18F-DOPA-PET and advanced MRI improve treatment response assessment in IDH1/2-mutant gliomas treated with IDH inhibitors

Background: Small-molecule inhibitors targeting IDH1/2-mutant proteins (IDHi) have demonstrated benefit in IDH1/2-mutant gliomas. However, responses assessed by conventional MRI measurements are infrequent, delayed, and difficult to interpret, highlighting the need for early biomarkers of treatment benefit. Here, we investigated 3,4-Dihydroxy-6-[18F]-fluoro-L-phenylalanine PET (¹⁸F-DOPA-PET) and MRI responses in IDH1/2-mutant glioma patients receiving IDHi. Methods: IDH1/2-mutant glioma patients receiving IDHi as part of trials or expanded access programs with pre- and post-treatment MRI and ¹⁸F-DOPA-PET were included. Evaluations included 2D/3D measurements on T2-weighted FLAIR images, T1-post contrast, perfusion, and diffusion imaging for MRI, and metabolic tumor volume (MTV), total lesion glycolysis (TLG), and tumor-to-background ratios (TBRs) for ¹⁸F-DOPA-PET. Disease response evaluation using volumetric assessments, RANO 2.0 and PET RANO 1.0 criteria were compared and confronted to outcomes. Results: From 2021 to 2025, 20 patients with IDH1/2-mutant glioma (8 astrocytoma, 12 oligodendroglioma) receiving IDHi (4 ivosidenib, 16 vorasidenib) were analyzed. Significant reductions in 18F-DOPA-PET parameters including TBRmean, TBRmax, and MTV were observed in 10/20 patients, aligning with observed changes in perfusion and diffusion imaging. Nine partial responses and one complete response were identified using ¹⁸F-DOPA-PET, while both volumetric and standard 2D morphological MRI assessments indicated stable disease as best response. PET response on metabolic tumor volume (MTV) was correlated with prolonged tumor control. Conclusions: These results highlight the potential of ¹⁸F-DOPA-PET and advanced MRI sequences as valuable complements to standard RANO 2.0 MRI evaluations for assessing treatment response in glioma patients undergoing IDHi therapy.