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Ivosidenib: A Review in Advanced Cholangiocarcinoma

  • Adis Drug Evaluation
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Abstract

Ivosidenib (Tibsovo®), a first-in-class, oral small molecule, potent and selective inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), is approved in the EU and USA for the treatment of adults with pretreated, advanced, mIDH1 cholangiocarcinoma (CCA). It is presumed to exert its cytostatic effects in this setting by suppressing 2-hydroxyglutarate, an oncometabolite produced by mIDH1 that impairs cellular differentiation and promotes tumorigenesis. In the multinational phase 3 ClarIDHy study in patients with pretreated, advanced mIDH1 CCA, monotherapy with ivosidenib once daily significantly prolonged progression-free survival (PFS) and almost doubled the disease control rate compared with placebo. Moreover, it had a favourable effect on overall survival (OS), which was also significantly prolonged after correcting for a high rate of crossover from the placebo group (permitted by the trial protocol). Ivosidenib treatment preserved health-related quality of life (HRQOL) relating to physical function, pain and appetite loss/eating and was generally well tolerated, with the most common treatment-emergent adverse events being low-grade diarrhoea, nausea and fatigue. Thus, ivosidenib represents a novel and valuable targeted therapy for the subset of patients with pretreated, advanced CCA tumors harbouring mIDH1.

Plain Language Summary

Cholangiocarcinoma (CCA) is often diagnosed at an advanced stage when the prognosis is poor due to limited treatment options, including standard-of-care (palliative) chemotherapy. Around 40% of patients with CCA have a tumor that can be targeted for treatment due to the presence of a molecular abnormality implicated in tumor formation and/or maintenance. One such abnormality (present in ≈14% of patients with intrahepatic CCA), is a mutated form of the isocitrate dehydrogenase 1 (IDH1) enzyme (‘mutant IDH1’) that inappropriately catalyses the production of 2-hydroxyglutarate (2-HG), an oncometabolite that promotes tumorigenesis. Ivosidenib (Tibsovo®), a first-in-class, small molecule, oral inhibitor of mIDH1, exerts a cytostatic (stabilizing) effect on mIDH1 CCA tumors, presumably by suppressing the production of 2-HG. Compared with placebo, ivosidenib resulted in a statistically significant, near-doubling of progression-free survival and, similarly, a near doubling of the disease control rate in a pivotal study in patients with pretreated, advanced, mIDH1 CCA. Overall survival was also significantly improved after controlling for the high rate of crossover. Health-related quality of life was maintained and ivosidenib treatment was generally well tolerated. Ivosidenib represents a novel and valuable targeted therapy for patients with advanced mIDH1 CCA tumors.

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Acknowledgments

During the peer review process, the manufacturer of ivosidenib was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

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    James E. Frampton

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Correspondence to James E. Frampton.

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The preparation of this review was not supported by any external funding.

Authorship and Conflict of Interest

James E. Frampton is a salaried employee of Adis International Ltd/Springer Nature, and declares no relevant conflicts of interest. All authors contributed to the review and are responsible for the article content.

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Additional information

The manuscript was reviewed by: C. Hierro, Medical Oncology Department. Catalan Institute of Oncology-Badalona, Badalona-Applied Research Group in Oncology (B-ARGO), Badalona, Barcelona, Spain; A. Manne, Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

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Frampton, J.E. Ivosidenib: A Review in Advanced Cholangiocarcinoma. Targ Oncol 18, 973–980 (2023). https://doi.org/10.1007/s11523-023-01002-3

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