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Brigatinib in Patients With NF2-Related Schwannomatosis With Progressive Tumors
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
NF2-related schwannomatosis (NF2-SWN, formerly called neurofibromatosis type 2) is a tumor predisposition syndrome that is manifested by multiple vestibular schwannomas, nonvestibular schwannomas, meningiomas, and ependymomas. The condition is relentlessly progressive with no approved therapies. On the basis of preclinical activity of brigatinib (an inhibitor of multiple tyrosine kinases) in NF2-driven nonvestibular schwannoma and meningioma, data were needed on the use of brigatinib in patients with multiple types of progressive NF2-SWN tumors.
METHODS
In this phase 2 platform trial with a basket design, patients who were 12 years of age or older with NF2-SWN and progressive tumors were treated with oral brigatinib at a dose of 180 mg daily. A central review committee evaluated one target tumor and up to five nontarget tumors in each patient. The primary outcome was radiographic response in target tumors. Key secondary outcomes were safety, response rate in all tumors, hearing response, and patient-reported outcomes.
RESULTS
A total of 40 patients (median age, 26 years) with progressive target tumors (10 vestibular schwannomas, 8 nonvestibular schwannomas, 20 meningiomas, and 2 ependymomas) received treatment with brigatinib. After a median follow-up of 10.4 months, the percentage of tumors with a radiographic response was 10% (95% confidence interval [CI], 3 to 24) for target tumors and 23% (95% CI, 16 to 30) for all tumors; meningiomas and nonvestibular schwannomas had the greatest benefit. Annualized growth rates decreased for all tumor types during treatment. Hearing improvement occurred in 35% (95% CI, 20 to 53) of eligible ears. Exploratory analyses suggested a decrease in self-reported pain severity during treatment (-0.013 units per month; 95% CI, -0.002 to -0.029) on a scale from 0 (no pain) to 3 (severe pain). No grade 4 or 5 treatment-related adverse events were reported.
CONCLUSIONS
Brigatinib treatment resulted in radiographic responses in multiple tumor types and clinical benefit in a heavily pretreated cohort of patients with NF2-SWN.
Additional Info
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Brigatinib in NF2-Related Schwannomatosis with Progressive Tumors
N. Engl. J. Med 2024 Jun 27;390(24)2284-2294, SR Plotkin, KH Yohay, PL Nghiemphu, CT Dinh, D Babovic-Vuksanovic, VL Merker, A Bakker, G Fell, L Trippa, JO BlakeleyFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
NF2-related schwannomatosis (NF2-SWN), previously known as neurofibromatosis type 2, is a devastating condition characterized by the development of multiple types of tumors, including vestibular schwannomas, nonvestibular schwannomas, meningiomas, and ependymomas. NF2-SWN is caused by germline or mosaic pathogenic variants in the NF2 gene located in the long arm of chromosome number 22 (22q12.2). This progressive syndrome currently has no approved therapies, leaving patients to experience significant health declines over time.
A recent phase II clinical trial investigated the efficacy of brigatinib, an inhibitor of multiple tyrosine kinases, in treating NF2-SWN. The primary outcome of the trial was to measure the radiographic response of target tumors, with secondary outcomes including the response rate of all tumors, hearing improvement, and patient-reported outcomes. The results showed some promise: 10% of the target tumors had a radiographic response, and, notably, brigatinib achieved a 25% response rate amoang patients with meningiomas and a 20% response rate among patients with nonvestibular schwannomas, far surpassing the historical control benchmark of approximately 2%. This indicates that brigatinib is significantly more effective than bevacizumab, which has shown only modest activity for NF2-associated tumors. Additionally, brigatinib treatment led to clinical improvements, with up to one-third of the patients experiencing better hearing. After 12 months, 89% maintained hearing sensitivity, and 74% retained hearing intelligibility, showing significant benefits over existing treatments.
Despite its strengths, the trial has limitations, such as the lack of a placebo control and its restriction to patients at specialty centers, potentially limiting generalizability. Moreover, the small sample size resulted in broad confidence intervals for some outcomes. Importantly, the trial reported no severe treatment-related adverse events, and most adverse events (grade 3) were generally manageable, suggesting that brigatinib has a more favorable safety profile compared with bevacizumab, which is known for its cumulative toxicity. However, in another way of analysis about the adverse events caused by brigatinib, it may suggest the need for retrospective analysis of adverse drug reactions and the establishment of adverse event monitoring systems for long-term treatment to patients.
In summary, this trial demonstrates that brigatinib can provide clinical benefit to patients with NF2-SWN, but continued research and development to understand the cause of the disease are essential to improve the lives of those affected by this challenging disease. The support of organizations like the Children’s Tumor Foundation and the continued investigation through trials like the INTUITT-NF2 are vital steps in this ongoing effort.