Inclusion Criteria:
* Age ≥ 18 years at the time of informed consent.
* Provide written informed consent and comply with the study protocol as judged by the Investigator. Of note, If the subject has an impairment that prevents him/her from providing written consent, the site may follow local institutional procedures for obtaining consent.
* Histologically confirmed diagnosis of cutaneous melanoma with radiographically confirmed metastases to the brain.
* Must have a tumor with known RAS, BRAF, and NF1 mutation status using a validated testing method prior to enrollment.
* Cohort A: RAS, BRAF, NF1, or triple wildtype
* Cohort B: BRAF V600E or BRAF V600K
* Must have at least 1 untreated (no prior resection or radiation of the target lesion) parenchymal brain metastasis with minimal dimensions of ≥ 0.5 cm diameter and maximal dimensions ≤ 4 cm diameter, measured from a gadolinium enhanced MRI T1 sequence.
* Note: Subject may have received prior resection or radiation therapy for prior brain metastases.
* Must have received at least 1 line of prior systemic immunotherapy.
* For Cohort B, may have received 1 or more lines of prior BRAF or MEK inhibitor therapy.
* An ECOG Performance Status of 0 or 1, or Karnofsky score \>= 70
* Adequate bone marrow, organ function and laboratory parameters:
* ANC ≥ 1.5 × 109/L;
* Hemoglobin ≥ 9 g/dL with or without transfusions;
* Platelets ≥100,000/mm2;
* AST and ALT ≤ 2.5 × ULN; in patients with liver metastases ≤ 5 × ULN;
* Total bilirubin ≤ 1.5 × ULN; NOTE: Patients with documented Gilbert syndrome or hyperbilirubinemia due to non-hepatic cause (e.g., hemolysis, hematoma) may be enrolled
* Serum creatinine ≤ 1.5 × ULN; OR calculated creatinine clearance \> 50 mL/min by Cockcroft-Gault formula; OR estimated glomerular filtration rate \> 50 mL/min/1.73m2.
* International normalized ratio (INR), prothrombin time (PT), or activated partial thromboplastin time (aPTT) as follows:
* In the absence of therapeutic intent to anticoagulate the patient:
* INR \< 1.5 × ULN.
* PT \< 1.5 × ULN.
* aPTT \< 1.5 × ULN.
* Adequate cardiac function with left ventricular ejection fraction ≥ 55% by echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan.
* For women (any individual assigned female at birth) who are not postmenopausal (ie, \< 2 years after last menstruation) or surgically sterile (absence of ovaries and/or uterus) and who are sexually active, must have a negative serum pregnancy test and agree to use a highly effective method of contraception for the duration of the study and for 90 days following the last dose of study drug.
* Male patients (any individual assigned male at birth) of reproductive potential must avoid pregnancy in partners who are women of childbearing potential, and such partners should not consider getting pregnant during the study and for at least 90 days after treatment is discontinued or longer if requested by local authorities. Male patients are considered to be of reproductive potential unless permanently sterile by bilateral orchidectomy or vasectomized with appropriate post-vasectomy documentation of absence of sperm in ejaculate.
* Adequate recovery to baseline or ≤ Grade 1 CTCAE v5 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy per the treating investigator. Exceptions include alopecia and peripheral neuropathy grade ≤ 2.
Exclusion Criteria:
* Receiving other investigational agents.
* Prior systemic anti-cancer therapy or any investigational therapy ≤ 28 days or within five half-lives prior to starting study treatment, whichever is shorter.
* Patients with symptomatic brain metastasis, defined as neurologic symptoms with localization attributable to an untreated brain metastases with severity \>= Grade 2 by CTCAE criteria.
* History of allergy or hypersensitivity to any of the study treatments or any of their excipients.
* Inability to swallow and retain study treatment.
* Uveal or mucosal melanoma.
* History of or current leptomeningeal metastases.
* QTcF \> 450 msec if male and QTcF \> 470 msec if female.
