KEYNOTE-859 Interim Analysis: Overall Survival Benefit for First-Line Pembrolizumab in Advanced Gastric Cancer

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Results of the interim analysis of KEYNOTE-859 are in, and they confirm the overall survival benefit of first-line immunotherapy plus chemotherapy in advanced gastric cancer. Pembrolizumab plus a fluoropyrimidine- and platinum-containing doublet provided a statistically significant improvement in overall survival, progression-free survival, and objective response rate in patients with locally advanced or metastatic HER2-negative gastric or gastroesophageal adenocarcinoma with any degree of expression of PD-L1. These results were presented by Rha et al during the February 2023 European Society for Medical Oncology (ESMO) Virtual Plenary (Abstract VP1-2023).  

Median overall survival was 12.9 months with pembrolizumab plus chemotherapy vs 11.5 months with chemotherapy alone, resulting in a 22% relative risk reduction that was highly significant (P < .0001), with results generally consistent across subgroups, said Sun Young Rha, MD, of Yonsei University in Seoul, Republic of Korea.

“The data support pembrolizumab plus chemotherapy as a new treatment option for this patient population,” added Dr. Rha.

The study’s invited discussant, Elizabeth Smyth, MD, consultant in gastrointestinal oncology, Cambridge University Hospitals NHS Foundation Trust in the United Kingdom, called the findings “practice-changing” and in line with “the large pantheon” of global phase III trials showing “very consistently” that immune checkpoint inhibition plus chemotherapy can improve overall survival, at least in patients with higher levels of PD-L1 expression.

KEYNOTE-859 showed that pembrolizumab plus fluorouracil/platinum chemotherapy can provide “variably” meaningful improvements in overall survival that are often dependent on PD-L1 expression, and these findings “are likely to support” pembrolizumab as a new treatment option for locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma, Dr. Smyth commented.

KEYNOTE-859 Details

KEYNOTE-859 was a double-blind, placebo-controlled trial evaluating the addition of pembrolizumab to fluoropyrimidine- and platinum-containing doublet chemotherapy in 1,579 patients with locally advanced or metastatic HER2-negative gastric or gastroesophageal cancer, with known a PD-L1 combined positive score (CPS). At baseline, 78% of patients were documented to have PD-L1 CPS ≥ 1, while 35% had tumors with CPS ≥ 10. 

Patients were randomly assigned 1:1 to receive pembrolizumab at 200 mg or placebo every 3 weeks for ≤ 35 cycles, given with investigator’s choice of fluorouracil plus cisplatin or, for 86% of patients, capecitabine plus oxaliplatin. The primary endpoint was overall survival by blinded central review.


  • The phase III KEYNOTE-859 trial has shown an overall survival benefit for the addition of pembrolizumab to chemotherapy in previously untreated patients with locally advanced or metastatic gastric or gastroesophageal cancer.
  • The combination resulted in a median overall survival of 12.9 months vs 11.5 months for chemotherapy alone. Progression-free survival and response rates were also significantly improved, without much increase in toxicity.
  • KEYNOTE-859 joins several other phase III trials showing the benefit of immune checkpoint inhibitors in gastric cancer.

Multiple Outcomes Improved With Pembrolizumab

At a median follow-up of 31.0 months, median overall survival was 12.9 months with pembrolizumab plus chemotherapy vs 11.5 months with chemotherapy alone (hazard ratio [HR] = 0.78, P < .0001), with the benefit of pembrolizumab observed in all key subgroups. Median progression-free survival was 6.9 months vs 5.6 months, respectively (HR = 0.76, P < .0001).

Risk reduction was especially notable in several subgroups, including patients with microsatellite-high status, who had a 66% relative reduction in the risk of death, and patient with PD-L1 CPS ≥ 10, whose risk was reduced by 36%, Dr. Rha reported.

Objective responses were achieved by 51.3% of patients on the pembrolizumab arm and 42.0% of the control arm (P = .00009). Responses in the pembrolizumab arm were more durable, she said, with median durations of response of 8.0 months vs 5.7 months, respectively.

Grade 3 to 5 treatment-related adverse events occurred in 59.4% of patients in the pembrolizumab arm and 51.1% of the control arm. As expected, immune-related toxicities, especially hypothyroidism, were more common with pembrolizumab/chemotherapy (27.1% vs 9.3%) but were mostly grade 1 or 2.

“Importantly, adding pembrolizumab to chemotherapy did not increase the incidence of treatment-related adverse events leading to death,” Dr. Rha said. “Eight patients in the pembrolizumab arm (1.0%) and 16 in the placebo arm (2.0%) died from adverse events attributed to study treatment.”

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