— Phase II trial reveals brigatinib surpasses historical benchmarks by reducing 10% of targeted tumors

A Phase II platform trial presented promising findings for patients suffering from NF2-related schwannomatosis with advancing tumors. The ALK inhibitor brigatinib (Alunbrig) demonstrated potential across various tumor types, showing measurable tumor shrinkage and enhancements in hearing, along with improvements in other clinical parameters.

Among 40 individuals diagnosed with either vestibular schwannoma, nonvestibular schwannoma, meningioma, or ependymoma, 10% of target tumors exhibited radiographic regression. This result notably surpassed the historical benchmark of just 2% (P=0.02), according to Dr. Scott R. Plotkin, MD, PhD, of Massachusetts General Hospital and Harvard Medical School, and his research collaborators.

The team's comprehensive analysis, spanning 153 tumors, revealed a response rate of 23%, as discussed in the New England Journal of Medicine.

"With an oral chemotherapy agent that is well tolerated, we observed shrinkage across multiple tumor types linked to NF2-related schwannomatosis, particularly in meningiomas and nonvestibular schwannomas," Plotkin explained to MedPage Today.

Notably, as NF2-related tumors can progressively lead to hearing impairment, roughly one-third of the study's patients experienced improvements in hearing following brigatinib treatment, highlighting benefits that extend beyond just tumor reduction. Plotkin shared these outcomes while presenting the study at the 2024 Global NF Conference in Brussels.

Of the 37 ears evaluated, measurable hearing improvements occurred in 13, while enhanced hearing sensitivity was observed in 10 out of 44 ears.

NF2-related schwannomatosis, formerly categorized as neurofibromatosis type 2, is a rare genetic disorder wherein individuals inherit only one functional copy of the NF2 gene, Plotkin noted. This genetic predisposition results in the development of multiple tumor types along the brain's lining, as well as along various nerves in the brain, spine, and other regions.

Brigatinib, a treatment previously FDA-approved for ALK-positive metastatic non-small cell lung cancer, was the first drug tested in the INTUITT-NF2 platform trial. Preclinical models had already indicated its efficacy in addressing NF2-associated nonvestibular schwannomas and meningiomas.

"Without intervention, progressive tumors could result in complete hearing loss, general weakness, immobility, and even death," researchers stated, pointing out that while surgery remains the standard care approach, repeated procedures increase the risk of neurological damage.

A primary challenge, Plotkin noted, is "developing strategies to treat patients who present multiple tumor types."

He further explained, "We aim to design innovative clinical trials to effectively study treatments for such rare patient populations." The trial provided insights into both the strengths and areas of improvement within this model, indicating a step forward in refining the clinical approach for this condition.

In this basket trial — designed to study multiple therapies across different groups — 40 patients with progressive vestibular and nonvestibular schwannomas, meningiomas, and ependymomas were enrolled. This cohort included ten patients with vestibular schwannomas, eight with nonvestibular schwannomas, twenty with meningiomas, and two with ependymomas.

While the trial focused on assessing shrinkage in the target tumors, investigators also evaluated non-target tumors in these patients.

The median age of participants was 26, with 70% being female and of white ethnicity. Each, 10% of the cohort identified as Black or Asian. Most patients had a history of surgery (90%), chemotherapy (55%), or radiation (20%) prior to enrollment. At the outset, the median volume of the 38 target vestibular schwannomas, meningiomas, and nonvestibular schwannomas was 6.0 mL (range: 0.5 to 111.2 mL), while the median volume across all 164 tumors was 4.3 mL.

Stage 1 of the trial enrolled 20 patients spanning the four tumor categories. Following results from an interim analysis, an additional 20 patients were recruited, specifically into the meningioma and nonvestibular schwannoma cohorts for Stage 2.

All patients initially received a daily dose of 90 mg of oral brigatinib for the first 7 days, with an escalated daily dose of 180 mg in the absence of adverse events. Each treatment cycle was defined as 28 days.

Out of the group, 18 patients discontinued treatment, primarily due to radiographic tumor progression (n=8) or personal choice (n=6).

Results revealed responses in four out of the target tumors: none in vestibular schwannomas, one in nonvestibular schwannomas, three in meningiomas, and none in ependymomas. Among non-targeted tumors, there were 35 responses: 10 out of 43 vestibular schwannomas, 11 out of 54 nonvestibular schwannomas, 13 out of 51 meningiomas, and 1 out of 5 ependymomas.

A total of 18 patients demonstrated tumor response, observed in 16 adults and 2 younger participants.

Overall, the projected mean annual growth rate of all tumors dropped from 65% pre-treatment to just 8% during treatment.

Moreover, pain severity, measured on a scale from 0 (no pain) to 3 (severe pain), decreased by 0.013 units per month.

Across the 40 patients, 462 adverse events of any cause were reported. Thirty-nine patients experienced treatment-related adverse events (AEs), with 12 patients reporting grade 3 events.

Grade 3 AEs included hypertension in five patients, elevated creatine kinase levels in two, and a single case each of diarrhea, dyspnea, pulmonary hypertension, rash, and scleritis. Significantly, there were no grade 4 or 5 AEs, treatment-related serious events, or any instances of interstitial pneumonitis.

Due to AEs, the dosage was reduced for eight patients and temporarily interrupted for six.

Plotkin and his team acknowledged several study limitations. The absence of a placebo control was a notable drawback, although justified due to the rarity of NF2-related schwannomatosis and the ongoing tumor growth in the patient cohort.

They also noted that the trial was conducted exclusively at specialized centers, which may limit the broader application of the findings.

Disclosures

This study received financial support from the Children's Tumor Foundation, among others.

Dr. Plotkin reported affiliations with Akouos, NF2 Therapeutics, NFlection Therapeutics, and SonALAsense.

Several co-authors disclosed relationships with industry partners.

Primary Source

New England Journal of Medicine

Source Reference: Plotkin SR, et al, "Brigatinib in NF2-related schwannomatosis with progressive tumors" N Engl J Med 2024; DOI: 10.1056/NEJMoa2400985.

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