
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-|[[#Bevacizumab_.26_Interferon_alfa-2a|Bevacizumab & Interferon alfa-2a]]
+! style="width: 20%" |Study
-| style="background-color:#d73027" |Inferior PFS
+! style="width: 20%" |Dates of enrollment
-|-
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651074/ Rini et al. 2008 (CALGB 90206)]
+! style="width: 20%" |Comparator
-| style="background-color:#1a9851" |Phase III (C)
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|[[#Bevacizumab_.26_Interferon_alfa-2a|Bevacizumab & Interferon alfa-2a]]
-| style="background-color:#d73027" |Inferior PFS
-|-
-|[http://jco.ascopubs.org/content/27/8/1280.long Escudier et al. 2009]
-| style="background-color:#1a9851" |Randomized Phase II (C)
-|[[#Sorafenib_monotherapy|Sorafenib]]
-| style="background-color:#ffffbf" |Seems not superior
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835851/ Gore et al. 2010 (MRC RE04/EORTC GU 30012)]
-| style="background-color:#1a9851" |Phase III (C)
+|2001-2006
-|Chemoimmunotherapy
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#ffffbf" |Seems not superior
+|[[#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)]
-| style="background-color:#1a9851" |Phase II/III (C)
+|2007-2010
-|Naptumomab estafenatox + IFNα
+| style="background-color:#1a9851" |Phase 2/3 (C)
-| style="background-color:#ffffbf" |Seems not superior
+|[[#Naptumomab estafenatox_.26_Interferon_alfa_999|Naptumomab estafenatox + IFNα]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
-*[[Interferon alfa-2a (Roferon-A)]] 9 million 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 million 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">
-===Variant #2, 9 MU TIW, with lead-in {{#subobject:2c65a4|Variant=1}}===
+===Regimen variant #3, 9 MU daily, with lead-in {{#subobject:5f04fc|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 20%" | Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa065044 Motzer et al. 2007]
+|[https://doi.org/10.1200/JCO.2000.18.16.2972 Motzer et al. 2000]
-| style="background-color:#1a9851" |Phase III (C)
+|1994-1996
-|[[#Sunitinib_monotherapy_2|Sunitinib]]
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#d73027" |Inferior PFS
+|[[#Interferon_alfa_.26_13-CRA_999|IFN alfa & 13-CRA]]
+| 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 million units SC 3 times per week
+**Cycle 1: 3,000,000 units SC once per day on days 1 to 7
-**Week 2 (if prior dose tolerated): 6 million units SC 3 times per week
+**Cycle 2: 6,000,000 units SC once per day on days 1 to 7
-**Week 3 onwards (if prior dose tolerated): 9 million units SC 3 times per week
+**Cycle 3 onwards: 9,000,000 units SC once per day on days 1 to 7
+'''7-day cycles'''
-'''Given indefinitely'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-===Variant #3, 10 MU TIW {{#subobject:800dd5|Variant=1}}===
+===Regimen variant #4, 10 MU TIW, with lead-in {{#subobject:leadd5|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+! style="width: 20%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-! style="width: 25%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+! 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 Medical Research Council Renal Cancer Collaborators 1999 (MRC RE01)]
-| style="background-color:#1a9851" |Phase III (E)
-|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)]
+|[https://doi.org/10.1016/S0140-6736(98)03544-2 Ritchie et al. 1999 (MRC RE01)]
-| style="background-color:#1a9851" |Phase III (C)
+|1992-1997
-|Chemoimmunotherapy
+| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
-| style="background-color:#ffffbf" |Seems not superior
+|[[Renal_cell_carcinoma_-_historical#Medroxyprogesterone_acetate_monotherapy|MPA]]
-|-
+| 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)
-|}
-====Immunotherapy====
-*[[Interferon alfa-2a (Roferon-A)]] 10 million units SC 3 times per week
-**In MRC RE01, the first two doses were 5 million units
-'''Given for 12 weeks (MRC RE01) or indefinitely (MRC RE04/EORTC GU 30012)'''
-===Variant #4, 18 MU TIW, with lead-in {{#subobject:b28245|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-| rowspan="2" |[http://www.nejm.org/doi/full/10.1056/NEJMoa066838 Hudes et al. 2007 (ARCC)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
-|Interferon alfa-2a & Temsirolimus
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|[[#Temsirolimus_monotherapy|Temsirolimus]]
-| style="background-color:#d73027" |Inferior OS
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
 *[[Interferon alfa-2a (Roferon-A)]] as follows:
-**Week 1: 3 million 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): 9 million 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): 18 million units SC 3 times per week
+'''7-day cycle for 12 cycles'''
-**If higher doses cannot be tolerated, highest tolerable doses of 3, 4.5, or 6 million units can be used
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-'''Given indefinitely'''
+===Regimen variant #5, 10 MU TIW {{#subobject:800dd5|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-===References===
+! style="width: 20%" |Study
-# 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]
+! style="width: 20%" |Dates of enrollment
-# '''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. [http://www.nejm.org/doi/full/10.1056/NEJMoa065044 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17215529 PubMed]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-## '''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. [http://jco.ascopubs.org/content/27/22/3584.long 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]
+! style="width: 20%" |Comparator
