Biomarkers predictive of response to pembrolizumab in head and neck cancer

David G Pfister; Robert I Haddad; Francis P Worden; Jared Weiss; Ranee Mehra; Laura Q M Chow; Stephen V Liu; Hyunseok Kang; Nabil F Saba; Lori J Wirth; Ammar Sukari; Erminia Massarelli; Mark Ayers; Andrew Albright; Andrea L Webber; Robin Mogg; Jared Lunceford; Lingkang Huang; Razvan Cristescu; Jonathan Cheng; Tanguy Y Seiwert; Joshua M Bauml

doi:10.1002/cam4.5434

Biomarkers predictive of response to pembrolizumab in head and neck cancer

Cancer Med. 2023 Mar;12(6):6603-6614. doi: 10.1002/cam4.5434. Epub 2022 Dec 7.

Authors

David G Pfister¹, Robert I Haddad², Francis P Worden³, Jared Weiss⁴, Ranee Mehra^{5

6}, Laura Q M Chow^{7

8}, Stephen V Liu⁹, Hyunseok Kang^{10

11}, Nabil F Saba¹², Lori J Wirth¹³, Ammar Sukari¹⁴, Erminia Massarelli¹⁵, Mark Ayers¹⁶, Andrew Albright¹⁶, Andrea L Webber¹⁶, Robin Mogg¹⁶, Jared Lunceford¹⁶, Lingkang Huang¹⁶, Razvan Cristescu¹⁶, Jonathan Cheng^{16

17}, Tanguy Y Seiwert^{18

19}, Joshua M Bauml^{20

21}

Affiliations

¹ Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
³ Division of Medical Oncology, University of Michigan, Ann Arbor, Michigan, USA.
⁴ Department of Medicine, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
⁵ Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
⁶ University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, Maryland, USA.
⁷ Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA.
⁸ The University of Texas at Austin, Dell Medical School, Texas, Austin, USA.
⁹ Department of Medicine, Georgetown University Medical Center, Washington, DC, USA.
¹⁰ Department of Medical Oncology, Johns Hopkins University, Baltimore, Maryland, USA.
¹¹ University of California, San Francisco, California, USA.
¹² Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.
¹³ Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁴ Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA.
¹⁵ Department of Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
¹⁶ Department of Medical Oncology, Merck & Co., Inc., Rahway, New Jersey, USA.
¹⁷ Bristol Myers Squibb, Philadelphia, Pennsylvania, USA.
¹⁸ Section of Hematology-Oncology, University of Chicago Department of Medicine, Chicago, Illinois, USA.
¹⁹ Johns Hopkins University, Baltimore, Maryland, USA.
²⁰ Division of Hematology and Oncology, Department of Internal Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²¹ Janssen Research and Development, Philadelphia, Pennsylvania, USA.

Abstract

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 (Tcell_inf GEP), 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 Tcell_inf GEP. TMB, PD-L1, and Tcell_inf GEP 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 Tcell_inf GEP (Spearman ρ = -0.03 and ρ = -0.13, respectively); PD-L1 and Tcell_inf GEP were moderately correlated (Spearman ρ = 0.47). In multivariate models, TMB, PD-L1, and Tcell_inf GEP 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 Tcell_inf GEP had the highest ORRs. Within HPV subgroups, higher versus lower distributions of biomarkers (PD-L1, TMB, and Tcell_inf GEP) 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 Tcell_inf GEP, assessed alone or together, may be useful for characterizing clinical response to pembrolizumab in R/M HNSCC.

Keywords: biomarker; head and neck squamous cell carcinoma; immunotherapy; pembrolizumab; tumor microenvironment; tumor mutational burden.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents, Immunological* / adverse effects
B7-H1 Antigen
Biomarkers, Tumor / genetics
Head and Neck Neoplasms* / drug therapy
Humans
Papillomavirus Infections* / complications
Squamous Cell Carcinoma of Head and Neck / chemically induced
Squamous Cell Carcinoma of Head and Neck / drug therapy

Substances

pembrolizumab
B7-H1 Antigen
Antineoplastic Agents, Immunological
Biomarkers, Tumor

Grants and funding

P30 CA008748/CA/NCI NIH HHS/United States