Pembrolizumab Combo Approved in HER2+, PD-L1+ Gastric/GEJ Adenocarcinoma

The FDA has granted traditional approval to pembrolizumab (Keytruda) plus trastuzumab (Herceptin), fluoropyrimidine- and platinum-containing chemotherapy as a frontline treatment for adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1.¹

The pembrolizumab combination received accelerated approval for the same indication in May 2021. These approvals are based on findings from the KEYNOTE-811 trial (NCT03615326), in which pembrolizumab plus trastuzumab and chemotherapy improved overall survival (OS) in the intention-to-treat (ITT) population, with the most substantial benefit seen in patients whose tumors expressed PD-L1 with a combined positive score (CPS) of at least 1.

Patients (n = 698) were randomized 1:1 to 200 mg of pembrolizumab or placebo in combination with trastuzumab and either fluorouracil plus cisplatin or capecitabine plus oxaliplatin, with 594 (85%) patients having a PD-L1 CPS of 1 or greater.¹

Outcomes and safety

In patients with a PD-L1 CPS of at least 1, the median progression-free survival (PFS) was 10.9 months (95% CI, 8.5-12.5) in the pembrolizumab arm vs 7.3 months (95% CI, 6.8-8.4) in the placebo arm (HR, 0.72; 95% CI, 0.60-0.87), according to an announcement from the FDA.¹

The median OS for those receiving the pembrolizumab combo was 20.1 months (95% CI, 17.9-22.9) compared with 15.7 months (95% CI, 13.5-18.5) in the placebo arm (HR, 0.79; 95% CI, 0.66-0.95). Objective response rates (ORR) in the respective arms were 73% (95% CI, 68-78) and 58% (95% CI, 53-64) and median duration of response (DOR) was 11.3 months (95% CI, 9.9-13.7) and 9.6 months (95% CI, 7.1-11.2), respectively.¹

Data simultaneously presented at the 2023 ESMO Congress and published in The Lancet from the second interim analysis of KEYNOTE-811 found that at a median follow-up of 28.3 months (interquartile range [IQR], 19.4-34.3) for the pembrolizumab arm (n = 350) and 28.5 months (IQR, 20.1-34.3) for the placebo arm (n = 348), patients experienced a median PFS of 10.0 months (95% CI, 8.6-11.7) vs 8.1 months (95% CI, 7.0-8.5), respectively (hazard ratio [HR], 0.72; 95% CI, 0.60-0.87; P = .0002).^2,3

Likewise, for patients with a PD-L1 CPS of at least 1, the median PFS was 10.8 months (95% CI, 8.5-12.5) for the pembrolizumab arm (n = 298) and 7.2 months (95% CI, 6.8-8.4) for the placebo arm (n = 296; HR, 0.70; 95% CI, 0.58-0.85).^2,3

The third interim analysis found that with a median follow-up of 38.4 months (IQR, 29.5-44.4) in the pembrolizumab group and 38.6 months (IQR, 30.2-44.4) in the placebo group, the median PFS for the ITT population in the pembrolizumab arm was 10.0 months (95% CI, 8.6-12.2) compared with 8.1 months (95% CI, 7.1-8.6) for those in the placebo arm (HR, 0.73; 95% CI, 0.61-0.87).^2,3

The pembrolizumab combination’s safety profile was consistent with pembrolizumab’s known safety profile.

The recommended dose of pembrolizumab is consistent with the accelerated approval at 200 mg every 3 weeks or 400 mg every 6 weeks in combination with trastuzumab and chemotherapy.

Reference

1. FDA. FDA approves pembrolizumab for HER2 positive gastric or gastroesophageal junction adenocarcinoma expressing PD-L1 (CPS ≥1). March 19, 2025. Accessed March 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-her2-positive-gastric-or-gastroesophageal-junction-adenocarcinoma.
2. Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Survival results from the phase III, randomized, double-blind, placebo-controlled KEYNOTE-811 study. Ann Oncol. 2023;34(suppl 2):S851-S852. doi:10.1016/j.annonc.2023.09.1424
3. Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: survival results from the phase 3, randomized, double-blind, placebo-controlled KEYNOTE-811 study. Lancet Oncol. 2023;402(10418):2197-2208. doi: 10.1016/S0140-6736(23)02033-0