Ivosidenib is well tolerated and leads to improved overall survival compared to placebo in advanced cholangiocarcinoma patients with an isocitrate dehydrogenase 1 (IDH1) mutation, according to the results of a randomized phase 3 clinical trial published in JAMA Oncology.

“These data, coupled with supportive quality of life data and a tolerable safety profile, demonstrate the clinical benefit of ivosidenib,” the authors of the study wrote.

IDH1 variations are seen in about 20% of cholangiocarcinoma cases. The IDH1 enzyme plays an important role in cellular metabolism, and mutations in the IDH1 gene play a central role in the pathogenesis of cholangiocarcinoma.

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Ivosidenib, also known as AG-120, is an oral targeted inhibitor of the IDH1 variant that is already approved for the treatment of acute myeloid leukemia in patients with a susceptible IDH1 variant under the brand name Tibsovo®.

ClarIDHy was a multicenter, randomized, double-blind, placebo-controlled study that aimed to assess the safety and efficacy of ivosidenib in previously treated advanced cholangiocarcinoma patients with IDH1 mutations, aged 18 years and older.

It was conducted at 49 hospitals in the United States, France, Italy, Spain, the United Kingdom, and the Republic of Korea between February 20, 2017, and May 31, 2020, and it recruited 187 patients.  

Patients received either 500 mg of ivosidenib or a placebo once a day. The primary outcome measure was progression-free survival. Secondary outcome measures included adverse events and serious adverse events, overall survival, overall response rate, quality of life, and health economic outcomes.

The results showed that the median overall survival times were 10.3 months with ivosidenib and 7.5 months with placebo. When adjusted for crossover, ie, patients who crossed over to ivosidenib from placebo due to their disease progressing, the median overall survival with placebo was 5.1 months.

The most common treatment-emergent adverse event was ascites, in both the treatment and placebo groups. Serious treatment-emergent adverse events related to ivosidenib occurred in 3 patients (2%), and there were no treatment-related deaths. Finally, there was no apparent decline in the quality of life of patients treated with ivosidenib compared to those who received the placebo.

“Taken together, the efficacy data and tolerable safety profile, as well as supportive [quality of life] data, demonstrate the clinical benefit of ivosidenib compared with placebo for patients with this aggressive disease in which there is an unmet need for new therapies,” the authors concluded.


Zhu AX, Macarulla T, Javle MM, et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clinical ClarIDHy trial. JAMA Oncol. Published online September 23, 2021. doi:10.1001/jamaoncol.2021.3836

Study of AG-120 in previously treated advanced cholangiocarcinoma with IDH1 mutations (ClarIDHy) (ClarIDHy). ClinicalTrials.gov. December 12, 2016. Updated May 21, 2021. Accessed September 28, 2021.