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Clinical Trial
. 2022 Mar;603(7903):942-948.
doi: 10.1038/s41586-022-04508-4. Epub 2022 Mar 23.

Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer

Kohei Shitara  1 , Jaffer A Ajani  2 , Markus Moehler  3 , Marcelo Garrido  4 , Carlos Gallardo  5 , Lin Shen  6 , Kensei Yamaguchi  7 , Lucjan Wyrwicz  8 , Tomasz Skoczylas  9 , Arinilda Campos Bragagnoli  10 , Tianshu Liu  11 , Mustapha Tehfe  12 , Elena Elimova  13 , Ricardo Bruges  14 , Thomas Zander  15 , Sergio de Azevedo  16 , Ruben Kowalyszyn  17 , Roberto Pazo-Cid  18 , Michael Schenker  19 , James M Cleary  20 , Patricio Yanez  21 , Kynan Feeney  22 , Michalis V Karamouzis  23 , Valerie Poulart  24 , Ming Lei  24 , Hong Xiao  24 , Kaoru Kondo  24 , Mingshun Li  24 , Yelena Y Janjigian  25
Affiliations
Clinical Trial

Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer

Kohei Shitara et al. Nature. 2022 Mar.

Abstract

Standard first-line chemotherapy results in disease progression and death within one year in most patients with human epidermal growth factor receptor 2 (HER2)-negative gastro-oesophageal adenocarcinoma1-4. Nivolumab plus chemotherapy demonstrated superior overall survival versus chemotherapy at 12-month follow-up in gastric, gastro-oesophageal junction or oesophageal adenocarcinoma in the randomized, global CheckMate 649 phase 3 trial5 (programmed death ligand-1 (PD-L1) combined positive score ≥5 and all randomized patients). On the basis of these results, nivolumab plus chemotherapy is now approved as a first-line treatment for these patients in many countries6. Nivolumab and the cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor ipilimumab have distinct but complementary mechanisms of action that contribute to the restoration of anti-tumour T-cell function and induction of de novo anti-tumour T-cell responses, respectively7-11. Treatment combining 1 mg kg-1 nivolumab with 3 mg kg-1 ipilimumab demonstrated clinically meaningful anti-tumour activity with a manageable safety profile in heavily pre-treated patients with advanced gastro-oesophageal cancer12. Here we report both long-term follow-up results comparing nivolumab plus chemotherapy versus chemotherapy alone and the first results comparing nivolumab plus ipilimumab versus chemotherapy alone from CheckMate 649. After the 24.0-month minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in overall survival versus chemotherapy alone in patients with PD-L1 combined positive score ≥5 (hazard ratio 0.70; 95% confidence interval 0.61, 0.81) and all randomized patients (hazard ratio 0.79; 95% confidence interval 0.71, 0.88). Overall survival in patients with PD-L1 combined positive score ≥ 5 for nivolumab plus ipilimumab versus chemotherapy alone did not meet the prespecified boundary for significance. No new safety signals were identified. Our results support the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastro-oesophageal adenocarcinoma.

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Conflict of interest statement

