Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial

doi:10.1136/jitc-2020-000891

Clinical Trial

. 2020 Jul;8(2):e000891.

doi: 10.1136/jitc-2020-000891.

Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial

Robert J Motzer¹, Bernard Escudier², David F McDermott³, Osvaldo Arén Frontera⁴, Bohuslav Melichar⁵, Thomas Powles⁶, Frede Donskov⁷, Elizabeth R Plimack⁸, Philippe Barthélémy⁹, Hans J Hammers¹⁰, Saby George¹¹, Viktor Grünwald^{12

13}, Camillo Porta¹⁴, Victoria Neiman^{15

16}, Alain Ravaud¹⁷, Toni K Choueiri¹⁸, Brian I Rini^{19

20}, Pamela Salman²¹, Christian K Kollmannsberger²², Scott S Tykodi^{23

24}, Marc-Oliver Grimm²⁵, Howard Gurney^{26

27}, Raya Leibowitz-Amit^{28

29}, Poul F Geertsen³⁰, Asim Amin³¹, Yoshihiko Tomita³², M Brent McHenry³³, Shruti Shally Saggi³³, Nizar M Tannir³⁴

Affiliations

¹ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA motzerr@mskcc.org.
² Department of Medical Oncology, Gustave Roussy, Villejuif, France.
³ Department of Medicine, Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts, USA.
⁴ Centro de Investigación Clínica Bradford Hill, Santiago, Chile.
⁵ Department of Oncology, Palacky University, and University Hospital Olomouc, Olomouc, Czech Republic.
⁶ Department of Genitourinary Oncology, Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free National Health Service Trust, London, UK.
⁷ Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.
⁸ Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
⁹ Department of Medical Oncology, Hôpitaux Universitaires de Strasbourg / ICANS, Strasbourg, France.
¹⁰ Division of Hematology and Oncology, UT Southwestern Kidney Cancer Program, Dallas, Texas, USA.
¹¹ Divisions of Medical Oncology and Urology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
¹² Interdisciplinary Genitourinary Oncology, West German Cancer Center Essen, Essen, Germany.
¹³ Clinic for Medical Oncology and Clinic for Urology, Essen University Hospital, Essen, Germany.
¹⁴ Department of Internal Medicine, University of Pavia, Pavia, Italy.
¹⁵ Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel.
¹⁶ Tel Aviv University, Tel Aviv, Israel.
¹⁷ Department of Medical Oncology, Bordeaux University Hospital, Bordeaux, France.
¹⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, The Lank Center for Genitourinary Oncology, Boston, Massachusetts, USA.
¹⁹ Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, USA.
²⁰ Dr. Rini is now with the Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
²¹ Instituto Oncológico Fundación Arturo López Pérez, Santiago, Chile.
²² Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
²³ Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, Washington, USA.
²⁴ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
²⁵ Department of Urology, Jena University Hospital, Jena, Germany.
²⁶ Department of Medical Oncology, Westmead Hospital, Sydney, New South Wales, Australia.
²⁷ Department of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia.
²⁸ Oncology Institute, Shamir Medical Center, Be'er Yaakov, Israel.
²⁹ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
³⁰ Department of Oncology, Herlev Hospital, Copenhagen, Denmark.
³¹ Department of Medical Oncology, Levine Cancer Institute, Atrium Health, Charlotte, North Carolina, USA.
³² Departments of Urology and Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
³³ Bristol Myers Squibb, Princeton, New Jersey, USA.
³⁴ Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.

PMID: 32661118
PMCID: PMC7359377
DOI: 10.1136/jitc-2020-000891

Clinical Trial

Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial

Robert J Motzer et al. J Immunother Cancer. 2020 Jul.

. 2020 Jul;8(2):e000891.

doi: 10.1136/jitc-2020-000891.

