Abstract OT2-23-01: A Phase 1b/2a, open-label platform study to evaluate mirdametinib in combination with fulvestrant in ER+ metastatic breast cancers harboring MAPK-activating mutations
Authors: Rosen Ezra Y. , Patel Payal , Sarapa Nenad , Edris Badreddin , Iasonos Alexia , Jhaveri Komal , Razavi Pedram , Robson Mark , Drilon Alexander , Berger Michael F. , Solit David B. , Chandarlapaty Sarat 
Published: March 2022

Abstract
Background: Approximately 70% of all metastatic breast cancers (MBCs) express estrogen receptor (ER). Hormonal therapies targeting ER are highly active against these cancers and have been remarkably successful in improving outcomes. Unfortunately, resistance to hormonal therapy is nearly universal and over 90% of patients develop resistance to various drugs targeting ER. We have identified mutations in three non-overlapping gene sets that are associated with the hormone-resistant phenotype: (1) ESR1, (2) MAPK pathway, and (3) transcription factors. The finding of mutations that might activate MAPK signaling was particularly striking given the known oncogenic function of this pathway in other cancers and the potential to target this pathway with selective inhibitors. Indeed, in preclinical models, the combination of an allosteric MEK inhibitor with an ER antagonist induced tumor regression in NF1-null, ER+ xenografts that were resistant to antiestrogen monotherapy. These data suggest that MAPK pathway alterations promote resistance to ER-targeted therapies in MBC and lead us to hypothesize that MAPK-targeted therapies will prove highly effective in such patients. However, NF1 (prevalence 6%) is only one of several RAS modulators that are associated with hormone resistance, and KRAS and HRAS mutations were also present in this dataset. Further, receptor tyrosine kinase (RTK) alterations (EGFR amplification and ERBB2 somatic mutations) and mutations in the RAF/MEK kinase cascade (BRAF and MEK1) are present and may comparably confer resistance to hormonal therapy and sensitivity to MAPK pathway inhibition. We hypothesize that MAPK pathway-activated MBCs can be effectively treated using MAPK targeted therapies in combination with hormonal therapy. Patient Accrual:The workflow to enroll patients to clinical trials at MSKCC is automated such that genomic alterations that are deposited on the cBioPortal are matched with appropriate clinical trials using database queries. A recent query of cBioPortal data from ER+ MBC patients treated at MSKCC showed 216 patients harboring actionable alterations in the MAPK pathway. Clinical Trial Design: This investigator-initiated trial being performed in collaboration with SpringWorks Therapeutics is IRB-approved and anticipated to open at MSKCC in August 2021. This is a Phase IB/IIA clinical trial of the allosteric MEK1/2 inhibitor mirdametinib (oral, daily) with the ER antagonist fulvestrant (500mg IM monthly). Inclusion criteria for the study will include ER+ tumor (ASCO-CAP guidelines), MAPK-activating genomic alteration documented by a CLIA-certified NGS assay at any time before the start of treatment, measurable disease, and at least one line of prior endocrine therapy. The feasibility of the combination will be established in a brief safety run-in of full-dose fulvestrant together with mirdametinib with dose de-escalation planned if two Dose Limiting Toxicities (DLT) are observed in the first six patients. This drug combination will then be expanded in three cohorts of patients defined by tumor genotype: (1) RAS activating: NF1 loss, KRAS or HRAS activating mutation, (2) RTK: EGFR amplification or ERBB2 hotspot mutation, (3) RAF/MEK: activating mutation in BRAF, CRAF, or MEK1/2. The primary endpoint for the study will be safety and tolerability of mirdametinib in combination with fulvestrant, and secondary endpoints include Overall Response Rate (ORR), Progression Free Survival (PFS), Clinical Benefit Rate (CBR), and Duration of Response (DOR) for the drug combination in each cohort and for the total study population. Overall survival is not an endpoint of this protocol.
Citation Format: Ezra Y. Rosen, Payal Patel, Nenad Sarapa, Badreddin Edris, Alexia Iasonos, Komal Jhaveri, Pedram Razavi, Mark Robson, Alexander Drilon, Michael F. Berger, David B. Solit, Sarat Chandarlapaty. A Phase 1b/2a, open-label platform study to evaluate mirdametinib in combination with fulvestrant in ER+ metastatic breast cancers harboring MAPK-activating mutations [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-23-01.