ClarIDHy Trial: IDH1 Inhibitor Ivosidenib Improves Survival in Cholangiocarcinoma

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Ivosidenib, an inhibitor of isocitrate dehydrogenase 1 (IDH1), improved overall survival by almost 3 months in previously treated patients with advanced IDH1-mutated cholangiocarcinoma, compared with placebo, researchers of the global phase III ClarIDHy trial reported at the 2021 Gastrointestinal Cancers Symposium.1 The favorable overall survival trend became statistically significant after adjusting for the 70% of patients crossing over to ivosidenib after radiographic disease progression. In that adjusted analysis, risk was reduced by 51% (P < .0001), according to Andrew X. Zhu, MD, PhD, Professor of Medicine at Massachusetts General Hospital Cancer Center, Harvard Medical School and Director of Jiahui International Cancer Center, Shanghai.

Ivosidenib is a first-in-class oral small-molecule inhibitor of mutant IDH1. It is already approved in the treatment of patients with acute myeloid leukemia (AML) harboring the IDH1 mutation.

“The ClarIDHy study represents the first phase III study of a targeted, oral therapeutic with a noncytotoxic mechanism of action in advanced IDH1-mutant cholangiocarcinoma,” said Dr. Zhu.

The ClarIDHy study represents the first phase III study of a targeted, oral therapeutic with a noncytotoxic mechanism of action in advanced IDH1-mutant cholangiocarcinoma.
— Andrew X. Zhu, MD, PhD

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ClarIDHy Details

The study randomly assigned 187 patients with unresectable or metastatic IDH1-mutated cholangiocarcinoma 2:1 to receive ivosidenib or placebo. More than two-thirds of patients in both arms had an IDH1 R132C mutation. More than 90% of patients in each arm had metastatic disease, and approximately 90% had intrahepatic cholangiocarcinoma. Crossover from placebo to ivosidenib was allowed at radiographic disease progression, which was the case for 43 placebo-treated patients (70.5%).

The study’s primary endpoint, which was previously reported, was improvement in progression-free survival by independent radiology review.2 Median progression-free survival was 2.7 months with ivosidenib and 1.4 months with placebo (hazard ratio [HR] = 0.37; P < .0001). “No patients on placebo were progression-free at 6 months, whereas the progression-free survival rates at 6 months and 12 months for the ivosidenib arm were 32% and 22%, respectively, at the time of analysis,” stated Dr. Zhu. “Ivosidenib also resulted in a greater disease control rate than placebo [53% vs 28%]. The treatment effect on progression-free survival was consistent across subgroups.”

In the final analysis of overall survival, reported by Dr. Zhu, median overall survival was 10.3 months with ivosidenib and 7.5 months with placebo (HR = 0.79; P = .093), which was a numerical but not statistically significant improvement. The 12-month overall survival rate was 43% with ivosidenib vs 36% with placebo, he noted.

Due to heavy crossover, the researchers adjusted the survival analysis using the prespecified rank-preserving structural failure time model, an accepted statistical approach. Application of this model resulted in an adjusted median overall survival of 5.1 months with placebo, rendering the overall survival advantage of ivosidenib highly significant (HR = 0.49; P < .0001).

Grade ≥ 3 treatment-emergent adverse events were reported in 53% of patients given ivosidenib and 37% of patients given placebo, with the most common being ascites, anemia, and increased blood bilirubin. Side effects leading to treatment discontinuation were more common with placebo (8.5%) than with ivosidenib (6.6%). “The ­safety profile was tolerable overall and consistent with previously published data,” Dr. Zhu said.


  • The IDH1 inhibitor ivosidenib significantly improved overall survival in the ClarIDHy trial, when the analysis adjusted for the 70% of patients who crossed over to active treatment during the study.
  • In the adjusted survival analysis, median overall survival was 10.3 months with ivosidenib vs 5.1 months with placebo (HR = 0.49; P < .0001). Health-related quality of life was also improved.
  • The study previously met its primary endpoint of progression-free survival (HR = 0.37; P < .0001).

“The progression-free and overall survival data coupled with a tolerable safety profile and supportive health-related quality of life data demonstrate the clinical benefit of ivosidenib in this aggressive disease, for which there is an unmet need for new therapies,” he concluded.

Future Directions

Dr. Zhu indicated that research is underway to “get a sense of synergy” with other agents. He hopes the results of preclinical studies with ivosidenib will “lead to novel trial designs.”

Based on the effects of the IDH1 mutation on tumors, for instance, a role in DNA repair, one possibility is to combine IDH1 inhibitors with inhibitors of poly (ADP-ribose) polymerase, suggested Dr. Zhu. Another possible option, based on modulation of the immune microenvironment, is to combine these drugs with checkpoint inhibitors. Early studies of these approaches are beginning, he said. 

DISCLOSURE: Dr. Zhu has served as a consultant or advisor to AstraZeneca, Bayer, Eisai, Exelixis, Gilead Sciences, Lilly, Merck, Roche/Genentech, and Sanofi/Aventis and has received institutional research funding from Bayer, Bristol Myers Squibb, Lilly, Merck, and Novartis.


1. Zhu AX, Macarulla T, Javle MM, et al: Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib versus placebo in patients with previously treated cholangiocarcinoma and an isocitrate dehydrogenase 1 (IDH1) mutation. 2021 Gastrointestinal Cancers Symposium. Abstract 266. Presented January 17, 2021. 

2. Abou-Alfa GK, Macarulla T, Javle MM, et al: Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): A multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 21:796-807, 2020.


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