Experts Discuss Evolving Paradigms in Glioma Treatment

IDH-mutant gliomas represent a rare subset of brain tumors, affecting approximately 12% to 20% of adult patients with glioma.¹ Typically diagnosed in younger populations, these tumors generally offer a more favorable prognosis compared to IDH wild-type cases.

These tumors are biologically diverse and inherently progressive. Over time, they lead to significant neurological dysfunction and, ultimately, mortality. Therefore, a multidisciplinary and highly individualized approach is essential.

In a virtual Case-Based Roundtable, Timothy F. Cloughesy, MD, professor and co-director of the UCLA Brain Tumor Center; director of the UCLA Neuro-Oncology Program; and co-director of the Henry F. Singleton Brain Cancer Research Program, and participants discussed the management of these patients considering recent research and novel approved agents that have changed treatment paradigms.

CASE SUMMARY

• A 39-year-old woman presented with IDH-mutant grade 2 astrocytoma on January 8, 2024.
• Symptoms between December 2023 and January 2024
  • Episodic speech arrest
  • Right facial twitch
  • Preserved awareness
  • 2 events over 3 weeks
• Emergency department visit on January 8, 2024
  • Neurological exam normal
  • Started on levetiracetam 500 mg twice daily
• Brain MRI on January 10, 2024
  • Nonenhancing T2/FLAIR hyperintensity, left superior frontal gyrus, 3.6 cm, ill-defined borders
  • No diffusion restriction
  • Negligible mass effect
  • Provisional impression: adult-type diffuse glioma; tumor board referral
• Surgical decision in February 2024
  • Preoperative mapping: fMRI and DTI tractography; anticipated low eloquence risk
  • Goal: gross total resection (GTR) while preserving language and executive networks
  • Surgery on February 15, 2024: asleep-awake-asleep craniotomy; >95% resection by intraoperative MRI
  • Immediate postoperative MRI on February 16: no contrast enhancement; residual FLAIR “penumbra” likely infiltrative
  • Diffuse biology persists
• Histopathology and grading
  • WHO diagnosis: astrocytoma, IDH-mutant, CNS WHO grade 2 (adult-type)
  • Histology: diffuse astrocytic proliferation, low mitotic index, microvascular proliferation absent, necrosis absent
  • Co-markers: 1p/19q noncodeleted, MGMT promoter methylated
• Immunohistochemistry (IHC) vs next-generation sequencing (NGS)
  • IHC: IDH1 R132H negative (rapid)
  • Comprehensive NGS on March 12, 2024: Confirms IDH1 R132C; no IDH2; TERT promoter wild type; ATRX loss, TP53 mutated. Pattern consistent with astrocytoma.
  • Reflex to NGS post resection for complete IDH1/IDH2 ascertainment
• The patient is cognitively intact and wants to keep teaching.

DISCUSSION QUESTIONS

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

Leia Nghiemphu, MD: I think overall extent of resection is probably the easiest decision point. We know that in the INDIGO trial [NCT04164901], they were patients who had residual or recurrent disease somewhat.² If they have residual disease, we know it's most likely going to grow in a shorter amount of time than if they had a GTR.

I think the harder decision is always if we start treatment early on someone with a GTR. I think that's where some of the other factors would come in, like if they're symptomatic from their tumor or if they're still having seizures, because I think there's good data that may help with seizures.

Timothy F. Cloughesy, MD: For astrocytoma vs oligodendroglioma, if you had a GTR, do you think of those differently?

Karan Dixit, MD: I would observe oligodendrogliomas for longer. I think all of us have experience in observing them. It’s a completely different disease. I tend to be a bit more aggressive with astrocytomas, meaning I would start vorasidenib [Voranigo] sooner. I do tend to wait a few months after surgery at the very least. I don’t think these patients need treatment immediately. I like to give patients time to understand their disease and grapple with the fact that they have a lifelong, incurable brain cancer. If I recall INDIGO, was that [given] 12 months from surgery?

