On March 22, 2021, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda®) for use in combination with platinum- and fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or gastroesophageal junction (GEJ) (tumors with an epicenter 1–5 cm above the gastroesophageal junction) carcinoma who are not candidates for surgical resection or definitive chemoradiation. 

FDA Approves Pembrolizumab for Esophageal or GEJ Carcinoma

Efficacy was evaluated in a multicenter, randomized, placebo-controlled trial (KEYNOTE-590; NCT03189719) of 749 patients with metastatic or locally advanced esophageal or GEJ carcinoma who were not candidates for surgical resection or definitive chemoradiation. PD-L1 status was centrally determined in tumor specimens in all patients using the PD-L1 IHC 22C3 pharmDx kit. Patients were randomized 1:1 to receive either pembrolizumab in combination with cisplatin and fluorouracil or placebo with cisplatin and fluorouracil until they experienced unacceptable toxicity or disease progression. 

The main efficacy outcome measures were overall survival (OS) and progression-free survival (PFS) as assessed by the investigator according to the response evaluation criteria in solid tumors 1.1 (modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ). The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to receive pembrolizumab with chemotherapy. Median OS was 12.4 months (95% CI = 10.5, 14.0) for the pembrolizumab arm versus 9.8 months (95% CI = 8.8, 10.8) for the chemotherapy arm (hazard ratio = 0.73; 95% CI = 0.62, 0.86; p < 0.0001). Median PFS was 6.3 (95% CI = 6.2, 6.9) and 5.8 months (95% CI = 5.0, 6.0), respectively (hazard ratio = 0.65; 95% CI = 0.55, 0.76; p < 0.0001). 

The most common adverse reactions (≥ 20%) were nausea, constipation, diarrhea, vomiting, stomatitis, fatigue, decreased appetite, and weight loss. 

The recommended pembrolizumab dose for esophageal cancer is 200 mg every three weeks or 400 mg every six weeks. 

View the full prescribing information for pembrolizumab

The review was conducted under Project Orbis, an initiative of FDA’s Oncology Center of Excellence. 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 Swissmedic. The application reviews are ongoing at the other regulatory agencies. 

The review used the Real Time Oncology Review pilot program, which streamlines data submission prior to the filing of the entire clinical application, and Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment. FDA approved the application approximately three weeks ahead of its goal date. 

FDA granted the application priority review. A description of FDA expedited programs is in the Guidance for Industry—Expedited Programs for Serious Conditions—Drugs and Biologics

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

For assistance with single-patient oncology investigational new drug applications, contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov