Window-of-Opportunity Study Utilizing Preoperative Cetuximab in Patients with Head and Neck Cancer

Abstract Purpose: AXL is a receptor tyrosine kinase implicated in epidermal growth factor receptor resistance. The primary objective of this study was to test the hypothesis, generated in preclinical studies, that low AXL correlates with clinical response to cetuximab in patients with head and neck cancer (HNC). The secondary objectives were to further describe the feasibility and safety of preoperative administration of cetuximab. Patients and Methods: We performed a single-site, single-arm, open-label, window-of-opportunity study utilizing preoperative cetuximab in 15 patients with HNC. Patients received two doses of cetuximab and underwent resection of their tumors. Biopsies were used to assess AXL expression and changes in Ki67 staining and to establish patient-derived xenografts (PDX). Single-cell RNA sequencing (scRNA-seq) of treated xenograft tissue was used to assess differences between sensitive and resistant tumors. Results: Fifteen subjects were registered for treatment in the study, and fourteen completed treatment with cetuximab prior to surgical resection. No correlation between AXL expression at baseline and change in tumor size in response to cetuximab was observed. Preoperative cetuximab did not delay surgical resection, and no unexpected treatment-related adverse events were reported. scRNA-seq identified that cetuximab sensitivity is marked by transcriptional remodeling, whereas resistance is associated with stable human epidermal growth factor receptor signaling and elevated Tyro, AXL, and MerTK (TAM) activity. Conclusions: Delivery of preoperative cetuximab is safe, and a short course can be utilized to identify patients with HNC responding to single-agent cetuximab treatment. Significance: Preoperative cetuximab is safe and feasible in HNC, identifying early responders without delaying surgery. Although AXL was not validated as a resistance biomarker—possibly due to COVID-19–related early closure—concordance among patient outcomes, circulating tumor cells, and PDXs strongly supports this translational pipeline for future studies.