Precision oncology has changed the management of advanced non-small-cell lung cancer (NSCLC). Biomarker-matched therapies now improve outcomes in an increasing number of molecularly defined subgroups. In this second paper in a Series on therapeutics in lung cancer, we summarise recent advances in NSCLC with established alterations, including EGFR, ALK, ROS1, KRAS, BRAF, RET, HER2, MET, and NTRK, and discuss emerging targets, such as NRG1 fusions, MTAP loss, and SMARCA4 deficiency. Newer generations of tyrosine kinase inhibitors, the introduction of bispecific antibodies, and antibody-drug conjugates have improved response durability, intracranial disease control, and in some settings, overall survival. However, durable benefit can remain limited by acquired resistance, tumour heterogeneity, lineage plasticity, and off-target escape, supporting repeat tissue biopsy and circulating-tumour DNA profiling to guide subsequent treatment. With several options available such as monotherapy and combination approaches, individualised treatment selection is becoming increasingly complex. We discuss these choices, including the management of CNS disease and oligoprogression, and long-term tolerability. As drug development extends beyond canonical drivers to rarer alterations and adverse co-mutations, the range of targetable disease is increasing. Further progress will depend on more effective and adaptive treatment strategies together with equitable access to comprehensive molecular profiling, timely biomarker testing, and next-generation targeted therapies.
L. Hendriks, Jessica J. Lin, D. S. Tan et al.· The Lancet Respiratory Medic...· 2 citations
Brain metastases (BM) are a common and clinically significant complication of non-small cell lung cancer (NSCLC), representing a major contributor to its high mortality. Among all metastatic sites, involvement of the central nervous system (CNS) is associated with a particularly profound deterioration in patients' quality of life. The incidence of BM varies considerably across different histological subtypes and molecularly defined groups of NSCLC. The development of BM is a multistep process involving primary tumor invasion, hematogenous dissemination, blood-brain barrier (BBB) transmigration, and successful colonization of the brain. This process is strongly shaped by reciprocal interactions between the tumor cells and the unique brain tumor microenvironment (TME). Brain endothelial cells, pericytes, astrocytes, microglia, neurons, and recruited peripheral immune and stromal cells collectively regulate BBB permeability, immune evasion, extracellular matrix remodeling, and metastatic outgrowth. Compared with primary lung tumors, BM displays a distinct immune landscape characterized by reduced lymphocyte infiltration, enrichment of immunosuppressive myeloid populations, impaired antigen presentation, and extensive crosstalk with CNS-resident cells. These features contribute to therapeutic resistance and help explain the heterogeneous intracranial efficacy of systemic treatments. While immune checkpoint inhibitors and chemotherapy combinations provide benefit in selected patients, the most pronounced intracranial responses are observed with CNS-penetrant targeted therapies in molecularly defined subsets. Emerging strategies aim to directly target the metastatic niche, including myeloid cells, tumor vasculature, immune checkpoints, and cellular immunotherapies. A deeper understanding of the brain metastatic ecosystem may enable the development of more effective, biology-driven therapeutic approaches for NSCLC BM.
Marcel Kemper, Lea Reitnauer, A. Leonetti et al.· Cancer Biome and Targeted Th...· 0 citations
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