K.S. reports receiving personal fees for advisory roles from AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Novartis, Pfizer, and Takeda; receiving advisory role or research funding from Astellas Pharma, Eli Lilly, Ono Pharmaceutical, Merck Pharmaceutical, and Taiho Pharmaceutical; receiving honoraria (lecture fees) from AbbVie, Novartis, and Yakult Honsha; and receiving research funding from Amgen, Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, Medi Science, and Eisai, outside the submitted work. J.A.A. reports receiving research grants from Amgen, Astellas Pharma, Bristol Myers Squibb, Daiichi Sankyo, Delta-Fly Pharma, Gilead Sciences, Lilly/ImClone, Merck, Novartis, ProLynx, Roche/Genentech, Taiho Pharmaceutical, Takeda, and Zymeworks; serving as a consultant or in an advisory role for American Cancer Society, BeiGene, Bristol Myers Squibb, Insys Therapeutics, Merck, and Vaccinogen; receiving royalties from or holding patents and other intellectual property with Amgen, Bristol Myers Squibb, Genentech, Lilly, Medimmune, Merck, Roche, and Taiho Pharmaceutical; and receiving honoraria from Acrotech BioPharma, Aduro Biotech, Amgen, Astellas Pharma, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, DAVA Pharmaceuticals, Fresenius Kabi, Gilead Sciences, Grail, Lilly, Merck, Novartis, Servier, and Zymeworks, outside the submitted work. M.M. reports receiving research grants from Amgen, Leap Therapeutics, Merck Serono, and Merck Sharp & Dohme; serving as a consultant or in an advisory role for Amgen, Bayer, Beigene, Bristol Myers Squibb, Lilly, Merck Serono, Merck Sharp & Dohme, Pfizer, Roche, Servier, and Taiho Pharmaceutical; receiving travel and accommodation expenses from American Society of Clinical Oncology, Amgen, Bayer, European Society for Medical Oncology, German Cancer Society, Merck Serono, Merck Sharp & Dohme, and Roche; and receiving honoraria from Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme Oncology, Roche/Genentech, Pierre Fabre, Sanofi, and Servier, outside the submitted work. M.G. reports receiving research grants from Bristol Myers Squibb and Novartis; receiving speakers’ bureau fees from Bayer, Bristol Myers Squibb, and Merck; receiving travel and accomodations expenses from Roche; and serving as a consultant or in an advisory role for Merck Sharp & Dohme and Roche, outside the submitted work. C.G. reports receiving research grants from Bristol Myers Squibb and Merck Sharp & Dohme; receiving speakers’ bureau fees from AstraZeneca, Merck Sharp & Dohme, and Novartis; receiving travel and accomodation expenses from Roche; serving as a consultant or in an advisory role for Merck Sharp & Dohme, Novartis, and Roche; and providing expert testimony for AstraZeneca, outside the submitted work. L.S. reports receiving research grants from Beijing Xiantong Biomedical Technology, Qilu Pharmaceutical, ZaiLab Pharmaceutical (Shanghai), Beihai Kangcheng (Beijing) Medical Technology, Jacobio Pharmaceuticals, and Beijing Xiantong Biomedical Technology; receiving consulting fees from Boehringer Ingelheim, Haichuang Pharmaceutical, Herbour Biomed, Merck, Merck Sharp & Dohme, and Mingji Biopharmaceutical; receiving speakers’ fees from CSTONE Pharmaceutical, Hutchison Whampoa, Hengrui, and ZaiLab; and participating on a Data Safety Monitoring Board or Advisory Board for Bristol Myers Squibb, CSTONE Pharmaceutical, Rongchang Pharmaceutical, and ZaiLab, outside the submitted work. K.Y. reports receiving research grants from Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharma, Daiichi Sankyo, Eisai, Gilead Sciences, Lilly, Merck Sharp & Dohme Oncology, Ono Pharmaceutical, Sanofi, Taiho Pharmaceutical, and Yakult Honsha; receiving speakers’ bureau fees from Bristol Myers Squibb Japan, Chugai Pharma, Daiichi Sankyo, Lilly, Merck, Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda; and serving as a consultant or in an advisory role for Bristol Myers Squibb Japan and Daiichi Sankyo, outside the submitted work. L.W. reports receiving research grants from National Cancer Research Institute; receiving speakers’ bureau fees from Amgen, Roche, Sanofi, and Servier; and serving in a consulting or advisory role for Amgen and Servier, outside the submitted work. T.S. has no competing interests to disclose. A.B. has no competing interests to disclose. T.L. has no competing interests to disclose. M.T. reports receiving research funding from Celgene; receiving honoraria from Bristol Myers Squibb, Celgene, Eisai, Merck, Pfizer, and Taiho Pharmaceutical; and serving in a consulting or advisory role for Bayer, Bristol Myers Squibb, Celgene, Eisai, Merck, Taiho Pharmaceutical, and Takeda, outside the submitted work. E.E. reports receiving research funding from Bristol Myers Squibb and Zymeworks; serving as a consultant or in an advisory role for Bristol Myers Squibb, Zymeworks, and Adaptimmune; and having an immediate family member employed by Merck, outside the submitted work. R.B. reports serving as a medical adviser for AstraZeneca, Bristol Myers Squibb, Merck Serono, Novartis, and Pfizer; receiving clinical research funding from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche; and serving as a speaker for AstraZeneca, Bristol Myers Squibb, Merck, and Pfizer, during the conduct of the study. T.Z. reports serving as a consultant or in an advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche, outside the submitted work. S.d.A. reports receiving honoraria from AstraZeneca, Bristol Myers Squibb, Genentech, Merck Sharp & Dohme, Novartis, and Roche, outside the sumbitted work. R.K. reports receiving research grants from Amgen, Astellas, AstraZeneca, Athenex, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Nektar, Novartis, Pfizer, Roche, and Sanofi; receiving non-financial support from Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, and Roche; and receiving personal fees from Astellas, Bristol Myers Squibb, Gador, Merck Sharp & Dohme, Novartis, and Pfizer, outside the submitted work. R.P.-C. has no competing interests to disclose. M.S. reports receiving research funding from Abbvie, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pfizer/EMD Serono, Regeneron, and Roche; and receiving travel, accommodations, and expenses from Bristol Myers Squibb, outside the submitted work. J.M.C. reports receiving research funding to his institution from Abbvie, Merus, Roche, and Bristol Myers Squibb; receiving research funding from Merck, AstraZeneca, Esperas Pharma, Bayer, and Tesaro; receiving consulting fees from Bristol Myers Squibb; receiving an honorarium for advisory board participation from Syros Pharmaceuticals; and receiving travel funding from Bristol Myers Squibb, outside the submitted work. P.Y. has no competing interests to disclose. K.F. has no competing interests to disclose. M.K. reports serving in an advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Ipsen, Roche, Sandoz, Sanofi, and Servier, outside the submitted work. V.P., M. Lei, H.X., K.K. and M. Li report being employees of Bristol Myers Squibb. Y.Y.J. reports receiving research funding from Bayer, Bristol Myers Squibb, Cycle for Survival, Department of Defense, Fred’s Team, Genentech/Roche Lilly, Merck & Co, National Cancer Institute, and Rgenix; serving as a consultant or in an advisory role for Basilea Pharmaceutical, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Imugene, Lilly, Merck, Merck Serono, Michael J Hennessy Associates, Paradigm Medical Communications, Pfizer, Rgenix, Seagen, and Zymeworks; receiving stock options from Rgenix; and nonfinancial relationships with Clinical Care Options, Axis Medical Education, and Research to Practice, outside the submitted work.

