Background <p>There is no established treatment for patients with recurrent/metastatic (R/M) olfactory neuroblastoma (ONB), a rare sinonasal tumor. We conducted the first immunotherapy clinical trial (NCT05012098) in patients with R/M ONB, to evaluate the activity of the bifunctional TGF-β “trap”/anti-PD-L1 fusion protein bintrafusp alfa (BA).</p> Methods <p>Patients received BA (1200 mg, intravenously) every 2 weeks. Primary endpoint was overall response rate (ORR); secondary objectives included safety, progression-free survival (PFS), and overall survival (OS).</p> Results <p>Between June 2022 and June 2023, 11 patients received treatment (Cohort 1, no prior immunotherapy, n=9; Cohort 2, prior immunotherapy received, n=2); enrollment was stopped due to BA development discontinuation. No objective responses were observed. In Cohort 1, 4 patients (of 8 evaluable, 50%) had stable disease (SD), three confirmed and long lasting; median PFS was 3.7 months, median OS was not reached; and one of SD patients had a complete metabolic response on ⁶⁸Ga-DOTATATE imaging. In Cohort 2, 1 patient had SD; median PFS was 3 months, and median OS was 6.8 months. Grade 3/4 treatment-related adverse events occurred in 3 patients (immune-mediated diabetes, esophageal hemorrhage, anemia, epistaxis).</p> Conclusions <p>Although the primary endpoint was not met, BA showed a manageable safety profile and a subset of patients derived clinical benefit with prolonged stable disease, including one patient with a complete metabolic response. This first clinical trial of systemic therapy in R/M ONB serves as proof of clinical trials feasibility in this setting and supports further investigation of combinatorial immunotherapy strategies in this patient population.</p> <p><i>Trial registration</i> ClinicalTrials.gov Identifier: NCT05012098, <a href="https://clinicaltrials.gov/ct2/show/NCT05012098">https://clinicaltrials.gov/ct2/show/NCT05012098</a>. Registered 18 August 2021.</p>