Ivonescimab and other anti-programmed death-1/ligand 1 (PD-(L)1)/vascular endothelial growth factor (VEGF) bispecific antibodies: progress and prospects in cancer therapy

Abstract In cancer therapy, the synergistic interaction between immunotherapy and anti-angiogenic therapy has been validated by both preclinical and clinical studies, and has laid the foundation for the development of anti-PD-(L)1/VEGF bispecific antibodies. In the HARMONi-2 trial, ivonescimab demonstrated superior efficacy over pembrolizumab for the first time. This milestone may open a new era of immunotherapy with bispecific antibodies replacing anti-PD-1 monoclonal antibodies. Subsequently, the HARMONi-6 trial confirmed that ivonescimab combined with chemotherapy also outperformed tislelizumab plus chemotherapy, adding further evidence. Currently, dozens of anti-PD-(L)1/VEGF bispecific antibodies with distinct molecular structures have entered clinical stages; and only ivonescimab has completed Phase 3 clinical trial validation in multiple clinical trials and obtained approval in China. A growing body of clinical evidence indicates that in immunotherapy-sensitive tumors (e.g. lung cancer), bispecific antibodies have demonstrated superior efficacy compared with monoclonal antibodies. Even in tumors traditionally refractory to immunotherapy (such as colorectal cancer and pancreatic cancer), bispecific antibodies exhibit promising therapeutic effects while maintaining a favorable safety profile. Nevertheless, several issues require further investigation, such as predictive biomarkers and resistance mechanisms. Future investigations surrounding this class of agents are highly anticipated, including anti-PD-(L)1/VEGF bispecific antibodies-based combination therapy in a broader range of tumor types, as well as the development of trispecific antibodies and bispecific antibody–drug conjugates.