Mirdametinib for Adult and Pediatric Patients With Neurofibromatosis Type 1 With Plexiform Neurofibromas

In the largest multicenter trial for patients with neurofibromatosis type 1 with plexiform neurofibroma (NF1-PN), mirdametinib significantly improved the objective response rate (ORR) as assessed by blinded independent central review (BICR), with deep and durable PN volume reduction and early, sustained, clinically meaningful improvement in pain and health-related quality of life measures.

There are limited treatment options for patients with NF1-PN — surgery has been the primary treatment but comes with “life-altering morbidities and tumor regrowth,” as Christopher L. Moertel, MD, University of Minnesota, Minneapolis, and coauthors, wrote. The MEK inhibitor selumetinib is approved for pediatric patients “but is only available as capsules, limiting its use in young children or those with difficulty in swallowing,” and there are currently “no therapies…approved for adults with NF1-PN.”

Mirdametinib is an investigational small-molecule MEK1/2 inhibitor that is highly selective, potent, allosteric, and penetrates the central nervous system. This therapy can be administered orally as a capsule or tablet for oral suspension without any fasting requirement.

The multicenter, open-label, single-arm, phase 2b ReNeu trial enrolled 58 adults, ≥18 years of age, and 56 children, 2 to 17 years of age, with NF1-PN that has caused significant morbidities. Patients received 2 mg/m2 mirdametinib (maximum of 4 mg twice daily) in 28-day cycles consisting of 3 weeks on and 1 week off. The primary end point was confirmed ORR assessed by BICR of volumetric magnetic resonance imaging. ORR was defined as the proportion of patients with a ≥20% reduction of target PN volume from baseline on consecutive scans during the 24-cycle treatment phase. Secondary efficacy end points included duration of response and a change from baseline to cycle 13 for patient-reported outcome, or parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and health-related quality of life.

There were 24 of 58 adults (41%) and 29 of 56 children (52%) who achieved a BICR-confirmed ORR during the treatment phase. An additional 2 adults and 1 child had a confirmed response during long-term follow-up. Of the 24 adults with ORR, 23 remained durable at the data cut-off date. All 29 children who achieved ORR remained durable at the data cut-off date. In both the adult and child cohorts, the median durations of response had not been reached. The median target PN volumetric best response was –41% among the adult cohort and –42% among the child cohort. Of the adults and children who achieved an ORR, 62% and 52%, respectively, achieved a maximum reduction from baseline of >50%.

There was a significant and clinically meaningful improvement in patient- or parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and health-related quality of life for both adult and child cohorts. These improvements were observed early and sustained during the treatment. The most frequent treatment-related adverse events were dermatitis acneiform, diarrhea, and nausea among the adult cohorts, and dermatitis acneiform, diarrhea, and paronychia among the child cohort.

Dr Moertel, et al, concluded, “given these data, along with availability as a tablet for oral suspension, mirdametinib has the potential to be a new treatment option in adults and children with NF1-PN.”

Journal of Clinical Oncology associate editor Jonathan P. S. Knisely, MD, Weill Cornell Medicine, New York, New York, called these results “a quantum leap forward for this disease,” adding that “studies evaluating mirdametinib’s ability to prevent the development of new plexiform neurofibromas in NF1 patients and identifying optimal chronic dosing regimens are needed.”

Source:

Moertel CL, Hirbe AV, Shuhaiber HH, et al. ReNeu: A pivotal, phase IIb trial of mirdametinib in adults and children with symptomatic neurofibromatosis type 1-associated plexiform neurofibroma. J Clin Oncol. Published online November 8, 2024. doi:10.1200/JCO.24.01034