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  • Review Article
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PD-L1 as a biomarker of response to immune-checkpoint inhibitors

Nature Reviews Clinical Oncology volume 18, pages 345–362 (2021)Cite this article

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Abstract

Immune-checkpoint inhibitors targeting PD-1 or PD-L1 have already substantially improved the outcomes of patients with many types of cancer, although only 20–40% of patients derive benefit from these new therapies. PD-L1, quantified using immunohistochemistry assays, is currently the most widely validated, used and accepted biomarker to guide the selection of patients to receive anti-PD-1 or anti-PD-L1 antibodies. However, many challenges remain in the clinical use of these assays, including the necessity of using different companion diagnostic assays for specific agents, high levels of inter-assay variability in terms of both performance and cut-off points, and a lack of prospective comparisons of how PD-L1+ disease diagnosed using each assay relates to clinical outcomes. In this Review, we describe the current role of PD-L1 immunohistochemistry assays used to inform the selection of patients to receive anti-PD-1 or anti-PD-L1 antibodies, we discuss the various technical and clinical challenges associated with these assays, including regulatory issues, and we provide some perspective on how to optimize PD-L1 as a selection biomarker for the future treatment of patients with solid tumours.

Key points

  • The clinical utility of PD-L1 testing varies greatly between cancer types and treatment settings.

  • The selection of specific PD-L1 assays for testing should be fit-for-purpose and determined by clinical utility; testing should be organ-specific and selected based on consultation between oncologists and pathologists.

  • While multiple commercial PD-L1 assays are available, these are not equal in terms of analytical performance and care should be taken in the interpretation of results given these differences.

  • Pre-analytical and analytical factors, scoring algorithms, and the site and timing of tissue acquisition can all influence the results of PD-L1 testing.

  • Further standardization of PD-L1 laboratory-based assay development and reporting is warranted.

  • The prospective internal review of assay performance and participation in external quality assurance programmes is recommended.

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Fig. 1: PD-L1 scoring formulas.
Fig. 2: Analytical comparison of percentage tumour cell staining, by patient, for each assay.
Fig. 3: Comparative staining features of five PD-L1 IHC assays on the same NSCLC sample.
Fig. 4: A proposed approach to assay standardization.

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Acknowledgements

The authors thank Adrian Sacher, Princess Margaret Cancer Center, Toronto, ON, Canada, for input to the manuscript.

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Authors and Affiliations

  1. Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Deborah Blythe Doroshow, Sheena Bhalla & Fred R. Hirsch

  2. Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Mary Beth Beasley

  3. Department of Pathology, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA

    Lynette M. Sholl

  4. Department of Pathology, Aberdeen University School of Medicine and Aberdeen Royal Infirmary, Aberdeen, UK

    Keith M. Kerr

  5. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Sacha Gnjatic

  6. Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA

    Ignacio I. Wistuba

  7. Department of Pathology, Yale University School of Medicine, New Haven, CT, USA

    David L. Rimm

  8. Department of Laboratory Medicine and Pathobiology, Princess Margaret Cancer Center, Toronto, ON, Canada

    Ming Sound Tsao

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D.B.D. has acted as a consultant of Boehringer Ingelheim. L.M.S. has acted as a consultant of AstraZeneca, EMD Serono, and Genentech and has received research funding (through Harvard Medical School) from Genentech. K.M.K. has acted as a consultant of AbbVie, Amgen, AstraZeneca, Archer Diagnostics, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Debiopharm, Diaceutics, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Roche, and Roche Diagnostics/Ventana and has received speaker’s fees from AstraZeneca, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Roche Diagnostics/Ventana, Medscape, Prime Oncology, and PeerVoice. S.G. has acted as a consultant and/or advisor of Merck and OncoMed and has received research funding from Agenus, Bristol-Myers Squibb, Genentech, Immune Design, Janssen R&D, Pfizer, Regeneron, and Takeda as well as being a named co-inventor on a patent relating to the use of multiplex immunohistochemistry to characterize tumours and treatment responses. This patent is filed through Icahn School of Medicine at Mount Sinai (ISMMS) and non-exclusively licensed to Caprion. ISMMS has received payments associated with the licensing of this technology and both ISMMS and S.G. are entitled to future payments. M.S.T. has acted as a consultant of AstraZeneca, Bristol-Myers Squibb, and Merck and has received a research grant (through the University Health Network) from Merck. F.R.H. has acted as an advisor of Amgen, AstraZeneca/Daiichi, Bristol-Myers Squibb, Genentech/Roche, Merck, Novartis, OncoCyte, Regeneron/Sanofi, and Ventana and has received research grants (through University of Colorado) from Abbvie, Amgen, Bayer, Biodesix, Cetya Pharmaceuticals, Dako, Leica, Merck, Rain Therapeutics and Ventana. The other authors declare no competing interests.

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Doroshow, D.B., Bhalla, S., Beasley, M.B. et al. PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nat Rev Clin Oncol 18, 345–362 (2021). https://doi.org/10.1038/s41571-021-00473-5

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