Patient must have histologically proven melanoma that is clinically evident (macroscopic lymphadenectomy [LAD]) stage III B/C/D, (American Joint Committee on Cancer [AJCC] 8th edition) of cutaneous origin or unknown primary. Patient must have at least one clinically evident lymph node metastasis (N1c patients are not eligible). Patients with stage IV melanoma are not eligible
* This may be an initial presentation with primary tumor and nodal metastases or locoregional nodal relapse with history of resected primary melanoma
* Stage IIIB
** T0-3a N1b M0
** T1a-3a N2b M0
* Stage IIIC
** T0 or T3b-4b N2b M0
** T3b-4b N1b M0
** Any T N2c M0 (at least 1 clinically evident node)
** T0-4a N3b M0
* Stage IIID
** T4b N3b/c M0 (if 3c: at least 1 clinically evident node)

Patient must have measurable disease on baseline imaging scans, obtained within 4 weeks prior to registration as defined by RECIST and by the following criteria
* The melanoma tumors must be completely resectable as determined by a surgical oncologist or experienced melanoma surgeon prior to registration
** Extensive satellitosis or extensive in transit metastases are not considered completely resectable

Patient must have BRAF V600 mutation positive based on report from Clinical Laboratory Improvement Act (CLIA) certified laboratory

Patient must be medically fit to undergo surgery

Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (obtained =< 14 days prior to registration)

Hemoglobin >= 8 g/dL without transfusion (obtained =< 14 days prior to registration)

Platelets >= 100 x 10^9/L without transfusion (obtained =< 14 days prior to registration)

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.0 x institutional upper limit of normal (ULN) (obtained =< 14 days prior to registration)

Total bilirubin =< 1.5 x institutional ULN and < 2 mg/dL; OR total bilirubin > 1.5 x institutional ULN with indirect bilirubin < 1.5 x institutional ULN (obtained =< 14 days prior to registration)

Serum creatinine =< 1.5 x institutional ULN, or calculated creatinine clearance > 50 mL/min by Cockcroft-Gault formula (obtained =< 14 days prior to registration)

Prothrombin time (PT), international normalized ratio (INR), and partial thromboplastin time (PTT) =< 1.5 x institutional ULN (obtained =< 14 days prior to registration)

Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1

Patient must not have any prior treatment with BRAF inhibitor (BRAFi) or MEK inhibitor (MEKi)

Patient must not have any evidence of distant metastases

Patient must be able to take oral medications

Patient must not have any prior adjuvant therapy at this disease presentation; prior immune therapy (such as adjuvant interferon or checkpoint inhibitors) is permitted if date of registration is >= 6 months from last treatment

Patient must not have any prior radiation to the site of evaluable disease

Patient must not have active infection requiring treatment with parenteral antibiotics

Patient must be able to lie still during the 18F-FLT PET/CT scan for the duration of the imaging study (up to 1.5 hours), have no previous indication of allergic reaction to the radiotracer, and meet the size limits of the qualified PET/CT scanner

Patient must be participating in this study at an institution which has completed the ECOG-American College of Radiology Imaging Network (ACRIN) defined PET/CT scanner qualification procedures and received ECOG-ACRIN PET scanner approval

Patient must not have active hepatitis B, and/or active hepatitis C infection given concerns for drug interactions or increased toxicities. Testing is not required

Patients known to be human immunodeficiency virus (HIV) positive are eligible if they have undetectable HIV viral load and stable and adequate CD4 counts (>= 500 mm^3) on screening labs provided they meet all other protocol criteria for participation and that there is no high risk drug interactions

Patient must not have other significant medical, surgical, or psychiatric conditions that in the opinion of the investigator may interfere with compliance, or make the administration of study medications hazardous

Patient must not have had previous or concurrent other malignancy with the following exceptions:
* Adequately treated basal cell or squamous cell carcinoma of the skin, in situ carcinoma of the cervix
* Other solid tumor: if treated and without evidence of recurrence for at least 2 years prior to date of registration

Patient must not be pregnant or breast-feeding due to potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the systemic antineoplastic medications, as well as surgery and radiation being used. All patients of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy. A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

Patients must not expect to conceive or father children by using accepted and effective method(s) of contraception or to abstain from sexual intercourse from the time of registration, while on study treatment and for at least 30 days after the last dose of protocol treatment for female patients, and for at least 90 days after the last dose of protocol treatment for male patients. In addition, patients must not donate ova from the time of registration until 30 days after the last dose of study treatment or donate sperm from the time of registration until 90 days after the last dose of protocol treatment

