Evaluating the Safety of Immune Checkpoint Inhibitors and Combination Therapies in the Management of Brain Metastases: A Comprehensive Review

Abstract

Brain metastases (BM) are a frequent and severe complication in patients with lung cancer, breast cancer, and melanoma. Immune checkpoint inhibitors (ICIs) have become a crucial treatment option for BM, whether used alone or in combination with chemotherapy and stereotactic radiosurgery (SRS). However, ICIs are associated with immune-related adverse events (irAEs) that can affect multiple organ systems, complicating their use in BM patients. This review examines the mechanisms of irAEs and their effects on different organs and evaluates the safety of ICIs across various treatment strategies for BM. Our analysis indicates that ICIs significantly improve survival and disease control in BM patients, but their use increases the risk of irAEs, including dermatologic, gastrointestinal, endocrine, pulmonary, and neurologic toxicities. Neurotoxic events, particularly treatment-associated brain necrosis (TABN) and encephalitis, are more common in BM patients. While the overall incidence of irAEs is similar between patients with and without BM, the neurotoxicity risk is higher in the BM population. Combining ICIs with chemotherapy and SRS enhances efficacy but also heightens the risk of adverse events across organ systems. ICIs offer substantial benefits for BM patients but require careful management to mitigate the risks of irAEs. Close patient monitoring, individualized treatment protocols, and prompt intervention are essential for optimizing the outcomes. Future research should focus on refining combination strategies and improving the management of irAEs, particularly neurotoxicity, to maximize therapeutic benefits for BM patients.

Keywords: brain metastasis; immune checkpoint inhibitors; immune-related adverse events; melanoma; non-small-cell lung cancer; stereotactic radiosurgery.

Figure 1

Adverse events associated with immune checkpoint inhibitors (ICIs). The upregulation of immune checkpoints PD-1 and CTLA-4 on T-cells inhibit immune responses, causing immune invasion. ICIs like anti-CTLA-4 and anti-PD-1 reverse this process and activate an immune response against tumor cells (left panel). However, although ICIs enhance the immune system via increased T-cell proliferation and activation, the inhibition of cytokine release (IL-10 and TGF-β) via regulatory T-cell (Treg) downregulation increases the humoral autoimmune reaction (middle panel). As a result, the upregulation of immunity causes immune cells to infiltrate various organs, leading to many immune-related adverse events (right panel). Created with BioRender.com.