Advanced Human Papillomavirus–Negative Head and Neck Squamous Cell Carcinoma: Unmet Need and Emerging Therapies

Despite notable progress in the treatment of advanced head and neck squamous cell carcinoma (HNSCC), survival remains poor in patients with recurrent and/or metastatic (R/M) human papillomavirus (HPV)-negative HNSCC. Worse outcomes in patients who are HPV-negative may be partly related to loss of cell-cycle regulators and tumor suppressors as well as a noninflamed and hypoxic tumor microenvironment, both of which contribute to treatment resistance and disease progression. Anti-programmed cell death protein 1-based regimens as current standard-of-care treatment for R/M HNSCC are associated with durable responses in a limited number of patients. The anti-EGFR mAb, cetuximab, has antitumor activity in this treatment setting, but responses are short-lived and inevitably curtailed due to treatment resistance. Crosstalk between the EGFR and hepatocyte growth factor-dependent mesenchymal-epithelial transition (c-MET) receptor tyrosine kinase pathway is a known mechanism of resistance to cetuximab. Dual targeting of EGFR and c-MET pathways may overcome resistance to cetuximab in patients with HPV-negative HNSCC. Here, we review clinical data of treatments evaluated in patients with R/M HPV-negative HNSCC and highlight the potential role of combining hepatocyte growth factor/c-MET and EGFR pathway inhibitors to overcome cetuximab resistance in this population.