Figures

Fig. 1
Fig. 1. Kaplan–Meier estimates of overall survival.
a, b, Overall survival with nivolumab plus chemotherapy versus chemotherapy in patients with PD-L1 CPS ≥ 5 (a) and in all randomized patients (b). Minimum follow-up, 24.0 months. c, d, Overall survival with nivolumab plus ipilimumab versus chemotherapy in patients with PD-L1 CPS ≥ 5 (c) and in all randomized patients (d). Minimum follow-up, 35.7 months. Chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; IPI, ipilimumab; NIVO, nivolumab; OS, overall survival.
Fig. 2
Fig. 2. Kaplan–Meier estimates of duration of response.
a, b, Duration of response per BICR with nivolumab plus chemotherapy versus chemotherapy in patients with PD-L1 CPS ≥ 5 (a) and in all randomized patients (b). c, d, Duration of response with nivolumab plus ipilimumab versus chemotherapy in patients with PD-L1 CPS ≥ 5 (c) and in all randomized patients (d). Number of responders (n) is indicated. Number of randomized patients who had target lesion measurements at baseline per BICR assessment for PD-L1 CPS ≥ 5: NIVO + chemo, n = 378; chemo, n = 390; all randomized: NIVO + chemo, n = 603; chemo, n = 607; PD-L1 CPS ≥ 5: NIVO + IPI, n = 196; chemo, n = 183; and all randomized: NIVO + IPI, n = 333; chemo, n = 299. BICR, blinded independent central review; DOR, duration of response.
Fig. 3
Fig. 3. Forest plot of efficacy outcomes by PD-L1 CPS with nivolumab plus chemotherapy versus chemotherapy.
a, Overall survival. PD-L1 CPS expression indeterminate, not evaluable or not reported for n = 19 patients. Data are presented as unstratified hazard ratios and 95% confidence interval. b, Objective response rate among randomized patients who had target lesion measurements at baseline, per blinded independent central review assessment. PD-L1 CPS expression indeterminate, not evaluable or not reported for n = 14 patients; percentages may not reflect an exact difference, owing to rounding. Data are presented as unweighted ORR differences and 95% confidence interval.
Extended Data Fig. 1
Extended Data Fig. 1. CONSORT diagram for patient disposition.
aIncluded death (n = 36), adverse events (n = 24), poor/noncompliance (n = 15), administrative reasons (n = 5), pregnancy (n = 1) and additional reasons (n = 43); bIncludes patients concurrently randomized to the nivolumab plus chemotherapy, nivolumab plus ipilimumab, and chemotherapy groups. Relevant protocol deviations were noted in 21 (1%) patients concurrently randomized to nivolumab plus chemotherapy versus chemotherapy: usage of prohibited on-treatment anti-cancer therapy (n = 12), baseline ECOG PS >1 (n = 5), incorrect cancer diagnosis (n = 2), prohibited prior anti-cancer therapy (at study entry) (n = 1) and no baseline (measurable or evaluable) disease (n = 1); Relevant protocol deviations were noted in 10 (1%) patients concurrently randomized to nivolumab plus ipilimumab versus chemotherapy: usage of prohibited on-treatment anti-cancer therapy (n = 5), incorrect cancer diagnosis (n = 2), no baseline PD-L1 result (n = 2) and baseline ECOG PS > 1 (n = 1); c363 patients overlapped between the two chemotherapy groups from the 1:1:1 randomization period; dThe median follow-up for survival (time from concurrent randomization to last known date alive or death) was 13.1 months (range 0.1–49.5) and 11.2 months (range 0.0–47.9) in the nivolumab plus chemotherapy versus chemotherapy groups, respectively, and 11.4 months (range 0.0–52.1) and 11.5 months (range 0.0–52.8) in the nivolumab plus ipilimumab versus chemotherapy groups, respectively; eIncluded adverse events unrelated to study treatment (n = 47), maximum clinical benefit (n = 11), lost to follow-up (n = 2), patient no longer met trial criteria (n = 1), poor/noncompliance (n = 1) and other reasons (n = 9); fIncluded adverse events unrelated to study