Treatment of IDH-mutant glioma in the INDIGO era

Abstract

Gliomas are the most common primary brain tumor and are uniformly lethal. Despite significant advancements in understanding the genetic landscape of gliomas, standard-of-care has remained largely unchanged. Subsets of gliomas are defined by gain-of-function mutations in the metabolic genes encoding isocitrate dehydrogenase (IDH). Efforts to exploit mutant IDH activity and/or directly inhibit it with mutant IDH inhibitors have been the focus of over a decade of research. The recently published INDIGO trial, demonstrating the benefit of the mutant IDH inhibitor vorasidenib in patients with low-grade IDH-mutant gliomas, introduces a new era of precision medicine in brain tumors that is poised to change standard-of-care. In this review, we highlight and contextualize the results of the INDIGO trial and introduce key questions whose answers will guide how mutant IDH inhibitors may be used in the clinic. We discuss possible combination therapies with mutant IDH inhibition and future directions for clinical and translational research.

Fig. 1. IDH-mutant gliomas and response to vorasidenib.

Left: Role of mutant IDH in untreated glioma tumors. Collateral vulnerabilities include druggable synthetic lethal targets of mutant IDH. Middle: Schematic of mutant IDH inhibitor treatment in IDH-mutant gliomas responsive to mutant IDH inhibition. It is unknown whether strategies that target collateral vulnerabilities conferred by mutant IDH may still be utilized effectively in these settings. Right: IDH-mutant gliomas with de novo or acquired resistance to mutant IDH inhibitors. As in mutant IDH inhibitor-sensitive IDH-mutant gliomas, tumors resistant to mutant IDH inhibition may be candidates for therapies that target collateral vulnerabilities, depending on the mechanism of action.