On 19 March 2025, the US Food and Drug Administration (FDA) granted traditional approval to pembrolizumab (Keytruda, Merck) with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastro-oesophageal junction (GEJ) adenocarcinoma whose tumours express PD-L1 (CPS ≥1).
Pembrolizumab previously received accelerated approval for this indication on 5 May 2021, based on interim analysis of the trial described below.
Efficacy was evaluated in KEYNOTE-811 (NCT03615326), a multicentre, randomised, double-blind, placebo-controlled trial enrolling 698 patients with HER2-positive advanced gastric or GEJ adenocarcinoma not previously treated with systemic therapy for metastatic disease. Among the 698 patients, 594 (85%) had tumours expressing PD-L1 with a CPS ≥1 using the PD-L1 IHC 22C3 pharmDx kit. Patients were randomised 1:1 to pembrolizumab 200 mg or placebo, in combination with trastuzumab and either fluorouracil plus cisplatin or capecitabine plus oxaliplatin.
The major efficacy outcome measures assessed in patients were progression-free survival (PFS) by blinded independent central review and overall survival (OS). Additional outcome measures included overall response rate (ORR) and duration of response (DoR). A statistically significant improvement in OS and PFS was demonstrated in patients randomised to pembrolizumab in combination with trastuzumab and chemotherapy compared with placebo in combination with trastuzumab and chemotherapy. In patients with tumours that were PD-L1 CPS ≥1, median PFS was 10.9 months (95% confidence interval [CI] 8.5, 12.5) in the pembrolizumab arm and 7.3 months (95% CI 6.8, 8.4) in the placebo arm (hazard ratio [HR] 0.72 [95% CI 0.60, 0.87]). Median OS was 20.1 months (95% CI 17.9, 22.9) and 15.7 months (95% CI 13.5, 18.5) in the respective arms (HR 0.79, 95% CI 0.66, 0.95). ORR was 73% (95% CI 68, 78) and 58% (95% CI 53, 64) and median DoR was 11.3 months (95% CI 9.9, 13.7) and 9.6 months (95% CI 7.1, 11.2).
The adverse reaction profile observed in patients receiving pembrolizumab was consistent with the known pembrolizumab safety profile.
The recommended pembrolizumab dose is 200 mg every 3 weeks or 400 mg every 6 weeks in combination with trastuzumab and chemotherapy.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This drug development programme was consistent with Project FrontRunner, an FDA Oncology Center of Excellence (OCE) initiative to encourage sponsors to develop cancer drugs for advanced or metastatic disease in an earlier line of treatment.
This application was granted orphan drug designation.
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 OCE’s Project Facilitate.