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Clinical Trial
. 2020 Nov;5(6):e001079.
doi: 10.1136/esmoopen-2020-001079.

Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial

Laurence Albiges  1 , Nizar M Tannir  2 , Mauricio Burotto  3 , David McDermott  4 , Elizabeth R Plimack  5 , Philippe Barthélémy  6 , Camillo Porta  7 , Thomas Powles  8 , Frede Donskov  9 , Saby George  10 , Christian K Kollmannsberger  11 , Howard Gurney  12 , Marc-Oliver Grimm  13 , Yoshihiko Tomita  14 , Daniel Castellano  15 , Brian I Rini  16 , Toni K Choueiri  17 , Shruti Shally Saggi  18 , M Brent McHenry  19 , Robert J Motzer  20
Affiliations
Clinical Trial

Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial

Laurence Albiges et al. ESMO Open. 2020 Nov.

Abstract

Purpose: To report updated analyses of the phase III CheckMate 214 trial with extended minimum follow-up assessing long-term outcomes with first-line nivolumab plus ipilimumab (NIVO+IPI) versus (vs) sunitinib (SUN) in patients with advanced renal cell carcinoma (aRCC).

Methods: Patients with aRCC with a clear cell component were stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk and randomised to NIVO (3 mg/kg) plus IPI (1 mg/kg) every three weeks ×4 doses, followed by NIVO (3 mg/kg) every two weeks; or SUN (50 mg) once per day ×4 weeks (6-week cycle). Efficacy endpoints included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) per independent radiology review committee in patients with intermediate/poor-risk disease (I/P; primary), intent-to-treat patients (ITT; secondary) and in patients with favourable-risk disease (FAV; exploratory).

Results: Overall, 1096 patients were randomised (ITT: NIVO+IPI, n=550, SUN, n=546; I/P: NIVO+IPI, n=425, SUN, n=422; FAV: NIVO+IPI, n=125, SUN, n=124). After 4 years minimum follow-up, OS (HR; 95% CI) remained superior with NIVO+IPI vs SUN in ITT (0.69; 0.59 to 0.81) and I/P patients (0.65; 0.54 to 0.78). Four-year PFS probabilities were 31.0% vs 17.3% (ITT) and 32.7% vs 12.3% (I/P), with NIVO+IPI vs SUN. ORR remained higher with NIVO+IPI vs SUN in ITT (39.1% vs 32.4%) and I/P (41.9% vs 26.8%) patients. In FAV patients, the HRs (95% CI) for OS and PFS were 0.93 (0.62 to 1.40) and 1.84 (1.29 to 2.62); ORR was lower with NIVO+IPI vs SUN. However, more patients in all risk groups achieved complete responses with NIVO+IPI: ITT (10.7% vs 2.6%), I/P (10.4% vs 1.4%) and FAV (12.0% vs 6.5%). Probability (95% CI) of response ≥4 years was higher with NIVO+IPI vs SUN (ITT, 59% (0.51 to 0.66) vs 30% (0.21 to 0.39); I/P, 59% (0.50 to 0.67) vs 24% (0.14 to 0.36); and FAV, 60% (0.41 to 0.75) vs 38% (0.22 to 0.54)) regardless of risk category. Safety remained favourable with NIVO+IPI vs SUN.

Conclusion: After long-term follow-up, NIVO+IPI continues to demonstrate durable efficacy benefits vs SUN, with manageable safety.

Trial registration details: ClinicalTrials.gov identifier: NCT02231749.

Keywords: advanced renal cell carcinoma; checkmate 214; dual checkpoint inhibition; long-term follow-up; nivolumab plus ipilimumab.

