Ivosidenib in second-line improves OS in IDH1-mutant cholangiocarcinoma

Presented by

Dr Andrew Zhu, Harvard Medical School, USA

Conference

ASCO GI 2021

Trial

Phase 3, ClarIDHy

The final overall survival (OS) analysis of the phase 3 ClarIDHy trial demonstrated that oral ivosidenib therapy achieved a 21% reduction in second-line in the risk of death in patients with IDH1-mutant cholangiocarcinoma compared with placebo.

Approximately 13% of patients with intrahepatic cholangiocarcinoma have somatic mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1), which confers a poor clinical outcome. Dr Andrew Zhu (Harvard Medical School, USA) presented the final OS analysis of the international phase 3 ClarIDHy study (NCT02989857), which tested the efficacy and safety of ivosidenib, oral, first-in class, oral small molecule IDH1 inhibitor, in patients with previously treated IDH1-mutant cholangiocarcinoma [1].

Patients were randomised 2:1 to receive 500 mg ivosidenib daily (n=126) or placebo (n=61). Crossover from the placebo arm to ivosidenib was allowed upon radiographic progression; with the longer follow-up, 70.5% of patients had crossed over to receive ivosidenib. The primary endpoint of the trial was progression-free survival (PFS) by blinded independent review; key secondary end points were OS, objective response rate, PFS by local review, safety and tolerability, pharmacokinetics and pharmacodynamics, as well as health-related quality-of-life. The primary endpoint was previously met; median PFS 2.7 months in the ivosidenib arm versus 1.4 months in the placebo arm (HR 0.37; 95% CI 0.25–0.54, P<0.0001) [2].

The presentation at ASCO GI focused on the updated OS results, which showed that the median OS was 10.3 months in patients who received ivosidenib compared with 7.5 months for those who received placebo (HR 0.79; 95% CI 0.56-1.12; 1-sided P=0.093). The 6-month OS rates were 69% and 57% for ivosidenib and placebo, respectively, and 43% and 36% at 1 year. Adjusting for crossover to ivosidenib showed that the median OS for patients in the placebo arm was 5.1 months (HR 0.49; 95% CI 0.34-0.70; P <0.0001).

Regarding safety, updated results showed that the most common treatment-emergent adverse effects (AEs) in the total ivosidenib and placebo groups comprised of nausea (38.0% vs 28.8%), diarrhoea (33.1% vs 16.9%), fatigue (28.9% vs 16.9%), abdominal pain (22.3% vs 15.3%), cough (21.7% vs 8.5%), decreased appetite (21.7% vs 18.6%), ascites (19.9% vs 15.3%), vomiting (19.9% vs 18.6%), and anaemia (18.1% vs 5.1%). Grade 3 or higher treatment-emergent AEs were seen in 53% of ivosidenib-treated patients, which includes those who also crossed over from placebo, compared with 37.3% for placebo-treated patients. The most common grade 3 or higher treatment-emergent AEs reported in the ivosidenib and placebo groups, respectively, were ascites (9.0% vs 6.8%, respectively), blood bilirubin increase (5.4% vs 1.7%), and anaemia (7.2% vs 0%).

Dr Zhu concluded: “The ClarIDHy study represents the first phase 3 study of a targeted, oral therapeutic with a noncytotoxic mechanism of action in advanced IDH1-mutant cholangiocarcinoma. Along with a tolerable safety profile and supportive quality of life, these final efficacy results demonstrate the clinical benefit of ivosidenib in this patient population, for which there is an urgent need for new therapies.”

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