Mutations in the tyrosine kinase (TKD) domain of the epidermal growth factor receptor (EGFR) are involved in the unfavorable therapeutic response through resistance to targeted molecular therapy. Data from the clinical experience of non-small cell lung carcinoma (NSCLC) treatment demonstrate the benefit of tyrosine kinase inhibitors (TKIs) in cases of EGFR mutation. The next generation sequencing technique (NGS) allows the identification of hot spots involved in mutations, exon 20 insertion being associated with the unfavorable response. Exon 20 insertions are more common in head and neck squamous cell carcinoma (HNSCC) compared to NSCLC, which could explain a resistance to targeted therapy in head and neck cancers. Taking into account the data reported in the NSCLC, Amivantamab, a bi-specific EGFR-MET antibody with potential immune cell modulation of activity, but also other innovative therapies validated in exon20 EGFR mutation could be part of the therapy of sino-nasal cancer, but also of other HNSCC sites exon 20 mutant EFGR.