Ivosidenib for cholangiocarcinoma and acute myeloid leukaemia

Background:
The gene product of isocitrate dehydrogenase-1 (IDH1) is an enzyme with a central role in cellular metabolism and DNA repair.¹

Cholangiocarcinoma is a rare, aggressive tumour, with a poor prognosis. Median survival in advanced disease is less than 12 months, with 5-year survival rates less than 10%.² IDH1 variations occur in up to approximately 20% of patients with cholangiocarcinoma.²

Acute myeloid leukemia (AML) is a heterogenous myeloid cancer. It mainly affects older people, who are often unable to tolerate the intensive cancer therapies required for treatment.³ Mutant IDH1 is present in 6 to 10% of patients with AML, offering a target for potentially lower intensity treatment.³

Ivosidenib is a first-in-class, oral, potent, targeted small-molecule inhibitor of mutant IDH1 with clinical activity in solid and haematological malignancies.^2,3

Mechanism of action:
Ivosidenib inhibits certain mutant alleles of the IDH1 gene, including IDH1 R132.¹ It intervenes in the IDH1 metabolic pathway to prevent accumulation of 2-hydroxyglutarate (an onco-metabolite that promotes oncogenic transformation of cells, cell proliferation and metastasis) in plasma and bone marrow.^1,2,4

Clinical trials:
For IDH1-mutated cholangiocarcinoma , the evidence supporting the use of ivosidenib comes predominantly from the phase 3 ClarIDHy trial.^2,5 Patients who had received at least one, and up to two, prior systemic therapies for advanced disease,were randomised to receive ivosidenib (n=126) or placebo (n=61). After a median follow-up of 6.9 months, the median progression-free survival was 2.7 months in the ivosidenib group and 1.4 months with placebo (p<0.0001).⁵ Median overall survival was 10.3 months with ivosidenib and 7.5 months with placebo (p=0.09).²

For refractory or relapsed AML with an IDH1 mutation, the efficacy of ivosidenib monotherapy was established by a single-arm phase 1 trial.⁶ In the primary efficacy population (125 patients), there was an overall response rate of 41.6%; median overall survival was 8.8 months.⁶

For newly diagnosed IDH1-mutated AML, ivosidenib monotherapy was evaluated in a single-arm phase 1 trial involving 34 patients (median age 76.5 years) who had comorbidities precluding the use of intensive chemotherapy.⁷ The overall remission rate was 42.4%, with a median overall survival of 12.6 months, at 23.5 months median follow-up.⁷ The efficacy of ivosidenib in combination with azacitidine* was established in the phase 3 AGILE study,³ in which patients with newly diagnosed IDH1-mutated AML were randomised to receive azacitidine and ivosidenib (n=72) or azacitidine and placebo (n=74). Complete remission occurred in 47% of patients with the combination and 15% with placebo (p<0.001).³ At longer term follow-up (median 28.6 months), this response was maintained. Median overall survival was 29.3 months for the combination and 7.9 months for placebo (p<0.0001).⁸

Adverse effects:
Commonly reported adverse effects include nausea and vomiting, abdominal pain, diarrhoea, fatigue, cough, anaemia, headache and anorexia.^2-10

In studies with cholangiocarcinoma, ivosidenib-related serious adverse effects included hyponatraemia, hyperbilirubinaemia, cholestatic jaundice and pleural effusion.^2,5 QT interval prolongation was reported in 8% of patients receiving ivosidenib.^2,5

In AML studies, adverse effects were similar but, as expected, serious adverse effects reflected the nature of the disease and use with azacitidine. Most common severe adverse effects (grade 3 or higher) were febrile neutropenia, anaemia, neutropenia, thrombocytopenia and pneumonia. Differentiation syndrome, a potentially life-threatening condition associated with rapid proliferation and differentiation of myeloid cells, was reported in up to 14% of patients.^3,6-8 Guillain–Barré syndrome has occurred uncommonly in patients with haematological malignancies.⁴

Precautions:
Perform an electrocardiogram (ECG) at baseline, weekly for 3 weeks after commencing treatment, then at least monthly during treatment to check for QT interval prolongation.⁴ Concomitant QT-prolonging drugs, such as fluoroquinolones, azole antifungals and antiarrhythmics, may further increase the risk. More frequent ECGs are recommended for patients at higher risk of QT prolongation.^4,9,10 Any QT interval abnormalities should be promptly managed with dose interruption or reduction as required.^9,10

In AML, monitoring for differentiation syndrome is paramount. A full blood count should be measured at baseline, at least weekly in the first month of therapy, fortnightly for the second month, then at least monthly thereafter.¹⁰ For cholangiocarcinoma, baseline then monthly monitoring of full blood count is sufficient.⁹

