Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma

doi:10.1002/cncr.34180

Randomized Controlled Trial

. 2022 Jun 1;128(11):2085-2097.

doi: 10.1002/cncr.34180. Epub 2022 Apr 5.

Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma

Robert J Motzer¹, David F McDermott², Bernard Escudier³, Mauricio Burotto⁴, Toni K Choueiri⁵, Hans J Hammers⁶, Philippe Barthélémy⁷, Elizabeth R Plimack⁸, Camillo Porta⁹, Saby George¹⁰, Thomas Powles¹¹, Frede Donskov¹², Howard Gurney¹³, Christian K Kollmannsberger¹⁴, Marc-Oliver Grimm¹⁵, Carlos Barrios¹⁶, Yoshihiko Tomita¹⁷, Daniel Castellano¹⁸, Viktor Grünwald¹⁹, Brian I Rini²⁰, M Brent McHenry²¹, Chung-Wei Lee²², Jennifer McCarthy²³, Flavia Ejzykowicz²⁴, Nizar M Tannir²⁵

Affiliations

¹ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
² Division of Medical Oncology, Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts.
³ Department of Medical Oncology, Gustave Roussy, Villejuif, France.
⁴ Bradford Hill Clinical Research Center, Santiago, Chile.
⁵ Department of Medical Oncology, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
⁶ Department of Medical Oncology, University of Texas Southwestern Kidney Cancer Program, Dallas, Texas.
⁷ Medical Oncology, Strasbourg European Cancer Institute, Strasbourg, France.
⁸ Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
⁹ Department of Internal Medicine, University of Pavia, Pavia, Italy.
¹⁰ Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York.
¹¹ Department of Genitourinary Oncology, Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Center, Queen Mary University of London, Royal Free National Health Service Trust, London, United Kingdom.
¹² Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.
¹³ Department of Medical Oncology, Westmead Hospital and Macquarie University, Sydney, New South Wales, Australia.
¹⁴ Department of Medicine, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
¹⁵ Department of Urology, Jena University Hospital, Jena, Germany.
¹⁶ Oncology Research Unit, Saint Luke Hospital, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil.
¹⁷ Departments of Urology and Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
¹⁸ Medical Oncology Department, October 12th University Hospital, Cancer Network Biomedical Research Center, Madrid, Spain.
¹⁹ Interdisciplinary Genitourinary Oncology, West German Cancer Center Clinic for Internal Medicine and Clinic for Urology, University Hospital Essen, Essen, Germany.
²⁰ Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, Tennessee.
²¹ Department of Biostatistics, Bristol Myers Squibb, Princeton, New Jersey.
²² Department of Clinical Trials, Bristol Myers Squibb, Princeton, New Jersey.
²³ Department of Clinical Scientists, Bristol Myers Squibb, Princeton, New Jersey.
²⁴ Department of Health Economics and Outcomes Research, Bristol Myers Squibb, Princeton, New Jersey.
²⁵ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

PMID: 35383908
PMCID: PMC9543316
DOI: 10.1002/cncr.34180

Randomized Controlled Trial

Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma

Robert J Motzer et al. Cancer. 2022.

. 2022 Jun 1;128(11):2085-2097.

doi: 10.1002/cncr.34180. Epub 2022 Apr 5.

