Three-Year Follow-Up Data From the KEYNOTE-966 Demonstrates the Combination of Pembrolizumab With Gemcitabine and Cisplatin Is More Effective for Patients With Advanced BTC

The results of KEYNOTE-966 (NCT04003636) showed that the addition of pembrolizumab (pembro) to gemcitabine and cisplatin (gem/cis) led to a significant improvement in overall survival (OS) as first-line therapy for patients with biliary tract cancer (BTC), with a median OS of 12.7 months for pembro + gem/cis compared with 10.9 months with placebo + gem/cis after a median follow-up of 25.6 months.¹ The updated efficacy and safety data after 11 months of additional follow-up were presented at ASCO 2024.

The key eligibility requirements of this phase 3, randomized, double-blind study² included being aged ≥18 years; having previously untreated, histologically confirmed metastatic or unresectable locally advanced BTC measurable by RECIST v1.1; and having an ECOG performance status of 0 or 1.¹ Patients were randomly assigned to receive either pembro 200 mg or placebo once every 3 weeks for up to 35 cycles along with gem 1000 mg/m² on days 1 and 8 once every 3 weeks until disease progression, and cis 25 mg/m² on days 1 and 8 for <8 cycles. Patients were stratified by region (Asia vs non-Asia), disease stage (locally advanced vs metastatic), and site of origin (gallbladder vs intrahepatic vs extrahepatic). The primary end point was OS; secondary end points included progression-free survival (PFS), objective response rate, and duration of response (DOR) assessed per RECIST v1.1 by blinded independent central review, and safety. The data cutoff for this analysis was November 14, 2023.¹

A total of 1069 participants were randomly assigned to receive either pembro + gem/cis (n=533) or placebo + gem/cis (n=536). After a median follow-up of 36.6 months (range, 29.2-49.4), the combination of pembro + gem/cis continued to show a survival benefit over gem/cis alone (hazard ratio, 0.86; 95% confidence interval [CI], 0.75-0.98). The median OS was 12.7 months (95% CI, 11.5-13.6) for the pembro + gem/cis arm compared with 10.9 months (95% CI, 9.9-11.6) for the placebo + gem/cis arm. At 24 months, the OS rate was 25% in the pembro arm and 19% in the placebo arm. The OS benefit of pembro was consistent across key subgroups.¹ The median PFS was 6.5 months (95% CI, 5.7-6.9) for the placebo arm and 5.6 months (95% CI, 4.9-6.5) for the pembro arm. The objective response rate was 28.7% in both the pembro and placebo arms. The DOR was 8.3 months (range, 1.2+ to 44.3+) for the pembro arm compared with 6.9 months (1.1+ to 41.1+) for the placebo arm. Of 529 treated patients in the pembro arm, 370 (69.9%) experienced grade 3-4 treatment-related adverse events, whereas of 534 treated patients in the placebo arm, 367 (68.7%) experienced the same. In the pembro arm, 8 (1.5%) patients had a treatment-related death compared with 3 (0.6%) in the placebo arm.¹

The clinically significant improvement in OS with pembro + gem/cis was sustained, with no new safety concerns, compared with placebo + gem/cis in patients with unresectable or advanced BTC, with a median follow-up of 36.6 months. These findings provide evidence for pembro + gem/cis as a viable first-line treatment for patients with advanced BTC.¹

Sources:

1. Finn RS, Ueno M, Yoo C, et al. Three-year follow-up data from KEYNOTE-966: pembrolizumab (pembro) plus gemcitabine and cisplatin (gem/cis) compared with gem/cis alone for patients (pts) with advanced biliary tract cancer (BTC). Chicago, IL, & online: presented at 2024 ASCO Annual Meeting; abstract 4093. 
2. ClinicalTrials.gov. Pembrolizumab (MK-3475) plus gemcitabine/cisplatin versus placebo plus gemcitabine/cisplatin for first-line advanced and/or unresectable biliary tract carcinoma (BTC) (MK-3475-966/KEYNOTE-966) (KEYNOTE-966). Accessed August 13, 2024. https://clinicaltrials.gov/study/NCT04003636?term=NCT04003636&rank=1