On 22 March 2021, the US Food and Drug Administration approved pembrolizumab (Keytruda, Merck Sharp & Dohme Corp.) in combination with platinum and fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced oesophageal or gastro-oesophageal (tumours with epicenter 1 to 5 centimeters above the gastro-oesophageal junction) carcinoma who are not candidates for surgical resection or definitive chemoradiation.

Efficacy was evaluated in KEYNOTE-590 (NCT03189719), a multicentre, randomised, placebo-controlled study that enroled 749 patients with metastatic or locally advanced oesophageal or gastro-oesophageal carcinoma who were not candidates for surgical resection or definitive chemoradiation. PD-L1 status was centrally determined in tumour specimens in all patients using the PD-L1 IHC 22C3 pharmDx kit. Patients were randomised (1:1) to pembrolizumab in combination with cisplatin and fluorouracil or placebo with cisplatin and fluorouracil, until 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 RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ).

The study demonstrated a statistically significant improvement in OS and PFS for patients randomised to pembrolizumab with chemotherapy. Median OS was 12.4 months (95% confidence interval [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 [HR] 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 (HR 0.65; 95% CI 0.55, 0.76; p < 0.0001).

Most common adverse reactions reported in ≥20% of patients who received the pembrolizumab combination in KEYNOTE-590 were nausea, constipation, diarrhoea, vomiting, stomatitis, fatigue/asthenia, decreased appetite, and weight loss.

The recommended pembrolizumab dose for oesophageal cancer is 200 mg every 3 weeks or 400 mg every 6 weeks.

Full prescribing information for Keytruda is available here.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence (OCE). 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, Health Canada, and Switzerland’s Swissmedic. The application reviews are ongoing at the other regulatory agencies.

This review used the Real-Time Oncology Review pilot programme, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

The FDA approved this application approximately 3 weeks ahead of the FDA goal date.

This application was granted priority review.

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.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate.