In what circumstances would you consider use of IDH inhibitors in high-grade astrocytomas?

Please forgive me for the length and directness of my response, but I believe it is important to first go over the INDIGO trial and explain why, in my opinion, it was a highly questionable study, with multiple significant methodological flaws and dubious evidence of Vorasidenib's efficacy.

INDIGO trial was presented as a phase 3 RCT aimed at evaluating the efficacy of vorasidenib in patients with residual or recurrent grade 2 IDH-mutant oligodendroglioma or astrocytoma. However, anyone familiar with phase 3 RCTs would recognize that these trials are typically designed to compare a new treatment to the standard of care, rather than to a placebo, as was done in this case.

INDIGO trial specifically included patients with gross macroscopic diseas...

INDIGO has stirred up the blues, as can clearly be seen by the responses here. The issues raised are extremely valid and rather than rehash the critical points already brought out by both Drs. @Dr. First Last and @Dr. First Last, let me direct the readers to a very detailed summary paper that contextualizes these issues in greater detail: Kotecha et al., PMID 38833641.

For patients with grade 3 IDH-mutant glioma, adjuvant therapy (after maximal safe resection) with RT followed by TMZ or PCV is generally considered the standard-of-care for all patients. Institutional practice varies regarding the choice of TMZ or PCV due to an often greater toxicity profile with PCV and the lack of modern randomized clinical trial data directly comparing the efficacy of TMZ vs. PCV in this setting. The recently published INDIGO trial investigated Vorasidenib for low-grade gliomas and demonstrated a clinical benefit from the mIDH1/2 inhibition, adding new options for LGG patients. Vorasidenib (Vora) and Ivosidenib (Ivo) are oral medications that target the mutant IDH1 and IDH2 protein thus inhibiting its function and thereb...