Anti-PD 1 Brain Collaboration + Radiotherapy Extension (ABC-X Study)

Inclusion Criteria: 1. Female or male patients, ≥18 years of age. 2. Signed, written, informed consent. 3. AJCC Stage IV \[any T, any N, M1d (0) or M1D(1)\] histologically confirmed cutaneous, acral or mucosal unresectable melanoma or unknown primary melanoma and at least 1 radiological definitive brain metastasis that is ≥ 5mm and ≤40mm, measurable per RECIST version 1.1 guidelines (modified for brain metastases, enabling up to 5 target lesions in the brain as well as up to 5 extracranial target lesions). There is no upper limit restriction in the number of brain metastases, provided the remaining eligibility criteria are met. 4. The BRAF mutation status must be available prior to randomisation. 5. The treating clinician(s) should consider the intracranial disease amenable to stereotactic radiotherapy over whole brain radiotherapy. Patients for whom there is a definite and immediate indication for radiotherapy (e.g. rapidly progressing disease with associated clinical signs and /or symptoms) should not be considered for enrolment. 6. Brain metastases must be untreated with any modality of radiotherapy or systemic treatment. Previous surgery for melanoma brain metastases is permitted if it resulted in gross total resection and no radiotherapeutic cavity boost was required. 7. No prior systemic treatment for brain metastases is permitted unless given in the neoadjuvant or adjuvant settings for systemic drug the treatment for extracranial disease only. At the time of neoadjuvant or adjuvant systemic therapy for extracranial disease, there should be radiological evidence of the absence of brain metastases. The presenting diagnosis of brain metastases at the time of enrolment in this study must have occurred a minimum of 6 months after stopping neoadjuvant or adjuvant systemic therapy (prior anti PD1, anti PD-L1, anti CTLA-4, BRAF / MEK inhibitors or clinical trial agents) are acceptable in the setting of neoadjuvant or adjuvant treatment 8. Asymptomatic from brain metastases at the time of study enrolment without corticosteroids, analgesia or any other treatment for the management of neurological symptoms (with the exception of antiepileptics prescribed for any reason, provided patient is asymptomatic). Resolved neurological symptoms are permitted if complete resolution, without any intervention, has been sustained for a minimum of 7 days prior to randomisation. 9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2. 10. A life expectancy \> 30 days. 11. Able to undergo MRI with Gadolinium contrast agent. CT of the brain is not an acceptable alternative should patients be unable to safely undergo a contrast MRI. 12. Adequate haematological, hepatic and renal organ function as defined by: 1. White cell count ≥ 2.0 × 10x9/L 2. Neutrophil count ≥ 1.5 × 10x9/L 3. Haemoglobin ≥ 90 g/L 4. Platelet count ≥ 100 x 10x9/L 5. Total bilirubin ≤ 1.5 x ULN 6. Alanine transaminase ≤ 3.0 x ULN 7. Aspartate aminotransferase ≤ 3.0 x ULN 8. Serum creatinine ≤ 1.5 x the upper limit of normal (ULN). If serum creatinine is \> 1.5 x ULN, calculate creatinine clearance using standard Cockcroft-Gault formula. Creatinine clearance must be 40ml/min to be eligible. 13. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days of the first dose of study treatment and agree to use effective contraception from 14 days prior to commencing study treatment, throughout the treatment period and for 23 weeks \* after the last dose of study treatment. Effective contraception includes: 1. Intrauterine device with a documented failure rate of less than 1% per year. 2. Vasectomised partner who is sterile prior to the female partner patient's commencement of study treatment and is the sole sexual partner for that female. 3. Combined (oestrogen and progestogen) hormonal contraception associated with inhibition of ovulation or progestogen only hormonal contraception associated with inhibition of ovulation. Women who are not of childbearing potential are defined as any female who has had a documented hysterectomy, bilateral oophorectomy or bilateral tubal ligation or any female who is post-menopausal (≥ one year without menses and \>50 years of age in the absence of hormone replacement therapy). \* These durations have been calculated using the upper limit of the half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 days. Exclusion Criteria 1. Patients whose intracranial disease changes between the diagnostic MRI scan and the baseline / SRS planning MRI scan and who are no longer suitable for SRS and / or require a specific alternative treatment outside of this protocol. 2. Melanoma brain metastasis greater than 40mm. 3. Evidence of leptomeningeal disease, with the exception of pathological findings seen at a previous resection of brain disease, but with no evidence of leptomeningeal disease elsewhere at the time of resection or at study entry. 4. History of, or current ocular melanoma (patients with mucosal and acral melanoma are eligible). 5. Neurological symptoms from brain metastases present at baseline (resolved neurological symptoms, prior to enrolment, are permitted). 6. Prior radiotherapy to the brain (surgery permitted). 7. Prior systemic drug therapy for melanoma, unless given in the neoadjuvant or adjuvant setting and completed 6 months before enrolment in this study. 8. Patients with active, known or suspected autoimmune disease. Patients with the following are permitted to enrol: 1. Vitiligo 2. Type I diabetes mellitus 3. Residual hypothyroidism due to an autoimmune condition only requiring hormone replacement 4. Psoriasis not requiring systemic treatment 5. Autoimmune conditions not expected to recur in the absence of an external trigger. 9. Current systemic treatment with corticosteroids, or within 7 days of randomisation, with the exception of prednisone at non-immunosuppressive doses of ≤ 10 mg/day (or equivalent, e.g. e.g. prednisone 10mg = dexamethasone 1.6mg = hydrocortisone 40mg). Patients with the following circumstances are permitted to enrol: 1. Past treatment for non-neurological symptoms allowed, if this was ceased 7 days prior to randomisation 2. Inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if the patient is on a stable dose 3. Non-absorbed intra-articular steroid injections. During the study, treatment with systemic corticosteroids is permitted during radiotherapy if the patient experiences radiation related symptoms but this should be tapered per standard clinical practice as soon as possible and before the next infusion of study drug is due. This also refers to steroids for drug related signs or symptoms. 10. Any active infection requiring treatment. 11. A history of interstitial lung disease. 12. Any concurrent malignancy requiring any treatment or a history of another malignancy, unless the patient has been disease-free for 3 years. 13. Serious or unstable pre-existing medical conditions or other conditions that could interfere with the patient's safety, consent, or compliance. 14. Pregnant or breastfeeding females. 15. Administration of any form of live vaccine within 30 days of starting the trial and during the trial. Administration of any other vaccine is cautionary within 30 days of starting the trial and for the duration of the treatment phase of the trial. 16. Hypersensitivy to study treatments.