FDA Grants Full Approval to Pembrolizumab Combination for HER2+, PD-L1+ Gastric and GEJ Adenocarcinoma

Published: 21 Mar 2025

Author: Precedence Research

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The administration of pembrolizumab (Keytruda) in combination with trastuzumab (Herceptin) and chemotherapy has been granted traditional approval by the FDA for the frontline treatment of adult patients with locally advanced, unresectable, or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1. This approval was underpinned by firm evidence from multiple clinical trials showing that this combination significantly prolongs patient survival and progression-free survival (PFS), particularly of patients with PD-L1 CPS of 1 or greater.

Background and Initial Approval

Currently, in keeping with ulterior indications, the introduction of pembrolizumab is now moving from accelerated to standard approval. The KEYNOTE-811 trial, a worldwide multicenter randomized placebo-controlled phase 3 study, revealed that survival outcomes in the ITT population were significantly improved for the combination of pembrolizumab with trastuzumab and chemotherapy. The main improvement was seen within the PD-L1-expressing tumor category. Among the 698 enrolled patients, 594 (85%) had tumors with PD-L1 CPS 1 or greater and were the main subgroup assessed for efficacy. So what the trial showed is that there is good evidence supporting the efficacy of the treatment.

Key Efficacy Findings

The research has found that the pembrolizumab combination for progression-free survival (PFS) was statistically significant as compared to placebo among patients with PD-L1 CPS of at least one. The median PFS was 10.9 months, with a Hazard Ratio of 0.72. Again, overall survival showed significantly extended median OS of 20.1 months against 15.7 months for the pembrolizumab arm and placebo, respectively. The study also demonstrated a significant improvement in response rates and duration of response for the pembrolizumab arm.

Data from Key Interim Analyses

A presentation at the 2023 ESMO Congress and subsequent publication in The Lancet reinforced further findings regarding the efficacy of pembrolizumab in HER2-positive gastric/GEJ adenocarcinoma:

Second Interim Analysis (Median Follow-Up: 28.3 Months)

• PFS Median for PD-L1 CPS ≥1
• Pembrolizumab arm: 10.9 months (95% CI, 8.5-12.5)
• Placebo arm: 7.3 months (95% CI, 6.8-8.4)(HR: 0.70 ;95% CI, 0.58-0.85)

Third Interim Analysis (Median Follow-Up: 38.4 Months)

• Median PFS for ITT population
• Pembrolizumab arm: 10.0 months (95% CI, 8.6-12.2)
• Placebo arm: 8.1 months (95% CI, 7.1-8.6)(HR: 0.73;95% CI, 0.61-0.87)

Safety Profile

The safety profile of pembrolizumab in combination with trastuzumab and chemotherapy was consistent with the recognized adverse effects of pembrolizumab, namely

• Common Side Effects: Fatigue, nausea, diarrhea, decreased appetite
• Immune-Related Adverse Events: Pneumonitis, colitis, hepatitis, endocrinopathies

There were no new safety signals identified in this study, and the risk-benefit profile supported Full Approval for this indication.

Clinical Implications

The FDA recently approved pembrolizumab to be used together with trastuzumab and chemotherapy, thereby significantly improving the management of gastric and GEJ adenocarcinoma with HER2 positivity. Except for those patients having PD-L1 CPS <1, this treatment used in advanced cases appears to improve survival outcomes well. Therefore, this transition of pembrolizumab from accelerated to full regulatory approval guarantees the long-term availability of pembrolizumab for all patients who qualify for it. Henceforth, the role of immunotherapy in gastric adenocarcinomas will continue with ongoing investigations and the collection of real-world data to further optimize treatment protocols and improve patient outcomes.