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Variability in lung cancer response to ALK inhibitors cannot be explained by the diversity of ALK fusion variants

Natalia V Mitiushkina1, Vladislav I Tiurin1, Aglaya G Iyevleva2

  • 1N.N. Petrov Institute of Oncology, St.-Petersburg, Pesochny, Leningradskaya 68, 197758, Russia.

Biochimie
|August 3, 2018
PubMed

Insights

Distinct anaplastic lymphoma kinase (ALK) fusion variants in non-small cell lung cancer (NSCLC) show similar responses to ALK tyrosine kinase inhibitors (TKIs). This suggests variant type does not impact treatment effectiveness for ALK-rearranged NSCLC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Anaplastic lymphoma kinase (ALK) translocations are key drivers in a subset of non-small cell lung cancer (NSCLC).
  • Preclinical data suggest varying biochemical properties and inhibitor responsiveness among different ALK fusion variants.
  • Clinical evidence is emerging regarding differential responses to ALK tyrosine kinase inhibitors (TKIs) based on specific ALK variants.

Purpose of the Study:

  • To investigate the clinical impact of distinct anaplastic lymphoma kinase (ALK) translocation variants on treatment outcomes in patients with ALK-rearranged non-small cell lung cancer (NSCLC).
  • To compare the efficacy of crizotinib, ceritinib, and alectinib across different ALK fusion variants.

Main Methods:

  • Retrospective analysis of 64 Russian patients with ALK-rearranged NSCLC treated with crizotinib, ceritinib, or alectinib.
  • Genotyping of ALK fusion variants using polymerase chain reaction (PCR).
  • Comparison of progression-free survival (PFS) and objective response rates (ORR) between different ALK variant groups.

Main Results:

  • No significant differences in median PFS or ORR were observed between patients with 'short' (v.3a/b, v.5a/b) versus 'long' (TAPE-domain containing) ALK fusion variants.
  • Similarly, EML4/ALK variant 1 showed comparable outcomes to other ALK translocations regarding PFS and ORR.
  • ALK variants did not influence outcomes when analyzed separately for crizotinib and ceritinib treatments.
  • Ceritinib demonstrated significantly longer PFS compared to crizotinib (p=0.022).

Conclusions:

  • Distinct anaplastic lymphoma kinase (ALK) translocation variants exhibit similar clinical responsiveness to ALK tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC).
  • Treatment outcomes were not significantly influenced by the specific ALK fusion variant.
  • Ceritinib showed superior efficacy over crizotinib in this patient cohort.
Keywords:
ALK fusion variantsNon-small cell lung cancerTreatment outcomeTyrosine kinase inhibitors

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