Assessing Frontline TKIs and Treatment Considerations in ROS1-Positive Advanced NSCLC

ROS1-Positive NSCLC Treatment Evolution

ROS1 fusions occur in approximately 1% of patients with non–small cell lung cancer (NSCLC), typically in younger, never-smoking individuals, representing another successful targeted therapy paradigm. The evolution from crizotinib to entrectinib addressed the critical limitation of central nervous system (CNS) activity, though overall progression-free survival improvements remained modest. Crizotinib provided excellent systemic control with some patients maintaining responses for 4 to 5 years, but CNS progression remained problematic due to poor brain penetration.

Repotrectinib represents the next-generation ROS1 inhibitor, designed to target acquired resistance mutations including the common G2032R alteration. The TRIDENT-1 study demonstrated impressive first-line efficacy with 35.7-month median progression-free survival, nearly 3 years of disease control that significantly exceeds historical data from crizotinib and entrectinib. This substantial improvement establishes repotrectinib as a preferred first-line option for ROS1-positive patients.

However, repotrectinib's efficacy comes with increased toxicity, particularly dizziness occurring in approximately two-thirds of patients. This dose-limiting toxicity can significantly impact quality of life, though dose reductions often provide relief. The risk-benefit assessment favors using repotrectinib first-line given the impressive progression-free survival benefit, with careful monitoring and proactive toxicity management strategies essential for optimal outcomes.