Background: Cutaneous squamous cell carcinoma (cSCC) is among the most frequent malignancies worldwide, and an increasing incidence has been documented over the past decades. For those not amenable to treatment with curative intent, immune checkpoint blockade (ICP) with anti-PD-1 monoclonal antibodies emerged as a novel therapeutic option, supported by evidences of high mutational burden and expression of PD-L1. In this single-arm study, we sought in investigate the activity of NIVO in pts with advanced cSCC (AcSCC). Methods: We conducted a Simon two-stage, open-label, phase II study to evaluate the safety/efficacy of NIVO for up to 24 systemic-treatment-naïve pts with metastatic and/or locaally advanced cSCC. NIVO at 3mg/kg was administered intravenously every 2 weeks (w) until disease progression, unacceptable toxicity or 12 months of treatment. The primary endpoint was the best objective response rate (bORR) at 24w as per RECIST criteria. Tumor measurements were performed every 12w. Secondary endpoints included safety/tolerability, progression-free survival (PFS) and overall survival (OS). Results: Between October 2018 and October 2019, 24 pts with AcSCC were enrolled, with a median age of 74 years (range 48-93) and a male/female ratio of 1.4:1. Most frequent primary sites were head/neck (42%), trunk (29%) and extremities (25%); identified risk factors included chronic sun exposure or burn scars in 66 % and 12.5 %, respectively. Upon enrolment, the proportions of patients with locally advanced, locoregional (regional lymph node involvement) and metastatic disease were 16.6%, 66.6% and 16.6%, respectively. At data cut off (median number of doses of NIVO: 15), 15 pts (62.5%) remain on treatment and 6 pts have progressed and/or died. Three pts completed 12 months of treatment and entered surveillance. Among 22 pts evaluable for response (n = 2 have not reached 12w of treatment), the bORR was 54.5% (12/22), and disease control (stable disease or objective response) was achieved in 77% (17/22). Median duration of response, PFS and OS have not been reached. Grade ≥3 treatment-related adverse events occurred in 21% of the pts, and 1 patient discontinued NIVO due to toxicities. Conclusions: NIVO resulted in robust antitumor activity and good tolerability in systemic treatment-naïve pts with AcSCC. There were no new safety signals, despite the inclusion of individuals at advanced ages. These data provide further evidence to support the use of ICP as the standard treatment option for pts with AcSCC. Clinical trial information: NCT03834233