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

Abstract

TPS4246 Background: Gastroesophageal adenocarcinoma (GEA) is a major cause of global cancer-related mortality. A common standard of care for frontline advanced GEA is 5-fluorouracil and oxaliplatin (FOLFOX), with the addition of immune checkpoint inhibitors (ICI) in patients with a PD-L1 combined positive score (CPS) of > 1. Adding ICIs improves median overall survival (OS) by 2-4 months, with increased benefit seen with higher CPS scores (Leone et al, ESMO Open , 2024). There remains a significant need to improve ICI outcomes and expand the portion of patients who benefit. In GEA, vascular endothelial growth factors (VEGF) are associated with poor prognosis, influencing immune suppression and T cell exhaustion. There is strong mechanistic rationale for cooperativity between anti-VEGF antibodies and ICI in GEA, as well as evidence of clinical benefit in treatment-refractory gastric cancer (Kim et al, Cancer Immunol Res , 2025). Ivonescimab is a novel bispecific antibody that simultaneously targets PD-1 and VEGF, in a spatially constrained manner, impairing neoangiogenesis and remodeling the suppressive tumor microenvironment. Ivonescimab has evidence of safety and efficacy in colorectal and hepatocellular cancers and is approved for the treatment of PD-L1+ lung cancer in China (Deng et al, ESMO 2024; Li et al, ESMO 2025; Xiong et al, Lancet , 2025). Methods: This single-arm, multi-institutional phase II study seeks to evaluate ivonescimab in combination with FOLFOX as frontline therapy in GEA. Adults with locally advanced unresectable or metastatic HER-2 negative GEA are eligible. Patients must have disease that can be evaluated radiographically and may not have received prior systemic therapy for advanced disease. Positive PD-L1 expression is not required for eligibility. We plan to enroll 40 patients. To allow for collection of early immune modulation data, patients will commence therapy with a single dose of ivonescimab 20 mg/kg at discretion of the treating investigator. Subsequent cycles will continue with the addition of FOLFOX (dosed per institutional standards) to ivonescimab, given on day 1 and day 15 of a 28-day cycle. Imaging will be performed every 6 weeks until week 24, at which point imaging will change to every 9 weeks. Treatment will continue until disease progression, withdrawal of consent, or death. The primary objective is to define efficacy of ivonescimab in combination with FOLFOX as measured by the 6-month progression-free survival (PFS) rate. Secondary objectives include safety and tolerability, objective response and clinical benefit rates, median PFS and OS. Translational correlative studies are planned to explore tumor and immunologic determinants of response. This study is currently open and enrolling (NCT07070466). Clinical trial information: NCT07070466 .