Clinical trialPhase 3Stomach cancerOesophageal cancer

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

Lancet · 20211581 patients randomised concurrently (789 nivolumab + chemotherapy and 792 chemotherapy alone)

Janjigian YY, Shitara K, Moehler M, et al. Lancet. 2021. 398:27-40

A newer report of this study has been published: Nivolumab plus chemotherapy as first-line treatment for advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: 5-year follow-up results from CheckMate 649 (2026)

Study type: Clinical trial
Study name: CheckMate 649
Phase: Phase 3
Design: Randomised, open-label, multicentre trial at 175 centres in 29 countries
Sample size: 1581 patients randomised concurrently (789 nivolumab + chemotherapy and 792 chemotherapy alone)
Source: Lancet · 2021
Trial registration: NCT02872116

In plain words

In advanced stomach or oesophageal cancer of the adenocarcinoma type that is not HER2-positive, chemotherapy alone was the first treatment for years. This large worldwide study showed that adding the immunotherapy drug nivolumab to chemotherapy helps patients live longer, especially those whose tumour makes more of a protein called PD-L1 (a CPS of 5 or more) (median about 14.4 months versus 11.1 months), and it shrinks the tumour in a larger share of patients. Serious side effects are a little more common with this combination, so regular checks for immunotherapy side effects are important. A PD-L1 test on the tumour sample helps your doctor decide how much this treatment is likely to help you.

Key results

14.4 vs 11.1 months

Median overall survival (CPS ≥5)

HR 0.71 (98.4% CI 0.59–0.86); P<0.0001

7.7 vs 6.05 months

Median progression-free survival (CPS ≥5)

HR 0.68 (98% CI 0.56–0.81); P<0.0001

HR 0.77

Overall survival (CPS ≥1)

99.3% CI 0.64–0.92; P<0.0001

HR 0.80

Overall survival (all randomised patients)

99.3% CI 0.68–0.94; P=0.0002

60% vs 45%

Objective response (CPS ≥5)

226 of 378 vs 177 of 391 patients

Drugs in this study:Capecitabine (Xeloda)Fluorouracil (5-FU)Nivolumab (Opdivo)Oxaliplatin (Eloxatin)Ipilimumab (Yervoy)

Dose and schedule cards

Nivolumab + CAPOX or mFOLFOX6 (CheckMate 649 trial)

Advanced or metastatic gastric, gastroesophageal junction or oesophageal adenocarcinoma, HER2-negative; FDA label: PD-L1 CPS ≥1 (greatest benefit at CPS ≥5)On the page “Stomach cancer” · Advanced or metastatic disease, first-line: HER2-negative

Advanced or metastatic gastric, gastroesophageal junction or oesophageal adenocarcinoma, HER2-negative; FDA label: PD-L1 CPS ≥1 (greatest benefit at CPS ≥5)

Drug	Dose	Route	Schedule
3-weekly regimen (CAPOX)
Nivolumab	360 mg	IV (30 min)	Day 1
Oxaliplatin	130 mg/m²	IV	Day 1
Capecitabine	1000 mg/m² twice daily	Oral	Days 1–14
Or 2-weekly regimen (FOLFOX)
Nivolumab	240 mg	IV (30 min)	Day 1
Oxaliplatin	85 mg/m²	IV	Day 1
Leucovorin	400 mg/m²	IV	Day 1
Fluorouracil	400 mg/m²	IV (bolus)	Day 1
Fluorouracil	1200 mg/m² per day (continuous infusion)	IV, continuous infusion	Days 1–2

Cycle length: Every 21 days (CAPOX) or every 14 days (FOLFOX)
Duration: Until disease progression or unacceptable toxicity; nivolumab for a maximum of 2 years

Nivolumab dose from the FDA label and chemotherapy doses from the original CheckMate 649 publication. If chemotherapy is stopped, nivolumab monotherapy (240 mg every 2 weeks, 360 mg every 3 weeks or 480 mg every 4 weeks) continues for up to 2 years from the start of treatment. The same two chemotherapy regimens without immunotherapy are the backbone treatment for tumours without a targetable marker (including PD-L1 below 1).

On the page “Stomach cancer” · Advanced or metastatic disease, first-line: HER2-negative

HER2-negative adenocarcinoma: nivolumab + CAPOX or mFOLFOX6 (CheckMate 649 trial)

Advanced HER2-negative adenocarcinoma of the oesophagus, gastroesophageal junction or stomach; FDA label: PD-L1 ≥1 (greatest benefit with CPS ≥5). Pembrolizumab + chemotherapy (KEYNOTE-590 regimen) is another alternativeOn the page “Oesophageal cancer” · Advanced or metastatic disease, first-line: adenocarcinoma

Drug	Dose	Route	Schedule
3-week regimen (CAPOX)
Nivolumab	360 mg	IV (30 minutes)	Day 1
Oxaliplatin	130 mg/m²	IV	Day 1
Capecitabine	1000 mg/m² twice daily	Oral	Days 1–14
Or 2-week regimen (FOLFOX)
Nivolumab	240 mg	IV (30 minutes)	Day 1
Oxaliplatin	85 mg/m²	IV	Day 1
Leucovorin	400 mg/m²	IV	Day 1
Fluorouracil	400 mg/m² bolus on Day 1, then 1200 mg/m² per day continuous infusion on Days 1–2	IV	Days 1–2

Cycle length: Every 21 days (CAPOX) or every 14 days (FOLFOX)
Duration: Until progression or unacceptable toxicity; nivolumab for up to 2 years

Nivolumab dose from the FDA label and chemotherapy doses from the primary CheckMate 649 publication; 5-year follow-up. In PD-L1-negative tumours, doublet chemotherapy alone is the backbone of treatment.

