FDA approves pembrolizumab for HER2 positive gastric or gastroesophageal junction adenocarcinoma expressing PD-L1 (CPS ≥1)

Regulatory approval: On March 19, 2025, the FDA granted traditional approval to pembrolizumab with trastuzumab plus fluoropyrimidine- and platinum-containing chemotherapy for first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma with PD-L1 expression (CPS ≥1). The decision was supported by KEYNOTE-811, which showed statistically significant improvements in overall survival and progression-free survival versus placebo with trastuzumab and chemotherapy. Pembrolizumab had received accelerated approval for this indication in 2021.

FDA regulatory update (traditional approval)

Date: 2025-03-19
Agency: US FDA

The FDA granted traditional approval to pembrolizumab (Keytruda) in combination with trastuzumab and fluoropyrimidine- and platinum-containing chemotherapy for first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1). Pembrolizumab previously received accelerated approval for this indication on May 5, 2021 based on interim KEYNOTE-811 data.

Supporting evidence: KEYNOTE-811 (NCT03615326)

KEYNOTE-811 was a multicenter, randomized, double-blind, placebo-controlled trial enrolling 698 patients with HER2-positive advanced gastric/GEJ adenocarcinoma without prior systemic therapy for metastatic disease; 594 (85%) had PD-L1 CPS ≥1 by PD-L1 IHC 22C3 pharmDx. Patients were randomized 1:1 to pembrolizumab 200 mg or placebo with trastuzumab plus fluorouracil/cisplatin or capecitabine/oxaliplatin.

In the PD-L1 CPS ≥1 subgroup, pembrolizumab combination therapy improved:

  • PFS (BICR): 10.9 vs 7.3 months (HR 0.72; 95% CI 0.60–0.87)
  • OS: 20.1 vs 15.7 months (HR 0.79; 95% CI 0.66–0.95)
  • ORR: 73% vs 58%; median DOR: 11.3 vs 9.6 months

Adverse reactions were reported as consistent with known pembrolizumab safety.

Dosing (label)

Recommended pembrolizumab dosing: 200 mg every 3 weeks or 400 mg every 6 weeks, in combination with trastuzumab and chemotherapy.

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