Abstract B091: Interleukin-1 Receptor Accessory Protein (IL1RAP) overexpression is associated with worse outcome in PDAC and can be reversed by nadunolimab treatment

Abstract Background: IL1RAP is a co-receptor of IL-1 family signaling, expressed on tumor cells and in the microenvironment of pancreatic ductal adenocarcinoma (PDAC). In PDAC, oncogenic KRAS signaling and IL-1 driven inflammatory pathways mediate tumor progression, chemoresistance and immune suppression. High IL1RAP mRNA levels in pancreatic tumors correlate with significantly shorter overall survival (OS). Nadunolimab is a fully humanized, ADCC-enhanced IgG1 antibody that targets IL1RAP and disrupts IL-1 signaling. In the CANFOUR trial (NCT03267316), 73 patients with previously untreated, locally advanced or metastatic PDAC, received nadunolimab with gemcitabine/nab-paclitaxel (GN). Patients with high tumor cell expression of IL1RAP had the longest OS, indicating that IL1RAP is targetable by nadunolimab. In the current study, a matching cohort of patients from the Danish BIOPAC biobank (NCT03311776) was analyzed for tumor cell expression of IL1RAP and correlated to OS. IL-1α expression and KRAS status were also investigated since KRAS mutations, especially G12D, correlate with a higher IL1RAP and IL-1α mRNA expression. Methods: Pre-treatment biopsies from 53 previously untreated, locally advanced or metastatic PDAC patients subsequently treated with GN were stained for the expression of IL1RAP and IL-1α by immunohistochemistry and grouped into high and low expression on tumor cells. DNA extracted from tumor tissue was sequenced using Oncomine™ Focus DNA Assay including KRAS gene exon 2, 3, and 4 (codon 1-37, 38-73, and 109-150). Results: In patients treated with GN (BIOPAC cohort), patients with high IL1RAP expression on tumor cells tended to have a shorter OS (8.5 vs 10 months, p=0.12) and lower 2-year survival (3.5% vs 18%) than patients with low IL1RAP expression. When comparing BIOPAC patients to patients treated with nadunolimab + GN (CANFOUR study), patients with low IL1RAP expression showed a similar OS (10 vs 11.6 months) and 2-year survival (18% vs 15.8%) while patients with high IL1RAP expression had a substantially longer OS and higher 2-year survival in the CANFOUR cohort compared to the BIOPAC cohort (14.2 vs 8.5 months, 35.8% vs 3.5%). In BIOPAC patients with KRAS mutations, the correlation between high protein levels of IL1RAP on tumor cells and shorter OS was more pronounced (7.8 vs 10.2 months, p=0.03) and this was even more notable in the KRASG12D subgroup (6.7 vs 11.5 months, p=0.03). IL-1α expression correlated with outcome specifically in patients with a KRASG12D mutation where high levels of IL-1α predicted worse OS (6.8 vs 12.8 months, p=0.03). Conclusions: IL1RAP expression is associated with oncogenic KRAS driver mutations and poor survival in PDAC. High expression of tumor cell IL1RAP is associated with worse outcomes in patients treated with GN, while the inverse is seen in patients treated with GN + nadunolimab. These data collectively suggest that IL1RAP is highly relevant in PDAC and associated with poor prognosis but can be meaningfully targeted by nadunolimab. Citation Format: Camilla Rydberg Millrud, Henrik Löfvall, Petter Skoog, Estrid Högdall, Louise Laurberg Klarskov, Inna Makovna Chen, Gina Al Farra, Julia Sidenius Johansen, Annika Sanfridson, David Liberg. Interleukin-1 Receptor Accessory Protein (IL1RAP) overexpression is associated with worse outcome in PDAC and can be reversed by nadunolimab treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B091.