Biomarkers predictive of response to pembrolizumab in head and neck cancer

• Published in: Cancer medicine (Malden, MA) Vol. 12; no. 6; pp. 6603 - 6614
• Main Authors: Pfister, David G., Haddad, Robert I., Worden, Francis P., Weiss, Jared, Mehra, Ranee, Chow, Laura Q. M., Liu, Stephen V., Kang, Hyunseok, Saba, Nabil F., Wirth, Lori J., Sukari, Ammar, Massarelli, Erminia, Ayers, Mark, Albright, Andrew, Webber, Andrea L., Mogg, Robin, Lunceford, Jared, Huang, Lingkang, Cristescu, Razvan, Cheng, Jonathan, Seiwert, Tanguy Y., Bauml, Joshua M.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.03.2023; John Wiley and Sons Inc; Wiley
• Subjects: Antineoplastic Agents, Immunological - adverse effects; B7-H1 Antigen; biomarker; Biomarkers; Biomarkers, Tumor - genetics; Cancer therapies; Gene expression; Head & neck cancer; Head and Neck Neoplasms - drug therapy; head and neck squamous cell carcinoma; Human papillomavirus; Humans; Immunohistochemistry; Immunotherapy; Inflammation; Lymphocytes T; Monoclonal antibodies; Mutation; Papillomavirus Infections - complications; Patients; PD-L1 protein; Pembrolizumab; Regression analysis; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - chemically induced; Squamous Cell Carcinoma of Head and Neck - drug therapy; Statistical analysis; tumor microenvironment; tumor mutational burden; Tumors; Viruses; pembrolizumab; tumor microenvironment; biomarker; tumor mutational burden; immunotherapy; head and neck squamous cell carcinoma
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.5434

Background We performed an integrated biomarker evaluation in pembrolizumab‐treated patients with R/M HNSCC enrolled in KEYNOTE‐012 or KEYNOTE‐055. The relationship between biomarkers and HPV status was explored. Methods We evaluated PD‐L1 (combined positive score [CPS]), TMB, T‐cell‐inflamed gene expression profile (TcellinfGEP), and HPV status. Associations between biomarkers were evaluated by logistic regression (ORR) and Cox regression (PFS, OS). Results Two hundred and fifty‐seven patients (KEYNOTE‐012, n = 106; KEYNOTE‐055, n = 151) had TMB data available; of these, 254 had PD‐L1 and 236 had TcellinfGEP. TMB, PD‐L1, and TcellinfGEP were each significantly associated with ORR (p < 0.01). Kaplan–Meier curves at prespecified cutoffs generally showed PFS and OS separation in the anticipated direction for these biomarkers, except for OS and TMB. TMB did not correlate with PD‐L1 or TcellinfGEP (Spearman ρ = −0.03 and ρ = −0.13, respectively); PD‐L1 and TcellinfGEP were moderately correlated (Spearman ρ = 0.47). 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 when dichotomized using prespecified cutoffs; patients with higher versus lower levels of TMB and PD‐L1 or TMB and TcellinfGEP had the highest ORRs. Within HPV subgroups, higher versus lower distributions of biomarkers (PD‐L1, TMB, and TcellinfGEP) were associated with response. HPV detection by p16‐immunohistochemistry and WES showed good concordance (81%); results were generally similar by HPV status, regardless of the detection method. Conclusions 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. TMB and inflammatory biomarkers PD‐L1 and T‐cell‐inflamed GEP, assessed alone or together, may be useful for characterizing clinical response to pembrolizumab in R/M HNSCC. Greater responses to pembrolizumab were associated with higher levels of TMB and inflammatory biomarkers than were lesser responses, an observation that was consistent regardless of HPV status, suggesting that biomarkers representing complementary measures of tumor antigenicity and a T‐cell‐inflamed tumor microenvironment may be useful in characterizing response to pembrolizumab.