Oncologists Discuss IDH Inhibition Vs Chemo + RT for Grade 2 Glioma

Grade 2 gliomas occur in younger adults and often necessitate surgical resection and further treatment. In a virtual Case-Based Roundtable event, Jan Drappatz, MD, associate professor at the University of Pittsburgh School of Medicine and the director of the neuro-oncology program at the University of Pittsburgh Medical Center, surveyed participants on treatment options after surgery for a case patient and discussed the advantages and disadvantages of the IDH inhibitor vorasidenib (Voranigo) vs chemotherapy and radiation therapy (RT).

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CASE SUMMARY

• A 39-year-old woman initially presented to the emergency department in January of 2024​.
• Symptoms (Dec 2023–Jan 2024): episodic speech arrest, right facial twitch, preserved awareness; 2 events over 3 weeks.​
• Neurological exam normal; started on levetiracetam 500 mg twice daily.​
• Brain MRI: non-enhancing T2/FLAIR hyperintensity, left superior frontal gyrus, 2.6 cm, ill-defined borders; no diffusion restriction; negligible mass effect.​
• Provisional impression: adult-type diffuse glioma; tumor board referral.​
• Surgery on February 15: ​greater than 90% resection
  • Immediate postop MRI (Feb 16): no contrast enhancement; residual FLAIR “penumbra” likely infiltrative.​
  • Gross total resection is not a molecular cure; diffuse biology persists.​​
• WHO diagnosis: astrocytoma, IDH-mutant, central nervous system WHO grade 2 (adult-type).​
  • Histology: diffuse astrocytic proliferation; low mitotic index; microvascular proliferation absent; necrosis absent.​
  • Co-markers: 1p/19q non-codeleted, MGMT promoter methylated.
  • Immunohistochemistry: IDH1 R132H negative (rapid).​
• Comprehensive next-generation sequencing (Mar 12 report): confirms IDH1 R132C; no IDH2; TERT promoter wild type; ATRX loss; TP53 mutated—pattern consistent with astrocytoma.​
• The patient is cognitively intact and wants to continue her teaching job.

Jan Drappatz, MD: The majority of participants chose vorasidenib. RT and temozolomide and a clinical trial were also mentioned. You can make an argument for any of the choices, largely dependent on this patient’s life goals. For low-grade glioma, RT and chemotherapy has been shown to be associated with long and durable disease control, yet there are concerns about potential toxicities of treatment, both due to the chemotherapy and RT, which can be challenging for this patient population who has a long life ahead of them. Clinical trial is always preferred, but the majority chose vorasidenib.

Aneel Chowdhary, MD: I chose chemotherapy plus RT, and the reason was, I know she’s young, but I was looking at a time-limited approach. In the near term, there are more adverse events, but I still don’t know if we should commit her to lifelong or long-term therapy. [For vorasidenib], you’re going to watch the liver function tests, [and] the risk of grade 3 hepatotoxicity is 10% or less.¹ It’s not very toxic, but I still felt like chemotherapy and RT may afford her a much longer time off therapy.

Drappatz: That’s an excellent thought. If you look at the durability of disease control, chemotherapy and RT has been shown to be very effective in achieving it. The concern as neuro-oncologists…is that the survivorship after RT and chemotherapy for some patients can be challenging. These are not toxicities that are necessarily captured in the clinical trial. Some of the clinical trials that have been conducted include quality-of-life measurements, but they’re performed at relatively short intervals, and there are long-term toxicities of RT that we as neuro-oncologists see, including premature strokes or cognitive decline, [or] patients who are diagnosed with a grade 2 tumor in their 30s, but then in their 50s they have to stop working because they struggle.

Jerome Graber, MD: This is a great example that not all [tumor] locations are created equal. This is probably one of my anxiety-inducing locations, so I’d talk to the surgeon. Why didn’t they remove that residual infiltrative disease? I’m guessing it’s because if they tried to, it would cause dysfunction. So presumably, if tumor grows there, you’re going to risk deficits that later treatment would not fix. That would probably guide the discussion with the patient. I chose vorasidenib, but there’s a practical consideration for patients that committing to 6 weeks of RT is a big deal.

