Voranigo (vorasidenib)

P1, N=20, Not yet recruiting, Institut de Recherches Internationales Servier (I.R.I.S.)

P=N/A, N=150, Not yet recruiting, iOMEDICO AG

P1, N=28, Recruiting, Institut de Recherches Internationales Servier (I.R.I.S.)

P1, N=28, Recruiting, Institut de Recherches Internationales Servier (I.R.I.S.)

Inhibiting IDH mutations with vorasidenib lowers D-2HG and is beneficial to patients. Other drugs like ONC201 and metformin can metabolically suppress oncogenic chromatin states in pediatric gliomas. This dynamic cross talk between metabolism and epigenetics not only underpins tumor biology but also presents opportunities for innovative therapeutic strategies.

This review will highlight the molecular and genetic underpinnings of these tumors and how targeted therapeutic strategies led to the US Food and Drug Administration's approvals of combination therapy with dabrafenib and trametinib for pediatric patients with BRAF V600E mutant low-grade glioma; tovorafenib, a pan-RAF inhibitor, for pediatric BRAF mutant glioma; and vorasidenib, an inhibitor of mutant IDH1/2 enzymes, for patients with mutant IDH low-grade glioma. Integration of these targeted therapies into currently accepted treatment paradigms remains to be fully understood, along with the long-term impact on patient quality of life and prognosis.

Vorasidenib reduced tumour growth rate and improved seizure control compared with placebo, with no observed negative effects on HRQOL or neurocognition. Additional follow-up supported the robustness of progression-free survival and time to next intervention in patients with grade 2 IDH1/2-mutant diffuse glioma. These findings support the use of vorasidenib in patients with grade 2 IDH1/2-mutant gliomas who only had surgical intervention and are not in immediate need of radiotherapy or chemotherapy.

P3, N=408, Not yet recruiting, Alliance for Clinical Trials in Oncology

Selective inhibitors like ivosidenib (AG-120) and enasidenib (AG-221), targeting mutant IDH1 and IDH2 respectively, block 2- HG production and induce differentiation, achieving clinical success - particularly in AML...In response, novel approaches have emerged, such as covalent inhibitors like LY3410738, which irreversibly bind mutant residues, and dual inhibitors like vorasidenib (AG-881), which act on both IDH1 and IDH2 mutations and penetrate the blood-brain barrier for treating solid tumors...We underscore that discovering new antitumor compounds targeting IDH requires a collaborative effort across biomedical fields. These advancements aim to overcome resistance, broaden therapeutic options, and improve the effectiveness of IDH-targeted treatments.

It highlights the potential of vorasidenib for seizure management and the value of F-DOPA PET for early treatment assessment. Further studies are required to evaluate long-term seizure control and potential reduction of ASM in IDH-mutant low-grade gliomas treated with vorasidenib.

Vorasidenib, which suppresses D-2HG production, is the first precision therapy to be approved for IDHm glioma patients. We show that PHGDH-driven restoration of D-2HG production mediates intrinsic resistance to vorasidenib in IDHm gliomas. Importantly, deuterium metabolic imaging of D-2HG production from diethyl-[3,3'- 2 H]-α-ketoglutarate enables non-invasive assessment of resistance in IDHm gliomas.

PFS was considered an appropriate endpoint for this disease considering the long natural history and the randomized design allowed for interpretation of the treatment effect in this rare malignancy. This was the first FDA approval of a targeted therapy for IDH-mutant, Grade 2 gliomas.