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 ...
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