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Precision medicine against ALK-positive non-small cell lung cancer: beyond crizotinib

Biagio Ricciuti1, Andrea De Giglio2, Carmen Mecca3

  • 1Department of Medical Oncology, Santa Maria della Misericordia Hospital, University of Perugia, Piazzale L. Severi n. 1, 06132, Perugia, Italy. biagio.ricciuti@gmail.com.

Medical Oncology (Northwood, London, England)
|April 19, 2018
PubMed

Insights

Next-generation anaplastic lymphoma kinase (ALK) inhibitors offer improved survival for ALK-positive non-small cell lung cancer (NSCLC) patients, including those with brain metastases. Re-testing for ALK mutations at progression is crucial for personalized treatment selection.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Anaplastic lymphoma kinase (ALK) rearrangements drive a subset of non-small cell lung cancers (NSCLCs).
  • Acquired resistance to the first-generation ALK inhibitor crizotinib develops in most ALK-positive NSCLC patients within a year.
  • Next-generation ALK inhibitors have been developed to overcome crizotinib resistance and improve patient outcomes.

Purpose of the Study:

  • To review current knowledge on ALK tyrosine kinase inhibitors (TKIs) for advanced ALK-positive NSCLC.
  • To focus on the role of novel ALK inhibitors in treating ALK-positive NSCLC.
  • To discuss the management of ALK-positive brain metastases with these agents.

Main Methods:

  • Literature review of ALK tyrosine kinase inhibitors (TKIs) in advanced ALK-positive NSCLC.
  • Analysis of clinical activity, including efficacy against central nervous system (CNS) metastases.
  • Evaluation of sequential TKI therapy and the necessity of re-genotyping at progression.

Main Results:

  • Next-generation ALK inhibitors demonstrate significant clinical activity in ALK-positive NSCLC, including CNS metastases.
  • Sequential therapy with ALK TKIs shows efficacy in patients who have progressed on prior ALK TKI treatment.
  • Different ALK inhibitors exhibit varying activity against crizotinib resistance mutations.

Conclusions:

  • Personalized treatment selection based on re-genotyping at disease progression is essential due to differing activity profiles of ALK TKIs against resistance mutations.
  • Non-invasive methods for detecting and monitoring ALK rearrangements are under investigation to avoid repeated invasive procedures.
Keywords:
ALK rearrangementBrain metastasisNSCLCTyrosine kinase inhibitors

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