-# '''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. [http://www.nejm.org/doi/full/10.1056/NEJMoa066838 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538086 PubMed]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-# '''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/abstract 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. [http://jco.ascopubs.org/content/28/13/2144.long 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. [http://jco.ascopubs.org/content/26/33/5422.long 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]
-## '''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. [http://jco.ascopubs.org/content/28/13/2137.long 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. [http://jco.ascopubs.org/content/27/8/1280.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19171708 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://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]
-# 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]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835851/ Gore et al. 2010 (MRC RE04/EORTC GU 30012)]
-|}
+|2001-2006
-===Regimen {{#subobject:89bca8|Variant=1}}===
+| style="background-color:#1a9851" |Phase 3 (C)
-{| class="wikitable" style="width: 100%; text-align:center;"
+|[[#Fluorouracil.2C_Interferon_alfa-2a.2C_Interleukin-2_999|5-FU, Interferon alfa-2a, IL-2]]
-! style="width: 25%" |Study
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJM199804303381805 Negrier et al. 1998]
-| style="background-color:#1a9851" |Phase III (E)
-|[[#High-dose_Interleukin-2|HD IL-2]]<br> [[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
-| style="background-color:#1a9850" |Superior EFS
 |-
 |}
-''Of historic interest.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Immunotherapy====
-*[[Interferon alfa-2a (Roferon-A)]]
+*[[Interferon alfa-2a (Roferon-A)]] 10,000,000 units SC once per day on days 1, 3, 5 (3 times per week)
-*[[Aldesleukin (Proleukin)]]
+'''7-day cycles'''
-===References===
+</div></div><br>
-# 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]
+<div class="toccolours" style="background-color:#eeeeee">
-==Interferon alfa-2b monotherapy {{#subobject:6b5be6|Regimen=1}}==
+===Regimen variant #6, 18 MU TIW, with lead-in {{#subobject:b28245|Variant=1}}===
-{| class="wikitable" style="float:right; margin-left: 5px;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1093/oxfordjournals.annonc.a058185 Fosså et al. 1992]
-|}
+|1985-1986
-===Regimen {{#subobject:39f1ab|Variant=1}}===
+| style="background-color:#1a9851" |Phase 3 (C)
-{| class="wikitable" style="width: 100%; text-align:center;"
+|[[#Interferon_alfa-2a_.26_Vinblastine_999|IFN alfa-2a & Vinblastine]]
-! style="width: 50%" |Study
+| style="background-color:#ffffbf" |Did not meet efficacy endpoints
-! 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)]
+| rowspan="2" |[https://doi.org/10.1056/NEJMoa066838 Hudes et al. 2007 (ARCC)]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+| rowspan="2" |2003-2005
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#Interferon_alfa-2a_.26_Temsirolimus_999|Interferon alfa-2a & Temsirolimus]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa003013 Flanigan et al. 2001 (SWOG 8949)]
+|2. [[#Temsirolimus_monotherapy|Temsirolimus]]
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+| style="background-color:#d73027" |Inferior OS
 |-
 |}
-''Of historic interest.''
+''Note: Interferon alfa-2a dose was increased only if the prior dose was tolerated.''
-====Preceding treatment====
+<div class="toccolours" style="background-color:#b3e2cd">
-*Nephrectomy versus no preceding treatment
 ====Immunotherapy====
-*[[Interferon alfa-2b (Intron-A)]]
+*[[Interferon alfa-2a (Roferon-A)]] as follows:
+**Cycle 1: 3,000,000 units SC once per day on days 1, 3, 5
-===References===
+**Cycle 2: 9,000,000 units SC once per day on days 1, 3, 5
-# '''EORTC 30947:''' Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R; European Organisation for Research and Treatment of Cancer (EORTC) Genitourinary Group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001 Sep 22;358(9286):966-70. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(01)06103-7/fulltext link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/11583750 PubMed]
+**Cycle 3 onwards: 18,000,000 units SC once per day on days 1, 3, 5
-# '''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]
+'''7-day cycles'''
+</div>
-==Ipilimumab & Nivolumab {{#subobject:7bc416|Regimen=1}}==
+<div class="toccolours" style="background-color:#fff2ae">
-{| class="wikitable" style="float:right; margin-left: 5px;"
+====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
-|[[#top|back to top]]
+</div></div>
-|}
+=== References===
-===Variant #1 {{#subobject:aa43c1|Variant=1}}===
+# Fosså SD, Martinelli G, Otto U, Schneider G, Wander H, Oberling F, Bauer HW, Achtnicht U, Holdener EE. Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: results of a European multi-center phase III study. Ann Oncol. 1992 Apr;3(4):301-5. [https://doi.org/10.1093/oxfordjournals.annonc.a058185 link to original article] [https://pubmed.ncbi.nlm.nih.gov/1390305/ PubMed]
-{| class="wikitable" style="width: 100%; text-align:center;"
+# 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]
-! style="width: 25%" |Study
+#'''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]
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+#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]
-! style="width: 25%" |Comparator
+#'''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]
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
+#'''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]
-|-
+#'''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]
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa1712126 Motzer et al. 2018 (CheckMate 214)]
-| style="background-color:#1a9851" |Phase III (E)
-|[[#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'''
-===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'''
