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P. Leia Nghiemphu, MD, discusses INTUITT-NF2 trial findings, the NCCN inclusion of brigatinib, and unmet needs in NF2-related schwannomatosis.
Brigatinib (Alunbrig) produced radiographic responses across multiple tumor types in patients with progressive NF2-related schwannomatosis, with the greatest benefit seen in meningiomas and nonvestibular schwannomas.¹ The agent has since been added to the National Comprehensive Cancer Network (NCCN) Guidelines for Central Nervous System Cancers,² providing the basis to seek insurance approval for off-label use of the agent for this indication, according to P. Leia Nghiemphu, MD.
“Because NF2-related schwannomatosis is so rare, it’s hard to have a clinical trial that can lead to FDA approval of medications,” Nghiemphu said in an exclusive interview with OncLive®. “By placing [brigatinib] on the guidelines, we can go to insurance companies, for instance, and ask for approval for patients who receive this agent.”
In the phase 2 INTUITT-NF2 platform trial (NCT04374305), 40 patients with progressive NF2-related schwannomatosis received brigatinib at 180 mg daily.¹ The radiographic response rate was 10% (95% CI, 3%-24%) among target tumors (n = 40) and 23% (95% CI, 16%-30%) among all tumors, with hearing improvement reported in 35% (95% CI, 20%-53%) of eligible ears. No grade 4 or 5 treatment-related adverse effects (AEs) were reported.
In the interview, Nghiemphu discussed the rationale for the trial, key efficacy and safety findings with brigatinib, the significance of the agent’s inclusion in the NCCN guidelines, and remaining unmet needs in NF2-related schwannomatosis.
Nghiemphu is a professor of clinical neurology, director of the Neuro-Oncology Clinical Service, and clinical director of the UCLA Neurofibromatosis Program at UCLA Health in Los Angeles, California.
Nghiemphu: NF2-related schwannomatosis is considered a rare genetic disease. It occurs in approximately 1 out of 30,000 people.³
Patients with NF2-related [schwannomatosis] have many different tumor types. The most common is bilateral vestibular schwannomas, but they can also have meningiomas and ependymomas, as well as schwannomas outside the cranium or outside the skull base, which we call nonvestibular schwannomas. The reason we decided to do a platform trial is that most previous clinical trials for patients with NF2-related schwannomatosis usually just looked to see if therapies could help the vestibular schwannomas, because those are the most common tumor type in that condition, but [they did] not address all the other tumor types that patients may have. This platform trial allowed us to enroll any patients with NF2-related schwannomatosis who had tumor growth, no matter what type of tumor was growing. Then it was a matter of choosing the best treatment option possible. In this clinical trial, we used brigatinib, which was found [to be effective] in a previous high-throughput drug screening program to look for the best possible option for the management of NF2-related schwannomatosis. Brigatinib came up at the top of the list, so that’s why we chose that agent to go into this clinical trial.
Brigatinib in NF2-Related Schwannomatosis: Key Highlights
The trial was done in 2 stages. For the first stage, we enrolled patients with all the different tumor types. We found that patients who were enrolled with meningiomas and those enrolled with nonvestibular schwannomas had the best response to brigatinib, so those 2 arms were open for more patient enrollment. At the end of the trial, we found that, although patients with meningioma probably had the best response with brigatinib, there were patients who responded to the agent in all the other tumor types. Response for us was defined as shrinkage of tumor by at least 20% by volumetric measurement.
Brigatinib was found to be well tolerated. There were rare instances of grade 3 or 4 moderate-to-severe toxicity, but most of the toxicity was mild. Patients were able to tolerate the agent well. We also have some long-term data with patients having received this therapy for longer than a couple years, and we see more tumor response the longer the patients stay on it. Patients were able to stay on the agent for at least 2 years.
Usually for [practice-changing clinical] trials, we have to have a randomized setting or a large patient population. When we conduct a small trial like our INTUITT-NF2 clinical trial, we can treat a smaller number of patients, complete the trial faster, and find that there’s a response. Unfortunately, that doesn’t mean that we get FDA approval for the agent, so the drug can only be used off label. The NCCN guideline shows that it is an accepted therapy for patients with NF2-related schwannomatosis. The guidelines are put together by experts in nervous system tumors, and they agreed that there is strong evidence that this agent can help this population of patients.
As an oral agent that is well tolerated, brigatinib can easily be the first medical agent that a patient can try to control tumors that are growing because of NF2-related schwannomatosis. Some of [the INTUITT-NF2] data showed a reduced [tumor] growth rate once patients received this agent. [NF2-related schwannomatosis] is a condition where tumors grow slowly over time without causing too many symptoms until they grow large. If we can slow that growth and help patients avoid more surgery for their tumors, that will improve their quality of life [QOL]. Now we have an agent on the NCCN guideline that [more broadly] allows the ability to prescribe this type of therapy earlier in the disease course to try to control tumor growth.
One important factor to point out is that in some patients, these tumors are not growing much, and in others, the tumors are growing. Our clinical trials enroll patients with growing tumors, so I do not place patients on medical therapies unless there’s proven growth of their tumors or it’s worrisome that the tumors may lead to neurological deficits. That’s when we consider a medical treatment. A lot of my patients are receiving [brigatinib] and tolerating it well.
At the end of the day, brigatinib is not leading to tumor response in all patients. It’s just a small subset of patients in whom some tumors respond; even within 1 patient, a few tumors may shrink, but other tumors may grow. There are still a lot of unmet needs to look at additional agents for treatment for this patient population, or even combination therapies. We’re hoping to adapt more agents onto this clinical trial platform to find the best treatment associated with the least AEs for our patients.
In general, it’s important to know that this is a rare condition that can cause a lot of morbidity for patients. Unfortunately, that makes it hard to gather interest, especially from pharmaceutical companies, for instance, to allow us to use therapies in clinical trial for this patient population. They don’t have millions of patients that they can sell medications to, but there is so much need because our patients need better treatment for better QOL. I hope we can find more support from our partners throughout the country and throughout the world to do more trials and find better treatments for our patients with NF2-related schwannomatosis.
Editor’s Note: This transcript has been edited for grammar and clarity using artificial intelligence tools.
