Phase II study of NC410 and FOLFIRINOX in combination with nivolumab with or without ipilimumab in patients with treatment-naive metastatic pancreatic cancer.

Abstract

TPS4260 Background: Pancreatic adenocarcinoma (PDAC) is now the third leading cause of cancer-related death in the United States (1). Median overall survival for patients with metastatic PDAC is 11.1 months with first-line FOLFIRINOX chemotherapy (2) and more effective treatments are needed. A major resistance mechanism to immunotherapy in PDAC is the desmoplastic stroma (3). Collagen physically hinders T cell infiltration and suppresses immune cells in the tumor microenvironment (TME) through the Leukocyte Associated Immunoglobulin-like Receptor-1 (LAIR-1) (4). Both collagen and the complement protein C1q, overexpressed in the PDAC TME, are primary ligands for the inhibitory LAIR-1 receptor on myeloid and lymphoid cells, and binding results in immune cell downregulation (5-7). LAIR-2, primarily made by CD4+ T cells, is a competitive inhibitor of LAIR-1 that reverses the immunosuppressive effect (8). NC410 is a dimeric fusion protein of LAIR-2 with human IgG1 Fc that remodels collagen, reduces tumor growth, enhances T cell tumor infiltration, and overcomes neutrophil-mediated T cell suppression in preclinical studies (7,9,10). NC410 binds the collagen-rich PDAC TME with high avidity when compared across tumor types (7). Our group contributed to the recent phase Ib/II study demonstrating clinical activity of NC410 with pembrolizumab in patients with advanced colorectal and ovarian cancer (NCT05572684). Based on these promising results, our study combines NC410 and immunotherapy with FOLFIRINOX in the first-line setting to assess safety and clinical efficacy in patients with metastatic PDAC. Methods: This is a single-center, open-label, two-arm phase II study evaluating safety and efficacy of NC410 and FOLFIRINOX in combination with nivolumab with or without ipilimumab in patients with untreated metastatic PDAC. The two arms enroll sequentially. In Cycle 1, NC410 and FOLFIRINOX are given with nivolumab (Arm 1, n =10) or nivolumab + ipilimumab (Arm 2, n = 10). In Cycle 2 and beyond, patients in both arms receive NC410 and FOLFIRINOX every 2 weeks and can continue to receive treatment per investigator discretion. On study scans are obtained every 8 weeks. Eligible patients have untreated metastatic PDAC, measurable disease per RECIST 1.1, and are willing to undergo tumor biopsy at baseline and on treatment. Primary endpoint is safety. Secondary endpoints are disease control rate, objective response rate, progression free survival, and overall survival. Correlative studies will profile circulating neutrophils and markers of immune activation in paired whole blood and tumor biopsy samples at baseline and on-treatment at Cycle 4. Enrollment began in August 2025 and is ongoing. 10 of planned 20 patients have been enrolled; awaiting 8-week primary safety endpoint evaluation in Arm 1. Trial information: NCT06941857. References upon request. Clinical trial information: NCT06941857 .