The incidence of advanced cutaneous squamous cell carcinoma (cSCC) is increasing; of the 1.3 million nonmelanoma skin cancers that arise each year, approximately 20% are cSCC, and between 2-5% of these cases ultimately metastasize. However, there is no established consensus on first-line systemic treatment for those patients who have locally advanced or metastatic disease. Major classes of systemic agents include chemotherapy, epidermal growth factor receptor (EGFR)-targeted therapy, and immunotherapy; each is associated with a distinct set of adverse effects, and availability of data from randomized controlled trials (RCTs) to definitively guide treatment are limited. While several chemotherapeutic agents have been described in case studies or small patient cohorts, only one RCT has been conducted, demonstrating a 34% overall response rate for a cisplatin-based regimen. EGFR-inhibitors evaluated for use in cSCC by RCT include cetuximab, panitumumab, and gefitinib; response rates ranged from 15-31% for these agents. Inhibitors of the immune checkpoint programmed death-1 (PD-1) have yielded promising outcomes in advanced cSCC; indeed, the PD-1 inhibitor cemiplimab recently received FDA approval for use in advanced cSCC. Despite these advances, the preferred regimen for systemic treatment of cSCC remains unclear, particularly in immunocompromised populations. Herein we provide a review of the literature supporting the use of these modalities and a discussion of their clinical utility.

The incidence of advanced cutaneous squamous cell carcinoma (cSCC) is increasing; of the 1.3 million nonmelanoma skin cancers that arise each year, approximately 20% are cSCC, and between 2-5% of these cases ultimately metastasize.