Clinical trialPhase 3Stomach cancer

Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial

Lancet Oncol · 20231579 patients (790 pembrolizumab + chemotherapy and 789 placebo + chemotherapy)

Rha SY, Oh DY, Yañez P, et al. Lancet Oncol. 2023. 24:1181-1195

A newer report of this study has been published: 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 (2026)

Study type: Clinical trial
Study name: KEYNOTE-859
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled, multicentre trial at 207 centres in 33 countries (1:1 randomisation)
Sample size: 1579 patients (790 pembrolizumab + chemotherapy and 789 placebo + chemotherapy)
Source: Lancet Oncol · 2023
Trial registration: NCT03675737

In plain words

This large international study looked at whether adding the immunotherapy drug pembrolizumab to the usual chemotherapy helps in advanced HER2-negative stomach cancer. The answer was yes: patients in the pembrolizumab group lived longer on average, and this benefit was clearer in patients whose tumour had more PD-L1 (CPS 10 or more) (median 15.7 versus 11.8 months). Serious side effects were slightly more common but were reported as manageable. Doctors now use the PD-L1 test to decide whether this drug is suitable for a patient.

Key results

12.9 vs 11.5 months

Median overall survival (ITT)

HR 0.78 (95% CI 0.70–0.87); p<0.0001

13.0 vs 11.4 months

Median overall survival (CPS ≥1)

HR 0.74 (0.65–0.84); p<0.0001

15.7 vs 11.8 months

Median overall survival (CPS ≥10)

HR 0.65 (0.53–0.79); p<0.0001

23% vs 19%

Serious treatment-related adverse events

184 vs 146 patients

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 on day 1 every 3 weeks for up to 35 cycles (about 2 years), with one of two regimens at the physician's choice:

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

2Placebo + chemotherapy (control group)

IV placebo on day 1 every 3 weeks for up to 35 cycles, with FP or CAPOX at the same doses and schedules.

Source of the regimen details: Abstract of the paper (Lancet Oncol 2023) and ClinicalTrials.gov NCT03675737 (doses and schedule of pembrolizumab, FP and CAPOX)

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 histologically or cytologically confirmed, previously untreated, locally advanced or metastatic HER2-negative gastric or gastro-oesophageal junction adenocarcinoma and ECOG performance status 0 or 1.

Endpoints

Primary endpoint: overall survival (OS) in the intention-to-treat (ITT) population, in patients with PD-L1 CPS ≥1 and in patients with CPS ≥10.

Secondary endpoints: including progression-free survival, objective response and safety (details in the full text of the paper).

Safety and side effects

Most common grade 3 to 5 adverse events (any cause): anaemia (12% in the pembrolizumab group versus 10% in the placebo group) and decreased neutrophil count (10% versus 8%). Serious treatment-related adverse events occurred in 23% versus 19%. Treatment-related deaths were reported in 8 patients (1%) in the pembrolizumab group and 16 patients (2%) in the placebo group. No new safety signals were seen.

Clinical significance and place in guidelines

On the basis of KEYNOTE-859, in 2023 the FDA approved pembrolizumab with fluoropyrimidine-‎ and platinum-containing chemotherapy for first-line treatment of advanced or metastatic HER2-negative gastric and gastro-oesophageal junction adenocarcinoma; in the current FDA label this indication is restricted to tumours with PD-L1 CPS ≥1. The NCCN guideline (version 2.2025) lists this combination as a preferred first-line option for CPS ≥1 and a category 1 preferred option for CPS ≥5.

Limitations

The results come from an interim analysis. The benefit is smaller in patients with low CPS, and HER2-positive patients were not enrolled. Most participants were male and white. The study was funded by the manufacturer.

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.