Real world efficacy and safety of ivosidenib in US veterans with IDH1 mutated cholangiocarcinoma.

4086 Background: IDH1 mutations occur in 13% of patients with intrahepatic cholangiocarcinoma. Ivosidenib is FDA approved for the treatment of advanced, previously treated, IDH1-mutated cholangiocarcinoma. In the ClarIDHy trial, ivosidenib led to an objective response rate of 2%, stable disease rate of 51%, median progression-free survival (PFS) of 2.7 months, and median overall survival (OS) of 10.3 months. Treatment-emergent adverse events resulted in study drug discontinuation in 7% of patients. Data on the real-world efficacy and safety of ivosidenib in cholangiocarcinoma remains limited. Methods: Patients with IDH1-mutated cholangiocarcinoma who were prescribed ivosidenib before December 1, 2024, were retrospectively identified from the national Veterans Affairs (VA) Corporate Data Warehouse. Demographic, clinical, and molecular data were abstracted from the National Precision Oncology database and electronic medical records. Response was assessed based on provider notes and radiology reports. Survival was assessed by the Kaplan-Meier method, and covariates evaluated by the Cox proportional hazards model. Results: Of 1094 veterans with cholangiocarcinoma who underwent molecular testing, 82 (7.5%) had an IDH1 mutation. 33 (40%) patients received ivosidenib at 27 VA medical centers. The median age was 74 years (range 46–82). 2 patients (6%) had a partial response (PR), 10 (30%) had stable disease (SD), 19 (58%) had progressive disease, and 2 were not assessed. 20 patients (60%) had received one and 5 patients (15%) received two prior lines of therapy. Of the 8 patients (24%) who received first-line ivosidenib, 2 (25%) had a PR and 3 (38%) had SD. Most patients (94%) started ivosidenib at the labeled dose (500 mg daily). Two patients who started ivosidenib at reduced dose (250 mg daily) had PR and SD as their best response. The median PFS from start of ivosidenib was 4.0 months, and the median OS was 10.5 months. In a multivariable analysis, PFS and OS were not significantly associated with age, line of therapy, IDH1 variant allele frequency, or IDH1 mutation (17 IDH1 R132C vs. 8 other). Patients with IDH1-mutated, advanced cholangiocarcinoma treated with ivosidenib had a median OS of 25.3 months from diagnosis, compared to 8.7 months for patients who did not receive ivosidenib. Toxicities leading to dose reduction, interruption, or discontinuation of ivosidenib occurred in 3 patients (9%). Conclusions: In this real-world cohort, patients with IDH1-mutated advanced cholangiocarcinoma treated with ivosidenib had similar response rate, PFS, and OS compared to ClarIDHy. Toxicities leading to dose reduction, interruption, or discontinuation were rare. The only two partial responses were observed in the first-line setting, including one with a reduced starting dose. This suggests that frontline ivosidenib may be a reasonable alternative for patients with advanced cholangiocarcinoma.