Safety, tolerability, and preliminary efficacy of nadunolimab, a first-in-class monoclonal antibody against IL1RAP, in combination with pembrolizumab in subjects with solid tumors.
Authors: Jauhari Shekeab , Jimeno Antonio , Hreno Jennifer , Bauml Joshua Michael , Garcia-Ribas Ignacio , Wallén Öhman Marie , Rydberg-Millrud Camilla , Cohen Roger B. 
Published: June 2022

2527 Background: Interleukin-1 Receptor Accessory Protein (IL1RAP) is expressed on cancer and stromal cells of many solid tumors. IL1RAP interacts with IL-1R1, modulating downstream factors (e.g. IL-6, IL-8) and CRP level. Nadunolimab (CAN04), a fully humanized ADCC-enhanced IgG1 antibody, targets IL1RAP and blocks IL-1α and IL-1β. IL-1 promotes an immune suppressive microenvironment, e.g. by recruitment of MDSC which may induce checkpoint inhibitor resistance. Here, initial data are reported from the phase Ib clinical trial CIRIFOUR, evaluating nadunolimab combined with pembrolizumab in solid tumor patients (pts) progressed on prior anti-PD-(L)1 therapy. Methods: Primary objective was evaluating safety and tolerability of nadunolimab combined with pembrolizumab in pts with metastatic NSCLC (n = 5), head and neck squamous cancer (n = 9) or malignant melanoma (n = 1), progressed on prior anti-PD-(L)1 therapy of ≥12 weeks (wks). Dosing started with a priming dose of 0.5 mg/kg nadunolimab on Day -7, followed by 5 mg/kg nadunolimab weekly combined with standard pembrolizumab dosing. A safety lead-in phase 3+3 design was employed. Secondary objectives included preliminary efficacy and responses based on RECIST/iRECIST. Serum biomarkers and tumor biopsies were also analyzed. Results: Fifteen pts received at least one dose of 5 mg/kg nadunolimab with pembrolizumab: median age 63 years (50-79), 27% female, 100% Stage IV, 93% and 7% received prior pembrolizumab or nivolumab respectively, 7% ECOG 0, 93% ECOG 1. The pts had received a mean of 2.3 (range 1-6) previous lines of treatment. SAE were reported in 47% with one considered treatment-related (febrile neutropenia). Two treatment-related grade 3 AE were reported: one febrile neutropenia (DLT), one pneumonitis. No pts discontinued treatment due to treatment-related AE. One patient (7%) had unconfirmed PR as best response, 8 (53%) showed SD, and 6 (40%) iUPD. At time of analysis, 5 pts (33%) received ongoing treatment. Of these, two pts had received therapy for over 31 wks, another two for over 49 wks. Decreased IL-6 was observed after four wks and persisted during treatment. Reduced neutrophil-lymphocyte ratio (NLR) was observed throughout the study, appeared after first treatment, and was driven by a moderate reduction in circulating neutrophils. Decreased IL-6 and NLR were most pronounced in pts with longest disease control duration. IL1RAP expression on cancer and stromal cells was confirmed in tumor biopsies. Conclusions: The nadunolimab and pembrolizumab combination was considered safe and tolerable with preliminary evidence of prolonged disease control. The favorable safety provides basis for evaluation of further therapy with this combination. Next, nadunolimab and pembrolizumab will be assessed with carboplatin/pemetrexed in non-squamous NSCLC. Clinical trial information: NCT04452214.