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Trial Data Reveals Progression Delay in Cholangiocarcinoma with Targeted IDH1 Drug

BARCELONA – Investigators have obtained Phase III clinical trial data suggesting that a targeted treatment can delay disease progression in a molecularly defined subset of individuals with advanced cholangiocarcinoma, an aggressive bile duct cancer with poor patient outcomes.

Based on the strength of the data from the ClarIDHy study, Chris Bowden, chief medical officer at Agios Pharmaceuticals, said in a statement that the company hopes to submit a supplemental new drug application for the IDH-1 inhibitor ivosidenib (Tibsovo) as a treatment for previously treated IDH1 mutant cholangiocarcinoma by year end.

For the randomized double-blind, controlled trial, a team from the US, Spain, Korea, and the UK compared ivosidenib to placebo in 185 advanced cholangiocarcinoma patients with IDH1 mutation-positive tumors.

The participants — who had received one to two previous lines of chemotherapy in the past and fared relatively well on that treatment — were randomized two-to-one to the trial's targeted treatment arm, with 124 receiving ivosidenib and 61 receiving placebo, initially.

Ghassan Abou-Alfa, a medical oncologist and gastrointestinal cancer specialist at the Memorial Sloan-Kettering Cancer Center, presented the results at a presidential symposium here Monday at the European Society for Medical Oncology Congress. Based on the findings, he suggested that IDH1 gene testing should become standard in cholangiocarcinoma patients.

The outcomes and safety profiles so far "all support the clinical benefit of ivosidenib in patients with IDH1-mutated cholangiocarinoma," Abou-Alfa said during a briefing with reporters, suggesting that genomic testing should become the standard of care for these patients.

"Other than this drug itself, [trial results] will open the possibility for more target-specific trials in this rare indication, where little progress has been made in the last decade," he added.

As of the last data cut-off for the trial at the end of January, the use of ivosidenib increased progression-free survival to 2.7 months in the advanced cholangiocarcinoma patients with IDH1-mutant tumors — up from just 1.4 months in the trial's placebo arm.

After just six months, no patients were left on the placebo arm of the trial, due to disease progression or crossover to open-label ivosidenib, Abou-Alfa explained. At that time point, 32 percent of patients in the ivosidenib arm remained progression-free. By 12 months, 22 percent of the ivosidenib-treated cholangiocarcinoma IDH1-mutant tumors were progression-free.

In an early overall survival analysis, the average overall survival in the patients who got the IDH1 inhibitor was 10.8 months compared to 9.7 months in the placebo group. But after adjusting for patient crossover from the placebo to treatment arms — which occurred in more than half of the patients who started on placebo — the team estimated overall survival time at just six months, on average, in the placebo arm and 10.8 months in the ivosidenib arm.

The Royal Marsden NHS Foundation Trust's Ian Chau, who was not involved in the trial,

commented on the ClarIDHy findings at Monday's presidential symposium at ESMO. He noted that the model used to adjust for crossover assumes that more than half of patients have moved from the placebo arm to the treatment arm, which was the case in ClarIDHy.

However, it remains unclear whether the benefit of targeted treatment is the same before and after crossing over from placebo, Chau added. Based on the results presented so far, he also pointed to the importance of molecular testing for advanced cholangiocarcinoma patients.

Targetable alterations in that gene are estimated to occur in more than 15 percent of advanced cholangiocarcinoma cases.

Last year, the US Food and Drug Administration approved ivosidenib — in combination with a PCR-based companion diagnostic RealTime IDH1 assay from Abbott Laboratories — as a targeted treatment for adults with IDH1-mutated, relapsed, or treatment refractory acute myeloid leukemia. Prior to that, Agios inked a deal with Thermo Fisher Scientific related to the development of a sequencing-based companion diagnostic for the IDH1 inhibitor.

In the ClarIDHy trial, investigators reported that they prospectively confirmed IDH1 mutation status in the randomized patients using formalin-fixed, paraffin-embedded tumor samples profiled with the Thermo Fisher Scientific Oncomine Focus next-generation sequencing assay.