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    Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clinical ClarIDHy trial

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    Authors
    Zhu, A. X.
    Macarulla, T.
    Javle, M. M.
    Kelley, R. K.
    Lubner, S. J.
    Adeva, J.
    Cleary, J. M.
    Catenacci, D. V. T.
    Borad, M. J.
    Bridgewater, J. A.
    Harris, W. P.
    Murphy, A. G.
    Oh, D. Y.
    Whisenant, J. R.
    Lowery, M. A.
    Goyal, L.
    Shroff, R. T.
    El-Khoueiry, A. B.
    Chamberlain, C. X.
    Aguado-Fraile, E.
    Choe, S.
    Wu, B.
    Liu, H.
    Gliser, C.
    Pandya, S. S.
    Valle, Juan W
    Abou-Alfa, G. K.
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    Affiliation
    Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston
    Issue Date
    2021
    
    Metadata
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    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.
    Citation
    Zhu AX, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, et al. Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation. JAMA Oncology. American Medical Association (AMA); 2021.
    Journal
    JAMA Oncology
    URI
    http://hdl.handle.net/10541/624667
    DOI
    10.1001/jamaoncol.2021.3836
    PubMed ID
    34554208
    Additional Links
    https://dx.doi.org/10.1001/jamaoncol.2021.3836
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1001/jamaoncol.2021.3836
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