-===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.  [http://www.nejm.org/doi/full/10.1056/NEJMoa1712126 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29562145 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" style="width: 100%; text-align:center;"
-!Study
-![[Levels_of_Evidence#Evidence|Evidence]]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-!Comparator
-!Comparator [[Overall response rate|'''ORR''']]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/28/3/475.long Hutson et al. 2010]
-| style="background-color:#91cf61" |Phase II
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[http://jco.ascopubs.org/content/28/6/1061.long Sternberg et al. 2010 (VEG105192)]
-| style="background-color:#1a9851" |Phase III (E)
-|30% (95% CI 25-36%)
-|[[#Placebo_2|Placebo]]
-|3% (95% CI 0-6%)
-| style="background-color:#1a9850" |Superior PFS
-|-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa1303989 Motzer et al. 2013 (COMPARZ)]
-| style="background-color:#1a9851" |Phase III (E)
-|31% (95% CI 27-34%)
-|[[#Sunitinib_monotherapy_2|Sunitinib]]
-|25% (95% CI 21-28%)
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-|[https://jamanetwork.com/journals/jamaoncology/fullarticle/2588465 Cirkel et al. 2017 (ROPETAR)]
-| style="background-color:#1a9851" |Randomized (C)
-|
-|Pazopanib/Everolimus
-|
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|}
-====Chemotherapy====
-*[[Pazopanib (Votrient)]] 800 mg PO once per day, given 1 hour before or 2 hours after meals
-**Dose may be decreased to 600 mg or 400 mg PO once per day depending on tolerability
-'''Continued indefinitely'''
-===References===
-# 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. [http://jco.ascopubs.org/content/28/3/475.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20008644 PubMed]
-# '''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. [http://jco.ascopubs.org/content/28/6/1061.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20100962 PubMed]
-## '''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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1303989 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23964934 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. [http://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. [http://ascopubs.org/doi/full/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]
-==Placebo==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJM199804303381804 Gleave et al. 1998]
-| style="background-color:#1a9851" |Phase III (C)
-|Interferon gamma-1b
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|[http://jco.ascopubs.org/content/28/6/1061.long Sternberg et al. 2010 (VEG105192)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Pazopanib_monotherapy|Pazopanib]]
-| style="background-color:#d73027" |Inferior PFS
-|-
-|}
-''No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.''
-===References===
-# Gleave ME, Elhilali M, Fradet Y, Davis I, Venner P, Saad F, Klotz LH, Moore MJ, Paton V, Bajamonde A, Bell D, Ernst S, Ramsey E, Chin J, Morales A, Martins H, Sanders H; Canadian Urologic Oncology Group. Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma. N Engl J Med. 1998 Apr 30;338(18):1265-71. [https://www.nejm.org/doi/full/10.1056/NEJM199804303381804 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9562580 PubMed]
-# '''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. [http://jco.ascopubs.org/content/28/6/1061.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20100962 PubMed]
-## '''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/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23321547 PubMed]
-==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: 100%; 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]
-| style="background-color:#91cf61" |Phase II
-|40% (90% CI 28-53%)
-|-
-|}
-====Chemotherapy====
-*[[Regorafenib (Stivarga)]] 160 mg PO once per day on days 1 to 21, given while fasting or after a light meal
-'''28-day cycles'''
-===References===
-# 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">
-|-
+===Regimen {{#subobject:90ba4d|Variant=1}}===
-|[[#top|back to top]]
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-|}
+! style="width: 20%" |Study
-===Regimen {{#subobject:b76687|Variant=1}}===
+! style="width: 20%" |Dates of enrollment
-{| class="wikitable" style="width: 100%; text-align:center;"
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!Study
+! style="width: 20%" |Comparator
-![[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-!Comparator
-!Comparator [[Overall response rate|'''ORR''']]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/27/8/1280.long Escudier et al. 2009]
-| style="background-color:#1a9851" |Randomized Phase II (E)
-|5%
-|[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
-|9%
-| style="background-color:#ffffbf" |Seems not superior
 |-
-|[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)]
+|2005-06 to 2006-07
 | style="background-color:#91cf61" |Non-randomized
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 |-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2012.47.4940 Motzer et al. 2013]
+|[https://doi.org/10.1016/j.ejca.2018.11.001 Retz et al. 2018 (SWITCH-II)]
-| style="background-color:#1a9851" |Phase III (C)
+|2012-06-14 to 2016-11-14
-|
+| style="background-color:#1a9851" |Phase 3 (C)
-|Tivozanib
+|[[#Pazopanib_monotherapy|Pazopanib]]
-|
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior tPFS
-| style="background-color:#fc8d59" |Seems to have inferior PFS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70465-0/abstract Hutson et al. 2013 (A4061051)]
-| style="background-color:#1a9851" |Phase III (C)
-|15%
-|[[#Axitinib_monotherapy|Axitinib]]
-|32%
-| style="background-color:#fee08b" |Might have inferior PFS (*)
 |-
 |}
-''Note: in the 2016 update to A4061051, there is no difference in OS.''
