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Background Sinonasal malignancies are rare, accounting for approximately 3% of all head and neck cancers, with an incidence of 0.556 per 100,000 population. 1 Among these, squamous cell carcinoma (SCC) of the nasal cavity and paranasal sinuses (SNSCC) is the most common histologic subtype, representing over 50% of cases. The maxillary sinus is the most frequent site of origin (about 60%), followed by the nasal cavity and ethmoid sinus.2 Despite oncologic advances, the 5-year overall survival (OS) for patients with SNSCC has remained around 50% over the past three decades.3 Due to their rarity, SNSCC patients have historically been excluded from large-scale head and neck SCC clinical trials, such as Keynote-048.4 Given the demonstrated efficacy of immune checkpoint inhibitors (ICIs) in other anatomic subtypes of head and neck SCC, this study aims to evaluate the potential role of ICIs in the management of SNSCC.Methods We retrospectively reviewed records of patients that were treated with ICI systemic therapy for histologically confirmed recurrent/metastatic SNSCC at USC Norris Comprehensive Cancer Center and Los Angeles General Medical Center (LAGMC) from 2016 to 2023. Data on follow-up was reviewed through June 1, 2025.Results We identified a total of 13 patients who received treatment with an ICI for recurrent/metastatic SNSCC. The demographic and clinical characteristics are described in table 1. 11 out of 13 patients had known PD-L1 status, with 9 patients having a PD-L1 CPS >=1 (81.8%). Four patients were TMB high, and 2 were MSI-high. All patients were either EBV/HPV negative (46.2%, 53.8%) or unknown (30.8%, 53.8%). The most common ICI agent used was pembrolizumab (92.3%), with 7 patients receiving ICI as a first-line systemic therapy and 6 patients receiving it as a second line or beyond. The median treatment duration was 5.5 months (95% CI 1.8 – 18.1). Most patients discontinued for progression of disease or clinical deterioration (69.2% n = 9). Two patients discontinued due to complete response (CR) and 2 patients are continuing therapy at the time of data cutoff. The median OS was 15.0 months (95% CI 4.4 – 57.0).Conclusions Despite limited numbers, there is evidence of activity of ICIs in patients with primary SNSCC. This warrants further investigation in prospective trials and identification of predictive biomarkers to optimize selection of patients most likely to benefit from ICIs.References Turner JH, Reh DD. Incidence and survival in patients with sinonasal cancer: a historical analysis of population-based data. Head Neck. 2012;34(6):877–885. doi:10.1002/hed.21830Ferrari M, Taboni S, Carobbio ALC, et al. Sinonasal squamous cell carcinoma, a narrative reappraisal of the current evidence. Cancers (Basel). 2021;13(11). doi:10.3390/cancers13112835Elgart K, Faden DL. Sinonasal squamous cell carcinoma: etiology, pathogenesis, and the role of human papilloma virus. Curr Otorhinolaryngol Rep. 2020;8(2):111–119. doi:10.1007/s40136-020-00279-6Burtness B, Lerzo G. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomized, open-label, phase 3 study. The Lancet. 2019 Nov 23;394(10212):1915–1928. doi: 10.1016/S0140-6736(19)32591-7. Epub 2019 Nov 1.Abstract 436 Table 1