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Treatment with Brigatinib Results in Radiographic Responses and Clinical Benefit in a Heavily Pretreated Cohort of Patients with NF2-Related Schwannomatosis

Findings from the INTUITT-NF2 study
04 Jul 2024
Targeted Therapy;  Cancer in Adolescents and Young Adults (AYA)
Central Nervous System Malignancies

In a prospective phase II, adaptive platform–basket INTUITT-NF2 study, brigatinib showed broad antitumour activity in patients with NF2-related schwannomatosis who had progressive tumours. The study investigators documented the greatest activity for meningiomas and nonvestibular schwannomas, with responses in 25% and 20% of tumours. Treatment with brigatinib resulted in a decrease in the growth of all tumour types, most prominently for meningiomas.

Treatment with brigatinib was safe and associated with improvement in hearing, and a decrease in pain. The findings are reported at 2024 Global NF Conference (20-25 June 2024, Brussels Belgium) along with a simultaneous publication by Dr. Scott R. Plotkin of the Massachusetts General Hospital in Boston, MA, US and colleagues from the INTUITT-NF2 Consortium on 20 June 2024 in The New England Journal of Medicine.

The authors wrote in the background that NF2-related schwannomatosis, previously called neurofibromatosis type 2, is a rare tumour-suppressor syndrome characterised by a predisposition to the development of multiple schwannomas, meningiomas, and ependymomas. It is dominantly inherited and caused by pathogenic variants in the NF2 gene. Without treatment, progressive tumours can lead to complete deafness, multifocal weakness, immobility, and death.

Since patients with NF2-related schwannomatosis have multiple tumours throughout the nervous system, most patients undergo multiple surgical procedures that cause neurologic injury and reduce the patient’s quality-of-life (QoL). Intravenous treatment with bevacizumab has shown activity in some patients with progressive vestibular schwannomas, but not in those with other NF2-associated tumours. However, bevacizumab treatment has been associated with cumulative toxicity. Other agents with modest activity for progressive tumours include everolimus and lapatinib.

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. Subsequent studies of brigatinib, an ALK-IN-1 derivative, showed potent inhibitory activity in mouse models of NF2-related nonvestibular schwannoma and meningioma. This antitumour effect in NF2-deficient cells is not mediated by ALK, but by nonreceptor tyrosine kinases such as FAK, FAK2, and FER.

The investigators designed the Innovative Trial for Understanding the Impact of Targeted Therapies in NF2 (INTUITT-NF2) platform study with a basket design to address core challenges in clinical therapeutic development for NF2-related schwannomatosis and to accelerate drug discovery for schwannomas, meningiomas, and ependymomas with NF2 loss. They report the results of a phase II study of brigatinib, which was selected as the first drug to be evaluated in INTUITT-NF2.

In this study, patients who were 12 years of age or older with NF2-related schwannomatosis and progressive tumours were treated with oral brigatinib at a dose of 180 mg daily. A central review committee evaluated one target tumour and up to five nontarget tumours in each patient. The primary outcome was radiographic response in target tumours. Key secondary outcomes were safety, response rate in all tumours, hearing response, and patient-reported outcomes.

A total of 40 patients with a median age of 26 years and progressive target tumours (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 tumours with a radiographic response was 10% (95% confidence interval [CI] 3 to 24) for target tumours and 23% (95% CI 16 to 30) for all tumours. Meningiomas and nonvestibular schwannomas had the greatest benefit.

Annualised growth rates decreased for all tumour types during treatment. At 12 months, the percentage of tumours without progression was 77% in patients with meningiomas and 83% in those with nonvestibular schwannomas. This finding is particularly noteworthy given that meningioma is associated with an increased risk of death in patients with NF2-related schwannomatosis.

Treatment with brigatinib also resulted in clinical improvement. 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. No patients had interstitial pneumonitis, and side effects were managed with dose reductions or dose delays. A high incidence of elevated creatine kinase was noted, but was not considered to be an adverse event unless the elevation became symptomatic.

The study design allowed to focus on the most promising treatment targets among a limited number of eligible trial patients with a rare disease. The study embraced the complexity of the population with NF2-related schwannomatosis by following the response to treatment across multiple tumours and tumour types, by assessing key factors that impair QoL in these patients, and by enrolling adults and adolescents or young adults.

The study design did not call for a placebo control, given the rarity of NF2-related schwannomatosis and the inclusion of patients with actively growing tumours. In addition, the study was limited to patients who were already enroled at specialty centres, a factor that potentially limits the generalisability of the findings.

The authors commented that an oral agent that treats multiple types of NF2-associated tumours and has an acceptable side-effect profile for long-term use would reduce the need for high-risk interventions and avert subsequent complications in patients with NF2-related schwannomatosis. In this prospective study of brigatinib in patients with NF2-related schwannomatosis and progressive tumours, treatment with brigatinib was safe and associated with shrinkage of multiple tumour types, improvement in hearing, and a decrease in pain.

The study was supported by the Children’s Tumor Foundation, the Andrea Cahill Foundation, Takeda Pharmaceuticals, and a grant from the US National Cancer Institute.


Plotkin SR, Yohay KH, Nghiemphu PL, et al. for the INTUITT-NF2 Consortium. Brigatinib in NF2-Related Schwannomatosis with Progressive Tumors. NEJM; Published online 20 June 2024. DOI: 10.1056/NEJMoa2400985



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