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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1370-1385 |
| Number of pages | 16 |
| Journal | The Lancet Oncology |
| Volume | 20 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 2019 |
ASJC Scopus subject areas
- Oncology
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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. / CheckMate 214 investigators.
In: The Lancet Oncology, Vol. 20, No. 10, 10.2019, p. 1370-1385.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma
T2 - extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial
AU - CheckMate 214 investigators
AU - Motzer, Robert J.
AU - Rini, Brian I.
AU - McDermott, David F.
AU - Arén Frontera, Osvaldo
AU - Hammers, Hans J.
AU - Carducci, Michael A.
AU - Salman, Pamela
AU - Escudier, Bernard
AU - Beuselinck, Benoit
AU - Amin, Asim
AU - Porta, Camillo
AU - George, Saby
AU - Neiman, Victoria
AU - Bracarda, Sergio
AU - Tykodi, Scott S.
AU - Barthélémy, Philippe
AU - Leibowitz-Amit, Raya
AU - Plimack, Elizabeth R.
AU - Oosting, Sjoukje F.
AU - Redman, Bruce
AU - Melichar, Bohuslav
AU - Powles, Thomas
AU - Nathan, Paul
AU - Oudard, Stéphane
AU - Pook, David
AU - Choueiri, Toni K.
AU - Donskov, Frede
AU - Grimm, Marc Oliver
AU - Gurney, Howard
AU - Heng, Daniel Y.C.
AU - Kollmannsberger, Christian K.
AU - Harrison, Michael R.
AU - Tomita, Yoshihiko
AU - Duran, Ignacio
AU - Grünwald, Viktor
AU - McHenry, M. Brent
AU - Mekan, Sabeen
AU - Tannir, Nizar M.
N1 - Funding Information: During the extended follow-up of the CheckMate 214 trial, a significant overall survival benefit was maintained with nivolumab plus ipilimumab versus sunitinib with an early and consistent separation of the Kaplan-Meier survival curves in both the intermediate-risk poor-risk and intention-to-treat populations. The intention-to-treat group included patients with IMDC favourable, intermediate, and poor-risk disease, whereas the primary objective of the study was to assess overall survival and other efficacy endpoints in the intermediate-risk and poor-risk population. 30-month overall survival was 60% for intermediate-risk or poor-risk patients treated with nivolumab plus ipilimumab versus 47% for those treated with sunitinib (64% vs 56% in the intention-to-treat population). A late progression-free survival benefit was observed in both intermediate-risk or poor-risk patients and in the intention-treat-population, with the Kaplan-Meier curves separating after 9 and 12 months. 30-month progression-free survival was higher with nivolumab plus ipilimumab than with sunitinib in both intermediate-risk or poor-risk patients (28% vs 12%) and in the intention-to-treat population (28% vs 18%), and was consistent with nivolumab plus ipilimumab regardless of risk category. In the intention-to-treat population, in patients treated with nivolumab and ipilimumab, the median time to confirmed response was less than 3 months, and the proportion of patients achieving an objective response was higher and more patients had an ongoing response compared with the sunitinib group. These observations suggest that nivolumab plus ipilimumab resulted in rapid disease volume control. Notably, more responses to nivolumab plus ipilimumab were complete (11%) and durable (88% ongoing complete responses; 59% ongoing responses) compared with sunitinib. A high proportion of responders who discontinued nivolumab plus ipilimumab still had a treatment-free survival benefit (ie, remained progression-free or were alive) without subsequent systemic therapy, regardless of risk category. Historically, favourable-risk patients have less aggressive disease and respond well to tyrosine kinase inhibitors, and many such patients can be managed at diagnosis with surveillance followed by delayed therapeutic intervention. 