Ivosidenib as a promising new contender against advanced cholangiocarcinoma


Cholangiocarcinoma (CCA) is a highly aggressive, heterogeneous disease that currently accounts for 15% of all liver cancers and approximately 3% of gastrointestinal malignancies. While rare, the incidence of CAA is on the rise globally. The heterogeneity nature of this tumor type at the genomic, epigenetic and molecular levels severely hamper the efficacy of available therapies, and prognosis is poor. Seeking out new, more potent treatment paradigms that hone in on the molecular makeup of CAA therefore represents an unmet clinical need.

Aimed at improving outcomes for previously treated patients with unresectable or metastatic CCA, whose tumors express an isocitrate dehydrogenase 1 mutation (IDH1), the phase III multicenter, randomized ClarlDHy (1) clinical trial assessed the performance and safety of ivosidenib, a first-in-class targeted inhibitor of IDH1, that is already approved for the treatment of acute myeloid leukemia (AML) in some patients with this genetic variant.

Recently published as an open access article in JAMA Oncology (2), results from this double-blind, placebo-controlled study, conducted from February 2017 to May 2020, report the final overall survival (OS) and safety profile of ivosidenib in patients with IDH1-mutated CCA whose disease had progressed on one or two previous treatment lines with chemotherapy.

“Progression-free survival among patients with advanced biliary cancer treated with chemotherapy is only between two to three months. By putting ivosidenib to the therapeutic test, we sought to open up a new, more effective and less toxic treatment avenue to target this highly aggressive malignancy,” said Teresa Macarulla, Principal Investigator of VHIO’s  Gastrointestinal and Endocrine Tumors Group (Director: Josep Tabernero), and a co-author of this present study.

A total of 187 patients at 49 hospitals spanning six countries, were randomly assigned to receive ivosidenib (82 patients) or placebo (37 patients), with 43 patients who crossed over from placebo to ivosidenib. The endpoints of this study were first, progression-free survival (PFS) and second, overall survival (OS).

The ClarlDHy Investigators, led by Andrew X. Zhu, Massachusetts General Hospital Cancer Center, Harvard Medical School (Boston, USA), showed that ivosidenib numerically improved OS versus placebo, despite a high rate of crossover, maintained quality of life (QOL), and was well tolerated.  Specifically, median OS was 10.3 months with ivosidenib versus 7.5 months with placebo. Factoring in the crossover of patients, median OS with placebo dropped to 5.1 months.

“Our data demonstrates the clinical benefit of ivosidenib compared with placebo for these patients. As such, this targeted therapy could potentially respond to the unmet need for new therapies against advanced cholangiocarcinoma with IDH1 mutation,” added Teresa Macarulla, a Medical Oncologist and Clinical Investigator of Vall d’Hebron’s Medical Oncology Department, headed by VHIO’s Director, Josep Tabernero.

She continued, “While these results point to a paradigm shift in the treatment of this tumor type, the option for crossover included in our study has likely confounded the treatment effect estimate on our primary OS analysis.” The authors also note that their analyses of quality of life data were limited by small sample size due to the rapid disease progression and withdrawal from the study, which is common in this patient population.

“Moving forward, our research will aim at achieving a deeper understanding of mechanisms of resistance. Additional translational studies are already under way to investigate disease relapse using circulating DNA sequencing,” concluded Teresa Macarulla.




  1. A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-controlled Study of AG-120 in Previously-treated Subjects With Nonresectable or Metastatic Cholangiocarcinoma With an IDH1 Mutation. NCT02989857.
  2. Zhu AX, Macarulla T, Javle MM, et al. Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial. JAMA Oncol. Published online September 23, 2021. doi:10.1001/jamaoncol.2021.3836.

Related Posts