Abstract
Simple SummarySquamous cell carcinoma of the head and neck (SCCHN) is a debilitating disease that affects hundreds of thousands of individuals worldwide and has a high mortality rate. Mainstay treatment largely consists of surgery, radiation, and chemotherapy which has been met with significant morbidity. The epidermal growth factor receptor is one that which plays a major role in cell signaling and has been extensively studied in locally advanced (LA) and recurrent metastatic (RM) SCCHN. This review paper details the major roles of the epidermal growth factor receptor (EGFR), previous and current EGFR inhibition therapeutics, resistance mechanisms, and the possible integration of immunotherapy and EGFR inhibition in this disease process. Recurrent metastatic (RM) and locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) are devasting disease states with limited therapeutic options and poor overall survival. Targeting the epidermal growth factor receptor (EGFR) is one area that has helped improve outcomes in this disease. Anti-EGFR based therapies have been shown to improve overall survival and mitigate the significant toxicities incurred from standard radiation, chemotherapy, and/or surgical options. Cetuximab, the most well-studied anti-EGFR monoclonal antibody, has demonstrated a positive impact on outcomes for RM and LA SCCHN. However, the development of early resistance to cetuximab highlights the need for a wider arsenal of therapy for RM and LA diseases. The use of immune checkpoint inhibitors has recently transformed the treatment of recurrent SCCHN. Drugs such as pembrolizumab and nivolumab have demonstrated success in recent clinical trials and have been approved for the treatment of advanced disease. Given the positive results of both EGFR targeted agents and immune checkpoint inhibitors, ongoing trials are studying their synergistic effects.
Highlights
progression free survival (PFS) was shorter in the nivolumab arm (2.0 vs. 2.3 months), the rate of PFS at 6 months was higher in the nivolumab arm (19.7% vs. 9.9%) [77]
The Standard of Care (SOC) group had more grade 3 or higher adverse effects. These results suggested that pembrolizumab monotherapy in progressive Recurrent metastatic (RM) SCCHN could be an alternative to more traditional cytotoxic chemotherapies [85]
10.3 months, hazard ratio 0.77, 95% CI 0.63–0.93). These findings suggest pembrolizumab plus platinum based chemotherapy is appropriate for first line RM SCCHN, and pembrolizumab monotherapy can be used for programmed cell death ligand 1 (PD-L1) positive RM disease [86]
Summary
Ligand binding exposes domain II, promoting either homodimerization with other EGFR proteins or heterodimerization with other RTK family members This dimerization induces autophosphorylation of the intracellular tyrosine residues and activates the eventual signaling cascades influencing gene expression, proliferation, apoptosis inhibition, metastasis, and cell mobility [3,5,7]. The EGFR is a free-flowing complex within the lipid bilayer; when in close proximity to other EGFR complexes it can stimulate autophosphorylation and activate downstream signaling cascades This ligand independent dimerization is extremely relevant in tumor cells where overexpression of the EGFR molecule can lead to increased activation, thereby promoting pathways for tumorigenesis [7,8]
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