A pilot study of neoadjuvant cetuximab in locally advanced squamous cell carcinomas of skin (SCCS)

Background: The incidence of SCCS has increased over the past two decades, including a high risk subset with aggressive behavior. Due to a lack of high-quality clinical trials in this population, there is no standard systemic therapy for advanced SCCS. The epidermal growth factor receptor (EGFR), often highly expressed in SCCS, is implicated in UV- induced skin carcinogenesis and SCCS development. Cetuximab, a monoclonal antibody that competitively inhibits EGFR, improved disease control as first line therapy in unresectable SCCS in a single arm phase II trial. Despite impressive responses with cetuximab in some, most treated SCCS patients do not respond, and there is a need for predictive biomarkers. We hypothesize that the use of cetuximab will improve clinical outcomes in patients with advanced SCCS in the neoadjuvant setting, and that measures of antibody dependent cytotoxicity (ADCC) in tumor and/or specific genomic features of the tumor may predict response to therapy. Methods: In this pilot trial (NCT 02324608), we will enroll 20 patients with relapsed locally advanced SCCS or SCCS unamenable to definitive local therapy. The primary endpoint will measure response rate to cetuximab by RECIST criteria with secondary endpoints of progression free and overall survival, and conversion to resectability. Molecular tumor correlates include analyzing DNA mutations and measuring downstream activation of EGFR signaling and ADCC, correlating these with clinical benefit. Patients will receive cetuximab at 400mg/m2 X 1 followed by weekly doses of 250mg/m2 for 8 weeks prior to surgery. Patients will be evaluated for subsequent definitive surgical resection, or definitive radiotherapy if surgical resection is not possible. Postoperative adjuvant radiotherapy will be permitted. Patients will undergo pretreatment biopsies, and post-treatment tissue will be harvested at surgery or through a biopsy at the conclusion of cetuximab. Paired skin and tumor samples will be evaluated through partial DNA (FoundationOne™) and RNA sequencing, IHC analysis of EGFR signaling components, and measurement of ADCC. The trial is currently screening eligible subjects.