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Conflict of interest statement

Competing interests: LA reports consulting fees from Pfizer, Novartis, Bristol Myers Squibb (BMS), Ipsen, Roche, MSD, AstraZeneca, Merck, Amgen, Astellas and Exelixis; and other fees from Corvus Pharmaceuticals and Peloton Therapeutics. NMT reports research funding from BMS, Calithera Biosciences, Nektar Therapeutics, Exelixis, Pfizer, Novartis, Arrowhead Pharmaceuticals, Mirati Therapeutics, Takeda, Epizyme and Eisai Medical Research; consulting and advisory fees from BMS, Calithera Biosciences, Nektar Therapeutics, Exelixis, Pfizer, Novartis, Eisai Medical Research, Ipsen, Lilly Oncology, Neoleukin Therapeutics, Surface Oncology, ONO Pharmaceutical and Oncorena; and travel accommodations and expenses from BMS, Calithera Biosciences, Nektar Therapeutics, Exelixis, Pfizer, Novartis, Eisai Medical Research, Ipsen, Lilly Oncology, Neoleukin Therapeutics, Surface Oncology, ONO Pharmaceutical and Oncorena. MB reports advisory and speaker fees from Roche, MSD, BMS, AstraZeneca and Sanofi. DM reports research funding from BMS, Merck, Genentech/Roche, Novartis, Peloton Therapeutics, Alkermes and Prometheus Laboratories; consulting or advisory fees from BMS, Merck, Genentech/Roche, Pfizer, Exelixis, Novartis, X4 Pharma, Array BioPharma, Peloton Therapeutics, EMD Serono, Jounce Therapeutics, Alkermes and Lilly; and other fees from Beth Israel Deaconess Medical Center. ERP reports research funding (institutional) from BMS, AstraZeneca, Merck, Peloton Therapeutics, Pfizer and Astellas; consulting fees from AstraZeneca, BMS, Genentech, Merck, Pfizer, Clovis, Exelixis, Incyte, Seattle Genetics, Janssen, Flatiron Health, Infinity Pharma and McKesson; fees for development of educational presentations from BMS and Merck; and US Patent Application No. 14/588,503. PB reports consulting or advisory fees from BMS, Pfizer, MSD Oncology, Novartis, Ipsen, Roche and Janssen Cilag; travel accommodations and expenses from Amgen; and honoraria from Astellas Pharma. CP reports consulting or advisory fees from BMS, MSD, Pfizer, Ipsen Eusa, Eisai and General Electric; speaker fees from BMS, MSD, Pfizer, Ipsen, Eusa, Eisai, General Electric, Janssen and AstraZeneca; research funding from Pfizer; expert testimony fees from Pfizer and Eusa; and travel accommodations and expenses from Roche. TP reports consulting fees from AstraZeneca, BMS, Exelixis, Incyte, Ipsen, Merck/MSD, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai and Roche; honoraria from AstraZeneca, BMS, Exelixis, Incyte, Ipsen, Merck/MSD, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai and Roche; research funding (institutional) from AstraZeneca, Roche, BMS, Exelixis, Ipsen, Merck/MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson and Eisai; and travel accommodations and expenses from Roche, Pfizer, MSD, AstraZeneca and Ipsen. FD reports research funding (institutional) from MSD, Pfizer and Ipsen. SG reports research funding from Bayer, BMS, Pfizer, Novartis, Corvus, Pfizer, Acceleron, Merck, Agensys, Seattle Genetics, Calithera, Immunomedics, Corvus and Eisai; and consulting or advisory fees from Bayer, BMS, Exelixis, Corvus, Genentech, Sanofi/Genzyme, Pfizer, Seattle Genetics, Eisai, Merck and EMD Serono. CKK reports advisory board fees from Janssen, Astellas, Pfizer, Ipsen, Eisai, Roche, Merck and BMS; and lecture fees from Pfizer, Ipsen, Eisai and BMS. HG reports advisory board fees from Pfizer, Astellas, Ipsen, Roche and BMS. M-OG reports research funding from Novartis, BMS and Intuitive Surgical; advisory fees from Novartis, BMS, Pfizer, Bayer HealthCare, Astellas, Intuitive Surgical, AstraZeneca, MSD, Janssen Cilag, ONO Pharmaceutical, Ipsen Pharma and Merck Serono; and lecture fees from Novartis, BMS, Pfizer, Astellas, Hexal, Apogepha, AstraZeneca, MSD, ONO Pharmaceutical, Ipsen Pharma, Medac and Merck Serono. YT reports research funding from ONO Pharmaceutical, Pfizer and Takeda; consulting or advisory fees from ONO Pharmaceutical; and honoraria from ONO Pharmaceutical, BMS and Pfizer. DC reports research funding (institutional) from Janssen Oncology; consulting or advisory fees from Janssen Oncology, Roche/Genentech, Astellas Pharma, AstraZeneca, Novartis, Ipsen, BMS, MSD Oncology, Bayer, Lilly, Sanofi, Pierre Fabre and Boehringer Ingelheim; and travel accommodations and expenses from Pfizer, Roche, BMS and AstraZeneca Spain. BIR reports research funding from Pfizer, Merck, GNE/Roche, Aveo, AstraZeneca and BMS; consulting fees from BMS, Pfizer, GNE/Roche, Aveo, Novartis, Synthorx, Peloton, Compugen, Merck, Arravive, Surface Oncology and 3D Medicines; and stock ownership in PTC therapeutics. TKC reports clinical trial grants from BMS, Exelixis, Pfizer, Merck, AstraZeneca, Lilly, Eisai, Novartis, GSK and EMD Serono; consulting or advisory fees from BMS, Exelixis, Pfizer, Merck, AstraZeneca, Lilly, Eisai, Novartis, GSK and EMD Serono; manuscript preparation fees from BMS, Exelixis, Pfizer, Merck, AstraZeneca, Lilly, Eisai, Novartis, GSK and EMD Serono; travel accommodations and expenses from BMS, Exelixis, Pfizer, Merck, AstraZeneca, Lilly, Eisai, Novartis, GSK and EMD Serono; and patent related to biomarkers of immune-oncology and cfmethDNA pending. SSS is an employee of and has stock ownership in BMS. MBM is an employee of and has stock ownership in BMS. RJM reports research funding (institutional) from Pfizer, Novartis, Eisai, Genentech, Roche and BMS; and consulting or advisory fees from Pfizer, Novartis, Eisai, Exelixis, Merck, Genentech, Incyte, Lilly, Roche and BMS.

