IDH inhibitors in advanced cholangiocarcinoma: Another arrow in the quiver?

Cholangiocarcinomas (CCAs) are a heterogenous group of hepatobiliary tumors with poor prognosis and limited therapeutic options. In the last decade, the advent of genomic profiling has led to the identification of several putative actionable aberrations in CCAs, and genomic characterization is playing an increasing role in the management of these malignancies. Thus, a wide number of targetable mutations are currently under investigation, and early studies on this approach in CCAs have been recently presented or published. Among these, isocitrate dehydrogenase (IDH) mutations have been reported in approximately 15-20% of intrahepatic cholangiocarcinoma (iCCA) patients, while these aberrations are considered to be less frequent in perihilar CCA (pCCA), distal CCA (dCCA), and gallbladder cancer. Of note, the recent findings of the ClarIDHy phase III trial add to mounting evidence showing the potential advantages of molecularly targeted therapies in CCA, on the basis of a benefit in previously treated IDH1-mutant patients receiving ivosidenib versus placebo. However, although the results of this trial showed a statistically significant improvement in progression-free survival and overall survival for IDH-mutant CCAs treated with ivosidenib, several questions regarding the real impact of IDH inhibitors in this setting remain open. In this review, we will provide an overview on the biological rationale behind the use of IDH inhibitors in CCA patients and current clinical implications of these molecularly targeted agents. The recently published results of the ClarIDHy - as well as ongoing clinical trials in this setting - are highlighted and critically discussed.