From ‘Watch and Wait’ to Targeted Therapy: The Trial That Transformed Glioma Treatment

Creator: Danielle Cinone
Published: 2025-11-24T19:28:21-05:00

: Dr. Krishna Suthar Medical Source: Dr. Steve Braunstein
UCSF Health Written by: Danielle Cinone

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The Phase 3 INDIGO Trial

For decades, treatment for low-grade, IDH-mutant gliomas relied mainly on surgery, monitoring, and conventional therapies.
The phase 3 INDIGO trial showed that the oral once daily pill vorasidenib significantly improves progression-free survival, symptoms, and overall outcomes.
This targeted therapy is well tolerated and marks a major advance, offering new hope and treatment options for patients with these tumors.

For decades, patients with low-grade gliomas—especially those with IDH-mutant tumors, , which carry a change in the IDH1 or IDH2 gene that helps drive tumor growth—had extremely limited treatment options. Most care plans depended on surgery, followed by careful monitoring and, when necessary, radiation or chemotherapy. Thanks to new data from the landmark INDIGO trial, which tested a once-daily pill called vorasidenib in people with grade 2 IDH-mutant gliomas, healthcare providers are now rethinking everything from treatment timing to long-term care.

Dr. Steve Braunstein from University of California at San Francisco explains, “For a very long time we were somewhat limited in the tools that we had. We had surgery, we had radiation, and in some instances we had chemotherapies which were fairly cytotoxic that could be employed for these patients with lower gliomas.”

However, for the first time, a large, carefully controlled study showed that a pill targeting the exact gene mutation driving these tumors can meaningfully slow them down. Until now, most patients only had surgery and long periods of “watch and wait.” The INDIGO trial shows that a targeted therapy may be able to step in earlier and help keep the tumor stable for much longer — something doctors were not able to do before.

The INDIGO Trial Explained

The INDIGO trial was a phase 3, international, multicenter, randomized clinical trial evaluating a new class of targeted therapy: oral small-molecule inhibitors designed to block mutated isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) enzymes that play a role in glioma cancer growth.

“Small molecule inhibitors were studied on various clinical trials and ultimately led to the seminal INDIGO trial using the agent vorasidenib, which is an oral agent taken by patients,” Dr. Braunstein says.

The trial enrolled 331 patients ages 12 and older with:

Low-grade gliomas
Tumors that had been surgically resected
No prior radiation or chemotherapy
Evidence of progression months to years after surgery or progression months to years after surgery
A confirmed IDH 1 or 2 mutation

“These were patients who had lower grade gliomas that were resected and had evidence of progression following resection,” adds Dr. Braunstein

How the Trial Worked

Participants were randomized to receive either:

Vorasidenib, the IDH-mutant inhibitor, or
Placebo

Crossover was allowed, meaning patients on placebo could switch to the active drug if their tumor progressed.

“They were given this agent or randomized to placebo, and there was crossover that was allowed,” Dr. Braunstein states.

The Key Findings: Better Progression-Free Survival

For the first time, a large, carefully controlled study showed that a pill targeting the exact gene mutation driving these tumors can meaningfully slow them down. Until now, most patients only had surgery and long periods of “watch and wait.” This trial shows that a targeted therapy may be able to step in earlier and help keep the tumor stable for much longer — something we’ve never been able to do before.

Patients receiving the IDH inhibitor experienced:

Longer progression-free survival— meaning patients taking vorasidenib stayed stable for much longer. On average, their tumors did not grow for about 28 months, compared to about 11 months for people who took a placebo.
Reduced time to their next intervention — in other words, patients on vorasidenib had a longer period without needing more aggressive treatment.

Dr. Braunstein encapsulates the findings, saying, “patients who received the IDH mutant inhibitor had better progression-free survival as assessed by imaging and symptoms, but also overall survival… This really changed the way we think about the management of lower grade glioma patients.”

Radiation Therapy in the Treatment of Glioma: A Comprehensive Overview

Why IDH-Mutant Inhibitors Matter

The INDIGO trial ushered in a completely new class of treatment for glioma. Dr. Braunstein encapsulates this, saying, “We now have another agent… IDH mutant targeted therapies that are able to selectively inhibit this molecule in patients with lower grade gliomas… The emerging data shows it’s effective, fairly well tolerated, fairly safe, with a very limited toxicity profile.”

Safety and What Researchers Are Still Learning

On the topic of safety, Dr. Braunstein notes, “It’s something that’s in the grand scheme of glioma research relatively new. We’re still figuring out the timing, the sequencing of this agent with other therapies, and we’re very much interested in following patients who take this agent long-term to understand the full impact on functionality, quality of life, and neurocognition.

“But to date the safety profile of this has been excellent.”