Results: Patient with cholangiocarcinoma and a somatic (tumour) IDH1 variant

A 68-year-old woman has progressed through first line of treatment for cholangiocarcinoma. Somatic (tumour) testing via a multi-target massively parallel sequencing – also called next-generation sequencing – panel has revealed a variant in the IDH1 gene at R132.

Somatic (tumour) variants of the gene IDH1, which encodes isocitrate dehydrogenase 1, are found in approximately 13% of cholangiocarcinoma.

The majority (around 70%) of these are variants at codon 132, leading to a substitution of arginine (R) for another amino acid (X), represented as p.R132X or R132X (X may be replaced with another letter representing specific amino acid).

Preclinical work supports a role for mutant IDH1 in blocking liver progenitor cells from undergoing hepatocyte differentiation and in promoting carcinogenesis.

Ivosidenib is an oral inhibitor of altered IDH1.

A multinational, randomised, double-blind phase 3 clinical trial, “ClarIDHy “, compared ivosidenib with placebo in patients with an IDH1 variant and unresectable or metastatic cholangiocarcinoma who had received at least one and no more than two lines of previous treatment.

Ivosidenib significantly improved progression free survival compared to placebo (hazard ratio = 0.37, 95% confidence interval 0.25 to 0.54, p < 0.0001).

NICE have recommended ivosidenib as an option for treating locally advanced or metastatic cholangiocarcinoma with an IDH1 p.R132 variant in adults after one or more systemic treatments.

• Ivodenisib is available via the Cancer Drugs Fund for patients who meet the eligibility criteria.
• The finding of an IDH1 somatic (tumour) variant does not have any implications for constitutional (germline) genomic testing of this patient.

For clinicians

• NHS England: National Genomic Test Directory
• NICE: Ivosidenib for treating advanced cholangiocarcinoma with an IDH1 R132 mutation after 1 or more systemic treatments

References:

• Abou-Alfa GK, Macarulla T, Javle MM and others. ‘Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study’. The Lancet Oncology 2020: volume 21, issue 6, pages 796–807. DOI: 10.1016/S1470-2045(20)30157-1

For patients

• AMMF – The Cholangiocarcinoma Charity: Molecular profiling and targeted therapies
• Cholangiocarcinoma Foundation: Biomarker testing information