Ivosidenib may improve overall survival (OS) for patients with chemotherapy-refractory, IDH1-mutated cholangiocarcinoma, according to final results from a phase 3 trial published in JAMA Oncology.

The ClarlDHy trial (ClinicalTrials.gov Identifier: NCT02989857) included 187 evaluable adults with IDH1-mutated cholangiocarcinoma. The patients had documented disease progression after 1-2 prior treatment regimens for advanced disease, including a gemcitabine- or fluorouracil-based chemotherapy regimen.

The patients were randomly assigned 2:1 to receive ivosidenib at 500 mg once daily (126 patients) or placebo (61 patients). They were treated until disease progression, unacceptable toxicity, pregnancy, withdrawal of consent, loss to follow-up, death, or the end/unblinding of the trial.

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Baseline characteristics were similar between the treatment arms. In the overall cohort, the median age was 62 years (range, 33-83 years).

At the data cutoff, 70% of patients originally assigned to placebo had crossed over to the ivosidenib arm.

Without adjusting for crossover, the median OS was 10.3 months in the ivosidenib arm and 7.5 months in the placebo arm (hazard ratio [HR], 0.79; 95% CI, 0.56-1.12; P =.09). 

When the researchers adjusted for crossover, the median OS was 5.1 months with placebo, making the difference between the arms statistically significant (HR, 0.49; 95% CI, 0.34-0.70; P <.001).

The most common grade 3 or higher treatment-emergent adverse event was ascites, occurring in 9% of patients in the ivosidenib arm and 7% in the placebo arm.

Three patients experienced 4 serious adverse events that were considered related to ivosidenib — grade 4 hyperbilirubinemia, grade 3 cholestatic jaundice, grade 2 prolonged QT interval, and grade 3 pleural effusion.

No treatment-related deaths were reported.

When evaluating quality of life (QOL), the researchers found that patients assigned to ivosidenib had “no apparent decline” in QOL compared with patients in the placebo arm.

The researchers also noted that the patients included in this trial are representative of a real-world population “in that patients receiving second-line and third-line treatment were included, and there were no exclusions for comorbid conditions, such as ascites, pleural effusions, or biliary stents.”

“Ivosidenib provides an alternative therapeutic option for patients in need of new noncytotoxic treatments that can target tumors, delay progression, preserve QOL, and potentially extend survival,” the researchers wrote.

Disclosures: This research was supported by Agios Pharmaceuticals Inc. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


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 ClarlDHy trial. JAMA Oncol. Published online September 23, 2021. doi:10.1001/jamaoncol.2021.3836