Descriptive analysis of outcomes in participants with combined hepatocellular-cholangiocarcinoma in the phase 3 KEYNOTE-966 trial.

563 Background: In the phase 3 KEYNOTE-966 trial (NCT04003636), pembrolizumab (pembro) plus gemcitabine and cisplatin (gem/cis) significantly improved OS (HR, 0.83; 95% CI, 0.72-0.95; P = 0.0034) vs placebo (pbo) plus gem/cis in participants (pts) with advanced biliary tract cancer (BTC), including combined hepatocellular-cholangiocarcinoma (cHCC-CCA). The incidence of adverse events (AEs) and treatment-related AEs were similar between treatment groups. We report data for pts with cHCC-CCA, an understudied population. Methods: Pts aged ≥18 years with untreated unresectable locally advanced or metastatic BTC were randomly assigned 1:1 to pembro 200 mg or pbo every 3 weeks (Q3W) for ≤35 cycles plus gem 1000 mg/m 2 on days 1 and 8 Q3W until progressive disease (PD) and cis 25 mg/m 2 on days 1 and 8 Q3W for ≤8 cycles. Primary end point was OS. Secondary end points included PFS and ORR per RECIST v1.1 by blinded independent central review (BICR), and safety. No formal statistical comparison was made. Results: At data cutoff (Nov 14, 2023), 13 pts with cHCC-CCA were treated (pembro group, n = 8; pbo group, n = 5). Baseline characteristics were generally balanced between treatment groups. Overall, median age of pts was 65.0 years (range, 48-73), 8 (62%) were male, 5 (39%) were enrolled in Asia, and 11 (85%) had metastatic disease. The median duration on study treatment was 9.05 mo (range, 1.54-24.18) in the pembro group vs 6.97 mo (range, 3.52-14.29) in the pbo group. Of the 8 pts in the pembro group, 1 (13%) completed treatment and 7 discontinued, most commonly due to PD (n = 5; 63%). Of the 5 pts in the pbo group, all pts discontinued treatment, most commonly due to PD (n = 3; 60%). The median OS was 13.3 mo (95% CI, 2.9-33.2) in the pembro group vs 13.6 mo (95% CI, 9.5-not reached NR) in the pbo group (HR, 0.73; 95% CI, 0.22-2.44). The median PFS was 8.5 mo (95% CI, 2.6-NR) vs 5.6 mo (1.4-NR), respectively (HR, 0.58; 95% CI, 0.15-2.21). The ORR was 25.0% (95% CI, 3.2-65.1) in the pembro group vs 20.0% (95% CI, 0.5-71.6) in the pbo group (difference, 5.0%; 95% CI, -46.1 to 47.9). Treatment-related AEs of any grade occurred in all pts in the pembro group and 4 (80%) in the pbo group. Grade 3-5 treatment-related AEs occurred in 6 (75%) and 4 pts (80%), respectively. Discontinuations of any drug due to treatment-related AEs occurred in 4 pts (50%) in the pembro group and 1 (20%) in the pbo group. Deaths due to treatment-related AEs occurred in 1 pt (13%) in the pembro group (gem-related lower respiratory tract infection); no deaths due to treatment-related AEs were reported in the pbo group. Conclusions: Outcomes in pts with cHCC-CCA were generally consistent with the overall population of the KEYNOTE-966 trial, however, results should be interpreted with caution due to small sample size of the subgroup. Given the paucity of prospective data in this rare population, results suggest pembro plus gem/cis as an active treatment regimen. Clinical trial information: NCT04003636 .