FDA Grants Priority Review to Mirdametinib in Adult/Pediatric NF1-PN

A PDUFA date has been set for February 28, 2025, for the potential approval of mirdametinib in neurofibromatosis type 1-associated plexiform neurofibromas.

The FDA has granted priority review to a new drug application for mirdametinib for the treatment of pediatric and adult patients with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN), according to a news release from SpringWorks Therapeutics Inc.¹

A Prescription Drug User Fee Act date of February 28, 2025, has been set by the FDA. The agency does not plan to hold any advisory committees to discuss the submitted application.

The European Medicines Agency (EMA) has also validated a marketing authorization application for mirdametinib in the aforementioned population. If approved, this would be the first for this indication.

“These significant milestones bring us closer to our goal of delivering a transformative medicine to both adults and children with NF1-PN in the [United States] and Europe,” Saqib Islam, chief executive officer of SpringWorks, said in the press release. “[Patients] living with NF1-PN are in need of new advances and we look forward to working with the FDA and EMA during their review processes as we prepare to bring our second medicine to patients suffering from devastating diseases.”

The phase 2b ReNeu trial (NCT03962543) assessed the use of mirdametinib in patients 2 years and older with NF1-associated PN that caused significant morbidity. Efficacy and safety results were presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.²

The trial analyzed 114 patients for 24 cycles. Patients were given mirdametinib at 2 mg/m² orally twice daily with a maximum dose of 4 mg for 3 weeks. The primary end point was confirmed objective response rate (ORR). Secondary end points included duration of response, patient-reported outcomes, and safety and tolerability.

In the adult cohort (n = 58) the median patient age was 34 years old (range, 18-69); in the child cohort (n = 56) the median age was 10 years old (range, 2-17). Between the 2 cohorts, respectively, 64% and 54% were female, the median volume of target PN was 196 mL (range, 1-3457) and 99 mL (range, 5-3630), the progression of target PN at entry was 53% and 62%, and the primary location of target PN was the head and neck in 48% and 50% of patients. The most common type of morbidity was pain in 90% and 70% of patients.

For the adult cohort, the confirmed ORR was 41% (P <.001), the median best change in tumor volume was –41%, and those with a confirmed ORR who had a deep response (>50% tumor volume reduction) was 62%. Additionally, the median duration of treatment was 22 months, the median time to onset of response was 7.8 months (range, 4-19), and the median duration of response (DOR) was not reached.

In the pediatric cohort, the confirmed ORR was 52% (P <.001), the median best change in tumor volume was –42%, and a deep response was noted in 52% of those with a confirmed ORR. The median duration of response was 22 months, the median time to onset of response was 7.9 months (range, 4-19), and the median DOR was not reached.

Worse tumor pain was reported by patients in both groups. In the adult cohort, the least square mean change from baseline at cycle 13 was –1.3 (P <.001), and for the pediatric cohort the least square mean change from baseline at cycle 13 was –0.8 (P = .003).

Health-related quality of life was also assessed, and the least square mean change from baseline at cycle 13 in the adult cohort was 3.9 (P = .018), and in the pediatric cohort, it was 4.0 (P = .096) which was self-reported and 5.6 (P = .005) that was parent-proxy reported.

Any-grade treatment-related adverse effects (TRAEs) occurred in 98% of patients in the adult cohort and 95% in the pediatric cohort, the most common of which were dermatitis acneiform (78% vs 43%), diarrhea (48% vs 38%), and nausea (36% vs 21%).Grade 3 or higher TRAEs occurred in 16% and 25% of adult and pediatric patients, respectively, and comprised dermatitis acneiform (9% vs 2%), fatigue (2% vs 0%), and decreased ejection fraction (0% vs 2%), and increased blood creatinine phosphokinase (2% vs 7%). Serious TRAEs were noted in 2% vs 0% of adults and children.

“Plexiform neurofibromas may sit next to or surround vital organs and can cause serious medical complications for patients. While progress has been made, there remains a pressing need for more treatment options, particularly for adults who currently have no approved therapy,” Annette Bakker, PhD, chief executive officer of the Children’s Tumor Foundation (CTF) and board chair of CTF Europe, concluded in the press release.

References

1. 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 August 28, 2024. https://shorturl.at/aTRMO
2. Mortel CL, Hirbe AC, Shuhaiber HH, et al. ReNeu: A pivotal phase 2b trial of mirdametinib in children and adults with neurofibromatosis type 1 (NF1)-associated symptomatic inoperable plexiform neurofibroma (PN). J Clin Oncol. 2024;42(16):3016. doi.10.1200/JCO.2024.42.16_suppl.301