Head and neck squamous cell carcinoma (HNSCC) is now the seventh most common 
cancer worldwide. The median overall survival for patients with recurrent and/or 
metastatic (R/M) HNSCC remains <1 year despite modern systemic chemotherapy and 
targeted agents. Palliative systemic therapy for patients with R/M HNSCC 
typically includes a platinum-based doublet, with an understanding that the 
increase in efficacy compared with single agents is primarily related to 
improved response rate, and not survival. Till date, the only systemic therapy 
regimen to demonstrate survival superiority over platinum-5-fluorouracil (5-FU) 
doublet is platinum, FU, and cetuximab. Epidermal growth factor receptor 
inhibitors, including monoclonal antibodies and tyrosine kinase inhibitors, have 
achieved only a modest success in R/M HNSCC. Immunotherapy represents an 
attractive treatment option for R/M HNSCC, with encouraging preliminary data 
from studies involving immune checkpoint inhibitors (e.g., pembrolizumab, 
nivolumab) and toll-like receptor agonists (e.g., motolimod). Given the poor 
prognosis of R/M HNSCC, enrollment of patients into clinical trials to 
investigate novel systemic agents, is necessary for further improvement of 
oncologic outcomes in this patient population.