The following is a message from the Director of the FDA Oncology Center of Excellence, Dr. Richard Pazdur:
On November 16, 2023, the Food and Drug Administration approved pembrolizumab (Keytruda, Merck) with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma.
The full prescribing information for Keytruda will be posted here.
Efficacy was evaluated in KEYNOTE-859 (NCT03675737), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 1579 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 investigator’s choice of combination chemotherapy consisting either of 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 a day for 14 days (CAPOX) of each 21-day cycle.
The major efficacy outcome measure was overall survival (OS). Additional secondary efficacy outcome measures included progression free survival (PFS), overall response rate (ORR), and duration of response (DOR) as assessed by blinded independent central review (BICR) 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 (hazard ratio [HR] 0.78 [95% CI: 0.70, 0.87]; p-value <0.0001). Median PFS 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] in the respective arms. ORR was 51% (95% CI: 48, 55) and 42% (95% CI: 38, 45) (p-value<0.0001) in the respective arms; 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 pre-specified 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.
Permanent discontinuation of pembrolizumab due to adverse reactions occurred in 15% of patients. Adverse reactions resulting in permanent discontinuation in ≥1% were infections and diarrhea.
The recommended pembrolizumab dose is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression or unacceptable toxicity. Pembrolizumab should be administered prior to chemotherapy when given on the same day.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration (TGA), Health Canada, and Switzerland’s Swissmedic. The application reviews are ongoing at the other regulatory agencies.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This 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 1-800-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.
Follow the Oncology Center of Excellence on X (formerly Twitter) @FDAOncology.
