Phase 1/2a trial of nadunolimab, a first-in-class fully humanized monoclonal antibody against IL1RAP, in combination with cisplatin and gemcitabine (CG) in patients with non-small cell lung cancer (NSCLC).

9020 Background: Interleukin-1 Receptor Accessory Protein (IL1RAP) is expressed by cancer and stromal cells of many solid tumors. The IL-1 pathway is active in tumors and upregulated in response to chemotherapy. IL1RAP interacts with IL-1R1 and modulates 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 signaling. Here, results are reported from the phase 1/2a clinical trial CANFOUR evaluating nadunolimab combined with CG in NSCLC. Methods: Patients (pts) with unresectable, locally advanced or metastatic NSCLC, progressed on pembrolizumab or in first line for advanced disease, were eligible. Pts received 1 (n =17), 2.5 (n = 3) or 5 mg/kg (= 13) nadunolimab given Q1W in Cycle 1 and Q2W from Cycle 2, combined with standard CG. Due to risk of infusion-related reactions, a priming dose of 0.5 mg/kg nadunolimab was given one week before CG. Primary objective was safety; secondary objectives included ORR, PFS and OS, and exploratory objectives included effects on serum and tumor tissue biomarkers. Results: Thirty-three pts were enrolled: median age 64 years (39-77), 30% female, 42% ECOG 0, 55% non-squamous histology, 82% stage IV, 45% received previous pembrolizumab monotherapy. Treatment-related adverse events of grade≥3 were observed in 73% of pts, including neutropenia (58%), febrile neutropenia (9%), thrombocytopenia (30%) and anemia (18%). Neutropenia could be managed by G-CSF. Thirty pts received combination therapy and were included in the efficacy analysis. Three pts did not receive chemotherapy due to clinical deterioration (n = 2) or consent withdrawal (n = 1). ORR was 53% (95% CI 34-72%), disease control rate 80% (61-92%) and median duration of response 5.5 months (3.7-7.0) with 23% of pts still on treatment. The lower limit of the 95% CI for the observed ORR excludes the pre-specified 30%. ORR in pts with squamous histology was 46% and non-squamous 56%. Median PFS was 6.7 months (5.5-7.3) and median OS 13.7 months. The neutrophil-lymphocyte ratio was reduced throughout the trial and was driven by the reduction in circulating neutrophil numbers. IL1RAP expression on both cancer and stromal cells was confirmed in tumor biopsies. Conclusions: Nadunolimab combined with CG shows manageable safety and promising efficacy with a response rate of 53% in NSCLC pts. Nadunolimab is currently evaluated in several clinical trials investigating chemotherapy or IO combinations, including carboplatin and pemetrexed in non-squamous NSCLC. Clinical trial information: NCT03267316.