Encorafenib and biNimetinib Followed by CEmiplimab and FiAnLimab in Patients With BRAF Mutant melanOma and Symptomatic Brain Metastases

Inclusion Criteria: Patients eligible for inclusion in this study must meet all the following criteria: * Written informed consent approved by the Independent Ethics Committee (IEC), prior to the performance of any trial activities. * Histologically confirmed diagnosis of unresectable metastatic BRAF-mutated melanoma (stage IV, AJCC v9), with one or more brain metastases with a diameter of 5 to 50 mm, measured by contrast enhanced MRI. * Patients with brain metastasis that debut as symptomatic, regardless of corticosteroid use. The definition of symptoms will be: 1. Any symptom related with intracranial hypertension, providing the patient has an Eastern cooperative Oncology Group performance status (ECOG PS) 0-2 and the other inclusion and exclusion criteria are met. 2. Any symptom related to focal neurologic deficit. 3. Epilepsy Note: Patients could have or not these symptoms controlled with corticosteroids at the inclusion of the clinical trial. * A documented mutation in BRAF-V600 in the tumor tissue. * Modified Barthel Index of Activities of Daily Living \> 10 (see Appendix 5). * Subjects aged ≥ 18 years. * Performance status ECOG PS 0-2 (see Appendix 7). * Able to swallowing * Adequate hematologic function: 1. Haemoglobin ≥ 9 g/dL (may have been transfused). 2. Platelet count ≥ 75 × 109/L. 3. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L. * Adequate hepatic function defined by a total bilirubin level ≤ 2.0 × the upper limit of normality (ULN) and AST and ALT levels ≤ 2.5 × ULN; or AST and ALT levels ≤ 5 x ULN (for subjects with documented metastatic disease to the liver). * Serum Creatinine ≤ 2.0 x ULN or estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method). * Immunotherapy allowed if administered in the adjuvant/neoadjuvant setting, any grade 3-4 prior toxicity must be resolved to grade 0 or at baseline levels. Steroids or anticonvulsants are allowed if clinically needed. No dose limit of steroids is pre-specified as long as they are not in an increasing dose for the last 5 days prior to start of study treatment. \- Female subjects of childbearing potential (WOCBP) must provide a negative urine pregnancy test at screening, and must agree to use a medically accepted and highly effective birth control method (i.e. those with a failure rate less than 1%; refer to Appendix 8) for the duration of the study treatment and for 6 months after the last dose of study treatment. A woman is considered of childbearing potential ( i.e. fertile) following menarche and until becoming postmenopausal unless permanently sterile. Women will be considered postmenopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply: 1. Amenorrheic for ≥1 year in the absence of chemotherapy and/or hormonal treatments 2. Luteinizing hormone (LH) and/or follicle stimulating hormone and/or estradiol levels in the postmenopausal range 3. Radiation induced oophorectomy with last menses \>1 year ago 4. Chemotherapy induced menopause with \>1 year interval since last menses 5. Surgical sterilization (bilateral oophorectomy or hysterectomy) 6. Women \<50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy) 7. Women ≥50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). * Male study participants with WOCBP partners are required to use condoms during the study and until 6 months after the last dose of study treatment unless they are vasectomized or practice sexual abstinence. * WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the entire trial and until 6 months after last treatment. All men must agree not to donate sperm during the trial and for 6 months after receiving the last therapy dose. * Willingness and ability to attend scheduled visits, follow the treatment schedule and undergo clinical tests and other study procedures. Exclusion Criteria: Patients meeting any of the following criteria are excluded from the study: * Uveal melanoma. * History of leptomeningeal metastases unless they are a finding in the Brain MRI that does not explain the main neurological symptoms of the patient, according to physician criteria. * Another non-cured cancer in the last 2 years, except for in situ carcinoma of the cervix, breast, prostate or squamous cell carcinoma of the skin adequately treated or limited basal cell skin cancer adequately controlled. Patients with cured cancer should be free of any adjuvant treatment (i.e chemotherapy or targeted therapy/monoclonal antibodies) with the exception of hormonal therapy for completed cured localized breast cancer or localized prostate cancer. * History of allogeneic organ transplant. * History of or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or history of retinal degenerative disease (RDD). * History of interstitial lung disease. * Systemic immunotherapy treatment for melanoma would be allowed only in the adjuvant/neoadjuvant setting (regardless if the brain relapse was during or after that) providing that ALL the following criteria are met: 1. The immunotherapy regimen did not contain anti LAG-3 treatment. 2. Patient did not have brain metastases (whether they were symptomatic or asymptomatic) prior to this adjuvant/neoadjuvant immunotherapy setting. 3. Patient was treated with adjuvant/neoadjuvant for at least 6 months. 4. No other treatments different than the one in adjuvant/neoadjuvant before symptomatic brain metastases were applied. 