Authors

Affiliations

¹ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
² Division of Medical Oncology, Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts.
³ Department of Medical Oncology, Gustave Roussy, Villejuif, France.
⁴ Bradford Hill Clinical Research Center, Santiago, Chile.
⁵ Department of Medical Oncology, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
⁶ Department of Medical Oncology, University of Texas Southwestern Kidney Cancer Program, Dallas, Texas.
⁷ Medical Oncology, Strasbourg European Cancer Institute, Strasbourg, France.
⁸ Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
⁹ Department of Internal Medicine, University of Pavia, Pavia, Italy.
¹⁰ Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York.
¹¹ Department of Genitourinary Oncology, Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Center, Queen Mary University of London, Royal Free National Health Service Trust, London, United Kingdom.
¹² Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.
¹³ Department of Medical Oncology, Westmead Hospital and Macquarie University, Sydney, New South Wales, Australia.
¹⁴ Department of Medicine, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
¹⁵ Department of Urology, Jena University Hospital, Jena, Germany.
¹⁶ Oncology Research Unit, Saint Luke Hospital, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil.
¹⁷ Departments of Urology and Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
¹⁸ Medical Oncology Department, October 12th University Hospital, Cancer Network Biomedical Research Center, Madrid, Spain.
¹⁹ Interdisciplinary Genitourinary Oncology, West German Cancer Center Clinic for Internal Medicine and Clinic for Urology, University Hospital Essen, Essen, Germany.
²⁰ Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, Tennessee.
²¹ Department of Biostatistics, Bristol Myers Squibb, Princeton, New Jersey.
²² Department of Clinical Trials, Bristol Myers Squibb, Princeton, New Jersey.
²³ Department of Clinical Scientists, Bristol Myers Squibb, Princeton, New Jersey.
²⁴ Department of Health Economics and Outcomes Research, Bristol Myers Squibb, Princeton, New Jersey.
²⁵ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

PMID: 35383908
PMCID: PMC9543316
DOI: 10.1002/cncr.34180

Abstract

Background: Conditional survival estimates provide critical prognostic information for patients with advanced renal cell carcinoma (aRCC). Efficacy, safety, and conditional survival outcomes were assessed in CheckMate 214 (ClinicalTrials.gov identifier NCT02231749) with a minimum follow-up of 5 years.

Methods: Patients with untreated aRCC were randomized to receive nivolumab (NIVO) (3 mg/kg) plus ipilimumab (IPI) (1 mg/kg) every 3 weeks for 4 cycles, then either NIVO monotherapy or sunitinib (SUN) (50 mg) daily (four 6-week cycles). Efficacy was assessed in intent-to-treat, International Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk/poor-risk, and favorable-risk populations. Conditional survival outcomes (the probability of remaining alive, progression free, or in response 2 years beyond a specified landmark) were analyzed.

Results: The median follow-up was 67.7 months; overall survival (median, 55.7 vs 38.4 months; hazard ratio, 0.72), progression-free survival (median, 12.3 vs 12.3 months; hazard ratio, 0.86), and objective response (39.3% vs 32.4%) benefits were maintained with NIVO+IPI versus SUN, respectively, in intent-to-treat patients (N = 550 vs 546). Point estimates for 2-year conditional overall survival beyond the 3-year landmark were higher with NIVO+IPI versus SUN (intent-to-treat patients, 81% vs 72%; intermediate-risk/poor-risk patients, 79% vs 72%; favorable-risk patients, 85% vs 72%). Conditional progression-free survival and response point estimates were also higher beyond 3 years with NIVO+IPI. Point estimates for conditional overall survival were higher or remained steady at each subsequent year of survival with NIVO+IPI in patients stratified by tumor programmed death ligand 1 expression, grade ≥3 immune-mediated adverse event experience, body mass index, and age.

Conclusions: Durable clinical benefits were observed with NIVO+IPI versus SUN at 5 years, the longest phase 3 follow-up for a first-line checkpoint inhibitor-based combination in patients with aRCC. Conditional estimates indicate that most patients who remained alive or in response with NIVO+IPI at 3 years remained so at 5 years.

Keywords: CheckMate 214; advanced renal cell carcinoma; dual checkpoint inhibition; durable response; long-term follow-up; nivolumab plus ipilimumab; phase 3.

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Conflict of interest statement

