The Controversy Around Radiation Oncologists, Medical Oncologists, and the Use of Vorasidenib for Gliomas

Gliomas, particularly IDH-mutant low-grade gliomas, present a significant treatment challenge in oncology. With the FDA approval of vorasidenib in 2024, the field has witnessed a shift toward targeted therapies.

Vorasidenib, a dual inhibitor of mutant IDH1 and IDH2 enzymes, has demonstrated promise in delaying disease progression. However, its adoption has sparked debate among medical professionals who treat gliomas, highlighting differing perspectives on its use.

Evidence Supporting Vorasidenib

The INDIGO Trial, published in 2023, which led to vorasidenib’s approval, showed that the drug significantly improved progression-free survival (PFS) compared to placebo (27.7 months vs. 11.1 months) and delayed the need for subsequent interventions like radiation or chemotherapy. This finding is particularly relevant for patients seeking to maintain quality of life while managing their disease.

Vorasidenib’s ability to cross the blood-brain barrier and target specific IDH mutations marks a major advance, especially for patients who may benefit from delaying treatments with significant side effects. These attributes have positioned vorasidenib as a novel tool for managing IDH-mutant low-grade gliomas.

“The main take-home point from [the INDIGO Trial] is that there is a definite improvement in progression-free survival in patients with IDH mutant, low-grade glioma when they took vorasidenib versus placebo — and also improvement in time to next intervention,” Dr. Katherine Peters, a neurologist at Duke Health, tells SurvivorNet Connect. “These are really significant results because we have not reached the median for either of those values.

“Moreover, this treatment was very well-tolerated and we now finally have the first signal that it can help control seizures, too, which is a huge problem with our patients with low glioma,” Dr. Peters adds.

Criticisms and Concerns

A recent article published in Nature Reviews Clinical Oncology , authored by two radiation oncologists from Mt. Sinai, discussed criticisms of the INDIGO trial and implied results. Below are some of the highlighted concerns of the trial.

Trial Design Limitations: Critics have pointed out that the INDIGO trial compared vorasidenib to a placebo rather than standard care (radiation and chemotherapy), which has been the established approach for many high-risk patients. They argue that withholding proven therapies could potentially compromise long-term survival.

Counterpoint: The trial targeted a specific patient subset. Those in a watch-and-wait population, where immediate radiation and chemotherapy are not always standard. This approach aimed to evaluate vorasidenib’s effectiveness in a real-world scenario for patients without immediate indications for more aggressive treatment.

Uncertain Long-Term Outcomes: While PFS improvements are significant, vorasidenib has not demonstrated overall survival (OS) benefits during the trial period. Critics have raised concerns that without OS data, the drug’s long-term value remains uncertain.

Counterpoint: Proponents argue that delaying disease progression and the need for additional interventions provides meaningful quality-of-life benefits, even in the absence of direct OS improvements.

Cost Concerns: The high cost of vorasidenib adds another layer of complexity to its adoption. Compared to radiation and chemotherapy, which are relatively cost-effective, vorasidenib’s annual expense of approximately $500,000 raises concerns about its accessibility and sustainability.

Counterpoint: Supporters of targeted therapy highlight its precision approach, potentially reducing the long-term costs associated with managing side effects from more traditional treatments.

Cross-trial Comparisons: While the INDIGO trial showed improved PFS, this was significantly lower than what has been observed with standard chemoradiotherapy in high-risk gliomas in other trials (e.g., 2-year PFS of 50.7% with vorasidenib vs. 85% with chemoradiotherapy).

Counterpoint: The comparison between INDIGO and other trials is not directly applicable due to differences in patient populations. The INDIGO trial enrolled patients with stable, low-grade gliomas in a watch-and-wait setting, whereas chemoradiotherapy studies often target higher-risk populations.

“With all these cases, we review them with our radiation oncologists,” Dr. Alexandra Miller, a neuro-oncologist at NYU Langone Health, tells SurvivorNet Connect. “…We know that almost all of these patients, unfortunately, are still going to get radiation and chemotherapy. It’s just a matter of when — and I think we just want to extend the timeline … We know that radiation and chemotherapy is an extremely powerful tool that we have to keep these tumors under control, but if we can do that in two years or in five years or in 10 years, great, then we’ve reserved that tool for the future.”

Balancing Radiation and Targeted Therapy

Radiation therapy remains a cornerstone of glioma treatment, particularly for patients with more aggressive or higher-risk disease. However, vorasidenib can offer an opportunity to delay radiation in select cases, sparing patients the potential long-term effects of this intervention.

The balance between these modalities depends on individual patient characteristics, including tumor behavior, progression risk, and quality-of-life considerations. A multidisciplinary approach that includes input from radiation oncologists, medical oncologists, and neuro-oncologists is essential for making these decisions.

As Dr. Peters explains, at major cancer centers, experts have the ability to meet and discuss different aspects of a patient’s diagnosis — and they are excited to have a new tool to add to the treatment options.

“We’re really excited to have a new tool,” she explains. “It doesn’t mean the old tools are bad or blunted. We still need neurosurgeons, we still need radiation oncologists, we need medical oncologists. It means that we come together, we have a new tool and we use it appropriately.”

Future Directions

As vorasidenib becomes more widely used, ongoing research will refine its role in glioma treatment. Key questions remain about its optimal duration, the management of resistance, and its integration with emerging and established therapies. Data from long-term follow-up studies and real-world evidence will help address these uncertainties.