For decades, the management of grade 2 diffuse glioma came down to a familiar trade-off: resect what you safely can, then choose between surveillance and the delayed toxicities of radiation and chemotherapy. That calculus is changing.

“Over the last two years or so, there have been advances for the first time in the management of glioma, in which we have new treatments called targeted therapies that target the mutation,” Dr. Yoshua Esquenazi, a neurosurgeon at UTHealth Houston who operates at Memorial Hermann-Texas Medical Center, tells SurvivorNet.

Dr. Esquenazi, who completed his surgical neuro-oncology fellowship at Memorial Sloan Kettering Cancer Center, points to two converging forces: increasingly safe, aggressive resection and the arrival of IDH-targeted therapy.

“Many of these patients can live for decades,” he says.

“I generally tell them sometimes that they’ll be able to see their kids grow. And I hope we have more advances in the future.”

Classification: Molecular First, Then Grade

Gliomas arise from glial cells or their precursors, the supporting cells of the central nervous system. Unlike most solid tumors, they are not staged by spread. They are classified and graded on CNS WHO grades 1 through 4.

The 2021 WHO CNS5 classification changed how that grade is assigned.

Tumors are now graded within types rather than across them, and molecular markers are built into both classification and grading.

Adult-type diffuse gliomas fall into three types, based on IDH mutation and 1p/19q codeletion status. IDH-mutant tumors are no longer called glioblastoma, even at grade 4.

The distinction matters clinically. A grade 4 IDH-mutant astrocytoma and an IDH-wildtype glioblastoma share a grade but differ in biology and prognosis.

IDH-wildtype diffuse astrocytic tumors with certain molecular features can be classified as glioblastoma even when they look lower-grade under the microscope.

Surgery: Safer and More Complete

Maximal safe resection remains the first and most consequential intervention for lower-grade glioma. Dr. Esquenazi says the field has changed dramatically.

“[There have] certainly been a lot of advances in the surgical field because we can do these surgeries very safely and very successfully. And that was not the case many decades ago,” he says.

His own practice integrates brain mapping for awake craniotomy, stereotactic navigation, fluorescence-guided microscopy, laser ablation, and intraventricular endoscopy to improve safety and maximize resection.

For lower-grade patients, he stresses early and aggressive treatment, followed by long-term surveillance.

“They can live many years if we are aggressive and if we treat them early,” Dr. Esquenazi says.

He adds that his team monitors patients closely after surgery, and that some patients may not need additional treatment when a complete resection of the visible tumor on imaging is achieved.

IDH Inhibition Moves Into the Clinic

IDH1 and IDH2 mutations define the astrocytoma and oligodendroglioma lineages under WHO CNS5. Mutant IDH produces the oncometabolite 2-hydroxyglutarate, making it a logical therapeutic target.

“This is a somatic mutation that leads to those tumors, particularly the [IDH-]mutant astrocytoma … and the [oligodendroglioma],” Dr. Esquenazi says. “And these patients can take a pill that is taken once a day.”

In August 2024, the FDA approved vorasidenib (Voranigo, Servier) for adult and pediatric patients 12 and older with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, following surgery including biopsy, subtotal resection or gross total resection.

It was the first FDA approval of a systemic therapy for this population.

The INDIGO Data

Approval rested on the double-blind phase 3 INDIGO trial (NCT04164901), published in NEJM in 2023. The trial randomized 331 patients with residual or recurrent grade 2 IDH-mutant glioma who had received no treatment other than surgery to vorasidenib 40 mg daily or placebo. Crossover from placebo was allowed at confirmed progression.

Vorasidenib significantly improved progression-free survival compared with placebo (median 27.7 vs. 11.1 months; hazard ratio 0.39) and delayed the time to next intervention (hazard ratio 0.26). Grade 3 or higher elevations in ALT occurred in 9.6% of patients on vorasidenib versus none on placebo.

At the interim analysis, median follow-up was 14.2 months, and the primary publication did not report overall survival. Given the hepatotoxicity signal, the prescribing information calls for liver function monitoring during treatment.

Dr. Esquenazi says the practical benefit is substantial for appropriately selected patients.

“Some of the novel studies have shown that in patients with the lower grade tumors, this therapy, which is noninvasive and the side effects are actually very limited and much easier to take than chemotherapy or radiation, can potentially delay the tumor progression and in addition, can delay the necessity to do radiation therapy,” he says.

“So there has certainly been a lot of excitement in that field.”

What Comes Next

Despite ongoing progress, open questions remain: how to sequence vorasidenib with radiation and chemotherapy, its long-term effects on survival and malignant transformation, and how to select patients for early IDH inhibition versus surveillance. Vorasidenib is also being studied in combination with pembrolizumab in an early-phase trial in grade 2/3 glioma.

Dr. Esquenazi sees the targeted-therapy era as one front among several, alongside precision medicine and artificial intelligence.

“We’ve had good advances and very exciting advances in the lower[-grade] glioma population, and certainly with precision therapies with AI and a lot of the new technologies,” he says.

“I do believe that there is hope for patients, and our job is to give them the best quality of life.”