Robert J. Motzer reports institutional grants or contracts from Aveo Pharmaceuticals, Bristol Myers Squibb (BMS), Eisai, Exelixis Inc, Genentech/Roche, Merck, Pfizer; and personal fees for advisory board participation from AstraZeneca, Aveo Pharmaceuticals, Eisai, EMD Serono, Exelixis Inc, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer, all outside the submitted work. David F. McDermott reports institutional research grants from Alkermes Inc, BMS, Genentech/Roche, Merck, Novartis, Peloton Therapeutics, and Prometheus Laboratories; consulting or advisory fees from Alkermes Inc, Array BioPharma, Aveo Pharmaceuticals, BMS, Calithera Biosciences, Checkmate Pharmaceuticals, CRISPR Therapeutics, Eisai, Eli Lilly and Company, EMD Serono, Exelixis Inc, Genentech/Roche, Iovance, Johnson & Johnson, Jounce Therapeutics, Merck, Novartis, Peloton Therapeutics, Pfizer, Synthekine Inc, Werewolf Therapeutics, and X4 Pharma; and other fees from the Beth Israel Deaconess Medical Center, all outside the submitted work. Bernard Escudier reports personal fees from Aveo Pharmaceuticals, BMS, Eisai, Ipsen, Oncorena, and Pfizer; honoraria from BMS, Ipsen, Oncorena, and Pfizer; and support for meetings and/or travel accommodations/expenses from BMS, Ipsen, and MSD, all outside the submitted work. Mauricio Burotto reports honoraria from AstraZeneca, BMS, Merck, Novartis, and Roche; and participation on a data safety monitoring board at AstraZeneca, BMS, Merck, and Roche, all outside the submitted work. Toni K. Choueiri reports support in part by grants from the National Cancer Institute to the Dana‐Farber/Harvard Specialized Program of Research Excellence (2P50CA101942‐16) and Program 5P30CA006516‐56, the Kohlberg Chair at Harvard Medical School, and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana Farber Cancer Institute; institutional research funding for clinical trials from the Alliance Cooperative Group, AstraZeneca, Aveo Pharmaceuticals, Bayer, BMS, Eisai, EMD Serono, Exelixis Inc, Eli Lilly and Company, GlaxoSmithKline (GSK), Merck, Nikang Therapeutics, Novartis, Orien, Peloton, Pfizer, Roche, Sanofi‐Aventis, and Takeda; royalties/licensing fees from Up‐To‐Date (online textbook); personal fees from Analysis Group, Aptitude Health, AstraZeneca, Aravive, Aveo Pharmaceuticals, Bayer, BMS, Calithera Biosciences, Circle Pharma, Eisai, Eli Lilly and Company, EMD Serono, Exelixis Inc, GSK, IQVIA, Infinity Pharmaceuticals, Ipsen, Kanaph, Merck, Nikang Therapeutics, Novartis, Nuscan, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up‐To‐Date, and continuing medical education events (PeerView, PER, MJH Life Sciences, Research to Practice, France Foundation, Springer, WebMed, ASiM Ce, and Caribou Publishing); honoraria from Advent Health, the American Society of Clinical Oncology (ASCO)‐Society for the Immunotherapy of Cancer, ASiM Ce, CancerNet, Ipsen, The University of Texas MD Anderson Cancer Center, MJH Life Sciences, NAMC, PeerView, PER, Research to Practice, Springer, and WebMD; participation on a data safety monitoring board at Aravive; a leadership or fiduciary role in KidneyCan (unpaid), ASCO, the European Society for Medical Oncology, the National Comprehensive Cancer Network, and the Genitourinary Steering Committee of the National Cancer Institute; stock ownership in Nuscan, Osel, Pionyr, and Tempest; and principal investigator fees (institutional) from GSK, Roche, and Surface Oncology, all outside the submitted work. Hans J. Hammers reports clinical research funding from Aravive, BMS, Merck, and Surface Oncology; personal fees from ARMO Biosciences, Aveo Pharmaceuticals, BMS, Corvus, Merck, Pfizer, and Surface Oncology; and receipt of drugs for clinical trials from BMS, all outside the submitted work. Philippe Barthélémy reports personal fees from Amgen, Astellas Pharma, Bayer, BMS, Eisai, Ipsen, Janssen‐Cilag, Merck, Merck Sharp & Dohme (MSD), Novartis, Pfizer, and Roche; honoraria from Amgen, Astellas