Clinical trialPhase 3Stomach cancerOesophageal cancer

Nivolumab plus chemotherapy as first-line treatment for advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: 5-year follow-up results from CheckMate 649

Ann Oncol · 20261581 patients (789 vs 792)

Janjigian YY, Shitara K, Ajani JA, Shen L, Garrido M, Gallardo C, et al. Ann Oncol. 2026. 37:787-797

Study type: Clinical trial
Study name: CheckMate 649
Phase: Phase 3
Design: Randomised trial (follow-up report with a minimum of 60 months)
Sample size: 1581 patients (789 vs 792)
Source: Ann Oncol · 2026
Trial registration: NCT02872116

In plain words

In this large study, patients with advanced stomach or oesophageal cancer (adenocarcinoma type) that was HER2-negative received either chemotherapy alone or chemotherapy together with the immunotherapy drug nivolumab. After 5 years, among patients whose tumour had higher PD-L1, 16% of the nivolumab group were alive compared with 6% of the chemotherapy-alone group.

Key results

HR 0.71

Overall survival in CPS ≥5

95% CI 0.61–0.81

16% vs 6%

5-year overall survival in CPS ≥5

HR 0.71

Progression-free survival in CPS ≥5

95% CI 0.61–0.82; 5-year PFS 10% vs 6%

58% vs 46%

Objective response (BICR) in CPS ≥5

Median duration of response 8.5 vs 6.9 months

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

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 IV every 3 weeks with XELOX/CAPOX (capecitabine 1000 mg/m² orally twice daily, days 1 to 14 + oxaliplatin 130 mg/m² IV 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).

Treatment until disease progression or unacceptable toxicity; nivolumab for a maximum of 2 years. If chemotherapy was stopped, nivolumab monotherapy (240 mg every 2 weeks, 360 mg every 3 weeks or 480 mg every 4 weeks) was allowed.

2Chemotherapy alone

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

Source of the regimen details: Full text of the primary CheckMate 649 report (Lancet 2021; PMC8436782, Procedures section) and the FDA label for Opdivo (section 14, CHECKMATE-649); the 5-year follow-up paper does not repeat the doses

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 with previously untreated, unresectable advanced or metastatic, HER2-negative gastric, gastro-oesophageal junction or oesophageal adenocarcinoma.

Endpoints

Primary endpoints: overall survival and progression-free survival in patients with PD-L1 CPS ≥5 (previously met and reported).

Safety and side effects

Grade 3 or 4 treatment-related adverse events occurred in 60% of patients in the nivolumab + chemotherapy group and 45% of the chemotherapy group; no new safety concerns were seen.

Clinical significance and place in guidelines

This report confirms the durability of the survival benefit of nivolumab plus chemotherapy in first-line HER2-negative gastric and oesophageal adenocarcinoma and supports its use as standard treatment in PD-L1-positive tumours.

Limitations

Based on the abstract: grade 3 and 4 adverse events were more frequent with the addition of nivolumab; other limitations (including the open-label design of the trial) are given in the full text of the paper.

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.