← Return to [[Biliary Tract Cancer Clinical Trials]] ---- Phase III | Global randomized double-blind placebo-controlled trial | n=1069 | Advanced biliary tract cancer | Lancet 2023 **Kelley et al.** Published in The Lancet, 2023 Enrollment: 2019–2021 [PubMed Link](https://pubmed.ncbi.nlm.nih.gov/37075781/) --- ### Essential Takeaway KEYNOTE-966 demonstrated that adding **pembrolizumab** to gemcitabine/cisplatin improved overall survival in advanced biliary tract cancer and further validated chemoimmunotherapy as the modern first-line treatment paradigm following TOPAZ-1. The study confirmed that PD-1/PD-L1 checkpoint inhibition provides clinically meaningful survival benefit when combined with Gem/Cis, although the magnitude of benefit remained modest and biomarker selection remains poorly defined. --- ### Clinical Question Does adding pembrolizumab to gemcitabine/cisplatin improve survival compared with chemotherapy alone in unresectable or metastatic biliary tract cancer? --- ### Population Included: - Unresectable locally advanced BTC - Metastatic BTC - Recurrent BTC Tumor types: - Intrahepatic cholangiocarcinoma - Extrahepatic cholangiocarcinoma - Gallbladder carcinoma Excluded: - Ampullary carcinoma - Active autoimmune disease Most patients had metastatic disease (~88%). --- ### Study Design Randomized 1:1 double-blind phase III trial. #### Arm 1 — Pembrolizumab + Gem/Cis - Pembrolizumab 200 mg q3 weeks - Gemcitabine 1000 mg/m² - Cisplatin 25 mg/m² - Cisplatin capped at 8 cycles - Gemcitabine allowed beyond 8 cycles #### Arm 2 — Placebo + Gem/Cis Identical chemotherapy backbone with placebo substitution. --- ### Endpoints #### Primary Endpoint - Overall survival (OS) #### Secondary Endpoints - Progression-free survival (PFS) - Objective response rate (ORR) - Duration of response - Safety --- ### Key Results ### Overall Survival - 12.7 vs 10.9 months - HR 0.83 - p = 0.0034 24-month OS: - 25% vs 18% Survival curves separated early and remained separated throughout follow-up. --- ### Progression-Free Survival - 6.5 vs 5.6 months - HR 0.86 PFS did not meet the prespecified significance boundary. --- ### Objective Response Rate - 29% vs 29% No major ORR difference was observed. However, responses were more durable with pembrolizumab: - median duration of response: - 9.7 vs 6.9 months --- ### Subgroup Findings Benefit appeared generally consistent across: - ICC - EHCC - gallbladder carcinoma - Asian and non-Asian populations - PD-L1 low and PD-L1 high groups Importantly: - PD-L1 expression did not clearly predict benefit similar to TOPAZ-1. --- ### Toxicity #### [[CTCAE Grading|Grade 3-4 Adverse Events]] - 79% vs 75% #### Immune-Related Toxicity More common with pembrolizumab: - hypothyroidism - pneumonitis - immune-mediated adverse events Overall safety profile remained manageable without major unexpected toxicity signals. --- ### Interpretation KEYNOTE-966 was important less because it introduced a new concept and more because it independently validated the chemoimmunotherapy paradigm established by TOPAZ-1. Together, TOPAZ-1 and KEYNOTE-966 strongly established: PD-1/PD-L1 inhibition + Gem/Cis as the modern first-line standard in advanced BTC. One important distinction from TOPAZ-1 was that gemcitabine continuation beyond 8 cycles was permitted in KEYNOTE-966, reflecting real-world practice variation and potentially contributing to the earlier separation of survival curves. Unlike classic cytotoxic intensification strategies, benefit appeared driven primarily by: - improved long-term disease control - more durable responses - prolonged survival tail rather than dramatic response rate increases. --- ### Important Limitations #### Modest Absolute Benefit Median OS improvement remained relatively small: - 12.7 vs 10.9 months --- ### Biomarker Uncertainty No clear predictive role for: - PD-L1 - MSI status in most patients. --- ### Heterogeneous Disease Grouping Combined: - ICC - EHCC - gallbladder carcinoma despite major biologic differences. --- ### Predominantly Metastatic Population Limited applicability to localized unresectable disease. --- ### Relationship to TOPAZ-1 TOPAZ-1 first established: - durvalumab + Gem/Cis KEYNOTE-966 then confirmed the broader principle that checkpoint inhibition improves outcomes when added to Gem/Cis in BTC. Together, these trials firmly established chemoimmunotherapy as standard first-line treatment for advanced BTC. --- ### Current Practice Relevance KEYNOTE-966 supports: - pembrolizumab + Gem/Cis as a first-line option in advanced BTC. More broadly, it reinforced: - immunotherapy integration - durable disease control strategies - ongoing biomarker discovery efforts in BTC and further validated the post-ABC-02 chemoimmunotherapy era. --- ### Practice Impact KEYNOTE-966 confirmed that checkpoint inhibition meaningfully improves survival in advanced BTC when combined with Gem/Cis. Alongside TOPAZ-1, it helped solidify chemoimmunotherapy as the modern global first-line treatment paradigm in biliary tract cancer.