Background: Cutaneous squamous cell carcinoma (cSCC) is the second most frequent skin cancer and considered as a tumor with strong immunogenicity. Consistently, immune checkpoint-inhibition with programmed death (PD)-1 antibodies has become the novel standard of care in the treatment of advanced cSCC. In this study, we evaluated efficacy and safety of the PD-1 antibody nivolumab in patients with locally advanced or metastatic cSCC, including individuals with concomitant hematological malignancies (CHM) – a highly vulnerable subgroup of cSCC patients typically excluded from clinical trials. Methods: This phase II, open-label, single-arm multicentre study included patients aged ≥ 18 years with histologically confirmed locally advanced and/or metastatic cSCC and at least one measurable lesion according to RECIST v1.1. Enrolled patients received nivolumab 240 mg intravenously over 30 min every 2 weeks for up to 2 years. A sample size of 31 patients was needed to provide 90% power to detect an objective response rate (ORR) of at least 12.6% after 24 weeks with a type I error of 5% assuming a dropout-rate of 15%. The primary endpoint was investigator assessed ORR as per RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Results: Between July 2017 and October 2020, 31 patients with advanced cSCC, including 11 patients with CHM, were enrolled and received at least one dose of nivolumab. The median age was 80 years (range 66-92) and the majority of patients was male (71%). Upon enrollment, 19.4% of patients had locally advanced, 51.6% loco-regional metastatic and 25.8% distant metastasic disease. Seven patients (22.6%) had received one prior systemic therapy for cSCC. At data-cut-off (March 2021; week-24 RECIST assessment completed in all available patients), five patients (16.1%) were still on treatment, one patient completed treatment per protocol, whereas 25 patients had discontinued therapy. Of 29 patients who were evaluable for response assessment, 12 patients achieved a partial and 7 a complete response, resulting in a best ORR of 65.2% (95% CI: 45.7% - 82.1%), a DCR of 68.9% (95% CI: 50.8%-82.7%) and a median PFS of 11.1 months (95% CI: 3.7 - 12.9). Treatment related adverse events occurred in 18 patients (58.1%) and led to nivolumab discontinuation in two patients (6.5%). Subgroup analysis of patients with CHM revealed a best ORR of 55.6% (95% CI: 21.2% - 86.3%), a DCR of 66.7% (95% CI: 35.4% -87.9%) and a median PFS of 10.9 months (95% CI: 0.6 - 21.4). Median OS in this subgroup was 20.7 months (95% CI: 6.5 - 35.0), whereas overall median OS was not reached. Conclusions: Nivolumab showed a robust antitumor-activity similar to other anti-PD-1 agents in advanced cSCC. Although ORR and OS were slightly reduced in patients with CHM, nivolumab proved effectiveness also in this subgroup while no new safety signals occurred. Clinical trial information: NCT04204837.