Background: Patients (pts) with advanced squamous cell carcinoma of the skin (SCCS) have a poor prognosis. Response rate (RR) of 46% with an anti PD-1 (REGN2810) was recently shown in 25 pre-treated pts. CARSKIN is an open-label, phase II study evaluating pembrolizumab (Pembro) in unresectable SCCS. We report preliminary efficacy and safety findings. Methods: Chemotherapy naive pts who had unresectable SCCS, with an ECOG PS of < 2 were eligible. Baseline PD-L1 expression was centrally assessed on tumor. Pembro kindly provided by Merck was administered IV (200 mg Q3W) for a period up to 24 mths. CT evaluation was performed at baseline, 9, 15, 24 wks and thereafter Q12W and was independently reviewed. The primary endpoint was RR at 15 wks (RECIST criteria). Using Simon two-stage design, ≥4 responses were required out of 19 pts in stage 1 to continue accrual to 39 pts. Results of stage 1 are reported. Results: Nineteen pts (6, 7 and 6 with local, regional and distant metastasis, respectively) were recruited between March and July 2017, of which 15 (79%) were male. Median age was 80 yrs (range, 61-88); 61% of pts were PS 1. Median number of Pembro infusions was 9 (range, 0-13). Median follow-up was 7 mths. Seventeen pts were evaluable for tumor response, and 19 for toxicity. RR at 15 wks in the ITT population was 42 % (95% CI: 23–63%) corresponding to 7 PR (2 unconfirmed) and 1 CR. Disease control rate at 15 wks was 58% (11/19 including 3 SD). Only 1 responder progressed. Median PFS is 7 mths and median OS is not reached. There was no Pembro-related death or SAE. One pt discontinued Pembro due to grade 2 colitis. Pembro-related AE occurred in 63% of pts, the most frequent AEs being rash (32%), pruritus (16%), fatigue (26%), dysthyroidism (10%), and diarrhea (10%). Baseline PD-L1 expression was positive in 11 cases (58%). Median PD-L1 expression (Q1-Q3) was 28% (1-75%) in responders vs 0% (0-3%) in non-responders at 15 wks (P = .15). Conclusions: As first line treatment, pembrolizumab monotherapy provided encouraging clinical activity characterized by a high RR and durable response and was well tolerated in these elderly pts. The second stage of CARSKIN is ongoing. Clinical trial information: NCT02883556