* Any hemorrhage or bleeding event that is ≥ Grade 3 based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) or Grade 2 intracranial hemorrhage within 4 weeks prior to the start of study treatment.
* Uncontrolled or severe cardiac disease (eg, history of unstable angina, myocardial infarction, coronary stenting, or bypass surgery within the last 6 months prior to initiation of study treatment), symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation), requirement for inotropic support or use of devices for cardiac conditions (eg, pacemakers/defibrillators), or hypertension (patients with systolic blood pressure \[BP\] of \> 160 mm Hg or diastolic BP of \> 100 mm Hg despite optimal medical management are to be excluded).
* History of interstitial lung disease, history of slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis, or symptomatic pleural effusion.
* Active, known, or suspected uncontrolled autoimmune disease, which required therapy in the past 2 years, including but not limited to systemic lupus erythematosus, Hashimotos thyroiditis, scleroderma, polyarteritis nodosa, or autoimmune hepatitis.
* Known HIV infection with a detectable viral load within 6 months of the anticipated start of treatment. Note: Participants on effective antiretroviral therapy with an undetectable viral load within 6 months of the anticipated start of treatment are eligible for this trial.
* Systemic active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination, radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), or hepatitis C. Note: Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Participants positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
* History of bleeding diathesis (irrespective of severity) in the absence of therapeutic anticoagulation.
* Uncontrolled intercurrent illness including, but not limited to ongoing or active infection.
* Any condition that could make the patient noncompliant with the study procedures and/or study requirements, as judged by the Investigator.
* Active skin disorder that has required systemic therapy within the past 1 year.
* History of rhabdomyolysis.
* Concurrent ocular disorders:
* Patients with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes.
* Patients with history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO, intraocular pressure \> 21 mm Hg as measured by tonometry, or other significant ocular pathology, such as anatomical abnormalities that increase the risk for RVO.
* Patients with active or chronic, visually significant corneal disorders, other active ocular conditions requiring ongoing therapy or clinically significant corneal disease that prevents adequate monitoring of drug-induced keratopathy. Examples of visually significant corneal disorders include corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions. Visually significant corneal disorders do NOT include dry eyes, blepharitis, and uncomplicated corneal erosions.
* Patients with a history of hypersensitivity to any of the active (avutometinib, defactinib, encorafenib) or inactive ingredients of the investigational products.
* Exposure to medications (with or without prescriptions), supplements, herbal remedies, or foods with potential for drug-drug interactions with study interventions within 14 days prior to the first dose of study intervention and during the course of therapy, including:
* Strong CYP3A4 inhibitors or inducers, due to potential drug-drug interactions with both avutometinib and defactinib.
* Strong CYP2C9 inhibitors or inducers, due to potential drug-drug interactions with defactinib.
* Strong P-glycoprotein (P-gp) inhibitors or inducers, due to potential drug-drug interactions with both avutometinib and defactinib.
* Strong breast cancer resistance protein (BCRP) inhibitors or inducers, due to potential drug-drug interactions with avutometinib.
* Concomitant treatment with warfarin. Patients who require anticoagulation but cannot discontinue warfarin must be excluded from the study.
* Participants taking other prohibited medications in protocol, including anticancer therapy or investigational agents and colony-stimulating factors (CSFs). A washout period of prohibited medications for a period of at least five half-lives or as clinically indicated should occur before the start of treatment.
* The diagnosis of another malignancy within ≤ 2 years before study enrollment, except for those considered to be adequately treated with no evidence of disease or symptoms and/or will not require therapy during the study duration (i.e., basal cell or squamous cell skin cancer, carcinoma in situ of the breast, bladder or of the cervix, or low-grade prostate cancer with Gleason Score ≤ 6)
* Any other condition that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, \[subjects may not receive the drug through a feeding tube\], social/ psychological issues, etc.)
* Medical, psychiatric, cognitive, or other conditions that may compromise the subject's ability to understand the subject information, give informed consent, comply with the study protocol or complete the study.
Moderate burden on patient
