Influence of tumor mutational burden, inflammatory gene expression profile, and PD-L1 expression on response to pembrolizumab in head and neck squamous cell carcinoma

Background To characterize genomic determinants of response to pembrolizumab in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 study. Methods Associations between biomarkers (tumor mutational burden (TMB), neoantigen load (NL), 18-gene T-cell-inflamed gene expression profile (Tcell(inf)GEP), and PD-L1 combined positive score (CPS)) and clinical outcomes with pembrolizumab were assessed in patients with R/M HNSCC (n=192). Tumor human papillomavirus (HPV) status was also evaluated with the use of p16 immunohistochemistry and whole exome sequencing (WES; HPV+, mapping >20 HPV reads) in pretreatment tumor samples (n=106). Results TMB, clonality-weighted TMB, and Tcell(inf)GEP were significantly associated with objective response (p=0.0276, p=0.0201, and p=0.006, respectively), and a positive trend was observed between NL and PD-L1 CPS and clinical response (p=0.0550 and p=0.0682, respectively). No correlation was observed between TMB and Tcell(inf)GEP (Spearman rho=-0.026) or TMB and PD-L1 (Spearman rho=0.009); a correlation was observed between Tcell(inf)GEP and PD-L1 (Spearman rho=0.511). HPV status by WES and p16 immunohistochemistry showed concordance (84% kappa=0.573) among patients whose HPV results were available using both methods. Conclusions TMB and inflammatory biomarkers (Tcell(inf)GEP and PD-L1) may represent distinct and complementary biomarkers predicting response to anti-programmed death 1 therapies in HNSCC; further study of these relationships in randomized clinical trials is needed.

Automated summary

This study found that tumor mutational burden (TMB), neoantigen load (NL), and T-cell-inflamed gene expression profile (Tcell(inf)GEP) were associated with response, and inflammatory biomarkers (Tcell(inf)GEP and PD-L1) showed a trend towards clinical response. The study also found concordance between HPV status detected by whole exome sequencing (WES) and p16 immunohistochemistry. These findings contribute to predicting response to anti-PD-1 therapy.