Binimetinib Encorafenib Pembrolizumab +/- Stereotactic Radiosurgery in BRAFV600 Melanoma With Brain Metastasis

This is a Phase 2, randomised, controlled, open-label, multicentric, parallel trial with a safety lead-in phase, to assess the efficacy and safety of adding upfront SRS to binimetinib-encorafenib-pembrolizumab combination therapy in the treatment of BRAFⱽ⁶⁰⁰ mutation-positive MBM. The study will incorporate a safety lead-in (SLI) phase to assess the tolerability of binimetinib-encorafenib-pembrolizumab combination therapy +/- SRS in the first six patients enrolled. Safety will be assessed by the occurrence of predefined dose limiting toxicity (DLT) events. The safety data will be reviewed by an independent data monitoring committee (IDMC). The trial plans to enrol 150 patients who will be randomly assigned (1:1) to receive treatment with either: * Arm A: Encorafenib + binimetinib + pembrolizumab * Arm B: Upfront stereotactic radiosurgery of all lesions ≥5 mm in diameter (or ≥3 mm if other cerebral metastases \>5 mm); followed by encorafenib + binimetinib + pembrolizumab . The treatment should be started more than 24 hours and less than 8 days (excluded) after the SRS. Patients will be treated until disease progression. Pembrolizumab will be discontinued after a maximum of 35 administrations. Treatment may also be terminated early at the initiative of either the patient or the investigator for any reason that would be beneficial to the patient All patients will be followed for a total of 5 years post-randomisation.