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.

Keywords: ROS1 fusion; non–small cell lung cancer; targeted therapy; tyrosine kinase inhibitor.

Figure 1:

Circos plot of ROS1 fusion partners observed in patients with non–small cell lung cancer obtained from the cBioPortal publicdata set. The thickness of the joining line is directly proportional to the frequency of the specific fusion plotted in a patient cohort obtained bypooling together multiple studies (Memorial Sloan Kettering–Metastatic Events and Tropisms, China Pan-Cancer, and The Cancer GenomeAtlas Pan-Cancer Atlas). Red joining segments denote intrachromosomal fusions. Blue joining segments denote interchromosomal fusions.

Figure 2:

Objective response rate (y-axis) and median progression-free survival (x-axis) across tyrosine kinase inhibitor–naive patientstreated with ROS1 TKIs. The diameter of the bubble is directly proportional to the number of patients evaluated for activity in the respectiveclinical trial. The color of the bubble is dependent on the subclass of ROS1 TKI. NSCLC indicates non–small cell lung cancer; TKI, tyrosinekinase inhibitor.

Figure 3:

(A) Structural models of crizotinib (purple), entrectinib (yellow), lorlatinib (orange), and repotrectinib (cyan) in complex withwild-type ROS1. (B) Effect of ROS1 L2086 (highlighted in red). (C) Effect of ROS1 G2032R (highlighted in red). (D) Effect of ROS1 D2033N(highlighted in red)