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For patients with NF2-related schwannomatosis and progressive tumors, the ALK inhibitor brigatinib (Alunbrig) was associated with radiographic response for multiple tumor types, as well as improvements in hearing and other clinical factors, a small phase II platform trial showed.

Among 40 patients with vestibular schwannoma, nonvestibular schwannoma, meningioma, or ependymoma, the percentage of target tumors with a radiographic response was 10%, exceeding the historical control of 2% (P=0.02), reported Scott R. Plotkin, MD, PhD, of Massachusetts General Hospital and Harvard Medical School in Boston, and colleagues.

The percentage of patients who had a response in all 153 evaluable tumors was 23%, they noted in the .

"In an orally available, well-tolerated chemotherapy, we can see shrinkage of multiple types of tumors associated with NF2-related schwannomatosis, but most particularly for meningiomas and nonvestibular schwannomas," Plotkin told 名媛直播.

Additionally, for a condition that can eventually lead to hearing loss, treatment with brigatinib improved hearing in one-third of patients, "really suggesting some benefit to hearing as well as to tumor shrinkage," added Plotkin, who also presented results from the study at the in Brussels.

Among 37 eligible ears, hearing improved in 13 during treatment, while improvement in hearing sensitivity occurred in 10 of 44 ears.

NF2-related schwannomatosis (previously called neurofibromatosis type 2) is a rare, progressive genetic condition in which people are born with only one normal copy of the NF2 gene, Plotkin explained. For that reason they are predisposed to multiple tumors -- as well as multiple tumor types -- that develop on the covering of the brain or grow along the nerves in the brain, spinal cord, and other locations.

Brigatinib -- the first drug the researchers evaluated in the platform trial -- is approved by the FDA for the treatment of adult patients with ALK-positive, metastatic non-small cell lung cancer, and has demonstrated preclinical activity in NF2-driven nonvestibular schwannoma and meningioma.

"Without treatment, progressive tumors can lead to complete deafness, multifocal weakness, immobility, and death," Plotkin and colleagues wrote, adding that while surgery is the standard of care, the risk of iatrogenic neurologic injury increases with each surgery.

One of the challenges, Plotkin said, "is how do you treat patients who have these multiple tumor types?"

"We're looking for novel clinical trial designs to help us better evaluate drugs for rare patients," he noted. "And to a certain degree, this was successful in showing some of the strengths of this model, as well as maybe some of the weaknesses that we're going to continue to work on. I also think it's a step forward in terms of our clinical infrastructure for this condition."

The researchers designed the trial (in which they are evaluating multiple drugs) with a basket design, enrolling 40 patients who had progressive tumors of the four tumor types (10 vestibular schwannomas, eight nonvestibular schwannomas, 20 meningiomas, and two ependymomas).

While the trial was designed to assess tumor shrinkage in these target tumors, the researchers also identified non-target tumors in these patients for evaluation as well.

Median patient age was 26 years, 70% were female, 70% were white, and 10% each were Black or Asian. Prior to the trial, patients had undergone surgery (90%), chemotherapy (55%), or radiation (20%). At baseline, the median volume for 38 target vestibular schwannomas, meningiomas, and nonvestibular schwannomas was 6.0 mL (ranging 0.5 to 111.2), with a median volume for all 164 tumors of 4.3 mL.

Twenty patients across all four tumor types were enrolled in stage 1 of the trial. Based on the results from a prespecified interim analysis, 20 more were enrolled into the baskets for meningioma and nonvestibular schwannoma in stage 2.

Patients were treated with oral brigatinib at a dose of 90 mg daily for 7 days, with the dose eventually increased to 180 mg daily in the absence of toxic events. One cycle of treatment was defined as a 28-day period.

Eighteen patients discontinued treatment, mostly due to radiographic progression of target tumors (n=8), or patient choice (n=6).

Of the four responses among target tumors, there were none in vestibular schwannomas, one in nonvestibular schwannomas, three in meningiomas, and none in ependymomas. The 35 responses in the non-target tumors included 10 of 43 vestibular schwannomas, 11 of 54 nonvestibular schwannomas, 13 of 51 meningiomas, and one of five ependymomas.

At least one tumor response occurred in 18 patients, which was reported in 16 of 28 adults and in two of 12 adolescents or young adults.

The projected mean annualized growth rate for all tumors decreased from 65% before treatment to 8% during treatment.

The severity of reported pain decreased by 0.013 units per month, based on a scale from 0 (no pain) to 3 (severe pain).

A total of 462 adverse events of any cause occurred in all 40 patients. Treatment-related AEs of any grade occurred in 39 patients, and grade 3 AEs occurred in 12 patients.

Grade 3 AEs included hypertension (five patients); elevated creatine kinase level (two patients); and diarrhea, dyspnea, pulmonary hypertension, rash, and scleritis (one patient each). No grade 4 or 5 AEs, treatment-related serious AEs, or events of interstitial pneumonitis occurred.

AEs led to dose reductions in eight patients and dose interruptions in six patients.

Plotkin and colleagues acknowledged several limitations to their study. For example, they pointed out that it did not include a placebo control, "given the rarity of [NF2-related schwannomatosis] and the inclusion of patients with actively growing tumors."

They also noted that the trial only included patients at specialty centers, potentially limiting the generalizability of the findings.

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