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PURPOSE: We report long-term survival and comprehensive molecular biomarker analyses of a phase II trial evaluating the combination of cetuximab and nivolumab in R/M HNSCC.PATIENTS AND METHODS: The long-term follow up data were obtained from a phase II trial (NCT03370276). Archived tumors and serially collected plasma cell-free DNA were characterized by comprehensive genomic analyses. Immune markers were measured in tumor core and margins by multiplex immunohistochemistry (mIHC).RESULTS: At a median follow-up of 47.4 months, median overall survival (OS) and 2-year OS rate were 12.7 months and 32% in all evaluable patients (n=88) and 17.5 months and 35% in patients who had no prior therapy for R/M HNSCC (n=43), respectively. The survival efficacy was similar between patients with p16-negative and p16-positive tumors, but the response rate was significantly higher in patients with p16-negative tumors. The clonal tumor mutation burden, hypoxia score, and EGFR pathway score were significantly higher in p16-negative compared to p16-positive tumors. Loss of heterozygosity of MHC-I was significantly more frequent in non-responders, and APOBEC-associated mutagenesis was elevated in responders. Gene expression profiling and mIHC analyses revealed a more inflamed tumor microenvironment in responders regardless of the p16 status.CONCLUSIONS: Our long-term follow-up study indicates that the combination of cetuximab and nivolumab is efficacious and tolerable, and that p16-negative R/M HNSCC patients may have greater benefit from this combination.