Glioma Breakthrough Sparks Hope
- In this new era of targeted therapy in glioma treatment, the field is still grappling with sequencing, timing, and the overall benefit for some patients, for whom there is some doubt about its use. There are many unanswered questions. Multidisciplinary experts convened to develop a framework addressing some of these questions.
- Vorasidenib meaningfully delays tumor growth and the need for chemotherapy and/or radiation in carefully selected, post-operative patients with IDH-mutant grade 2 glioma.
- While vorasidenib meaningfully extends the time before patients require more aggressive treatment, it has not yet proven to have an overall survival advantage.
- The major open questions include: When to start therapy? How to sequence or combine vorasidenib with chemoradiation? And which patients should still receive upfront cytotoxic therapy?
SurvivorNet continues to bridge the gap between cutting-edge research and the people who need this information by creating a space where top specialists share insights and answer pressing questions.
At ASTRO 2025, SurvivorNet brought together a panel of leading experts in the field to discuss advances in treatment for IDH-mutant grade 2 diffuse gliomas. The conversation highlighted not only the scientific progress but also the real-world impact these treatments can have on patients and their families.
The introduction of vorasidenib, the first targeted therapy for gliomas with isocitrate dehydrogenase (IDH) mutations, marks a profound shift in how we approach these tumors. It represents a “remarkable achievement” and has been called “the most important advance in the treatment of low-grade gliomas in the last decade”.
For decades, the treatment landscape for diffuse gliomas has been defined by surgery, radiation therapy, and alkylating chemotherapy, interventions that offer survival benefit but carry significant long-term neurocognitive and physical toxicities.
However, this breakthrough, primarily driven by the striking results of the Phase 3 INDIGO trial, immediately injects complexity into our clinical decision-making. We are now grappling with critical questions surrounding the optimal sequencing and patient selection: Who is the right candidate, and exactly when should we deploy this novel agent?
The Case for Targeting IDH
“This is the first time in the treatment of glioma that we have a targeted therapy. So whatever the conversation is surrounding, when to give it, who to give it to, it represents a remarkable achievement to have a targeted therapy in gliomas. It’s unprecedented in so many ways and really has changed our thinking.” – Dr Erik Sulman, a radiation oncologist and Chair of the Department of Radiation Oncology at Duke University School of Medicine, told SurvivorNet.
Most adult lower-grade gliomas harbor IDH1 or IDH2 mutations. These mutant enzymes generate the oncometabolite D-2-hydroxyglutarate (2-HG), which disrupts epigenetic regulation and helps drive the biology of these tumors. Vorasidenib is an oral, brain-penetrant inhibitor designed to block both mutant IDH1 and IDH2. In perioperative studies, it crossed the blood–brain barrier and reduced intratumoral 2-HG by >90%, which is exactly what you want to see from a targeted agent before you ask if it changes outcomes.
What This Means—and What It Doesn’t (Yet)
- What it means now: For the post-surgery patient who qualifies for observation, vorasidenib can delay radiotherapy and chemotherapy, often for years, without adding the long-term toxicities those treatments can cause. That’s meaningful for cognition, career, and family plans.
- What it doesn’t prove yet: Overall survival. IDH-mutant lower-grade gliomas have long natural histories, and INDIGO allowed substantial crossover from placebo to vorasidenib, which will blur any OS difference for a while. Also, you cannot directly compare INDIGO’s PFS to historical chemoradiation trials—they enrolled different patients for different clinical questions.
“Understanding how to or if to combine these newer approaches with older approaches is still very much an area of controversy,” Dr. David Raleigh, a radiation oncologist specializing in brain tumors at UCSF, told SurvivorNet.
“We are in a gray area. Maybe with a tumor that has a significant residual disease or is perhaps progressing in somebody who’s young, understanding if it’s time to move forward with cytotoxic therapy, or if that therapy is good enough by itself or might be better in combination with or in sequence with a newer therapy.”
“There’s a lot of debate, and I don’t think that there’s much consensus about how to do that. I know that because that’s an active area of developing clinical trials.”
