Review Article | Published:

Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-generation TKI?

Nature Reviews Clinical Oncology (2018) | Download Citation

Abstract

The traditional approach to the treatment of patients with advanced-stage non-small-cell lung carcinoma (NSCLC) harbouring ALK rearrangements or EGFR mutations has been the sequential administration of therapies (sequential treatment approach), in which patients first receive first-generation tyrosine-kinase inhibitors (TKIs), which are eventually replaced by next-generation TKIs and/or chemotherapy upon disease progression, in a decision optionally guided by tumour molecular profiling. In the past few years, this strategy has been challenged by clinical evidence showing improved progression-free survival, improved intracranial disease control and a generally favourable toxicity profile when next-generation EGFR and ALK TKIs are used in the first-line setting. In this Review, we describe the existing preclinical and clinical evidence supporting both treatment strategies — the ‘historical’ sequential treatment strategy and the use of next-generation TKIs — as frontline therapies and discuss the suitability of both strategies for patients with EGFR-driven or ALK-driven NSCLC.

Key points

  • Patients with EGFR-driven or ALK-driven non-small-cell lung carcinoma (NSCLC) benefit from therapies targeting those alterations, but relapse occurs systematically.

  • Several generations of tyrosine kinase inhibitors (TKIs) have been developed to address the acquisition of therapeutic resistance.

  • The historical treatment approach involving sequential administration of TKIs is associated with long overall survival durations.

  • Clinical evidence from the past few years indicates that the use of next-generation TKIs in the frontline setting is associated with major improvements in progression-free survival, control of intracranial disease and tolerability.

  • For most patients with EGFR-driven or ALK-driven NSCLC, the choice of first-line of treatment should favour next-generation TKIs.

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US National Institutes of Health ClinicalTrials.gov database: https://www.clinicaltrials.gov

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Acknowledgements

The authors would like to thank T. Sourisseau for fruitful discussions and critical reading of the manuscript. The work of G.R. is supported by a grant from the Nelia & Amadeo Barletta Foundation. The work of L.F. is supported by a European Research Council (ERC) starting grant (agreement number 717034).

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Affiliations

  1. INSERM U981, Gustave Roussy Cancer Campus, Université Paris Saclay, Villejuif, France

    • Gonzalo Recondo
    • , Ken A. Olaussen
    • , Benjamin Besse
    •  & Luc Friboulet
  2. Medical Oncology Unit, University Hospital of Parma, Parma, Italy

    • Francesco Facchinetti
  3. Department of Cancer Medicine, Gustave Roussy Cancer Campus, Villejuif, France

    • Benjamin Besse

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All authors made substantial contributions to all aspects of manuscript preparation.

Competing interests

B.B. has received institutional grants for clinical and translational research from AstraZeneca, Boehringer-ingelheim, Bristol-Myers Squibb (BMS), Inivata, Lilly, Loxo, OncoMed, Onxeo, Pfizer, Roche-Genentech, Sanofi-Aventis, Servier, and OSE Pharma. All other authors declare no competing interests.

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Correspondence to Luc Friboulet.

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https://doi.org/10.1038/s41571-018-0081-4