Pharma, AstraZeneca, Bayer, BMS, Ipsen, Janssen‐Cilag, Merck, Novartis, Pfizer, and Seagen; and support for travel accommodations/expenses from BMS, Ipsen, Janssen‐Cilag, Merck, MSD, Novartis, and Pfizer, all outside the submitted work. Elizabeth R. Plimack reports grants for clinical research from Astellas Pharma, BMS, Genentech, and Merck; personal fees from Astellas Pharma, AstraZeneca, Aveo Pharmaceuticals, BMS, Calithera Biosciences, Flatiron, Genentech, Infinity Pharmaceuticals, Janssen, MEI Pharma, Merck, Pfizer, Regeneron, and Seattle Genetics; honoraria from ACHL, Clinical Care Options, Creative Educational Solutions, CUA, Fox Chase Cancer Center, Georgetown University, American Society of Clinical Oncology Genitourinary Cancers Symposium (GU ASCO), JADPRO Bladder, Medscape, Mount Sinai, the National Comprehensive Cancer Network, Ohio State University, OncLive, Peak Medicals GmbH, PER, Research to Practice, Spire Learning, Total CME, the University of Hawaii, and the University of Pennsylvania; has applied for a patent for Screening Muscle Invasive Bladder Cancer Patients for Neoadjuvant Chemotherapy Responsiveness (US Patent Application No. 14/588,503); participates on a data safety monitoring board or advisory board for AstraZeneca, Infinity Pharmaceuticals, and Pfizer; and serves on the ASCO board of directors and the Bladder Cancer Advocacy Network Scientific Advisory Board, all outside the submitted work. Camillo Porta reports personal fees from Angelini, AstraZeneca, BMS, Eisai, EUSA Pharma, General Electric, Ipsen, Janssen, Merck, MSD, and Novartis; honoraria from Angelini, AstraZeneca, BMS, Eisai Medical Research, EUSA Pharma, General Electric, Ipsen, Janssen, Merck, MSD, Novartis, and Pfizer; fees for expert testimony from EUSA Pharma and Pfizer; steering committee member fees from BMS, Eisai, and EUSA Pharma; and support for travel accommodations/expenses from Roche, all outside the submitted work. Saby George reports institutional research funding from Aravive, Agensys, Aveo Pharmaceuticals, Bayer, BMS, Calithera Biosciences, Corvus Pharmaceuticals, Eisai, Exelixis Inc, Gilead, Merck, Novartis, Pfizer, Seattle Genetics, and Surface Oncology; personal fees from Aveo Pharmaceuticals, Bayer, BMS, Corvus Pharmaceuticals, Eisai, EMD Serono, Exelixis Inc, Merck, Immunomedics, Pfizer, QED Therapeutics, Sanofi, and Seattle Genetics; and honoraria from Aptitude Health, Curio Science, and DAVA Oncology, all outside the submitted work. Thomas Powles reports institutional research grants from Astellas Pharma, AstraZeneca, BMS, Eisai, Exelixis Inc, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; personal fees from Astellas Pharma, AstraZeneca, BMS, Eisai, Exelixis Inc, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; and support for travel accommodations/expenses from Ipsen, MSD, Pfizer, and Roche, all outside the submitted work. Frede Donskov reports institutional research grants from Ipsen, MSD, and Pfizer outside the submitted work. Howard Gurney reports honoraria from BMS, Ipsen, Merck, and Pfizer; and participation on advisory boards for AstraZeneca, BMS, Ipsen, Janssen, Merck, MSD, and Pfizer, all outside the submitted work. Christian K. Kollmannsberger reports personal fees from Astellas Pharma, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, and Pfizer outside the submitted work. Marc‐Oliver Grimm reports institutional research funding as a local/coordinating principal investigator from BMS, Intuitive Surgical, and Novartis; support for travel/accommodations from AstraZeneca, Ipsen, Merck, and Pfizer; participation on a data safety monitoring board or advisory board for Astellas, AstraZeneca, Bayer, BMS, Eisai, EUSA Pharma, Ipsen, Janssen‐Cilag, Merck Serono, MSD, Roche, and Takeda; honoraria from Astellas, AstraZeneca, BMS, EUSA Pharma, Ipsen, Janssen, Merck Serono, MSD, Oncinfo, and Pfizer; and is a member of the board of directors of Deutsche Gesellschaft fur Urologie, all outside the submitted work. Carlos Barrios reports institutional research funding