+<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
+====Targeted therapy ====
-*[[Sorafenib (Nexavar)]] 400 mg PO BID
+*[[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>
-'''Continued until progression or intolerance'''
+<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===
-# 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. [http://jco.ascopubs.org/content/27/8/1280.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19171708 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://doi.org/10.1002/cncr.24864 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20082451/ PubMed] [https://clinicaltrials.gov/study/NCT00111020 NCT00111020]
-# 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]
+#'''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]
-# 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. [http://ascopubs.org/doi/full/10.1200/JCO.2012.47.4940 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24019545 PubMed]
-# '''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/abstract 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]
 ==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" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!Study
+! style="width: 20%" |Study
-![[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-![[Levels_of_Evidence#Efficacy|Efficacy]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!Comparator
+! style="width: 20%" |Comparator
-!Comparator [[Overall response rate|'''ORR''']]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa065044 Motzer et al. 2007 (A618-1034)]
-| style="background-color:#1a9851" |Phase III (E)
-|31%
-|[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
-|6%
-| style="background-color:#1a9850" |Superior PFS
 |-
-|[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)]
-| style="background-color:#91cf61" |Non-randomized
+|2005-2007
-|17%
+| style="background-color:#91cf61" | Non-randomized
-| style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 |-
-|[http://clincancerres.aacrjournals.org/content/16/22/5539 Amato et al. 2010]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
-| style="background-color:#1a9851" |Phase III (C)
+|2009-2011
-|
+| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
-|Sunitinib & MVA-5T4
-|
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa1303989 Motzer et al. 2013 (COMPARZ)]
-| style="background-color:#1a9851" |Phase III (C)
-|25% (95% CI 21-28%)
-|[[#Pazopanib_monotherapy|Pazopanib]]
-|31% (95% CI 27-34%)
-| style="background-color:#eeee01" |Non-inferior PFS
-|-
-|[http://jco.ascopubs.org/content/32/25/2765.long Motzer et al. 2014 (RECORD-3)]
-| style="background-color:#1a9851" |Randomized Phase II (E)
-|
 |[[#Everolimus_monotherapy|Everolimus]]
-|
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS (primary endpoint)
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879109/ Tannir et al. 2015 (ESPN)]
+|[https://doi.org/10.1016/j.eururo.2015.04.017 Eichelberg et al. 2015 (SWITCH)]
-| style="background-color:#1a9851" |Randomized Phase II (E)
+|2009-2011
-|
+| style="background-color:#1a9851" | Phase 3 (C)
-|[[#Everolimus_monotherapy|Everolimus]]
+|[[#Sorafenib_monotherapy|Sorafenib]]
-|
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
-| style="background-color:#ffffbf" |Seems not superior
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00515-X/abstract Armstrong et al. 2016 (ASPEN)]
+|[https://doi.org/10.1016/S0140-6736(19)30723-8 Rini et al. 2019 (IMmotion151)]
-| style="background-color:#1a9851" |Randomized Phase II (E)
+|2015-05-20 to 2016-10-12
-|
+| style="background-color:#1a9851" |Phase 3 (C)
-|[[#Everolimus_monotherapy|Everolimus]]
+|[[#Atezolizumab_.26_Bevacizumab|Atezolizumab & Bevacizumab]]
-|
-| style="background-color:#d9ef8b" |Might have superior PFS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30408-9/fulltext Rini et al. 2016 (IMPRINT)]
-| 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/PMC5455807/ Choueiri et al. 2016 (CABOSUN)]
-| style="background-color:#1a9851" |Phase III (C)
-|
-|[[#Cabozantinib_monotherapy|Cabozantinib]]
-|
 | style="background-color:#fc8d59" |Seems to have inferior PFS
-|-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa1712126 Motzer et al. 2018 (CheckMate 214)]
-| style="background-color:#1a9851" |Phase III (C)
-|
-|[[#Ipilimumab_.26_Nivolumab|Ipilimumab & Nivolumab]]
-|
-| style="background-color:#d73027" |Inferior OS
-|-
-|[https://www.nejm.org/doi/10.1056/NEJMoa1803675 Méjean et al. 2018 (CARMENA)]
-| style="background-color:#1a9851" |Phase III (E)
-|
-|Nephrectomy & Sunitinib
-|
-| style="background-color:#eeee01" |Non-inferior OS
 |-
 |}
-====Chemotherapy====
+<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]]
+</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===
-# '''A618-1034:''' 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa065044 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17215529 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]
-## '''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. [http://jco.ascopubs.org/content/27/22/3584.long 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]
+#'''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]
-# '''Retrospective:''' Choueiri TK, Plantade A, Elson P, Negrier S, Ravaud A, Oudard S, Zhou M, Rini BI, Bukowski RM, Escudier B. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol. 2008 Jan 1;26(1):127-31. [http://jco.ascopubs.org/content/26/1/127.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18165647 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]
+#'''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]
-# 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]
+#'''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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1303989 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23964934 PubMed]
