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

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Evolving Therapeutic Landscape of ROS1-Positive Non-Small Cell Lung Cancer: An Updated Review

Hervé Bischoff1, Sébastien Gendarme2, Laura Somme1

  • 1Department of Medical Oncology, Institut de Cancérologie Strasbourg Europe, F-67200 Strasbourg, France.

Current Oncology (Toronto, Ont.)
|November 26, 2025
PubMed

Insights

ROS1 gene rearrangements drive a non-small cell lung cancer subtype. Next-generation tyrosine kinase inhibitors (TKIs) show promise against resistance, but optimal sequencing and overcoming resistance remain challenges.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • ROS1 gene rearrangements define a specific non-small cell lung cancer (NSCLC) subtype, affecting ~2% of patients.
  • This subtype is linked to younger, non-smoking individuals and frequent brain metastases.
  • Targeted therapies, including tyrosine kinase inhibitors (TKIs), have been developed to treat ROS1-positive NSCLC.

Purpose of the Study:

  • To provide an updated review of ROS1 biology and its role in NSCLC.
  • To summarize diagnostic approaches and clinical outcomes with available TKIs.
  • To discuss resistance mechanisms and future therapeutic challenges.

Main Methods:

  • Literature review of ROS1 biology, diagnostics, and TKI therapies.
  • Analysis of clinical outcomes and resistance patterns associated with ROS1-targeted agents.
  • Synthesis of current knowledge on the evolving therapeutic landscape for ROS1-positive NSCLC.

Main Results:

  • Crizotinib was the first TKI, but limitations like poor CNS penetration and resistance emerged.
  • Next-generation TKIs (entrectinib, lorlatinib, repotrectinib, taletrectinib, zidesamtinib) offer improved intracranial activity and efficacy against resistance mutations (e.g., ROS1^G2032R).
  • Despite advances, resistance remains a significant challenge, and optimal treatment sequencing is not yet defined.

Conclusions:

  • Targeted therapies have significantly improved outcomes for ROS1-positive NSCLC.
  • Ongoing research focuses on overcoming resistance mechanisms and defining optimal treatment strategies.
  • The therapeutic landscape for ROS1-driven NSCLC is rapidly evolving, requiring continuous updates in clinical practice.
Keywords:
ROS1brain metastasesnon-small cell lung cancerrepotrectinibresistance mutationstaletrectinibtargeted therapytyrosine kinase inhibitorzidesamtinib

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