The Fair Debate
Some oncologists would have preferred a head-to-head comparison against chemoradiation in patients with measurable residual disease. Others point out that INDIGO asked a very specific, clinically common question: in people we would otherwise observe, does a targeted oral agent buy meaningful time? The answer looks like yes. For patients with clear high-risk features or early progression, chemoradiation remains standard because that’s where we have survival data.
How I Use This In Practice (Today)
- Candidates: Post-operative, IDH-mutant grade 2 glioma; appropriate for observation; good hepatic reserve.
- Counseling: “This pill often buys you more time before we need radiation or chemotherapy. We’ll monitor your liver tests closely, your MRI on schedule, and how you feel day to day.”
When should we still favor chemoradiation upfront: Rapid radiographic growth, symptomatic progression, or other features that push risk high enough that delaying definitive therapy doesn’t feel safe.
The Open Questions We Need Answered
“There’s still a lot that we don’t know. And while the revolutionary INDIGO study was very exciting, it’s left a lot of questions unanswered,” Dr Jennie Taylor, a neuro-oncologist at UCSF, told SurvivorNet.
“It takes a lot of multidisciplinary coordinated care, and in many instances, it takes shared decision making with patients, not only to figure out what is the best course of therapy, but when that course of therapy should be initiated.”
- Timing: Should vorasidenib start earlier than the 1 – 5-year post-surgery window used in INDIGO?
- Sequencing: Is it better before or after radiotherapy? What about combining with alkylating chemotherapy (TMZ or PCV) after radiation?
- Combination Strategy: Whether combining vorasidenib with post-radiation chemotherapy (TMZ or PCV) will improve overall survival.
- Long-term outcomes: Will early vorasidenib ultimately improve overall survival, or primarily shift when we deliver other therapies?
Practical Implementation: Who Needs Upfront Cytotoxic Therapy?
While vorasidenib offers a significant delay, it is crucial to recognize that the single-agent activity remains “modest” compared to combined chemoradiation in historical trials. For patients exhibiting clear high-risk features or rapid disease progression, conventional cytotoxic therapy remains the standard of care, as that is where we have long-term survival data.
“Patients who have lots of residual disease that clearly is progressing, or patients who have neurologic symptoms that are not controlled. These are areas where we have less debate about what to do,” Dr. Sulman said.
“Say you have [residual tumor] and the tumor is still growing, still present, and the patient has seizures or they have other neurologic deficits. There’s a general consensus that probably requires a more immediate, earlier cytotoxic intervention, which is radiation and chemotherapy, and not as much of a gray area.”
What INDIGO Actually Tested
INDIGO was a phase 3, randomized, placebo-controlled trial in patients with IDH-mutant grade 2 glioma who’d had surgery only and were considered appropriate for observation. 331 patients were randomized 1:1 to vorasidenib 40 mg daily or placebo.
Key Efficacy Results:
- Progression-Free Survival (primary): 27.7 months with vorasidenib vs 11.1 months with placebo (HR 0.39; P<0.001).
- Time to Next Intervention (key secondary): HR 0.26; P<0.001. At 18 months, 85.6% of patients on vorasidenib were alive without needing the next treatment vs 47.4% on placebo.
The benefit signal was seen across major molecular subtypes (oligodendroglioma and astrocytoma).
- Safety in plain terms: Most side effects were low-grade. Grade ≥3 adverse events occurred in 22.8% on vorasidenib vs 13.5% on placebo; treatment discontinuation due to AEs was 3.6%. The lab issue to watch is transaminase elevation (ALT any-grade ~39%, grade ≥3 ~10%; AST any-grade ~29%, grade ≥3 ~4%). “COVID-19” appears on the adverse-event list because of when the study ran; it reflects intercurrent infections, not a drug-specific signal.
Bottom Line to Share With Families
Vorasidenib won’t cure an IDH-mutant grade 2 glioma, but for the right person at the right moment, it can keep life on its current track longer – and that time matters.
