Emerging EGFR-Targeted Therapy in Head and Neck Cancer

Importance Head and neck squamous cell carcinoma (HNSCC) represents a significant global health burden with limited therapeutic options for patients with recurrent or metastatic disease. Epidermal growth factor receptor (EGFR) is overexpressed in most patients with HNSCC and represents a biologically compelling target, yet current EGFR-directed therapies have demonstrated only modest clinical benefit. Observations This review describes the evolving landscape of EGFR-targeted therapeutics in HNSCC, including cetuximab-based combination regimens as well as novel agents, such as bispecific antibodies, antibody-drug conjugates, immune cell engagers, and adaptive cell therapies. The biological rationale behind these approaches, and the results of early-phase trials, are presented in this review. Notably, cetuximab and other EGFR-targeted therapies have demonstrated inferior efficacy in patients with human papillomavirus (HPV)–positive disease. Conclusions and Relevance The emerging data of combinatorial approaches and novel EGFR-targeting therapeutic agents offer renewed optimism for patients with advanced HNSCC who have limited treatment options. Future progress will depend on novel agents leveraging a deeper understanding of tumor biology, innovative approaches to reduce on-target off-tumor toxic effects of targeting EGFR, and improving efficacy in the growing population of patients with HPV-positive HNSCC.