# Melanoma Brain Metastases: Immunotherapy or Targeted Therapy? A Systematic Review and Meta-Analyses
## 1 Introduction  
One of the primary factors contributing to the mortality of patients with metastatic melanoma is brain metastasis, which is considered among the major factors of poor prognosis [1]. After breast and lung cancer, melanoma causes the most metastases to the brain. During their clinical history, more than half of subjects' brain metastases are detectable during staging scans. [2]. Central nervous system involvement is characterised in approximately 15% of stage III melanoma [3] and 75% of stage IV. Prognostic factors in individuals with melanoma are based not only on the presence or absence of brain involvement but also on the metastases' number and localisation, intraand extracranial disease extension, leptomeningeal involvement, Eastern Cooperative Oncology Group (ECOG) performance status, patient's age, LDH levels, and mostly the tumour burden. _BRAF_ mutation presence or absence, the patient's clinical conditions, ECOG performance status, comorbidities, and eventual autoimmune disease are factors that may influence the therapeutic strategy. Chemotherapeutic, such as fotemustine [4], temozolomide [5], carmustine, and dacarbazine [6], were the first drugs tested for the treatment of melanoma brain metastases. Nevertheless, due to the inconsistent evidence of chemotherapy efficacy, in recent years, we have been exploring the path of immunotherapy, targeted therapy, and more recently adoptive therapy. Moreover, different drugs such as BRAF/MEK inhibitors have been tested in several studies with encouraging results [7; 8; 9; 10; 11; 12; 13]. Recent findings of trials that tested immunotherapy [14; 15; 16; 17; 18] have opened a new scenario and led to new studies on the combination of immunotherapy and targeted therapy (TT) [19; 20; 21; 22] or chemotherapy [23]. Locoregional treatments, such as surgery and radiotherapy, have been considered the gold standard for the treatment of melanoma brain metastases for several years. Recent discoveries of the efficacy of BRAK/MEK inhibitors and immunotherapy in the central nervous system changed the systemic treatment of metastatic melanoma. The most recent studies have shown the effectiveness of combining radiotherapy and immune check-point inhibitors [23; 24; 25]. The efficacy of stereotactic radiotherapy within 6 months of receiving anti-PD-1 nivolumab in 26 pretreated patients with advanced resected and unresectable melanoma with brain metastases was demonstrated in a retrospective study by [PERSON] et al. [23]. This retrospective analysis showed a 12-month local brain metastasis control rate in 85% of cases and a distant brain metastasis control rate in 53% of cases, due to a synergic effect with the anti-PD-1 inhibitor and stereotactic radiation. Furthermore, they demonstrated a median OS of 12 months from the date of immunotherapy initiation and 11.8 months from the date of radiation. Interestingly, the administration of nivolumab before, during, or after the radiotherapy showed a lower rate of neurotoxic compared to the exclusive radiation treatment [24]. [PERSON] et al. performed a phase I study involving 16 eligible patients, with the aim of evaluating the maximum tolerable dose (MTD) and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole-brain radiotherapy (WBRT) in patients with brain metastases (BMs) from melanoma. Five patients were treated with whole-brain radiation therapy (WBRT) (arm A) and eleven with stereotactic radiosurgery (SRS) (arm B). Seven patients overall in arms A and B received ipilimumab 3 mg/kg and nine patients received a dose of 10 mg/kg. The authors concluded that the concomitance of ipilimumab 3 mg/kg and 10/kg with SRS is safe. The overall intracranial response, defined by the irRC, was immune-related SD in five patients (3%) and immune-related PR in one patient (7%) [25]. This systematic review and meta-analysis aimed to estimate intracranial responses to different treatments in melanoma metastatic to the brain and investigate factors influencing responses to immunotherapy and targeted therapy in brain metastases.