**6.6 Immune therapy**

Although the immune system plays a role in all stages of the development of cerebral metastasis, so far therapeutic interference was limited to the immune response around the tumor cells present in the brain. The inflammatory microenvironment of brain metastases mainly consists of infiltration by tumor-infiltrating lymphocytes (TIL) expressing immunosuppressive factors like programmed death-1 (PD-1) ligand (PD-L1). Immunotherapeutic agents include anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), anti- PD-1, and PD-L1 monoclonal antibodies (mAbs). There are limited data available on the efficacy and safety of immunotherapy for patients with NSCLC brain metastasis. Approximately, 15% of patients participated in studies and all had stable BM or had been treated for BM, while patients with symptomatic BM were excluded from trials [16]. The available data were derived from single-arm phase I/II trials [141–143], pre-arranged analyses of phase III trials [143–145], and expanded access programs [146, 147]. In the phase I multi-cohort CheckMate 012 study of the tolerability and safety of nivolumab in patients with NSCLC with BM only twelve patients were included. Their median PFS and OS were 1.6 months and 8.0 months, respectively, and no more than two intracranial responses were observed [143].

In a phase 2 trial, the PD-1 blockade by pembrolizumab was studied in patients with advanced NSCLC with untreated brain metastases. Forty-two patients were treated with Pembrolizumab. The cohort with PD-L1 ≥1% 1, 29.7% of patients had a BM response,

while the patients with PD-L1 <1% did not show a response. The median OS and PFS of patients in cohort 1 was 9.9 months and 1.9 months, respectively¸ confirming that pembrolizumab activity in CNS metastasis is limited to NSCLC with higher PD-L1 expressions. Moreover, the PD-L1 expression was associated with long-term OS [142]. In two nivolumab EAP studies conducted in Italy and France, 409 and 130 patients respectively, were included with advanced NSCLC and asymptomatic and stable BM. Part of the patients received corticosteroids and the other part underwent concomitant brain radiotherapy. The OR was 17% in the Italian study and 12% in the French study; the OS was 8.6 and 6.6 months, respectively [146, 147]. In another pooled analysis of larger trials on pembrolizumab monotherapy (KEYNOTE 001, 010, 024, and 042) and pembrolizumab combined with chemotherapy (KEYNOTE 021, 189 and 407), the OS of patients who received pembrolizumab alone or with chemotherapy was better as compared to patients who received chemotherapy alone [144, 145].