17 Although the 30-month overall survival probability in favourable-risk patients was slightly higher with sunitinib than with nivolumab and ipilimumab, survival probabilities between groups were similar. Compared with the results from the primary analysis, 1 the magnitude of difference between groups regarding overall survival in the favourable-risk subgroup decreased with longer follow-up, and as median overall survival was not reached in either treatment group, the overall survival data could still be considered immature in this group. Although updated response was measured per investigator instead of per IRRC assessment, the responses with nivolumab plus ipilimumab in favourable-risk patients were durable. In this relatively small exploratory group, nine (90%) of ten favourable-risk patients in the nivolumab plus ipilimumab group have ongoing complete response compared with only two (40%) of five patients in the sunitinib group. Available data in favourable-risk patients suggest that further follow-up will continue to inform the benefit–risk ratio for nivolumab plus ipilimumab versus sunitinib in this group of patients. The exploratory multivariable analysis showed that the IMDC baseline risk factors anaemia, neutrophilia, thrombocytosis, and time from diagnosis to treatment were not prognostic of overall survival with nivolumab plus ipilimumab. Interestingly, the results of the mutivariable analysis also suggest that baseline tumour PD-L1 expression of 1% or more predicts poor overall survival with sunitinib but not with nivolumab plus ipilimumab in advanced renal cell carcinoma. Neutrophil-to-lymphocyte ratio (a parameter indicating relative lymphocyte counts and marker of systemic inflammation) has shown previous prognostic value in advanced renal cell carcinoma with immune checkpoint inhibitors, and was an independent prognostic variable in both groups in the present analysis. 18,19 In the current era of immune checkpoint inhibitor-based therapies, these findings highlight a need for improved prognostic models based on understanding the host response and underlying tumour biology. 20 No new safety signals emerged in the nivolumab plus ipilimumab group with longer follow-up, and no treatment-related deaths occurred since the primary analysis database lock. Discontinuation of nivolumab plus ipilimumab, in part, reflected the protocol design, which specified that patients who required treatment discontinuation due to adverse events arising during nivolumab plus ipilimumab induction were not allowed to continue study treatment with nivolumab monotherapy. Interestingly, in a exploratory analysis of CheckMate 214, 21 similar efficacy outcomes were observed in all patients who discontinued because of treatment-related adverse events relative to the overall nivolumab plus ipilimumab efficacy population. The toxicity profiles for nivolumab plus ipilimumab and sunitinib were expected to differ on the basis of disparate underlying mechanisms of action. When comparing treatment groups, common grade 3 or 4 treatment-related adverse events in the nivolumab plus ipilimumab group arose early and generally resolved within the first 4–6 months of treatment. By contrast, both early and chronic toxicity were apparent in the sunitinib group, despite dose adjustments. Chronic toxicities commonly observed with tyrosine kinase inhibitors, including hypertension and palmar-plantar erythrodysaesthesia, were both evident in this analysis with sunitinib and in other reports of tyrosine kinase inhibitor and immunotherapy combinations. 22,23 Most treatment-related select adverse events occurring within 30 days of the last dose in the nivolumab plus ipilimumab group were low-grade, and the majority resolved and were manageable using established algorithms. However, vigilance for safety events by the health-care team throughout and after immunotherapy treatment completion is recommended. Reporting of corticosteroid use for immune checkpoint drugs has not been uniform among various studies. The initial CheckMate 214 presentation reported higher systemic corticosteroid use with nivolumab plus ipilimumab than in our current analysis; 24 that figure reflected a very broad definition of any systemic corticosteroid use from all-cause adverse events, and included corticosteroid use for adverse events related and unrelated to study treatment. The present analysis reported use of corticosteroids (≥40 mg prednisone daily or equivalent) to manage treatment-related select adverse events occurring within 30 days of last dose with an appropriate denominator of all treated patients (157 [29%] of 547 patients treated with nivolumab plus ipilimumab). This definition is more clinically meaningful than that used for the prior CheckMate 214 analyses, 24 and is in line with corticosteroid-use definitions used in recent PD-L1 and VEGFR combination trials. 