+##'''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. [http://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. [http://ascopubs.org/doi/full/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. [http://jco.ascopubs.org/content/32/25/2765.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25049330 PubMed]
-# '''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] [https://www.ncbi.nlm.nih.gov/pubmed/26626617 PubMed]
-# '''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/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26794930 PubMed]
-# '''IMPRINT:''' Rini BI, Stenzl A, Zdrojowy R, Kogan M, Shkolnik M, Oudard S, Weikert S, Bracarda S, Crabb SJ, Bedke J, Ludwig J, Maurer D, Mendrzyk R, Wagner C, Mahr A, Fritsche J, Weinschenk T, Walter S, Kirner A, Singh-Jasuja H, Reinhardt C, Eisen T. IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2016 Nov;17(11):1599-1611. [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]
-# '''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. [http://ascopubs.org/doi/full/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]
-# '''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.  [http://www.nejm.org/doi/full/10.1056/NEJMoa1712126 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29562145 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]
 ==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;"
-|}
+! style="width: 20%" |Study
-===Regimen {{#subobject:f56815|Variant=1}}===
+! style="width: 20%" |Dates of enrollment
-{| class="wikitable" style="width: 100%; text-align:center;"
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!Study
+! style="width: 20%" |Comparator
-![[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-!Comparator
-!Comparator [[Overall response rate|'''ORR''']]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-| rowspan="2" |[http://www.nejm.org/doi/full/10.1056/NEJMoa066838 Hudes et al. 2007]
+| rowspan="2" |[https://doi.org/10.1056/NEJMoa066838 Hudes et al. 2007 (ARCC)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (E)
+| rowspan="2" |2003-2005
-|9% (95% CI 5-12%)
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
-|[[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
+|1. [[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
-|5% (95% CI 2-8%)
+| 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)
-| style="background-color:#1a9850" |Superior OS
 |-
-|
+|2. [[#Interferon_alfa-2a_.26_Temsirolimus_999|Interferon alfa-2a & Temsirolimus]]
-|Interferon alfa-2a & Temsirolimus
-|8% (95% CI 4-12%)
 | style="background-color:#d3d3d3" |Not reported
 |-
 |}
-====Chemotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Temsirolimus (Torisel)]] 25 mg IV over 30 minutes once per week
+====Targeted therapy====
+*[[Temsirolimus (Torisel)]] 25 mg IV over 30 minutes once on day 1
-====Supportive medications====
+====Supportive therapy====
-*[[Diphenhydramine (Benadryl)]] or similar H1 blocker 25 to 50 mg IV once 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
+'''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. [http://www.nejm.org/doi/full/10.1056/NEJMoa066838 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17538086 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. [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]
 =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" style="width: 100%; text-align:center;"
-!Study
-![[Levels_of_Evidence#Evidence|Evidence]]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-!Comparator
-!Comparator [[Overall response rate|'''ORR''']]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961613-9/fulltext Rini et al. 2011 (AXIS)]
-| style="background-color:#1a9851" |Phase III (E)
-|19% (95% CI 15-24%)
-|[[#Sorafenib_monotherapy_2|Sorafenib]]
-|9% (95% CI 7-13%)
-| style="background-color:#1a9850" |Superior PFS
-|-
-|}
-====Chemotherapy====
-*[[Axitinib (Inlyta)]] as follows:
-**5 mg PO BID for at least 2 weeks
-**Then if tolerated and BP not greater than 150/90, increased to 7 mg PO BID
-**Then if tolerated and BP not greater than 150/90, increased to 10 mg PO BID
-**Dose can be reduced to 2 to 3 mg PO BID if needed based on tolerability
-===References===
-# 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/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23598172 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" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275324/ Yang et al. 2003]
-| style="background-color:#1a9851" |Randomized Phase II (E)
-|[[#Placebo_3|Placebo]]
-| style="background-color:#1a9850" |Superior TTP
-|-
-|}
-====Chemotherapy====
-*[[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 1,252: / Line 647: @@
 |-
 |}
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!Study
+! style="width: 20%" |Study
-![[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-![[Overall response rate|'''ORR''']]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!Comparator
+! style="width: 20%" | Comparator
-!Comparator [[Overall response rate|'''ORR''']]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[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)]
-| style="background-color:#1a9851" |Phase III (E)
+|2020-07-28 to 2021-12-27
-| style="background-color:#88419d; color:white " |21% (95% CI 16-28%)
+| style="background-color:#1a9851" | Phase 3 (C)
-|[[#Everolimus_monotherapy_2|Everolimus]]
+|[[#Cabozantinib_.26_Atezolizumab_999|Cabozantinib & Atezolizumab]]
-| style="background-color:#6e016b; color:white " |5% (95% CI 2-9%)
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of PFS/OS
-| style="background-color:#1a9850" |Superior OS
 |-
 |}
-''Patients had progressed after [[:Category:VEGFR_inhibitors|VEGFR TKI]] treatment.''
