On November 16, 2023, the U.S Food and Drug Administration (FDA) approved pembrolizumab (Keytruda®) with fluoropyrimidine- and platinum-containing chemotherapy for first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma.

FDA update

Efficacy was evaluated in KEYNOTE-859 (NCT03675737), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 1,579 patients with HER2-negative advanced gastric or GEJ adenocarcinoma who had not previously received systemic therapy for metastatic disease. Patients were randomized 1:1 to receive pembrolizumab 200 mg or placebo with the investigator’s choice of combination chemotherapy consisting either of cisplatin 80 mg/m2 plus 5-fluorouracil 800 mg/m2 per day for five days or oxaliplatin 130 mg/m2 on day 1 plus capecitabine 1,000 mg/m2 twice a day for 14 days of each 21-day cycle.

The major efficacy outcome measure was overall survival (OS). Additional secondary efficacy outcome measures were progression-free survival (PFS), overall response rate (ORR), and duration of response (DOR) as assessed by blinded independent central review according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

Treatment with pembrolizumab and chemotherapy resulted in a statistically significant improvement in OS, PFS, and ORR. Median OS was 12.9 months (95% CI = 11.9, 14.0) in the pembrolizumab arm compared to 11.5 months (95% CI = 10.6, 12.1) in the placebo arm (HR = 0.78 [95% CI = 0.70, 0.87]; p < 0.0001). Median PFS was 6.9 months (95% CI = 6.3, 7.2) and 5.6 months (95% CI = 5.5, 5.7), respectively (HR = 0.76 [95% CI = 0.67, 0.85]; p < 0.0001). ORR was 51% (95% CI = 48, 55) and 42% (95% CI = 38, 45) in the respective arms (p < 0.0001); median DOR was 8 months (95% CI = 7.0, 9.7) in the pembrolizumab arm and 5.7 months (95% CI = 5.5, 6.9) in the placebo arm. An additional prespecified analysis showed a statistically significant improvement in OS, PFS, and ORR in patients receiving pembrolizumab based on tumors expressing PD-L1 CPS ≥ 1 and CPS ≥ 10.

Fifteen percent of patients permanently discontinued pembrolizumab because of adverse reactions, including infections and diarrhea.

The recommended pembrolizumab dose is 200 mg every three weeks or 400 mg every six weeks until patients experience disease progression or unacceptable toxicity. Pembrolizumab should be administered prior to chemotherapy when given on the same day.

View the full prescribing information for pembrolizumab.

The review was conducted under Project Orbis, an FDA Oncology Center of Excellence initiative. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For the review, FDA collaborated with the Australian Therapeutic Goods Administration, Health Canada, and Switzerland’s Swissmedic. The application reviews are ongoing at the other regulatory agencies.

FDA’s review used the Assessment Aid, a voluntary submission from the applicant to facilitate the  assessment. The application was granted orphan drug designation. FDA-expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.