Concurrent use with strong cytochrome P450 (CYP) 3A4 inhibitors requires dose reduction and increased vigilance for toxicity.^4,9,10 Avoid co-administration of strong CYP3A4 inducers.⁴

Dosage and administration:
The recommended dose is ivosidenib 500 mg orally once daily until disease progression or unacceptable toxicity.^4,9 Administration with a high-fat meal should be avoided, as it increases ivosidenib absorption.⁴

Dose reduction for ivosidenib is recommended in patients with low white blood cell, neutrophil or platelet counts. Caution is needed with estimated glomerular filtration rate less than 30 mL/min/1.73 m², as ivosidenib has not been studied in this setting. No dose modification is required for mild-to-moderate hepatic dysfunction but ivosidenib has not been studied in severe hepatic dysfunction.^4,9,10

In AML, ivosidenib can be combined with 7 days of intravenous or subcutaneous azacitidine every 28 days.^3,4,10

Use in pregnancy and lactation:
Ivosidenib can potentially cause fetal harm. Use of barrier contraception is recommended, as ivosidenib may decrease systemic concentrations of hormonal contraceptives.⁴ Although definitive data are lacking, breastfeeding should be discontinued during treatment and for at least 1 month after the last dose of ivosidenib.⁴

Place in therapy:
As testing for IDH1 variants in solid and haematological malignancies becomes more routine, so will the use of IDH1 inhibitors such as ivosidenib.

Currently, ivosidenib is reserved for patients who have previously received other therapies and have disease progression or are not suitable for more standard treatments.

In locally advanced or metastatic IDH1-mutated cholangiocarcinoma, ivosidenib has a role after progression on traditional fluorouracil-based therapies. The potential to use ivosidenib in selected patients with newly diagnosed disease requires further exploration.

In IDH1-mutated AML, ivosidenib can be used as monotherapy in patients who have relapsed or have refractory disease. In newly diagnosed patients who are deemed not fit to receive traditional induction therapies, ivosidenib can be used in combination with azacitidine. Ivosidenib monotherapy can also be considered for newly diagnosed patients unable to tolerate a combination regimen. A barrier to the routine use of ivosidenib for AML is that, in contrast to cholangiocarcinoma, at the time of writing, it is not funded by the Pharmaceutical Benefits Scheme and the cost is likely to be prohibitive for routine use.

* Azacitidine is an analogue of cytidine, one of the nucleosides that make up nucleic acids. When azacitidine is incorporated into DNA it inhibits DNA methyltransferase, leading to hypomethylation, and has a direct cytotoxic effect on abnormally proliferating cells.

This new drug comment was finalised on 09 December2025. It was prepared by John Coutsouvelis, Lead Clinical Pharmacist, Cancer Program and Medical Specialties, Alfred Health and Adjunct Senior Clinical Lecturer, Centre for Medicine Use and Safety, Monash University, Melbourne.

At the time this new drug comment was prepared, the Australian Public Assessment Report (AusPAR) was available from the Therapeutic Goods Administration. The sponsor did not provide the Clinical Evaluation Report.

 

References

1. Therapeutic Goods Administration. Australian Public Assessment Report for Tibsovo. Department of Health, Disability and Ageing; 2024. [cited 2025 Nov 20]
2. Zhu AX, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, 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;7:1669-77.
3. Montesinos P, Recher C, Vives S, Zarzycka E, Wang J, Bertani G, et al. Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia. N Engl J Med 2022;386:1519-31.
4. Therapeutic Goods Administration. Australian Product Information - TIBSOVO ivosidenib 250 mg film-coated tablet bottle. Department of Health, Disability and Ageing; 2023. [cited 2025 Nov 20]
5. Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2020;21:796-807.
6. DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, et al. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N Engl J Med 2018;378:2386-98.
7. Roboz GJ, DiNardo CD, Stein EM, de Botton S, Mims AS, Prince GT, et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood 2020;135:463-71.
8. Montesinos P, Marchione DM, Recher C, Heuser M, Vives S, Zarzycka E, et al. Long-term results from the AGILE study of azacitidine plus ivosidenib vs placebo in newly diagnosed IDH1-mutated AML. Blood Adv 2025;9:5177-89.
9. eviQ. Biliary and gallbladder advanced ivosidenib 2025 V.1. Cancer Treatments Online. Cancer Institute NSW; 2025. [cited 2025 Dec 3]
10. eviQ. Acute myeloid leukaemia azacitidine and ivosidenib. Cancer Treatments Online. Cancer Institute NSW; 2024. [cited 2025 Dec 3]

 

The new drug comments in Australian Prescriber are prepared by the editors and reviewed by the subject matter experts. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. Before new drugs are prescribed, it is important that more detailed information is obtained from the approved product information, a medicines information centre or some other appropriate source.

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