Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial
Year: 2021
Type: article
Study design: Clinical Trial
Abstract: IMPORTANCE: 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 MEASURES: The 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 (≥5%) 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. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02989857.
Source: JAMA Oncology
Authors: Andrew X. Zhu, Teresa Macarulla, Milind M. Javle, R. Kate Kelley, Sam J. Lubner, Jorge Adeva, James M. Cleary, Daniel V. T. Catenacci, Mitesh J. Borad, John A. Bridgewater, William P. Harris, Adrian G. Murphy, Do-Youn Oh, Jonathan R. Whisenant, Maeve A. Lowery, Lipika Goyal, Rachna T. Shroff, Anthony B. El-Khoueiry, Christina X. Chamberlain, Elia Aguado-Fraile, Sung Choe, Bin Wu, Hua Liu, Camelia Gliser, Shuchi S. Pandya, Juan W. Valle, Ghassan K. Abou-Alfa
Institutions: Harvard University, Massachusetts General Hospital, Vall d'Hebron Hospital Universitari, The University of Texas MD Anderson Cancer Center, University of California, San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center, University of Wisconsin–Madison, University of Wisconsin Carbone Cancer Center, Hospital Universitario 12 De Octubre, Dana-Farber Cancer Institute, University of Chicago Medical Center, Mayo Clinic, Mayo Clinic in Arizona, University College London, University of Washington, Johns Hopkins University, Seoul National University, Seoul National University Hospital, Utah Cancer Specialists, Trinity College Dublin, University of Arizona Cancer Center, University of Southern California, USC Norris Comprehensive Cancer Center, Boston University, Agios Pharmaceuticals (United States), Bristol-Myers Squibb (United States), University of Manchester, The Christie NHS Foundation Trust, Memorial Sloan Kettering Cancer Center, Cornell University, Weill Cornell Medicine
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Amgen, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, Ariad Pharmaceuticals, Celgene, Array BioPharma, Exelixis, Ionis Pharmaceuticals, Halozyme, Agios Pharmaceuticals, BeiGene, Incyte, NuCana, Puma Biotechnology, MacroGenics, Eisai, Toray Industries, Servier, Sirtex Medical, Genentech, EMD Serono, Loxo Oncology, National Cancer Institute
Award: Cancer Center Support Grant
OpenAlex ID: W3199253355