From Monoclonal to Bispecific Antibodies, The Next Step of Immunotherapy for Non-Small Cell Lung Cancer

Abstract Lung cancer remains the leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors (ICIs) and bispecific antibodies (bsAbs) are transforming the treatment landscape, particularly in non-small cell lung cancer (NSCLC). Perioperative immunotherapy trials, such as RATIONALE-315, have demonstrated significant improvements in pathological response rates and event-free survival for resectable NSCLC. Ivonescimab, a bsAb targeting PD-1 and VEGF , has shown promising efficacy in patients with EGFR mutations or PD-L1-positive tumors. The HARMONi-A trial highlighted improved progression-free survival (PFS) with ivonescimab compared to standard regimens, while HARMONi-2 revealed significant benefits in first-line PD-L1-positive NSCLC, including those with squamous histology. These advancements underscore the potential of bsAbs to overcome treatment resistance and improve outcomes. However, challenges remain, including optimizing treatment cycles, managing toxicity, and identifying predictive biomarkers. Future research should focus on refining therapeutic strategies, exploring combination therapies, and addressing unresolved questions regarding long-term efficacy and safety. Integrating these approaches has the potential to transform NSCLC management and improve patient survival globally.