INTRODUCTION
The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing worldwide, with risk factors including cumulative exposure to ultraviolet light, photosensitizing agents, industrial carcinogens, smoking, immunosuppression, chronic wounds, inflammation, ionizing radiation, or rare inherited disorders. Most cSCC are curable with surgery alone.1
Locoregional or distant metastases occur in up to 5% of patients with cSCC. While cSCC, a malignancy of epidermal keratinocytes, often highly expresses the epidermal growth factor receptor (EGFR), EGFR mutation is uncommon.2 Primary cSCC of a sun-exposed area generally harbors a high tumor mutation burden (TMB) and often expresses programmed cell death ligand 1 (PD-L1) which can facilitate metastatic spread.3 These biomarkers and others such as the presence of tumor infiltrating lymphocytes (TIL) and the expression of interferon gamma are being evaluated to help guide treatment decisions.4 Monoclonal antibodies are often used to treat metastatic cSCC. FDA approved anti-programmed cell death 1 protein (anti-PD-1) antibodies include cemiplimab5 or pembrolizumab,6 other anti-PD-1 antibodies, like nivolumab,7 are also active. In small studies, anti-PD1 antibodies have response rates of 34 - 49% with responses lasting a median of 7–8 months. EGFR antibodies like cetuximab8 or panitumumab9 function as signal transduction inhibitors, while cetuximab also has anti-tumor immunogenic properties.10 Both anti-EGFR antibodies have similar response rates of 30 percent, lower than seen with anti-PD1 antibodies.11 It is to be determined whether these two treatment approaches can be safely combined for improved outcomes.
In one case report in 2018, cSCC of the auricle that was rapidly progressive despite surgery and radiation was successfully treated with the combination of cetuximab and nivolumab. The cetuximab was stopped early for cutaneous toxicity, while the nivolumab continued for a year, achieving a complete response (CR).12 It is indeterminate whether the tumor would have responded to nivolumab alone.
Locoregional or distant metastases occur in up to 5% of patients with cSCC. While cSCC, a malignancy of epidermal keratinocytes, often highly expresses the epidermal growth factor receptor (EGFR), EGFR mutation is uncommon.2 Primary cSCC of a sun-exposed area generally harbors a high tumor mutation burden (TMB) and often expresses programmed cell death ligand 1 (PD-L1) which can facilitate metastatic spread.3 These biomarkers and others such as the presence of tumor infiltrating lymphocytes (TIL) and the expression of interferon gamma are being evaluated to help guide treatment decisions.4 Monoclonal antibodies are often used to treat metastatic cSCC. FDA approved anti-programmed cell death 1 protein (anti-PD-1) antibodies include cemiplimab5 or pembrolizumab,6 other anti-PD-1 antibodies, like nivolumab,7 are also active. In small studies, anti-PD1 antibodies have response rates of 34 - 49% with responses lasting a median of 7–8 months. EGFR antibodies like cetuximab8 or panitumumab9 function as signal transduction inhibitors, while cetuximab also has anti-tumor immunogenic properties.10 Both anti-EGFR antibodies have similar response rates of 30 percent, lower than seen with anti-PD1 antibodies.11 It is to be determined whether these two treatment approaches can be safely combined for improved outcomes.
In one case report in 2018, cSCC of the auricle that was rapidly progressive despite surgery and radiation was successfully treated with the combination of cetuximab and nivolumab. The cetuximab was stopped early for cutaneous toxicity, while the nivolumab continued for a year, achieving a complete response (CR).12 It is indeterminate whether the tumor would have responded to nivolumab alone.
