Update 2025: Management of Non‑Small-Cell Lung Cancer

Abstract

Lung cancer remains the leading cause of cancer-related mortality worldwide. Since 2024, the non-small-cell lung cancer (NSCLC) landscape has undergone a transformative shift, driven by 11 FDA approvals. Recent advances in molecular profiling, targeted therapies, and immunotherapies have revolutionized NSCLC management, ushering in an era of personalized treatment with improved patient outcomes. The increased adoption of low-dose computed tomography (LDCT) for screening has enhanced early detection, enabling intervention at more curable stages. Molecular diagnostics now play a pivotal role in guiding treatment strategies, with actionable genomic alterations (AGAs) informing the use of EGFR, ALK, ROS1, KRAS, NRG1, and other targeted inhibitors in both early and advanced settings. For instance, targeted therapies are increasingly being integrated into early-stage management, with adjuvant osimertinib for EGFR-mutated NSCLC and alectinib for ALK-positive NSCLC demonstrating substantial survival benefits. Immunotherapy, particularly immune checkpoint inhibitors, has become a cornerstone of treatment for AGA-negative NSCLC, either as monotherapy or in combination with chemotherapy, and is increasingly being utilized in the perioperative setting. Furthermore, emerging therapies such as bispecific antibodies, antibody-drug conjugates (ADCs), and novel immunotherapeutic agents show promise in addressing resistance mechanisms and improving outcomes in advanced-stage disease. Although new challenges arise, the evolving NSCLC treatment paradigm continues to prioritize precision medicine, offering hope for prolonged survival and enhanced quality of life for patients.

Keywords: Actionable Genomic Alterations; Immunotherapy; Lung Cancer Management; NSCLC; Targeted Therapy.

Fig. 1

Simplified schematic of initial management of NSCLC. AGA actionable genomic alterations, CIO chemoimmunotherapy, CT chemotherapy, IO immunotherapy, NSCLC non-small-cell lung cancer