NeuroVoices: Katherine Peters, PhD, on Vorasidenib’s Impact on Quality of Life, Neurocognition, and Seizures in the Treatment of Gliomas

Katherine Peters, PhD

Gliomas, the most common malignant primary brain tumor in adults, are categorized into distinct tumor subtypes and tumor grades according to a combination of histologic and molecular features. Mutations in the genes encoding the metabolic enzymes isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) are present in nearly all grade 2 diffuse gliomas in adults and are known to cause considerable disability and premature death. Patients with Gliomas experience both general cancer-related symptoms such as fatigue, anxiety, and depression, and disease-specific symptoms including seizures, cognitive deficits, motor dysfunction, and symptoms caused by elevated intracranial pressure, which may impair quality of life.

The phase 3 INDIGO study (NCT04164901) was a randomized, placebo-controlled trial that assessed vorasidenib, an oral, brain-penetrant mutant isocitrate dehydrogenase (mIDH) 1/2 inhibitor, in patients with grade 2 mIDH1/2 diffuse gliomas previously treated with surgery only. At the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Denver, Colorado, researchers presented an additional analysis from the study, assessing the therapy’s impact on additional secondary end points, including health-related quality of life (HRQoL), as well as exploratory end points such as neurocognition and seizure activity.

After 13 months of treatment with vorasidenib, Functional Assessment of Cancer Therapy–Brain (FACT-Br) questionnaire total scores, used to assess HRQoL, were 163.3 (SD, 25.05) in patients on vorasidenib and 161.4 (SD, 23.60) in patients on placebo. Minor changes of neurocognitive function were observed in both arms up to cycle 13, with no suggestion of a treatment effect. In addition, the frequency of patients self-reporting at least 1 seizure was similar in both arms through cycle 13.

During the meeting, lead investigator Katherine Peters, PhD, sat down with NeurologyLive^® to discuss the results and the significance behind them. As part of a new iteration of NeuroVoices, Peters, a neurologist and neuro-oncologist at the Preston Robert Tisch Brain Tumor Center at Duke University, gave commentary on the therapeutic potential behind vorasidenib in this patient population, which faces serious quality of life threats. Peters, who also serves as a professor of neurology and neurosurgery at Duke University, also discussed some of the next steps following this research, including exploring vorasidenib’s effect in a less restricted patient population.

NeurologyLive: Can you describe vorasidenib’s mechanism of action and why we believe it can be effective in the treatment of diffuse gliomas?

Katherine Peters, PhD: Vorasidenib is an IDH 1/2 mutant inhibitor, and it stands for isocitrate dehydrogenase. It is an enzyme of the krebs cycle, and when mutated, it produces a chemical called 2-hydroxy glutamate. 2-hydroxy glutamate actually drives the development of brain tumors in particularly low grade glioma, which are a type of tumor that affects roughly, I'd say, a third of people with glioma tumors, which is the most common malignant tumor in patients with primary brain tumor.

What are the greatest takeaways from this analysis of the INDIGO study presented at AAN?

The INDIGO study was designed to enroll patients with newly diagnosed low-grade glioma that harbored the IDH 1 or 2 mutation. These patients only underwent surgery and could not have had other therapies because one of the questions we were answering is, could we use this drug to sort of delay the use of other therapies that can cause severe neurotoxicity like cranial radiation? We enrolled of 331 patients who were randomized 1:1 fashion to vorasidenib or placebo. If they did fail placebo, they were able to crossover to the vorasidenib arm.

The primary objective was progression-free survival, as determined by MRI imaging. Patients had to have growing tumor, or a large enough tumor to evaluate, to go into the study. The key secondary endpoint was time to next intervention. This was important because we wanted to try to delay the time to that next intervention, which could be chemotherapy, radiation, or surgery.

