Simple Summary

The prognosis of recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) remains poor. However, human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) patients live longer than those that are negative for HPV infection. In addition, some R/M HNSCC patients respond well to immune checkpoint blockade (ICB) therapies including pembrolizumab and nivolumab, but whether HPV infection is correlated with a good response to ICB is unclear. Here we attempt to understand if ICB treatment improves survival outcomes of HPV and/or surrogate marker p16−positive OPSCC and non-OP HNSCC. We also investigate other potential biomarkers and mutations that may predict improved response to ICB in both HPV−positive and -negative HNSCC patients. With better biomarkers, future treatment can be better tailored to individual patients to improve survival.