Intracranial activity of antibody-drug conjugates in advanced non-small cell lung cancer: What have we accomplished so far?

Antibody-drug conjugates (ADCs) represent a rapidly evolving class of therapeutics in non-small cell lung cancer (NSCLC), offering targeted delivery of cytotoxic payloads to tumor cells while minimizing off-target toxicity. Although ADCs have demonstrated promising results in NSCLC, their efficacy in treating central nervous system (CNS) metastases has been uncertain due to concerns over blood-brain barrier (BBB) penetration and the lack of dedicated CNS-specific evaluations in clinical trials. However, emerging evidence challenges this paradigm. While earlier-generation ADCs such as T-DM1 exhibited limited CNS efficacy, newer ADCs employing optimized linkers and cytotoxins demonstrate more favorable efficacy and toxicity profiles. Selected agents, including trastuzumab deruxtecan, datopotamab deruxtecan and patritumab deruxtecan, have all shown intracranial responses in patients with advanced NSCLC with brain metastases (BM). Proposed mechanisms facilitating CNS activity include BBB disruption by BM, membrane-permeable and highly potent cytotoxic payloads, and bystander effects that enable tumor cell killing beyond the target antigen. Nevertheless, several limitations remain, including variability in trial designs, limited number of patients with untreated CNS disease, and a lack of CNS-specific endpoints. Given the high incidence of BM in NSCLC and their significant impact on patient outcomes, there is an urgent need to better understand the intracranial activity of ADCs and whether they can prevent the development of CNS metastases, especially as some of these ADCS are being tested in the curative-intent setting. This review synthesizes current evidence and highlights ongoing trials, with a focused examination of the evolving role of ADCs in the management of BM.