Non-small cell lung cancer brain metastases and the immune system: From brain metastases development to treatment

Abstract

Brain metastases (BM) are diagnosed frequently in non-small cell lung cancer (NSCLC) patients. Despite the high incidence of BM (up to 40% in unselected patients), patients with untreated and/or unstable BM were excluded from pivotal immune checkpoint inhibitors (ICI) NSCLC trials. Percentage of patients with stable and treated BM in these trials ranged from 9.1 to 14.7% and ICI benefit over chemotherapy was not always demonstrated. Only small trials have been completed that demonstrated ICI efficacy in locally untreated, selected BM patients. With 33%, cranial objective response rate (ORR) was comparable to extracranial ORR and responses were often durable. With the promising survival benefits of ICI, in daily practice also unstable and/or untreated BM patients will often receive treatment with ICI and extrapolating clinical trial data to these patients can be challenging. In this review, we will summarize the preclinical rationale and potential concerns for the use of ICI in BM patients. Furthermore, we will summarize BM subgroup data from the pivotal NSCLC trials, retrospective series, the NSCLC BM specific ICI trials and the use of cranial radiation and ICI. Last, we provide an overview of response measurement criteria and future directions.

Nivolumab and brain metastases in patients with advanced non-squamous non-small cell lung cancer

“…Immune checkpoint inhibitors work by activating the immune system against tumor cells, which may explain the potential effect of immunotherapy on CNS metastases [13]. Moreover, NSCLC-derived brain lesions show a higher expression of PD-L1 than the respective primary tumor [14].…”

Stereotactic radiosurgery in the era of novel systemic therapy for lung cancer brain metastases

“…Overall, in the small subgroups of BM patients included in these trials, ICI appears safe [29] . However, outcomes were mixed as some trials demonstrated benefit over chemotherapy and others did not [29] . A rationale for positive response to ICIs includes the inflammatory microenvironment of BM, with the presence of significant tumor-infiltrating lymphocytes (TILs).…”

“…Present data on ICIs for BM from advanced NSCLC is limited. Most ICI clinical trials in NSCLC excluded patients with untreated or unstable BM, yet included stable and treated BM, comprising 6%-17% of included patients [29] . Overall, in the small subgroups of BM patients included in these trials, ICI appears safe [29] .…”

“…Most ICI clinical trials in NSCLC excluded patients with untreated or unstable BM, yet included stable and treated BM, comprising 6%-17% of included patients [29] . Overall, in the small subgroups of BM patients included in these trials, ICI appears safe [29] . However, outcomes were mixed as some trials demonstrated benefit over chemotherapy and others did not [29] .…”

Current challenges in the management of nonsmall cell lung cancer brain metastases

“…Furthermore, guidelines for BM management recommendations are not consensual (reviewed by LEVY et al [4]), and high-level evidence regarding screening and treatment is scarce. Randomised trials specifically including NSCLC BM patients are largely lacking, and patients with untreated and/or unstable, or even all, BM were excluded from most clinical trials (reviewed by EL RASSY et al [5] and MCCOACH et al [6]).…”