22,25 Additionally, in a separate analysis of CheckMate 214 based on the primary database lock, health-related quality of life was maintained or significantly improved from baseline with nivolumab plus ipilimumab compared with sunitinib in intention-to-treat patients, further supporting the favourable benefit–risk profile of nivolumab plus ipilimumab versus sunitinib. 6 Limitations should be considered when interpreting the results. Outcomes in the relatively small subset of favourable-risk patients characterised by wide 95% CIs should be considered exploratory. To this point, the favourable-risk patients were included in the intention-to-treat population along with intermediate-risk and poor-risk patients, and efficacy endpoints of objective response, progression-free survival, and overall survival were formally assessed as secondary endpoints for the trial. Additionally, the present response outcomes were analysed per investigator versus IRRC and minor differences between outcomes based on these different methods could be expected. Ongoing work and future directions include exploring the potential role for nivolumab plus ipilimumab in treating novel patient populations including the adjuvant renal cell carcinoma setting in patients with high risk of relapse after nephrectomy (CheckMate 914, NCT03138512 ), and advanced renal cell carcinoma subpopulations with unmet need. A post-hoc exploratory analysis 26 of CheckMate 214 showed improved overall survival and progression-free survival benefits with nivolumab plus ipilimumab (60 patients) compared with sunitinib (52 patients) in intermediate-risk or poor-risk patients with sarcomatoid features, with a higher proportion of patients treated with nivolumab plus ipilimumab achieving an objective response (56·7% vs 19·2%; p<0·0001) and a higher proportion of patients achieving a complete response (18·3% vs 0%) compared with sunitinib; the magnitude of benefit from nivolumab plus ipilimumab compared with sunitinib was greater in these sarcomatoid-positive patients compared with the overall intermediate-risk or poor-risk population, and detailed analyses are ongoing. Furthermore, a prospective phase 3b–4 study of nivolumab plus ipilimumab in treatment-naive patients with advanced renal cell carcinoma with clear cell disease, non-clear cell disease, or non-active brain metastases (all with Karnofsky performance status ≥70%), or any histology or non-active brain metastasis with a Karnofsky performance status of 50–60% (CheckMate 920; NCT02982954 ), and a phase 2 study of nivolumab plus ipilimumab versus sunitinib in patients with non-clear cell advanced renal cell carcinoma (SUNIFORECAST; NCT03075423 ) are ongoing. The updated CheckMate 214 results support ongoing studies combining nivolumab plus ipilimumab with novel drugs (eg, with NKTR-214 in PIVOT-02; NCT02983045 ). Ongoing molecular and genomic analyses of CheckMate 214 and other studies might indicate predictive biomarkers of response or prognostic factors to nivolumab plus ipilimumab. Additional CheckMate 214 analyses beyond the scope of this report, such as outcomes in patients who discontinued therapy before finishing nivolumab plus ipilimumab induction, updated health-related quality of life after extended follow-up, and further details of treatment-related adverse event kinetics, could be done in future investigations. In summary, with extended follow-up, improved overall survival was maintained with nivolumab plus ipilimumab compared with sunitinib in both the intention-to-treat population and the intermediate-risk or poor-risk populations, and overall survival was similar between the treatment groups in the relatively small favourable-risk subgroup of patients in CheckMate 214. An improvement was also observed in progression-free survival with nivolumab plus ipilimumab over sunitinib in the intention-to-treat population and intermediate-risk or poor-risk patients with longer follow-up, with a notable proportion of intention-to-treat patients remaining progression-free at 30 months. Complete and durable responses were observed with nivolumab plus ipilimumab regardless of IMDC-risk based prognosis. This online publication has been corrected. The corrected version first appeared at thelancet.com/oncology on August 21, 2019 Contributors RJM, SM, and NMT contributed to the conception and design of the study. All authors provided study materials or patients. MBH completed the statistical analyses. SM reviewed the clinical data. All authors contributed to the data analysis and interpretation, drafting and revising of the manuscript, and provided final approval to submit the manuscript for publication. 