Authors

Affiliations

¹ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA motzerr@mskcc.org.
² Department of Medical Oncology, Gustave Roussy, Villejuif, France.
³ Department of Medicine, Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts, USA.
⁴ Centro de Investigación Clínica Bradford Hill, Santiago, Chile.
⁵ Department of Oncology, Palacky University, and University Hospital Olomouc, Olomouc, Czech Republic.
⁶ Department of Genitourinary Oncology, Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free National Health Service Trust, London, UK.
⁷ Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.
⁸ Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
⁹ Department of Medical Oncology, Hôpitaux Universitaires de Strasbourg / ICANS, Strasbourg, France.
¹⁰ Division of Hematology and Oncology, UT Southwestern Kidney Cancer Program, Dallas, Texas, USA.
¹¹ Divisions of Medical Oncology and Urology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
¹² Interdisciplinary Genitourinary Oncology, West German Cancer Center Essen, Essen, Germany.
¹³ Clinic for Medical Oncology and Clinic for Urology, Essen University Hospital, Essen, Germany.
¹⁴ Department of Internal Medicine, University of Pavia, Pavia, Italy.
¹⁵ Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel.
¹⁶ Tel Aviv University, Tel Aviv, Israel.
¹⁷ Department of Medical Oncology, Bordeaux University Hospital, Bordeaux, France.
¹⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, The Lank Center for Genitourinary Oncology, Boston, Massachusetts, USA.
¹⁹ Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, USA.
²⁰ Dr. Rini is now with the Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
²¹ Instituto Oncológico Fundación Arturo López Pérez, Santiago, Chile.
²² Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
²³ Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, Washington, USA.
²⁴ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
²⁵ Department of Urology, Jena University Hospital, Jena, Germany.
²⁶ Department of Medical Oncology, Westmead Hospital, Sydney, New South Wales, Australia.
²⁷ Department of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia.
²⁸ Oncology Institute, Shamir Medical Center, Be'er Yaakov, Israel.
²⁹ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
³⁰ Department of Oncology, Herlev Hospital, Copenhagen, Denmark.
³¹ Department of Medical Oncology, Levine Cancer Institute, Atrium Health, Charlotte, North Carolina, USA.
³² Departments of Urology and Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
³³ Bristol Myers Squibb, Princeton, New Jersey, USA.
³⁴ Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.

PMID: 32661118
PMCID: PMC7359377
DOI: 10.1136/jitc-2020-000891

Erratum in

Correction: Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial.
[No authors listed] [No authors listed] J Immunother Cancer. 2021 May;9(5):e000891corr1. doi: 10.1136/jitc-2020-000891corr1. J Immunother Cancer. 2021. PMID: 33941652 Free PMC article. No abstract available.

Abstract

Background: The extent to which response and survival benefits with immunotherapy-based regimens persist informs optimal first-line treatment options. We provide long-term follow-up in patients with advanced renal cell carcinoma (aRCC) receiving first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the phase 3 CheckMate 214 trial. Survival, response, and safety outcomes with NIVO+IPI versus SUN were assessed after a minimum of 42 months of follow-up.

Methods: Patients with aRCC were enrolled from October 16, 2014, through February 23, 2016. Patients stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk and region were randomized to nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks for four doses, followed by nivolumab (3 mg/kg) every 2 weeks; or SUN (50 mg) once per day for 4 weeks (6-week cycle). Primary endpoints: overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) per independent radiology review committee in IMDC intermediate-risk/poor-risk patients. Secondary endpoints: OS, PFS, and ORR in the intention-to-treat (ITT) population and safety. Favorable-risk patient outcomes were exploratory.

Results: Among ITT patients, 550 were randomized to NIVO+IPI (425 intermediate/poor risk; 125 favorable risk) and 546 to SUN (422 intermediate/poor risk; 124 favorable risk). Among intermediate-risk/poor-risk patients, OS (HR, 0.66; 95% CI, 0.55-0.80) and PFS (HR, 0.75; 95% CI, 0.62-0.90) benefits were observed, and ORR was higher (42.1% vs 26.3%) with NIVO+IPI versus SUN. In ITT patients, both OS benefits (HR, 0.72; 95% CI, 0.61-0.86) and higher ORR (39.1% vs 32.6%) were observed with NIVO+IPI versus SUN. In favorable-risk patients, HR for death was 1.19 (95% CI, 0.77-1.85) and ORR was 28.8% with NIVO+IPI versus 54.0% with SUN. Duration of response was longer (HR, 0.46-0.54), and more patients achieved complete response (10.1%-12.8% vs 1.4%-5.6%) with NIVO+IPI versus SUN regardless of risk group. The incidence of treatment-related adverse events was consistent with previous reports.

Conclusions: NIVO+IPI led to improved efficacy outcomes versus SUN in both intermediate-risk/poor-risk and ITT patients that were maintained through 42 months' minimum follow-up. A complete response rate >10% was achieved with NIVO+IPI regardless of risk category, with no new safety signals detected in either arm. These results support NIVO+IPI as a first-line treatment option with the potential for durable response.

