Post-Vorasidenib Approval: Practical Insights for Use in IDH-Mutant Low-Grade Gliomas

The recent FDA approval of Vorasidenib has ushered in a new era of targeted therapy for patients with IDH-mutant low-grade gliomas. It is the first new drug approved to treat gliomas in the last 25 years. As healthcare providers begin to incorporate this treatment into practice, several critical questions emerge, such as: How do we start therapy? When should it be stopped? What do treatment plans look like?

In addition, there’s much to learn about identifying suitable patients for this therapy and ensuring its appropriate use.

Identifying the Right Patients for Vorasidenib

The cornerstone of Vorasidenib’s efficacy lies in its ability to target tumors with IDH mutations. Molecular testing, including next-generation sequencing (NGS), plays an important role in identifying these mutations.

“We know that Vorasidenib is more effective in patients who have early-stage, low-grade disease, so grade 2 tumors,” Dr. Alexandra Miller, Director of the Neuro-Oncology Division at NYU Langone Health, tells SurvivorNet Connect. “…we know that the IDH mutation is really important in the progression of these tumors in early-stage disease and that as these tumors progress, the patients pick up additional alterations and other pathways that may begin to help the tumors grow and pick up steam.”

Because molecular testing is needed to identify which patients have IDH mutations, all patients with gliomas should undergo testing. Fortunately, “molecular testing is covered by insurance for all patients with gliomas,” Dr. Miller explains.

Providers must prioritize access to molecular diagnostics to ensure proper patient selection. Initiating Vorasidenib therapy without confirmation of an IDH mutation risks exposing patients to unnecessary treatment and costs.

Starting Therapy: Timing Matters

Timing is another critical factor. Vorasidenib is most effective in the early stages of tumor progression, following definitive treatment, particularly in low-grade gliomas where the IDH mutation is actively driving tumor growth.

The decision to initiate treatment should be based on a combination of:

• Molecular profiling confirming the IDH mutation
• Radiological evidence of progression, as assessed by advanced imaging techniques
• Symptom burden, including neurological deficits or functional impairments

Monitoring patients closely for early signs of progression through routine imaging and clinical evaluations is essential to identify the optimal window for starting therapy.

A recent study (the INDIGO Trial) revealed that in patients with grade 2 (low-grade) IDH-mutant glioma, Vorasidenib significantly improved progression-free survival.

When to Stop Vorasidenib Therapy

The question of when to stop Vorasidenib is still evolving, with limited data available from long-term real-world use. Current recommendations suggest continuing therapy as long as the patient demonstrates clinical stability or response without significant adverse effects.

However, discontinuation may be necessary in cases of:

• Tumor progression: Clear evidence of progression despite therapy, including radiographic or symptomatic worsening
• Intolerable side effects: Although Vorasidenib is generally well-tolerated, side effects such as elevated liver enzymes or persistent gastrointestinal symptoms may necessitate dose adjustments or discontinuation
• Resistance or lack of response: Emerging resistance mechanisms in IDH-mutant gliomas underscore the need for ongoing research to identify alternative strategies

“Vorasidenib is an incredibly well-tolerated drug,” Dr. Miller explains. “It’s taken daily in the morning with a meal and people usually tolerate the drug very well without a lot of significant side effects. You do have to monitor a patient’s blood [more often] while they’re on the medication at the beginning … it becomes less and less often as time goes on.”

The Role of Molecular and Radiological Monitoring

Advances in molecular testing and imaging are essential to optimizing Vorasidenib therapy. Regular monitoring with blood-based biomarkers, such as circulating tumor DNA (ctDNA), may provide early indications of treatment response or resistance. Similarly, advanced imaging techniques, such as MR spectroscopy or dynamic contrast-enhanced MRI, can help differentiate true tumor progression from pseudoprogression—an ongoing debate area.

Educating providers on how to interpret these results is critical to ensuring accurate diagnosis and treatment decisions.

Ensuring Appropriate Use of Vorasidenib

One of the biggest challenges in the post-approval era is ensuring that Vorasidenib is used appropriately. This means targeting the patients who will benefit most while avoiding unnecessary treatment for those unlikely to respond.

Strategies to ensure appropriate use can include:

• Widespread education on molecular testing, focusing on providers at smaller or non-specialized centers
• Multidisciplinary decision-making involving neuro-oncologists, radiologists, and pathologists to confirm eligibility
• Standardized guidelines to help oncologists navigate complex cases and avoid over- or under-treatment

Future Directions: Learning as We Go

As Vorasidenib enters broader clinical use, the neuro-oncology community will continue to learn about its optimal application.

For oncologists and healthcare providers, understanding these nuances is crucial to delivering high-quality, evidence-based care. With ongoing research and shared knowledge, we can continue to expand the potential of Vorasidenib while ensuring it reaches the patients who need it most.