Vorasidenib may be chemo–RT-sparing in certain low-grade gliomas

The oral drug vorasidenib delays disease progression compared with placebo in patients with residual or recurrent grade 2 gliomas harbouring an isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) mutation in the phase III INDIGO trial.

Median progression-free survival (PFS) was 16.6 months longer with vorasidenib (27.7 months vs 11.1 months with placebo), with a hazard ratio (HR) for progression or death of 0.39 (p<0.001).

Additionally, vorasidenib was associated with a significantly longer time to next anticancer therapy such as chemotherapy and radiation therapy (RT; p<0.001), reported study author Dr Ingo Mellinghoff from Memorial Sloan Kettering Cancer Center in New York, US at ASCO 2023.

Vorasidenib is a potent, reversible, brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes that has shown preliminary activity in IDH-mutant glioma. With the INDIGO findings, experts said the drug could break the 20-year gap in treatment advances for IDH-mutant low-grade glioma, which although slowly progressive has a poor long-term prognosis.

“With vorasidenib, tumour growth may be controlled, and patients who typically have long-term survival can be spared of chemotherapy and radiotherapy which can be associated with significant toxicities,” Mellinghoff exclaimed.

Sign of efficacy

Patients in INDIGO were between 12 and 80 years old, with residual or recurrent grade 2 IDH1- or IDH2-mutant glioma, and had no previous treatments other than surgery. They received vorasidenib 40 mg once daily (n=168) or placebo (n=163) in 28-day cycles. Median PFS by blinded independent central review was the primary endpoint. Time to the next anticancer therapy was the key secondary endpoint. Crossover to vorasidenib was allowed in case of disease progression. Safety was also assessed. [ASCO 2023, abstract LBA1]

At a median follow-up of 14.2 months, 226 patients (68.3 percent) remained on treatment (131 with vorasidenib, 95 with placebo). “Vorasidenib reduced the risk of tumour progression by 61 percent,” Mellinghoff said during the media briefing. “This is a significant sign of efficacy, with the potential to change the IDH-mutant glioma landscape.”

“Additionally, patients generally tolerated the drug well,” he continued. “Only aminotransferase elevations and diarrhoea occurred more frequently with the drug compared with placebo.”

The findings were simultaneously published in a peer-reviewed journal. [N Engl J Med 2023;doi:10.1056/NEJMoa2304194]

Practice-changing results

ASCO discussant Dr Rimas Vincas Lukas from the Malnati Brain Tumor Institute at Northwestern University in Chicago, Illinois, US described the findings as practice-changing.

“IDH-mutated tumours have a very high incidence of seizure activity, and if we look at preclinical models, we can see that vorasidenib can help decrease seizure activity,” he said.

Vorasidenib received fast-track designation from the US FDA in March for IDH+ low-grade glioma. A phase I trial of vorasidenib, in combination with pembrolizumab, for grade 2/3 glioma is ongoing. [https://classic.clinicaltrials.gov/ct2/show/NCT05484622]