Figures

Figure 1
Figure 1
OS in ITT, I/P-risk and FAV-risk patients. FAV, favourable; I/P, intermediate/poor; ITT, intent-to-treat; NE, not estimable; NIVO+IPI, nivolumab plus ipilimumab; NR, not reached; OS, overall survival; SUN, sunitinib.
Figure 2
Figure 2
PFS per IRRC in ITT, I/P-risk and FAV-risk patients. FAV, favourable; I/P, intermediate/poor; IRRC, independent radiology review committee; ITT, intent-to-treat; NIVO+IPI, nivolumab plus ipilimumab; PFS, progression-free survival; SUN, sunitinib.
Figure 3
Figure 3
DOR per IRRC in ITT, I/P-risk and FAV-risk patients. DOR, duration of response; FAV, favourable; I/P, intermediate/poor; IRRC, independent radiology review committee; ITT, intent-to-treat; NE, not estimable; NIVO+IPI, nivolumab plus ipilimumab; NR, not reached; SUN, sunitinib.
Figure 4A
Figure 4A
Figure 4B
Figure 4B
Treatment-free interval and response outcomes in patients with confirmed complete response (A) and confirmed partial response (B) in I/P-risk and FAV-risk patients. Of all-risk patients with confirmed complete response, 13 versus 8 received subsequent systemic therapy with NIVO+IPI versus SUN. Of all-risk patients with confirmed partial response, 61 versus 115 received subsequent systemic therapy with NIVO+IPI versus SUN. These patients may have stopped therapy due to investigator-assessed progression or other protocol-specified reason such as toxicity (data not shown). The decision to start subsequent systemic therapy in either arm was made by the investigator based on expert opinion and treatment guidelines, and these data were not formally collected. *Denotes patients who were treated beyond confirmed blinded independent central review–assessed progression. CR, complete response; FAV, favourable; I/P, intermediate/poor; NIVO+IPI, nivolumab plus ipilimumab; PR, partial response; SUN, sunitinib.
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