treatment (n = 35), maximum clinical benefit (n = 30), poor/noncompliance (n = 4), other reasons (n = 8), lost to follow-up (n = 2) and death (n = 1); gIncluded adverse events unrelated to study treatment (n = 21), death (n = 3), poor/noncompliance (n = 1), other reasons (n = 6) and not reported (n = 5); hIncluded adverse events unrelated to study treatment (n = 15), maximum clinical benefit (n = 13), lost to follow-up (n = 2), poor/noncompliance (n = 2) and other reasons (n = 4). ECOG PS, Eastern Cooperative Oncology Group performance status; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival.
Extended Data Fig. 2
Extended Data Fig. 2. Kaplan-Meier estimates of progression-free survival.
Progression-free survival with nivolumab plus chemotherapy versus chemotherapy in patients with PD-L1 CPS ≥ 5 (a) and in all randomized patients (b). Progression-free survival with nivolumab plus ipilimumab versus chemotherapy in patients with PD-L1 CPS ≥ 5 (c) and in all randomized patients (d). aPer BICR. BICR, blinded independent central review; chemo, chemotherapy; CI, confidence interval; CPS, combined positive score; HR, hazard ratio; IPI, ipilimumab; mo, months; NIVO, nivolumab; PD-L1, programmed death ligand 1; PFS, progression-free survival.
Extended Data Fig. 3
Extended Data Fig. 3. Kaplan-Meier plot of progression-free survival on subsequent therapy with nivolumab plus chemotherapy versus chemotherapy.
a, Patients with PD-L1 CPS ≥ 5. b, All randomized patients. Chemo, chemotherapy; CI, confidence interval; CPS, combined positive score; HR, hazard ratio; mo, months; NIVO, nivolumab; PD-L1, programmed death ligand 1; PFS2, time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death, whichever is earlier.
Extended Data Fig. 4
Extended Data Fig. 4. Waterfall plot of best percentage reduction in tumour burden with nivolumab plus chemotherapy versus chemotherapy.
a, Patients with PD-L1 CPS ≥ 5. b, All randomized patients. Patients who had measurable disease at baseline per BICR and at least one on-treatment tumour assessment. Best reduction is maximum reduction in sum of diameters of target lesions. Horizontal reference line indicates the 30% reduction consistent with a RECIST v1.1 response. Asterisk symbol represents responders. Blue bars indicate nivolumab plus chemotherapy; grey bars indicate chemotherapy. BICR, blinded independent central review; chemo, chemotherapy; CPS, combined positive score; NIVO, nivolumab; PD-L1, programmed death ligand 1; RECIST, Response Evaluation Criteria in Solid Tumors.
Extended Data Fig. 5
Extended Data Fig. 5. Forest plot of overall survival in prespecified subgroups with nivolumab plus chemotherapy versus chemotherapy in patients with PD-L1 CPS ≥ 5.
aNot reported, n = 28; bUnknown, n = 1; cInvalid/not reported, n = 74. Data are presented as unstratified hazard ratios and 95% CI. CapeOX, capecitabine plus oxaliplatin; chemo, chemotherapy; CI, confidence interval; CNS, central nervous system; CPS, combined positive score; EAC, oesophageal adenocarcinoma; ECOG PS, Eastern Cooperative Oncology Group performance status; FOLFOX, 5-fluorouracil plus leucovorin plus oxaliplatin; GC, gastric cancer; GEJC, gastro-oesophageal junction cancer; HR, hazard ratio; MSI, microsatellite instability; MSI-H, microsatellite instability-high; MSS, microsatellite stable; NIVO, nivolumab; OS, overall survival; PD-L1, programmed death ligand 1.
Extended Data Fig. 6
Extended Data Fig. 6. Forest plot of overall survival in prespecified subgroups with nivolumab plus chemotherapy versus chemotherapy in all randomized patients.
