Bispecific Antibodies Targeting PD-1/PD-L1 and VEGF in Non-Small Cell Lung Cancer

Abstract

Immune checkpoint inhibition has transformed the treatment of advanced non-small cell lung cancer (NSCLC), but primary and acquired resistance remain common. Vascular endothelial growth factor (VEGF) contributes to both tumor angiogenesis and immune suppression by promoting abnormal vasculature, limiting lymphocyte trafficking, and fostering an immunosuppressive tumor microenvironment. These complementary mechanisms provide a rationale for simultaneously targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and VEGF pathways. Bispecific antibodies integrating checkpoint blockade and VEGF neutralization within a single molecule have therefore emerged as a rapidly developing therapeutic strategy in NSCLC. Ivonescimab, a PD-1/VEGF bispecific antibody, currently has the most mature evidence, with randomized phase III trials demonstrating improvements in progression-free survival and, in selected settings, overall survival compared with established PD-1-based regimens. Other PD-1/VEGF agents, including PF-08634404, MK-2010, and JS207, have shown encouraging early activity but require randomized validation. Among PD-L1/VEGF bispecific antibodies, pumitamig, HB0025, and IMM2510 have demonstrated promising antitumor activity, although evidence is derived predominantly from early-phase or single-arm studies. Multiple phase III trials are evaluating these agents in first-line, post-immunotherapy, epidermal growth factor receptor (EGFR)-mutated, and stage III consolidation settings. VEGF-associated toxicities, including hypertension, proteinuria, hemorrhage, and thromboembolism, remain clinically relevant. Moreover, differences in checkpoint target, molecular architecture, target affinity, fragment crystallizable (Fc) engineering, pharmacokinetics, and VEGF-binding strategy preclude the assumption of a uniform class effect. The fixed bispecific configuration also prevents independent dose adjustment of the checkpoint and antiangiogenic components, which may complicate toxicity management. Mature randomized survival data, longer-term safety assessment, and biomarker development are needed to define optimal patient selection and the clinical role of PD-(L)1/VEGF bispecific antibodies in NSCLC.