Vorasidenib Breaks Through as the First Systemic Therapy for Select Patients With Glioma

The introduction of vorasidenib (Voranigo) to the IDH1/2-mutant glioma treatment paradigm fills an unmet need for this patient population with a tolerable, targeted therapy, although patient characteristics and preferences should play a role in decision-making surrounding this agent, according to Seema Nagpal, MD.

On August 6, 2024, the FDA granted approval to vorasidenib for the treatment of adult and pediatric patients at least 12 years of age with grade 2 oligodendroglioma or astrocytoma with a susceptible IDH1 or IDH2 mutation who have undergone surgery including biopsy, sub-total resection, or gross total resection. This regulatory decision was supported by findings from the phase 3 INDIGO trial (NCT04164901), in which, at a median follow-up of 14.0 months (IQR, 10.1-17.9) for the vorasidenib arm (n = 168) and 14.3 months (IQR, 10.0-18.1) for the placebo arm (n = 163), the median progression-free survival (PFS) was 27.7 months (95% CI, 17.0-not estimated) with vorasidenib vs 11.1 months (95% CI, 11.0-13.7) with placebo (HR, 0.39; 95% CI, 0.27-0.56; P < .001).1,2

“It’s exciting for patients and treating clinicians to have access to a drug that’s tolerated and new,” Nagpal said in an interview with OncLive®.

In the interview, Nagpal, a clinical professor of neurology and neurological sciences at Stanford University in California, discussed the significance of this approval, key findings from the INDIGO trial, and considerations for the optimal use of vorasidenib given the broad patient population that this agent is indicated for.

OncLive: What is the significance of this approval?

Nagpal: [This regulatory decision] represents the first approval [of a systemic] medication for patients with low-grade glioma in more than 20 years, and [vorasidenib] is the first truly targeted therapy for a large population of patients with glioma.

Please describe the key efficacy findings from the INDIGO trial.

[The investigators] did a nice job of choosing the end points for this study. [The primary end point was] a traditional end point, PFS measured by magnetic resonance imaging, and a correlated clinical exam. A secondary end point was time to the next intervention, which from a practical level [is defined as] the period until we decide we need to do something else for the patient, such as take them to surgery or [administer] radiation or new chemotherapy. The choice of end points was nice for this population of patients.

[This trial showed] a clear PFS benefit for patients receiving vorasidenib vs placebo, with a median [PFS] of 27.7 months in the vorasidenib arm compared with 11.1 months in the placebo arm. [The median] time to next intervention was not reached in the vorasidenib arm and was 17.8 months in the placebo arm. Those curves divide nicely.

What is the safety profile of vorasidenib?

In general, compared with the chemotherapies we’re used to using, and even compared with the TKIs we might be used to using in [patients with] brain metastases, [vorasidenib] is a well-tolerated drug. Most patients [in INDIGO] didn’t have a major adverse effect [AE]. The most common high-grade AEs were increased aspartate aminotransferase and alanine aminotransferase, and 3.6% of patients [in the vorasidenib arm] had to stop the drug due to AEs. However, for the most part, [patients had] low levels of other significant AEs. There is some fatigue associated with the drug, as well as a bit of headache and some nausea, but [those AEs were mostly] grade 1, so they did not interfere with patients’ ability to do what they want to do.

Based on this approval, where does vorasidenib fit into the glioma treatment paradigm?

The FDA approval label is different than the INDIGO [trial population]. For me, the INDIGO population is the first group where I would use this drug. These are patients who are more than 1 year out from surgery and maybe have residual or recurrent disease at that time point, as well as non-enhancing low-grade glioma.

Why would I not necessarily use it immediately postoperatively? A lot of patients with low-grade glioma, in particular patients with oligodendroglioma, may have a long PFS time with surgery as their only intervention. Even though we described the tolerable AE profile [with vorasidenib], what is important to remember about this patient population is they’re young. These are people who want to have families, who work, who might [even] be working 2 or 3 jobs. That little bit of fatigue [associated with vorasidenib] is a big deal, and so is taking a drug that might impair fertility or mean they have to delay childbearing.

The label indication is much broader than the INDIGO population, which is a double-edged sword. There is a group of patients that is at risk of over treatment, but there’s also a big group of patients who were not directly [represented] in the INDIGO study that this drug might be appropriate to use in. For example, in patients who had their initial surgery and who received radiation and chemotherapy early in whom there is concern that they have non-enhancing recurrent disease, [vorasidenib may be considered].

If I were the patient and were given the option of trying vorasidenib or going back to temozolomide or taking something even more toxic like lomustine, I would want to be given the option of vorasidenib. The label allows for that. [This indication will] allow for careful conversations between patients and providers, but those will have to be thoughtful discussions.

References

1. FDA approves vorasidenib for grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation. FDA. August 6, 2024. Accessed September 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vorasidenib-grade-2-astrocytoma-or-oligodendroglioma-susceptible-idh1-or-idh2-mutation
2. Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al. Vorasidenib in IDH1- or IDH2-mutant low-grade glioma. N Engl J Med. 2023;389(7):589-601. doi:10.1056/NEJMoa2304194