On 7 November 2023, the US Food and Drug Administration (FDA) revised 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 HER2-positive gastric or gastro-oesophageal 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.

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

Full prescribing information for Keytruda is available here.

Efficacy was evaluated in KEYNOTE-811 (NCT03615326), a multicentre, randomised, double-blind, placebo-controlled study 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 randomised (1:1) to receive pembrolizumab 200 mg intravenously or placebo every 2 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 approval on 5 May 2021 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 randomised. ORR was 74% (95% confidence interval [CI] 66, 82) in the pembrolizumab plus chemotherapy arm and 52% (95% CI 43, 61) in the placebo plus chemotherapy arm (p-value < 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 enroled study (N=698), in a subgroup analysis conducted in patients with PD-L1 CPS <1 (N= 104), the hazard ratio (HR) 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 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months. Pembrolizumab should be administered prior to trastuzumab and chemotherapy when given on the same day.

The FDA approved this application approximately 7 months ahead of the FDA 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.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact FDA’s Oncology Center of Excellence Project Facilitate.