On November 11, 2024 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a commercial-stage biopharmaceutical company focused on severe rare diseases and cancer, reported that data from the pivotal, Phase 2b ReNeu trial of mirdametinib, an investigational MEK inhibitor, in adult and pediatric patients with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN), were published online in the Journal of Clinical Oncology (JCO) (Press release, SpringWorks Therapeutics, NOV 11, 2024, View Source [SID1234648076]). Data from ReNeu, which is a multi-center, single arm trial, were previously presented at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. The JCO e-publication can be accessed at the following link: View Source
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"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," said Christopher Moertel, M.D., Medical Director, Pediatric Neuro-Oncology and Neurofibromatosis Programs and Kenneth and Betty Jayne Dahlberg Professor of Pediatrics, University of Minnesota and lead author of the JCO publication. "The deep tumor volume reductions and significant improvements in pain and other quality of life 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."
As of the data cutoff of September 20, 2023, the ReNeu trial met its primary endpoint of confirmed objective response rate (ORR), as assessed by blinded independent central review. During the 24-cycle treatment phase (approximately 22 months), the ORR was 41% (95% CI, 29 to 55; n=24/58) in adults and 52% (95% CI, 38 to 65; n=29/56) in children receiving mirdametinib treatment. An efficacy analysis that also included patients who achieved a confirmed objective response after 24 cycles of mirdametinib treatment resulted in an ORR of 45% in adults (n=26/58) and 54% in pediatric (n=30/56) patients. Of the patients who achieved a confirmed objective response during the treatment phase, 96% of adults and 100% of children had durable responses at the time of data cut-off, with 75% of adults and 76% of children having met or exceeded 12 months in response. The median time to onset of confirmed response was 7.8 months (range: 4 to 19) in adults and 7.9 months (range: 4.1 to 18.8) in children. The median duration of treatment at data cutoff was 21.8 months (range: 0.4 to 45.6) in adults and 22 months (range: 1.6 to 40.0) in children, and the median duration of response had not been reached in either cohort.
Tumor volume reductions were deep and durable during the course of the study. The median best percentage change in target PN volume was –41% (range: –90 to 13%) in adults and –42% (range:–91 to 48%) in children. Among those with a confirmed objective response, 62% of adults and 52% of children achieved a best percent reduction in target tumor volume from baseline of >50%. From baseline to Cycle 13, both cohorts reported significant and clinically meaningful improvement in patient- or parent proxy-reported secondary endpoint outcome measures of worst tumor pain severity, pain interference, and health-related quality of life that began early and were sustained during treatment. These improvements began early and were generally sustained at the majority of timepoints over the course of the study. In addition, through an exploratory analysis, the tablet for oral suspension formulation of mirdametinib demonstrated high acceptability by patients and caregivers, providing a dosing option for patients with swallowing difficulties such as young children and adults with tumors in the head and neck region.
Mirdametinib was generally well tolerated in the ReNeu trial, with the majority of adverse events (AEs) being Grade 1 or 2. The most commonly reported treatment-related adverse events (TRAEs) occurring in >20% of adults were dermatitis acneiform (78%), diarrhea (48%), nausea (36%), vomiting (28%) and fatigue (21%). The most commonly reported TRAEs occurring in >20% of children were dermatitis acneiform (43%), diarrhea (38%), paronychia (30%; infection of the tissue adjacent to a fingernail or toenail), nausea (21%), ejection fraction decreased (20%), and increased blood creatine phosphokinase (20%). Among all study participants, 22% of adults and 9% of children discontinued treatment due to AEs.
"ReNeu is the largest multicenter trial conducted to date in patients with NF1-PN and we are very pleased that the JCO publication will serve as an important resource to further disseminate the robust efficacy and safety data of mirdametinib to the broader scientific and clinical community," said Jim Cassidy, M.D., Ph.D., Chief Medical Officer, SpringWorks Therapeutics. "We look forward to continuing to work with the FDA and EMA as they review our applications and are excited by the opportunity to make a meaningful impact on this underserved patient community."
