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

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. 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, we identified 22 studies that were included in the final review. Data from the reported studies were compiled into the largest analysis on this topic to date, comprising 130 patients. Overall response rate (ORR), complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) were compared using Fisher’s exact tests. Median progression free survival (PFS) and overall survival (OS) were pooled using a sample-size–weighted approach. 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) inhibition represents the current best treatment strategy for advanced cSCC following anti-PD-1 failure, supported by favourable reported outcomes including ORR, PFS and OS. Other treatment strategies including ipilimumab and oncolytic therapy show clinical promise warranting further investigation.