I usually tell people, given their risk factors, it is very likely that we’ll see some tumor growth in the next 2 or 3 years, and then you would have to do RT. For some people, being able to choose and plan when they do RT, a minority of patients would say, let me plan it now around my work, my family, and my living situation. I would not pick observation, but I’d talk a lot about the location and potential deficits whenever the tumor grew. You might decide to do RT and definitive treatment now. You could do vorasidenib and close observation, but you should be prepared if anything shows growth to [use] RT…quickly.

Drappatz: It can be challenging to determine the amount of residual disease…and can be challenging to determine infiltrative disease vs surgical change.

Thomas Kaley, MD: I chose vorasidenib as well for this patient. The constellation of clinical factors you describe overall lead me towards wanting to treat this patient. I’m surprised we didn’t see any [votes for] observation, but I too would have treated here. She is 39, she had a small tumor to begin with, and she is clinically asymptomatic. I’m not sure if at 39 she’s already had children. When it comes to the left frontal lobe, I get a little squeamish with RT, especially in these younger functional individuals. That’s the one lobe of brain where it tends to see the most neurocognitive dysfunction. She’s young, she’s working, so I want to preserve that for as long as possible.

Drappatz: What would you predict would happen with observation?

Kaley: I think we’ve all seen these patients who have a grade 2 glioma, moreso oligodendroglioma than astrocytoma, that is grossly resected and they have a very long survival in the absence of any intervention. It’s very hard to predict who those patients are. The majority of them will grow and progress. The INDIGO trial [NCT04164901] was constructed in such a way where the requirement was for a subtotal resection or to have some residual disease. This was a practical artifact of the trial design [needing] to have some disease to follow, but…waiting until there is measurable, bulky disease seems counterintuitive to me.

Maciej Mrugala, MD: I also chose vorasidenib. We need to take into account her profession. She’s a teacher. She probably wants to continue teaching. She has at least 15 years or more of her career ahead of her, and having RT now could potentially impact how she will function in the future. [Vorasidenib] would be a great choice for her, considering her life goals, and we could defer RT for as long as possible.

Joyce Huang, MD: Is there any choice for adjuvant temozolomide for 1 year without RT? My patient with oligodendroglioma after gross total resection back in 2016 didn’t receive any RT. It was a right frontal lobe tumor. She received 1 year of temozolomide and was doing very well for a few years before recurrent disease and another resection, and then started the IDH inhibitor.

Drappatz: I’m glad you brought this up. Temozolomide alone or chemotherapy alone has been a longstanding consideration to potentially avoid toxicities of RT and preserve cognitive functioning. Temozolomide or chemotherapy alone has been studied as a potential treatment option, particularly for oligodendrogliomas, which tend to be more chemotherapy sensitive.² I [treat] patients similar to yours, who have received chemotherapy with durable responses. Generally speaking, chemotherapy alone tends to have more of a prospect of benefit in situations of oligodendroglioma as opposed to astrocytoma. The data and support [for] it is not robust, but there are many anecdotal cases of patients who have been managed successfully with durable responses. My sense would be that this would be less likely to work for an astrocytoma.

David Reardon, MD: It’s not unreasonable, although thinking about the potential risks, at least in my experience, the IDH inhibitors…are much more favorable than what we’ve had to rely on historically. Dr Huang is right to point that out. That was something many of us used in the past and try to delay or defer the use of RT in these young patients. But in the current era with IDH inhibitors, the risk-benefit ratio relative to chemotherapy short term and long term, in my experience, favors the IDH inhibitor as a priority now and deferring chemotherapy.

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_{DISCLOSURES: Drappatz previously disclosed stock ownership in Pfizer and Gilead Sciences, royalties from Elsevier and Wolters Kluwer, and consulting fees from Servier.}

_REFERENCES

_{1. Cloughesy TF, van den Bent MJ, Touat M, et al. Vorasidenib in IDH1-mutant or IDH2-mutant low-grade glioma (INDIGO): secondary and exploratory endpoints from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2025;26(12):1665-1675. doi:10.1016/S1470-2045(25)00472-3}

_{2. Jaeckle KA, Ballman KV, van den Bent M, et al. CODEL: phase III study of RT, RT + TMZ, or TMZ for newly diagnosed 1p/19q codeleted oligodendroglioma. Analysis from the initial study design. Neuro Oncol. 2021;23(3):457-467. doi:10.1093/neuonc/noaa168}