Revision of Pembrolizumab Indication for Gastric Cancer

Gastric cancer.

The FDA has amended the existing indication of pembrolizumab (Keytruda®, Merck) with trastuzumab, fluoropyrimidine, and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)–positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. While this indication remains approved under the accelerated approval regulations, this revision restricts its use to patients whose tumors express programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 as determined by an FDA-approved test. 

In addition to this revision, the FDA approved the companion diagnostic device Agilent PD-L1 IHC 22C3 pharmDx to select patients with gastric or GEJ adenocarcinoma whose tumors express PD-L1 (CPS ≥1).    

What to know: The initial approval, made on May 5, 2021, was based on an interim analysis of 264 randomized patients enrolled in the KEYNOTE-811 trial (NCT03615326), a double-blind, placebo-controlled, phase 3 trial of patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma who had not received prior systemic therapy for metastatic disease.

What they studied: Patients were randomized 1:1 to receive either 200 mg of pembrolizumab or placebo every two weeks with trastuzumab and either fluorouracil plus cisplatin or capecitabine plus oxaliplatin. The primary end points measured were overall survival and progression-free survival.

At the time of the interim analysis which led to the initial approval in 2021, the objective response rate was 74% in the pembrolizumab plus chemotherapy arm compared with 52% in the placebo arm, and the median duration of response was 10.6 months in the pembrolizumab arm compared with 9.5 months in the placebo arm.

What they found: In a recent prespecified analysis of the fully enrolled trial, among a subgroup of 104 patients with a PD-L1 CPS <1, the overall survival hazard ratio was 1.41 and the progression-free survival hazard ratio was 1.03.

The safety profile for participants treated with pembrolizumab and trastuzumab plus chemotherapy was generally consistent with the known safety profiles of either trastuzumab plus chemotherapy alone or pembrolizumab monotherapy.

Conclusion: “Compared with placebo, pembrolizumab significantly improved progression-free survival when combined with first-line trastuzumab and chemotherapy for metastatic HER2-positive gastroesophageal cancer, specifically in patients with tumors with a PD-L1 combined positive score of 1 or more,” concluded Yelena Janjigian, MD, Chief of Gastrointestinal Oncology at Memorial Sloan Kettering Cancer Center, and colleagues, in their updated results of the KEYNOTE-811 trial, on which revision was made.

Instructions: The recommended dosage is 200 mg of pembrolizumab every three weeks or 400 mg every six weeks, up to 24 months, or until disease progression or unacceptable toxicity. Pembrolizumab should be administered prior to trastuzumab and chemotherapy when given on the same day.

For More Information

Janjigian YY, Kawazoe A, Yañez P, et al (2021). The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature, 600(7890):727-730. DOI:10.1038/s41586-021-04161-3

Janjigian YY, Kawozoe A, Bai Y, et al (2023). Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet. [Epub ahead of print] DOI:10.1016/S0140-6736(23)02033-0 (2023). Pembrolizumab/placebo plus trastuzumab plus chemotherapy in human epidermal growth factor receptor 2 positive (HER2+) advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma (MK-3475-811/KEYNOTE-811). NLM identifier: NCT03615326.

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

US Food and Drug Administration (2023). FDA amends pembrolizumab’s gastric cancer indication. Available at:

Image credit: Calicut Medical College, Department of Pathology. Licensed under CC BY-SA 4.0 DEED

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