Mirdametinib Improves HRQOL in Adult and Pediatric Patients With NF1-PN

Treatment with the oral, highly selective, small-molecule MEK1/2 inhibitor mirdametinib (PD-0325901) led to sustained, significant, and clinically meaningful improvements in health-related quality of life (HRQOL) from baseline in adult and pediatric patients with neurofibromatosis type 1–associated plexiform neurofibroma (NF1-PN), according to data from the phase 2 ReNeu trial (NCT03962543). Data from this study, which also met its primary end point of overall response rate (ORR), were presented at the 2024 Society for Neuro-Oncology (SNO) Annual Meeting.¹

In adult patients, mirdametinib generated improvements in HRQOL per the Pediatric Quality of Life (PedsQL) Total Score, with a least square (LS) mean change from baseline to cycle 13 of 3.9 (standard error [SE], 1.6; P = .018). In children, the LS mean change from baseline to cycle 13 was 4.0 (SE, 2.4; P = .096) in the patient-report group and 5.6 (SE, 1.9; P = .005) in the parent proxy–report group. These scores improved by cycle 3 and were sustained at most time points through cycle 13.

“We had multiple points where there was significant change from baseline to cycle 13,” presenting author Rene Y. McNall-Knapp, MD, a pediatric hematologist-oncologist with the Jimmy Everest Center at Oklahoma Children’s Hospital, OU Health, in Oklahoma City, explained in a presentation of the data. “In physical functioning, all populations showed significant improvement from baseline. In emotional functioning, the parents [of pediatric patients] reported improved outcomes, and in social functioning, [these outcomes were] the same. In school/work functioning, adult patients had a significant improvement in QOL.”

Trial Rationale and Design

Between 30% and 50% of patients with NF1 develop nonmalignant peripheral nerve sheath tumors, or PN, which can lead to pain, disfigurement, impaired physical functioning, and substantial deterioration in HRQOL. Because no pharmacologic therapies have been approved for adults with this disease, there is a need for effective and tolerable NF1-PN treatment options that improve HRQOL in patients. The investigational, potent, allosteric, central nervous system–penetrating agent mirdametinib is therefore under investigation in patients with NF1-PN.

Patients 2 years of age and older with inoperable NF1-PN causing significant morbidity were eligible for enrollment in ReNeu and stratified into 2 treatment groups: adults 18 years and older (n = 58) and children ages 17 years and younger (n = 56).

Each treatment phase was 24 cycles, and each cycle was 28 days. Eligible patients were treated with mirdametinib in a capsule or tablet form for oral suspension at 2 mg/m2 twice a day at a maximum of 2 mg twice daily for 3 weeks on and 1 off; no fasting was required for enrolled patients. Following treatment, patients went to a safety-follow up period for 30 days or an optional long-term follow-up into the 30-day safety follow-up.

The primary end point of the trial was confirmed ORR by blinded independent central review, and secondary end points included duration of response (DOR), patient/parent proxy-reported outcomes from baseline at cycle 13 (worst tumor pain severity [NRS-11], pain interference, and HRQOL [PedsQL]), and safety and tolerability.

Previously Reported Efficacy Findings

The median age of the adult patients was 34 years (range, 18-69); the pediatric patients had a median age of 10 years (range, 2-17). Most patients in both groups were female (adult, 64%; pediatric, 54%). Types of PN-related morbidities included pain (90%; 70%), disfigurement or major deformity (52%; 50%), motor dysfunction or weakness (40%; 27%), and airway dysfunction (5%; 12%); other PN-related morbidities were also reported (17%; 21%).

Previously reported data from ReNeu presented at the 2024 ASCO Annual Meeting showed that the confirmed ORR with mirdametinib was 41% (P < .001) among the adult patients and 52% (P < .001) in the pediatric patients enrolled during the treatment phase, though an additional 2 adults and 1 child achieved confirmed responses during the long-term follow-up phase. In both adults and children, the median best target PN volume reduction from baseline was greater than 40%. More than 50% of patients with a confirmed response achieved a deep response (> 50% best PN volume reduction from baseline). Additionally, the median duration of treatment was 22 months, and the median DOR was not reached.