Trial registration number: NCT02231749.

Keywords: CTLA-4 antigen; clinical trials, phase III as topic; immunotherapy; kidney neoplasms; programmed cell death 1 receptor.

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Conflict of interest statement

Competing interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. RJM reports consulting or advisory roles with Eisai, Exelixis, Genentech/Roche, Incyte, Lilly, Merck, Novartis, and Pfizer, and research funding/travel/accommodations/expenses from Bristol-Myers Squibb Company (BMS), Eisai, Exelixis, Genentech/Roche, Novartis, and Pfizer. BE reports honoraria, consulting, or advisory roles with BMS, EUSA Pharma, Ipsen, Novartis, Pfizer, and Roche. DFM reports consulting or advisory roles with Array BioPharma, BMS, Exelixis, Genentech/Roche, Lilly, Merck, Novartis, and Pfizer, and research finding from BMS (Inst), Genetech/Roche (Inst), Merck (Inst), Novartis (Inst), and Prometheus (Inst). OAF reports employment, stock or other ownership, and honoraria from Pfizer (I); consulting or advisory roles with BMS Chile and BMS Colombia; and travel, accommodations, expenses from Roche and Tecnofarma. BM reports honoraria from and advisory roles with Bayer, MSD, Merck Serono, Sanofi, Servie, AstraZeneca, Amgen, Janssen, Eisai, and Eli Lilly, and travel expenses from Merck Serono. TP reports honoraria from Merck, BMS, Pfizer, Roche, Ipsen, Novartis, Exelixis, and AstraZeneca, and research funding from AstraZeneca (Inst), Roche (Inst), and Novartis (Inst). FD reports research funding from Ipsen (Inst), Novartis (Inst), and Pfizer (Inst). ERP reports consulting or advisory roles with BMS, Genentech/Roche, Merck, Clovis, Exelixis, Seattle Genetics, Incyte, Janssen, and Flatiron Health; research funding from Astellas Pharma (Inst), AstraZeneca (Inst) BMS (Inst), Genentech/Roche (Inst), Merck (Inst), Peloton (Inst), and Pfizer (Inst); patents, royalties, and other intellectual property: US Patent Application No 14/588,503, pending, filed January 2, 2015; and the following other relationships: BMS (fees for development of educational presentations); Merck (fees for development of educational presentations); Roche (fees for development of educational presentations); Novartis (fees for development of educational presentations), and Exelixis (personal fees). PB reports consulting or advisory roles with BMS, Pfizer, MSD Oncology, Novartis, Ipsen, Roche, Janssen Cilag, and EUSA Pharma, and honoraria from Astellas Pharma and Amgen. HJH reports consulting or advisory roles with BMS, Pfizer, Exelixis, Merck, Corvus, Surface Oncology, Armo Biosciences, and Novartis, and research funding from BMS and Merck. SG reports consulting or advisory roles with Astellas, BMS, Novartis, Bayer, Pfizer, Exelixis, AstraZeneca, Janssen Oncology, Corvus Pharmaceuticals, Genentech/Roche, EMD Serono, and Sanofi, and research funding from Pfizer (Inst), Acceleron Pharma (Inst), Merck (Inst), Agensys (Inst), Novartis (Inst), BMS (Inst), Bayer (Inst), Eisai (Inst), and Corvus (Inst). VG reports consulting or advisory roles with BMS, Pfizer, Novartis, Lilly, MSD Oncology, Ipsen, Janssen Cilag, and Onkowissen; consulting or advisory roles with Bayer, BMS, Pfizer, Ipsen, and AstraZeneca; stock or other ownership in MSD, BMS, and AstraZeneca; honoraria from BMS, Pfizer, Novartis, Ipsen, Eisai, Bayer, MSD Oncology, Merck Serono, Roche, Lilly, PharmaMar, AstraZeneca, EUSA Pharma, Janssen Cilag, Asklepios Clinics, Diakonie Clinic, Dortmund Hospital, and Clinic of Oldenburg; and research funding from Novartis (Inst). CP reports consulting or advisory roles with BMS, MSD, Pfizer, Ipsen, EUSA, Eisai, and General Electric; speakers’ bureau fees from BMS, MSD, Pfizer, Ipsen EUSA, Eisai, General Electric, Janssen, and AstraZeneca; research funding from Pfizer (Inst); expert testimony fees from Pfizer and EUSA; and travel, accommodations, and expenses from Roche. VN reports honoraria from MSD and TEVA. AR reports consulting or advisory roles with Pfizer, BMS, Roche, Ipsen, Merck, and