Background: Cemiplimab, a PD-1-axis blocking agent, has recently been approved for unresectable cSCCs. We report results of the CARSKIN study evaluating pembrolizumab in the first-line setting. Methods: Chemotherapy naive patients (pts) with unresectable cSCCs, either locally or regionally advanced or metastatic, and ECOG PS ≤1 were accrued to this multi-institutional phase II trial to assess tumor response rate (RR) and safety of pembrolizumab administered IV (200 mg Q3W) for a period up to 24 months (mo). Baseline PD-L1 expression was centrally assessed on tumor. The primary endpoint was the RR at 15 weeks (wks) per RECIST v1.1 (independent review). A Simon two-stage design was used. Results: From 03/2017 to 01/2018, 39 pts (79% males, median age 79 years) were enrolled. Disease was local (18%), regional (62%) or metastatic (21%); 38% of pts were PS 0. The median number of infusions was 8. The median follow-up was 10.2 mo; 15 pts are still on pembrolizumab. Thirty-four pts were evaluable for tumor response, and 39 for toxicity. The RR at 15 wks was 38.5 % (95% CI: 24–55%) in the ITT population corresponding to 2 CR and 13 PR. The best responses were 3 CR and 12 PR. The DCR was 51% (20/39 including 5 SD) at 15 wks. The median PFS was 8.4 mo and the median OS was not reached. No responder has progressed to date including 2 pts who discontinued pembrolizumab for 6 to 12 mo. Treatment-related AEs (TRAEs) occurred in 67% of pts, including 8% with severe TRAEs (1 gr 3 cholestasis, 1 gr 3 colitis and 1 death due to recurrence of a non-related head and neck cancer) and 10% who discontinued because of a TRAE. Centrally assessed baseline PD-L1 expression was positive in 77% of patients (1% tumor staining threshold), but it failed to predict response at 15 wks with a median PD-L1 expression of 10% in responders and non-responders at 15 wks (P = .55). Conclusions: In this series of 39 elderly pts with unresectable cSCCs, the safety profile was consistent with previous pembrolizumab studies. First-line pembrolizumab provided robust antitumor activity regardless of PD-L1 expression levels. Clinical trial information: NCT02883556