The current landscape and prospects of antibody-drug conjugates for lung cancer brain metastases: a narrative review.

Background and Objective: As the most common cancer to progress to brain metastases (BMs), lung cancer presents with intracranial involvement in approximately 20% of patients at the time of diagnosis and lung cancer BMs constitute approximately half of all BMs. The current clinical strategy for managing lung cancer BMs involves a combination of systemic anticancer therapies with local radiation or surgical interventions. The efficacy of systemic treatments is often constrained by the blood-brain barrier (BBB) and the poor inhibition effect of the drug itself. Despite these treatments, the median survival for patients with lung cancer BMs frequently does not exceed 2 years, underscoring the urgent need for novel and effective therapeutic approaches. Antibody-drug conjugate (ADC) consists of three components: monoclonal antibodies, payload, and linkers. Novel ADCs have demonstrated therapeutic advantages in a variety of tumors, including BMs. This review aims to summarize the latest advancements of ADCs in lung cancer BM. Methods: For this review, we searched the literature published in the field of ADCs for lung cancer BMs over the past 10 years. Key Content and Findings: New-generation ADCs, represented by trastuzumab deruxtecan (T-DXd) and others, have demonstrated prominent intracranial antitumor activities and have shown significant therapeutic advantages on lung or breast cancer BMs in both preclinical and clinical studies. Several factors may contribute to the efficacies of ADCs in the intracranial cancers including specific payload, a higher and uniform drug:antibody ratio (DAR) as well as potent bystander effect. Whether intracranial tumors express these target antigens should also be taken into consideration. Conclusions: ADCs have demonstrated promising antitumor activities in non-small cell lung cancer (NSCLC) patients with BMs and could offer a new systemic treatment option for this subset population of patients. More research exploring the efficacy, safety and mechanism of ADCs in BMs are needed. Combining ADCs with conventional treatments for BMs, such as radiotherapy and immunotherapy, may be a new direction for future treatment.