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  • Review Article
  • Published:

Refining the treatment of NSCLC according to histological and molecular subtypes

Nature Reviews Clinical Oncology volume 12, pages 511–526 (2015)Cite this article

Subjects

Key Points

  • Our understanding of non-small-cell lung cancer (NSCLC) has evolved from a single disease entity that was treated with a one-size-fits-all approach to a disease comprising clinically, histologically and genetically diverse subtypes

  • Further subtypes of tumours with EGFR mutations and ALK translocations are now recognized based on the type of resistance mechanism to targeted therapy; these subtypes have important therapeutic implications

  • Whereas several NSCLC subtypes that are responsive to targeted therapies have been identified, at present, no single molecular determinant of response to an immunotherapeutic agent has been identified

  • Although the importance of genotype-driven treatment decisions is recognized, challenges relating to tissue acquisition and processing, biomarker platforms, tumour heterogeneity, and evaluation of molecular markers and drugs pose practical barriers to clinical application of this paradigm

  • With further development of targeted therapies and immunotherapies, clinicians will probably face the daunting task of elucidating the ideal timing and sequence of molecularly targeted therapy, immunotherapy, and chemotherapy

  • Despite improvements in outcome for select patient subgroups, progress is needed in the adjuvant setting, squamous-cell lung cancers, KRAS-mutated tumours, and tumours with no detectable genetic alterations

Abstract

In the past decade, the characterization of non-small-cell lung cancer (NSCLC) into subtypes based on genotype and histology has resulted in dramatic improvements in disease outcome in select patient subgroups. In particular, molecularly targeted agents that inhibit EGFR or ALK are approved for the treatment of NSCLC harbouring genetic alterations in the genes encoding these proteins. Although acquired resistance usually limits the duration of response to these therapies, a number of new agents have proven effective at tackling specific resistance mechanisms to first-generation inhibitors. Large initiatives are starting to address the role of biomarker-driven targeted therapy in squamous lung cancers, and in the adjuvant setting. Immunotherapy undeniably holds great promise and our understanding of subsets of NSCLC based on patterns of immune response is continuing to evolve. In addition, efforts are underway to identify rare genomic subsets through genomic screening, functional studies, and molecular characterization of exceptional responders. This Review provides an overview of the key developments in the treatment of NSCLC, and discusses potential strategies to further optimize therapy by targeting disease subtypes.

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Figure 1: Timeline depicting the historical milestones in the development of therapies for NSCLC.
Figure 2: Schematic representation of the current paradigm for the pharmacological management of advanced-stage NSCLC.
Figure 3: Potential algorithm for incorporating chemotherapies, immunotherapy and targeted therapies into the management of NSCLC in the future.

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Acknowledgements

The work of A.T. is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

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Authors and Affiliations

  1. Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, Building 10, 4-4553

    Anish Thomas

  2. National Cancer Institute, National Institutes of Health, Bethesda, 20892-1201, MD, USA

    Anish Thomas

  3. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road North West, Washington, 20057, DC, USA

    Stephen V. Liu, Deepa S. Subramaniam & Giuseppe Giaccone

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  1. Anish Thomas
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  2. Stephen V. Liu
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  3. Deepa S. Subramaniam
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  4. Giuseppe Giaccone
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All authors contributed substantially to researching the data for the article, discussions of content, writing the article, and review/editing of the manuscript before submission.

Corresponding author

Correspondence to Giuseppe Giaccone.

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The authors declare no competing financial interests.

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Thomas, A., Liu, S., Subramaniam, D. et al. Refining the treatment of NSCLC according to histological and molecular subtypes. Nat Rev Clin Oncol 12, 511–526 (2015). https://doi.org/10.1038/nrclinonc.2015.90

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