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Almost half of adults and children with neurofibromatosis type 1 (NF1) responded to the investigational MEK inhibitor mirdametinib, a large multicenter study of the rare condition showed.

Overall, 53 of 114 patients met response criteria, defined as ≥20% reduction in target plexiform neurofibroma (PN) volume on consecutive MRI scans. Responses occurred in 24 of 58 adults and 29 of 56 children. PN reductions as great as 80% were observed.

The treatment was generally well tolerated, as the most common treatment-related adverse events (TRAEs) in adults and children were dermatitis acneiform and diarrhea, reported Christopher L. Moertel, MD, of the University of Minnesota in Minneapolis, and co-authors in the (JCO).

"The key take-home is that this is definitely a new therapy for adults with NF1," Moertel told MedPage Today. "In that respect, it's a breakthrough for our patients. The second thing is that the toxicity was acceptable and we really showed that people could remain on this therapy for a good long time. Some of the responses were what SpringWorks [the sponsor] called ... deep responses. Some patients had reductions in tumor size of well into 80%."

In the context section of the publication, JCO associate editor Jonathan P.S. Knisely, MD, of Weill Cornell Medicine in New York City, noted that the study "is a quantum leap forward for this disease."

"Studies evaluating mirdametinib's ability to prevent the development of new plexiform neurofibromas in NF1 patients and identifying optimal chronic dosing regimens are needed," he wrote.

An autosomal-dominant genetic condition, NF1 loss-of-function variants occur in about one per 2,500 births worldwide. The neurofibromin dysfunction and persistent MAP kinase (MEK) pathway activation. PNs are non-malignant nerve-sheath tumors that develop in 30-50% of patients, often causing pain, organ displacement/compression, impaired physical function, and disfigurement. The tumors also cause a substantial detriment in quality of life, Moertel and co-authors noted in their introduction.

Historically, surgery has been the primary option for NF1 but leads to life-altering morbidities, and tumor regrowth frequently occurs. MEK pathway inhibition is a validated treatment strategy, the authors noted, and the MEK inhibitor selumetinib (Koselugo) has FDA approval for patients ages 2 to 17 years with symptomatic, inoperable NF1-PN. Adults with NF1-PN have no approved therapies. Additionally, selumetinib is available only in tablets, which limits use in young children and patients with swallowing difficulties.

Mirdametinib is orally administered as a capsule or tablet for oral suspension. In a , eight of 19 patients (adults and children) with NF1-PN achieved partial responses with the drug, providing impetus for the pivotal phase IIb trial.

An for adults and children with NF1-PN is expected in early 2025, according to SpringWorks Therapeutics.

The investigators in the multicenter, open-label, single-arm trial enrolled adults and children with NF1 and inoperable, radiologically measurable PN causing significant morbidity. Patients received mirdametinib as a capsule or tablet for oral suspension, taken twice daily in 28-day cycles, with a schedule of 3 weeks on treatment and 1 week off. Planned treatment continued for 24 cycles. Patients had the option to continue treatment in a long-term follow-up phase of the study.

To assess the effect of mirdametinib on the natural history of PN, the investigators compared yearly change from baseline in PN volume and progression-free survival in ReNeu and the .

The primary endpoint was ≥20% reduction from baseline in target PN volume at any time during the 24 cycles of therapy. Data analysis included all 114 patients enrolled in the trial. Enrollment occurred from October 2019 to December 2021, and data cutoff occurred Sept. 20, 2023.

The results showed that 41% of adult patients met the prespecified primary endpoint, which significantly exceeded the prespecified minimum clinical relevant response rate of 23% for adults (P<0.001). All but one of the objective responses remained durable to data cutoff. Two additional patients achieved partial response during the long-term follow-up phase (cycle 28 and cycle 32).

Median time to response was 7.8 months, and median duration of response had yet to be reached. Median treatment duration was 21.8 months. Median best percentage change in target PN volume was -41%, and 62% of responding patients had a maximum reduction greater than 50%.

In the pediatric cohort, 52% of patients achieved a confirmed objective response, significantly (P<0.001) greater than the prespecified clinically relevant response rate for children of 20%. One additional patient had a confirmed partial response during cycle 32. All of the 29 initial responses remained durable at data cutoff, and 22 (76%) responses lasted 12 months or longer.

Median time to response was 7.9 months, and median response duration had yet to be reached. Median best percentage change in target PN volume was -42%, and 15 (52%) responding patients had a maximum achieved volume reduction greater than 50%.

The most common TRAEs in adults were dermatitis acneiform (78%), diarrhea (48%), nausea (36%), vomiting (28%), and fatigue (21%). The most common grade ≥3 TRAE was dermatitis acneiform (9%).

Among children, the most common TRAEs were dermatitis acneiform (43%), diarrhea (38%), paronychia (30%), nausea (21%), decreased ejection fraction (20%), and increased blood creatinine phosphokinase (CPK; 20%). The most common grade ≥3 TRAE was increased CPK (7%).

Increased experience with MEK inhibitors, including selumetinib, has led to improved management of toxicities, said Moertel.

"Skin care is particularly important," he said. "By being on top of that and helping patients with the skin side effects, we were able to keep patients on the therapy longer and achieve better responses over the long term. And it was great for quality of life."

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