IDH1+ cholangiocarcinoma: phase 3 results show improved PFS

New data have shown for the first time that targeted therapy can improve the outcome of patients diagnosed with advanced cholangiocarcinoma.

Results of the ClarIDHy phase 3 trial have shown that ivosidenib, an oral drug targeting the IDH1 mutation to inhibit the production of a metabolite (D-2-hydroxyglutarate) that promotes oncogenesis -expected in around 15% of advanced cholangiocarcinoma patients- significantly improved progression-free survival (PFS) with a trend to improved overall survival compared with placebo [1].

The study randomised 185 patients with advanced cholangiocarcinoma and IDH1 mutations to ivosidenib or matched placebo. Patients could crossover from placebo to ivosidenib when their disease progressed.

Median PFS was 2.7 months for patients treated with ivosidenib compared with 1.4 months with placebo (HR 0.37; 95% CI 0.25 to 0.54; P<0.001). The median PFS rate at 6 months was 32.0% with ivosidenib, while no patients randomised to placebo were free from progression.

Results showed a favourable trend in overall survival with ivosidenib. Median overall survival was 10.8 months for ivosidenib and 9.7 months for placebo (HR 0.69; one-sided P=0.06). Adjusting the overall survival results to take account of 57% of placebo patients crossing over to ivosidenib gave an adjusted overall survival of 6 months for placebo, which was significantly shorter than with ivosidenib (HR 0.46; P=0.0008).

Ivosidenib was generally well tolerated, with grade 3 or higher adverse events reported in 46% of patients on the targeted agent and 36% of those on placebo. There were no treatment-related deaths.

“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 PFS and gives a favourable trend in overall survival in patients with advanced IDH1-mutated cholangiocarcinoma,” said presenting author Dr Ghassan Abou-Alfa (Memorial Sloan-Kettering Cancer Center, New York, USA).

Commenting on the relevance of the new data, Dr Chris Verslype (University Hospital Leuven, Belgium) said: “What we see in this study is really unprecedented. We previously had no options for patients with cholangiocarcinoma who failed systemic therapy, and they had very limited survival. These are important data. There is a gain in PFS with ivosidenib that is clinically relevant for this patient population.”

Dr Verslype considered there were few limitations. Patients selected for the study had to have good performance status after previous chemotherapy, so results may not be representative of patients whose disease progresses rapidly on chemotherapy. “But it is still a strong study because of the randomisation to placebo. It showed a real effect.” The study had a high crossover rate from placebo to ivosidenib, making the overall survival endpoint difficult to assess, but he pointed out that allowing patients to crossover was important from an ethical perspective. “Additional analysis suggested a benefit in overall survival if there had been no crossover.”

1. Abou-Alfa G et al. ESMO Congress 2019. Abstract LBA10_PR.

Posted on 26 November, 201918 March, 2021