How Experts Are Rethinking IDH Inhibition as Gliomas Progress

  • Glioma experts agree that IDH inhibitors like vorasidenib are becoming central to managing IDH‑mutant gliomas, but key questions remain, including when to initiate therapy, how long to continue it, and how to adapt treatment as tumors progress from low‑grade to higher‑grade disease.
  • Updated ASCO 2026 data show vorasidenib achieving 44.1 months median progression-free survival, reinforcing its role as a long-term treatment rather than a time-limited one.
  • Experts say deciding when to start and stop vorasidenib remains individualized — radiographic or functional change is the most common trigger, but the updated data have shifted practice toward continuing indefinitely until clear failure.
  • As IDH-mutant tumors progress to higher grades, they acquire secondary molecular drivers that make IDH inhibition alone insufficient; enhancing tumors showed a 0% response rate to IDH inhibition in a 2025 study.
  • Panelists highlighted growing interest in combination strategies, noting that monotherapy may be insufficient for aggressive or enhancing tumors; emerging approaches include pairing IDH inhibition with chemotherapy or immunotherapy, such as reducing 2‑HG–driven immunosuppression to improve T‑cell infiltration when combined with checkpoint blockade.

A panel of glioma experts shared their thoughts on a critical challenge in IDH‑mutant disease: how to use IDH inhibitors like vorasidenib as tumors evolve.

Even with the INDIGO trial reshaping the landscape for low‑grade gliomas, clinicians say the field still lacks clear answers on when to start therapy, how long to continue it, and which combinations will be necessary as progression emerges.

Updated results from the trial presented at ASCO 2026 demonstrate the impact of vorasidenib. With more than three years of follow-up, median progression-free survival reached 44.1 months, and only 23.8% of patients on vorasidenib required a next intervention.

When to Start & Stop IDH Inhibition

During a panel hosted by SurvivorNet, Dr. Omar Butt of WashU Medicine notes that IDH inhibition is poised to become “an integral part of the management of all IDH‑mutant gliomas” within the next decade. But the unanswered questions remain substantial.

“The question is going to be how in terms of timing,” Dr. Butt says. “… When is the best time to start it, when is the best time to stop it? And finally, what to combine it with.”

Dr. Butt says the INDIGO study had a very broad initiation time, and they all seemed to respond based on the initial presentation. He explains that he currently relies on radiographic or functional change to justify initiating vorasidenib, especially when patients are not already inclined toward early treatment.

Historically, Dr. Butt says that he treated for about two years due to uncertainty around duration. But with updated data, his approach has shifted.

“Now… I will be continuing it ad nauseam until I see clear evidence of failure.”

Monotherapy’s Limitations for Higher‑Grade Disease

As tumors progress from grade 2 to grade 3 or 4, Dr. Butt explains that their biology changes and the disease is no longer simply IDH-driven.

He cautioned that monotherapy is unlikely to be sufficient for these more aggressive “cousin tumors.”

“I do think the inclusion of multiple agents — IDH inhibition with chemotherapy like temozolomide, PCV, lomustine, or immune‑based therapies — is a viable pathway,” Dr. Butt tells the panel.

A 2025 study in Neuro-Oncology Advances examining ivosidenib, an earlier IDH inhibitor, found that patients with contrast-enhancing tumors had a 0% response rate, with more than half progressing on treatment. Patients with non-enhancing tumors, by contrast, showed 85.7% stable disease. That gap tells the story of what’s happening biologically.

Anither expert on the panel, Dr. Nick Castro Gonzalez of Dana-Farber Cancer Institute, explains that IDH-mutant gliomas start as an epigenetic disease, driven by the IDH mutation’s production of 2-hydroxyglutarate (2-HG), a metabolite that dysregulates gene expression and fuels early tumor growth.

Over time, tumors accumulate secondary changes — loss of tumor suppressor genes, gain of oncogenes — that allow them to proliferate independently of the IDH mutation. “There’s a clear evolution,” Dr. Castro says. “And we have to define the window of opportunity to treat patients with an IDH inhibitor better.”

A Wider Window & New Combinations May Be Emerging

Dr. Castro emphasizes that while high‑grade enhancing tumors have historically shown limited benefit from IDH inhibitors, the therapeutic window may be broader than previously thought.

He also described a promising strategy under investigation, which is combining IDH inhibition with immunotherapy.

“2‑hydroxyglutarate (2‑HG) is a strong immunosuppressant that limits T‑cell infiltration into the tumor tissue. By reducing 2‑HG levels and priming T‑cells with an immune checkpoint inhibitor, we might have a better chance of an immune‑based therapy to clear the tumor cells,” Dr. Castro explains.

A Phase I trial at UCSF is currently testing exactly this — vorasidenib combined with pembrolizumab in recurrent IDH-1 mutant glioma — and will evaluate T-cell infiltration in tumor tissue as a key endpoint.

This concept is being tested in a study pairing an IDH inhibitor with pembrolizumab, and similar approaches are emerging internationally.

In Germany, researchers who developed an IDH1-targeted peptide vaccine are now combining it with IDH inhibition, attempting to leverage both arms simultaneously against the mutation.

None of these approaches has produced definitive answers yet.