Therefore, in this in vitro study, we investigated the effectiveness of afatinib, an irreversible EGFR/HER2/HER4 tyrosine kinase inhibitor, in combination with cisplatin, the most common chemotherapy used in HNSCC, in various sequences of treatment in two human EGFR wild-type HNSCC cell lines. The gene discussed is ERBB4; the disease is head and neck squamous cell carcinoma.