“In both adults and children, this was a very durable response, and [the agent] had a very manageable safety profile, with most of the adverse effects [AEs] being grade 1 or 2,” McNall-Knapp continued.

Additional HRQOL Outcomes

“[For] the HRQOL end points, we used the PedsQL Index. It is validated in both pediatrics and adults despite its name,” she explained in the presentation.

In the adult patients, the mean PedsQL score at baseline was 67 (range, 24-100). In the pediatric patients, PedsQL scores were reported by patients (n = 50) and parent proxies (n = 55). At baseline, the mean patient-reported score for children was 76 (range, 18-100), and the mean parent proxy–reported score was 72 (range, 23-99).

Functioning subscales of the PedsQL score included physical, emotional, social, and school/work. At baseline, the physical PedsQL functioning subscale scores in the adult reports, child patient reports, and child parent proxy reports were 58 (range, 0-100), 78 (range, 12-100), and 74 (range, 0-100), respectively. The baseline emotional scores in these respective populations were 68 (range, 5-100), 75 (range, 5-100), and 73 (range, 35-100). The baseline social scores in these respective populations were 80 (range, 10-100), 81 (range, 20-100), and 73 (range, 5-100). The baseline school/work scores in these respective populations were 67 (range, 15-100), 70 (range, 15-100), and 66 (range, 0-100).

In an analysis of patients who could have achieved clinically meaningful improvements in PedsQL total score, 37% of adult patients (n = 27), 45% of pediatric patients according to patient-reported outcomes (n = 29), and 47% of pediatric patients according to parent proxy–reported outcomes (n = 32) achieved a clinically meaningful improvement in HRQOL at cycle 13 from baseline with the agent.

Regarding physical functioning among adults (n = 29), children (patient-reported; n = 23), and children (parent proxy–reported; n = 26), 28%, 44%, and 50% of patients in these respective subgroups achieved clinically meaningful improvements from baseline to cycle 13. Clinically meaningful improvements in emotional functioning among adults (n = 26), children (patient-reported; n = 25), and children (parent proxy–reported; n = 33), were observed in 23%, 56%, and 64% of patients in these respective subgroups.

Regarding social functioning among adults (n = 17), children (patient-reported; n = 18), and children (parent proxy–reported; n = 25), 35%, 56%, and 48% of patients in these respective subgroups achieved clinically meaningful improvements from baseline to cycle 13. Clinically meaningful improvements in school/work functioning among adults (n = 24), children (patient-reported; n = 24), and children (parent proxy–reported; n = 28), were observed in 21%, 46%, and 39% of patients in these respective subgroups.

“Approximately one-quarter of adults…and approximately half of children…had clinically relevant improvements [in total HRQOL across the subscales],” she added.

Safety Findings

Regarding safety, any-grade treatment-related AEs (TRAEs) occurred in 98% of adults (n = 58) and 95% (n = 56) of children; these included AEs of grade 3 severity in both adult (16%) and children (25%). In adults, the most frequently reported any-grade TRAEs were dermatitis acneiform (78%), diarrhea (48%), and nausea (36%), whereas the most frequently reported any-grade AEs in children were dermatitis acneiform (43%), diarrhea (38%), and paronychia (30%).

Serious TRAEs occurred in 2% of adults and no pediatric patients. Treatment interruptions due to TRAEs were reported in 9% of adults and 14% of children; dose reductions due to TRAEs occurred in 17% of adults and 12% of children; and discontinuations due to TRAEs were observed 21% of adults and 9% of children.

“Mirdametinib has the potential to be a new treatment option for children and adults with NF-related PNs,” McNall-Knapp concluded.

Disclosures: Dr McNall-Knapp disclosed receiving institutional research funding from AstraZeneca, Incyte, Jazz Pharmaceuticals, Pfizer, and SpringWorks Therapeutics, Inc.; the ReNeu trial was sponsored by SpringWorks Therapeutics, Inc.

Reference

Babovic-Vuksanovic D, Hirbe AC, Moertel CL, et al. Health-related quality of life (HRQoL) in adults and children with neurofibromatosis type 1-associated plexiform neurofibroma (NF1-PN) treated with mirdametinib in the pivotal phase 2b ReNeu trial. Presented at: 2024 SNO Annual Meeting; November 21-24, 2024; Houston, TX. Abstract QOL-08.