SpringWorks Therapeutics Announces Phase 1b/2a Clinical Trial of Mirdametinib in Patients with Advanced Solid Cancers Harboring MAPK-Activating Mutations

SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, today announced that the Company will be evaluating mirdametinib, an investigational MEK inhibitor, in a platform study sponsored by Memorial Sloan Kettering Cancer Center (MSK) and supported by SpringWorks exploring the compound both as a monotherapy and as a combination therapy in advanced solid tumors harboring MAPK-activating mutations. The trial, which is expected to begin recruiting patients during the third quarter of 2021, will initially explore mirdametinib in two patient cohorts: the first in combination with fulvestrant, a selective estrogen receptor degrader (SERD) in patients with estrogen receptor positive (ER+) metastatic breast cancer (mBC) with MAPK alterations (particularly inactivating mutations in NF1), and as a monotherapy in advanced solid tumors harboring oncogenic MEK1 or MEK2 mutations.

“Emerging evidence points to alterations in the MAPK pathway playing a key role in mediating resistance to hormone therapy in ER+ mBC, which represents a significant unmet medical need,” explained Ezra Rosen, M.D., Ph.D., Medical Oncologist, Assistant Member of MSK’s Early Drug Development Service, and the study’s principal investigator. “Based on emerging preclinical data, combinations of MAPK pathway inhibitors with ER-targeted therapy could potentially address this resistance mechanism and we look forward to studying mirdametinib to evaluate whether this MEK inhibitor can provide a clinical benefit. Separately, given the preclinical evidence that activating mutations in MEK1 and MEK2 can also act as oncogenic drivers in cancer, we’re looking to explore a potential role for mirdametinib monotherapy in solid tumors harboring these driver mutations.”

Approximately 70% of breast cancers are ER+. Hormonal therapies targeting ER, such as SERDs, can be effective in treating ER+ mBC, but over 90% of patients eventually develop resistance to ER-targeted therapy. Loss of NF1 function has been shown to be responsible for enhanced ER transcriptional activity and reduced sensitivity to fulvestrant in preclinical models, with up to 6% of ER+ mBC patients harboring a detectable NF1 mutation.1 Combinations of MAPK pathway inhibitors and ER-targeted therapy could potentially address this resistance, as demonstrated by a combination of a MEK inhibitor and fulvestrant showing anti-tumor activity in fulvestrant-refractory NF1-deficient ER+ mBC preclinical models.1,2

In addition, MEK1 and MEK2 mutations are present in up to 2% of solid tumors and have been validated as oncogenic drivers. Recent publications demonstrate the activity of MEK inhibitors, including mirdametinib, in preclinical models driven by a subset of these MEK mutations.3,4

“This biomarker-driven platform study will enable us to evaluate mirdametinib’s ability to address subsets of patients with solid tumors that harbor specific MAPK pathway mutations,” said Mike Burgess, M.B.Ch.B., Ph.D., Head of Research and Development at SpringWorks. “We are committed to exploring the full potential of mirdametinib on behalf of patients with devastating cancers and look forward to collaborating with Dr. Rosen and his colleagues at MSK on this important trial.”

About the MSK-Sponsored Phase 1b/2a Trial

The open-label Phase 1b/2a parallel design, platform study will evaluate the safety and tolerability, efficacy, and pharmacokinetics of mirdametinib in two study arms: (1) in combination with fulvestrant in postmenopausal patients with ER+ mBC harboring NF1 loss of function or other alterations of the MAPK pathway and (2) as a monotherapy in adult patients with advanced solid cancers driven by the alterations of the MAPK pathway, including MEK1 or MEK2 mutations.

The primary objectives of the trial will be to evaluate the safety and tolerability and anti-tumor efficacy of mirdametinib in combination with fulvestrant and as a single agent. The efficacy endpoints will include best objective response by RECIST 1.1, disease control rate, duration of response, progression-free survival, and pharmacokinetic endpoints. Biomarker analyses will also be conducted to evaluate the changes from baseline in the biomarkers of tumor biology and anti-tumor activity and characterize potential mechanisms of resistance.

About Mirdametinib

Mirdametinib is an oral, potent, allosteric, brain-penetrant small molecule designed to inhibit MEK1 and MEK2, which are proteins that occupy pivotal positions in the MAPK pathway and that play a central role in multiple oncology and rare disease indications. To date, over 250 subjects have been exposed to treatment with mirdametinib across clinical trials, with preliminary evidence of clinical activity against tumors driven by over-activated MAPK signaling.5

Mirdametinib is being evaluated as a monotherapy in a Phase 2b trial for pediatric and adult patients with NF1-associated plexiform neurofibromas (NF1-PN), and in a Phase 1/2 trial for patients with pediatric low-grade gliomas. In addition, mirdametinib is being evaluated in a Phase 1b/2 trial in combination with BeiGene’s RAF dimer inhibitor, lifirafenib, in patients with advanced or refractory solid tumors harboring RAS mutations, RAF mutations, and other MAPK pathway aberrations.

About SpringWorks Therapeutics

SpringWorks is a clinical-stage biopharmaceutical company applying a precision medicine approach to acquiring, developing and commercializing life-changing medicines for patients living with severe rare diseases and cancer. SpringWorks has a differentiated targeted oncology portfolio of small molecule product candidates and is advancing 15 development programs, including two potentially registrational clinical trials in rare tumor types as well as several programs addressing highly prevalent, genetically defined cancers. SpringWorks’ strategic approach and operational excellence in clinical development have enabled it to rapidly advance its two lead product candidates into late-stage clinical trials while simultaneously entering into multiple shared-value partnerships with innovators in industry and academia to expand its portfolio and create more solutions for patients with cancer.