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

ROS1 gene rearrangements define a distinct molecular subtype of non-small cell lung cancer (NSCLC), occurring in approximately 2% of cases and frequently associated with younger age, non-smoker status, and a high incidence of brain metastases. The discovery of ROS1 as an oncogenic driver has led to...

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Bibliographic Details
Published in:Current oncology (Toronto) Vol. 32; no. 11; p. 626
Main Authors: Bischoff, Hervé, Gendarme, Sébastien, Somme, Laura, Chouaid, Christos, Schott, Roland
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 06.11.2025
Subjects:
Antimitotic agents
Antineoplastic agents
brain metastases
Cancer
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - pathology
Development and progression
Drug Resistance, Neoplasm
Genetic aspects
Genetic research
Health aspects
Humans
Lung cancer, Non-small cell
Lung cancer, Small cell
Lung Neoplasms - drug therapy
Lung Neoplasms - genetics
Lung Neoplasms - pathology
Medical research
Medicine, Experimental
Metastasis
non-small cell lung cancer
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - therapeutic use
Protein-Tyrosine Kinases - antagonists & inhibitors
Protein-Tyrosine Kinases - genetics
Protein-Tyrosine Kinases - metabolism
Proto-Oncogene Proteins - antagonists & inhibitors
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
resistance mutations
ROS1
targeted therapy
Tyrosine
tyrosine kinase inhibitor
France
Spain
non-small cell lung cancer
targeted therapy
repotrectinib
taletrectinib
brain metastases
tyrosine kinase inhibitor
ROS1
resistance mutations
zidesamtinib
ISSN:1718-7729, 1198-0052, 1718-7729
Online Access:Get full text
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Summary:ROS1 gene rearrangements define a distinct molecular subtype of non-small cell lung cancer (NSCLC), occurring in approximately 2% of cases and frequently associated with younger age, non-smoker status, and a high incidence of brain metastases. The discovery of ROS1 as an oncogenic driver has led to the development of targeted tyrosine kinase inhibitors (TKIs). Crizotinib first demonstrated substantial clinical benefit, but its limitations, including poor central nervous system (CNS) penetration and acquired resistance, highlighted the need for next-generation inhibitors. Several agents have since been developed, including entrectinib, lorlatinib, repotrectinib, taletrectinib, and zidesamtinib, each offering improved intracranial (IC) activity and efficacy against resistance mutations, notably ROS1^G2032R. Despite these advances, optimal sequencing strategies remain undefined, and resistance ultimately emerges in most patients. This review provides an updated overview of ROS1 biology, diagnostic approaches, clinical outcomes with currently available TKIs, mechanisms of resistance, and ongoing challenges, emphasizing the rapidly evolving therapeutic landscape.
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ISSN:1718-7729
1198-0052
1718-7729
DOI:10.3390/curroncol32110626