In multivariate models, TMB, PD-L1, and TcellinfGEP were each independently predictive for ORR (p < 0.001). ORR was higher in patients with high versus low levels of biomarkers…patients with higher versus lower levels of TMB and PD-L1 or TMB and TcellinfGEP had the highest ORRs....TMB and the inflammatory biomarkers PD-L1 and TcellinfGEP, assessed alone or together, may be useful for characterizing clinical response to pembrolizumab in R/M HNSCC.