Abstract 2172: Tumor IL1RAP levels and reduction in serum biomarkers correlate with response in PDAC patients treated with nadunolimab, an anti-IL1RAP monoclonal antibody, in combination with gemcitabine and nab-paclitaxel
Authors: Van Cutsem Eric , Collignon Joelle , Eefsen Rikke , Ochsenreither Sebastian , Zvirbule Zanete , Ivanauskas Audrius , Millrud Camilla Rydberg , Skoog Petter , Losic Nedjad , Magnusson Susanne , Sanfridson Annika , Liberg David 
Published: April 2023

Abstract
Background: Interleukin-1 Receptor Accessory Protein (IL1RAP) is expressed on cancer and stromal cells in pancreatic ductal adenocarcinoma (PDAC), and high tumor IL1RAP RNA expression is a negative prognostic marker1. Dimerization between IL1RAP and the IL-1 receptor is required for IL-1 signaling, and the IL-1 axis has been implicated in the tumor microenvironment and immune response to PDAC. Nadunolimab (CAN04), a fully humanized ADCC-enhanced IgG1 anti-IL1RAP antibody, blocks IL-1α and IL-1β signaling. Preliminary efficacy from the clinical phase 1/2a trial CANFOUR, where PDAC patients (n=73) received nadunolimab with gemcitabine and nab-paclitaxel (GN), show median iPFS of 7.2 months (iRECIST; 95% CI 5.2-8.5), median OS of 12.7 months (10.0-19.1) with 59% of patients alive, and 1-year survival of 57%2.
Methods: Patients with previously untreated, locally advanced or metastatic PDAC received nadunolimab at doses from 1 to 7.5 mg/kg, in combination with GN. The exploratory objective was to measure serum and tumor biomarkers related to treatment outcome. Pre-treatment tumor biopsies were assessed for IL1RAP expression by immunohistochemistry. Serum from all patients was analyzed for biomarkers by Meso Scale Discovery (MSD) and Olink.
Results: IL1RAP was expressed on tumor and stromal cells in all biopsies analysed and IL1RAP-positive infiltrating immune cells were detected in biopsies from 94% of patients (n=38). The level of IL1RAP on tumor cells was associated with response (PR vs SD and PD; p=0.082). Patients with PR had a median IL1RAP H-score of 200, while patients with SD or PD as best response had a median H-score of 110. The data suggest a relationship between high IL1RAP expression and increased iPFS and OS. Reductions in serum biomarkers downstream of IL-1, detected by MSD, were also associated with response. Patients with the largest treatment-related decreases in IL-6 displayed a prolonged iPFS (p&lt;0.023), while patients with a decrease in IL-8 showed prolonged iPFS (p&lt;0.025) and OS (p&lt;0.041). Patients with the most decreased CRP levels following treatment also showed extended iPFS (p&lt;0.009) and OS (p&lt;0.008). A reduction in other IL-1-related biomarkers, such as CXCL5, VEGFA, EGF, Angiopoietin 1 and TWEAK, was also detected by Olink post-treatment.
Conclusions: Nadunolimab combined with GN shows promising iPFS and OS in 73 PDAC patients. In these patients, high tumor cell expression of IL1RAP, the molecular target for nadunolimab, correlated with response. Reduction of the downstream biomarkers IL-6 and IL-8, as well as CRP, were most pronounced in responding patients and correlated with efficacy. These data strongly suggest that nadunolimab interaction with IL1RAP is important for the treatment effects observed in the CANFOUR study.
1TCGA Database2Van Cutsem et al; ASCO 2022
Citation Format: Eric Van Cutsem, Joelle Collignon, Rikke Eefsen, Sebastian Ochsenreither, Zanete Zvirbule, Audrius Ivanauskas, Camilla Rydberg Millrud, Petter Skoog, Nedjad Losic, Susanne Magnusson, Annika Sanfridson, David Liberg. Tumor IL1RAP levels and reduction in serum biomarkers correlate with response in PDAC patients treated with nadunolimab, an anti-IL1RAP monoclonal antibody, in combination with gemcitabine and nab-paclitaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2172.