Background: Sinonasal epithelial tumors are rare diseases with several histotypes and poor prognosis. Multimodal approach including surgery is widely used, although no standard therapy has been established in prospective trials. This study assessed activity and safety of an innovative integration of multimodality treatment - IC, surgery and RT - modulated by histology, molecular profile and response to IC. Methods: Pts with untreated, operable squamous cell carcinoma (SCC), p53 wild type intestinal type adenocarcinoma (ITAC), sinonasal undifferentiated and neuroendocrine carcinoma (SNUC, SNEC) were enrolled in a single-arm, phase II, multicenter clinical trial from 2014 to 2018. Pts was treated with up to 5 IC cycles, whose regimen was selected according to histotype, followed either by curative radio-chemotherapy (CRT) (pts with ≥80% reduction of initial tumor volume (TV)) or surgery and adjuvant (C)RT. Photon and/or proton/carbon ion-based RT was employed according to disease site and stage. Primary endpoint was 5 years PFS, secondary endpoints were OS, IC ORR per RECIST 1.1 and safety. Results: Out of 39 enrolled pts, 35 pts were evaluable for primary endpoint. Two pts were only considered for safety analyses because definitive diagnosis on surgical specimen did not meet the study entry criteria; other two pts were screening failure due to inoperable disease. Five-year PFS was 38% (95% CI, 21 – 69), with a median PFS of 26 months. Five-year OS was 46% (95% CI, 28 – 75), with a median OS of 36 months. Responses to IC are reported in table. Globally, 15 pts avoided surgery. Overall treatment safety was in line with multimodality intensive head and neck cancer treatments (5% of pts with G3-4 adverse event during IC). One sudden cardiac death was recorded. At a median follow up of 27 months, 5 G3-4 RT related late adverse events have been recorded (1 G3 neurotoxicity, 2 G3 hearing impairment, 2 G3 xerostomia). Three-year PFS - OS for pts achieving PR/CR vs SD/PD to IC were 49.8% - 56.7% vs 43.2% - 53%, respectively. Conclusions: Treatment of advanced SNC with histology-driven IC followed by locoregional therapy tailored to response to IC was safe and showed survival rate similar to surgery containing case series. In the first prospective study, a surgery sparing multimodal approach proved feasible and effective in IC responsive pts. Clinical trial information: NCT02099175

^*Docetaxel, cisplatin, 5fluorouracil; ^†Cisplatin, 5fluorouracil, Leucovorin; ^‡ Cisplatin, Etoposide alternated to Doxorubicin; Ifosfamide.