Vorasidenib Significantly 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, chair of the Department of Neurology and incumbent of the Evnin Family Chair in Neuro-Oncology at Memorial Sloan Kettering Cancer Center, during a plenary session at the American Society of Clinical Oncology 2023 Annual Meeting. Low-grade, diffuse glioma generally affects adults aged approximately 40 years, according to Mellinghoff.

Credit: ibreakstock - stock.adobe.com

“These are young patients at the heights of their professional careers, personal lives, and family obligations,” Mellinghoff said. “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 phase 1 studies, the oral, brain-penetrant, dual inhibitor of mutant (m)IDH1/2 enzymes vorasidenib (VOR; Servier) has shown a tolerable safety profile and preliminary clinical activity.

When a mutation is present in glioma, a new metabolite is made, according to Mellinghoff. 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 gliomas who need surgery receive 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 vorasidenib further, researchers in the global, randomized, double-blinded, phase 3 INDIGO trial (NCT04164901) assessed vorasidenib vs placebo (PBO) in patients with residual or recurrent grade 2 glioma with an IDH1/2 mutation.

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

During the trial, patients were randomized 1:1 to receive VOR at 40 mg given daily or PBO 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 include being 12 years of age or older, KPS over 80, residual or recurrent grade 2 IDH1m or IDH2m oligodendroglioma or astrocytoma, measurable non-enhancing disease, no prior treatment for glioma with most recent surgery 1-5 years from randomization, and no immediate need of chemotherapy/radiation. Further, the primary endpoint of the trial was radiographic progression-free survival (PFS) by blinded independent radiology committee (BIRC). The key secondary endpoint 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 PBO with a manageable safety profile.”

By the second planned interim analysis data cutoff of September 6, 2022, 331 patients were randomized across 10 countries, with 168 randomized to VOR and 163 to PBO. Among the 331 patients enrolled, the median age was 40.4 years (range 16 to 71), and median KPS =100 was 53.5%. For histological subtype, 172 patients had oligodendroglioma and 159 had astrocytoma. Further, the median time from last surgery until randomization was 2.4 years.

Of the 331 patients, 226 (68.3%) remained on treatment (131VOR; 95PBO), with PFS by BIRC statistically significantly in favor of the VOR arm (HR, 0.39; 95% CI, (0.27, 0.56); P=0.000000067). The median PFS for VOR was 27.7 months and for PBO 11.1 months.

TTNI was also statistically significant in favor of the VOR arm (HR, 0.26; 95% CI, (0.15, 0.43); P=0.000000019). The median TTNI for PBO was 17.8 months, and was not reached for VOR. Mellinghoff additionally noted that all reported P values are one-sided.

For the safety profile, all-grade adverse events (AEs) occurring in more than 20% of patients receiving VOR vs PBO were alanine aminotransferase increased (38.9% vs 14.7%, respectively), COVID-19 (32.9% vs 28.8%, respectively), fatigue (32.3% vs 31.9%, respectively), aspartate aminotransferase increase (28.7% vs 8.0%, respectively), headache (26.9% vs 27.0%, respectively), diarrhea (24.6% vs 16.6%, respectively), nausea (21.6% vs 22.7%, respectively). Further, common grade 3 or higher AEs occurring in more than 5% was ALT increased (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 in Chicago, IL at press conference on June 3, 2023. Accessed June 3, 2023. https://meetings.asco.org/2023-asco-annual-meeting/15047.