Treatment Strategies for Advanced Cutaneous Squamous Cell Carcinoma Following Anti-PD-1 Immunotherapy Failure: A Systematic Review of the Literature and Ongoing Trials

Background: While anti-PD-1 immunotherapy has led to significant improvements in the outcome of advanced cutaneous squamous cell carcinoma (cSCC), over half of patients fail to respond, and there remains no established second-line therapy, representing a clear unmet need. Aim/Methods: Here, we present a systematic review of the literature and ongoing clinical trials to evaluate current evidence on treatment strategies in this setting. Following a comprehensive search, and quality control assessment of each paper, we identified 20 studies that were included in the final review: 11 published papers, 1 conference poster and 8 ongoing clinical trials. Data from the 12 reported studies were presented in a study-by-study format. Outcomes were reported descriptively and included the overall response rate (ORR), complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD), progression-free survival (PFS) and, where available, overall survival (OS). Results: Although the review is limited by small sample sizes and the frequent use of combination rather than monotherapy regimens, the evidence suggests that epidermal growth factor receptor (EGFR) inhibitor-containing treatment strategies are the most frequently reported salvage approach and demonstrate preliminary evidence of treatment activity in advanced cSCC following anti-PD-1 failure. Conclusions: However, current evidence is insufficient to establish superiority over alternative treatments. Other treatment strategies, such as ipilimumab, oncolytic virotherapy and chemo-immunotherapy, show clinical promise warranting further investigation.