Brigatinib Shows Clinical Benefit Across Multiple Tumor Types in Patients with NF2-Related Schwannomatosis with Progressive Tumors

Image credit: kh_art | stock.adobe.com

Results from the Phase II INTUITT-NF2 trial (NCT04374305) show brigatinib produced radiographic responses across multiple tumor types with a clinical benefit in heavily pretreated patients with NF2-related schwannomatosis (NF2-SWN). The relentlessly progressive tumor predisposition syndrome is manifested via multiple vestibular schwannomas, nonvestibular schwannomas, meningiomas, and ependymomas.^1,2

There are currently no FDA-approved treatments for NF2-SWN, formerly known as neurofibromatosis type 2. If left untreated, the progressive tumors can cause complete deafness, multifocal weakness, immobility, and death, according to the authors of the study, published in The New England Journal of Medicine.¹

The current standard of care for NF2-SWN is surgery; however, the risk of iatrogenic neurologic injury is elevated with each procedure. Because patients with the disease have multiple tumors throughout their nervous system, the majority must undergo multiple surgical procedures that lead to neurologic injury and lower their quality of life.

“In 2013, a comprehensive screening of preclinical molecules for activity against cellular models of NF2-deficient schwannoma and meningioma identified ALK-IN-1 (an inhibitor of ALK and multiple other tyrosine kinases) as a potentially active compound,” the study authors wrote. “Subsequent trials of brigatinib, an ALK-IN-1 derivative, showed potent inhibitory activity in mouse models of NF2-related nonvestibular schwannoma and meningioma. This antitumor effect in NF2-deficient cells is not mediated by ALK but by nonreceptor tyrosine kinases such as FAK, FAK2, and FER.”¹

The multicenter, adaptive platform trial was conducted with a basket design, which allows investigators to evaluate drug activity across multiple tumor types driven by NF2 loss, including vestibular schwannomas, nonvestibular schwannomas, meningiomas, and ependymomas.

The trial enrolled patients aged 12 years and above with NF2-SWN and progressive tumors. The primary outcome was radiographic response in target tumors, with key secondary outcomes that included safety, response rate in all tumors, hearing response, and patient-reported outcomes.

Patients in the trial had progressive target tumors, of which 10 were vestibular schwannomas, eight were nonvestibular schwannomas, 20 were meningiomas, and two were ependymomas. Patients were administered oral brigatinib at a dose of 90 mg daily for seven days, with the dose increased to 180 mg daily if no toxic events occurred. Investigators defined one cycle of treatment as a 28-day period.

At a median follow-up of 10.4 months, 10% of target tumors showed a radiographic response (95% confidence interval [CI], 3 to 24), whereas 23% of all tumors showed a radiographic response (95% CI, 16 to 30). The investigators observed that meningiomas and nonvestibular schwannomas achieved the greatest benefit from treatment.

Annualized growth rates were reduced across all tumor types during treatment. Hearing improvement was reported in 35% (95% CI, 20 to 53) of eligible ears. In terms of safety, there were no grade 4 or 5 treatment-related adverse events reported.

Notably, at 12 months, the percentage of tumors without progression was 77% among those with meningiomas and 83% in patients with nonvestibular schwannomas. In prior real-world studies of bevacizumab in the treatment of NF2-SWN meningioma, the 12-month percentage was 62%.

“In this prospective phase 2, adaptive platform–basket trial, brigatinib showed broad antitumor activity in patients with NF2-SWN who had progressive tumors. The trial was designed to identify tumor types that were the most responsive to brigatinib treatment,” the study authors wrote. “We documented the greatest activity for meningiomas and nonvestibular schwannomas, with responses in 25% and 20% of tumors, respectively. This objective response exceeds the historical control benchmark of approximately 2%. Treatment with brigatinib resulted in a decrease in the growth of all tumor types, most prominently for meningiomas.”¹

References

1. Plotkin S, et al. Brigatinib in NF2-Related Schwannomatosis with Progressive Tumors. N Engl J Med 2024;390:2284-2294 DOI: 10.1056/NEJMoa2400985. Vol. 390 No. 24.

2. Innovative Trial for Understanding the Impact of Targeted Therapies in NF2-Related Schwannomatosis (INTUITT-NF2) (INTUITT-NF2). ClinicalTrials.gov. March 13, 2024. https://clinicaltrials.gov/study/NCT04374305.https://clinicaltrials.gov/study/NCT04374305