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Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation

医学 IDH1 安慰剂 内科学 临床终点 耐受性 无进展生存期 胃肠病学 异柠檬酸脱氢酶 随机对照试验 肿瘤科 外科 总体生存率 不利影响 病理 突变 化学 替代医学 基因 生物化学
作者
Andrew X. Zhu,Teresa Macarulla,Milind Javle,Robin Kate Kelley,Sam Joseph Lubner,Jorge Adeva,James M. Cleary,Daniel V.T. Catenacci,Mitesh J. Borad,John Bridgewater,William Proctor Harris,Adrian Murphy,Do‐Youn Oh,Jonathan 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
出处
期刊:JAMA Oncology [American Medical Association]
卷期号:7 (11): 1669-1669 被引量:249
标识
DOI:10.1001/jamaoncol.2021.3836
摘要

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 withIDH1mutation.

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 withIDH1mutation 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-sidedP = .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-sidedP < .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 withIDH1mutation.

Trial Registration

ClinicalTrials.gov Identifier:NCT02989857
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