Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial

Abstract

Background: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.

Methods: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.

Findings: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months [IQR 13·4-36·3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35·6-not estimable] vs 26·6 months [22·1-33·4]; hazard ratio [HR] 0·66 [95% CI 0·54-0·80], p<0·0001), progression-free survival (median 8·2 months [95% CI 6·9-10·0] vs 8·3 months [7·0-8·8]; HR 0·77 [95% CI 0·65-0·90], p=0·0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37·9 months [32·2-not estimable]; HR 0·71 [95% CI 0·59-0·86], p=0·0003), progression-free survival (median 9·7 months [95% CI 8·1-11·1] vs 9·7 months [8·3-11·1]; HR 0·85 [95% CI 0·73-0·98], p=0·027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0·015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.

Interpretation: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.

Funding: Bristol-Myers Squibb and ONO Pharmaceutical.

Conflict of interest statement

Declaration of interests

RJM reports grants from Bristol-Myers Squibb during the conduct of the study; and grants and personal fees from Pfizer, Novartis, Eisai, Exelixis, and Genentech/Roche, personal fees from Merck, grants and personal fees from Eisai and Pfizer, and personal fees from Novartis, outside the submitted work.

BIR reports grants and personal fees from Bristol-Myers Squibb, outside submitted work.

DFM reports personal fees from Exelixis, Array BioPharma, Bristol-Myers Squibb, Merck, Genentech, Novartis, Pfizer, and Eisai, grants from Prometheus, Bristol-Myers Squibb, Merck, Genentech/Roche, Pfizer, Exelixis, Novartis, and X4 Pharma, and personal fees from Alkermes, Inc., outside the submitted work.

OAF reports personal fees from Roche, Tecnofarma, Novartis, and Bristol-Myers Squibb, and other from Pfizer, outside the submitted work.

HJH reports grants and personal fees from Bristol-Myers Squibb, personal fees from Pfizer and Exelixis, grants and personal fees from Merck, and personal fees from Armo Biosciences and Novartis, during the conduct of the study.

MAC reports personal fees from Astellas Pharma, AbbVie, Roche/Genentech, Pfizer, and Foundation Medicine, grants from Bristol-Myers Squibb, AstraZeneca, Gilead Sciences, EMD Serono, and Effector, outside the submitted work.

PS has nothing to disclose.

BE reports honoraria from Ipsen, Novartis, Pfizer, Bristol-Myers Squibb, Exelixis, EUSA, Aveo, and Roche.

BB reports grants and personal fees from Pfizer and Bristol-Myers Squibb, and personal fees from Ipsen, outside the submitted work.

AA reports grants, personal fees, and non-financial support from Bristol-Myers Squibb and Merck, grants and personal fees from Dynavax, personal fees and non-financial support from Pfizer, Exelixis, Bioarray, and Novartis, outside the submitted work.

CP reports personal fees from Bristol-Myers Squibb and MSD, grants and personal fees from Pfizer, personal fees from Novartis, Ipsen, EUSA, Eisai, Janssen, AstraZeneca, and General Electric, outside submitted work.

SG reports personal fees from AstraZeneca, grants and personal fees from Bayer, Bristol-Myers Squibb and Novartis, personal fees from Exelixis and Janssen, grants and personal fees from Corvus, personal fees from Genentech and Sanofi/Genzyme, grants and personal fees from Pfizer, grants from Acceleron, Merck, Agensys, and Eisai, and personal fees from EMD Serono, outside the submitted work.

VN has nothing to disclose.

SB reports non-financial support from Novartis, personal fees, non-financial support and other from Astellas, personal fees and non-financial support from Janssen, personal fees, non-financial support and other from Pfizer, non-financial support and other from Bristol-Myers Squibb, non-financial support and other from Roche, personal fees and non-financial support from MSD, non-financial support from Exelixis, and non-financial support from AstraZeneca, outside the submitted work.

SST reports clinical trial support received on behalf of his institution from Bristol-Myers Squibb, non-financial support from Bristol-Myers Squibb, during the conduct of the study; clinical trial support received on behalf of his institution from Peloton Therapeutics, Merck, Nektar Therapeutics, and Calithera Biosciences, personal fees from Calithera Biosciences, clinical trial support received on behalf of his institution from Jounce Therapeutics, Pfizer, Genentech, and Prometheus Laboratories, personal fees from Prometheus Laboratories, and clinical trial support received on behalf of his institution from ARGOS Therapeutics, outside the submitted work.

