First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial

Abstract

Background: First-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone.

Methods: In this multicentre, randomised, open-label, phase 3 trial (CheckMate 649), we enrolled adults (≥18 years) with previously untreated, unresectable, non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression from 175 hospitals and cancer centres in 29 countries. Patients were randomly assigned (1:1:1 while all three groups were open) via interactive web response technology (block sizes of six) to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab, or chemotherapy alone. Primary endpoints for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review, in patients whose tumours had a PD-L1 combined positive score (CPS) of five or more. Safety was assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT02872116.

Findings: From March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, we concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was 13·1 months (IQR 6·7-19·1) for nivolumab plus chemotherapy and 11·1 months (5·8-16·1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59-0·86]; p<0·0001) and PFS (HR 0·68 [98 % CI 0·56-0·81]; p<0·0001) versus chemotherapy alone in patients with a PD-L1 CPS of five or more (minimum follow-up 12·1 months). Additional results showed significant improvement in OS, along with PFS benefit, in patients with a PD-L1 CPS of one or more and all randomly assigned patients. Among all treated patients, 462 (59%) of 782 patients in the nivolumab plus chemotherapy group and 341 (44%) of 767 patients in the chemotherapy alone group had grade 3-4 treatment-related adverse events. The most common any-grade treatment-related adverse events (≥25%) were nausea, diarrhoea, and peripheral neuropathy across both groups. 16 (2%) deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group were considered to be treatment-related. No new safety signals were identified.

Interpretation: Nivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients.

Funding: Bristol Myers Squibb, in collaboration with Ono Pharmaceutical.

Conflict of interest statement

Declaration of interests YYJ reports receiving consulting or advisory board fees from AstraZeneca, Daiichi Sankyo, Imugene, Jounce Therapeutics, Merck Serono, Michael J Hennessy Associates, Paradigm Medical Communications, Pfizer, Seattle, Genetics, and Zymeworks; receiving consulting or advisory and research funding from Eli Lilly, Bristol Myers Squibb, and Merck & Co; receiving research funding from Bayer, Boehringer Ingelheim, Genentech/Roche, MSK Cancer Center Support Grant/Core Grant (P30 CA008748), and Ono Pharmaceutical; receiving speaker's bureau fees from the American Society of Clinical Oncology; and receiving stock options from Rgenix, outside the submitted work. KS reports receiving personal fees for advisory roles from AbbVie, Bristol Myers Squibb, GlaxoSmithKline, Novartis, Ono Pharmaceutical Company, Pfizer, and Takeda; receiving advisory role or research funding from Astellas Pharma, Eli Lilly, Merck Pharmaceutical, and Taiho Pharmaceutical; receiving honoraria (lecture fees) from AbbVie, Novartis, and Yakult Honsha; and receiving research funding from Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, and Medi Science, outside the submitted work. MM reports receiving research grants from AIO, Amgen, German Federal Ministry of Education and Research, Bristol Myers Squibb, European Organisation for Research and Treatment of Cancer, German Cancer Aid, Merck Serono, Merck Sharp & Dohme, and Pfizer; receiving personal fees from Bristol Myers Squibb, Falk Foundation, Lilly, MCI Group, Merck Serono, Merck Sharp & Dohme, Pfizer, and Roche; and receiving non-financial support from AIO, Amgen, Bristol Myers Squibb, German Federal Ministry of Education and Research, European Organisation for Research and Treatment of Cancer, and German Cancer Aid, outside the submitted work. MG reports receiving grants and personal fees from Bristol Myers Squibb and Novartis; and receiving personal fees from Merck Sharp & Dohme and Roche, outside the submitted work. KY reports receiving grants and personal fees from Daiichi-Sankyo, Ono Pharmaceutical Company, Taiho Pharmaceutical, and Yakult Honsha; receiving personal fees from Chugai, Lilly, and Takeda; receiving grants from Sanofi; and receiving personal fees from Bristol Myers Squibb, Merck Serono, and Takeda, outside the submitted work. MS reports receiving personal fees for clinical research from Bristol Myers Squibb, during the conduct of the study; and receiving personal fees for clinical research from Astellas, AstraZeneca, Eli Lilly, GlaxoSmithKline, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, and Roche, outside the submitted work. MT reports receiving research funding from Bristol Myers Squibb, during the conduct of the study. RK reports receiving grants from Amgen, AstraZeneca, Athenex, Eli Lilly, Nektar, and Sanofi; receiving grants and non-financial support from Roche; grants and personal fees from Astellas and Novartis; grants, personal fees, and non-financial support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pfizer; and personal fees from Gador, outside the submitted work. MVK reports serving in an advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Ipsen, Roche, Sandoz, Sanofi, and Servier, outside the submitted work. RB reports serving as a medical adviser for Merck Serono and Novartis; receiving clinical research funding from Novartis; serving as a medical adviser and speaker for AstraZeneca, Bristol Myers Squibb, and Pfizer; receiving clinical research funding from Bristol Myers Squibb, Merck Sharp & Dohme, and Roche; and serving as a speaker for Merck, during the conduct of the study. TZ reports receiving personal advisory board fees from AstraZeneca, Bristol Myers Squibb, Lilly, Merck Sharp & Dohme, Novartis, Roche, and Sanofi, outside the submitted work. JMC reports personal fees and consulting and travel support from Bristol Myers Squibb; and research funding from AstraZeneca, Esperas Pharma, Merck, and Tesaro, outside the submitted work. VP, DC, MLe, HX, KK, and MLi report employment with Bristol Myers Squibb and ownership of stock in Bristol Myers Squibb. JAA reports receiving clinical research grants and receiving personal advisory board fees from Bristol Myers Squibb, during the conduct of the study. All other authors declare no competing interests.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. Trial profile

