Ivosidenib on the PBS

Ivosidenib has recently been added to the Pharmaceutical Benefits Scheme (PBS) for the treatment of locally advanced or metastatic cholangiocarcinoma. Eligibility requires the presence of an IDH1 R132 mutation and prior treatment with systemic therapy.

Isocitrate dehydrogenase (IDH) is a key enzyme in cellular metabolism, catalysing the rate-limiting step in the citric acid cycle. Mutations in the genes encoding IDH, particularly the IDH1 and IDH2 isoforms, are implicated in several malignancies. Mutant IDH1 has altered enzymatic function, causing it to produce 2-hydroxyglutarate, an oncometabolite that can disrupt several enzymes involved in cellular growth and differentiation.

Ivosidenib is a potent inhibitor of mutated IDH1. Its efficacy and safety were evaluated in a clinical study involving patients with previously treated IDH1-mutant cholangiocarcinoma. Ivosidenib was associated with a significant improvement in median progression-free survival (2.7 months [95% CI 1.6–4.2]) compared to placebo (1.4 months [95% CI 1.4–1.6]). The most common adverse events were low-grade diarrhoea, nausea, and fatigue.

The recommended dose of ivosidenib is 500 mg once daily, continued until disease progression or unacceptable toxicity. Tablets may be taken with or without food, but should not be taken with a high fat meal. As ivosidenib is primarily metabolised by CYP3A4, co-administration with strong CYP3A4 inhibitors should be avoided. If unavoidable, dose reduction is required. Ivosidenib may prolong QTc interval and patients should be monitored closely during therapy. Concurrent use of other QTc-prolonging medications should also be avoided.