The U.S. Food and Drug Administration (FDA) has granted traditional approval to the PD-L1 inhibitor pembrolizumab (Keytruda) with trastuzumab, fluoropyrimidine-, and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (Combined Positive Score [CPS] ≥ 1).
Pembrolizumab previously received accelerated approval for this indication on May 5, 2021, based on an interim analysis of the KEYNOTE-811 trial (ClinicalTrials.gov identifier NCT03615326).
Efficacy and Safety in KEYNOTE-811
Efficacy of the agent was evaluated in the multicenter, randomized, double-blind, placebo-controlled trial. Investigators enrolled 698 patients with HER2-positive advanced gastric or GEJ adenocarcinoma not previously treated with systemic therapy for metastatic disease. Among the 698 patients, 594 (85%) had tumors expressing PD-L1, with a CPS ≥ 1 per the PD-L1 IHC 22C3 pharmDx kit. Patients were randomly assigned 1:1 to receive either pembrolizumab at 200 mg or placebo, in combination with trastuzumab and either fluorouracil plus cisplatin or capecitabine plus oxaliplatin.
The major efficacy outcome measures assessed in patients were progression-free survival by blinded independent central review and overall survival; additional outcome measures included overall response rate and duration of response. A statistically significant improvement in overall and progression-free survival was demonstrated in patients receiving pembrolizumab in combination with trastuzumab and chemotherapy compared with placebo in combination with trastuzumab and chemotherapy. In patients with tumors expressing PD-L1, with a CPS ≥ 1, median progression-free survival was 10.9 months (95% confidence interval [CI] = 8.5–12.5 months) in the pembrolizumab arm and 7.3 months (95% CI = 6.8–8.4 months) in the placebo arm (hazard ratio [HR] = 0.72, 95% CI = 0.60–0.87). Median overall survival was 20.1 months (95% CI = 17.9–22.9 months) vs 15.7 months (95% CI = 13.5–18.5 months) in the respective arms (HR = 0.79, 95% CI = 0.66–0.95). The overall response rates were 73% (95% CI = 68%–78%) and 58% (95% CI = 53%–64%), respectively, and the median durations of response were 11.3 months (95% CI = 9.9–13.7 months) and 9.6 months (95% CI = 7.1–11.2 months).
The adverse reaction profile observed in patients receiving pembrolizumab was consistent with the known safety profile of the drug.
The recommended pembrolizumab dose is 200 mg every 3 weeks or 400 mg every 6 weeks in combination with trastuzumab and chemotherapy.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This drug development program was consistent with Project FrontRunner, an FDA Oncology Center of Excellence initiative to encourage sponsors to develop cancer drugs for advanced or metastatic disease in an earlier line of treatment.
This application was granted Orphan Drug designation.