OS=overall survival. PFS=progression-free survival. CPS=combined positive score. *Enrolled patients included all concurrently randomised patients to nivolumab plus chemotherapy or chemotherapy, as well as patients enrolled before the nivolumab plus ipilimumab group was closed and not randomised to any of the treatment groups. The total number of patients randomised to three groups was 2031. The nivolumab plus ipilimumab group will remain blinded until final analysis, and the results will be reported at a later time. †Included death (n=35), adverse events (n=24), poor/noncompliance (n=15), and additional reasons (n=54). ‡Includes patients concurrently randomised to the nivolumab plus chemotherapy and chemotherapy groups. Relevant protocol deviations were noted in 21 (1%) patients. This included usage of prohibited on-treatment anti-cancer therapy (n=12), baseline ECOG PS > 1 (n=5), incorrect cancer diagnosis (n=2), and one case each of prohibited prior anti-cancer therapy (at study entry) and no baseline (measurable or evaluable) disease. §Included completion of treatment (n=20); maximum clinical benefit (n=10); two cases each of death, decline in performance, lost to follow-up, and patient relocation; and one case each of clinical worsening (hand synovitis G2), patient no longer met trial criteria, patient request to receive treatment at home, poor/noncompliance, treatment on hold due to adverse event, and unclear lung and bone lesions. ||Included maximum clinical benefit (n=25); poor/noncompliance (n=4); three cases each of patient no longer met trial criteria and death; two cases each of lost to follow-up and surgery; and one case each of bad performance status, carcinomatoses meninges, clinical progression, disease progression confirmed by central imaging (per blinded independent central review), failure after cranial progression, investigator decision, patient pursuing alternative treatment, treatment delay/discontinuation (per protocol), patient unable to tolerate treatment, and patient request to discontinue.

Figure 2:. Overall survival

PD-L1=programmed death ligand 1. CPS=combined positive score. CI=confidence interval.

Figure 2:. Overall survival

PD-L1=programmed death ligand 1. CPS=combined positive score. CI=confidence interval.

Figure 3:. Progression-free survival

PD-L1=programmed death ligand 1. CPS=combined positive score. CI=confidence interval. *Per blinded independent central review assessment.

Figure 3:. Progression-free survival

PD-L1=programmed death ligand 1. CPS=combined positive score. CI=confidence interval. *Per blinded independent central review assessment.