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Mirdametinib Produces Sustained Reduction of Plexiform Neurofibroma in Phase 2b ReNeu Trial
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For up to 24 months, patients on mirdametinib demonstrated significant improvements in pain severity, pain interference, and health-related quality of life, in addition to deep and durable plexiform neurofibroma volume reductions.
Christopher L. Moertel, MD
Recently presented data from the pivotal phase 2b ReNeu study (NCT03962543), the largest such trial of patients with neurofibromatosis type 1 (NF1)-associated symptomatic inoperable plexiform neurofibroma (PN), showed that treatment with investigational mirdametinib (SpringWorks Therapeutics) resulted in statistically significant objective response rate (ORR) and sustained reductions in PN volume. Coupled with improvements in pain severity, pain interference, and health-related quality of life (HRQoL), the tablet therapy may be a potentially therapeutic option for patients with NF1 PN across all ages.
PN is an irregular, thick, and noncircumscribed tumor of peripheral nerve sheath which can involve multiple nerve fascicles. This disease is a rare entity and occurs in approximately 5-15% of patients with NF1. ReNeu, a multicenter, open-label study, featured 114 patients with NF1 PN, 58 adult and 56 pediatric, who received mirdametinib, a MEK1/2 inhibitor, for up to 24 months.
Presented at the 2024 ASCO Annual Meeting, patients in the study received the investigational therapy as a capsule or dispersible tablet (2 mg/m2 BID, max 4 mg BID) without regard to food in 3 week on/1 week off 28-day cycles. Minimum clinically relevant ORR, the primary end point, was defined as at least a 23% reduction of target PN volume for adults (≥18 yrs) and 20% for pediatrics (2-17 yrs). As of the September 20, 2023 data cutoff, blinded independent central review (BICR)-confirmed ORR during the treatment phase was 41% (95% CI, 29-55; P <.001 vs null) in adults and 52% (95% CI, 38-65; P <.001 vs null) in pediatric patients.
Led by Christopher L. Moertel, MD, medical director of the Pediatric Neuro-Oncology and Neurofibromatosis Programs at the University of Minnesota, patients were able to enter an long-term follow-up phase where 2 adult participants and 1 pediatric participant had a confirmed response. In the regular initial phase, median target PN volumetric best response from baseline was –41% (min: –90, max: 13) and –42% (–91, 48) in adult and pediatric patients, respectively. As of the data cutoff, median treatment duration was 22 months for each cohort and median duration of response was not reached.
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Between the adult and pediatric populations, the median time to response was 7.8 (4-19) months and 7.9 (4-19) months, respectively. Both groups demonstrated statistically significant improvements after 13 cycles of treatment on pain severity, defined through Numerical Rating Scale-11, pain interference, assessed through Pain Interference Index, and key QoL (PedsQL).
In terms of safety, the most frequent treatment-emergent adverse events (TEAEs), occurring in more than 35% of patients, were dermatitis acneiform, diarrhea, nausea, and vomiting in adults. For pediatrics, diarrhea, dermatitis acneiform, and vomiting were mostly observed. In total, 16% and 25% of adult and pediatric patients, respectively, had at least grade 3 treatment-related AEs, and 22% and 9%, respectively, discontinued because of TEAEs.
PN can occur anywhere in the body outside of the brain and spinal cord. They can occur on the face, neck, arms, legs, back, chest, abdomen, and internal organs. These neurofibromas can cause severe pain, mobility problems, vision and hearing loss, high blood pressure, and other medical problems. Treatment options for PNs include surgery, medications like MEK inhibitors, and debulking procedure. In 2020, the FDA approved selumetinib (Koselugo; AstraZeneca), a MEK inhibitor, as a treatment option for patients aged 3 to 18 years with symptomatic, inoperable PN.2
