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Nadunolimab is an IL1RAP (IL-1 receptor accessory protein)-targeting antibody that blocks IL-1\u03b1\/IL-1\u03b2 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\u2009\u2265\u20093 adverse events were reported for 7 patients (47%). There was one dose-limiting toxicity of febrile neutropenia. The most frequent grade\u2009\u2265\u20093 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\u20138.6). Median OS was 19.7 months (95% CI 4.3\u201328.7) with 67% 1-year survival. Survival was significantly longer in patients with higher baseline tumor infiltration of CD163\u2009+\u2009macrophages 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.<\/jats:p>","DOI":"10.1007\/s10637-025-01538-3","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T03:02:37Z","timestamp":1746068557000},"page":"609-620","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["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"],"prefix":"10.1007","volume":"43","author":[{"given":"Roger B.","family":"Cohen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Jimeno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Hreno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lova","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Wall\u00e9n-\u00d6hman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla Rydberg","family":"Millrud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Sanfridson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Garcia-Ribas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,1]]},"reference":[{"key":"1538_CR1","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1146\/annurev-pathol-042020-042741","volume":"16","author":"S Bagchi","year":"2021","unstructured":"Bagchi S, Yuan R, Engleman EG (2021) Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. 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The study protocol was approved by independent review boards at each participating site. Safety data were periodically reviewed by a Safety Review Committee comprised of study investigators and a medical representative of the sponsor.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"All patients provided written informed consent prior to enrollment.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Roger B Cohen has received consulting fees from Cantargia AB, Actuate and Ono, and AstraZeneca, and institutional funding from Cantargia AB, AstraZeneca, Chugai, Iconovir, Janux, and Sensei.Antonio Jimeno reports consulting for Bluedot Bio and Purple Biotech, NIH support from NCI R01 CA149456, R01DE024371, and P50 CA261605. His institution has contracts with Cantargia AB, DebioPharm, Iovance, Khar Biopharma, Merck, Moderna, Pfizer, Sanofi, and SQZ for trials where he is the local principal investigator. Lova Sun has received institutional funding from Blueprint, Seagen, IO Biotech, Erasca, Immunocore, and Abbvie, and has received honoraria\/been on advisory boards for GenMab, Seagen, Bayer, Medscape, Sanofi Genzyme, and Regeneron. Marie Wall\u00e9n \u00d6hman is an employee of Cantargia AB and holds stock in Cantargia. Camilla Rydberg Millrud is an employee of Cantargia AB and holds stock in Cantargia. Annika Sanfridson is an employee of Cantargia AB and holds stock in Cantargia. Ignacio Garcia-Ribas was an employee of Cantargia AB at the time of the study, is currently a paid consultant, and holds stock in Cantargia. Jennifer Hreno has nothing to declare.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}