FDA Grants Standard Approval to Pembrolizumab Plus Trastuzumab/Chemo for HER2+, PD-L1+ Gastric Cancer

US FDA

• The FDA granted standard approval to pembrolizumab (Keytruda) plus trastuzumab (Herceptin) and chemotherapy for the treatment of patients with HER2-positive locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.
• This approval is based on findings from the phase 3 KEYNOTE-811 trial (NCT03615326).
• Pembrolizumab previously was granted accelerated approval from the FDA for this indication on May 5, 2021, based on interim analysis of the KEYNOTE-811 trial.

The FDA approved pembrolizumab plus trastuzumab and chemotherapy for the first-line treatment of patients with HER2-positive, PD-L1–positive (CPS ≥1) locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma.¹

This approval is supported by data from the phase 3 KEYNOTE-811 trial, which showed that the combination led to a clinically meaningful and statistically significant improvement in overall survival (OS) vs placebo in patients with HER2-positive locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma, meeting the primary end point of the study.^2,3

In the multicenter, randomized, double-blind, placebo-controlled trial, 698 patients with HER2-positive advanced gastric or GEJ adenocarcinoma who had not been previously treated with systemic therapy for metastatic disease were enrolled.¹ A total of 594 (85%) of the 698 patients had tumors that expressed PD-L1 with a CPS ≥1 using the PD-L1 IHC 22C3 pharmDx kit.

Stomach cancer, gastric cancer, symptoms, stages, treatment, 3d illustration: © Crystal Light - stock.adobe.com

Once enrolled, patients were randomly assigned in a 1:1 fashion to receive pembrolizumab 200 mg or placebo, in combination with trastuzumab and either fluorouracil plus cisplatin or capecitabine plus oxaliplatin.

The primary end points were progression-free survival (PFS) by blinded independent central review (BICR) and OS. Additional end points included overall response rate (ORR) and duration of response (DOR).

Among patients with tumors that were PDL1 CPS ≥1, the median PFS was 10.9 months (95% CI, 8.5-12.5) in the pembrolizumab group vs 7.3 months (95% CI, 6.8-8.4) in the placebo group (HR, 0.72; 95% CI, 0.60-0.87). In the pembrolizumab vs placebo arms, the median OS was 20.1 months (95% CI, 17.9-22.9) vs 15.7 months (95% CI, 13.5-18.5), the ORR was 73% (95% CI, 68-78) vs 58% (95% CI, 53-64), and the median DOR was 11.3 months (95% CI, 9.9-13.7) vs 9.6 months (95% CI, 7.1-11.2), respectively.

The safety profile for pembrolizumab in this study was consistent with the known pembrolizumab safety profile."We have improved treatment options for gastric and esophageal cancer. Although they are difficult tumor types to treat given their nature and their impact, there have been big steps forward. We should be treating our patients in the first-, second-, and even third-line setting in the metastatic setting because patients are deriving benefits from some of these treatments,” Ronan Kelly, MD, MBA, director of the Charles A. Sammons Cancer Center Baylor University Medical Center, chief of oncology at Baylor Scott & White Health System, clinical professor at Texas A&M University College of Medicine, adjunct associate professor of oncology at the Sidney Kimmel Comprehensive Cancer Center Johns Hopkins, and professor of the clinical sciences division at the Translational Genomics Research Institute, told Targeted Oncology.

The FDA-recommended dose of pembrolizumab for this indication is 200 mg every 3 weeks or 400 mg every 6 weeks in combination with trastuzumab and chemotherapy.

In May 2021, the FDA granted accelerated approval to the combination of pembrolizumab, trastuzumab, and fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced, unresectable, or metastatic HER2-positive gastric or GEJ adenocarcinoma, based on ORR data from the first interim analysis of KEYNOTE-811.⁴

REFERENCES:

1. FDA approves pembrolizumab for HER2 positive gastric or gastroesophageal junction adenocarcinoma expressing PD-L1 (CPS ≥1). News release. 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. Merck announces phase 3 KEYNOTE-811 trial met dual primary endpoint of overall survival (OS) as first-line treatment in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. News release. Merck. May 1, 2024. Accessed May 1, 2024. https://tinyurl.com/bdvc86tw

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 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

4. FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer. News release. 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