Isocitrate dehydrogenase (IDH)-status of gliomas is a well-recognized prognostic indicator of outcomes. In fact, in recent years it has come to define molecular subtypes of gliomas. What’s an even more desirable victory to achieve with understanding this pathway? That’s right, a targeted therapeutic. In the double-blind phase 3 INDIGO trial 331 patients with recurrent or residual grade 2 IDH-mutant glioma after treatment with surgery alone were randomized to oral vorasidenib, an inhibitor of mutant IDH1 and IDH2 enzymes, versus placebo. You might be thinking to yourself, maybe I missed the standard of care arm with chemoradiation that results in survival times measured in years? Well, the authors pulled the old switcheroo and designed the study to include only patients who were candidates for watch-and-wait after surgery. In other words, INDIGO tested whether vorasidenib could prolong the time until progression and further definitive treatment. Compared to placebo, vorasidenib significantly prolonged median PFS from 11 → 28 months. Vorasidenib also prolonged the time to initiation of next-line therapy. At 24 months, 73% of patients on watch-and-wait required treatment compared to just 16.6% on vorasidenib. The most apparent grade 3+ toxicity attributable to vorasidenib was a rise in ALT which occurred in 10% of patients. In conclusion, treatment with vorasidenib in patients with IDH-mutated grade 2 glioma delays time to further treatment compared to no treatment at all. But more importantly, INDIGO demonstrates that vorasidenib is active against IDH-mutated gliomas and may help further improve outcomes for this tumor type. | Mellinghoff, N Engl J Med 2023