Patient must not have known hypersensitivity or contraindication to any component of binimetinib or encorafenib or their excipients

Patient must not have impaired cardiovascular function or clinically significant cardiovascular disease including, but not limited to, any of the following:
* History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) < 6 months prior to registration
* Congestive heart failure requiring treatment (New York Heart Association grade >= 2)
* Left ventricular ejection fraction (LVEF) < 50% as determined by multigated acquisition scan (MUGA) or echocardiogram (ECHO)
* Uncontrolled hypertension defined as persistent systolic blood pressure >= 150 mmHg or diastolic blood pressure >= 100 mmHg despite current therapy
* History or presence of clinically significant cardiac arrhythmias (including resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia)
* Baseline corrected QT (QTc) interval >= 480 ms

Patient must not have impairment of gastrointestinal function or disease which may significantly alter the absorption of study drug (e.g., active ulcerative disease, uncontrolled vomiting or diarrhea, malabsorption syndrome, small bowel resection with decreased intestinal absorption), or recent (=< 3 months) history of a partial or complete bowel obstruction, or other conditions that will interfere significantly with the absorption of oral drugs

Patient must not have any known history of acute or chronic pancreatitis

Patient must not have any concurrent neuromuscular disorder that is associated with elevated creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)

Patient must not have any known history or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity, factor V Leiden or activated protein C resistance); history of retinal degenerative disease

Patient must not use any medication (including herbal medications, supplements, or foods), or use of a prohibited medication =< 1 week prior to registration

Patient may be on anticoagulation at prophylactic or therapeutic levels. Patients must not be using specific anticoagulants at therapeutic levels that may interfere with encorafenib and binimetinib

Patient must not have a history of thromboembolic or cerebrovascular events =< 12 weeks prior to registration. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (i.e. massive or sub-massive) deep vein thrombosis or pulmonary emboli
* NOTE: Patients with thromboembolic events related to indwelling catheters or other procedures may be registered
* NOTE: Patients with either deep vein thrombosis or pulmonary emboli that does not result in hemodynamic instability are allowed to register as long as they are on a stable dose of anticoagulants for at least 4 weeks

PRIMARY CLINICAL OBJECTIVE:
I. To evaluate the pathologic complete response (pCR) rate of neoadjuvant treatment with encorafenib and binimetinib.

SECONDARY CLINICAL OBJECTIVES:
I. To determine response rate (RR) (Response Evaluation Criteria in Solid Tumors [RECIST]), disease-free survival (DFS) and overall survival (OS).
II. To describe correlation of pCR with RR, DFS and OS.
III. To assess safety and toxicity.

CORRELATIVE SCIENCE OBJECTIVES:
I. To evaluate CD8 positive (+) T cell infiltration and Ki-67 status in tumor or tumor bed pre, during, and post neoadjuvant treatment and the change in CD8+ tumor infiltrating lymphocyte (TIL) with neoadjuvant treatment and correlate with clinical response.
II. To compare local review for pathologic response with central pathology review.

IMAGING OBJECTIVES:
I. To compare the change in fluorothymidine F-18 (18F-FLT) PET/CT uptake (from baseline to post-neoadjuvant therapy) among patients with and without pathologic complete response.
II. To compare post-neoadjuvant 18F-FLT PET/CT uptake among patients with and without pathologic complete response.
III. To estimate an optimal threshold for prediction of pathologic complete response using i) change in 18F-FLT PET/CT uptake, and ii) post-neoadjuvant 18F-FLT PET/CT uptake.
IV. To assess the correlation between change in 18F-FLT PET/CT uptake and change in Ki-67.

OUTLINE:

NEOADJUVANT TREATMENT: Patients receive 18F-FLT intravenously (IV) and undergo a PET/CT scan approximately 60 minutes later. Within 2 weeks, patients receive encorafenib orally (PO) once daily (QD) and binimetinib PO twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive 18F-FLT IV and undergo a second PET/CT scan approximately 60 minutes later.

SURGICAL RESECTION: Within 2 weeks of completing therapy with encorafenib and binimetinib, patients undergo surgery.

ADJUVANT TREATMENT: Within 2-7 days after surgery, patients resume treatment with encorafenib PO QD and binimetinib PO BID on days 1-28. Treatment repeats every 28 days for up to 11 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, then every 6 months for 3 years.