Perioperative Therapy in Oncogene-Driven Non-Small Cell Lung Cancer: Current Strategies and Unanswered Questions

Perioperative therapy has become a critical component in the management of resectable non-small cell lung cancer (NSCLC), particularly in the era of precision medicine. Although molecular testing is standard in metastatic NSCLC, its incorporation into early-stage disease remains essential for guiding treatment decisions. Reflex molecular testing pathways are necessary to optimize tissue utilization and ensure timely results. However, liquid biopsies, although valuable in advanced disease, have limited sensitivity in early-stage NSCLC, reinforcing the need for tissue-based next-generation sequencing. Targeted therapies have revolutionized treatment for oncogene-driven NSCLC, with adjuvant osimertinib now standard for EGFR-mutant disease and ongoing investigations into ALK tyrosine kinase inhibitors (TKIs). However, unanswered questions remain regarding the inclusion of perioperative TKI therapy, the role of molecular residual disease assessment, and whether specific TKIs offer greater benefit for high-risk subgroups. The role of immunotherapy (IO) in oncogene-driven NSCLC remains controversial. Although perioperative chemo-IO has demonstrated survival benefits in unselected NSCLC, its efficacy in EGFR, ALK, and other actionable alterations is unclear. Tumors harboring KRAS and BRAF mutations may respond better because of a more immune-inflamed microenvironment, and remains an active area of investigation. As the landscape of perioperative therapy continues to evolve, ongoing trials will help define the optimal integration of targeted therapies and IO in oncogene-driven NSCLC. Addressing these unanswered questions will be crucial in refining treatment strategies and improving patient outcomes.