Preserved IDH mutation and methylation class in vorasidenib non-responders: a report of two cases

Background The INDIGO trial recently showed that vorasidenib improves progression-free survival in patients with grade 2 IDH-mutated glioma. However, 20-25 % of patients experienced disease progression within the first year, referred to here as non-responders. This finding raises the question of whether such resistance may be linked to the selection of an IDH-wild type clone, potentially decreasing subsequent response to conventional treatments. Case Summary We present two patients in whom postoperative administration of vorasidenib following initial resection failed to prevent the progression of residual tumor. After vorasidenib discontinuation, both patients were successfully managed with a combination of conventional treatments, including new surgery, chemotherapy, and radiation therapy. Molecular analysis confirmed the preservation of the IDH mutation, MGMT status, and methylation class in the recurrent tumor in both cases. At last follow-up 3 years after vorasidenib discontinuation, disease remained stable in one patient, while the other one had recurred. Conclusions Vorasidenib does not appear to select an IDH-wild type clone that would potentially reduce the tumor’s sensitivity to standard therapies typically used in IDH-mutated glioma.