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Cancer Treatment with Anti-PD-1/PD-L1 Agents: Is PD-L1 Expression a Biomarker for Patient Selection?

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Abstract

Strategies to help improve the efficacy of the immune system against cancer represent an important innovation, with recent attention having focused on anti-programmed death (PD)-1/PD-ligand 1 (L1) monoclonal antibodies. Clinical trials have shown objective clinical activity of these agents (e.g., nivolumab, pembrolizumab) in several malignancies, including melanoma, non-small-cell lung cancer, bladder cancer, squamous head and neck cancer, renal cell cancer, ovarian cancer, microsatellite-unstable colorectal cancer, and Hodgkin’s lymphoma. Expression of PD-L1 in the tumor microenvironment appears to be crucial for therapeutic activity, and initial trials suggested positive PD-L1 tumor expression was associated with higher response rates. However, subsequent observations have questioned the prospect of using PD-L1 expression as a biomarker for selecting patients for therapy, especially since many patients considered PD-L1-negative experience a benefit from treatment. Importantly, there is not yet a definitive test for determination of PD-L1 and a cut-off reference for PD-L1-positive status has not been established. Immunohistochemistry with different antibodies and different thresholds has been used to define PD-L1 positivity (1–50 %), with no clear superiority of one threshold over another for identifying which patients respond. Moreover, the type of cells on which PD-L1 expression is most relevant is not yet clear, with immune infiltrate cells and tumor cells both being used. In conclusion, while PD-L1 expression is often a predictive factor for treatment response, it must be complemented by other biomarkers or histopathologic features, such as the composition and amount of inflammatory cells in the tumor microenvironment and their functional status. Multi-parameter quantitative or semi-quantitative algorithms may become useful and reliable tools to guide patient selection.

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Acknowledgments

The authors would like to thank Alessandra Trocino for providing excellent bibliography service and assistance.

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Authors and Affiliations

  1. Istituto Nazionale Tumori Fondazione “G. Pascale”, Via Mariano Semmola, 80131, Naples, Italy

    Lucia Festino, Gerardo Botti & Paolo A. Ascierto

  2. University of Manchester/The Christie NHS Foundation Trust, Manchester, UK

    Paul Lorigan

  3. Department of Oncology-Pathology, Karolinska Institutet and Hospital, Stockholm, Sweden

    Giuseppe V. Masucci

  4. Bristol-Myers Squibb, Princeton, NJ, USA

    Jason D. Hipp & Christine E. Horak

  5. CIMA and CUN, University of Navarra, Pamplona, Spain

    Ignacio Melero

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  1. Lucia Festino
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  2. Gerardo Botti
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  8. Paolo A. Ascierto
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Correspondence to Paolo A. Ascierto.

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This study was not a clinical study and did not include patient data.

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No funding was requested or received for the preparation of this manuscript by the authors.

Conflict of interest

Dr Jason D. Hipp and Dr Christine E. Horak are BMS employees and stockholders. Dr Paul Lorigan had consultant role for MSD, Amgen, BMS, GSK, Novartis, Roche and Celgene. Prof. Ignacio Melero had advisory role for BMS, AstraZeneca, Roche-Genentech, Leadartis, Boehringer Ingelheim. He also received research grant from Pfizer. Dr. Ignacio Melero rehas a conslutant/advisory role for BMS, AstraZeneca, Incyte, Boehringer ingelheim, novartis and alligator. Dr Paolo A. Ascierto has/has a consultant/advisory role for BMS, Roche-Genentech, MSD, GSK, Ventana, Novartis, Amgen. He also received research grant from BMS, Roche-Genentech and Ventana. Dr Lucia festino, Dr Gerardo Botti, and Dr Giuseppe V. Masucci have no conflict of interest to disclose.

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Festino, L., Botti, G., Lorigan, P. et al. Cancer Treatment with Anti-PD-1/PD-L1 Agents: Is PD-L1 Expression a Biomarker for Patient Selection?. Drugs 76, 925–945 (2016). https://doi.org/10.1007/s40265-016-0588-x

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