Safety, efficacy and biomarker data in patients with non-small cell lung cancer treated with the anti-IL1RAP antibody nadunolimab in combination with platinum doublet.

Abstract

9089 Background: Interleukin-1 Receptor Accessory Protein (IL1RAP), expressed in various tumors, is essential for IL-1α and IL-1β signaling. IL-1α/IL-1β are implicated in tumor progression and therapy resistance, and chemotherapy can upregulate IL-1α in e.g. non-small cell lung cancer (NSCLC). Nadunolimab (CAN04), a fully humanized ADCC-enhanced IgG1 antibody, targets IL1RAP and blocks IL-1α/IL-1β signaling. Here, data are reported from clinical phase 1/2 trials in NSCLC pts given nadunolimab and platinum doublet. Methods: Pts with advanced NSCLC, 1st line or progressed on pembrolizumab, received nadunolimab at 1 (n=16), 2.5 (n=3) or 5 mg/kg (n=11) with cisplatin/gemcitabine (NCG), or at 2.5 mg/kg with carboplatin/pemetrexed (NCP) (n=5). Four additional pts, 3rd line or beyond, received NCG at 1 or 1.75 mg/kg nadunolimab. Primary objective was safety; efficacy was evaluated as a secondary objective and effects on serum and tumor tissue biomarkers explored. Results: The 30 1st or 2nd line pts given NCG had a median PFS of 7.2 months (95% CI 5.5-8.2), ORR of 53% (34-72) and DoR of 5.8 months (3.7-7.5). A dose-response trend was observed for PFS and DoR (Table). Twenty non-progressing pts continued nadunolimab as monotherapy post chemo; 8 of these remained in disease control for a further 12-131 wks. Nadunolimab monotherapy was well tolerated with ≥grade 3 adverse events reported less frequently. Two pts (non-squamous, 2nd line post pembrolizumab) showed complete responses, one observed after >40 wks of nadunolimab monotherapy. Furthermore, confirmed partial responses were observed in 3 of 5 pts given NCP, and 2 of 4 3rd line or beyond pts given NCG. NCG reduced several serum markers, e.g. CRP and tumor-promoting HGF, effects which were maintained by nadunolimab monotherapy. Additionally, a decrease of MCP-3 and 4 was observed during monotherapy. NCG also reduced IL-1- and tumor microenvironment (TME)-related markers in serum (angiopoietin 1, CXCL5, IL-8, TWEAK and VEGFA). Spatial analyses of protein and RNA markers in tumor biopsies are ongoing to verify potential effects in the TME. Conclusions: NCG shows promising efficacy in NSCLC with a trend for dose response, and long-term disease control by nadunolimab monotherapy post chemo with good safety. These observations are supported by changes in TME-related serum biomarkers. Preliminary data suggest similar efficacy with NCP, and in more heavily pretreated pts. Clinical trial information: NCT03267316 , NCT05116891 . [Table: see text]