from AB Science, AbbVie, Abraxis Biosciences, Amgen, Asana Biosciences, Astellas Pharma, AstraZeneca, BioMarin, BMS, Boehringer Ingelheim, Celgene, Clinica Atlantas, Covance, Daiichi Sankyo, GSK, Eli Lilly and Company, Exelixis Inc, Halozyme, ImClone Systems, INC Research, inVentiv Health, Janssen, LEO Pharma, Medivation, Merck KGaA, Merrimack, Millennium, Mylan, Novartis, Pfizer, PharmaMar, Polyphor, Roche/Genentech, Sanofi, Shanghai Henlius Biotech, and Taiho Pharmaceutical; consulting or advisory fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Eisai, GSK, Libbs, MSD Oncology, Novartis, Pfizer, Roche/Genentech, and United Medical; honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, Eli Lilly and Company, GSK, MSD, Novartis, Pfizer, Roche/Genentech, Sanofi, and Zodiac Pharma; participation on an independent data monitoring committee for Roche/Genentech; travel accommodations/expenses from AstraZeneca, BMS Brazil, Eli Lilly and Company, MSD Oncology, Novartis, Pfizer, and Roche/Genentech; and stock ownership in Biomark, MEDSIR, and Tummi, all outside the submitted work. Yoshihiko Tomita reports institutional research grants from Astellas Pharma, Ono Pharmaceutical, and Takeda; and honoraria from Astellas Pharma, BMS, Ono Pharmaceutical, and Pfizer, all outside the submitted work. Daniel Castellano reports institutional research grants from Janssen Oncology; and personal fees from Astellas Pharma, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Eli Lilly and Company, Ipsen, Janssen Oncology, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, and Sanofi, alloutside the submitted work. Viktor Grünwald reports institutional research grants from BMS, Ipsen, MSD, and Pfizer; personal fees from BMS, Eisai, EUSA Pharma, Ipsen, Janssen‐Cilag, Merck Serono, MSD, Nanobiotix, Pfizer, and Roche; honoraria from Apogepha, AstraZeneca, BMS, Eisai, EUSA Pharma, Ipsen, Janssen‐Cilag, Merck Serono, MSD, Pfizer, and Roche; support for travel/accommodations from AstraZeneca, BMS, and Pfizer; is on the faculty of the European Society for Medical Oncology; owns stock in AstraZeneca, BMS, GenMab, MSD, and Seattle Genetics; and is a member of the BMS, Ipsen, and Novartis steering committees, all outside the submitted work. Brian I. Rini reports institutional research funding from Aravive, Arrowhead, AstraZeneca, BMS, Merck, and Pfizer; grants from Aravive, Arrowhead Pharmaceuticals, AstraZeneca, BMS, Dragonfly Therapeutics, Exelixis Inc, Hoffmann‐La Roche, Immunomedics, Incyte, Janssen, Merck, Mirati Therapeutics, Pfizer, Seattle Genetics, and Surface Oncology; personal fees from 3DMedicines, Alkermes, Aravive, Arrowhead, Aveo Pharmaceuticals, BMS, Compugen, Corvus, Eisai, Genentech/Roche, GSK, Merck, Nikang Therapeutics, Pfizer, Shionogi, Surface Oncology, and Synthorx; support for travel/accommodations from Merck and Pfizer; participation on an AstraZeneca data safety monitoring board or advisory board; and owns stock in PTC Therapeutics, all outside the submitted work. M. Brent McHenry is an employee of BMS and owns stock in the company. Chung‐Wei Lee is an employee of BMS and owns stock in the company. Jennifer McCarthy is an employee of BMS. Flavia Ejzykowicz is an employee of BMS and owns stock in the company. Nizar M. Tannir reports institutional funding for clinical trials from Arrowhead, BMS, Calithera Biosciences, Eisai, Nektar Therapeutics, and Novartis; personal fees or honoraria from BMS, Calithera Bioscience, Eisai, Eli Lilly and Company, Exelixis Inc, Ipsen, MSD, Nektar Therapeutics, Novartis, Oncorena, Pfizer, and Surface Oncology; participation as a member of the US Renal Cell Carcinoma Advisory Board Committee; and owns stock in Amgen, Arcturus, Arcus, Bellus Health, BioCryst Pharmaceuticals, Corvus Pharmaceuticals, First Trust Amex Biotech, Johnson & Johnson, Merck, Nuvation Bio Inc Cl A (NUVB), Revolution Medicines, Spdr S&P Pharmaceuticals ETF, Surface Oncology, Vanguard Health Care ETF, and Xencor, all outside the submitted work.

