Antibody therapeutics: A new era for EGFR-mutant NSCLC treatment

Epidermal growth factor receptor (EGFR) mutations represent a central oncogenic driver in non-small cell lung cancer (NSCLC). While EGFR tyrosine kinase inhibitors (TKIs) have revolutionized the management of NSCLC, acquired resistance remains a major hurdle. In response, antibody-based therapeutic strategies have gained increasing attention as a means to overcome TKI resistance and extend disease control. This review synthesizes the rapidly evolving landscape of antibody-based therapeutics for EGFR-mutant NSCLC. We first summarize the mechanisms of monoclonal antibodies directly targeting EGFR, including cetuximab and necitumumab, and discuss their therapeutic limitations. We then highlight the emergence of bispecific antibodies designed to simultaneously target EGFR and key resistance pathways, such as MET. In addition, we review combination strategies integrating EGFR inhibition with antibodies directed against alternative oncogenic pathways or the tumor microenvironment, including anti-angiogenic agents such as bevacizumab. A major focus of this review is antibody-drug conjugates (ADCs) targeting novel surface antigens, including HER2, HER3, and TROP2. By delivering highly potent cytotoxic payloads selectively to tumor cells, these ADCs have demonstrated remarkable clinical efficacy in EGFR TKI-resistant settings. Furthermore, we examine the complex and evolving role of immunotherapy in EGFR-mutant NSCLC. Beyond immune checkpoint blockade, we discuss emerging immunomodulatory strategies targeting the adenosine pathway (CD73), phagocytosis checkpoints (CD24), and complement regulatory proteins (CD55/CD59). Finally, we explore advanced antibody modalities, including immune-engaging bispecific antibodies and next-generation ADCs. Collectively, antibody-based therapies are reshaping the treatment landscape through diverse mechanisms, offering renewed promise for overcoming resistance and improving outcomes in EGFR-mutant NSCLC.