Clinical trialPhase 3Stomach cancer

Pembrolizumab plus chemotherapy as first-line therapy for advanced HER2-negative gastric or gastroesophageal junction adenocarcinoma: 4.5-year follow-up from the randomized phase III KEYNOTE-859 study

ESMO Open · 20261579 patients

Rha SY, Wyrwicz LS, Yañez P, Bai Y, Ryu MH, Lee J, et al. ESMO Open. 2026. 11:108536

Study type: Clinical trial
Study name: KEYNOTE-859
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled trial (1:1 ratio)
Sample size: 1579 patients
Source: ESMO Open · 2026
Trial registration: NCT03675737

In plain words

In this study, patients with advanced HER2-negative stomach cancer received chemotherapy with pembrolizumab or a placebo. After about 4.5 years of follow-up, adding pembrolizumab helped patients live longer, and the benefit was greater in tumours with higher PD-L1.

Key results

12.9 vs 11.5 months

Median overall survival in all patients

HR 0.78 (95% CI 0.70–0.86)

13.0 vs 11.4 months

Median overall survival in CPS ≥1

HR 0.74 (95% CI 0.66–0.84)

15.8 vs 11.8 months

Median overall survival in CPS ≥10

HR 0.64 (95% CI 0.53–0.77)

6.9 vs 5.6 months

Median progression-free survival (all patients)

HR 0.76 (95% CI 0.68–0.85); 24-month progression-free survival 17% vs 9% (full text of the paper)

28%, 19% and 14% vs 19%, 10% and 8%

24-, 36- and 48-month overall survival (all patients)

Full text of the paper

51.1% vs 42.0%

Objective response (all patients)

Median duration of response 8.0 vs 5.7 months (full text of the paper)

Drugs in this study:Capecitabine (Xeloda)Cisplatin (Platinol)Fluorouracil (5-FU)Oxaliplatin (Eloxatin)Pembrolizumab (Keytruda)

Dose and schedule cards

Pembrolizumab + FP or CAPOX (KEYNOTE-859 trial)

Advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, HER2-negative; FDA label: PD-L1 CPS ≥1 (greater benefit at CPS ≥10)Cycle length: Every 21 daysOn the page “Stomach cancer” · Advanced or metastatic disease, first-line: HER2-negative

Advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, HER2-negative; FDA label: PD-L1 CPS ≥1 (greater benefit at CPS ≥10)

Drug	Dose	Route	Schedule
Pembrolizumab	200 mg (or 400 mg every 6 weeks)	IV (30 min), before chemotherapy	Day 1
FP
Cisplatin	80 mg/m²	IV	Day 1
Fluorouracil	800 mg/m² per day	IV, continuous infusion	Days 1–5
Or CAPOX
Oxaliplatin	130 mg/m²	IV	Day 1
Capecitabine	1000 mg/m² twice daily	Oral	Days 1–14

Cycle length: Every 21 days
Duration: Pembrolizumab until progression, unacceptable toxicity or a maximum of 24 months (up to 35 cycles); platinum for 6 or more cycles according to local guidelines

Doses from the FDA label and the KEYNOTE-859 publication.

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

First-line HER2-negative gastric/GEJ and oesophageal cancer + chemotherapy

CPS 1 or more; KEYNOTE-859 and KEYNOTE-590Cycle length: Every 3 weeksOn the page “Pembrolizumab (Keytruda)” · Standard doses and combination regimens (FDA label)

CPS 1 or more; KEYNOTE-859 and KEYNOTE-590

Drug	Dose	Route	Schedule
Pembrolizumab	200 mg every 3 weeks or 400 mg every 6 weeks	IV infusion over 30 minutes	Day 1
Cisplatin + fluorouracil	80 mg/m² (day 1) + 800 mg/m²/day (days 1 to 5)	IV	Every 3 weeks (cisplatin up to 6 cycles in KEYNOTE-590)
Gastric option
CAPOX: oxaliplatin + capecitabine	130 mg/m² + 1000 mg/m² twice a day	IV / oral	Day 1 / days 1 to 14, every 3 weeks

Cycle length: Every 3 weeks
Duration: Until progression, unacceptable toxicity or up to 24 months

In HER2-positive gastric cancer: pembrolizumab before trastuzumab and chemotherapy.

On the page “Pembrolizumab (Keytruda)” · Standard doses and combination regimens (FDA label)

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

1Pembrolizumab + chemotherapy

Pembrolizumab 200 mg IV every 3 weeks for up to 35 cycles, with chemotherapy of investigator's choice (chosen before randomisation):

FP: cisplatin 80 mg/m² IV day 1 + fluorouracil 800 mg/m² per day as a continuous IV infusion on days 1 to 5, every 3 weeks; or
CAPOX: capecitabine 1000 mg/m² orally twice daily on days 1 to 14 + oxaliplatin 130 mg/m² IV day 1, every 3 weeks.

2Placebo + chemotherapy

Placebo every 3 weeks for up to 35 cycles, with FP or CAPOX at the same doses and schedule.

Source of the regimen details: Full text of the paper (ESMO Open 2026; PMC13595130, Randomisation and treatment section)

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, locally advanced unresectable or metastatic HER2-negative gastric or gastro-oesophageal junction adenocarcinoma, with measurable disease per RECIST 1.1, known PD-L1 status and ECOG performance status 0 or 1. About 86% of patients received CAPOX and 14% FP.

Endpoints

Primary endpoint: overall survival. Secondary endpoints: progression-free survival, objective response and duration of response (RECIST version 1.1 by blinded independent central review) and safety.

Safety and side effects

Treatment-related grade 3 or 4 adverse events: 58.3% versus 49.3%; fatal treatment-related adverse events: 1.0% versus 2.0%. According to the full text, immune-mediated adverse events and infusion reactions of any grade occurred in 32.0% versus 13.7% and grade 3 to 5 in 10.1% versus 2.0%; discontinuation because of these events was 5.5% versus 1.8%.

Clinical significance and place in guidelines

This long follow-up confirms the survival benefit of pembrolizumab plus chemotherapy in first-line HER2-negative gastric adenocarcinoma; the size of the benefit increases with CPS.

Limitations

Based on the abstract: the absolute benefit in the overall population is modest (a 1.4-month gain in median survival), and grade 3 and 4 adverse events were more frequent with pembrolizumab.

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.