Phase 2 study of ivonescimab in patients with cutaneous squamous cell carcinoma.

TPS9615 Background: Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer. In the setting of unresectable locally advanced or metastatic disease, checkpoint inhibitors are standard of care and are associated with robust response rates and durable disease control. However, in those who do not respond or progress on immunotherapy, there are limited available standard therapies. Ivonescimab is a tetravalent bispecific antibody targeting programmed cell death protein 1 (PD-1) and vascular endothelial growth factor A (VEGF-A) that has shown promising activity in multiple tumor types. VEGF-mediated activities include driving angiogenesis creating a tortuous tumor vasculature and decreasing effector T-cells within the tumor microenvironment. Herein, we hypothesize that dual targeting of PD-1 and VEGF-A may overcome resistance to checkpoint inhibitors and extend the benefit of immunotherapy in CSCC. Methods: This phase 2, single-arm study will enroll up to 24 patients and will be conducted using a Bayesian optimal phase 2 (BOP2) design. Prespecified activity goal for the first stage of accrual was met; second stage accrual began in January 2026. Patients will receive Ivonescimab 20mg/kg intravenously every 3 weeks until progression, death, or intolerance. The main inclusion criteria include unresectable locally advanced or metastatic CSCC that is refractory to prior checkpoint inhibitors, Eastern Cooperative Oncology group performance score of 0-1, and measurable disease by RECIST version 1.1. Primary exclusion criteria comprise prior severe immunotherapy-associated toxicities, prior organ transplant, or major blood vessel invasion. There are no limits on lines of therapy. Primary objective and endpoint is objective response rate in CSCC. Key secondary endpoints include duration of response, disease control rate, progression free survival, and safety. Additional exploratory objectives include evaluating predictive biomarkers of treatment response or resistance utilizing a mandatory biopsy performed both pre-and on-treatment, with correlatives including whole exome sequencing, RNA sequencing, multiplex IHC. Active recruitment and enrollment are ongoing at The University of Texas MD Anderson Cancer Center, Houston, Texas. Copyright © 2026 AACR. Originally presented at AACR 2026. Reprinted with permission. Clinical trial information: NCT06567314 .