Perioperative Encobini in BRAFV600 Mutant Stage III (B/C/D) or Oligometastatic Stage IV Melanoma

Inclusion Criteria:

* Written informed consent to participate
* Aged ≥ 18 years old
* AJCC 8th edition stage III (B/C/D), or extracranial oligometastatic stage IV BRAFV600 mutant melanoma, based on histological/cytological and radiological assessments for which surgery is planned, and resection is expected to remove all known tumour(s) with R0 resection margins. 'Oligometastatic stage IV' is defined for the purpose of this trial as M stage disease confined to a single body organ excluding the brain that can be readily removed surgically with anticipated clear margins
* For stage III patients, confirmation of no evidence of distant metastatic disease using preferred imaging modalities including CT body or PET/CT and CT or MRI head
* For stage IV patients, confirmation of no evidence of unresectable metastatic disease, or metastatic disease in more than 1 body organ, using preferred imaging modalities including CT body or PET/CT and CT or MRI head. The site of metastasis should not be in bone, or CNS, or in any other body site where complete resection is not feasible
* The planned resectable disease must be radiologically measurable using standard imaging modalities.
* Baseline tumour assessments must be done within 28 days prior to randomisation
* BRAF V600E or V600K mutation confirmation
* Received no prior BRAF or MEK inhibitors
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Predicted life expectancy \>12 months
* Normal QTc interval (\<480msec) on ECG and left ventricular ejection fraction within normal limits, assessed by echocardiogram or MUGA
* Adequate bone marrow function defined as:
* Absolute neutrophil count (ANC) ≥1.5 x 109 /L
* Haemoglobin (Hb) ≥ 90 g/L
* Platelets ≥100 x 109 /L
* Adequate liver function defined as:
* Aspartate aminotransferase (AST) and/or alanine transaminase (ALT) ≤2.5 x upper limit of normal range (ULN)
* Total bilirubin \<1.5 x ULN (except if the patient has Gilbert Syndrome or liver metastases, in which case the bilirubin must be \<3 x ULN)
* Adequate renal function defined as:
* a serum creatinine ≤1.5 x ULN or
* calculated creatinine clearance by Cockcroft-Gault of ≥40 mL/min
* Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, completion of QoL and PROM questionnaires and other procedures described in the protocol
* Women of child-bearing potential (WCBP) and all sexually active male patients must agree to use effective contraception methods throughout treatment
* Be able to swallow the trial medication
* Confirmation of adequate diagnostic tumour tissue available for research studies

Exclusion criteria

* Prior adjuvant therapy for resected primary or loco-regional melanoma
* Other invasive malignancies diagnosed within the last 2 years which are not in complete remission, or for which additional therapy is required
* Brain or bone metastases
* Non-cutaneous primary site of melanoma
* Prior radiotherapy to the site planned for surgery
* History or current evidence of retinal vein occlusion (RVO) or risk factors for RVO (uncontrolled glaucoma, ocular hypertension, history of hyperviscosity, or hypercoagulability syndromes)
* Left ventricular function \<50%
* Significant acute or chronic medical or psychiatric condition, disease or laboratory abnormality which in the judgment of the investigator would place the patient at undue risk or interfere with the trial. Examples include, but are not limited to:
* Patients with uncontrolled ischaemic heart or other cardiovascular event (myocardial infarction (MI), new angina, stroke transient ischaemic attack (TIA), or new congestive cardiac failure (CCF)) within the last 6 months
* Uncontrolled hypertension
* Patients with stable but significant cardiovascular disease defined by heart failure (New York Heart Association Functional Classification (NYHF) III or IV or frequent angina
* Patients with baseline QTC interval \> 480 msec on electrocardiogram (ECG)
* Left ventricular ejection fraction below the lower limit of normal
* Presence of active infection
* Cirrhotic liver disease, known chronic active or acute hepatitis B, or hepatitis C
* Known allergy or hypersensitivity to Encorafenib or Binimetinib, or their excipients. Binimetinib contains lactose, so patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption will be excluded.
* Women who are pregnant, plan to become pregnant or are lactating during the trial period
* Use of any other investigational anti-cancer drugs (a washout period of 28 days would be required)
* Use of strong inducers and inhibitors of CYP3A4 (Appendix 4 - Prohibited Medication)
* Known HIV or active Hep B or Hep C infection
* Patients who have neuromuscular disorders associated with elevated creatine phosphokinase (CK, e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
* Autoimmune conditions requiring regular or intermittent use of any systemic steroid or immunosuppressive drugs, with the exception of steroid inhalers
* Any immunotherapy in the last 3 months
* Prior radiotherapy to the site of disease planned for resection
* Concurrent participation in an interventional clinical trial (observational studies allowed)