+<div class="toccolours" style="background-color:#b3e2cd">
-====Chemotherapy====
+====Targeted therapy====
-*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 60 mg PO once per day
+*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 60 mg PO once per day on days 1 to 28, taken at least 2 hours before or 1 hour after meals
-**At least 2 hours before or 1 hour after meals according to the [https://www.cabometyx.com/downloads/CABOMETYXUSPI.pdf Cabozantinib (Cabometyx) package insert]
+'''28-day cycles'''
+</div></div>
-'''Continued indefinitely'''
 ===References===
-# '''METEOR:''' Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1814-23. [http://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]
+#'''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]
-## '''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. [http://ascopubs.org/doi/full/10.1200/JCO.2017.75.2170 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29377755 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}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[[#top|back to top]]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
-|}
+|2009-2011
-===Regimen {{#subobject:9d436d|Variant=1}}===
+| style="background-color:#1a9851" | Randomized Phase 2 (E-switch-ic)
-{| class="wikitable" style="width: 100%; text-align:center;"
-!Study
-![[Levels_of_Evidence#Evidence|Evidence]]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-!Comparator
-!Comparator [[Overall response rate|'''ORR''']]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2808%2961039-9/fulltext Motzer et al. 2008 (RECORD-1)]
-| style="background-color:#1a9851" |Phase III (E)
-|1%
-|[[#Placebo_2|Placebo]]
-|0%
-| style="background-color:#1a9850" |Superior PFS
-|-
-|[http://jco.ascopubs.org/content/32/25/2765.long Motzer et al. 2014 (RECORD-3)]
-| style="background-color:#1a9851" |Randomized Phase II (E)
-|
 |[[#Sunitinib_monotherapy_3|Sunitinib]]
-|
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS (primary endpoint)
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior
-|-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa1510665 Motzer et al. 2015 (CheckMate 025)]
-| style="background-color:#1a9851" |Phase III (C)
-|5%
-|[[#Nivolumab_monotherapy|Nivolumab]]
-|25%
-| style="background-color:#d73027" |Inferior OS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024539/ Choueiri et al. 2015 (METEOR)]
-| style="background-color:#1a9851" |Phase III (C)
-|5% (95% CI 2-9%)
-|[[#Cabozantinib_monotherapy_2|Cabozantinib]]
-|21% (95% CI 16-28%)
-| style="background-color:#d73027" |Inferior OS
-|-
-| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext Motzer et al. 2015]
-| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (C)
-|
-|[[#Everolimus_.26_Lenvatinib | Everolimus & Lenvatinib]]
-|
-| style="background-color:#d73027" |Inferior PFS
-|-
-|
-|[[#Lenvatinib_monotherapy|Lenvatinib]]
-|
-| style="background-color:#fc8d59" |Seems to have inferior PFS
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006123/ Motzer et al. 2015 (RECORD-4)]
-| style="background-color:#91cf61" |Phase II
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
 |-
 |}
-''Patients in '''RECORD-1''' and '''METEOR''' had progressed after [[:Category:VEGFR_inhibitors|VEGFR TKI]] treatment. 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-3: [[#Sunitinib_monotherapy_2|Sunitinib]]
+*RECORD-3: [[#Sunitinib_monotherapy_2|Sunitinib]], with progression
-====Chemotherapy====
+</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
-'''Given until progression of disease or unacceptable toxicity'''
-===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. [http://jco.ascopubs.org/content/32/25/2765.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25049330 PubMed]
-# '''CheckMate 025:''' Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803-13. Epub 2015 Sep 25. [http://www.nejm.org/doi/full/10.1056/NEJMoa1510665 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26406148 PubMed]
-## '''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]
-# '''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. [http://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]
-# 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/abstract 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://academic.oup.com/annonc/article/27/3/441/2196469 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]
-==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" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext Motzer et al. 2015]
-| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E)
-|[[#Everolimus_monotherapy|Everolimus]]
-| style="background-color:#1a9850" |Superior PFS
-|-
-|[[#Lenvatinib_monotherapy|Lenvatinib]]
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|}
-''Patients had progressed after [[:Category:VEGFR_inhibitors|VEGFR TKI]] treatment.''
-====Chemotherapy====
-*[[Everolimus (Afinitor)]] 5 mg PO once per day
-*[[Lenvatinib (Lenvima)]] 18 mg PO once per day
 '''Continued indefinitely'''
+</div>
-===References===
+<div class="toccolours" style="background-color:#fff2ae">
-# 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]
+====Dose and schedule modifications====
-## '''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/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26758760 PubMed]
+*Everolimus dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability
+</div></div>
-==FC, then allo HSCT {{#subobject:1a1ed9|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-FC: '''<u>F</u>'''ludarabine & '''<u>C</u>'''yclophosphamide
-===Regimen {{#subobject:9ce8f1|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 50%" |Study
-! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
-|-
-|[https://www.nejm.org/doi/10.1056/NEJM200009143431101 Childs et al. 2000]
-| style="background-color:#ffffbe" |Non-randomized, <20 pts
-|-
-|}
-{{#lst:Allogeneic HSCT|9ce8f1}}
-===References===
