Adding pembrolizumab to frontline chemotherapy improves outcomes in patients with HER2-negative, advanced gastric or gastroesophageal junction (GEJ) cancers, according to results of the KEYNOTE-859 trial presented in an ESMO Virtual Plenary presentation.

The combination improved the rate and duration of response as well as progression-free survival (PFS) and overall survival (OS) without increasing toxicity, reported study presenter Sun Young Rha, MD, PhD, of Yonsei Cancer Center in Seoul, Republic of Korea.

The double-blind, phase 3 KEYNOTE-859 trial ( Identifier: NCT03675737) included 1579 patients with previously untreated, HER2-negative, locally advanced unresectable or metastatic gastric or GEJ cancer. 

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The patients were randomly assigned to receive investigator’s choice of chemotherapy plus either pembrolizumab (n=790) or placebo (n=789). Pembrolizumab was given at 200 mg every 3 weeks for up to 35 cycles. Chemotherapy consisted of 5-fluorouracil plus cisplatin or capecitabine plus oxaliplatin. 

Baseline characteristics were well balanced between the arms. The median follow-up was 31.0 months.

The primary endpoint, median OS, was significantly longer in the pembrolizumab arm than in the chemotherapy-alone arm — 12.9 months and 11.5 months, respectively (hazard ratio [HR], 0.78; 95% CI, 0.70-0.87; P <.0001). 

The 12-month OS rate was 52.7% in the pembrolizumab arm and 46.7% in the chemotherapy-alone arm. The 24-month OS rate was 28.2% and 18.9%, respectively.

OS outcomes favored the pembrolizumab arm across subgroups, including by tumor location, histologic type, microsatellite instability status, and type of chemotherapy.

PFS was also longer in the pembrolizumab arm. The median PFS was 6.9 months in the pembrolizumab arm and 5.6 months in the chemotherapy-alone arm (HR, 0.76; 95% CI, 0.67-0.85; P <.0001). 

The 12-month PFS rate was 28.9% with pembrolizumab and 19.3% with chemotherapy alone. The 24-month PFS rate was 17.89% and 9.4%, respectively. PFS outcomes favored the pembrolizumab arm across subgroups.

The objective response rate was 51.3% with pembrolizumab and 42.0% with chemotherapy alone (P =.00009). Complete responses were seen in 9.5% and 6.2% of patients, respectively. The median duration of response was 8.0 months in the pembrolizumab arm and 5.7 months in the chemotherapy-alone arm.

The rates of grade 3-5 treatment-related adverse events (TRAEs) were similar between the arms, at 59.4% with pembrolizumab and 51.1% with chemotherapy alone. In the pembrolizumab arm, the most common grade 3-5 TRAEs were neutropenia and neutrophil count decrease, anemia, platelet count decrease, diarrhea, and vomiting. 

Grade 3-5 immune-mediated AEs occurred in 7.9% of patients treated with pembrolizumab, with the most common being colitis, severe skin reactions, and pneumonitis.

Fatal TRAEs were seen in 8 patients in the pembrolizumab arm and 16 patients in the chemotherapy-alone arm. The rate of treatment discontinuation was 26.4% in the pembrolizumab arm and 20.1% in the chemotherapy-alone arm.

Dr Rha concluded that the data support adding pembrolizumab to chemotherapy as a new treatment option for patients with HER2-negative, locally advanced or metastatic gastric or GEJ cancers.

Disclosures: This research was supported by Merck Sharp & Dohme, LLC. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


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