Dr Ku Highlights Bispecific Antibody Approaches in Gastric/GEJ Cancers

Geoffrey Y. Ku, MD, a gastrointestinal medical oncologist and cellular therapist at Memorial Sloan Kettering Cancer Center, discusses the emergence of bispecific antibodies as a therapeutic approach in the treatment paradigm for patients with gastric and gastroesophageal junction (GEJ) cancers.

Ku explains how many bispecific antibodies can act as molecular bridges, binding a tumor-associated antigen such as claudin-18.2 (CLDN18.2) or HER2 on cancer cells, while simultaneously engaging an immune-cell target such as CD3 or 4-1BB. This brings immune cells into proximity with tumor cells and promotes an antitumor immune response.

He next discusses immune checkpoint inhibitor–based bispecifics. With these agents, one arm of the bispecific binds to an immune checkpoint, such as PD-1, PD-L1, or CTLA-4, while the other arm binds to a tumor-associated antigen, such as HER2 or CLDN18.2. These agents, Ku explains, allow the antibody to target the tumor while simultaneously disrupting an inhibitory immune signal, stimulating the immune system through 2 different mechanisms. for patients with gastric and GEJ cancers, these approaches could broaden treatment options by combining tumor targeting with immune activation and potentially overcoming limitations associated with established therapies.

Ku adds that bispecific antibodies targeting PD-1 and VEGF are showing promise in solid tumors overall. He notes that at the 2026 American Society of Clinical Oncology Annual Meeting, data from the phase 3 HARMONi-6 trial (NCT05840016), presented in a late-breaking abstract, showed that the PD-1/VEGF antibody ivonescimab significantly improved progression-free survival compared with tislelizumab (Tevimbra) plus chemotherapy in patients with previously untreated advanced squamous non–small cell lung cancer.1

In his concluding remarks, Ku says that bispecific antibodies work mechanistically in a variety of ways, but the key focus with all of these agents is to move beyond first-generation antibodies, such as trastuzumab (Herceptin), zolbetuximab (Vyloy), and zanidatamab (Ziihera). “Hopefully there will be more effective second-generation therapies,” says Ku.

REFERENCE

1. Zhiwei C, Yang F, Luo Y, et al. Ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy in previously untreated advanced squamous non–small cell lung cancer: overall survival results of the phase 3 HARMONi-6 trial. J Clin Oncol. 2026;44(suppl 17):LBA4. doi:10.1200/JCO.2026.44.17_suppl.LBA4