Review Article | Published:

Comparing and contrasting predictive biomarkers for immunotherapy and targeted therapy of NSCLC

Nature Reviews Clinical Oncology (2019) | Download Citation

Abstract

The era of personalized medicine for advanced-stage non-small-cell lung cancer (NSCLC) began when biomarker-based evidence of molecular pathway and/or oncogene addiction of the tumour became mandatory for the allocation of specific targeted therapies. More recently, the immunotherapy revolution, specifically, the development of immune-checkpoint inhibitors (ICIs), has dramatically altered the NSCLC treatment landscape. Herein, we compare and contrast the clinical development of immunotherapy and oncogene-directed therapy for NSCLC, focusing on the role of predictive biomarkers. Immunotherapy biomarkers are fundamentally different from oncogene biomarkers in that they are continuous rather than categorical (binary), spatially and temporally variable and reliant on multiple complex interactions rather than a single, dominant determinant. The performance of predictive biomarkers for ICIs might be improved by combining different markers to reduce the assumptive risks associated with each one. Novel combinations with chemotherapy and ICIs complicate biomarker discovery but do not decrease the value of the markers identified. Perfectly predictive biomarkers of benefit from immunotherapy are unlikely to be identified, although exclusionary biomarkers of minimal benefit or an unacceptable risk of toxicity might be feasible. The clinical adoption and applicability of such biomarkers might vary depending on line of treatment, the available therapeutic alternatives and health economic considerations.

Key points

  • Immunotherapy biomarkers are fundamentally different from the core driver oncogene biomarkers identified for molecularly targeted therapies: they are continuous rather than categorical (binary), spatially and temporally variable and influenced by multiple complex interactions rather than a single, dominant determinant.

  • Immunotherapy biomarkers enrich for clinical benefit but are currently unable to guarantee or exclude benefit and, therefore, have predominantly been used to identify subgroups of patients with a sufficient likelihood of benefit to suggest immunotherapy as the preferred option in a particular line of therapy.

  • Biomarkers related to the initiation of an immune cascade (such as tumour mutational burden) could be used to enrich for benefit from any potential immunotherapy; those more towards the final effector phase of the immune cascade (such as programmed cell death 1 ligand 1 (PD-L1)) are more likely to enrich for drug-specific effects.

  • The next steps in improving the performance of predictive biomarkers of responsiveness to immunotherapy in patients with non-small-cell lung cancer might involve combining different markers to lessen the assumptive risks associated with each one.

  • The use of chemotherapy–immunotherapy combinations adds additional complexities to the study of immunotherapy biomarkers but does not negate the value of such markers.

  • Currently, perfectly predictive biomarkers of benefit from immunotherapy seem unattainable, but exclusionary biomarkers based on minimal benefit or maximal toxicity risk might be attainable; their adoption and applicability might vary by line of therapy, available therapeutic alternatives and health economic considerations.

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Acknowledgements

The work of D.R.C. and R.C.D. is partially supported by the University of Colorado Lung Cancer SPORE (P50CA058187).

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Nature Reviews Clinical Oncology thanks R. Rosell, M. Reck and other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Division of Medical Oncology, Department of Medicine, University of Colorado Cancer Center, Aurora, CO, USA

    • D. Ross Camidge
    •  & Robert C. Doebele
  2. Department of Pathology, Aberdeen University Medical School, Aberdeen Royal Infirmary, Aberdeen, UK

    • Keith M. Kerr

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All authors contributed equally to this article, including researching data, discussions of content and writing and editing the manuscript before submission and after peer review.

Competing interests

D.R.C. has ad hoc advisory roles with ARIAD, Arrys/Kyn, AstraZeneca, Bio-Thera DSMB, Celgene, Clovis, Daiichi Sankyo (interstitial lung disease adjudication committee), G1 Therapeutics (DSMB), Genoptix, Hansoh SRC, Hengrui, Ignyta, Lycera, Mersana Therapeutics, Novartis, Orion, Regeneron, Revolution Med, Roche/Genentech and Takeda and has received research funding from Takeda. R.C.D. is an advisory board member for ARIAD, AstraZeneca, Ignyta, Spectrum and Takeda; has received research sponsorship from Ignyta and licensing fees from Abbott Molecular, Ignyta and Rain Therapeutics; and owns stock in Rain Therapeutics. K.M.K. has been a consultant for and has received speaker’s honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Serono, Merck Sharp and Dohme, Novartis, Pfizer, Roche and Ventana and has been a consultant for AbbVie.

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Correspondence to D. Ross Camidge.

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https://doi.org/10.1038/s41571-019-0173-9