Immune Checkpoint Inhibition in Locally Advanced, Recurrent, and Metastatic Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) is a potentially aggressive non-melanoma skin cancer with rising incidence attributed to ultraviolet radiation exposure, chronic inflammation, aging, immunosuppression, and improved detection technology. Immune checkpoint inhibitors (ICIs) have transformed treatment for advanced cSCC. Cemiplimab and pembrolizumab are programmed cell death 1 (PD-1) inhibitors and cosibelimab is a programmed death ligand 1 (PD-L1) inhibitor, all FDA approved for advanced cSCC. Herein we describe the latest updates in ICIs for treatment of aggressive, unresectable, or metastatic cSCC treatment, inclusive of on-going clinical trials exploring neoadjuvant and adjuvant applications. For unresectable locally advanced and metastatic disease, several trials investigating ICIs found ∼50% overall response rate. C-POST (NCT03969004) established adjuvant cemiplimab after surgery and radiation for patients at high risk of recurrence. In contrast, KEYNOTE-630, which evaluated adjuvant pembrolizumab, was stopped for futility after an independent data monitoring committee review determined it was not meeting its prespecified recurrence-free survival threshold. Neoadjuvant cemiplimab has generated high pathologic response rates and the randomized phase II MATISSE trial supports continued investigation of neoadjuvant nivolumab with or without ipilimumab. Despite the biologic rationale for biomarker-guided treatment, tumor mutational burden and PD-L1 expression have not shown sufficiently consistent predictable values for clinical selection. Active investigations into the efficacy of ICIs in advanced resectable and unresectable cSCC are rapidly shifting management with evidence revealing promises of greater disease-free survival through neoadjuvant and adjuvant approaches.