Long-term Survival and Molecular Biomarker Evaluation of a Phase II Cetuximab and Nivolumab Clinical Trial in Recurrent/Metastatic Head and Neck Cancer.

PURPOSE: We report long-term survival and comprehensive molecular biomarker analyses of a phase II trial evaluating the combination of cetuximab and nivolumab in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (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 cores and margins by multiplex IHC. RESULTS: At a median follow-up of 47.4 months, the 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). 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 mutational burden, hypoxia score, and EGFR pathway score were significantly higher in p16-negative compared with p16-positive tumors. Loss of heterozygosity of MHC class I was significantly more frequent in nonresponders, and APOBEC-associated mutagenesis was elevated in responders. Gene expression profiling and multiplex IHC analyses revealed a more inflamed tumor microenvironment in responders regardless of p16 status. CONCLUSIONS: Our long-term follow-up study indicates that the combination of cetuximab and nivolumab is efficacious and tolerable and that patients with p16-negative R/M HNSCC may have greater benefit from this combination.