US FDA approves pembrolizumab as first-line treatment for patients with HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma

Abstract

The US Food and Drug Administration (FDA) granted traditional approval of adding pembrolizumab to trastuzumab and standard chemotherapy (fluoropyrimidine- and platinum-containing chemotherapy) as a first-line treatment for patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 with a combined positive score (CPS) ≥1.¹

The approval comes on the heels of the FDA’s accelerated approval on May 5, 2021, of the regimen in this setting based on the first interim analysis of the KEYNOTE-811 trial² and a subsequent amendment to this accelerated approval in November 2023 restricting its use to only patients whose tumors express PD-L1 with a CPS ≥1 according to an FDA-approved test.³

KEYNOTE-811 is a phase 3, multicenter trial including 698 patients with HER2-positive advanced gastric or GEJ carcinoma who were randomized 1:1 to pembrolizumab (200 mg) or a placebo (each combined with trastuzumab and standard chemotherapy [fluoropyrimidine- and platinum-containing chemotherapy]) every 3 weeks for up to 35 cycles or until disease progression. Most of the patients in the trial had tumors that expressed PD-L1 with a CPS ≥1 (594 of 698 or 85%).

The traditional approval was based on the updated analyses of the trial, which showed significant improvements in progression-free survival (PFS) and overall survival (OS) for patients treated with the addition of pembrolizumab to trastuzumab and standard chemotherapy versus the placebo with trastuzumab and standard chemotherapy. For those patients making up the majority of the cohort (i.e., those with tumors expressing PD-L1 with a CPS ≥1), the median PFS was 10.9 and 7.3 months for the pembrolizumab and placebo groups, respectively; this represents a reduction in disease progression of 28% (hazard ratio [HR], 0.72; 95% CI, 0.60–0.87). The median OS was 20.1 and 15.7 months, respectively; this represents a reduction in the risk of death of 21% (HR, 0.79; CI, 0.66–0.95).^{4, 5}

Michael Gibson, MD, PhD, associate professor of medicine and director of Translational Research for Esophagogastric Cancer at the Vanderbilt University Medical Center, Nashville, Tennessee, gave an emphatic “yes” to whether the approval adds a new and needed treatment in this setting. “It is the first indication for combining immunotherapy with a targeted agent in this population,” he says.

He notes that current trials are underway to evaluate the combination of immunotherapy with another recently approved targeted agent, zolbetuximab, for patients whose tumors express CLDN18.2.⁶