Merck, known as MSD outside the United States and Canada, announced that Health Canada has granted approval of KEYTRUDA® (pembrolizumab), Merck's anti-PD-1 therapy, in combination with gemcitabine-based chemotherapy, for the treatment of adult patients with locally advanced unresectable or metastatic biliary tract carcinoma (BTC). This approval is based on the results from the Phase 3 KEYNOTE-966 trial, which demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) versus chemotherapy alone. KEYNOTE-966 was a multicentre, randomized, double-blind, placebo-controlled Phase 3 trial (ClinicalTrials.gov NCT04003636) evaluating pembrolizumab in combination with gemcitabine and cisplatin compared to placebo plus gemcitabine and cisplatin for the first-line treatment of advanced and/or unresectable BTC.

The primary endpoint was OS, and the secondary endpoints included progression-free survival (PFS), objective response rate (ORR), as assessed by BICR according to RECIST v1.1.  The trial enrolled 1,069 patients with locally advanced unresectable or metastatic BTC, who had not received prior systemic therapy in the advanced disease setting. Patients were randomized (1:1) to receive pembrolizumab (200 mg every three weeks for up to approximately two years) plus gemcitabine and cisplatin, or placebo plus gemcitabine and cisplatin. Treatment continued until unacceptable toxicity or disease progression.

For pembrolizumab, treatment continued for a maximum of 35 cycles, or approximately 24 months. For cisplatin, treatment could be administered for a maximum of 8 cycles and for gemcitabine, treatment could be continued beyond 8 cycles. Pembrolizumab with the gemcitabine/cisplatin arm demonstrated a clinically meaningful and statistically significant improvement versus the placebo with gemcitabine/cisplatin arm in OS.

In the study, there was a 17% reduction in the risk of death with pembrolizumab plus gemcitabine/cisplatin (HR=0.83 [95% CI, 0.72-0.95]; p=0.0034) versus gemcitabine/cisplatin alone. The median PFS was 6.5 months (95% CI, 5.7-6.9) for the pembrolizumab plus chemotherapy arm versus 5.6 months (95% CI, 5.1,6.6) for the placebo plus chemotherapy arm. The objective response rate at the pre-specified interim analysis was 28.7% (24.9, 32.8) versus 28.5% (24.8, 32.6) respectively. The most common treatment-related adverse events (reported in at least 20% of patients) were neutrophil count decreased, anemia, platelet count decreased, nausea, fatigue, and white blood cell count decreased.