For the first time, a targeted therapy has improved outcomes in patients with cholangiocarcinoma, a rare, aggressive, and often fatal subtype of bile cancer, according to late-breaking data presented at the ESMO Congress 2019.

Ivosidenib, an oral isocitrate dehydrogenase 1 (IDH1) inhibitor, showed clinical benefit in the phase 3 ClarIDHy trial, significantly improving progression-free survival (PFS) and demonstrating a promising improved overall survival (OS) trend, according to the study. Approximately 1 in 6 patients with cholangiocarcinoma have IDH1 mutations, which result in the production of a metabolite that promotes oncogenesis. This study is the first to demonstrate clinical benefit of targeting mutant IDH1 in patients with advanced IDH1-utated cholangiocarcinoma, according to the authors.

The study included 185 patients with advanced cholangiocarcinoma and an IDH1 mutation who received either ivosidenib or a matched placebo. Patients were able to crossover from placebo to ivosidenib when their disease progressed.

According to the results, the median PFS was 2.7 months for patients treated with ivosidenib compared with 1.4 months with placebo (hazard ratio [HR] 0.37; 95% confidence interval [CI]: 0.25, 0.54, p<0.001). At 6 months, the median PFS rate was 32% with ivosidenib, whereas no patients who received placebo were free from progression at this timepoint.

Additionally, the data pointed to a trend favoring ivosidenib in OS, with a median OS of 10.8 months for ivosidenib and 9.7 months for placebo (HR 0.69, one-sided p=0.06). After adjusting the OS results to take account for 57% of patients in the placebo arm who crossed over to the ivosidenib cohort, placebo patients showed an OS of 6 months.

In terms of safety, ivosidenib was shown to be generally well tolerated. Grade 3 or higher adverse events were reported in 46% of patients on ivosidenib versus 36% of placebo patients, with no treatment-treated deaths.

In his presentation on the findings, study author Ghassan Abou-Alfa, MD, Memorial Sloan-Kettering Cancer Center, said that the findings mean that all patients with cholangiocarcinoma should be tested for an IDH1 mutation.

“Tumor mutation profiling should be a new standard for the care for patients with heterogeneous tumor type,” he explained. Abou-Alfa also indicated that future studies should investigate ivosidenib as a first-line treatment for IDH1-mutated cholangiocarcinoma, in addition to its use in combination therapy and as adjuvant therapy.

“The reported median progression-free survival may seem short and some people may question whether this is clinically meaningful,” Angela Lamarca, MD, PhD, MSc, Christie NHS Foundation Trust, said. “However, for researchers working in cholangiocarcinoma it is a breakthrough. A treatment that increases the chance of being free from progression by 30% at 6 months after starting treatment and that prolongs survival from 6 months with placebo to 10.8 months with ivosidenib, after adjusting for crossover, is definitely meaningful for our patients with cholangiocarcinoma and their families.”

Reference

Abou-Alfa GK, Mercade M, Javie M, et al. ClarIDHy: A global, phase 3, randomized double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation. Annals of Oncology. Presented at: ESMO Congress 2019. September 27-October 1, 2019. Barcelona, Spain.