. 2023 Mar;12(6):6603-6614.

doi: 10.1002/cam4.5434. Epub 2022 Dec 7.

Biomarkers predictive of response to pembrolizumab in head and neck cancer

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.

PMID: 36479637
PMCID: PMC10067081
DOI: 10.1002/cam4.5434

Biomarkers predictive of response to pembrolizumab in head and neck cancer

David G Pfister et al. Cancer Med. 2023 Mar.

. 2023 Mar;12(6):6603-6614.

doi: 10.1002/cam4.5434. Epub 2022 Dec 7.

Authors

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.

PMID: 36479637
PMCID: PMC10067081
DOI: 10.1002/cam4.5434

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.

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Conflict of interest statement

DGP reports grants (clinical trial support) from AZ/MedImmune and Hookipa, personal fees (Data and Safety Monitoring Board member) from Boehringer Ingelheim, and personal fees (services other than consulting) from Incyte. RIH reports employment at Dana‐Farber Cancer Institute; leadership for the National Comprehensive Cancer Network; a consulting or advisory role for Celgene, Merck, Eisai, Bristol Myers Squibb, AstraZeneca, Pfizer, Loxo, Genentech, Immunomic Therapeutics, GlaxoSmithKline, Gilead Sciences, Vaccinex, EMD Serono, BioNTech AG, Achilles Therapeutics, Bayer, and Mirati Therapeutics; researching funding (to institution) from Boehringer Ingelheim, Merck, Bristol Myers Squibb, Celgene, AstraZeneca, VentiRx, Genentech, Pfizer, and Kura; other relationships with Nanobiotix and ISA Pharmaceuticals. FPW reports personal fees (advisory board and clinical trial support) from Merck; grants and personal fees (advisory board and clinical trial support) from Exelixis, Eli Lilly, and Eisai; grants (clinical trial support) from Pfizer; and personal fees (advisory board) from Bristol Meyers Squibb. JW has nothing to disclose. RM reports personal fees (advisory board) from Rakuten Medical and others (researching funding) from Merck and AstraZeneca. LQMC reports grants and personal fees from Merck (de minimus personal honoraria for lung cancer immunotherapy advisory board over the last 5 years, not directly associated with current topic; prior institution [University of Washington from 2012 to 2019] received grant funding for study enrollment and conduct); grants (research funding to prior institution) from Lilly/ImClone, Bristol Myers Squibb, AstraZeneca/MedImmune, Pfizer, Seattle Genetics, Dynavax, Alkermes, and Novartis; grants (current institutional study research funding) from Alkermes; personal fees (advisory board, lung cancer [spring 2021]) from AstraZeneca/MedImmune; personal fees (advisory board, cancer cachexia [2019]) from Pfizer; personal fees (advisory board, immunotherapy [2019]) from Dynavax; personal fees (advisory board, immunotherapy [2020]) from Alkermes; personal fees (brief consultation – de minimus honoraria 2019, 2020) from Cullinan; personal fees (brief consultation – de minimus honoraria 2020) from Elicio; personal fees (research funding to prior institution) from Genentech; personal fees (de minimus advisory board honoraria and study chair [2013–2019]; advisory board, targeted therapy lung cancer [2020]) from Novartis; personal fees (advisory board and consulting, lung cancer targeted therapy – de minimus payment 2020) from Daiichi Sankyo; personal fees (virtual advisory board, head and neck cancer and CD47 therapy di minimus payment November 2020) from Gilead; personal fees (virtual advisory board, immunotherapy and cutaneous skin cancer; advisory board di minimus payment December 2020) from Regeneron; personal fees (virtual advisory board, small cell lung cancer [spring 2021]) from Ipsen; personal fees (virtual targeted therapy lung cancer advisory board [spring 2021]) from Blueprint; personal fees (virtual advisory board [June 2021]) from Nanobiotix; personal fees (di minimus virtual advisory board, lung cancer [June 2021]) from Sanofi‐Genzyme; and personal fees (de minimus virtual lung cancer advisory board [June 2021]) from BeiGene. SVL reports grants from Alkermes, AstraZeneca, Bayer, Blueprint, Bristol Myers Squibb, Elevation Oncology, Genentech, Lilly, Merck, Merus, Pfizer, Rain Therapeutics, RAPT, Takeda, and Turning Point Therapeutics; and personal fees from Amgen, AstraZeneca, BeiGene, Blueprint, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech, Guardant Health, Inivata, Janssen, Jazz Pharmaceuticals, Eli Lilly, Merck, Novartis, Pfizer, Regeneron, Takeda, and Turning Point Therapeutics. HK reports personal fees (consulting fee) from Pin Therapeutics; other (data safety monitoring committee) from MitoImmune; and other (advisory board) from MitoImmune, Bayer, Exelixis, and Achilles Therapeutics. NFS reports personal fees (advisory role) from Merck, GlaxoSmithKline, and Kura and grants (funding for research) from BMS and Exelixis. LJW reports personal fees (advisory board) from Merck, Bayer HealthCare, Blueprint Medicines, Eli Lilly, Exelixis, Genentech USA, and Loxo Oncology; and personal fees (sits on Data and Safety Monitoring Committee) from Iovance Biotherapeutics and PSD Biotechnology. AS reports personal fees (speaker fees) from Merck. EM reports personal fees (speakers bureau) from AstraZeneca, Eli Lilly, Merck, and Takeda and personal fees (advisory board) from BMS, Genentech, Eli Lilly, Janssen, Merck, Mirati, and Sanofi. MA is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and a stockholder of Merck & Co., Inc., Rahway, NJ, USA. AA is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. ALW is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. RM is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. JL is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and a stockholder of Merck & Co., Inc., Rahway, NJ, USA. LH is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and a stockholder of Merck & Co., Inc., Rahway, NJ, USA. RC is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and a stockholder of Merck & Co., Inc., Rahway, NJ, USA. JC was an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA at the time of this study. TYS reports grants (other clinical trials) from Merck/MSD, BMS, Genentech/Roche, Regeneron, AstraZeneca, Cue Biopharma, Nektar, and KURA; other (education, advisory board) from Merck/MSD; other (advisory board) from Regeneron, Cue Biopharma, KURA, and Innate; and other (steering committee) from AstraZeneca and Nektar. JMB reports grants from Merck, Clovis, Carevive Systems, Novartis, Bayer, Janssen, AstraZeneca, Takeda, and Carisma Therapeutics; and personal fees from Clovis, Bristol Meyers Squibb, Astra Zeneca, Celgene, Boehringer Ingelheim, Janssen, Merck, Guardant Health, Genentech, Takeda, Ayala, Regeneron, Inivata, and Novartis.

