Targeting ROS1 rearrangements in non–small cell lung cancer: Current insights and future directions Review
| Authors: | Desilets, A.; Repetto, M.; Yang, S. R.; Drilon, A. |
| Review Title: | Targeting ROS1 rearrangements in non–small cell lung cancer: Current insights and future directions |
| Abstract: | ROS1 rearrangements define a molecular subset of non–small cell lung cancer (NSCLC) by accounting for 1%–2% of cases. Targeted therapy with ROS1 tyrosine kinase inhibitors (TKIs) has significantly improved the outcomes for these patients. First-generation inhibitors, such as crizotinib and entrectinib, have demonstrated impressive efficacy, with objective response rates exceeding 60%–70%. However, the emergence of resistance mechanisms, including solvent-front mutations such as ROS1 G2032R, and limited blood–brain barrier penetration have limited the long-term efficacy of early-generation agents. Next-generation TKIs, including lorlatinib, taletrectinib, and repotrectinib, have been developed to overcome these challenges. These agents show enhanced central nervous system (CNS) penetration and activity against on-target ROS1 resistance mutations. Repotrectinib, a potent, CNS-penetrant ROS1 inhibitor, has demonstrated superior activity in both TKI-naive and -resistant tumors, including those harboring the G2032R mutation. Zidesamtinib, a highly selective next-generation ROS1 inhibitor, further addresses TRK-mediated off-target neurological toxicities seen with prior agents, and is poised to offer improved tolerability. Ongoing research is focused on optimizing sequencing strategies for ROS1 inhibitors and exploring combination approaches to prevent or overcome resistance. In addition, the development of novel diagnostic tools, including RNA-based next-generation sequencing, has enhanced the detection of functional ROS1 fusions by ensuring that patients with actionable mutations receive appropriate targeted therapies. These advances highlight the evolving landscape of treatment for ROS1-positive NSCLC, with the aim of maximizing long-term survival and quality of life. © 2025 American Cancer Society. |
| Keywords: | genetics; mutation; proto-oncogene proteins; review; neurotoxicity; protein kinase inhibitor; carcinoma, non-small-cell lung; lung neoplasms; drug resistance; drug resistance, neoplasm; protein tyrosine kinase; pyrimidines; protein kinase inhibitors; lung tumor; gene rearrangement; diagnosis; blood brain barrier; targeted therapy; protein-tyrosine kinases; phase 1 clinical trial; drug therapy; tyrosine kinase inhibitor; pyrimidine derivative; non small cell lung cancer; molecularly targeted therapy; benzamide derivative; benzamides; indazoles; molecular targeted therapy; procedures; crizotinib; long term survival; high throughput sequencing; humans; human; entrectinib; non–small cell lung cancer; lorlatinib; ros1 fusion; repotrectinib; ros1 protein, human; indazole derivative; proto oncogene protein; taletrectinib; zidesamtinib |
| Journal Title: | Cancer |
| Volume: | 131 |
| Issue: | Suppl. 1 |
| ISSN: | 0008-543X |
| Publisher: | Wiley Blackwell |
| Date Published: | 2025-03-15 |
| Start Page: | e35784 |
| Language: | English |
| DOI: | 10.1002/cncr.35784 |
| PUBMED: | 40171848 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Review -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Alexander Drilon -- Source: Scopus |
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