AstraZeneca; research funding from Pfizer (Inst); and non-financial support from Pfizer, BMS, Ipsen, Merck, MSD, and AstraZeneca. TKC reports research (Institutional and personal) funding from AstraZeneca, Alexion, Bayer, BMS/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc, Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, and Takeda; honoraria from AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc, Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, UptoDate, Analysis Group, NCCN, Michael J Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, New England Journal of Medicine, Lancet Oncology, Heron Therapeutics, and Lilly; consulting or advisory roles with AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS/ER Squibb and Sons LLC, Cerulean, Eisai, Foundation Medicine Inc, Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, UptoDate, NCCN, and Analysis Group; and the following patents, royalties or other intellectual properties: International Patent Application No PCT/US2018/12209, entitled 'PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response', filed January 3, 2018, claiming priority to US Provisional Patent Application No 62/445,094, filed January 11, 2017, International Patent Application No PCT/US2018/058430, entitled 'Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy', filed October 31, 2018, claiming priority to US Provisional Patent Application No 62/581,175, filed November 3, 2017. BIR reports research funding from BMS, Pfizer, Merck, GNE, Roche, Aveo, and AstraZeneca; consulting or advisory roles with BMS, Pfizer, GNE/Roche, Aveo, Novartis, Synthorx, Peloton, Compugen, Merck, Arravive, Surface Oncology, and 3D Medicines, and stock or other ownership in PTC Therapeutics. CKK reports honoraria from BMS, Pfizer, Ipsen, and Eisai; and consulting or advisory roles with BMS, Pfizer, Ipsen, Eisai, Roche, Astellas, and Janssen. SST reports consulting or advisory roles with BMS, Calithera Biosciences, and Prometheus Laboratories; and research funding from BMS (Inst), Calithera Biosciences (Inst), Merck (Inst), Nektar Therapeutics (Inst), Peloton Therapeutics (Inst), Jounce Therapeutics (Inst), Pfizer (Inst), Genentech (Inst), Prometheus Laboratories (Inst), ARGOS Therapeutics (Inst), and Clinigen (Inst). M-OG reports lecture or advisory roles with Novartis, BMS, Pfizer, Bayer, Astellas, Intuitive Surgical, Hexal, Apogepha, AstraZeneca, MSD Janssen Cilag, ONO Pharmaceuticals, Ipsen, Medac Merck, and Serono; and research funding from Novartis, BMS, and Intuitive Surgical. HG reports consulting or advisory roles with Astellas, BMS, Novartis, Pfizer, MSD, AstraZeneca, Ipsen, and Roche. RL-A reports personal fees from BMS, MSD, and Pfizer. PFG reports research funding from BMS, Pfizer, Merck, MSD, and Roche. AA reports research funding from BMS, Pfizer, Merck, and Exelixis, and speakers’ bureau fees from Pfizer, Exelixis, BMS, and Merck. YT reports honoraria from Pfizer, Novartis, ONO Pharmaceutical Co, Ltd, Astellas, BMS, and Chugai; consulting or advisory roles with ONO Pharmaceutical Co, Ltd, Novartis, and Taiho; and research funding from Takeda (Inst), Pfizer (Inst), ONO Pharmaceutical Co, Ltd (Inst), Astellas (Inst), Novartis (Inst), and Chugai (Inst). MBM reports employment with and stock or other ownership in BMS. SSS reports employment with and stock or other ownership in BMS. NMT reports research funding from BMS, Calithera Biosciences, Nektar Therapeutics, Exelixis, Pfizer, Novartis, Arrowhead Pharmaceuticals, Mirati Therapeutics, Takeda, Epizyme, and Eisai Medical Research; consulting, advisory, travel accommodations and expenses from BMS, Calithera Biosciences, Nektar Therapeutics, Exelixis, Pfizer, Novartis, Eisai Medical Research, Ipsen, Lilly Oncology, Neoleukin Therapeutics, Surface Oncology, ONO Pharmaceutical, and Oncorena; and honoraria from BMS, Exelixis, Nektar Therapeutics, Calithera Biosciences, Eisai Medical Research, ONO Pharmaceutical, Eli Lilly, Oncorena, Ipsen, and Surface Oncology.