Figures

**FIGURE 1**
Association between biomarkers and response in all patients. (A) TMB, (B) TMB weighted by clonality, (C) neoantigen load, (D) PD‐L1 CPS, and (E) Tcell_infGEP

**FIGURE 2**
AUROC curve of TMB, PD‐L1 CPS, and Tcell_infGEP in all patients

**FIGURE 3**
Correlation between (A) PD‐L1 CPS and TMB, or Tcell_infGEP and TMB, or PD‐L1 CPS and Tcell_infGEP and the response rate (95% CI) of the dual biomarkers (B) TMB and PD‐L1 CPS, (C) TMB and Tcell_infGEP, and (D) Tcell_infGEP and PD‐L1 CPS in all patients. Data in panels B, C, and D are shown for patients who had data available for both biomarkers

**FIGURE 4**
Association between biomarkers and PFS and OS in all patients at prespecified cutoffs. (A) TMB and PFS, (B) TMB and OS, (C) PD‐L1 CPS and PFS, (D) PD‐L1 CPS and OS, (E) Tcell_infGEP and PFS, and (F) Tcell_infGEP and OS

See this image and copyright information in PMC

References

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Biomarkers predictive of response to pembrolizumab in head and neck cancer

Affiliations

Biomarkers predictive of response to pembrolizumab in head and neck cancer

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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Grants and funding

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Full Text Sources

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Research Materials