Non-Small Cell Lung Cancer — Year in Review Series on Relevant New Datasets and Advances in Therapeutic Targets Beyond EGFR

Targeted therapies for non-small cell lung cancer (NSCLC) have evolved significantly, shifting from early-generation inhibitors to highly potent, selective agents with superior progression-free survival (PFS). The discussion highlights the distinction between kinase mutations and gene fusions, noting that fusions often allow for more potent inhibition with fewer off-target toxicities. Key advancements include the use of Zongertinib for HER2-mutant NSCLC, which offers improved tolerability over earlier TKIs, and the emergence of next-generation KRAS G12C inhibitors that show high response rates when combined with immunotherapy. Furthermore, long-term data from the CROWN study demonstrates that Lorlatinib achieves a median PFS exceeding seven years in ALK-positive disease, fundamentally changing the natural history of the condition. Experts emphasize the importance of early detection of toxicities, such as interstitial lung disease with ADCs and chylous effusions with RET inhibitors, to optimize patient outcomes.