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

Get Permission

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.1 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.

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). A generally consistent benefit was seen across subgroups, including subsets stratified by geographic region, PD-L1 expression, and choice of chemotherapy, said Sun Young Rha, MD, of Yonsei Cancer Center, Yonsei University, in Seoul, Republic of Korea, who presented the interim analysis of the intent-to-treat population of KEYNOTE-859 at the February ESMO Virtual Plenary.1 “The data support pembrolizumab plus chemotherapy as a new treatment option for this patient population,” she said.

Sun Young Rha, MD

Sun Young Rha, MD

KEYNOTE-859 Details

As Dr. Rha pointed out, the 5-year overall survival rate for advanced gastric cancer is less than 10%. The addition to chemotherapy of PD-1 inhibitors—so far, pembrolizumab, nivolumab, and sintilimab—aims to improve upon this poor prognosis. “Although regulatory approvals and guideline recommendations vary globally, immunotherapy plus chemotherapy is becoming a standard of care for the first-line treatment of metastatic gastric cancer,” she said.

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 HER2-negative, locally advanced or metastatic gastric or gastroesophageal cancer, with a known PD-L1 combined positive score (CPS) using the 22C3Ab assay. Microsatellite instability-high (MSI-H) tumors were documented for 5% of patients, and for 13%, the MSI status was unknown. At baseline, 78% of patients were documented to have a PD-L1 CPS of at least 1, whereas nearly 35% had tumors with a CPS of at least 10.

Patients were randomly assigned 1:1 to receive pembrolizumab at 200 mg or placebo every 3 weeks for up to 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.

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. Risk reduction was especially notable in several subgroups, including patients with MSI-H status, who had a 66% relative risk reduction, and patients with a PD-L1 CPS of at least 10, whose risk was reduced by 36%, Dr. Rha reported.

Median progression-free survival was 6.9 months vs 5.6 months, respectively (HR = 0.76; P < .0001). At 12 months, the percentage of patients free of disease progression was 28.9% vs 19.3%; at 24 months, these rates were 17.8% and 9.4%, respectively. Again, benefit was seen in all key subgroups, especially patients with MSI-H tumors, whose risk was reduced by 73%.

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

Immunotherapy plus chemotherapy is becoming a standard of care for the first-line treatment of metastatic gastric cancer.
— Sun Young Rha, MD

Tweet this quote

Safety Profile

Grade 3 to 5 treatment-related adverse events occurred in 59.4% of 785 patients treated with pembrolizumab plus chemotherapy and in 51.1% of 787 treated with chemotherapy alone. As expected, immune-related toxicities, especially hypothyroidism, were more common with pembrolizumab plus chemotherapy (27.1% vs 9.3%) but were mostly grade 1 or 2. The overall incidence of these side effects was consistent with previous trials of pembrolizumab.

“Of note, adding pembrolizumab to chemotherapy did not increase the incidence of treatment-related adverse events leading to death,” Dr. Rha said. “A total of 8 patients in the pembrolizumab arm (1.0%) and 16 in the placebo arm (2.0%) died of adverse events attributed to study treatment.” 

DISCLOSURE: Dr. Rha has served as a speaker and/or held an advisory role with Amgen, Astellas, Daiichi Sankyo, Eisai, Indivumed, LG Biochemical, and MSD.


1. Rha SY, Wyrwicz LS, Yanez Weber PE, et al: Pembrolizumab plus chemotherapy as first-line therapy for advanced HER2-negative gastric or gastroesophageal junction cancer: Phase III KEYNOTE-859 study. ESMO Virtual Plenary. Abstract VP1-2023. Presented February 16, 2023.


Related Articles

Elizabeth Smyth, MD, Offers Insight on KEYNOTE-859 Findings

The invited discussant of KEYNOTE-859,1 Elizabeth Smyth, MD, consultant in gastrointestinal oncology at Cambridge University Hospitals NHS Foundation Trust in the United Kingdom, called the findings “practice-changing” but cautioned that better patient selection is needed to optimally apply them.