Safety and Preliminary Activity of Ivosidenib Plus Durvalumab With Gemcitabine and Cisplatin in IDH1-Mutant Cholangiocarcinoma: Phase 1b/2 Study Results

Cholangiocarcinoma (CCA) is a rare and aggressive malignancy that is frequently diagnosed at advanced stages and has limited treatment options. Durvalumab in combination with gemcitabine and cisplatin (GemCis) is approved as a first-line treatment option for advanced CCA. Ivosidenib is a first-in-class, oral small-molecule IDH1 inhibitor that is approved in 48 countries for previously treated, locally advanced or metastatic IDH1-mutant CCA. This ongoing phase 1b/2 study (NCT06501625) is evaluating ivosidenib in combination with durvalumab plus GemCis as first-line therapy in patients with locally advanced, unresectable or metastatic IDH1-mutant CCA, with results from the phase 1b safety lead-in phase recently presented at ASCO GI 2026.

Eligible patients enrolled in the safety lead-in phase were aged ≥18 years, had an ECOG Performance Status of 0 to 1, and had at least 1 measurable lesion per RECIST v1.1. Up to 1 prior cycle of durvalumab plus GemCis was allowed. Patients received oral ivosidenib 500 mg once daily plus durvalumab 1500 mg intravenously (IV) every 3 weeks for up to 8 cycles, with gemcitabine 1000 mg/m² and cisplatin 25 mg/m² IV on days 1 and 8, followed by ivosidenib 500 mg daily and durvalumab 1500 mg IV every 4 weeks. Dose-limiting toxicities (DLTs) were assessed during cycle 1.

As of July 10, 2025, enrollment in the phase 1b cohort was complete, with 7 patients enrolled. Six patients remained on treatment, and 1 discontinued treatment due to an adverse event (AE); treatment duration ranged from 1 to 4 months. Patients ranged in age from 37 to 75 years; 3 (42.9%) were female, and 3 (42.9%) had received 1 prior cycle of durvalumab plus GemCis. All patients experienced treatment-emergent adverse events (TEAEs), with 6 (85.7%) patients reporting grade ≥3 TEAEs. Four (57.1%) patients had a dose interruption, and 1 (14.3%) patient had a dose reduction. Two (29%) patients had a serious AE; 1 serious AE was the DLT of a drug-associated liver injury, and the other was non–treatment-related cholangitis that resolved with no treatment modification. At data cutoff, 1 patient had a partial response, and 4 patients had stable disease. Based on these findings, ivosidenib 500 mg plus durvalumab plus GemCis was confirmed as the recommended combination dose for the expansion phase.

In conclusion, ivosidenib in combination with durvalumab and GemCis demonstrated a safety profile consistent with the known profiles of the individual agents. An expansion phase has been initiated, enrolling approximately 40 patients to further evaluate clinical activity and confirm safety and tolerability.

Source

1. Oh DY, El-Khoueiry A, Modest DP, et al. Results from the safety lead-in for a phase 1b/2 study of ivosidenib plus durvalumab and gemcitabine/cisplatin as first-line therapy in patients with locally advanced, unresectable or metastatic cholangiocarcinoma with an IDH1 mutation. Presented at: ASCO Gastrointestinal Cancers Symposium. January 8-10, 2026; San Francisco, CA. Abstract 558.