Ongoing Trials Could Expand Role of IDH Inhibitors in Resected Glioma

IDH mutations offer an opportunity to apply targeted therapy in gliomas, with significant benefit in grade 2 gliomas after resection. However, questions remain about which patients should be treated and whether this trend can be expanded to other applications including high-grade disease. 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, moderated a discussion on how the IDH inhibitor vorasidenib (Voranigo) can be considered in patients who would otherwise be observed and how ongoing trials are looking at it in patients who would be considered for radiotherapy (RT) and chemotherapy.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

DISCUSSION QUESTIONS

• Which risk factors push you toward intervention?
• What impact if any does age have on IDH-mutant gliomas? ​

Jan Drappatz, MD: Does age have any impact in IDH-mutant gliomas? I’ve encountered IDH-mutant tumors in octogenarians. It’s rare, but it does happen. There’s this concept of age conferring shorter time to progression and poor prognosis. In fact, there was this concept…of poor risk, low-grade gliomas, to which “age above 40” was a criterion. But my sense is that this has largely been abandoned to molecularly defined risk. Age does not appear to be a valid risk stratification for these IDH-mutant tumors. Is there any differing opinion? Does age play a role?

Thomas Kaley, MD: Sometimes it feels like I see a 50-year-old or a 55-year-old with one of these, and I may veer more towards treatment more aggressively. But many times, those are patients who are trying to avoid treatment as well, so it varies.

DISCUSSION QUESTIONS

• How might the INDIGO trial (NCT04164901) results influence your threshold for initiating treatment in patients with grade 2 IDH-mutant glioma following surgery?​
• What patient or disease characteristics would make you favor vorasidenib vs traditional RT ± chemotherapy?​
• How do you foresee integrating IDH inhibition into long-term management?
• What are the practical considerations for implementing vorasidenib in clinical practice?

Drappatz: We’d like to discuss how might the INDIGO results influence your threshold for initiating treatment in patients with grade 2 IDH-mutant gliomas following surgery. This will depend on the extent of resection, whether patients are having symptoms, and their overall goals.

Ashley Ghiaseddin, MD: I think it just lowers the threshold for you wanting to use it when there’s even minimal residual disease. In the first case…I would have thought about vorasidenib. The only time I would have considered observation is if you talk with the surgeon and they feel intraoperatively, they’ve removed everything.

…Maybe that person wanted to delay because they’re still family planning, but these results put an emphasis on ensuring that there is no disease, if you’re choosing to observe, and that [those with] minimal residual disease may need to start with vorasidenib. Based on what we’re seeing from those results, I think it makes it hard to observe, but there may still be that patient whom you want to observe. It decreases the [number] of patients who we previously were observing.

Drappatz: I would agree with those comments.What patient or disease characteristics would make you favor vorasidenib vs traditional RT and chemotherapy?

David Reardon, MD: In terms of younger patients, [there are] fertility issues and concerns about potential short-term and long-term toxicities with RT and chemotherapy; a lot of factors in this patient population to think about a drug that would offer a more favorable toxicity profile and meaningful likelihood of benefit.

Drappatz: Thank you. And how does the panel foresee integrating IDH inhibition into long-term management, sequentially, in combination, or at recurrence? This question could potentially extend to non-label indications like high-grade disease. What is the vision for integration of IDH inhibition?

Maciej Mrugala, MD: We have clinical trials ongoing now with combinations, where there is a study with temozolomide combination and there are studies combining with immunotherapy. I think we need more data in terms of deciding how IDH inhibition is going to integrate into the paradigm of treatment. Right now, I think it’s still early on to make those decisions. We all have our own approaches, and we are still struggling [regarding] which patients should be chosen. What are the best patient characteristics? Should we do it right away? Should we wait? The power will be in the data. Maturing data from the INDIGO study but also new trials that are ongoing will inform how we will use this modality of treatment in the future.

Drappatz: Let’s talk about the practical considerations [such as] hepatotoxicity. How do you counsel your patients, and how do you monitor your patients?

Jerome Graber, MD: We’ve been following the study protocol and the packaging, but it is starting to feel like, do all these patients really have to get monthly [laboratory tests] forever? My feeling is yes, because I’ve definitely had people who many months or even a couple years in suddenly had pretty significant transaminitis changes. I was hoping we’d get more data from the INDIGO trial about [if] is there a timeframe where that risk reduces or goes away. But my experience has been no. We’re telling all our patients, you should plan on doing monthly [laboratory tests] forever while you’re on the drug.

Drappatz: In my personal experience, it does happen relatively early on, and I tend to loosen my monitoring intervals in patients who’ve been on that drug for several years to less frequently. Some patients only have blood work every couple of months.

Kaley: I’ve [taken a] similar approach, [but Dr Graber] is making me re-think. That’s interesting. I tend to see it mostly early on, but more with vorasidenib.

DISCUSSION QUESTION

• For patients with higher-grade or progressive IDH-mutant glioma, how do you individualize choice between radiotherapy (RT) plus procarbazine, lomustine and vincristine (PCV), RT plus temozolomide, and clinical trial enrollment?

Drappatz: [Looking at] all treatment considerations, observation vs vorasidenib vs radiation and chemotherapy or radiation and PCV as well as temozolomide alone, all these options were considerations. Durable disease control is seen with RT plus PCV and RT plus temozolomide, yet there are substantial toxicities for these often-younger patients with a long life ahead of them. The concern is quality-of-life preservation, fertility preservation, there’s a concern to minimize the risk of immunosuppression, immunocompromise, and hematologic toxicities. Then there’s observation, which has been the standard for gross totally resected patients. Treatment decisions need to be individualized. Vorasidenib is giving an additional treatment option of buying quality time. Even though it is daily treatment, it is shown to be effective to delay time to progression, and it can be a good option for some of these patients.

For a patient with higher grade or progressive IDH-mutant glioma, how do you individualize the choice between RT plus PCV, RT plus temozolomide, or clinical trial enrollment? We’ve covered low-grade disease. RT plus PCV is the treatment used in RTOG 9802 [NCT00003375]. RT plus temozolomide is the regimen used in the CATNON trial [NCT00626990]. [Dr Mrugala] mentioned the plan for combination trials with IDH inhibitors for high-grade disease, where vorasidenib or safusidenib, another IDH inhibitor in development, would be added on top of RT and chemotherapy and continued afterwards. These are trials that have been proposed.

Ghiaseddin: When it’s higher grade, if there are clinical trial options, it’s worth considering, because for so many years, we just didn’t have [trials], and that’s why a lot of us trended towards RT plus chemotherapy of choice. But those [trials] are not everywhere, and sometimes it may require a lot of travel for patients, and it may not be feasible. In those cases, we still think about RT plus PCV or temozolomide.

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DISCLOSURES: Drappatz previouslydisclosed stock ownership in Pfizer and Gilead Sciences, royalties from Elsevier and Wolters Kluwer, and consulting fees from Servier.