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Pembrolizumab Approved for HER2-Negative Gastric and Gastroesophageal Junction Cancer


The FDA has approved pembrolizumab (Keytruda®, Merck) with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor 2 (HER2)–negative gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Why it matters: "Programmed cell death protein 1 (PD-1) inhibitors combined with chemotherapy have shown efficacy in gastric or gastroesophageal junction cancer," wrote Sun Young Rha, MD, the Director of Songdang Institute for Cancer Research at the Yonsei University College of Medicine, Yonsei University Health System in Seoul, Korea, and colleagues, in their published results of the KEYNOTE-859 trial (NCT03675737), on which approval was based. "We compared the efficacy and safety of pembrolizumab plus chemotherapy with placebo plus chemotherapy in participants with locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma."

What they studied: Efficacy was studied in the phase 3, multicenter, double-blind, placebo-controlled trial in which 1,579 patients with HER2-negative advanced gastric or GEJ adenocarcinoma who had not previously received systemic therapy for metastatic disease were enrolled. Patients were randomized 1:1 to receive either 200 mg of pembrolizumab or placebo in addition to investigator's choice of combination chemotherapy consisting of either 80 mg/m2 of cisplatin plus 5-fluorouracil (5-FU) 800 mg/m2/day for five days, or 130 mg/m2 of oxaliplatin on Day 1 plus 1,000 mg/m2 of capecitabine twice a day for 14 days of each 21-day cycle.

The primary end point measured was overall survival. Secondary end points included progression-free survival, overall response rate, and duration of response as per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ, as assessed by blinded independent central review.

What they found: Those being treated with pembrolizumab saw statistically significant results in progression-free survival, overall survival, and overall response. The median overall survival was 12.9 months with pembrolizumab compared with 11.5 months in those being treated with placebo. The median progression-free survival was 6.9 months in those being treated with pembrolizumab compared with 5.6 months in those being treated with placebo. Overall response rate was seen at 51% in the pembrolizumab arm and 42% in the placebo arm. The median duration of response in the pembrolizumab arm was 8 months compared with 5.7 months in the placebo arm.

Additionally, in a prespecified analysis, a statistically significant improvement was observed in overall survival, progression-free survival, and overall response rate in patients receiving pembrolizumab based on tumors expressing programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 and CPS ≥10.

Adverse events: Pembrolizumab was permanently discontinued in 15% of patients due to adverse events. Permanent discontinuation due to adverse events in ≥1% of patients were infections and diarrhea.

Conclusion: "Participants in the pembrolizumab plus chemotherapy group had a significant and clinically meaningful improvement in overall survival with manageable toxicity compared with participants in the placebo plus chemotherapy group," concluded Dr. Rha and colleagues. "Therefore, pembrolizumab with chemotherapy might be a first-line treatment option for patients with locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma."

Instructions: The recommended dosage of pembrolizumab is 200 mg every three weeks or 400 mg every six weeks until disease progression or unacceptable toxicity. When given on the same day, pembrolizumab should be administered prior to chemotherapy.

For More Information

Rha SY, Oh DY, Yanez P, et al (2023). Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet, 24:11, 1181-1195. DOI:10.1016/S1470-2045(23)00515-6 (2023). Pembrolizumab (MK-3475) plus chemotherapy versus placebo plus chemotherapy in participants gastric or gastroesophageal junction (GEJ) adenocarcinoma (MK-3475-859/KEYNOTE-859). NLM identifier: NCT03675737.

Keytruda® (pembrolizumab) prescribing information (2023). Merck. Available at:

US Food and Drug Administration (2023). FDA approves pembrolizumab with chemotherapy for HER2-negative gastric or gastroesophageal junction adenocarcinoma. Available at:

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