Pembrolizumab plus gemcitabine/cisplatin improves survival in metastatic biliary tract cancer

Treatment with pembrolizumab (pembro) in combination with gemcitabine and cisplatin (gem/cis) results in a statistically significant, clinically meaningful improvement in overall survival (OS) when compared with placebo plus gem/cis in patients with previously untreated metastatic or unresectable biliary tract cancer (BTC), results of the KEYNOTE-966 study have shown.

“The safety profile of pembro + gem/cis was as expected and manageable,” said the researchers, led by Robin Kate Kelley from the University of California San Francisco, California, US. “These data support pembro + gem/cis as a new first-line treatment option in this setting.”

Kelley presented the findings of KEYNOTE-966, a randomized, double-blind, phase III trial of pembro vs placebo as first-line therapy for locally advanced or metastatic BTC, at the recent AACR 2023.

In this study, 1,069 patients with histologically confirmed, RECIST v1.1-measurable disease with no prior systemic therapy in the unresectable or metastatic setting were randomized to receive pembro 200 mg (n=533) or placebo (n=536) administered intravenously (IV) on day 1 Q3W for ≤35 cycles added to gemcitabine 1,000 mg/m² administered IV on days 1 and 8 Q3W until disease progression and cisplatin 25 mg/m² administered IV on days 1 and 8 Q3W for ≤8 cycles.

The researchers stratified patients by region (Asia vs non-Asia), stage (metastatic vs locally advanced), and tumour origin (gallbladder vs intrahepatic vs extrahepatic).

OS was the primary endpoint, progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) per RECIST v1.1 by blinded independent central review and safety were secondary. Final analysis of PFS and ORR was at the first interim analysis, and all the other data were from the protocol-specified final analysis.

Baseline characteristics were comparable between treatment arms. Of the patients, 45.5 percent were from Asia, 88.2 percent had metastatic disease, and 59.2 percent had intrahepatic origin. Median follow-up was 25.6 months. [AACR 2023, abstract CT008]

Median OS at final analysis was 12.7 months for pembro plus gem/cis and 10.9 months for placebo plus gem/cis (hazard ratio [HR], 0.83, 95 percent confidence interval [CI], 0.72‒0.95; p=0.0034), while the 24-month OS was 24.9 percent vs 18.1 percent, respectively. OS rates were consistent across subgroups.

At first interim analysis, median PFS was 6.5 months for pembro plus gem/cis and 5.6 months for placebo plus gem/cis (HR, 0.86, 95 percent CI, 0.75‒1.00; p=0.0225), while the 12-month PFS was 25.4 percent vs 19.8 percent. ORR was 28.7 percent vs 28.5 percent for pembro plus gem/cis and placebo plus gem/cis, respectively (difference, 0.2, 95 percent CI, ‒5.2 to 5.6; p=0.4735). In addition, the median DOR was 9.7 months for pembro plus gem/cis compared with 6.9 months for placebo plus gem/cis.

Grade 3‒5 adverse events (AEs) occurred in 85.3 percent of patients in the pembro plus gem/cis arm compared with 84.1 percent of those in the placebo plus gem/cis arm (drug-related: 71.3 percent vs 69.3 percent). Grade 5 AE incidence was 5.9 percent vs 9.2 percent (drug-related: 1.5 percent vs 0.6 percent), respectively. Finally, potentially immune-mediated AEs and infusion reactions were noted in 22.1 percent vs 12.9 percent.