Clinic Conversation of the Week: How to Talk to Patients About the INDIGO Trial in IDH-Mutant Glioma

What is Vorasidenib?

Vorasidenib is a small molecule inhibitor of IDH-mutant enzyme activity. By blocking the mutant IDH, the level of 2-hydroxyglutarate (2-HG), an oncometabolite, is reduced, and thereby the epigenetic changes caused by it. With this, tumor proliferation is decreased and growth inhibited. Vorasidenib was approved by the FDA in August 2024 for use in adult and pediatric patients 12 years and older with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, following surgery including biopsy, sub-total resection, or gross total resection, based on the efficacy and safety from the INDIGO trial.

What is the INDIGO Trial?

The INDIGO trial, which studied vorasidenib, was published last year in the New England Journal of Medicine, and an updated analysis was given at the Society for Neuro-Oncology (SNO) Annual Meeting last month. This was a double-blind phase 3 trial that enrolled patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery. Patients received either oral vorasidenib or placebo. If a patient asks about this trial, what would I tell them?

Here’s What I Would Say…

“When we talk about tumors, we mainly talk about three different ‘systemic’ therapy options. These are either chemotherapy, immunotherapy, or targeted therapy. When we talk about brain tumors, targeted therapy options were limited, or nonexistent, up until now. We knew for quite some time that the ‘driver’ in gliomas is a mutation in the IDH gene. The INDIGO trial was designed to study this very thing; that is what happens if we block this driver mutation. Patients who had residual or recurrent IDH-mutant glioma after surgery received vorasidenib or placebo. This was one pill once per day.

The primary end point of the study was progression-free survival, which is the time for the tumor to start growing again. Why is this important? Historically, standard of care in a low-grade glioma patient that does not require immediate therapy with radiation or chemotherapy is observation. The purpose of this trial was to see if giving a targeted therapy can delay progression or the time for the patient to require treatment. In the update from SNO 2024, the authors provided the updated time to next intervention, 20.1 months for the placebo arm versus not estimable in the vorasidenib arm.

Vorasidenib has thus been proven to reduce tumor volume, while the volume in the placebo group continued to increase, with a 15.9% difference between the two arms. Additionally, there was a reduction in seizure events in the vorasidenib arms, with a total number of on-treatment seizure events of 1,541 versus 5,124.

When we talk about brain tumors and therapies for brain tumors, one of our biggest concerns is the blood-brain barrier. This is like an extra layer of protection that was developed to protect our brain, like a sanctuary site. However, with that extra protection comes a drawback, which is that several drugs cannot then enter to treat a disease inside the brain. Vorasidenib is a small molecule inhibitor that was designed to penetrate the blood-brain barrier. It blocks the activity of mutant IDH1/2 enzymes, thereby reducing the concentration of 2-HG, which in turn decreases the tumor cell proliferation.

The benefit is clearly seen in the improved progression-free survival, from 11.4 months to not estimable in the vorasidenib arm. The additional benefit is that this treatment is a pill and is well-tolerated. The most frequent grade 3 treatment-related adverse event was elevated liver enzymes. Only 4.2% of patients in the treatment arm discontinued therapy due to toxicity.

So, in summary, this is really a big deal for neuro-oncology. A field that has very limited standard options has now gained another one, and it is the first truly successful targeted treatment option. This also gives us more options for future clinical trial designs with targeted therapies being included in multiagent designs. This also gives us hope for higher-grade tumors and incorporating immunotherapies to other approaches.”

About Dr. Vojnic

Morana Vojnic, MD, MBA, is an Assistant Professor of Medicine in the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health and a Medical Oncologist at Lenox Hill Hospital, where she serves as Director of Oncologic Services in the Brain and Spine Metastases Program. She specializes in thoracic and neuro-oncology, with expertise in the treatment of lung cancer, mediastinal tumors, head and neck cancer, brain cancer, and metastatic lesions of the brain and spine. With a background in molecular genetics, Dr. Vojnic designs personalized treatment plans and protocols using targeted drugs, immunotherapy, and chemotherapy for the treatment of patients with these diseases.