Pembrolizumab Receives FDA Approval for HER2-Negative Gastric–Gastroesophageal Adenocarcinoma

For adults with HER2-negative, locally advanced, unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, first-line treatment with pembrolizumab (Keytruda, Merck) immunotherapy received US Food and Drug Administration (FDA) approval on 16 November 2023 for use with fluorouracil- and platinum-containing chemotherapy.

FDA Approval Based on KEYNOTE-859

Efficacy was assessed in HER2-negative advanced gastric or GEJ adenocarcinoma in patients who had not received systemic treatment for metastatic disease: 1579 patients were enrolled in the multicentre, randomised, double-blind, placebo-controlled KEYNOTE-859 trial.

Patients were randomised (1:1) to pembrolizumab 200 mg or placebo with investigator-selected chemotherapy: cisplatin 80 mg/m2 plus 5-FU 800 mg/m2/day for 5 days (FP), or oxaliplatin 130 mg/m2 on day 1 plus capecitabine 1000 mg/m2 twice daily for 14 days (CAPOX), given in each 21-day cycle.

The primary efficacy outcome was overall survival (OS). Additional secondary outcomes included progression-free survival (PFS), overall response rate (ORR) and duration of response (DOR).

Results

Pembrolizumab plus chemotherapy produced statistically significant improvements in overall survival, progression-free survival and overall response rate.

Median overall survival in the pembrolizumab arm was 12.9 months (95% CI: 11.9, 14.0), versus 11.5 months (95% CI: 10.6, 12.1) with placebo (hazard ratio [HR] 0.78 [95% CI: 0.70, 0.87]; p-value <0.0001).

Median progression-free survival in the respective arms was 6.9 months (95% CI: 6.3, 7.2) and 5.6 months (95% CI: 5.5, 5.7) (HR 0.76 [95% CI: 0.67, 0.85]; p-value <0.0001).

Overall response rates were 51% (95% CI: 48, 55) and 42% (95% CI: 38, 45), respectively (p-value <0.0001). Median response duration was 8 months (95% CI: 7.0, 9.7) with pembrolizumab and 5.7 months (95% CI: 5.5, 6.9) with placebo.

An additional prespecified analysis showed statistically significant improvement in OS, PFS and ORR with pembrolizumab in patients whose tumours expressed PD-L1 CPS ≥ 1 and CPS ≥ 10.

The proportion of patients permanently stopping pembrolizumab because of adverse effects was 15%.

The recommended pembrolizumab dose is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression or unacceptable toxicity. When given on the same day as chemotherapy, pembrolizumab should be administered first.