Longitudinal PET RANO 1.0 and RANO 2.0 response assessment in vorasidenib-treated IDH -mutant gliomas: the VORAFET study

BACKGROUND: Conventional MRI may not fully reflect the biological activity of vorasidenib. PET may detect treatment-related metabolic changes before structural changes become evident on MRI. We evaluated longitudinal PET and MRI changes in patients with IDH-mutant gliomas receiving vorasidenib. METHODS: VORAFET is a longitudinal study of adults with IDH-mutant gliomas treated with vorasidenib. Eligible patients had predominantly non-enhancing WHO grade 2 or 3 gliomas, had not received prior radiotherapy or chemotherapy. The primary endpoint was longitudinal metabolic and structural imaging response according to PET RANO 1.0 and RANO 2.0. Integrated [¹⁸F]FET PET/MRI was performed at baseline and every 3 months. RESULTS: Thirty-nine patients were included; at baseline, 23 and 29 had PET and MRI-measurable disease. As best response, PET RANO 1.0 identified 2 complete and 12 partial responses, yielding an ORR of 60.9%; median time to first response was 4.5 months (range 3-12 months). RANO 2.0 showed no complete or partial responses, whereas 5 patients achieved minor response at a median of 9 months (range 6-12 months). Progressive disease occurred in 6 of 39 patients (15.4%) according to PET RANO 1.0 and in 1 of 39 (2.6%) according to RANO 2.0. Patients with PET-PD more often had subtle contrast enhancement and showed higher baseline FLAIR volume, MTV, TBRmax, and TBRmean. CONCLUSIONS: PET RANO 1.0 identified metabolic changes during vorasidenib treatment that were not always reflected by RANO 2.0 assessment. Longer follow-up is needed to clarify the relationship between PET metabolic changes and MRI findings and to determine their clinical significance.