5. Patient did not discontinue immunotherapy due to related adverse events. * Targeted therapy against BRAF and/or MEK will not be allowed in any setting, including adjuvant. * Chemotherapy will not be allowed in any setting. * Patients in the need of urgent brain surgery before inclusion. However, patients are allowed to enter in the clinical trial after brain surgery, providing they meet the rest of inclusion and exclusion criteria, especially having at least one measurable lesion as per modified RECIST criteria after this surgery. * Brain radiotherapy will not be allowed before entering the clinical trial. Patients can receive brain radiotherapy during the clinical trial, if they progress into the brain, as per institutional guidelines ONLY if (must fulfill the three): 1. They have received at least TWO doses of cemiplimab and fianlimab AND 2. The event of an intracranial progressive disease happens during cemiplimab and fianlimab AND 3. They comply to receive encorafenib and binimetinib as rechallenge. Encorafenib and binimetinib should be stopped 24h before, during and 24h after radiotherapy. * History or current evidence of significant (CTCAE grade ≥2) local or systemic infection (eg, cellulitis, pneumonia, septicemia) requiring systemic antibiotic treatment within 2 weeks prior to the first dose of trial medication. * Active infection requiring therapy. * Ongoing or recent (within 2 years) evidence of an autoimmune disease that required systemic treatment with immunosuppressive agents. The following are non-exclusionary: vitiligo, childhood asthma that has resolved, residual hypothyroidism that requires only hormone replacement, psoriasis not requiring systemic treatment. * Uncontrolled infection with HIV, HBV, or HCV infection; or diagnosis of immunodeficiency that is related to, or results in chronic infection. Notes: 1. Patients with known HIV who have controlled infection (undetectable viral load and CD4 count above 350 either spontaneously or on a stable antiviral regimen) are permitted. For patients with controlled HIV infection, monitoring will be performed per local standards. 2. Patients with known hepatitis B (HepBsAg+) who have controlled infection (serum hepatitis B virus DNA PCR that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of HBV DNA per local standards and must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study drug. 3. Patients who are known hepatitis C virus antibody positive (HCV Ab+) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted. 4. Patients with HIV or hepatitis must be reviewed by a qualified specialist (eg, infectious disease or hepatologist) managing this disease prior to commencing and regularly throughout the duration of their participation in the trial. * Impaired cardiovascular function or clinically significant (i.e., active) cardiovascular diseases such as: cerebrovascular accident/stroke (\< 6 months prior to enrolment), myocardial infarction (\< 6 months prior to enrolment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), a LVEF \< 50% evaluated as per institutional guidelines, or serious cardiac arrhythmia requiring medication or a triplicate average baseline QTc interval \> 500 ms, history of myocarditis. Note: Patients not fulfilling these cardiovascular criteria can be consulted to medical monitor and coordinating investigator for a case by case examination. * TnT or troponin I TnI \> 2x institutional ULN at baseline. Note: Patients with TnT or TnI levels between \> 1 to 2x ULN are permitted if repeat levels within 24 hours are ≤ 1x ULN. If TnT or TnI levels are \> 1 to 2x ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment by the investigator based on the medical judgment in the patient's best interest. * Uncontrolled arterial hypertension despite medical treatment. * Moderate (Child Pugh Class B) or severe (Child Pugh Class C) hepatic impairment. * Impairment of gastrointestinal function. Inability to swallow tablets or capsules. * Neuromuscular disorders associated with high concentrations of creatine kinase. * Subjects that have a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 14 weeks (28 days) prior to the first dose of trial treatment, other than steroids required for brain metastasis symptoms control. * History of pneumonitis within the last 5 years. * Active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis). * Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study. * Known hypersensitivity to the active substances or to any of the excipients. * Persisting toxicity related to prior therapy of Grade \>1 NCI-CTCAE v 5.0; however, alopecia and sensory neuropathy Grade ≤ 2 is acceptable. * Have received a live vaccine within 30 days of planned start of study therapy. Note: Live or live attenuated vaccination with replicating potential. If a patient intends to receive a COVID-19 vaccine before the start of study drug, participation in the study should be delayed at least 1 week after any COVID-19 vaccination. During the treatment period, it is recommended to delay COVID-19 vaccination until patients are receiving and tolerating a steady dose of study drug. A vaccine dose should not be less than 48 hours before or after study drug dosing. * Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 6 months after the last dose of study treatment. * Known alcohol or drug abuse. * Participation in any interventional drug or medical device study within 30 days prior to treatment start. * Total lactase deficiency or glucose-galactose malabsorption.