On the page “Oesophageal cancer” · Advanced or metastatic disease, first-line: adenocarcinoma

Advanced gastric, GEJ or oesophageal adenocarcinoma with PD-L1 1 or more (CheckMate 649)

With fluoropyrimidine and platinum chemotherapyCycle length: 14 or 21 daysOn the page “Nivolumab (Opdivo)” · Combination regimens with chemotherapy or cabozantinib (FDA label, revised 05/2026)

With fluoropyrimidine and platinum chemotherapy

Drug	Dose	Route	Schedule
Continuous
Nivolumab	240 mg every 2 weeks (with 2-weekly chemotherapy) or 360 mg every 3 weeks (with 3-weekly chemotherapy)	IV, 30-minute infusion	Day 1 (given first)
Fluoropyrimidine + platinum	As per those drugs' labels	IV	Same day, after nivolumab

Cycle length: 14 or 21 days
Duration: Until progression, unacceptable toxicity or a maximum of 2 years

On the page “Nivolumab (Opdivo)” · Combination regimens with chemotherapy or cabozantinib (FDA label, revised 05/2026)

Nivolumab + CAPOX

Advanced HER2-negative gastric cancerCycle length: Every 21 daysOn the page “Nivolumab with CAPOX or FOLFOX in gastric cancer (CheckMate 649)”

Advanced HER2-negative gastric cancer

Drug	Dose	Route	Schedule
Nivolumab	360 mg	IV	Day 1
Oxaliplatin	130 mg/m²	IV	Day 1
Capecitabine	1000 mg/m² twice a day	Oral	Days 1 to 14

Cycle length: Every 21 days
Duration: Until progression; nivolumab up to 2 years

As in CheckMate 649.

Dose source:.

On the page “Nivolumab with CAPOX or FOLFOX in gastric cancer (CheckMate 649)”

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Nivolumab + chemotherapy

Nivolumab 360 mg every 3 weeks with XELOX (capecitabine 1000 mg/m² orally twice daily, days 1 to 14 + oxaliplatin 130 mg/m² on day 1, every 3 weeks); or nivolumab 240 mg every 2 weeks with FOLFOX (leucovorin 400 mg/m² day 1, fluorouracil 400 mg/m² day 1 and 1200 mg/m² days 1 to 2, oxaliplatin 85 mg/m² day 1, every 2 weeks). All drugs IV except capecitabine (oral).

Treatment continued until disease progression, unacceptable toxicity or withdrawal; nivolumab for a maximum of 2 years.

2Chemotherapy alone (control group)

XELOX or FOLFOX at the same doses and schedules, at the investigator's choice, until disease progression or unacceptable toxicity.

3Nivolumab + ipilimumab (third group)

Nivolumab 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks for 4 cycles, then nivolumab 240 mg every 2 weeks. Enrolment in this group closed early and its results are not reported in this paper (they were published in a later report, Nature 2022).

Source of the regimen details: Full text of the paper (author manuscript in PMC8436782, Procedures section): doses of nivolumab, XELOX and FOLFOX; doses for the nivolumab + ipilimumab group from the full text of the later report of the same trial (Shitara et al., Nature 2022; PMC8967713)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults (18 years or older) with previously untreated, unresectable, advanced or metastatic, non-HER2-positive gastric, gastro-oesophageal junction or oesophageal adenocarcinoma, regardless of PD-L1 expression, with measurable or evaluable disease and ECOG performance status 0 or 1.

Endpoints

Primary endpoints (nivolumab + chemotherapy versus chemotherapy): overall survival (OS) and progression-free survival (PFS) by blinded independent central review in patients with PD-L1 CPS ≥5.

Hierarchically tested secondary endpoints: overall survival in patients with CPS ≥1 and in all randomised patients.

Safety and side effects

Among all treated patients, grade 3–4 treatment-related adverse events occurred in 462 of 782 patients (59%) in the nivolumab + chemotherapy group and 341 of 767 patients (44%) in the chemotherapy group. The most common treatment-related adverse events (25% or more) in both groups were nausea, diarrhoea and peripheral neuropathy. 16 deaths (2%) in the nivolumab + chemotherapy group and 4 deaths (1%) in the chemotherapy group were considered treatment-related.

Clinical significance and place in guidelines

On the basis of CheckMate 649, the FDA approved nivolumab in 2021 with fluoropyrimidine-‎ and platinum-containing chemotherapy for first-line treatment of advanced or metastatic gastric, gastro-oesophageal junction and oesophageal adenocarcinoma; in the current FDA label this indication is restricted to tumours with PD-L1 expression ≥1. The NCCN guideline (version 2.2025) lists nivolumab plus a fluoropyrimidine and oxaliplatin as a preferred first-line option for HER2-negative tumours with CPS ≥1 and a category 1 preferred option for CPS ≥5. The ESMO 2022 guideline also recommends nivolumab-chemotherapy for CPS ≥5 with level of evidence [I, A]. 3-year follow-up results have been published in J Clin Oncol 2024.

Limitations

The trial was open-label (no placebo). Benefit in patients with low CPS (below 1 or below 5) was small (OS HR for CPS below 1: 0.92 and for CPS below 5: 0.94, exploratory analyses), which led to use being restricted by PD-L1. Severe adverse events and treatment-related deaths were more frequent in the nivolumab group. HER2-positive patients were not enrolled.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.