About the ReNeu Trial
ReNeu (NCT03962543) is an ongoing, multi-center, open-label, single arm, Phase 2b trial evaluating the efficacy, safety, and tolerability of mirdametinib in patients ≥2 years of age with an inoperable NF1-associated PN causing significant morbidity. The trial enrolled 114 patients to receive mirdametinib at a dose of 2 mg/m2 twice daily (maximum dose of 4 mg twice daily) without regard to food. Mirdametinib was administered orally in a 3-week on, 1-week off dosing schedule as either a capsule or tablet for oral suspension. The primary endpoint is confirmed objective response rate assessed by proportion of patients with a ≥20% reduction in target tumor volume on consecutive scans during the 24 cycle treatment phase, as measured by MRI and assessed by blinded independent central review. Secondary endpoints include safety and tolerability, duration of response, and changes in patient reported outcomes from baseline to Cycle 13. The treatment phase of the trial is complete, and results were presented at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. Patients who completed the treatment phase were eligible to continue receiving treatment in the optional long-term follow up portion of the study, which is ongoing.
About NF1-PN
Neurofibromatosis type 1 (NF1) is a rare genetic disorder that arises from mutations in the NF1 gene, which encodes for neurofibromin, a key suppressor of the MAPK pathway.1,2 NF1 is the most common form of neurofibromatosis, with an estimated global birth incidence of approximately 1 in 2,500 individuals, and approximately 100,000 patients living with NF1 in the United States.3, The clinical course of NF1 is heterogeneous and manifests in a variety of symptoms across numerous organ systems, including abnormal pigmentation, skeletal deformities, tumor growth and neurological complications, such as cognitive impairment.5 Patients with NF1 have an 8 to 15-year mean reduction in their life expectancy compared to the general population.4
NF1 patients have approximately a 30-50% lifetime risk of developing plexiform neurofibromas, or PN, which are tumors that grow in an infiltrative pattern along the peripheral nerve sheath and that can cause severe disfigurement, pain and functional impairment; in rare cases, NF1-PN may be fatal.6,7 NF1-PNs are most often diagnosed in the first two decades of life.6 These tumors can be aggressive and are associated with clinically significant morbidities; typically, they grow more rapidly during childhood.8,9
Surgical removal of these tumors is challenging due to the infiltrative tumor growth pattern along nerves and can lead to permanent nerve damage and disfigurement.10 MEK inhibitors have emerged as a validated class of treatment for NF1-PN.11
About Mirdametinib
Mirdametinib is a potent, oral, CNS-penetrant, allosteric small molecule MEK inhibitor in development as a monotherapy treatment for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN) and low-grade glioma (LGG), and as a combination therapy for the treatment of several subsets of biomarker-defined metastatic solid tumors. Mirdametinib is an investigational drug for which safety and efficacy have not been established.
Mirdametinib is designed to inhibit MEK1 and MEK2, which occupy pivotal positions in the MAPK pathway. The MAPK pathway is a key signaling network that regulates cell growth and survival and plays a central role in multiple cancers and rare diseases when genetically altered.
The U.S. Food and Drug Administration (FDA) has accepted a New Drug Application (NDA) for mirdametinib in adults and children with NF1-PN. The NDA was granted Priority Review designation and has been given a Prescription Drug User Fee Act (PDUFA) action date of February 28, 2025. The European Medicines Agency (EMA) has validated the Marketing Authorization Application (MAA) for mirdametinib for the treatment of adult and pediatric patients with NF1-PN.
In addition, the FDA and the European Commission previously granted Orphan Drug designation for mirdametinib for the treatment of NF1. The FDA has also granted Fast Track designation for the treatment of patients ≥ 2 years of age with NF1-PN that are progressing or causing significant morbidity and Rare Pediatric Disease designation for the treatment of NF1.