Mirdametinib (MEK Inhibitor)
Mirdametinib is an oral, small molecule MEK inhibitor in development as a monotherapy treatment for neurofibromatosis type 1‑associated plexiform neurofibromas, or NF1‑PN, and as a combination therapy for the treatment biomarker defined metastatic cancers with mutations in the MAPK pathway, such as in RAS and RAF.
Mirdametinib is designed to inhibit MEK1 and MEK2. MEK proteins occupy a pivotal position in the MAPK pathway, which is a key signaling network that regulates cell growth and survival, and that plays a central role in multiple oncology and rare disease indications.
NF1 is a rare genetic disorder that arises from mutations in the NF1 gene. Patients with NF1 have a 30% to 50% lifetime risk of developing plexiform neurofibromas (PN), which are peripheral nerve sheath tumors that result in severe pain, disfigurement and a shortened life span.
A Phase 2 investigator-initiated trial of mirdametinib in adolescents and adults with NF1-PN showed encouraging efficacy results and mirdametinib was also generally well-tolerated in the study.
- The Phase 2 study enrolled 19 adolescents and adults with inoperable and symptomatic or growing NF1-PNs and demonstrated tumor shrinkage in 42 percent of patients.
- In this study, mirdametinib given at 2mg/m2 (up to 4mg) twice per day on a 3-week on, 1-week off schedule and was generally well-tolerated.
- The most commonly reported treatment-emergent grade 2 or higher adverse events were acneiform rash, fatigue and nausea. Five patients in the study required a dose reduction, all due to grade 2 events. No grade 4 or higher toxicities were reported.
SpringWorks is conducting a multi-center, open-label Phase 2b clinical trial (the ReNeu trial) to evaluate the efficacy, safety, and tolerability of mirdametinib in patients two years of age and older with an inoperable NF1-PN that is causing significant morbidity.
The U.S. Food and Drug Administration (FDA) and the European Commission granted Orphan Drug designation for mirdametinib for the treatment of NF1, and the FDA granted Fast Track designation for the treatment of patients ≥ 2 years of age with NF1-PN that are progressing or causing significant morbidity.
MEK inhibitors hold promise for use in targeted combination therapies for highly prevalent, genetically defined cancers owing to the critical role that the MAPK pathway plays in the growth and proliferation of a large number of cancer types (including lung cancer, pancreatic cancer, colorectal cancer, endometrial cancer, and ovarian cancer).
A Phase 1b/2 clinical trial, being conducted under a global clinical collaboration between SpringWorks and BeiGene, is evaluating mirdametinib in combination with lifirafenib, a RAF dimer inhibitor, in patients with advanced or refractory solid tumors that harbor RAS mutations, RAF mutations and other MAPK pathway aberrations.
The rationale for the Phase 1b/2 study is supported by data that demonstrated that the combination of mirdametinib and lifirafenib led to synergistic antitumor activity in preclinical models of RAS-mutated cancers. Vertical inhibition of the MAPK pathway, enabled by the combination of a MEK inhibitor with a RAF dimer inhibitor, has been further validated preclinically by multiple academic and industry investigators, and has the potential to overcome the drug resistance mechanisms that have impeded previous attempts to develop therapies for tumors with MAPK mutations and aberrations.
- Weiss, B, Plotkin S, Widemann B, et al. NFM-06. NF106: Phase 2 Trial of the MEK Inhibitor PD-0325901 in Adolescents and Adults with NF1-related Plexiform Neurofibromas: An NF Clinical Trials Consortium Study. Neuro-Oncology. 2018;20(supplement_2):143-i143. doi:10.1093/neuonc/noy059.514.
Combination Therapy in MAPK Mutated Solid Tumors
- Desai, J, Gan, H, Barrow C, et al. Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors. Journal of Clinical Oncology. 2020;38(19):2140-2150. doi:10.1200/jco.19.02654.
- Yuan, X, Tang, Z, Du R, et al. RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K‐RAS mutant tumors. Molecular Oncology. 2020;14(8):1833-1849. doi:10.1002/1878-0261.12698.
- Yuan, X, Zhang, X, Du R, et al. Abstract 6415 / 9 – RAF dimer inhibitor lifirafenib enhances the antitumor activity of MEK inhibitor mirdametinib in RAS mutant tumors. American Association for Cancer Research II 2020 Annual Meeting.