Brigatinib for NF2-Related Schwannomatosis

Schwannomatosis is a rare genetic disorder that causes tumors to develop in the nervous system. In this condition, benign tumors called schwannomas, arising from Schwann cells, can develop in different parts of the body. Schwannomatosis can commonly cause pain, loss of neurological function and other complications.

NF2 (neurofibromatosis type 2) is a subtype of schwannomatosis caused by mutations in the NF2 gene .

NF2 is a lifelong progressive disease that usually begins at a young age and is characterized by hearing loss, balance problems and other serious neurological symptoms.

NF2-related schwannomatosis (NF2-SWN, previously known as neurofibromatosis type 2) is a tumor syndrome characterized by multiple vestibular schwannomas (tumors on the hearing nerves), nonvestibular schwannomas (tumors on other nerves), meningiomas (tumors of the membranes covering the brain) and ependymomas (spinal cord tumors).

The disease progresses continuously, and there is currently no approved treatment.

Based on favorable preclinical results in NF2-associated nonvestibular schwannomas and meningiomas, brigatinib was investigated in the INTUITT-NF2 study in patients with progressive NF2-SWN tumors.

Brigatinib inhibits multiple tyrosine kinases and is used particularly in cancer treatment. The FDA first approved brigatinib for ALK-positive metastatic small cell lung cancer.

The INTUITT-NF2 Study

In this phase 2 INTUITT-NF2 platform trial, patients aged 12 years or older with NF2-SWN and progressive tumors received oral brigatinib at 180 mg daily. A central review committee assessed one target tumor and up to five nontarget tumors in each patient. The primary outcome was the radiographic response rate in target tumors. Key secondary outcomes were safety, response rate in all tumors, hearing response and patient-reported outcomes.

Findings

• Brigatinib was given to 40 patients (median age, 26 years) with progressive target tumors: 10 vestibular schwannomas, 8 nonvestibular schwannomas, 20 meningiomas and 2 ependymomas.
• After a median follow-up of 10.4 months, the radiographic response rate was 10% in target tumors (95% confidence interval [CI], 3-24%) and 23% in all tumors (95% CI, 16-30%).
• The greatest benefit was observed in meningiomas and nonvestibular schwannomas.
• Annual growth rates decreased in all tumor types during treatment.
• Hearing improvement was observed in 35% (95% CI, 20-53%).
• Exploratory analyses showed a reduction in self-reported pain severity during treatment (-0.013 units per month; 95% CI, -0.002 to -0.029).
• No treatment-related grade 4 or 5 adverse events were reported.

In conclusion, brigatinib treatment produced radiographic responses across several tumor types and clinical benefit in a heavily treated cohort of patients with NF2-SWN.

Why the Study Matters

This study represents an important advance in treating NF2-related schwannomatosis, demonstrating brigatinib's efficacy and safety across several tumor types. It offers a promising alternative for patients with NF2-SWN who have limited treatment options, with the potential to reduce tumor growth rates and improve quality of life. Further research and approval processes are therefore needed for the clinical use of brigatinib.