Abstract
Abstract Introduction: The pancreatic tumor microenvironment (TME) is a major driver of tumor progression, chemoresistance and immune suppression, and the IL-1 axis has been implicated in tumor-promoting signaling networks. The IL1RAP-IL1R1 receptor complex is required for both IL-1α and IL-1β signaling and is expressed on tumor and stromal/immune cells. Nadunolimab is a fully humanized, ADCC-enhanced IgG1 antibody that targets IL1RAP and disrupts both IL-1α/IL-1β signaling. In the phase 1/2a trial CANFOUR (NCT03267316) in which 73 PDAC patients with previously untreated, locally advanced or metastatic PDAC received nadunolimab with gemcitabine/nab-paclitaxel (GN), encouraging preliminary data show median iPFS of 7.2 mo, median OS of 12.9 mo and 1-year survival of 58%. The present analyses investigated the correlation between IL1RAP expression and disease severity as well as therapeutic efficacy of nadunolimab/GN. Methods: Evaluable screening biopsies from 46 CANFOUR PDAC patients were stained for IL1RAP by immunohistochemistry. mRNA data was obtained from the GTEx, TCGA and Pancreatic Cancer Action Network’s Know Your Tumor (KYT) databases and correlated to patient data (TCGA, KYT) and mutational data (KYT). Results: IL1RAP expression was detected on tumor cells, fibroblasts, and infiltrating immune cells in tumor biopsies. Notably, all tumor cells expressed IL1RAP and stratification of evaluable samples into high or low tumor cell expression of IL1RAP revealed significantly prolonged median OS on nadunolimab/GN in IL1RAP high compared to IL1RAP low patients (14.2 vs 10.6 mo, p=0.017). This was also reflected in longer iPFS (8.0 vs 5.8 mo), 1-year survival (69 vs 40%) and iORR (52 vs 32%). Although varying in intensity, IL1RAP expression on stromal cells did not correlate significantly with treatment efficacy. In interrogating bulk RNA seq data from the GTEx, TCGA and KYT databases, IL1RAP was overexpressed in pancreatic cancer compared to normal tissue, with higher expression in advanced stage disease. Moreover, as KRAS mutations promote tumor inflammation and KRASG12D has been implicated in activating the IL-1 axis, we observed that KRASG12D tumors had a higher expression of IL1RAP and IL-1α, but not IL-1β, compared to KRAS-wildtype tumors. In both early and late-stage PDAC, high levels of IL1RAP strongly correlated with poor survival (both p<0.0001). Patients responding to GN tended to have lower IL1RAP levels than patients with progressive or stable disease, in stark contrast to the results with nadunolimab/GN. To understand the effects of nadunolimab/GN in the TME, spatial transcriptomics in screening and on-treatment biopsies are being analyzed with Nanostring GeoMx. Conclusion: IL1RAP is upregulated in pancreatic cancer, its expression correlates with oncogenic KRAS driver mutations and is strongly associated with poor survival. The IL1RAP-targeting antibody nadunolimab has shown promising target-dependent efficacy in combination with 1st line chemotherapy, indicating that IL1RAP is a both highly relevant and targetable protein in PDAC. Citation Format: Eric Van Cutsem, Kawther Abdilleh, Jashodeep Datta, Manuel Hidalgo, Camilla Rydberg Millrud, Petter Skoog, Annika Sanfridson, Dominique Tersago, David Liberg. Interleukin-1 receptor accessory protein (IL1RAP) overexpression is associated with worse prognosis in PDAC and is targetable by nadunolimab [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C002.