aNot reported, n = 1; bNot reported, n = 49; cUnknown, n = 4; dInvalid/not reported, n = 159. Data are presented as unstratified HRs and 95% CI. CapeOX, capecitabine plus oxaliplatin; chemo, chemotherapy; CI, confidence interval; CNS, central nervous system; CPS, combined positive score; EAC, oesophageal adenocarcinoma; ECOG PS, Eastern Cooperative Oncology Group performance status; FOLFOX, 5-fluorouracil plus leucovorin plus oxaliplatin; GC, gastric cancer; GEJC, gastro-oesophageal junction cancer; HR, hazard ratio; MSI, microsatellite instability; MSI-H, microsatellite instability-high; MSS, microsatellite stable; NIVO, nivolumab; OS, overall survival; PD-L1, programmed death ligand 1.
Extended Data Fig. 7
Extended Data Fig. 7. Kaplan-Meier estimates of overall survival and objective response rate by microsatellite instability status in all randomized patients.
Overall survival with nivolumab plus chemotherapy in patients with MSI-H tumours (a) and those with MSS tumours (b). Overall survival with nivolumab plus ipilimumab in patients with MSI-H tumours (c) and those with MSS tumours (d). aRandomized patients who had target lesion measurements at baseline per BICR assessment were a, NIVO + chemo, n = 20; Chemo, n = 18; b, NIVO + chemo, n = 535; Chemo, n = 533; c, Patients with MSI-H: NIVO + IPI, n = 10; Chemo, n = 7. d, NIVO + IPI, n = 292; Chemo, n = 257. Chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; MSI-H, microsatellite instability-high; MSS, microsatellite stable; NIVO, nivolumab; ORR, objective response rate; OS, overall survival.
Extended Data Fig. 8
Extended Data Fig. 8. Forest plot of efficacy outcomes by PD-L1 CPS with nivolumab plus ipilimumab versus chemotherapy.
a, Overall survival. Data are presented as unstratified HRs and 95% CI. b, Objective response rate. aPD-L1 CPS expression indeterminate/not evaluable/not reported, n = 15; bRandomized patients who had target lesion measurements at baseline, per blinded independent central review assessment; cPD-L1 CPS expression indeterminate/not evaluable/not reported, n = 10; dPercentages may not reflect an exact difference due to rounding. Data are presented as unweighted ORR differences  and 95% CI. Chemo, chemotherapy; CI, confidence interval; CPS, combined positive score; HR, hazard ratio; IPI, ipilimumab; NIVO, nivolumab; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1.
Extended Data Fig. 9
Extended Data Fig. 9. Patient-reported outcomes.
Least squares mean (95% CI) change from baseline in FACT-Ga total score with nivolumab plus chemotherapy versus chemotherapy in patients with PD-L1 CPS ≥ 5 (nivolumab plus chemotherapy, n = 412; chemotherapy, n = 386) (a) and in all randomized patients (nivolumab plus chemotherapy, n = 679; chemotherapy, n = 639) (b). Data in panels a and b are presented as least squares mean change from baseline and 95% CI. Top and bottom dashed lines indicate minimally important difference in score. The primary meaningful change threshold is 15.1. The P-value for the difference in least squares means was computed as the two-tailed probability using the t distribution. No adjustments were made for multiple comparisons. *P < 0.05; in patients with PD-L1 CPS ≥ 5, P-value was 0.022 at week 19, 0.024 at week 31, 0.002 at week 49, 0.028 at week 55, 0.015 at week 73, 0.041 at week 97, 0.039 at week 115, and 0.025 at week 121. In all randomized patients, P-value was 0.026 at week 7, 0.020 at week 19, 0.012 at week 25, 0.006 at week 31, 0.025 at week 43, <0.001 at week 49, 0.002 at week 55, 0.037 at week 67, 0.030 at week 73, 0.033 at week 85, 0.028 at week 91, 0.012 at week 97, 0.024 at week 109, 0.004 at week 115, 0.013 at week 121, and 0.039 at week 133; not formally tested. FACT-Ga GP5 (“I am bothered by side effects of treatment”) item values in patients with PD-L1 CPS ≥ 5 (c) and in all randomized patients (d). Chemo, chemotherapy; CPS, combined positive score; FACT-Ga, Functional Assessment of Cancer Therapy-Gastric; NIVO, nivolumab; PD-L1, programmed death ligand 1.
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