Cloughesy: It was 12 months to 5 years postoperative.

Dixit: If the disease is progressing in the postoperative period, then the biology has already declared itself as being more aggressive. I do use the rate of growth. We try to do that these days to as many patients as possible and use their growth pattern trajectory. But there’s no good metric yet. Hopefully, RANO 2.0 gets used more frequently, and I’m a big believer in volumetrics, but I’m a believer in more data. These are 3-dimensional tumors. They invade the brain. I like seeing growth patterns and kinetics. I think that dictates how these patients do.

John de Groot, MD: Five years ago, I was basing a lot of treatment for patients on age. The INDIGO trial has changed my impression of the influence of age on the need for treatment. I think it would be great to redefine what is truly low risk and high risk. I think it’s not what we used to think.

DISCUSSION QUESTION

• What outcome matters most in terms of influencing your treatment decision-making?

Robert Yoo, DO: I think overall survival [OS] probably would have been the best. I think progression-free survival [PFS] is probably much more doable for a grade 2 population. Looking at the INDIGO trial, I think the PFS is striking. The long-term OS, if there is any updated analysis, will be great to see and practice-confirming.

DISCUSSION QUESTIONS

• How might the INDIGO 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 radiotherapy with or without chemotherapy?
• How do you foresee integrating IDH inhibition into long-term management?
• What are the practical considerations for implementing vorasidenib in clinical practice?

Dixit: Before a subtotal section, I'm more likely to use vorasidenib.

Cloughesy: Do you find it well tolerated by your patients?

Dixit: I think 1 patient may have had some gastrointestinal upset for the first week or so, and then that was it. It’s very well tolerated.

Robert Galamaga, DO: Reviewing the data, I think it certainly lowers the threshold for initiating treatments, certainly with measurable disease or residual disease. Historically, we may have observed some of these patients, but the sustained PFS and time to next treatment with a clean toxicity profile made it makes it more attractive, especially in younger patients, where delaying radiotherapy and alkylators really matters. Even with GTR cases, the FDA label gives us a lot of flexibility in terms of using it for these patients. INDIGO reassures us that the targeted therapy can meaningfully delay that that next intervention.

DISCLOSURES: Cloughesy reports grants or contracts from Roche, VBI, Merck, Novartis, BMS, and Servier via UCLA; royalties or licenses from Chimerix and Katmai; consulting fees from Katmai, the Global Coalition for Adaptive Research, Symbio, Mundipharma, Tango BlueRock, Vida Ventures, Lista Therapeutics, Stemline, Novartis, Roche, Sonalasense, Sagimet, Clinical Care Options, Ideology Health, Servier, Jubilant, Immvira, Gan & Lee, BrainStorm, Sapience, Inovio, Vigeo Therapeutics, DNATrix, Tyme, SDP, Kintara, Bayer, Merck, Boehringer Ingelheim, VBL, Amgen, Kiyatec, AbbVie, VBI, Deciphera, Agios, Novocure, Medscape, Third Rock, Curio Science, Novo Holdings, Modifi Bio, Telix, and Pathos; support for attending meetings and/or travel from Servier and the Global Coalition for Adaptive Research; stock or stock options for Chimerix, Katmai, and Erasca; other financial or nonfinancial interests with The Regents of the University of California who licensed intellectual property co-invented by Cloughesy to Katmai Pharmaceuticals; serving as a board member for the Global Coalition for Adaptive Research; and serving as a Director and on the Scientific Advisory Board for Katmai.

REFERENCES

1. Mellinghoff IK, Chang SM, Jaeckle KA, van den Bent M. Isocitrate Dehydrogenase Mutant Grade II and III Glial Neoplasms. Hematol Oncol Clin North Am. 2022 Feb;36(1):95-111. doi: 10.1016/j.hoc.2021.08.008. Epub 2021 Oct 25. PMID: 34711457; PMCID: PMC9549919.

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 Aug 17;389(7):589-601. doi:10.1056/NEJMoa2304194.