Isocitrate dehydrogenase 1 (IDH1) variations occur in up to approximately 20% of patients with intrahepatic cholangiocarcinoma. In the ClarIDHy trial, progression-free survival as determined by central review was significantly improved with ivosidenib vs placebo.OBJECTIVE To report the final overall survival (OS) results from the ClarIDHy trial, which aimed to demonstrate the efficacy of ivosidenib (AG-120)-a first-in-class, oral, small-molecule inhibitor of mutant IDH1-vs placebo for patients with unresectable or metastatic cholangiocarcinoma with IDH1 mutation. DESIGN, SETTING, AND PARTICIPANTS This multicenter, randomized, double-blind, placebo-controlled, clinical phase 3 trial was conducted from February 20, 2017, to May 31, 2020, at 49 hospitals across 6 countries among patients aged 18 years or older with cholangiocarcinoma with IDH1 mutation whose disease progressed with prior therapy.INTERVENTIONS Patients were randomized 2:1 to receive ivosidenib, 500 mg, once daily or matched placebo. Crossover from placebo to ivosidenib was permitted if patients had disease progression as determined by radiographic findings. MAIN OUTCOMES AND MEASURESThe primary end point was progression-free survival as determined by blinded independent radiology center (reported previously). Overall survival was a key secondary end point. The primary analysis of OS followed the intent-to-treat principle. Other secondary end points included objective response rate, safety and tolerability, and quality of life.RESULTS Overall, 187 patients (median age, 62 years [range, 33-83 years]) were randomly assigned to receive ivosidenib (n = 126; 82 women [65%]; median age, 61 years [range, 33-80 years]) or placebo (n = 61; 37 women [61%]; median age, 63 years [range, 40-83 years]); 43 patients crossed over from placebo to ivosidenib. The primary end point of progression-free survival was reported elsewhere. Median OS was 10.3 months (95% CI, 7.8-12.4 months) with ivosidenib vs 7.5 months (95% CI, 4.8-11.1 months) with placebo (hazard ratio, 0.79 [95% CI, 0.56-1.12]; 1-sided P = .09). When adjusted for crossover, median OS with placebo was 5.1 months (95% CI, 3.8-7.6 months; hazard ratio, 0.49 [95% CI, 0.34-0.70]; 1-sided P < .001). The most common grade 3 or higher treatment-emergent adverse event (Ն5%) reported in both groups was ascites (11 patients [9%] receiving ivosidenib and 4 patients [7%] receiving placebo). Serious treatment-emergent adverse events considered ivosidenib related were reported in 3 patients (2%). There were no treatment-related deaths. Patients receiving ivosidenib reported no apparent decline in quality of life compared with placebo.CONCLUSIONS AND RELEVANCE This randomized clinical trial found that ivosidenib was well tolerated and resulted in a favorable OS benefit vs placebo, despite a high rate of crossover. These data, coupled with supportive quality of life data and a tolerable safety profile, demonstrate the clinical benefit of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation.
Background: Advanced cholangiocarcinoma (CCA) is associated with considerable morbidity and mortality. Novel second-line treatments for advanced CCA underscore the need to understand treatment patterns and economic burden of illness in clinical practice. Methods: This retrospective, claims-based study using Optum's de-identified Clinformatics ® Data Mart Database [2007-2019] selected patients with CCA who experienced failure of a line of therapy containing either gemcitabine or fluorouracil. The index date was defined based on evidence of treatment failure: date of last administration of the gemcitabine-or fluorouracil-based regimen plus 28 days, or initiation date of the next-line systemic therapy. Treatment patterns, healthcare resource use (HRU), costs, and survival were assessed during the follow-up period (index until death or end of eligibility). Results: A total of 1,298 patients met inclusion criteria and had a mean age of 69.1 years. There were 958 patients (73.8%) with intrahepatic and 275 patients (21.2%) with extrahepatic CCA. Average follow-up was 7.5 months. Almost 40% of patients did not receive another line of therapy after the index date. Among the 784 patients who received another line of therapy, 40.3% used fluorouracil-based therapy, 30.7% used gemcitabine-based therapy, and 29.3% used capecitabine-based therapy. Total mean per patient per month
388 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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.