Next-generation tyrosine kinase inhibitors (TKIs) may be reshaping treatment for non–small cell lung cancer (NSCLC) with oncogenic driver alterations. Dr. Alexander Drilon, chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York, emphasizes that choosing and sequencing them now demands more strategy than ever. His framework for frontline selection across ALK, ROS1, RET, NTRK, and NRG1 fusions centers on three things: depth and durability of response, resistance mutation coverage, and tolerability. For ALK-positive disease, lorlatinib often emerges as a preferred option based on strong efficacy and central nervous system (CNS) activity, but its neurocognitive side effects mean alectinib or brigatinib may be better for some patients. In ROS1-, RET-, and NTRK-positive NSCLC, second- and later-generation TKIs are increasingly important, with taletrectinib, repotrectinib, selpercatinib, and larotrectinib commonly highlighted, while zenocutuzumab represents a distinct, antibody-based approach for NRG1 fusions.
After progression on a TKI, Drilon stresses the importance of re-biopsy—tumor and/or liquid—when feasible to distinguish on-target from off-target resistance and guide next steps. When resistance remains target-driven and a more advanced TKI generation exists, these newer agents may offer broader resistance coverage and improved CNS penetration. If no suitable TKI or trial is available, platinum-based chemotherapy remains appropriate. Across targets, understanding the specific resistance mutation is critical, because some alterations respond well to particular TKIs, while others confer broad resistance and necessitate pivoting away from targeted therapy altogether. Toxicity profiles—especially neurologic adverse events with some ROS1 and TRK inhibitors—can be as influential as efficacy in real-world decision-making, underscoring the need to match each drug not only to tumor biology, but also to the individual patient’s tolerability and quality of life.
Reference: Flaherty C. Newer Generations, Resistance Profiling, and Toxicity Trade-offs Guide Modern TKI Selection/Use in Oncogene-Driven NSCLC. OncLive. Published November 18, 2025. Accessed December 1, 2025. https://www.onclive.com/view/newer-generations-resistance-profiling-and-toxicity-trade-offs-guide-modern-tki-selection-use-in-oncogene-driven-nsclc
