Anti-EGFR therapy combined with immune checkpoint inhibitors in recurrent/metastatic head and neck squamous cell carcinoma: Current landscape and future directions.

Recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains a clinical challenge with poor prognosis. The EXTREME regimen (platinum, 5-fluorouracil, and cetuximab) was the former first-line standard, but the advent of immune checkpoint inhibitors (ICIs), particularly pembrolizumab based on the KEYNOTE-048 trial, has transformed the treatment landscape. However, primary and acquired resistance to ICI monotherapy persists, creating an urgent need for novel combination strategies. This review synthesizes current evidence on combining anti-EGFR therapy (primarily cetuximab) with ICIs in R/M HNSCC. The biological rationale is compelling, as cetuximab can induce antibody-dependent cellular cytotoxicity, remodel the hypoxic tumor microenvironment, and potentially enhance T-cell responses. Clinical trials of concurrent cetuximab and PD-1 inhibitors have demonstrated encouraging objective response rates and durable survival, offering a chemotherapy-free option. Notably, emerging data indicate that administering cetuximab-based therapy after ICI failure yields high salvage response rates, suggesting prior immunotherapy may sensitize tumors to subsequent EGFR inhibition. Conversely, prior cetuximab exposure may compromise ICI efficacy via STAT1 acetylation, underscoring the critical role of treatment sequencing. Predictive biomarkers under investigation include PD-L1 CPS, HPV/p16 status, 11q13 amplification, peripheral T-cell receptor clonality, and hypoxia signatures. The combination is generally tolerable, with manageable cutaneous and immune-related adverse events. Economic evaluations show cost-effectiveness varies by region. Future directions include novel bispecific agents, triplet regimens, and biomarker-guided patient selection to optimize outcomes in this challenging disease.