A single-arm, phase II study of ivonescimab in combination with FOLFOX in advanced HER2 negative gastroesophageal adenocarcinomas

Background Gastroesophageal adenocarcinoma (GEA) is a major cause of global cancer-related deaths. A first-line standard of care for advanced GEA is FOLFOX, with the addition of immune checkpoint inhibitors (ICIs) in patients with a programmed death-ligand 1 (PD-L1) combined positive score of ≥1. However, overall survival remains poor. There is a strong mechanistic rationale for cooperativity between anti-vascular endothelial growth factor (VEGF) antibodies and ICIs across cancers. Ivonescimab is a bispecific antibody that simultaneously targets programmed cell death protein 1 and VEGF, with evidence of safety and efficacy in colorectal, hepatocellular, and lung cancers. Design This single-arm, multi-institutional, phase II study seeks to evaluate ivonescimab in combination with FOLFOX as a first-line therapy in GEA. Adults with locally advanced unresectable or metastatic human epidermal growth factor 2 (HER2)-negative GEA are eligible. Positive PD-L1 expression is not required for eligibility. We plan to enroll 40 patients. Ivonescimab 20 mg/kg and FOLFOX are given on day 1 and day 15 of a 28-day cycle. Treatment will continue until disease progression, withdrawal of consent, or death. The primary objective is to define the efficacy of ivonescimab in combination with FOLFOX as measured by the 6-month progression-free survival rate. Translational correlative studies are planned to explore tumor and immunologic determinants of response.