Vorasidenib Improves PFS in Grade 2 Gliomas With Manageable Safety Profile

Grade 2 gliomas are slowly progressive, malignant brain tumors with a poor long-term prognosis, explained Ingo K. Mellinghoff, MD, FACP, during a plenary session at the 2023 American Society of Clinical Oncology Annual Meeting. Low-grade, diffuse glioma generally is first diagnosed in adults aged approximately 40 years, he said.

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“These are young patients at the heights of their professional careers, personal lives, and family obligations,” said Mellinghoff, chair of the Department of Neurology and Evnin Family Chair in Neuro-Oncology at Memorial Sloan Kettering Cancer Center in New York, New York. “The standard of care for this disease right now is 2 options: One is you watch and wait a little bit and let the tumor grow, because the tumor always grows in the absence of treatment, or you commit to radiation in the brain and chemotherapy, which does not cure and has significant toxicities.”

Because treatment does not cure the disease, many patients prefer to push treatment time out, according to Mellinghoff. “It is not a great choice to have to make,” Mellinghoff said. “Many patients, of course, prefer to push that decision out.”

Further, mutations in isocitrate dehydrogenase (IDH) 1 or 2 occur in approximately 80% and 4% of grade 2 gliomas, respectively, and are a disease-defining characteristic in the World Health Organization 2021 definition. In results from phase 1 studies, the oral, brain-penetrant, dual inhibitor of mutant (m)IDH1/2 enzymes vorasidenib (VOR; Servier) has shown a toler-able safety profile and preliminary clinical activity.

When a mutation is present in glioma, a new metabolite is made, Mellinghoff said. VOR works by binding to this mutant enzyme and turning it off, resulting in a dramatic reduction in the amount of the metabolite being made.

“This is not just an idea that this happens; we actually proved that this happened by conducting a surgical study that is separate from what I’m talking about today,” Mellinghoff said. “In that study, patients with IDH-mutated gliomas who needed surgery received this drug for several weeks, and we took out the tumors and measured the [mechanism of action] of the drug. We know for sure that the drug reduces the levels of the metabolite by over 90% while also reducing tumor cell proliferation, changing epigenetic gene expression, and so on.”

Additionally, because VOR was developed with brain cancer in mind, it has a high ability to cross the blood-brain barrier. “And that’s an important part here,” Mellinghoff said.

To investigate VOR further, researchers in the global, randomized, double-blinded, phase 3 INDIGO trial (NCT04164901) assessed VOR vs placebo in patients with residual or recurrent grade 2 glioma with an IDH1/2 enzyme mutation.

“Treatment with this precision oral therapy can reduce risk of tumor progression or death by 61% and also significantly delay the need for more toxic therapy when compared with [placebo], alongside a manageable safety profile,” Mellinghoff said. “That has potential to change the landscape of this disease.”

During the trial, patients were randomly assigned 1:1 to receive VOR at 40 mg given daily or placebo daily in 28-day cycles. Patients were then stratified by 1p19q status and baseline tumor size.

“Primary malignant brain tumors in adults are mostly diffuse gliomas, which are gliomas that infiltrate the brain or spinal cord and cause a lot of cognitive and physical disability,” Mellinghoff said. “You can think of diffuse glioma, which is 80% of all primary malignant brain cancers, in 2 big groups: There are the tumors without the IDH mutation and the tumors with the IDH mutation.”

During the INDIGO trial, key eligibility criteria for patients enrolled in the study included being 12 years or older and having a Karnofsky performance status of at least 80%, residual or recurrent grade 2 mIDH1 or mIDH2 oligodendroglioma or astrocytoma, measurable nonenhancing disease, no prior treatment for glioma with most recent surgery 1 to 5 years from being randomly assigned, and no immediate need for chemotherapy/radiation. Further, the primary end point of the trial was radiographic progression-free survival (PFS) by blinded independent radiology committee (BIRC). The key secondary end point was time to next intervention (TTNI).

“This is the first prospective, randomized phase 3 study of a targeted therapy in grade 2 mIDH glioma,” Mellinghoff said. “VOR significantly improved PFS by BIRC compared with [placebo] with a manageable safety profile.”

By the second planned interim analysis data cutoff of September 6, 2022, 331 patients were randomly assigned across 10 countries, with 168 randomly assigned to VOR and 163 to placebo. Among the 331 patients enrolled, the median age was 40.4 years (range, 16 to 71). Regarding histological subtype, 172 patients had oligodendroglioma and 159 had astrocytoma. Further, the median time from last surgery until being randomly assigned was 2.4 years.

Of the 331 patients, 226 (68.3%) remained on treat-ment (131 on VOR; 95 on placebo), with PFS by BIRC statistically significantly in favor of the VOR arm (HR, 0.39; 95% CI, 0.27-0.56; P = .000000067). The median PFS for VOR was 27.7 months and for placebo was 11.1 months.

TTNI was also statistically significant in favor of the VOR arm (HR, 0.26; 95% CI, 0.15-0.43; P = .000000019). The median TTNI for placebo was 17.8 months and was not reached for VOR. Melling-hoff additionally noted that all reported P values are 1-sided.

For the safety profile, all-grade adverse events (AEs) occurring in more than 20% of patients receiving VOR vs placebo were increased alanine aminotransferase (ALT; 38.9% vs 14.7%, respectively), COVID-19 (32.9% vs 28.8%, respectively), fatigue (32.3% vs 31.9%), increased aspartate aminotransferase (28.7% vs 8.0%), headache (26.9% vs 27.0%), diarrhea (24.6% vs 16.6%), and nausea (21.6% vs 22.7%). Further, common grade 3 or higher AEs occurring in more than 5% was increased ALT (9.6% vs 0%, respectively).

“We are really very excited about these results, and so are our patients,” Mellinghoff said. “These data demonstrate the clinical benefit of VOR in this patient population for whom chemotherapy and radiotherapy are being delayed.”

Reference

Mellinghoff IK. INDIGO: a global, randomized, double-blinded, phase 3 study of vorasidenib versus placebo in patients with residual or recurrent grade 2 glioma with an IDH1/2 mutation. Presented at: 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, IL. Accessed June 3, 2023. https://meetings.asco.org/2023-asco-annual-meeting/15047