Cholangiocarcinoma (CCA)

Tibsovo® (ivosidenib) is a first-in-class targeted isocitrate dehydrogenase (IDH) 1 inhibitor indicated for adult patients carrying a susceptible IDH1 mutation as detected by a US Food and Drug Administration (FDA)-approved test who have been previously treated for advanced or metastatic cholangiocarcinoma (CCA).1 Tibsovo was approved by the FDA for use in patients with CCA in May 2021.2

Cholangiocarcinoma is a group of rare cancers that develop in the bile ducts.3 CCA is often diagnosed in its advanced stages, with patients experiencing late symptoms, including jaundice, generalized itching, impaired liver function, progressive weight loss, and abdominal pain.2 Surgery remains the only curative option for these patients, however, advances in targeted therapy may offer new therapeutic options for the management of chemorefractory disease.2

Get full prescribing information for Tibsovo at MPR

Ivosidenib is an orally available inhibitor of isocitrate dehydrogenase type 1 (IDH1), with potential antineoplastic activity.
Credit: National Center for Biotechnology Information. PubChem Compound Summary for CID 71657455, Ivosidenib.

Mechanism of Action and Use of Tibsovo

Both IDH1 and IDH2 are enzymes involved in the metabolic pathway of cellular aerobic respiration. These enzymes convert isocitrate into α-ketoglutarate and reduce nicotinamide adenine dinucleotide phosphate (NADP) to NADPH.2,4 Mutations in the IDH1 and IDH2 genes have been linked to cancers such as CCA. IDH1 mutations have been observed in 10% to 20% of intrahepatic CCA cases and less than 1% of extrahepatic CCA cases.

The mutated IDH enzymes acquire a new catalytic function, promoting the accumulation of the oncometabolite D-2-hydroxyglutarate (2-HG). High levels of 2-HG contribute to oncogenesis by disrupting cellular metabolism and epigenetic regulation, with an important impact on different signaling pathways.2,4

The active ingredient in Tibsovo is ivosidenib, a specific, allosteric, and reversible inhibitor of the mutant IDH1 enzyme that acts by decreasing 2-HG levels in the tumor cells, thereby helping to restore normal cellular differentiation.2

The recommended dose of Tibsovo is 500 mg, taken orally every day with or without food (high-fat meals should be avoided) until disease progression or unacceptable toxicity is observed.1

The use of Tibsovo may result in QTc interval prolongation, therefore, patients should be monitored through electrocardiograms and electrolyte levels. Reducing the dose or withholding administration should be considered if required. Patients may also develop Guillain-Barré syndrome, which limits the administration of Tibsovo.1 

Common adverse reactions reported in patients with CCA taking Tibsovo include fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash. Laboratory abnormalities can also be observed in these patients, including decreased levels of hemoglobin and increased aspartate aminotransferase and bilirubin levels.1

Tibsovo in Clinical Trials

A phase 1 multicenter clinical trial was conducted to determine the safety, pharmacokinetics, pharmacodynamics, and clinical activity of Tibsovo in patients with advanced solid tumors who carried an IDH1 mutation (NCT02073994).5 This was a dose-escalation expansion study that enrolled 73 patients with CCA. Results from this trial reported a median progression-free survival of 3.8 months and a median overall survival of 13.8 months. The medication was well tolerated, and common adverse events included fatigue, nausea, diarrhea, abdominal pain, decreased appetite, and vomiting.6 

The approval of Tibsovo followed the results of the phase 3 clinical trial ClarIDHy (NCT02989857), which was performed to evaluate the safety and efficacy of the drug.7 This was a multicenter, randomized, double-blind, placebo-controlled, phase 3 clinical trial that included 185 adult patients with locally advanced or metastatic CCA who were harboring an IDH1 mutation. Patients’ disease in this study had progressed following previous therapy, and patients had up to 2 previous treatment regimens for their advanced disease.8 Patients were randomized 2:1 to receive 500 mg of Tibsovo once per day or a matched placebo. Crossover from placebo to Tibsovo was allowed when patients had disease progression.8

Results from the ClarIDHy trial showed that progression-free survival was significantly improved following the administration of Tibsovo when compared to the placebo. The median overall survival times were 10.8 months for patients treated with the drug and 9.7 months for patients in the placebo group.8 Patients receiving Tibsovo displayed better disease control, with more than 50% of the patients achieving stable disease, and a favorable safety profile was observed.8

A final analysis of the overall survival with updated data on safety and quality of life deriving from the ClarIDHy study was also reported, further supporting the clinical benefit of Tibsovo.9


1. Tibsovo. Prescribing information. Servier Pharmaceuticals LLC; 2022. Accessed December 19, 2022.

2. Lavacchi D, Caliman E, Rossi G, et al. Ivosidenib in IDH1-mutated cholangiocarcinoma: clinical evaluation and future directions. Pharmacol Ther. 2022;237:108170. doi:10.1016/j.pharmthera.2022.108170

3. Cholangiocarcinoma. National Organization for Rare Disorders (NORD). Accessed December 19, 2022.

4. Dhillon S. Ivosidenib: first global approval. Drugs. 2018;78(14):1509-1516. doi:10.1007/s40265-018-0978-3

5. Study of orally administered AG-120 in subjects with advanced solid tumors, including glioma, with an IDH1 mutation. February 28, 2014. Updated August 2, 2022. Accessed December 19, 2022.

6. Lowery MA, Burris HA III, Janku F, et al. Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study. Lancet Gastroenterol Hepatol. 2019;4(9):711-720. doi:10.1016/S2468-1253(19)30189-X

7. Study of AG-120 in previously treated advanced cholangiocarcinoma with IDH1 mutations (ClarIDHy) (ClarIDHy). December 12, 2016. Updated April 13, 2022. Accessed December 19, 2022.

8. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(6):796-807. doi:10.1016/S1470-2045(20)30157-1

9. 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. 2021;7(11):1669-1677. doi:10.1001/jamaoncol.2021.3836

Reviewed by Harshi Dhingra, MD, on 12/15/2022.