Mirdametinib Boosts Outcomes, QOL in NF1-PN

Mirdametinib led to confirmed responses, enduring plexiform neurofibroma (PN) reductions, and meaningful pain and health-related quality of life (HRQOL) improvements in both children and adults with neurofibromatosis type 1-associated PNs (NF1-PN), according to data from the phase 2b ReNeu trial (NCT03962543) published in The Journal of Clinical Oncology.¹

The confirmed objective response rate (ORR) was 41% (n = 24; 95% CI, 29%-55%) among adult patients, which significantly exceeded the predefined minimum clinically relevant response threshold of 23% in this group (P <.001). Of the 24 confirmed responses, 23 (96%) were ongoing at the time of data cutoff, and 18 (75%) met or surpassed a duration of 12 months.

The median best percentage change in PN volume among adults was –41% (range, –90% to 13%) following treatment with mirdametinib. Of those with a confirmed response, 62% (n = 15/24) experienced a maximum reduction of more than 50% from baseline.

The treatment produced a confirmed ORR of 52% (n = 29; 95% CI, 38%-65%) among pediatric patients, which significantly exceeded the clinically relevant response rate of 20% for this group (P <.001). All responses (100%; n = 29) were enduring at the time of data cutoff, and 76% (n = 22/29) of patients had ongoing responses for at least 12 months.

Among pediatric patients, the median best percentage change in target PN volume was –42% (range, –91% to 48%). A maximum reduction from baseline of more than 50% was highlighted in 52% (n = 15/29) of children who achieved a confirmed response to mirdametinib.

“Plexiform neurofibromas can cause extreme pain, disfigurement, compression of internal organs, and impaired physical function. There is a substantial unmet need for a highly effective and well tolerated systemic therapy for these patients,” lead study author Christopher Moertel, MD, medical director of Pediatric Neuro-Oncology and Neurofibromatosis Programs and Kenneth and Betty Jayne Dahlberg Professor of Pediatrics at the University of Minnesota, stated in a press release on these results.² “The deep tumor volume reductions and significant improvements in pain and other [QOL] measures that we saw in the ReNeu trial, as well as having a formulation option for young children or those who have difficulty swallowing, underscore the potential for mirdametinib to be a valuable new treatment option for adults and children with NF1-PN.”

In the open-label, multi-center ReNeu trial, 58 adult patients and 56 children between the ages of 2 and 17 years old who had NF1-PN were assigned to receive mirdametinib capsules or tablets at 2 mg/m2 twice daily for up to 4 mg twice daily for 3 weeks on and 1 week off as part of 28-day cycles.

The trial’s primary end point was confirmed ORR as assessed via blinded independent central review. Secondary end points included duration of response and changes from baseline in patient-reported outcomes (PRO) measures of worst tumor pain severity, pain interference, and HRQOL.

The median age was 34 years (range, 18-69) in the adult cohort and 10 years (range, 2-17) in the child cohort. In each respective group, most patients were female (64% vs 54%), had progressive target PN at trial entry (53% vs 62%), PNs located in the head and neck (48% vs 50%), and pain-related morbidity (90% vs 70%). Prior therapies in each respective cohort included surgery (69% vs 36%), targeted medications (19% vs 14%), and radiotherapy (2% vs 0%).

Adults who received mirdametinib reported significant improvements in worst tumor pain severity (P <.001), pain interference (P <.001), and HRQOL (P = .02). At cycle 13, 71% of adult patients highlighted an improvement in overall status following treatment with mirdametinib.

At cycle 13 in the pediatric cohort, PROs indicated significant improvements in worst tumor pain severity (P = .003), patient-reported pain interference (P = .02), parent-reported pain interference (P = .03), and parent-reported in HRQOL (P = .005). Overall, 79% of pediatric patients reported an improvement in their status following study therapy.

Common treatment-related adverse effects (TRAEs) in adult patients included dermatitis acneiform (78%), diarrhea (48%), nausea (36%), vomiting (28%), and fatigue (21%). Dose interruptions, reductions, and terminations due to AEs were reported in 31%, 17%, and 22% of adults, respectively. Investigators reported 1 death due to COVID-19 that was not related to study treatment.

Among pediatric patients, common TRAEs included dermatitis acneiform (43%), diarrhea (38%), paronychia (30%), nausea (21%), ejection fraction decreases (20%), and blood creatinine phosphokinase increases (20%). AEs leading to dose interruptions, reductions, and discontinuations occurred in 30%, 12%, and 9% of patients, respectively. No symptomatic ejection fraction decreases, retinal vein occlusion, or serious TRAEs occurred in the pediatric cohort.

The FDA previously granted priority review to mirdametinib for adult and pediatric NF1-PN in August 2024 based on findings from the phase 2b ReNeu trial.3 The Prescription Drug User Fee Act date for mirdametinib in this indication is February 28, 2025.

References

1. Moertel CL, Hirbe AC, 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

2. SpringWorks Therapeutics announces publication of the pivotal phase 2b ReNeu trial evaluating mirdametinib in adults and children with NF1-PN in the Journal of Clinical Oncology. News release. SpringWorks Therapeutics, Inc. November 11, 2024. Accessed November 12, 2024. https://tinyurl.com/2s4jt33h

3. FDA Grants priority review to SpringWorks Therapeutics’ new drug application for mirdametinib for the treatment of adults and children with NF1-PN. News release. SpringWorks Therapeutics. August 28, 2024. Accessed November 12, 2024. https://shorturl.at/aTRMO