Novel IDH1/2 Inhibitor Shows 'Dramatic Effect' in Low-Grade Glioma

CHICAGO -- Oral vorasidenib monotherapy significantly improved progression-free survival (PFS), and delayed the time to next therapy, in patients with mutated, low-grade glioma, according to an interim analysis of the INDIGO trial.

Among 331 patients with grade 2 isocitrate dehydrogenase (IDH)-mutant glioma, who received no prior treatment other than surgery, those randomly assigned to receive vorasidenib -- an investigational dual inhibitor of mutant IDH 1/2 enzymes -- experienced a PFS improvement of more than 16 months versus patients on placebo (27.7 months vs 11.1 months, HR 0.39 for disease progression or death, 95% CI 0.27-0.56, P<0.0001), reported Ingo Mellinghoff, MD, of Memorial Sloan Kettering Cancer Center in New York City. Results were simultaneously published in the New England Journal of Medicine.

"A treatment with an oral precision medicine therapy can reduce the risk of tumor progression by 61%," Mellinghoff said during a press briefing at the American Society of Clinical Oncology (ASCO) annual meeting. "That is, we think, a significant sign of efficacy that has the potential to change the landscape in this disease."

He also reported that the median time to next intervention was not reached with vorasidenib compared with 17.8 months with placebo (HR 0.26, 95% CI 0.15-0.43, P<0.001). And the likelihood of not receiving a next treatment intervention by 18 months was 85.6% (95% CI, 77.8 to 90.8) in the vorasidenib group versus 47.4% (95% CI 35.8-58.2) in the placebo group. By 23 months, it was 83.4% (95% CI 74.0-89.6) and 27.0% (95% CI 7.9-50.8), respectively.

"So, that's an even more dramatic effect ... in pushing out the time when they need the next therapy," Mellinghoff said.

Subgroup analyses of PFS and time to the next intervention favored vorasidenib across most subgroups, although the authors pointed out that "[t]he results in some subgroups should be interpreted with caution because of the small number of events."

Regarding safety, Mellinghoff and colleagues reported that vorasidenib was associated mainly with low-grade toxic effects, with adverse events (AEs) grade ≥3 seen in 22.8% of patients on vorasidenib versus 13.5% on placebo.

The most common grade ≥3 AEs were liver related, with increased alanine aminotransferase occurring in 9.6% of patients in the vorasidenib group and none in the placebo group. Other ≥3 AEs that occurred more frequently with vorasidenib included increased aspartate amino aminotransferase level (4.2% versus none with placebo) and an increased γ-glutamyltransferase level (3.0% and 1.2%, respectively).

AEs that led to the discontinuation of either agent occurred in 3.6% of patients in the vorasidenib group and in 1.2% in the placebo group. AEs leading to dose reduction occurred in 10.8% and 3.1%, respectively. Treatment interruption due to AEs occurred in 29.9% and 22.7%, respectively.

Mellinghoff pointed out that radiation therapy and chemotherapy have become the standard of care for the postoperative treatment of patients with low-grade glioma considered to be at risk for disease progression.

However, he noted, this therapeutic option is not curative and has significant toxicity, leading some patients to avoid immediate adjuvant chemotherapy by choosing a watch-and-wait strategy in order to delay long-term toxic effects, particularly those neurocognitive effects that can lead to memory loss and functional decline.

Furthermore, delaying this toxic therapy is particularly important for these patients since they are younger and more active, he said. In INDIGO, median age was 40.5 in the vorasidenib group and 39 in the placebo group.

ASCO discussant Glenn Lesser, MD, of Wake Forest Baptist Health in Winston-Salem, North Carolina, noted that the relative youth of these patients, combined with the toxicity of standard therapy and the prospect that it prolongs survival at the risk of neurocognitive damage, "is a perfect recipe for really decimating people in the prime of their life, their most productive years."

"As you can see, the results [of INDIGO] are quite striking and highly statistically significant, and more importantly they are clinically very, very significant and important," he observed. "The results of the study suggest that in selected patients with IDH-mutant, low-grade gliomas, we can potentially delay the use of these toxic chemotherapies and radiation, maybe for years, if not many years, and as a result delay long-term toxicities of those therapies in a group of patients who are typically experiencing long-term survival."

INDIGO was a double-blind, placebo-controlled, phase III study done in 10 countries. Patients were randomized to receive a daily oral dose of vorasidenib or placebo in 28-day cycles. About 60% of those in the vorasidenib group were male versus about 53% in the placebo group. Most patients were in North America.

Of the 331 patients, 172 had oligodendroglioma, and 159 patients had astrocytoma. All of the patients in the study had undergone previous brain-tumor surgery, with the median time from the last surgery until randomization of 2.5 years in the vorasidenib group and 2.2 years in the placebo group.

Vorasidenib was assigned fast track designation by the FDA in March, according to developer Servier. In a press release, the company said it's working with the agency to determine a timeline for submitting a new drug application for vorasidenib in glioma.