Mirdametinib Induces Significant Responses in NF1-Associated Plexiform Neurofibroma

Christopher L. Moertel, MD

Mirdametinib elicited significant responses and showcased a manageable toxicity profile when administered to adults and children with neurofibromatosis type 1 (NF1)–associated symptomatic inoperable plexiform neurofibroma (NF1-PN), according to data from the phase 2b ReNeu trial (NCT03962543) presented during the 2024 ASCO Annual Meeting.¹

With a median duration of therapy (DOT) of 22 months, the agent led to a confirmed objective response rate (ORR) of 41% by blinded independent central review (BICR) in adults (n = 24/58; P < .001 vs null hypothesis); the median best change in tumor volume was a reduction of 41% (range, –90 to 13). Moreover, 62% of responders experienced deep responses, with tumor volume reductions greater than 50%. The median time to onset of response was 7.8 months (range, 4-19) and the median duration of response (DOR) was not reached (NR).

The agent induced a confirmed ORR of 52% in children (n = 29/56; P < .001 vs null hypothesis) with a median DOT of 22 months; the median best change in tumor volume was a reduction of 42% (range, –91 to 48). Of the children who responded to the agent, 52% experienced a deep response, with a reduction in tumor volume greater than 50%. The median time to onset of response was 7.9 months (range, 4-19) and the median DOR was NR.

In the long-term follow-up phase, 2 additional adults and 1 additional child achieved a confirmed partial response.

“Mirdametinib demonstrated deep and sustained tumor volume reductions and improvement in patient (and parent proxy) reported pain and health-related quality of life [HRQOL] in adults and children [with NF1-associated symptomatic inoperable plexiform neurofibroma]," lead study author Christopher L. Moertel, MD, of University of Minnesota Health Clinics and Surgery Center and University of Minnesota Masonic Children’s Hospital, said in an oral presentation of the data during the meeting.

The multicenter, open-label, pivotal phase 2 ReNeu study enrolled adults aged 18 years or older (n = 58) and children between the ages of 2 and 17 years (n = 56) who had inoperable NF1-associated plexiform neurofibroma causing significant morbidity. Mirdametinib was administered as a capsule or a dispersible tablet at a dose of 2 mg/m² twice daily as part of a 3-weeks-on/1-week-off schedule for 24, 28-day cycles. After the treatment phase, patients were followed for safety for 30 days and optional long-term follow-up.

The primary end point of the study was confirmed ORR defined as the percentage of patients who achieved at least a 20% reduction in target tumor volume by MRI on consecutive scans assessed by BICR. Important secondary end points include DOR; patient-reported outcomes from baseline to cycle 13, including pain severity and HRQOL; and safety and tolerability.

The median patient age in the adult group was 34 years (range, 18-69). More than half of patients were female (64%). The median volume of target plexiform neurofibroma (PN) was 196 mL (range, 1-3457); 53% of target PNs were progressing at trial entry. The most common location of target PN was head and neck (48%), followed by lower or upper extremities (29%), paraspinal (9%), torso (9%), and other (5%).

In the children group, the median patient age was 10 years (range, 2-17), and slightly more than half of patients (54%) were female. The median volume of target PN in this group was 99 mL (range, 5-3630); 62% of target PNs were progressing at the time of trial entry. Location of target PN was head and neck (50%), lower or upper extremities (14%), torso (14%), other (14%), and paraspinal (7%).

Types of PN-related morbidity in the adult and children groups was pain (90%; 70%), followed by disfigurement of major deformity (52%; 50%), motor dysfunction or weakness (40%; 27%), other (17%; 21%), and airway dysfunction (5%; 12%).

“[This was the] largest multicenter NF1-PN trial to date, prospectively utilized BICR to confirm target tumor response…[and this was the] largest percentage reduction in target PN volume published in clinical trials of targeted agents,” the study authors wrote. “[An] improvement in pain severity [NRS-11] and HRQOL [PedsQL] from baseline [was observed.]”

Regarding safety in the adult population (n = 58), any-grade treatment-related adverse effects (TRAEs) occurred in 98% of patients and 16% experienced grade 3 or higher effects. The most common TRAEs experienced in 20% or more of patients in this group included dermatitis acneiform (any grade, 78%; grade ≥3, 9%), diarrhea (48%; 0%), nausea (36%; 0%), vomiting (28%; 0%), fatigue (21%; 2%), decreased ejection fraction (12%; 0%), increased blood creatinine phosphokinase (10%; 2%), and paronychia (2%; 0%). Serious TRAEs were experienced by 2% of patients. TRAEs led to dose reductions and interruptions for 17% and 9% of patients, respectively. Twenty-one percent of patients experienced TRAEs that led to discontinuations.

In the children group, any-grade TRAEs were experienced by 95% of patients and 25% experienced grade 3 or higher effects. The most common TRAEs experienced by at least 20% of patients in this group were dermatitis acneiform (any grade, 43%; grade ≥3, 2%), diarrhea (38%; 2%), paronychia (30%; 0%), nausea (21%; 0%), decreased ejection fraction (20%; 2%), increased blood creatinine phosphokinase (20%; 7%), vomiting (14%; 0%), and fatigue (9%; 0%). TRAEs led to dose reductions and interruptions for 12% and 14% of patients, respectively. TRAEs led to treatment discontinuation for 9% of patients.

“Together with a dispersible tablet formulation, these results underscore mirdametinib’s potential to become an important new treatment option for NF1-PN patients across all ages,” the study authors concluded.

In August 2024, the FDA accepted and granted priority review to the new drug application seeking the approval of mirdametinib for use in adult and pediatric patients with NF1-PN.² The decision date has been set for February 28, 2025. A marketing authorization application for the agent in the same population was also validated by the European Medicines Agency.

References

1. Moertel CL, Hirbe AC, Shuhaiber HH, et al. ReNeu: A pivotal phase 2b trial of mirdametinib in adults and children with neurofibromatosis type 1 (NF1)-associated symptomatic inoperable plexiform neurofibroma (PN). J Clin Oncol. 2024;42(suppl 16):3016. doi:10.1200/JCO.2024.42.16_suppl.3016
2. 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, Inc. August 28, 2024. Accessed September 2, 2024. https://ir.springworkstx.com/news-releases/news-release-details/fda-grants-priority-review-springworks-therapeutics-new-drug