The endpoints that I presented were particular to the other secondary endpoints, which was patient's health-reported quality of life. Neurocognition was an exploratory endpoint and the frequency of seizures, because unfortunately, patients with these types of tumors are more apt to have seizures. We did publish the primary endpoint and the key secondary endpoint, which were progression free survival, and time to next intervention, respectively, in the New England Journal of Medicine. Those were significantly positive, such that the progression-free survival for patients on vorasidenib was 27.7 months versus 11.1 months for patient's on placebo. For the time to next intervention, we haven't even reached our median value for the vorasidenib arm vs 17.7 months for the placebo arm. We're honing in on these results about the patient experience, what's happening with their quality of life, their neurocognition, and also their seizures.

How does this data build upon the primary and secondary end points previously seen? Talk about its significance.

The significance of it is that we used to use the tools to treat these patients like we treated high grade gliomas: we'd give them radiation, we give them chemo. And the median age for these patients is around 40 years. This could cause very significant quality of life impairment and cognitive impairment. What we were able to show is when we measured quality of life in these patients, we did not cause any detriment to their quality of life. There was really no change over time in their quality of life in both the vorasidenib and placebo group. So, we did enroll a very functional group of patients, but we weren't hurting them.

Now we have the opportunity to give this drug, extend not only their life that we know from what has already been published, but also to maintain their quality of life. We should also show that we did not interfere with neurocognition, which stayed stable throughout. And finally, with seizure frequency, as measured by patient reported diaries, and also the number of antiseizure medicines they were on, we did not cause any increase in seizures, and we did not lead to any escalation in antiseizure medicines. These patients on this drug do have an opportunity to maintain their quality of life, their cognition, and control of their seizures.

Following this analysis, what is next? Where do we go from here to continue to expand on this data?

We’re pretty excited about this. The study is still very active because even though we met our primary endpoint, our patients are still in study, they're still taking the drug, and we're looking hopefully towards an FDA approval of the agent for our patients. The next is, the study was designed in a very particular population where they were very functional, they had a Karnofsky Performance Scale of 80 or greater and they could not have seizures that were uncontrolled or interfering with their activities of daily living. They couldn't have failed three antiseizure regimens.

There needs to be more done looking at those patients that may be having neurologic challenges that precluded them from the study. We also look for patients that had to have measurable nonenhancing disease. But we didn't look at patients that had a gross total resection and maybe didn't have any disease remaining, or in contrast, had an enhancing disease, which can be a harbinger of a more aggressive type of tumor. We started with a very particular population, now we need to answer the question for all those other populations of patients that have these mutations.

The other thing about this medicine—and I think this is always important to note—it's oral, its brain penetrant, and it is extremely well tolerated. It can be taken for an extended period of time, but we don't know how long. So is this going to become a chronic medicine for our patients? What are the quality of life implications? What are the financial implications? What are the fertility implications? Given that they're in that ticket of life where there's a lot of changes going on, and a lot of life experience that we're hoping to provide for their patients to the best of their ability.

In general, what are some of the major unmet needs for patients with diffuse gliomas that need addressing?

We need to support them through the whole part of their disease. We need to not look just at the tumor, but we need to look at the patient and what is going on with the patient experience. What is happening with their neurocognition? What is happening to seizures? Are they able to work? Are they able to function? What are the fertility implications? I think this is highly important in asking patients, what do they want to learn? How do they want to grow and thrive? I do quality of life research and quality of life is about the being who you are, the belonging of who you are with in the sphere—and that can be the caregiver question—and the next is becoming, and what is the future? I hope in the future we can make this into a chronic condition that we can treat long term. I would love to reach for the cure, but as we can limit morbidity, I would greatly love for that to happen.

Transcript edited for clarity. Click here for more coverage of AAN 2024.

REFERENCE
1. Peters K, Mellinghoff I, Van Den Bent M, et al. A randomized, double-blind, phase 3 study of vorasidenib versus placebo in patients with mutant IDH 1/2 diffuse glioma (INDIGO): Analysis of health-related quality of life. Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO. Abstract 005113