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 the submitted work. DFM reports personal fees from Exelixis, Array BioPharma, Bristol-Myers Squibb, Merck, Genentech/Roche, 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 support from Pfizer, outside the submitted work. HJH reports grants and personal fees from Bristol-Myers Squibb and Merck, and personal fees from Pfizer and Exelixis, Armo Biosciences, and Novartis, during the conduct of the study. MAC reports personal fees from Astellas Pharma, AbbVie, Roche/Genentech, Pfizer, and Foundation Medicine, and grants from Bristol-Myers Squibb, AstraZeneca, Gilead Sciences, EMD Serono, and Effector, outside the submitted work. 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; and personal fees and non-financial support from Pfizer, Exelixis, Bioarray, and Novartis, outside the submitted work. CP reports personal fees from Bristol-Myers Squibb, Merck Sharpe & Dohme, Novartis, Ipsen, EUSA, Eisai, Janssen, AstraZeneca, and General Electric, and grants and personal fees from Pfizer, outside submitted work. SG reports personal fees from AstraZeneca, Exelixis and Janssen, Genentech, Sanofi/Genzyme, and EMD Serono; grants and personal fees from Bayer, Bristol-Myers Squibb, Novartis, Corvus, and Pfizer; and grants from Acceleron, Merck, Agensys, and Eisai, outside the submitted work. SB reports non-financial support from Novartis; personal fees, non-financial support, and other from Astellas and Pfizer; personal fees and non-financial support from Janssen and Merck Sharpe & Dohme; non-financial and other support from Bristol-Myers Squibb and Roche; and non-financial support from Exelixis and AstraZeneca, outside the submitted work. SST reports clinical trial support received on behalf of his institution from Bristol-Myers Squibb and 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, Calithera Biosciences, Jounce Therapeutics, Pfizer, Genentech, Prometheus Laboratories, and ARGOS Therapeutics; and personal fees from Calithera Biosciences and Prometheus Laboratories, outside the submitted work. PB reports advisory board funding from Bristol-Myers Squibb, Pfizer, Roche, Ipsen, Merck Sharpe & Dohme, Janssen Cilag, and Novartis, outside the submitted work. RL-A reports honoraria from Bristol-Myers Squibb, Merck Sharpe & Dohme, Roche, Isotopia, and Bayer; advisory role travel grant from Janssen and Pfizer; and advisory role from Sanofi and Astellas, outside the submitted work. ERP reports grants, consulting fees, 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, and Exelixis; funds for development of educational presentations from Bristol-Myers Squibb, Merck, Roche, and Novartis; grants to institution for conduct of clinical trials from AstraZeneca, Bristol-Myers Squibb, Merck, Peloton, Pfizer, and Astellas; and has a patent (US patent applications, numbers 14/588,503 and 15/226,474). SFO reports non-financial support from Bristol-Myers Squibb, during the conduct of the study; and grants from Celldex and Novartis, outside the submitted work. BM reports personal fees and honoraria for advisory boards, speeches, and travel support from Bristol-Myers Squibb, Roche, Merck Sharpe & Dohme, Merck Serono, and Novartis; and 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), 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 The Lancet Oncology ; and grants from Calithera and Takeda, outside the submitted work. FD reports grants from Novartis, Pfizer, and Ipsen, outside the submitted work. M-OG 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, Merck Sharpe & Dohme, Janssen Cilag, ONO Pharmaceutical, Ipsen Pharma, and Medac, outside the 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 Pharmaceutical, Pfizer, and Chugai, and personal fees from Astellas, Bristol-Myers Squibb, Novartis, ONO Pharmaceutical, Pfizer, and Taiho, outside the submitted work. ID