In an interview, Timothy F. Cloughesy, MD, discussed the recent approval of vorasidenib in IDH-mutant gliomas and data from the phase 3 INDIGO trial.
Timothy Cloughesy, MD
On August 6, 2024, the FDA granted approval to vorasidenib (Voranigo, formerly AG-881) for the treatment of patients with IDH-mutant gliomas, based on data from the phase 3 INDIGO trial (NCT04164901).1,2,3
The approval of vorasidenib, an oral, selective, highly brain-penetrant dual inhibitor of mutant IDH1 and IDH2 enzymes, marks the first approval by the FDA of a systemic therapy for patients with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation.1
In an interview with Targeted OncologyTM, Timothy F. Cloughesy, MD, director of UCLA’s neuro-oncology program and distinguished professor in neurology, discussed the significance of vorasidenib’s approval from the FDA in this patient population.
Targeted Oncology: Can you discuss the mechanism of action of vorasidenib?
Cloughesy: It started off when the Cancer Genome Atlas had just come out. We were evaluating, as a field, large-scale genomic evaluations of gliomas. Out of that evaluation came the identification of IDH mutations. Soon after that was understanding the biology of what that mutation did, how that mutation led to an oncogenic environment, and then the formation of these tumors in patients and developing into primary brain tumors. We then went on to identify the clinical characteristics associated with this mutation. We found these in specific types of disease that are usually a little lower grade, but still can be deadly, and identified both astrocytoma and oligodendroglioma subtypes out of that. In the end, this process led to disease-defining aspects of what was incorporated into the [World Health Organization (WHO)] criteria.
Then, there is the opportunity of drugging this target. This was fascinating, the ability to make a potent selective inhibitor of the mutant enzyme and to have it be penetrant and to be highly tolerable was an important feat. That has not been done a lot in our field. As always, we had to go through a phase 1 study and try to identify the population that responds best. The most obvious population was those in the early disease where they were identified and are close to newly diagnosed, that there were slower growing changes. This provided an opportunity to think about how to develop a later stage study. But before doing that, there was an opportunity to give drugs to patients for a month, and then do surgery to understand exactly what kind of changes were occurring. I think that the totality of this development was unique for drug development and glioma, and I think it really sets a blueprint of how to consider moving forward.
Can you discuss the background of the phase 3 INDIGO study?
The phase 3 INDIGO study was defined to carry forward the findings that were identified in the phase 1 setting. And again, this disease population was early on, slow growing, and interestingly, these are young patients, patients in their 40s. They have children, they are developing their careers, and the standard-of-care therapy is radiation and chemotherapy. Radiation has an impact on the brain. The biggest problem, of course, is that this could have cognitive issues. Now, the location of the tumor for the IDH-mutant tumors are the frontal lobe and the temporal lobes, and these are areas that are highly susceptible to radiation. So, the idea that patients may not be employable initiated this process of when you are diagnosed with a lower grade tumor, the ability to monitor and to evaluate and to see when there is significant growth, and then you initiate radiation chemotherapy.
This watchful waiting period offered a new opportunity for a drug to come in and to be utilized during this time. This is an indication that has never been used by a drug. Yet, this was the time for this particular drug that showed it to have its greatest effect early on. That was how a population was defined for this study.
What were the methods and design?
The study includes patients 12 years and older who may have these tumors, although the typical time frame is when they are in their 30s and 40s. They have had surgery, there was some residual tumor, they had at least a year from the time of the surgery and no longer than 5 years, but they had a measurable tumor that was present. We included astrocytomas and oligodendrogliomas, and all were grade 2. The patients were randomized in a 1:1 [fashion]. It was a placebo-controlled study, so it was an opportunity to understand what happens with this drug and what the impact was, even if there were unique toxicities that existed.
So, the study was set to enroll over 300 patients, so around 150 or more on each arm. The primary end point was progression-free survival, and the secondary end point was time to next intervention. Interestingly, when you initiate a study like this, you never know how it is going to enroll or what the interest is going to be with the population of investigators or with patients. It was a highly sought after therapy because patients attached to the idea that this may allow them to wait even longer before having to initiate radiation therapy, which is thought to be a real value. The trial went on with 1:1 randomization, and there was an opportunity to have a couple of interim evaluations. One of the interim evaluations was a futility evaluation. The second and third evaluations were going to evaluate superiority. The second evaluation took place, and that was in September of 2022, and it showed that there was a benefit.
3D illustration of brain anatomy: © PIC4U - stock.adobe.com
Can you discuss this benefit and other promising findings from the study?
The benefit was pretty striking. The effect size was large, and this was in the primary end point, which was progression-free survival. This hazard ratio was just under 0.4, which is a pretty dramatic effect. Not only is it statistically, but clinically meaningful as a benefit to patients. So that was a great finding.
The next evaluation was the time to next intervention. This is a placebo[-controlled] study, so that was double-blinded. When patients were thought to have progressed, they then were told whether or not they had the opportunity to cross over. This time to next intervention is a little bit tough, but what was not impacted was the idea of how long it took for those who were taking the treatment to be able to switch over to a different therapy such as radiation and chemotherapy, and there was a much longer delay. So, we saw this profound effect. It is interesting that there was still oversight on some of the patients who were still deciding on the treatment arm, which means these data still can mature and could show better outcomes because these are estimates of the difference between the populations. At this point, the median progression-free survival is around 27 months in the treatment arm and around 11 months in the placebo [arm].
Can you explain the significance of the approval for vorasidenib in this patient population?
I think this provides a real opportunity for all patients. Again, this opportunity to be able to hold off on radiation and chemotherapy for as long as possible allows these patients who are young, are either in the midst of their careers or are developing their careers or developing their families, to be able to be at their cognitive best during this time. And I think that is the huge value that we are seeing. Again, we will understand more as data matures, just how long a period that could be. But I could say, having treated patients in the phase 1 study, that I have patients who are still on the drug for over 7 years. So, we are really talking about substantial periods where people can feel they do not have to initiate radiation and chemotherapy and can maintain their cognitive abilities.
Vorasidenib opens up opportunities for the treatments of low-grade gliomas, again, to be able to get in early and to be able to control the disease as early as possible. Getting in there that early, hopefully having the most durable effect by getting in early, is new, and it is a new way of thinking about this disease. It is a whole new indication for treating these tumors with a nonmutating, very tolerable therapy that should not lead to hyperaggressive settings that occur from hypermutated settings with chemotherapy.
How do you foresee the role of oncologist evolving with the advent of new treatments such vorasidenib in brain cancer?
These gliomas are identified, usually, in their first interaction with physicians treating the disease, usually a surgeon. It is many times that the surgeons have been involved in this watchful waiting process, being able to do a resection, monitor [patients] over time, identify whether there has been significant growth, and determine whether there should be another resection or whether there would be the need for radiation chemotherapy. Of course, that is the time usually when there is a need for radiation and chemotherapy, when an oncologist would be involved. Now that is different because there is the opportunity to treat patients with an oral medication, a targeted therapy that would typically be given by an oncologist. That means oncologists in many settings are going to be engaged much earlier. I think in academic settings, this happens already. There are neuro-oncologists that are utilized, for the most part, in most academic settings. But out in the community, there will not be neuro-oncologists, but there will be a medical oncologist. They are very well trained, and I do not think it will take long for them to understand and be able to utilize this therapy and to engage them. I think they are going to be engaged much earlier.