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Updated: Jul 15, 2025

Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
07:59

Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer

Published on: September 8, 2023

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Treatment of advanced ALK-rearranged NSCLC following second-generation ALK-TKI failure

Akito Fukuda1, Tatsuya Yoshida1

  • 1Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.

Expert Review of Anticancer Therapy
|September 29, 2023
PubMed
Abstract

Insights

Resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) is common in non-small cell lung cancer (NSCLC). Treatment strategies for ALK-TKI resistance depend on identified resistance mechanisms, with lorlatinib as a key option.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Anaplastic lymphoma kinase (ALK) gene rearrangement occurs in 3-5% of non-small cell lung cancer (NSCLC).
  • ALK-tyrosine kinase inhibitors (TKIs) significantly improve survival in ALK-rearranged NSCLC.
  • Acquired resistance to ALK-TKIs is a major challenge, leading to disease progression via ALK-dependent and independent mechanisms.

Purpose of the Study:

  • To review mechanisms of resistance to second-generation ALK-TKIs.
  • To outline clinical management strategies for patients with ALK-rearranged NSCLC who develop resistance to second-generation ALK-TKIs.

Main Methods:

  • Literature review of resistance mechanisms to second-generation ALK-TKIs.
  • Analysis of clinical management strategies based on resistance profiles.

Main Results:

  • Resistance to second-generation ALK-TKIs can be ALK-dependent or ALK-independent.
  • Lorlatinib is a primary treatment option for patients with ALK mutations resistant to second-generation ALK-TKIs.
  • Specific resistance mutations (e.g., G1202R, L1196M) guide treatment selection, with lorlatinib showing broad coverage.

Conclusions:

  • Treatment strategies post-second-generation ALK-TKI failure must be tailored to resistance mechanisms.
  • Lorlatinib is recommended for ALK-dependent resistance mutations due to its broad activity.
  • For cases without resistance mutations, atezolizumab, bevacizumab, and platinum-based chemotherapy are alternative options.
Keywords:
ALKNSCLCalectinibbrigatinibceritiniblorlatinibsecond-generation ALK–TKI

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