Figures

**Figure 1**
(A) Overall survival (OS), (B) progression‐free survival (PFS), and (C) duration of response (DOR) are illustrated according to an independent radiology review committee using Response Evaluation Criteria in Solid Tumors, version 1.1, among patients in the intent‐to‐treat group. CI indicates confidence interval; HR, hazard ratio; NE, not estimable; NIVO+IPI, nivolumab plus ipilimumab; NR, not reached; SUN, sunitinib.

**Figure 2**
(A) Overall survival (OS), (B) progression‐free survival (PFS), and (C) duration of response (DOR) are illustrated according to an independent radiology review committee using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with intermediate‐risk/poor‐risk renal cell carcinoma according to the International Metastatic Renal Cell Carcinoma Database Consortium. CI indicates confidence interval; HR, hazard ratio; NE, not estimable; NIVO+IPI, nivolumab plus ipilimumab; NR, not reached; SUN, sunitinib.

**Figure 3**
(A) Overall survival (OS), (B) progression‐free survival (PFS), and (C) duration of response (DOR) are illustrated according to an independent radiology review committee using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with favorable‐risk renal cell carcinoma according to the International Metastatic Renal Cell Carcinoma Database Consortium. CI indicates confidence interval; HR, hazard ratio; NE, not estimable; NIVO+IPI, nivolumab plus ipilimumab; SUN, sunitinib.

**Figure 4**
Subgroup analysis of overall survival is illustrated in intent‐to‐treat patients. Note that hazard ratios (HRs) were not computed for subset categories that included <21 patients per treatment group. CI indicates confidence interval; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; mOS, median overall survival; N Europe, northern Europe; NE, not estimable; NIVO+IPI, nivolumab plus ipilimumab; PD‐L1, programmed death ligand 1; SUN, sunitinib; W Europe, western Europe.

**Figure 5**
(A) Conditional overall survival (OS), (B) conditional progression‐free survival (PFS), and (C) and conditional responses are illustrated among patients in the intent‐to‐treat (ITT) group, patients who had International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate‐risk/poor‐risk disease, and patients who had IMDC favorable‐risk disease. X‐axes indicate the landmark time from randomization (conditional OS and PFS) or the landmark time from the first confirmed response (conditional response). Error bars indicate 95% confidence intervals. OS, PFS, and response probabilities were conditioned on the time alive, the time progression‐free, or the time in response after time zero. NIVO+IPI indicates nivolumab plus ipilimumab; SUN, sunitinib.

**Figure 6**
Conditional overall survival (OS) is illustrated according to baseline clinical subgroups and complete responses among patients in the intent‐to‐treat group from the nivolumab plus ipilimumab arm. X‐axes indicate the landmark time from randomization. Error bars are 95% confidence intervals. OS probabilities were conditioned on the time survived after time zero and were stratified by (A) age (<65, 65‐75, or ≥75 years), (B) body mass index (BMI) (<30 or ≥30 kg/m²), (C) grade ≥3 immune‐mediated adverse event (IMAE) experience (yes or no), (D) tumor programmed death ligand 1 (PD‐L1) expression (<1% or ≥1%), and (E) and among patients who had a complete response (CR) as their best overall response (BOR).

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Comment in

Setting a new standard for long-term survival in metastatic kidney cancer.
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References

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[1] Choueiri TK, Motzer RJ. Systemic therapy for metastatic renal‐cell carcinoma. N Engl J Med. 2017;376:354‐366. - PubMed

[2] Choueiri TK, Motzer RJ. Systemic therapy for metastatic renal‐cell carcinoma. N Engl J Med. 2017;376:354‐366. - PubMed

[3] Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal‐cell carcinoma. N Engl J Med. 2018;378:1277‐1290. - PMC - PubMed

[4] Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal‐cell carcinoma. N Engl J Med. 2018;378:1277‐1290. - PMC - PubMed

[5] Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal‐cell carcinoma. N Engl J Med. 2019;380:1116‐1127. - PubMed

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Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma

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Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma

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