NEW YORK – SpringWorks Therapeutics on Tuesday said it will collaborate with Memorial Sloan Kettering to evaluate its investigational MEK inhibitor mirdametinib in patients with advanced solid tumors harboring MAPK-activating mutations.
The Phase Ib/IIa trial will be sponsored by MSK and supported by Stamford, Connecticut-based SpringWorks. Researchers will study the drug in combination with the SERD fulvestrant in estrogen receptor (ER)-positive, metastatic breast cancer patients with NF1 loss or other MAPK alteration in their tumors; and as a single agent in advanced solid tumors with MEK1/2 mutations or other MAPK pathway alterations.
MSK will begin enrolling patients into this two-cohort trial later this year. Researchers will follow them to track mirdametinib's safety, tolerability, and anti-tumor activity. The primary endpoints in the study are best objective response by RECIST criteria, disease control rate, duration of response, progression-free survival, and pharmacokinetics. Investigators will also conduct biomarker analysis to explore resistance mechanisms.
Based on preclinical data, SpringWorks believes that combining MAPK pathway inhibitors, such as mirdametinib and fulvestrant, can be particularly efficacious in patients with NF1-deficient, ER-positive, metastatic breast cancer. Up to 6 percent of ER-positive breast cancer patients harbor NF1 mutations, which can result in patients having a reduced response to fulvestrant. Researchers in this trial hope to bolster patients' response by adding mirdametinib.
"Emerging evidence points to alterations in the MAPK pathway playing a key role in mediating resistance to hormone therapy in ER-positive metastatic breast cancer, which represents a significant unmet medical need," Ezra Rosen, the study's principal investigator and a medical oncologist within MSK's early drug development service, said in a statement. "Based on emerging preclinical data, combinations of MAPK pathway inhibitors with ER-targeted therapy could potentially address this resistance mechanism."
Meanwhile, MEK1/2 mutations occur in around 2 percent of solid tumors, and in this trial, SpringWorks and MSK will be able to clinically test the promising activity seen preclinically in this subset of tumors.
In a separate Phase IIb trial, SpringWorks is evaluating mirdametinib in pediatric and adult patients with NF1-associated plexiform neurofibromas and in a Phase I/II trial in patients with pediatric low-grade gliomas. The company is also studying mirdametinib in a Phase Ib/II trial with BeiGene's RAF dimer inhibitor lifirafenib in advanced or refractory solid tumors with RAS/RAF mutations or other MAPK alterations.