-# Childs R, Chernoff A, Contentin N, Bahceci E, Schrump D, Leitman S, Read EJ, Tisdale J, Dunbar C, Linehan WM, Young NS, Barrett AJ. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med. 2000 Sep 14;343(11):750-8. [https://www.nejm.org/doi/10.1056/NEJM200009143431101 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10984562 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" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext Motzer et al. 2015]
-| rowspan="2" style="background-color:#1a9851" |Randomized Phase II (E)
-|[[#Everolimus_monotherapy|Everolimus]]
-| style="background-color:#91cf60" |Seems to have superior PFS
-|-
-|[[#Everolimus_.26_Lenvatinib | Everolimus & Lenvatinib]]
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|}
-====Chemotherapy====
-*[[Lenvatinib (Lenvima)]] 24 mg PO once per day
-'''Continued until progression or unacceptable toxicity'''
-===References===
-# 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/abstract 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]]
-|}
-===Variant #1, 0.3 mg/kg q3wk {{#subobject:6d0807|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2014.59.0703 Motzer et al. 2015 (CA209-010)]
-| style="background-color:#1a9851" |Randomized Phase II (E)
-|Nivo 2 mg/kg<br> Nivo 10 mg/kg
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|}
-====Immunotherapy====
-*[[Nivolumab (Opdivo)]] 0.3 mg/kg IV once on day 1
-'''21-day cycles'''
-===Variant #2, 2 mg/kg q3wk {{#subobject:e0b43a|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2014.59.0703 Motzer et al. 2015 (CA209-010)]
-| style="background-color:#1a9851" |Randomized Phase II (E)
-|Nivo 0.3 mg/kg<br> Nivo 10 mg/kg
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|}
-====Immunotherapy====
-*[[Nivolumab (Opdivo)]] 2 mg/kg IV once on day 1
-'''21-day cycles'''
-===Variant #3, 3 mg/kg q2wk {{#subobject:pyv2|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-!Study
-![[Levels_of_Evidence#Evidence|Evidence]]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-!Comparator
-!Comparator [[Overall response rate|'''ORR''']]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa1510665 Motzer et al. 2015 (CheckMate 025)]
-| style="background-color:#1a9851" |Phase III (E)
-|25%
-|[[#Everolimus_monotherapy_2|Everolimus]]
-|5%
-| style="background-color:#1a9850" |Superior OS
-|-
-|}
-====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'''
-===Variant #4, 10 mg/kg q3wk {{#subobject:6f2515|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://ascopubs.org/doi/full/10.1200/JCO.2014.59.0703 Motzer et al. 2015 (CA209-010)]
-| style="background-color:#1a9851" |Randomized Phase II (E)
-|Nivo 0.3 mg/kg<br> Nivo 2 mg/kg
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|}
-====Immunotherapy====
-*[[Nivolumab (Opdivo)]] 10 mg/kg IV once on day 1
-'''21-day cycles'''
-===References===
-# '''CA209-010:''' Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, Vaishampayan UN, Drabkin HA, George S, Logan TF, Margolin KA, Plimack ER, Lambert AM, Waxman IM, Hammers HJ. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. 2015 May 1;33(13):1430-7. Epub 2014 Dec 1. [http://ascopubs.org/doi/full/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]
-# '''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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1510665 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26406148 PubMed]
-## '''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]
-==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" style="width: 100%; text-align:center;"
-!Study
-![[Levels_of_Evidence#Evidence|Evidence]]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-!Comparator
-!Comparator [[Overall response rate|'''ORR''']]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://jco.ascopubs.org/content/28/3/475.long Hutson et al. 2010]
-| style="background-color:#91cf61" |Phase II
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|[http://jco.ascopubs.org/content/28/6/1061.long Sternberg et al. 2010 (VEG105192)]
-| style="background-color:#1a9851" |Phase III (E)
-|30% (95% CI 25-36%)
-|[[#Placebo_3|Placebo]]
-|3% (95% CI 0-6%)
-| style="background-color:#1a9850" |Superior PFS
-|-
-|[http://www.clinical-genitourinary-cancer.com/article/S1558-7673(13)00052-9/abstract Hainsworth et al. 2013]
-| style="background-color:#91cf61" |Phase II
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
-|-
-|}
-====Chemotherapy====
-*[[Pazopanib (Votrient)]] 800 mg PO once per day, given 1 hour before or 2 hours after meals
-**Dose may be decreased to 600 mg or 400 mg PO once per day depending on tolerability
-'''Given until progression of disease, unacceptable toxicity, death, or withdrawal of consent'''
-===References===
-# 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. [http://jco.ascopubs.org/content/28/3/475.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20008644 PubMed]
-# '''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. [http://jco.ascopubs.org/content/28/6/1061.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20100962 PubMed]
-## '''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]
-==Placebo==
-{| class="wikitable" style="float:right; margin-left: 5px;"
-|-
-|[[#top|back to top]]
-|}
-===Regimen===
-{| class="wikitable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa060655 Escudier et al. 2007 (TARGET)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Sorafenib_monotherapy|Sorafenib]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2808%2961039-9/fulltext Motzer et al. 2008 (RECORD-1)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Everolimus_monotherapy|Everolimus]]
-| style="background-color:#d73027" |Inferior PFS
-|-
-|[http://jco.ascopubs.org/content/28/6/1061.long Sternberg et al. 2010 (VEG105192)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Pazopanib_monotherapy|Pazopanib]]
-| style="background-color:#d73027" |Inferior PFS
-|-
-|}
-''No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.''
