Bispecific Antibodies in Non-Small Cell Lung Cancer: From Targeted Innovation to Real-World Integration

Bispecific antibodies have ushered in a transformative era in treating non-small cell lung cancer (NSCLC), enabling dual-pathway targeting with promising clinical outcomes in previously refractory disease subsets. Recent US Food and Drug Administration approvals-including amivantamab, an epidermal growth factor receptor (EGFR)/mesenchymal-epithelial transition factor-targeting monoclonal antibody for EGFR exon 20 insertions and frontline EGFR-mutant (Exon 19 and 21) NSCLC, and zenocutuzumab for tumors harboring neuregulin 1 fusions-highlight their expanding therapeutic footprint. However, a new spectrum of on-target toxicities and implementation challenges are essential considerations as part of this innovation. This review dissects the evolving clinical data for bispecific antibodies in NSCLC, focusing on amivantamab, and provides a practical framework for managing dermatologic, infusion-related, and class-specific adverse events. We explore quality-of-life outcomes, financial toxicity, and the role of subcutaneous formulations in improving patient adherence and treatment experience. Furthermore, we highlight an emerging PD-1/vascular endothelial growth factor-A bispecific antibody (ivonescimab) and its potential to reshape frontline therapy paradigms in NSCLC. By integrating clinical trial evidence with real-world considerations, this review aims to equip oncologists with the tools to optimize the use of bispecific antibodies in NSCLC and guide future therapeutic integration.