Regulatory Decision Summary for Keytruda

Authorization was based on an international, multicentre, randomized, double-blind, placebo-controlled trial KEYNOTE 590. Patients (n = 749) with locally advanced unresectable or metastatic esophageal carcinoma or HER2-negative adenocarcinoma of the esophagogastric junction (tumour centres 1 to 5 centimetre above the gastric cardia) received either Keytruda in combination with cisplatin and fluorouracil (FU) (n = 373) or placebo in combination with the cisplatin and FU regimen (n = 376). 

The primary outcome measures were overall survival (OS) and progression-free survival (PFS). The study demonstrated a statistically significant and clinically meaningful improvement in OS and PFS in patients treated with Keytruda in combination with cisplatin and FU (Keytruda group), compared to patients treated with placebo in combination with the cisplatin and FU regimen (placebo group). The median OS was longer in the Keytruda group versus the placebo group (12.4 vs. 9.8 months), and the hazard ratio (HR) was 0.73, corresponding to a 27% risk reduction in death. The median PFS was also longer in the Keytruda group versus the placebo group (6.3 months vs. 5.8 months), and the HR was 0.65, corresponding to a 35% reduction in the risk of disease progression or death. Objective response rate (ORR) was a secondary outcome measure. ORR was statistically higher in the Keytruda group vs. the placebo group (45.0% vs. 29.3%).

Adverse reactions (ARs) reported in patients treated with pembrolizumab in combination with cisplatin and FU were generally consistent with the known safety profiles of pembrolizumab, cisplatin and FU, respectively. The adverse reactions (ARs) reported in at least 20% of the patients in the Keytruda group were nausea, decreased appetite, anemia, fatigue, decreased neutrophil count, vomiting, diarrhea, neutropenia, stomatitis, and decreased white blood cells. The incidences of serious ARs (31.6% vs. 26.2%) and ARs resulting in discontinuation of pembrolizumab or placebo (7.3% vs. 1.6%) were higher in the Keytruda group versus the placebo group. Serious ARs reported in ≥ 2% of patients in the Keytruda group were pneumonia (3.5%), pneumonitis (3.2%), febrile neutropenia (2.4%), acute kidney injury (2.2%), and vomiting (2.2%). Adverse reactions resulting in discontinuation of Keytruda in ≥ 1% of patients were pneumonitis/interstitial lung disease (2.2%).

The benefit/risk profile is considered positive for Keytruda in combination with platinum and fluoropyrimidine based chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic carcinoma of the esophagus or HER2-negative adenocarcinoma of the esophagogastric junction (tumour centre 1 to 5 centimetres above the gastric cardia). 

The recommended dose of Keytruda is 200 mg every 3 weeks or 400 mg every 6 weeks administered as intravenous infusion until unacceptable toxicity, disease progression or up to 24 months.

Health Canada granted this submission priority review.