PRIMARY OBJECTIVES:~I. To determine whether the combination of fulvestrant and binimetinib improves progression-free survival (PFS) compared to treatment with fulvestrant alone in patients not previously treated with fulvestrant. (Cohort 1) II. To determine whether overall response rate (ORR) within 4 months in patients who have previously progressed on a fulvestrant-containing regimen is greater than 10%, as a historical comparison, when these patients receive combination fulvestrant and binimetinib therapy. (Cohort 2)~SECONDARY OBJECTIVES:~I. To estimate ORR at any time after the start of the treatment for Cohort 2 and separately for the two arms in Cohort 1.~II. To estimate PFS distribution in Cohort 2. III. To estimate clinical benefit rate separately for the two arms in Cohort 1 and Cohort 2.~IV. To determine the safety and toxicity profile in both cohorts. V. To estimate the overall survival (OS) in both cohorts. VI. Collect tissue and provide it to the ComboMATCH Registration Protocol to assess concordance between the diagnostic tumor mutation profile generated by the Designated Laboratories, the pre-treatment biopsy mutation profile, and the pre-treatment circulating tumor deoxyribonucleic acid (DNA) (ctDNA) mutation profile from plasma, as described in ComboMATCH Registration Protocol. For this treatment substudy, the outcome objective will be to report the proportion of cases providing sufficient tissue for that integrated scientific activity in the ComboMATCH Registration Protocol.~EXPLORATORY BIOMARKER OBJECTIVES:~I. To analyze the cell-free (cf)DNA at progression to determine the changes in cfDNA profile in order to understand blood-based mutation dynamics.~II. To analyze RNAseq at progression to determine potential pathways that are altered that may contribute to the sensitivity/resistance.~III. To discover/detect novel biomarkers using microscaled proteogenomics by analyzing the proteins and phosphor-proteins along with genomics to determine potential pathways that may correlate with the response to the combination treatment.~IV. To detect the loss of NF1, using immunohistochemistry staining to precisely measure the level of the NF1 protein.~V. To determine the variant allele frequency (VAF) of mutant NF1 measuring by using droplet digital polymerase chain reaction (ddPCR) for the targeted NF1 gene level.~OUTLINE: Patients who are fulvestrant naive are assigned to Cohort I, while patients who are fulvestrant resistant are assigned to Cohort II.~COHORT I: Patients are randomized to 1 of 2 arms.~ARM I: Patients receive fulvestrant intramuscularly (IM) and binimetinib orally (PO) throughout the trial. Patients also undergo a computed tomography (CT), magnetic resonance imaging (MRI), or bone scan and tumor biopsy during screening and on study.~ARM II: Patients receive fulvestrant IM throughout the trial. Patients who progress on fulvestrant alone are asked to reaffirm their willingness to enroll in cohort II. Patients not willing to transition to cohort II continue further therapy as clinically indicated. Patients undergo a CT, MRI, or bone scan and tumor biopsy during screening and on study.~COHORT II: Patients receive fulvestrant IM and binimetinib PO throughout the trial. If the patient progressed on fulvestrant, the loading dose of fulvestrant is omitted. Patients undergo a CT, MRI, or bone scan and tumor biopsy during screening and on study.
This ComboMATCH phase II trial compares the usual treatment alone (fulvestrant) to using binimetinib plus the usual treatment in patients with hormone receptor positive breast cancer that has spread to other places in the body (metastatic) and has an NF1 genetic change. Fulvestrant is a hormonal therapy that binds to estrogen receptors in tumor cells, resulting in estrogen receptor destruction and decreased estrogen binding, which may inhibit the growth of estrogen-sensitive tumor cells. Binimetinib is a targeted therapy that may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. The addition of binimetinib to fulvestrant in breast cancers with an NF1 genetic change could increase the percentage of tumors that shrink as well as lengthen the time that the tumors remain stable (without progression) as compared to fulvestrant alone.