On November 7, 2023, the U.S. Food and Drug Administration (FDA) revised the existing indication of pembrolizumab (Keytruda®) with trastuzumab, fluoropyrimidine, and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This updated indication, which remains approved under accelerated approval regulations, restricts its use to patients whose tumors express PD-L1 (CPS ≥ 1) as determined by an FDA-approved test.

FDA update

FDA also approved the Agilent PD-L1 IHC 22C3 pharmDx as a companion diagnostic device to select patients with gastric or GEJ adenocarcinoma whose tumors express PD-L1 (CPS ≥ 1).

Efficacy was evaluated in KEYNOTE-811 (NCT03615326), a multicenter, randomized, double-blind, placebo-controlled trial in patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma who have not previously received systemic therapy for metastatic disease. Patients were randomized 1:1 to receive pembrolizumab 200 mg via IV or placebo every two weeks with trastuzumab and either fluorouracil plus cisplatin or capecitabine plus oxaliplatin.

The major efficacy outcomes of KEYNOTE-811 are overall survival (OS) and progression-free survival (PFS). The May 5, 2021, approval was based on an interim analysis of objective response rate (ORR) and duration of response (DOR). At that time, ORR and DOR were assessed in the first 264 patients randomized. ORR was 74% (95% CI = 66, 82) in the pembrolizumab plus chemotherapy arm and 52% (95% CI = 43, 61) in the placebo plus chemotherapy arm (p < 0.0001). Median DOR was 10.6 months (range = 1.1+, 16.5+) and 9.5 months (range = 1.4+, 15.4+) in the respective arms.

In a recent, prespecified interim analysis of the fully enrolled trial (N = 698), in a subgroup analysis conducted in patients with PD-L1 CPS < 1 (n = 104), the hazard ratio for OS and PFS were 1.41 (95% CI = 0.90, 2.20) and 1.03 (95% CI = 0.65, 1.64), respectively.

The safety profile for participants treated with pembrolizumab and trastuzumab plus chemotherapy in KEYNOTE-811 was generally consistent with the known safety profiles of either trastuzumab plus chemotherapy alone or pembrolizumab monotherapy.

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

View the full prescribing information for pembrolizumab.

FDA approved the application approximately seven months ahead of its goal date.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.

For assistance with single-patient investigational new drug applications for oncology products, healthcare professionals may contact the Oncology Center of Excellence’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.