FDA Approves Pembrolizumab Plus Trastuzumab/Chemo for PD-L1+, HER2+ Gastric/GEJ Adenocarcinoma

The FDA has granted traditional approval to pembrolizumab (Keytruda) in combination with trastuzumab (Herceptin) and fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 with a combined positive score (CPS) of at least 1.1

The full approval was supported by data from the phase 3 KEYNOTE-811 trial (NCT03615326), which showed that 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 (n = 298) vs 7.3 months (95% CI, 6.8-8.4) in the placebo arm (n = 296; HR, 0.72; 95% CI, 0.60-0.87).1,2

Data from the final analysis of the study presented at the 2024 ESMO Congress showed that in the population of patients with a PD-L1 CPS of at least 1, the median overall survival (OS) was 20.1 months (95% CI, 17.9-22.9) in the pembrolizumab arm vs 15.7 months (95% CI, 13.5-18.5) in the placebo arm (HR, 0.79; 95% CI, 0.66-0.95).2

The combination received accelerated approval from the FDA in May 2021 for use in patients with locally advanced unresectable or metastatic HER2-positive gastric/GEJ cancer regardless of PD-L1 expression.3 Notably, the FDA amended the accelerated indication in November 2023 to limit the combination's use to patients with a PD-L1 CPS of 1 or more, as determined by an FDA-approved test.4

KEYNOTE-811 Overview

The randomized, placebo-controlled study enrolled patients with advanced, unresectable gastric/GEJ adenocarcinoma who had HER2-positive disease per central review–assessed immunohistochemistry.2 No prior systemic therapy in the advanced setting was permitted, and patients needed to have an ECOG performance status of 0 or 1.

Patients were randomly assigned 1:1 to receive pembrolizumab at 200 mg once every 3 weeks in combination with trastuzumab and chemotherapy; or placebo plus trastuzumab and chemotherapy. Chemotherapy regimens in both arms comprised 5-fluorouracil plus cisplatin (FP); or capecitabine plus oxaliplatin (CAPOX).

OS and PFS in the overall population served as the trial's primary end points. Secondary end points included overall response rate (ORR), duration of response (DOR), and safety.

Additional KEYNOTE-811 Data

Data from the study's final analysis showed that in the intention-to-treat (ITT) population, the median OS was 20.0 months (95% CI, 17.8-22.1) in the pembrolizumab arm (n = 350) vs 16.8 months (95% CI, 14.9-18.7) in the placebo arm (n = 348; HR, 0.80; 95% CI, 0.67-0.94; P = .0040). The median PFS was 10.0 months (95% CI, 8.6-12.2) vs 8.1 months (95% CI, 7.0-8.5), respectively (HR, 0.73; 95% CI, 0.61-0.87).

Furthermore, patients in the ITT population treated with the pembrolizumab regimen experienced an ORR of 72.6% (95% CI, 67.6%-77.2%) compared with 60.1% (95% CI, 54.7%-65.2%) for those given the placebo regimen. The median DORs were 11.3 months (range, 1.1+ to 60.8+) vs 9.5 months (range, 1.4+ to 60.5+), respectively.

In the population of patients with a PD-L1 CPS of at least 1, the ORR was 73.2% (95% CI, 67.7%-78.1%) in the pembrolizumab arm vs 58.4% (95% CI, 52.6%-64.1%) in the placebo arm. The respective median DORs were 11.3 months (range, 1.1+ to 60.8+) vs 9.5 months (1.4+ to 60.5+).

Regarding safety, any-grade adverse effects occurred in 99% of patients in the ITT population treated with the pembrolizumab regimen vs all patients given the placebo regimen. Any-grade treatment-related AEs occurred in 97% of patients in both groups. The rates of serious AEs were 26% and 23%, respectively, and grade 3/4 AEs were reported at rates of 58% and 50%, respectively. Grade 5 AEs occurred in 1% of patients in both arms, and the rates of AEs leading to treatment discontinuation of any drug were 37% in the pembrolizumab arm vs 34% in the placebo arm.

References

1. FDA approves pembrolizumab for HER2 positive gastric or gastroesophageal junction adenocarcinoma expressing PD-L1 (CPS ≥1). FDA. 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. Final overall survival for the phase III, KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for HER2+ advanced, unresectable or metastatic G/GEJ adenocarcinoma. Ann Oncol. 2024;35(suppl 2):S877-S878. doi:10.1016/j.annonc.2024.08.1466
3. FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer. FDA. May 5, 2021. Accessed March 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-her2-positive-gastric-cancer
4. FDA amends pembrolizumab’s gastric cancer indication. News release. FDA. November 7, 2023. Accessed March 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-amends-pembrolizumabs-gastric-cancer-indication