Selecting and Optimizing Therapy in ROS1+ NSCLC

Treatment decisions for ROS1-positive non-small cell lung cancer (NSCLC) are increasingly personalized, taking into account factors like central nervous system (CNS) involvement, resistance mutations, and prior treatments. Targeted therapies with strong CNS penetration, such as talotrectinib and repotrectinib, are preferred due to their ability to manage both systemic and intracranial disease. Resistance mutations, particularly G2032R, can emerge after earlier lines of therapy. Both of the newer agents mentioned have shown efficacy in this setting, with talotrectinib reporting over 60% response rates in patients with G2032R. Even in cases without detectable mutations, these next-generation TKIs remain viable second-line options.

The current standard of care for advanced ROS1-positive NSCLC is the use of a ROS1 tyrosine kinase inhibitor (TKI), ideally in the first-line setting. Recently approved agents like talotrectinib are now included in the latest guidelines due to their high response rates, strong progression-free survival data, and CNS activity. While earlier agents such as crizotinib and entrectinib are still used and can be effective, the newer options offer enhanced efficacy and resistance coverage. When choosing among these drugs, clinicians consider performance status, CNS involvement, and the potential for resistance mechanisms. Comparative efficacy and safety data often favor talotrectinib in treatment-naive patients.

For patients who experience acquired resistance to ROS1-targeted therapy, several strategies are available. If resistance mutations such as G2032R are identified, switching to a next-generation inhibitor like talotrectinib or repotrectinib is appropriate. Even in cases where no clear resistance mechanism is found, these drugs may still provide clinical benefit. Chemotherapy, particularly platinum combined with pemetrexed, is another effective option, especially in later lines of treatment. Immune checkpoint inhibitors are not recommended due to limited efficacy and potential for toxicity following targeted therapy. Clinical trials investigating additional ROS1-directed therapies also remain an important avenue for eligible patients.