Clinical trialPhase 3Oesophageal cancer

Pembrolizumab plus chemotherapy versus chemotherapy for advanced esophageal cancer: 5-year extended follow-up for the randomized phase III KEYNOTE-590 study

ESMO Open · 2025749 patients

Metges JP, Kato K, Sun JM, Shen L, Enzinger PC, Adenis A, et al. ESMO Open. 2025. 10:105854

Study type: Clinical trial
Study name: KEYNOTE-590
Phase: Phase 3
Design: Randomised, placebo-controlled trial (1:1 ratio)
Sample size: 749 patients
Source: ESMO Open · 2025
Trial registration: NCT03189719

In plain words

In this study, patients with advanced oesophageal (food pipe) cancer received chemotherapy together with pembrolizumab or a placebo. After 5 years, about 11% of patients in the pembrolizumab group were alive, compared with 3% in the other group.

Key results

12.3 vs 9.8 months

Median overall survival

HR 0.72 (95% CI 0.62–0.84)

10.6% vs 3.0%

5-year overall survival

6.3 vs 5.8 months

Median progression-free survival

HR 0.64 (95% CI 0.54–0.75)

12.7 vs 9.9 months

Median overall survival in CPS ≥1

HR 0.70 (95% CI 0.60–0.83); full text of the paper

13.9 vs 8.8 months

Median overall survival in squamous with CPS ≥10

HR 0.60 (95% CI 0.46–0.76); full text of the paper (Table 2)

No clear benefit

PD-L1 CPS less than 1

Squamous: HR 1.05 (0.59–1.85); adenocarcinoma: HR 0.73 (0.32–1.67); small subgroups (Table 2)

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

Dose and schedule cards

Pembrolizumab + cisplatin and fluorouracil (KEYNOTE-590 trial)

Oesophageal or gastroesophageal junction cancer (epicenter 1 to 5 cm above the junction), squamous cell carcinoma or adenocarcinoma, not amenable to surgical resection or definitive chemoradiotherapy; FDA label: PD-L1 CPS ≥1 (greater benefit with CPS ≥10)Cycle length: Every 21 daysOn the page “Oesophageal cancer” · Advanced or metastatic disease, first-line: squamous cell carcinoma (KEYNOTE-590 in both types)

Drug	Dose	Route	Schedule
Pembrolizumab	200 mg (or 400 mg every 6 weeks)	IV (30 minutes), before chemotherapy	Day 1
Cisplatin	80 mg/m² (maximum 6 cycles)	IV	Day 1
Fluorouracil	800 mg/m²/day	IV, continuous infusion	Days 1–5

Cycle length: Every 21 days
Duration: Pembrolizumab until progression, unacceptable toxicity or up to 24 months (35 cycles)

Doses from the FDA label (description of KEYNOTE-590) and the 5-year follow-up publication.

On the page “Oesophageal cancer” · Advanced or metastatic disease, first-line: squamous cell carcinoma (KEYNOTE-590 in both types)

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 fluorouracil 800 mg/m² on days 1 to 5 and cisplatin 80 mg/m² on day 1 (maximum 6 cycles), every 3 weeks.

2Placebo + chemotherapy

IV saline placebo every 3 weeks for up to 35 cycles, with fluorouracil and cisplatin at the same doses and schedule.

Source of the regimen details: Full text of the paper (ESMO Open 2025; PMC12670541, Study procedures 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 with previously untreated locally advanced unresectable or metastatic oesophageal adenocarcinoma or squamous cell carcinoma, or Siewert type 1 gastro-oesophageal junction adenocarcinoma, with at least one measurable lesion (RECIST 1.1) and ECOG 0 or 1, regardless of PD-L1 status (about 73% squamous; about half CPS ≥10).

Endpoints

Efficacy (overall survival and progression-free survival) and safety at a median follow-up of 58.8 months.

Safety and side effects

Treatment-related grade 3 or higher adverse events: 71.9% versus 67.6%; no new safety signal was seen. According to the full text, immune-mediated adverse events and infusion reactions occurred in 27.3% versus 15.7%, and three deaths from pneumonitis were reported (2 in the pembrolizumab group and 1 in the placebo group).

Clinical significance and place in guidelines

This 5-year follow-up confirms the durable benefit of pembrolizumab plus chemotherapy in first-line advanced oesophageal cancer; the authors consider it the standard of care for tumours with PD-L1 CPS ≥1.

Limitations

Based on the abstract: subgroup results by histology and PD-L1 are not reported in the abstract and 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.