FDA Approval and Trial Background

On March 19, 2025, the Food and Drug Administration (FDA) approved the combination of pembrolizumab(also known as Keytruda) with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy as first-line treatment for adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This drug approval is indicated for gastric or GEJ tumors expressing PD-L1 with a combined positive score greater than or equal to 1 (CPS ≥ 1).

In May 2021, Pembrolizumab previously received accelerated approval for the same indication based on an interim analysis of 264 patients in May 2021.

In the Phase 3 randomized, double-blind clinical trial, 698 patients with HER2-positive advanced gastric or GEJ adenocarcinoma who had not been previously treated with systemic therapy were enrolled. Among them, 85% had tumors expressing PD-L1 with a CPS ≥1, as measured by the PD-L1 IHC 22C3 pharmDx kit. Patients were randomized (1:1) to the pembrolizumab 200 mg group or the placebo group, each in combination with trastuzumab and either fluorouracil plus cisplatin or capecitabine plus oxaliplatin.

Efficacy and Safety

The primary efficacy outcome evaluated in patients measures progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). Other outcome measures overall response rate (ORR) and duration of response (DOR).

Compared to patients randomized to placebo in combination with trastuzumab and chemotherapy, a statistically significant improvement in OS and PFS was observed in patients randomized to pembrolizumab in combination with trastuzumab and chemotherapy.

In patients with tumors that were PD-L1 CPS≥1, below are the measured outcomes:

Median PFS:

Pembrolizumab: 10.9 months (95% CI: 8.5, 12.5) Placebo: 7.3 months (95% CI: 6.8, 8.4) HR: 0.72 (95% CI: 0.60, 0.87)

Median OS:

Pembrolizumab: 20.1 months (95% CI: 17.9, 22.9) Placebo: 15.7 months (95% CI: 13.5, 18.5) HR: 0.79 (95% CI: 0.66, 0.95)

ORR:

Pembrolizumab: 73% (95% CI: 68, 78) Placebo: 58% (95% CI: 53, 64)

Median DOR:

Pembrolizumab: 11.3 months (95% CI: 9.9, 13.7) Placebo: 9.6 months (95% CI: 7.1, 11.2)

Regarding safety, the observed adverse events were consistent with the known safety profile of pembrolizumab.

The recommended pembrolizumab dose by the FDA is 200mg every 3 weeks or 400mg every 6 weeks in combination with trastuzumab and chemotherapy.

For further information, please refer to the clinical trial details at clinicaltrials.gov (NCT03615326) and the FDA’s official announcement.