Figures

**Figure 1**
Overall survival. (A) In intermediate-risk/poor-risk patients. (B) In intent-to-treat patients. (C) In favorable-risk patients. mOS, median overall survival; NE, not estimable; NIVO+IPI, nivolumab plus ipilimumab; NR, not reached; SUN, sunitinib.

**Figure 2**
Progression-free survival and duration of response per independent radiology review committee. (A, B) In intermediate-risk/poor-risk patients. (C, D) In intent-to-treat patients. (E, F) In favorable-risk patients. mDOR, median duration of response; mPFS, median progression-free survival; NE, not estimable; NIVO+IPI, nivolumab plus ipilimumab; NR, not reached; SUN, sunitinib.

**Figure 3**
Treatment-free interval and response outcomes in complete responders. (A) In intermediate-risk/poor-risk (top) and favorable-risk (bottom) patients in the NIVO+IPI arm. (B) In intermediate-risk/poor-risk (top) and favorable-risk (bottom) patients in the SUN arm. TFI was defined as the time between protocol therapy discontinuation until subsequent therapy initiation or last known date alive. Bar indicates time on treatment/TFI. Time zero corresponds to first treatment date. Of all-risk patients, 11 versus 6 received subsequent systemic therapy with NIVO+IPI versus SUN. These patients may have stopped therapy due to investigator-assessed progression or other protocol-specified reason such as toxicity (data not shown). The decision to start subsequent systemic therapy in either arm was made by the investigator based on expert opinion and treatment guidelines, and these data were not formally collected. ITT, intention-to-treat; NIVO+IPI, nivolumab plus ipilimumab; TFI, treatment-free interval in patients who are off study treatment.

**Figure 4**
Six-month landmark analysis of overall survival by best overall response per RECIST V.1.1 (per IRRC). (A) In the NIVO+IPI arm. (B) In the SUN arm. CR, complete response; IRRC, independent radiology review committee; NIVO+IPI, nivolumab plus ipilimumab; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; SUN, sunitinib.

**Figure 5**
Six-month landmark overall survival analyses in intent-to-treat patients with nivolumab plus ipilimumab. (A) Immune-related adverse events (irAEs), yes versus no. (B) Treatment-related adverse events (TRAEs) leading to discontinuation, yes versus no. Includes events reported between first dose and 30 days after last dose of study therapy. mOS, median overall survival; NE, not estimable; NR, not reached.

**Figure 6**
Safety outcomes over time. (A) Treatment-related adverse events (AEs) over time by 6-month interval with nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN). (B) Select treatment-related AEs over time by 6-month interval with NIVO+IPI. (C) Corticosteroid use over time with NIVO+IPI. ^aN=patients at risk at the beginning of each 6-month interval, and patients may be counted more than once across intervals. ^bIncidence of grade 3–4 treatment-related AEs in all intervals with NIVO+IPI after 24 months was ≤2.4%. ^cN=patients at risk at the beginning of each 6-month interval, and patients may be counted more than once across intervals. ^dIncidence of grade 3–4 treatment-related select AEs in all intervals with NIVO+IPI after 12 months was ≤1.6%. ^e≥40 mg prednisone daily or equivalent. Treatment-related AEs and treatment-related select AEs were calculated by 6-month interval using the total number of new events out of the total number of patients at risk at the beginning of the interval.

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References

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[1] Rini BI, Battle D, Figlin RA, et al. . The Society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC). J Immunother Cancer 2019;7. 10.1186/s40425-019-0813-8 - DOI - PMC - PubMed

[2] Rini BI, Battle D, Figlin RA, et al. . The Society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC). J Immunother Cancer 2019;7. 10.1186/s40425-019-0813-8 - DOI - PMC - PubMed

[3] Atkins MB, Tannir NM. Current and emerging therapies for first-line treatment of metastatic clear cell renal cell carcinoma. Cancer Treat Rev 2018;70:127–37. 10.1016/j.ctrv.2018.07.009 - DOI - PubMed

[4] Atkins MB, Tannir NM. Current and emerging therapies for first-line treatment of metastatic clear cell renal cell carcinoma. Cancer Treat Rev 2018;70:127–37. 10.1016/j.ctrv.2018.07.009 - DOI - PubMed

[5] Motzer RJ, Tannir NM, McDermott DF, et al. . Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277–90. 10.1056/NEJMoa1712126 - DOI - PMC - PubMed

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Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial

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Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial

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