Update on IDH-targeting therapy

In this video, Dr Pieterjan Vanclooseter, resident in medical oncology at the University Hospital Antwerp, provides an overview of the contemporary landscape of IDH-targeting therapies in oncology.

Mutations in isocitrate dehydrogenase (IDH) genes, particularly IDH1 and IDH2, are common in several tumor types, including low-grade glioma, cholangiocarcinoma, and chondrosarcoma. These mutations lead to the accumulation of the oncometabolite 2-hydroxyglutarate, contributing to tumor development and progression. Recent clinical efforts have focused on targeting these mutations using specific IDH inhibitors.

In 2023, the INDIGO trial evaluated vorasidenib, a dual IDH1/IDH2 inhibitor, versus placebo in patients with low-grade oligodendrogliomas and astrocytomas. Subsequently, these data were complemented by the ClarIDHy and CHONQUER trials, which respectively investigated ivosidenib, a selective IDH1 inhibitor, in patients with IDH1-mutant cholangiocarcinoma or chondrosarcoma. These studies confirmed improved progression-free survival (PFS) with IDH targeting across these three tumor types. 

Interestingly, despite achieving disease control, the clinical responses to IDH inhibitors are characterized largely by disease stabilization rather than significant tumor shrinkage. In fact, complete responses are rare, and partial responses remain infrequent. As pointed out during discussions at ESMO 2025, the mechanism of action by which these agents exert their activity remains unclear.

A notable future direction involves the combination of IDH inhibitors with immunotherapy. In fact, IDH mutations create an immunosuppressive tumor microenvironment, and preclinical and early clinical findings suggest that IDH inhibition may reverse this effect, potentially enhancing immunotherapy efficacy. This approach is currently being explored in advanced glioma and could be extended to other tumor types, or treatment settings (neoadjuvant, adjuvant).