Nivolumab Plus Chemotherapy: New Standard of Care in Advanced Gastric Cancer?

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As first-line treatment for advanced gastric cancer, nivolumab plus chemotherapy leads to significantly improved progression-free and overall survival over chemotherapy alone, investigators reported during a Presidential Symposium of the European Society for Medical Oncology (ESMO) Virtual Congress 2020. The success achieved by immunotherapy in this challenging tumor type—extending survival beyond 14 months—represents a new standard of care, at least in patients with relatively high expression of PD-L1, experts said.

In the global phase III CheckMate 649 trial, nivolumab in combination with chemotherapy became the first PD-1 inhibitor to demonstrate superior overall survival and progression-free survival as first-line treatment.1 Additionally, in the phase II/III ATTRACTION-4 trial, which was conducted in Asia, progression-free survival was significantly improved.2

Elizabeth Smyth, MD

Elizabeth Smyth, MD

“It’s a good day for patients with gastric cancer! The results of these two trials represent a paradigm shift in the treatment of advanced disease,” said invited discussant Elizabeth Smyth, MD, of Cambridge University Hospitals NHS Foundation Trust in the United Kingdom. “Breaking through the 1-year overall survival barrier for patients with PD-L1 CPS [Combined Positive Score] ≥ 5 is a milestone.”

CheckMate 649 Details

Markus Moehler, MD, Professor of Medicine, Johannes-Gutenberg University Clinic, Mainz, Germany, reported the prespecified interim analysis of overall survival and the final progression-free survival analysis of CheckMate 649.1 “The study achieved statistical significance for both primary endpoints and all formally tested secondary endpoints. Nivolumab plus chemotherapy represents a potential standard first-line treatment,” Dr. Moehler said.

The phase III trial included 1,581 patients with previously untreated HER2-negative advanced/unresectable or metastatic gastric cancer (70% of the population), as well as gastroesophageal junction cancer and esophageal adenocarcinoma. Of these patients, 955 (60%) had tumors with a PD-L1 CPS ≥ 5 expression.

Markus Moehler, MD

Markus Moehler, MD

Patients were randomly assigned to one of three regimens: nivolumab at 260 mg every 3 weeks or 240 mg every 2 weeks plus chemotherapy; chemotherapy alone; or nivolumab plus ipilimumab (nivolumab/ipilimumab data will be presented at a later date). The chemotherapy regimen was either FOLFOX (fluorouracil, leucovorin, oxaliplatin) every 2 weeks or XELOX (capecitabine plus oxaliplatin) every 3 weeks. The dual primary endpoints were overall survival and progression-free survival in patients with a PD-L1 CPS ≥ 5.

Median Survival of 14.4 Months

“A statistically significant and clinically meaningful overall survival benefit was seen in patients whose tumors expressed a PD-L1 CPS ≥ 5 and in all randomly assigned patients. Overall survival consistently favored nivolumab plus chemotherapy vs chemotherapy across multiple prespecified subgroups,” Dr. Moehler said.

Median overall survival was 14.4 months with nivolumab plus chemotherapy vs 11.1 months for chemotherapy in the PD-L1 CPS ≥ 5 population (hazard ratio [HR] = 0.71; P < .0001). The differences were also statistically significant for the PD-L1 CPS ≥ 1 population (HR = 0.77; P = .0001) and for all randomly assigned patients (HR = 0.80; P = .0002). Median progression-free survival was 7.7 and 6.1 months, respectively (HR = 0.68; P < .0001), in the PD-L1 CPS ≥ 5 population, but benefits were also observed for the CPS ≥ 1 population and for all randomly assigned patients, Dr. Moehler reported.


  • A new standard of care in advanced gastric cancer may be established with nivolumab plus chemotherapy, based on studies presented at the ESMO Virtual Congress 2020.
  • In the global phase III CheckMate 640 trial, the combination led to improved overall and progression-free survival in patients with a PD-L1 CPS ≥ 5. In this population, median overall survival was 14.4 months, but patients with a CPS ≥ 1 and all randomly assigned patients also derived a survival benefit.
  • In the phase II/III ATTRACTION-4 trial, median progression-free survival was improved but overall survival was not, possibly due to heavy use of subsequent posttrial therapy.

