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Cited by 775Renal cell carcinoma treatmentCancer Immunotherapy and BiomarkersFerroptosis and cancer prognosis

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

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Motzer, Robert J, Rini, Brian I, McDermott, David F, Arén Frontera, Osvaldo, Hammers, Hans J, Carducci, Michael A, Salman, Pamela, Escudier, Bernard +30 more·2019·The Lancet Oncology
DOI 10.1016/s1470-2045(19)30413-9PMC PMC7497870
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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.

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  • Evidence for benefit of nivolumab plus ipilimumab compared to single agent ICI has been demonstrated in advanced renal cell cancer, MSI-hi/dMMR metastatic colorectal cancer, hepatocellular carcinoma, and non-small cell, EGFR/ALK wild type lung cancer.

    “Evidence for benefit of nivolumab plus ipilimumab compared to single agent ICI has also been demonstrated in patients with advanced renal cell cancer, microsatellite high/deficient mismatch repair (MSI-hi/dMMR) metastatic colorectal cancer12,14,15, hepatocellular carcinoma16, and non-small cell, EGFR/ALK wild type lung cancer17–19.”

    From A Phase I/II Trial of Nivolumab plus Ipilimumab in Children and Young Adults with Relapsed/Refractory Solid Tumors: A Children's Oncology Group Study ADVL1412 (2022) · cites this paper as [15]

    The Introduction and Discussion report benefit from nivolumab plus ipilimumab in advanced renal cell carcinoma, but the comparator was sunitinib, not a single-agent immune checkpoint inhibitor. This paper therefore does not demonstrate the specific comparison attributed to it. The other cancers have separate citations in the citing sentence. (LLM, conf=0.88)

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  • In the phase 3 CheckMate-214 study, nivolumab-ipilimumab significantly prolonged progression-free survival and overall survival compared with sunitinib, with 42% of patients achieving a response.

    “In that study, patients were randomized either to that regimen or to sunitinib (a VEGF inhibitor); significant prolongation of PFS and overall survival was observed, with 42% of patients achieving a response (many of these durable)11,12.”

    From Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial (2022) · cites this paper as [12]

  • Until now, the FDA has approved ipilimumab plus nivolumab for melanoma, RCC, MSI-H/dMMR colorectal cancer, HCC, PD-L1 positive NSCLC, and malignant pleural mesothelioma.

    “Until now, the FDA has approved the ipilimumab plus nivolumab for melanoma, RCC, MSI-H/dMMR colorectal cancer, HCC, PD-L1 positive NSCLC, and malignant pleural mesothelioma (Table 5) [132–138].”

    From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [135]

  • The data of CheckMate-214, CheckMate-227, and CheckMate-743 indicated the superior efficacy of ipilimumab plus nivolumab over the standard targeted therapy or chemotherapy.

    “Moreover, the data of CheckMate-214, CheckMate-227, and CheckMate-743 indicated the superior efficacy of ipilimumab plus nivolumab over the standard targeted therapy or chemotherapy [135–137].”

    From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [135]

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  1. [23]Motzer RJ, Powles T, Atkins MB, IMmotion151: A randomized phase III study of atezolizumab plus bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma (mRCC) Presented at: 2018 Genitourinary Cancers Symposium, February 8–10, 2018; San Francisco, CA, USA Poster 578.

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Authors
Motzer, R. J., Rini, B. I., McDermott, D. F., Arén Frontera, O., Hammers, H. J., Carducci, M. A., Salman, P., Escudier, B., Beuselinck, B., Amin, A., Porta, C., George, S., Neiman, V., Bracarda, S., Tykodi, S. S., Barthélémy, P., Leibowitz-Amit, R., Plimack, E. R., Oosting, S. F., Redman, B., Melichar, B., Powles, T., Nathan, P., Oudard, S., Pook, D., Choueiri, T. K., Donskov, F., Grimm, M.-O., Gurney, H., Heng, D. Y. C., Kollmannsberger, C. K., Harrison, M. R., Tomita, Y., Duran, I., Grünwald, V., McHenry, M. B., Mekan, S., & Tannir, N. M.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • Cleveland Clinic (US)
  • Beth Israel Deaconess Medical Center (US)
  • Johns Hopkins University (US)
  • Fundación Arturo López Pérez (CL)
  • Institut Gustave Roussy (FR)
  • Universitair Ziekenhuis Leuven (BE)
  • Levine Cancer Institute (US)
  • University of Pavia (IT)
  • Roswell Park Comprehensive Cancer Center (US)
  • Tel Aviv University (IL)
  • University of Washington (US)
  • Hôpitaux Universitaires de Strasbourg (FR)
  • Fox Chase Cancer Center (US)
  • University Medical Center Groningen (NL)
  • University of Michigan (US)
  • University Hospital Olomouc (CZ)
  • National Health Service (GB)
  • Mount Vernon Cancer Centre (GB)
  • Hôpital Européen Georges-Pompidou (FR)
  • Monash Health (AU)
  • Brigham and Women's Hospital (US)
  • Aarhus University Hospital (DK)
  • Jena University Hospital (DE)
  • Westmead Hospital (AU)
  • University of Calgary (CA)
  • BC Cancer Agency (CA)
  • Duke Cancer Institute (US)
  • Niigata University (JP)
  • Essen University Hospital (DE)
  • Bristol-Myers Squibb (United States) (US)
  • The University of Texas MD Anderson Cancer Center (US)
Corresponding author
Motzer, Robert J
ORCID
Venue
The Lancet Oncology
Publisher
Elsevier BV
Published
2019-10
Volume
20
Issue
10
Pages
1370-1385
ISSN
1470-2045 (ISSN-L)
DOI
10.1016/s1470-2045(19)30413-9
PMC
PMC7497870
OpenAlex
W2967350775
Cited by
775
References
22
Citations by year
2026: 38 · 2025: 47 · 2024: 86 · 2023: 131 · 2022: 130 · 2021: 168 · 2020: 163 · 2019: 12
FWCI
86.88
Type
journal article
Language
en
Update notices
Open access
Licence
Locations
  • The Lancet Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • Lirias (KU Leuven) (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
  • CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion, other-oa)
Funders
  • Memorial Sloan-Kettering Cancer Center
  • Bristol-Myers Squibb
  • Ono Pharmaceutical (P30 CA008748)
  • Agilent Technologies
  • Center for Outcomes Research and Evaluation, Yale School of Medicine
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
Keywords
nivolumab, ipilimumab, sunitinib, advanced renal cell carcinoma, immune checkpoint inhibitors, first-line therapy, overall survival, progression-free survival, objective response, long-term safety, immune-related adverse events, long-term follow-up, IMDC risk stratification, clear cell renal cell carcinoma, CheckMate 214
MeSH terms
Ipilimumab, Sunitinib, Nivolumab, Progression-Free Survival, Alanine Transaminase, Amylases, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Renal Cell, Fatigue, Follow-Up Studies, Humans, Hypertension, Kidney Neoplasms, Lipase, Paresthesia, Survival Rate, Intention to Treat Analysis

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