Evaluating taletrectinib in the treatment of patients with ROS1 fusion-positive non-small cell lung cancer.

ROS1 fusion-positive non-small cell lung cancer (NSCLC), occurring in 1-2% of patients, represents a rare but clinically important subset. Patients with ROS1 fusion-positive NSCLC are often younger and tend to have little or no history of smoking. Current first-generation tyrosine kinase inhibitors (TKIs) such as crizotinib and entrectinib provide meaningful benefit but are limited by poor central nervous system (CNS) penetration and the development of resistance mutations, particularly G2032R. To overcome the challenges of first‑generation ROS1 inhibitors, next‑generation ROS1 inhibitors have been developed. Repotrectinib was evaluated earlier, and taletrectinib followed. Both are considered next‑generation ROS1 inhibitors with excellent CNS penetration and the ability to tackle resistance mutations such as G2032R, and they have been FDA approved. While both drugs, repotrectinib and taletrectinib, provide impressive results regarding overall and intracranial efficacy, as well as responses seen even in the presence of the resistant G2032R mutation, their toxicity profiles appear different. Repotrectinib appears to have a higher incidence of neurological toxicities, whereas taletrectinib has a higher incidence of gastrointestinal toxicities. Zidesamtinib has recently been approved in the pre-treated population, and taletrectinib is also being evaluated in the adjuvant setting.