“There’s some enrichment for CPS ≥ 5, but we still see a clear signal that, in all randomly assigned patients, nivolumab plus chemotherapy has statistically and clinically meaningful benefits,” he commented during the discussion period.

No new safety signals were identified with the combination. The most common treatment-related toxicities across both arms were nausea, diarrhea, and peripheral neuropathy. Fewer than 5% of patients experienced grade 3 or 4 toxicities, and there were no grade 5 events.

“I am confident that with these positive data, we will change the future treatment of these patients,” Dr. Moehler commented.


In the ATTRACTION-4 (ONO-4538-37) trial, which was conducted in Asia, first-line treatment with nivolumab plus chemotherapy improved the co-primary progression-free survival endpoint but not overall survival, according to Narikazu Boku, MD, of the National Cancer Center Hospital in Tokyo.2

“Progression-free survival was significantly improved with nivolumab plus chemotherapy, achieving the primary objective,” Dr. Boku said. “The combination demonstrated clinically meaningful efficacy with a manageable safety profile but not a statistically significant improvement in overall survival. Nivolumab and chemotherapy can be considered a new first-line treatment option in advanced or recurrent gastric or gastroesophageal junction cancer.”

ATTRACTION-4 was similar to CheckMate 649 except for two important differences: It was performed in Asian patients only, and the primary endpoints were designed for all-comers, rather than for a population meeting a specific CPS threshold. The study randomly assigned 724 Asian patients to nivolumab plus chemotherapy (oxaliplatin plus S-1 or capecitabine). The co-primary endpoints were progression-free and overall survival; a significant result for either one meant the study met its objective.

Narikazu Boku, MD

Narikazu Boku, MD

Median progression-free survival was significantly improved with the combination, from 8.3 months with chemotherapy to 10.5 months with nivolumab plus chemotherapy (HR = 0.68; P = .0007), as were response rates. At the final analysis, with a median follow-up of 27 months, overall survival was similar, 17.2 and 17.5 months, respectively.

The incidence of grades 3 to 5 treatment-related adverse events was 57.9% with nivolumab plus chemotherapy and 49.2% with chemotherapy alone. 

DISCLOSURE: CheckMate 649 was supported by Bristol Myers Squibb. ATTRACTION-4 was supported by Ono Pharmaceutical and Bristol Myers Squibb. Dr. Smyth has served as a consultant or advisor to Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Merck Serono, and Servier; holds pending patent no: 1716712.3; and has been reimbursed for travel, accommodations, or other expenses by Bristol Myers Squibb and Servier. Dr. Moehler has received honoraria from Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, Lilly/ImClone, Merck Serono, MSD Oncology, Roche/Genentech, Servier, and Taiho Pharmaceutical; has served as a consultant or advisor to Amgen, Bayer, Lilly, Merck Serono, MSD, Nordic Group, Pfizer, Roche, Servier, Taiho Pharmaceutical, and Yakult; has received institutional research funding from Amgen, AstraZeneca, Jennerex, Leap Therapeutics, Merck Serono, and MSD; and has been reimbursed for travel, accommodations, or other expenses by Amgen, ASCO, Bayer, ESMO, the German Cancer Society, Merck Serono, MSD, and Roche. Dr. Boku has received honoraria from Bristol Myers Squibb Japan, Ono Pharmaceutical, and Taiho Pharmaceutical; and has received institutional research funding from Bristol Myers Squibb, Ono Pharmaceutical, Taiho, and Takeda.


1. Moehler M, Shitara K, Garrido M, et al: Nivolumab plus chemotherapy vs chemo as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma: First results of the CheckMate 649 study. ESMO Virtual Congress 2020. Abstract LBA6_PR. Presented September 21, 2020.

2. Boku N, Ryu M, Oh D, et al: Nivolumab plus chemotherapy vs chemotherapy alone in patients with previously untreated advanced or recurrent gastric/gastroesophageal junction cancer: ATTRACTION-4 (ONO-4538-37) study. ESMO Virtual Congress 2020. Abstract LBA7_PR. Presented September 21, 2020.

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