Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation: The Phase 3 Randomized Clinical ClarIDHy 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.

• 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
• Journal: JAMA oncology (JAMA Oncol) Vol. 7 Issue 11 Pg. 1669-1677 (Nov 01 2021) ISSN: 2374-2445 [Electronic] United States
• PMID: 34554208 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Pyridines
• Isocitrate Dehydrogenase
• IDH1 protein, human
• ivosidenib
• Glycine

Topics

• Adolescent
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bile Duct Neoplasms (drug therapy, genetics)
• Bile Ducts, Intrahepatic
• Cholangiocarcinoma (drug therapy, genetics)
• Double-Blind Method
• Female
• Glycine (analogs & derivatives)
• Humans
• Isocitrate Dehydrogenase (genetics)
• Middle Aged
• Mutation
• Pyridines
• Quality of Life