PB reports advisory board funding from Bristol-Myers Squibb, Pfizer, Roche, Ipsen, MSD, Janssen Cilag, and Novartis, outside the submitted work.

RLA reports honoraria from Bristol-Myers Squibb, MSD, Roche, Isotopia, and Bayer, advisory role travel grant from Janssen, advisory role from Sanofi, advisory role travel grant from Pfizer, and advisory role from Astellas, outside the submitted work.

ERP reports grants from Bristol-Myers Squibb, consulting fees from Bristol-Myers Squibb, and travel fees from Bristol-Myers Squibb during the conduct of the study; consultant fees from AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Merck, Novartis, Pfizer, Eli Lilly, SynerGene Therapeutics, Inovio, Clovis, Horizon Pharma, Exelixis, funds for development of educational presentations from Bristol-Myers Squibb, Merck, Roche, and Novartis; and grants to institution for conduct of clinical trial(s) from AstraZeneca, Bristol-Myers Squibb, Merck, Peloton, Pfizer, and Astellas. In addition, Dr. Plimack has a patent U.S. Patent Application No.: 14/588,503 issued, and a patent US Patent Application No: 15/226,474 issued.

SFO reports non-financial support from Bristol-Myers Squibb, during the conduct of the study; grants from Celldex, and grants from Novartis, outside the submitted work.

BR has nothing to disclose.

BM reports personal fees and honoraria for advisory boards, speeches, and travel support from Bristol-Myers Squibb, Roche, MSD, Merck Serono, and Novartis, personal fees from Pfizer, Ipsen, Sanofi, Astellas, Janssen, Eisai, AstraZeneca, and Amgen, outside the submitted work.

TP reports grants from AstraZeneca, Roche, Novartis, Merck, Bristol-Myers Squibb, Pfizer, Roche, Ipsen, Novartis, and Exelixis, outside the submitted work.

PN reports board membership, manuscript preparation, and travel fees from Bristol-Myers Squibb, outside the submitted work.

SO reports grants, personal fees and non-financial support from Bristol-Myers Squibb, Pfizer, Novartis, Eisai, and Bayer, outside the submitted work.

DP reports research funding from Bristol-Myers Squibb, during the conduct of the study; personal fees and advisory board fees from Bristol-Myers Squibb, and personal fees, research funding, and advisory board funding from Pfizer, outside the submitted work.

TKC reports grants, personal fees, and non-financial support from Pfizer and Exelixis during the conduct of the study; grants and personal fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, and Ipsen; grants from Tracon; personal fees from Alligent, Up-to-Date, NCCN, Analysis Group, Michael J. Hennessy (MJH) Associates, Inc. (Healthcare Communications Company and several brands such as OnClive 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, and Lancet Oncology; and grants from Calithera and Takeda, outside the submitted work.

FD reports grants from Novartis, Pfizer, and Ipsen, outside the submitted work.

MOG reports treatment fees from Bristol-Myers Squibb for participation in CheckMate 214 during the conduct of this trial; grants and personal fees from Novartis and Bristol-Myers Squibb; and personal fees from Pfizer, Bayer HealthCare, Astellas, Intuitive Surgical, Sanofi Aventis, Hexal, Apogepha, Amgen, AstraZeneca, MSD, Janssen Cilag, ONO Pharmaceutical, Ipsen Pharma, and Medac, outside submitted work.

HG reports personal fees from Bristol-Myers Squibb, during the conduct of the study; and personal fees from Pfizer, Astellas, Ipsen, and Roche, outside the submitted work.

DYCH reports personal fees from Bristol-Myers Squibb, Pfizer, and Novartis, outside the submitted work.

CKK reports personal fees from Bristol-Myers Squibb, Pfizer, Eisai, Ipsen, Roche, and AstraZeneca, outside the submitted work.

MRH reports grants from Pfizer, during the conduct of the study; grants from Argos, Bristol-Myers Squibb, Exelixis, and Genentech; personal fees from Argos, Exelixis, Genentech, and Bristol-Myers Squibb; consulting fees from Argos, Exelixis, and Pfizer; and speakers bureau fees from Exelixis and Genentech, outside the submitted work.