 ===References===
-# '''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. [http://www.nejm.org/doi/full/10.1056/NEJMoa060655 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17215530 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]
-## '''Update:''' 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]
-# '''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]
-# '''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. [http://jco.ascopubs.org/content/28/6/1061.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20100962 PubMed]
-## '''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/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23321547 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" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-!Study
+! style="width: 20%" |Study
-![[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Dates of enrollment
-![[Levels_of_Evidence#Efficacy|Efficacy]]
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-!Comparator
+! style="width: 20%" | Comparator
-!Comparator [[Overall response rate|'''ORR''']]
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[http://www.nejm.org/doi/full/10.1056/NEJMoa060655 Escudier et al. 2007 (TARGET)]
+|[https://doi.org/10.1002/cncr.24864 Stadler et al. 2010 (ARCCS)]
-| style="background-color:#1a9851" |Phase III (E)
+|2005-06 to 2006-07
-|10%
+| style="background-color:#91cf61" |Non-randomized expanded access study
-|[[#Placebo_2|Placebo]]
-|2%
-| style="background-color:#91cf60" |Seems to have superior OS
-|-
-|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.24864/abstract Stadler et al. 2010 (ARCCS)]
-| style="background-color:#91cf61" |Non-randomized
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 |-
-|[http://annonc.oxfordjournals.org/content/22/8/1812.long Beck et al. 2011 (EU-ARCCS)]
+|[https://doi.org/10.1093/annonc/mdq651 Beck et al. 2011 (EU-ARCCS)]
-| style="background-color:#91cf61" |Non-randomized
+|2005-2007
-| style="background-color:#d3d3d3" |
+| style="background-color:#91cf61" |Non-randomized expanded access study
-| style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
-|-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961613-9/fulltext Rini et al. 2011 (AXIS)]
-| style="background-color:#1a9851" |Phase III (C)
-|9% (95% CI 7-13%)
-|[[#Axitinib_monotherapy|Axitinib]]
-|19% (95% CI 15-24%)
-| style="background-color:#d73027" |Inferior PFS
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569683/ Hutson et al. 2013 (INTORSECT)]
-| style="background-color:#1a9851" |Phase III (C)
+|2007-2011
-|
+| style="background-color:#1a9851" |Phase 3 (C)
-|Temsirolimus
+|[[#Temsirolimus_monotherapy_999|Temsirolimus]]
-|
+| 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)
-| style="background-color:#ffffbf" |Seems not superior (*)
 |-
 |}
-''Note: 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>
-====Chemotherapy====
+''<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>
-*[[Sorafenib (Nexavar)]] 400 mg PO BID
+<div class="toccolours" style="background-color:#fdcdac">
-**Can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity
+====Prior treatment criteria====
+*INTORSECT: Sunitinib, with progression
-'''Continued until progression or intolerance'''
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
+*[[Sorafenib (Nexavar)]] 400 mg PO twice per day
+'''Continued indefinitely'''
+</div>
+<div class="toccolours" style="background-color:#fff2ae">
+====Dose and schedule modifications====
+*Sorafenib can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity
+</div></div>
 ===References===
-# '''TARGET:''' 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa060655 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17215530 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://doi.org/10.1002/cncr.24864 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20082451/ PubMed] [https://clinicaltrials.gov/study/NCT00111020 NCT00111020]
-## '''Update:''' 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]
+#'''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]
-# '''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]
+#'''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]
-# '''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. [http://annonc.oxfordjournals.org/content/22/8/1812.long 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/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23598172 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. [http://ascopubs.org/doi/full/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]
 ==Sunitinib monotherapy {{#subobject:f929da|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:955949|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1200/JCO.2005.02.2574 Motzer et al. 2005 (RTKC-0511-014)]
-|}
+|2003
-===Regimen {{#subobject:955949|Variant=1}}===
+| style="background-color:#91cf61" |Phase 2 (RT)
-{| class="wikitable" style="width: 100%; text-align:center;"
+| style="background-color:#d3d3d3" |
-!Study
+| style="background-color:#d3d3d3" |
-![[Levels_of_Evidence#Evidence|Evidence]]
-![[Levels_of_Evidence#Efficacy|Efficacy]]
-!Comparator
-![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970162-7/fulltext Gore et al. 2009]
+|[https://doi.org/10.1016/S1470-2045%2809%2970162-7 Gore et al. 2009 (A618-1037)]
+|2005-2007
 | style="background-color:#91cf61" |Non-randomized
-|17%
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 |-
-|[http://jco.ascopubs.org/content/32/25/2765.long Motzer et al. 2014 (RECORD-3)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
-| style="background-color:#1a9851" |Randomized Phase II (E)
+|2009-2011
-|
+| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 |[[#Everolimus_monotherapy|Everolimus]]
-| style="background-color:#ffffbf" |Inconclusive whether non-inferior
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS (primary endpoint)
 |-
 |}
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
-*RECORD-3: [[#Everolimus_monotherapy|Everolimus]]
+*RECORD-3: First-line [[#Everolimus_monotherapy|Everolimus]]
-====Chemotherapy====
+</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 [[Sunitinib (Sutent)]] 37.5 mg or 25 mg PO once per day depending on tolerability
 '''42-day cycles'''
+</div>
-===References===
+<div class="toccolours" style="background-color:#fff2ae">
-# 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]
+====Dose and schedule modifications====
-<!-- # '''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] -->
+*Dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability
-# '''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. [http://jco.ascopubs.org/content/32/25/2765.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25049330 PubMed]
+</div></div>
-=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" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70030-0/abstract Motzer et al. 2014]
-| style="background-color:#1a9851" |Phase III (C)
-|Dovitinib
-| style="background-color:#fee08b" |Might have inferior PFS
-|-
-|}
-====Chemotherapy====
-*[[Sorafenib (Nexavar)]] 400 mg PO BID
 ===References===
-# 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/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24556040 PubMed]
+#'''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]
-[[Category:Renal_cell_carcinoma regimens]]
+[[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