Sequencing ivosidenib post–first-line immunotherapy in biliary tract cancer: A real-world matched analysis.

Abstract

e16249 Background: The TOPAZ-1 trial established Gemcitabine-Cisplatin plus Durvalumab as the preferred first-line therapy for advanced biliary tract cancer (BTC) raising and important question regarding optimal sequencing of subsequent therapies. The pivotal ClarIDHy trial, which established Ivosidenib’s efficacy, was conducted in an immunotherapy-naïve population. It remains unclear whether immunotherapy sensitizes the tumor via 2-hydroxyglutarate suppression ("priming”) or selects for resistant, immune-exhausted phenotypes ("selection"). This study evaluated if the real-world efficacy of second-line Ivosidenib is altered by prior ICI exposure. Methods: We utilized the TriNetX global health research network to identify patients with IDH1 -mutated cholangiocarcinoma treated with Ivosidenib in the second line setting. Patients were stratified into two cohorts: Cohort A (Post-IO, n = 81)received prior Gemcitabine-Cisplatin plus an ICI, and Cohort B (IO-Naïve, n = 106) received prior chemotherapy alone. 1:1 propensity score matching (PSM) was performed for age, sex, ECOG performance status proxies, baseline liver function, albumin, chronic liver diseases and metastatic burden. Outcomes were 1-year overall survival (OS) and hepatic decompensation (composite for ascites, hepatic failure, ERCP, hepatopulmonary syndrome) calculated from the initiation of Ivosidenib. Kaplan-Meier survival analysis and Cox proportional hazards models were used to compare outcomes. Results: The final matched cohort included 124 patients (62 per arm) with well-balanced baseline characteristics. 1-year OS did not differ significantly between Post IO vs IO naïve cohorts (49.64% vs 44.20%; median survival 10.8 vs 10.4 months; p = 0.79). Rates of hepatic decompensation were also comparable, with a non-significant trend toward lower risk in the post-ICI group (43.55% vs. 51.61%; HR 0.84, 95% CI 0.58–1.22; p = 0.37). Conclusions: Prior exposure to immune checkpoint inhibitors did not diminish the survival benefit of second-line Ivosidenib. Our findings suggest that the metabolic benefit of IDH1 inhibition is independent of prior immune modulation, refuting the "Selection" hypothesis while also failing to demonstrate the synergistic "Priming" effect. This data provides providing real-world reassurance that Ivosidenib remains an effective second-line option in the post–TOPAZ-1 treatment landscape. Impact of ICI on survival and hepatic outcomes with ivosidenib (propensity-matched). Outcome POST IO cohort (n= 62) IO NAIVE cohort (n= 62) Hazard Ratio/ Risk Ratio (95% CI) p-value 1 year Survival Probability 49.64% 44.20% 0.92 (0.54, 1.57) 0.79 Hepatic Decompensation 43.55% 51.61% 0.84 (0.58, 1.22) 0.37