reports personal fees from Bristol-Myers Squibb, Novartis, Sanofi, Bayer, Pharmacyclics, Janssen, and Merck Sharpe & Dohme; personal fees and non-financial support from Ipsen; and grants, personal fees, and non-financial support from Genentech/Roche and AstraZeneca, outside the submitted work. VG reports grants and personal fees from Pfizer and EUSA Pharma; grants, personal fees, and non-financial support from Bristol-Myers Squibb and Ipsen; and personal fees and non-financial support from Roche, Novartis, and Eisai, during the conduct of the study; grants, personal fees, non-financial support, and stock holdings in Merck Sharpe & Dohme and Bristol-Myers Squibb; grants from Novartis; grants, personal fees, and stock holdings in AstraZeneca; personal fees and non-financial support from Merck Serono and PharmaMar; and personal fees from Roche, Pfizer, and Lilly, 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, Novartis, and Exelixis Inc; personal fees from Nektar Therapeutics, Oncorena, Eisai Medical Research, and ONO Pharmaceutical; and grants from Calithera Biosciences, outside the submitted work. PS, VN, and BR declare no competing interests. Funding Information: CheckMate 214 was funded by Bristol-Myers Squibb and ONO Pharmaceutical. A data confidentiality agreement was in place between Bristol-Myers Squibb and the investigators. All authors vouch for the completeness and accuracy of the data and analyses and for the adherence of the trial to the protocol. We thank the patients and their families who are making this study possible; the late Paul Gagnier, the initial medical monitor; Jennifer McCarthy, the CheckMate 214 protocol manager; and Dako, an Agilent Technologies Inc company, for collaborative development of the PD-L1 immunohistochemistry 28?8 pharmDx assay. Professional medical writing and editorial assistance were provided by Jennifer Tyson and Lawrence Hargett of Parexel, funded by Bristol-Myers Squibb. Patients treated at the Memorial Sloan Kettering Cancer Center were supported in part by Memorial Sloan Kettering Cancer Center Support Grant (Core Grant, number P30 CA008748). Funding Information: Bristol-Myers Squibb's policy on data sharing can be found at the company's website. Deidentified and anonymised datasets of clinical trial information, including patient-level data, will be shared with external researchers for proposals that are complete, for which the scientific request is valid and the data are available, consistent with safeguarding patient privacy and informed consent. Upon execution of an agreement, the deidentified and anonymised data sets can be accessed via a secured portal that provides an environment for statistical programming with R. The trial protocol and statistical analysis plan will also be available. Data will be available for 2 years from the study completion or termination of the programme (August, 2024). Acknowledgments CheckMate 214 was funded by Bristol-Myers Squibb and ONO Pharmaceutical. A data confidentiality agreement was in place between Bristol-Myers Squibb and the investigators. All authors vouch for the completeness and accuracy of the data and analyses and for the adherence of the trial to the protocol. We thank the patients and their families who are making this study possible; the late Paul Gagnier, the initial medical monitor; Jennifer McCarthy, the CheckMate 214 protocol manager; and Dako, an Agilent Technologies Inc company, for collaborative development of the PD-L1 immunohistochemistry 28–8 pharmDx assay. Professional medical writing and editorial assistance were provided by Jennifer Tyson and Lawrence Hargett of Parexel, funded by Bristol-Myers Squibb. Patients treated at the Memorial Sloan Kettering Cancer Center were supported in part by Memorial Sloan Kettering Cancer Center Support Grant (Core Grant, number P30 CA008748 ). Publisher Copyright: © 2019 Elsevier Ltd
PY - 2019/10
Y1 - 2019/10
N2 - 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.
AB - 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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U2 - 10.1016/S1470-2045(19)30413-9
DO - 10.1016/S1470-2045(19)30413-9
M3 - Article
C2 - 31427204
AN - SCOPUS:85072673151
VL - 20
SP - 1370
EP - 1385
JO - The Lancet Oncology
JF - The Lancet Oncology
SN - 1470-2045
IS - 10
ER -