Safety, tolerability, and preliminary efficacy of nadunolimab, an anti-IL- 1 receptor accessory protein monoclonal antibody, in combination with pembrolizumab in patients with solid tumors.

Interleukin (IL)-1 signaling has an essential role in tumor progression and immunosuppression and is linked to acquired resistance to anti-PD-1/PD-L1 treatment. Nadunolimab is an IL1RAP (IL-1 receptor accessory protein)-targeting antibody that blocks IL-1α/IL-1β signaling and has enhanced antibody-dependent cellular cytotoxicity. We investigated the safety and preliminary efficacy of nadunolimab with pembrolizumab in patients with metastatic solid tumors who had progressed on previous checkpoint inhibitor treatment, suggesting acquired checkpoint inhibitor resistance (NCT04452214). This phase 1b trial enrolled patients with metastatic disease who had exhausted or declined standard-of-care alternatives. Patients received nadunolimab (5 mg/kg) and standard-dose pembrolizumab. The primary objective was to assess safety. Secondary objectives were anti-tumor response as per iRECIST, pharmacokinetics, and changes in immune mediators. Fifteen patients with stage IV cancer (head and neck squamous cell carcinoma, non-small cell lung cancer, melanoma) entered the trial. Grade ≥ 3 adverse events were reported for 7 patients (47%). There was one dose-limiting toxicity of febrile neutropenia. The most frequent grade ≥ 3 adverse event was dysphagia (two patients). Seven patients (47%) had reductions in target lesion size. Median iPFS was 3.4 months (95% CI 1.4-8.6). Median OS was 19.7 months (95% CI 4.3-28.7) with 67% 1-year survival. Survival was significantly longer in patients with higher baseline tumor infiltration of CD163 + macrophages and natural killer cells and in patients with reduced on-treatment circulating IL-6 levels or neutrophil-to-lymphocyte ratio. Nadunolimab with pembrolizumab had an acceptable safety profile, and prolonged disease control was observed in a subset of patients. The results support further development of nadunolimab in combination with checkpoint inhibitors.