Pembrolizumab Approved for HER2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma
Expert Perspectives
By Lyn Brook
Published
The FDA has granted traditional approval to pembrolizumab (Keytruda®, Merck) in combination with trastuzumab and fluoropyrimidine/platinum–containing chemotherapy. This approval is for the first-line treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor (HER2)–positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express programmed death-ligand 1 (PD-L1) with a combined positive score (CPS) ≥1.
Pembrolizumab previously received accelerated approval for this indication on May 5, 2021, based on interim analysis of the KEYNOTE-811 trial (NCT03615326). This traditional approval solidifies its role as a first-line treatment option for this patient population.
Why This Approval Matters
The traditional approval of pembrolizumab in combination with trastuzumab and chemotherapy provides a reliable first-line treatment option for patients with HER2-positive gastric or GEJ adenocarcinoma whose tumors express PD-L1, offering improved survival outcomes. This approval solidifies pembrolizumab’s role in this patient population, ensuring clinicians have a validated and effective immunotherapy-based regimen to improve patient outcomes.
Breaking Down the KEYNOTE-811 Trial
The efficacy of pembrolizumab was evaluated in the KEYNOTE-811 trial, a multicenter, double-blind, placebo-controlled study. The trial enrolled 698 patients with HER2-positive advanced gastric or GEJ adenocarcinoma who had not previously received systemic therapy for metastatic disease. Patients were randomized 1:1 to receive either 200 mg of pembrolizumab or placebo, in combination with trastuzumab and either fluorouracil plus cisplatin or capecitabine plus oxaliplatin. Among the total population, 594 patients (85%) had tumors expressing PD-L1 with a CPS ≥1.
Key efficacy end points included progression-free survival (PFS) and overall survival (OS), with secondary end points including overall response rate (ORR) and duration of response (DOR).
The results demonstrated statistically significant improvements:
- Median PFS: 10.9 months in the pembrolizumab arm versus 7.3 months in the placebo arm
- Median OS: 20.1 months in the pembrolizumab arm versus 15.7 months in the placebo arm
- ORR: 73% in the pembrolizumab arm versus 58% in the placebo arm
- Median DOR: 11.3 months in the pembrolizumab arm versus 9.6 months in the placebo arm
Managing Adverse Events
The adverse reaction profile observed in patients receiving pembrolizumab was consistent with its known safety profile. Clinicians should monitor for immune-mediated adverse events and other side effects commonly associated with pembrolizumab.
Clinical Implications and Future Outlook
“First-line pembrolizumab plus trastuzumab and chemotherapy provided a statistically significant and clinically meaningful improvement in OS versus placebo plus trastuzumab and chemotherapy in all patients with unresectable, HER2-positive gastric or GEJ cancer,” wrote Yelena Janjigian, MD, Chief of Gastrointestinal Oncology at Memorial Sloan Kettering Cancer Center, and colleagues, in their final analysis of the KEYNOTE-811 trial. “Overall survival was longer in patients with PD-L1 CPS ≥1. These data support the approval of pembrolizumab plus trastuzumab and chemotherapy in patients with HER2-positive gastric or GEJ cancer and confirm this regimen as standard of care (SOC) in the first-line setting.”
Dosing and Administration
The recommended dose is 200 mg pembrolizumab every three weeks or 400 mg every six weeks, administered in combination with trastuzumab and chemotherapy. Treatment should continue until disease progression or unacceptable toxicity.