# Melanoma Brain Metastases: Immunotherapy or Targeted Therapy? A Systematic Review and Meta-Analyses
## 4 Discussion  
This is the largest comprehensive systematic review and meta-analysis carried out. We show that overall, the SE of the treatment response is low (36% with 95% CI 27%-47%), indicating that less than half of the patients responded; however, there is a large heterogeneity due to treatment and type of disease. Although we do not observe a meaningful difference between intracranial benefit in asymptomatic and symptomatic patients, subgroup analysis and meta-regression found a statistically significant better brain metastasis response in symptomatic patients who received immunotherapy compared to patients who received a combination (immunotherapy and TT): 47% vs. 9%, \(p\)-value = 0.001. Reduction in number of asymptomatic metastases was more substantial when patients received the combo-immunotherapy compared to those who had received monotherapy: 45% vs. 26.1%, \(p\)-value = 0.002. Our hypothesis is that maybe T-cell activation by immune check-point inhibitors should be more effective in at early stage of intracranial dissemination or in an asymptomatic disease. The onset of cerebral oedema could adversely affect the intracranial immune activity. The authors did not provide in-depth data regarding the different responses to immunotherapy in terms of gender and age. The lack of comparative trials between oral targeted therapy versus intravenous immunotherapy represents the main limitation influencing physician choice in clinical practice. For several years, locoregional treatment of melanoma brain metastases, such as surgery and radiotherapy, was considered the gold standard. The current analysis has provided a quantification of intracranial benefit for each type of treatment, aiming to find the best strategy in melanoma patients affected by brain metastasis. Similar to what was found in [PERSON]'s meta-analyses [30], which considered intracranial response for 12 clinical trials, there was no considerable difference in asymptomatic patients versus symptomatic ones. However, we observed that the clinical remission or partial response to different types of treatment exclusively depends on neurological symptoms. An important observation concerns the response of patients who have not previously received first-line immunotherapy, as this response is different in patients with symptomatic or asymptomatic brain metastases. The first randomised phase III trial [17] already showed that patients with untreated asymptomatic brain metastasis immunotherapy (\(p\)-value = 0.017) had significantly improved overall survival (OS) compared to fotemstine: patients receiving ipilimumab plus nivolumab, had a 4-year OS rate that was significantly higher than those receiving fotemstine (41% vs. 11%). Additionally, patients receiving ipilimumab plus nivolumab experienced significantly fewer high-grade adverse events (AEs) (30%) than those receiving either of the fotemstine-containing arms (48% and 69%, respectively). Furthermore, [PERSON] and co-authors [14] reported in the CheckMate 204 trial a remarkable rate of 72% for asymptomatic patients, with 3-year OS when treated with nivolumab plus ipilimumab. These impressive data on long-term outcomes turn dogma upside down, because the melanoma patients in this group have historically had very poor therapeutic outcomes and have been difficult to treat. Patients with melanoma and brain metastases were previously routinely excluded from industry-sponsored clinical trials with immune check-point inhibitors because of their poor prognosis and the prevailing dogma that the blood-brain barrier would prevent effector immune cells from migrating to the brain. Patients with untreated brain metastases have a better prognosis due to both a limited number and small metastases, which can be translated into a reduction in intracranial oedema and neurological symptoms. This explains the higher response rate to check-point inhibitors in asymptomatic patients.