Immunotherapy change overcomes acquired resistance after chemo-immunotherapy in unresectable biliary tract cancer

To assess the incidence, clinical characteristics, and post-progression management strategy of resistance to immunotherapy-chemotherapy combination in unresectable biliary tract carcinoma (uBTC).

DESIGN: Patients with uBTC from multiple centers who received immunotherapy-chemotherapy combination were retrospectively included. Baseline characteristics, treatments, pattern of progression, and posttreatment managements were recorded. The primary endpoint was post-progression survival (PPS).

Out of 194 patients, 130 (67.0%) developed resistance, including 78 (40.2%) with acquired resistance (AR) and 52 (26.8%) with primary resistance (PR). Normal CA19-9 level and combining target therapy were more common in patients with AR. Patients with both AR and PR commonly experience deterioration in general condition and systemic progression. Patients with AR and PR showed no difference in patterns of progression or current post-progression management strategies. A total of 103 (79.2%) patients receiving post-resistance antitumor treatments showed improved prognosis than those receiving best supportive care, while patients with AR received additional survival benefit than those with PR. Changing immunotherapy regimen after resistance brings significant survival benefit in patients with AR (mPPS: 15.1 vs. 9.50 months, HR = 0.41), but not those with PR. Adding/switching target therapy regimens (HR = 0.39) and local regional therapies (LRT) (HR = 0.36) after resistance brings potential benefit in patients with PR.

Changing immunotherapy regimen is a promising strategy for overcoming AR to first-line immunotherapy-chemotherapy combination in uBTC, while adjusting targeted therapy and adding LRT may help overcome PR.