Background: IVO—a first-in-class, oral, targeted inhibitor of the mutant IDH1 (mIDH1) protein, found mainly in intrahepatic CCAs (̃13% of patients globally)—is an FDA-approved therapy for the treatment of previously treated, locally advanced or metastatic mIDH1 CCA based on the results of the randomized, double-blind, phase 3 ClarIDHy study (NCT02989857). In this study, IVO significantly improved progression-free survival vs placebo (PBO) (HR = 0.37, p < 0.0001), resulted in a favorable overall survival trend vs PBO, and was well tolerated (Zhu JAMA Oncol 2021; Abou-Alfa Lancet Oncol 2020). Herein we describe the longitudinal assessment of HRQoL. Methods: A total of 126 and 61 patients were randomized to IVO 500 mg daily or PBO, respectively, with crossover to IVO permitted at radiographic disease progression. HRQoL was a secondary endpoint based on assessments with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Cholangiocarcinoma and Gallbladder Cancer module (QLQ-BIL21). Three domains of interest were prespecified: physical functioning (PF), pain, and appetite loss. After a protocol amendment, HRQoL was assessed predose on Cycle (C) 1 Day (D) 1, every 4 weeks on the first day of subsequent cycles until end of treatment (EOT), and every 12 weeks thereafter until start of new anticancer therapy (vs every 6 weeks between C1D1 and EOT in the original protocol). Mixed-effect models with repeated measurements were conducted on subscale score changes from baseline (BL). Results: At BL, EORTC QLQ-C30 and QLQ-BIL21 scores were available for 114 and 108 IVO patients and 53 and 52 PBO patients, respectively. Sample sizes for HRQoL analyses decreased in both arms over time, in part due to rapid disease progression, which is typical of CCA. No HRQoL assessments were available for PBO after C8 (Week 28), while change scores were available for some IVO patients beyond Week 52 (QLQ-C30 n = 17 at Week 52). From BL to C27D1, patients remaining on IVO tended to maintain their HRQoL, with no QLQ-C30 PF subscale change scores exceeding the threshold for clinically meaningful decline estimated from study data (12-13 points). For the small number of PBO patients with post-BL HRQoL assessments, clinically meaningful PF deterioration was observed at multiple cycles (C2D1, C3D1, C4D1, C5D1, C8D1). Similar preservation for IVO patients was observed on other prespecified subscales based on the published threshold of 10 points, indicating clinically meaningful change (ClarIDHy-based thresholds not estimable due to sample sizes). Conclusions: In ClarIDHy, patients with advanced mIDH1 CCA treated with IVO were likely to maintain their HRQoL over the duration of treatment, including those treated for relatively long periods of time (eg, 1 year). Clinical trial information: NCT02989857.