Final Overall Survival Results From a Phase 3 Study of Ivosidenib in IDH1-Mutant, Advanced Cholangiocarcinoma (ClarIDHy): A Randomized Clinical Trial

IMPORTANCE Isocitrate dehydrogenase 1 (IDH1) mutations occur in up to ~20% of intrahepatic cholangiocarcinomas. In the ClarIDHy study, progression-free survival (PFS) by central review was significantly improved with ivosidenib vs placebo (hazard ratio [HR], 0.37; 95% CI, 0.25¬-0.54; P < .001). OBJECTIVE To report the final overall survival (OS) results from ClarIDHy, a study aiming to demonstrate the efficacy of ivosidenib (AG-120)—a first-in-class, oral, small-molecule inhibitor of mutant IDH1 (mIDH1)—vs placebo in patients with unresectable or metastatic mIDH1 cholangiocarcinoma. DESIGN ClarIDHy is a multicenter, randomized, double-blind, placebo-controlled, phase 3 study. SETTING Study conducted at 49 hospitals across 6 countries. PARTICIPANTS Patients ≥18 years with mIDH1 cholangiocarcinoma who progressed on prior therapy. INTERVENTIONS Patients were randomized 2:1 to ivosidenib 500 mg once daily or matched placebo. Crossover from placebo to ivosidenib was permitted at radiographic progression. MAIN OUTCOMES AND MEASURES The primary end point was PFS by blinded independent radiology center (reported previously). OS was a key secondary end point. Other secondary end points included objective response rate, safety/tolerability, and quality of life (QOL). RESULTS Overall, 187 patients were randomized to ivosidenib (n = 126) or placebo (n = 61); 43 patients crossed over from placebo to ivosidenib. Median OS was 10.3 months (95% CI, 7.8-12.4) with ivosidenib vs 7.5 months (95% CI, 4.8-11.1) with placebo (HR, 0.79; 95% CI, 0.56-1.12; 1-sided P = .09). When adjusted for crossover, median OS for placebo was 5.1 months (95% CI, 3.8-7.6); HR, 0.49 (95% CI, 0.34-0.70; 1-sided P < .001). The most common grade ≥3 treatment-emergent adverse event (TEAEs) (≥5%) reported in both arms was ascites (11 [8.9%] patients receiving ivosidenib and 4 [7%] receiving placebo). Serious TEAEs considered ivosidenib-related were reported in 3 (2.4%) patients. There were no treatment-related deaths. Patients receiving ivosidenib reported no apparent decline in QOL compared with placebo. CONCLUSIONS AND RELEVANCE Ivosidenib was well tolerated and resulted in a favorable OS benefit vs placebo, despite a high rate of crossover. These data, coupled with supportive QOL data and tolerable safety profile, demonstrate the clinical benefit of ivosidenib in advanced mIDH1 cholangiocarcinoma. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02989857