Expanding therapeutic options for non-small cell lung cancer, especially for ROS1-positive and ALK-positive subtypes, have recently been investigated. The novel agent zidesamtinib exhibited durable efficacy in ROS1 TKI-pretreated NSCLC patients, including those with CNS involvement and resistant ROS1 G2032R mutations. Conversely, the Phase 3 E4512 trial found that crizotinib did not improve disease-free survival when used as adjuvant therapy for early-stage ALK-positive NSCLC. These findings refine therapeutic strategies for molecularly defined subsets of lung cancer, highlighting advances and limitations in targeted treatments.