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Practice-Changing Results: Ivosidenib First Targeted Therapy to Show Benefits in Patients with Cholangiocarcinoma and IDH1 Mutation

Web Exclusives — December 27, 2019

Barcelona, Spain—Ivosidenib (Tib­sovo), an oral therapy that targets isocitrate dehydrogenase-1 (IDH1) mutation, significantly improved progression-free survival (PFS) in patients with advanced cholangiocarcinoma (CCA) and an IDH1 mutation, in a phase 3 clinical trial reported lead investigator Ghassan K. Abou-Alfa, MD, Medical Oncologist, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York City, at the ESMO Congress 2019.

Genetic Testing

“The ClarIDHy study demonstrates for the first time the feasibility and clinical benefit of targeting a molecularly defined subgroup in cholangiocarcinoma. It shows that targeting mutated IDH1 with ivosidenib significantly improves progression-free survival and gives a favourable trend in overall survival in patients with advanced IDH1-mutated cholangiocarcinoma,” said Dr Abou-Alfa.

“The findings mean all patients with cholangiocarcinoma should be tested for IDH1 mutation. Tumour mutation profiling should be a new standard for the care of patients with this heterogeneous tumour type,” he said.

A mutation in the IDH1 gene results in the production of the metabolite D-2-hydroxyglutarate that promotes oncogenesis. Approximately 15% of patients with advanced CCA have this mutation and could potentially benefit from ivosidenib.

Improved Outcomes

In the global ClarIDHy phase 3 clinical trial, the median PFS was 2.7 months for patients randomized to ivo­sidenib compared with 1.4 months for those assigned to placebo (hazard ratio [HR], 0.37; P <.001). The data are the first to show clinical benefit with targeted therapy in CCA.

A favorable trend in overall survival (OS) with ivosidenib was also observed. The median OS was 10.8 months with ivosidenib versus 9.7 months with placebo (HR, 0.69; P = .06). When the OS results were adjusted to account for the 57% of patients who crossed over to ivosidenib, the adjusted median OS was 10.8 months in the ivosidenib arm versus 6 months in the placebo arm (HR, 0.46; P = .0008).

“The significant improvement in PFS by central review, the favorable OS trend, and the tolerable safety profile all support the clinical benefit of ivosidenib in patients with IDH1-mutated CCA,” said Dr Abou-Alfa. “This pivotal trial represents a practice-changing result, where genomic testing would become the standard of care and opens the door to more target-specific trials in this rare indication, where limited progress has been made over the past decade,” he emphasized.

Study Details

In ClarIDHy, 185 patients with advanced CCA and IDH1 mutations were randomized in a 2:1 ratio to ivosidenib 500 mg orally in continuous 28-day cycles, or to matched placebo. Eligible patients had received 1 or 2 previous lines of therapy, including at least 1 regimen that contained gemcitabine (Gemzar) or 5-fluorouracil. Patients could cross over from placebo to unblinded ivosidenib with disease progression.

At 6 months, the median PFS rate was 32% with ivosidenib versus 0% with placebo, and at 12 months, it was 22% versus 0%, respectively. The disease control rate was 53% in the ivosidenib arm (including 2% partial responses and 51% stable disease rate) and 28% in the placebo arm (0% partial response, 28% stable disease).

Ivosidenib was generally well-tolerated, with grade ≥3 adverse events reported in 46% of patients receiving the targeted agent and 36% of those receiving placebo. No treatment-related deaths were reported.

Expert’s Commentary

“From my point of view, these results are practice-changing, mainly because this is the first randomized clinical trial exploring precision medicine in CCA,” commented Angela Lamarca, MD, PhD, MSc, Consultant in Medical Oncology, Christie NHS Foundation Trust, Manchester, England. “Those patients who had an IDH1 mutation were benefiting from ivosidenib, mainly in the form of PFS. We are having 22% of patients free of progression at 12 months and 32% at 6 months, with 0 patients in the placebo arm.”

The extension in OS from 6 months to 10 months when adjusted for crossover is “definitely clinically meaningful for patients with CCA who unfortunately have a very poor prognosis,” Dr Lamarca said. “When we step forward, it is important that we make sure that all our patients have access to molecular profiling, which at the moment is a challenge in some countries.”

Future studies should investigate ivosidenib as first-line treatment for patients with CCA and IDH1 mutation, in addition to its use in combination therapy and as adjuvant therapy, said Dr Abou-Alfa.

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