For these reasons, results obtained with ICPs in patients enrolled in clinical trials with treated, asymptomatic BM should not be generalized to the whole population with CNS involvement. Factors such as the number of metastatic lesions, their size, location, and associated symptoms as well as the control of extracranial disease may describe very different conditions in terms of prognosis ( 12). These observations suggested an immunosuppressive tumor microenvironment within the CNS niche that can potentially affect the immunotherapy efficacy regardless of the molecular and immunohistochemical features of the primary disease.Īlthough patients with CNS metastases generally have a poorer prognosis than the general population, this subgroup of patients is rather heterogeneous. Furthermore, lower T-cell density and PD-L1 expression besides a contracted T-cell receptor repertoire were found in BM compared to the matched lung primary tumor ( 10, 11). Indeed genomic studies by next-generation sequencing on matched primary lung tumor and BM showed a significant heterogeneity in terms of somatic mutation and copy number alteration, potentially resulting in a different tumor mutational burden ( 8– 10). However, the molecular profile and the tumor microenvironment of BM substantially differs from primary lung cancer, suggesting a potentially different effect by immunotherapy. Moreover ICPs, not attacking cancer cells itself, can remove the T-cell blockage, peripherally allowing functional T-cells to reach the brain and leptomeningeal metastasis ( 6, 7). Consequently, the appropriate care of these patients is a recurrent clinical concern.īrain is traditionally considered an immune-privileged site, but some studies suggested that it can become accessible to immune check point inhibitors (ICPs) due to the blood–brain barrier disruption by brain tumors ( 5). Due to the remarkable results achieved by immunotherapy and the improvement in our ability to detect and treat other sites of the disease, the number of patients with CNS metastases is expected to increase. Twenty percent of patients have brain metastases (BM) at the time of diagnosis, while in 40 and 10% of cases, they develop brain and leptomeningeal involvement, respectively, during tracing of the history of the disease ( 2– 4). Non-small cell lung cancer (NSCLC) frequently metastasizes to the central nervous system (CNS) ( 1). Despite the fact that limited data are available in the literature, the purpose of this review is to show that the multimodal treatment of these patients with brain metastases and/or leptomeningeal disease should be discussed during tracing of the history of the disease, participating in the local and possibly systemic control of NSCLC. Nevertheless, neurological complications due to ICP treatment in patients with brain metastases have to be evaluated and carefully monitored. In contrast, few data are available about patients with leptomeningeal carcinomatosis. Despite important limitations, some real-life studies have described that the ICPs’ efficacy was maintained also in less selected patients with untreated or symptomatic brain metastases. This results in a similar clinical benefit in patients with stable, previously treated brain metastases compared to the general population. Although there are many aspects that would merit further investigation to explain the mechanism of intracranial response to immune checkpoint inhibitors (ICPs), some data suggest that they are able to cross the blood–brain barrier, resulting in local tumor microenvironment modification. Consequently, the appropriate care of these patients is a recurrent clinical concern. Nevertheless, NSCLC is the most common tumor to metastasize to the brain, and patients develop brain and meningeal involvement in approximately 40 and 10% of cases, respectively. However, the pivotal clinical trials that demonstrated its impressive efficacy often did not include patients with active, untreated brain metastases or leptomeningeal carcinomatosis. Immunotherapy has now been integrated as a treatment strategy for most patients with non-small cell lung cancer (NSCLC).
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