Immune checkpoint inhibitors as first-line treatment for brain metastases in stage IV NSCLC patients without driver mutations

Immune checkpoint inhibitors (ICI) therapy with or without chemotherapy has been established as the first-line treatment for patients with non-oncogene addicted advanced Non-Small Cell Lung Cancer (NSCLC). Yet some clinical settings, such as the treatment sequence in patients with brain metastases, have barely been evidenced. Although ICIs cannot directly cross the blood-brain barrier (BBB), evidence suggests that BBB damage could allow ICIs into the central nervous system, or that they can have an indirect effect on the tumor immune microenvironment (TIME) and cause an anti-tumor response. Pivotal phase III trials have included a highly selected population but offer few data on these patients. Here we first review how ICIs can indirectly shape the brain metastases microenvironment through different mechanisms, and some possible causes of ICIs resistance. We also analyze the evidence reported in pivotal phase III trials and phase II trials focused on NSCLC brain metastases for first-line treatment, and the evidence for upfront or delayed local brain therapy. Finally, we discuss the best evidence-based approach to treat NSCLC patients with brain metastases and propose future research.