YT reports grants from Astellas, AstraZeneca, ONO, Pfizer, and Chugai; and personal fees from Astellas, Bristol-Myers Squibb, Novartis, ONO, Pfizer, and Taiho, outside the submitted work.

ID reports personal fees from Bristol-Myers Squibb and Novartis, personal fees and non-financial support from Ipsen, grants, personal fees, and non-financial support from Roche Genentech and AstraZeneca, and personal fees from Sanofi, Bayer, Pharmacyclics, Jansen, and MSD, outside the submitted work.

VG reports grants and personal fees from Pfizer, grants, personal fees, and non-financial support from Bristol-Myers Squibb, personal fees and non-financial support from Roche, Novartis, and Eisai, grants, personal fees, and non-financial support from Ipsen, and grants and personal fees from EUSA Pharma, during the conduct of the study; grants, personal fees, non-financial support and stock holdings in MSD, grants from Novartis, grants, personal fees, and stock holdings in AstraZeneca, grants, personal fees, non-financial support, and stock holdings in Bristol-Myers Squibb, personal fees and non-financial support from Merck Serono, personal fees from Roche, Pfizer, and Lilly, and personal fees and non-financial support from PharmaMar, outside the submitted work.

MBM reports personal fees, and employment and stock holdings in Bristol-Myers Squibb, outside the submitted work.

SM reports personal fees from and employment by Bristol-Myers Squibb, outside the submitted work.

NMT reports grants and personal fees from Bristol-Myers Squibb, Pfizer, and Novartis, personal fees from Nektar Therapeutics and Oncorena, grants and personal fees from Exelixis, Inc, personal fees from Eisai Medical Research, grants from Calithera Biosciences, and personal fees from ONO Pharmaceutical, outside the submitted work.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. CONSORT diagram for patient disposition

*11 intermediate/poor-risk patients in the sunitinib arm crossed over in the nivolumab + ipilimumab (NIVO+IPI) arm, but were not analysed as part of the NIVO+IPI efficacy or safety population.

Figure 2:. Overall survival in IMDC intermediate/poor-risk patients

(A), in the ITT population (B), and in IMDC favourable-risk patients (C) CI = confidence interval; HR = hazard ratio; IMDC = International Metastatic Renal Cell Carcinoma Database Consortium; ITT = intention-to-treat; NE = not evaluable; NIVO+IPI = nivolumab plus ipilimumab; NR = not reached; SUN = sunitinib.

Figure 3:. Progression-free survival per investigator in IMDC intermediate/poor-risk patients

(A), in the ITT population (B), and in IMDC favourable-risk patients (C) CI = confidence interval; HR = hazard ratio; IMDC = International Metastatic Renal Cell Carcinoma Database Consortium; NIVO+IPI = nivolumab plus ipilimumab; PFS = progression-free survival; SUN = sunitinib.

Figure 4:. Duration of response in the NIVO+IPI and SUN arms

(A), treatment duration and treatment-free survival in responders in the NIVO+IPI arm (B), and in the SUN arm (C) NE = not evaluable; NIVO+IPI = nivolumab plus ipilimumab; NR = not reached; SUN = sunitinib.

Figure 5:. Any-grade treatment-related AEs occurring in >15% of patients in either arm with treatment-related grade 3–4 AEs (all treated patients)

(A) and proportion of patients with treatment-related grade 3–4 AEs by common system organ class over time in the NIVO+IPI arm (B) and in the SUN arm (C) *Additional patients reported common any-grade treatment-related AEs with longer follow-up compared with the primary database lock (NIVO+IPI arm: diarrhoea [n=9], pruritis, rash [both n=6], fatigue [n=5]; hypothyroidism [n=4]; asthenia, increased lipase, anaemia [all n=2]; PPE, nausea, mucosal inflammation, stomatitis, decreased appetite, vomiting, dyspepsia, thrombocytopenia [all n=1] vs SUN arm: vomiting, hypothyroidism [both n=5]; diarrhoea [n=4]; increased lipase, hypertension, nausea [all n=3]; fatigue, rash, PPE, mucosal inflammation, decreased appetite [all n=2]; asthenia, dysgeusia, stomatitis, dyspepsia [all n=1]; †< 1% reported grade 3–4 treatment-related AE; ‡No patients reported a grade 3–4 treatment-related AE. NIVO+IPI = nivolumab plus ipilimumab; PPE = palmoplantar erythrodysesthesia; SUN = sunitinib