Monoclonal antibody-guided targeted therapy, such as anti-EGFR, and immune checkpoint inhibitors (ICI), alone or in combination with chemotherapy, have been approved for R/M HNSCC by FDA/EMA but, at variance to other types of tumors (i.e., colon cancer for cetuximab or lung and melanoma for ICIs), the percent of long-term responding patients is lower. Here, EGFR is linked to head and neck squamous cell carcinoma.