The Long Run towards Personalized Therapy in Non-Small-Cell Lung Cancer: Current State and Future Directions

This editorial addresses the evolving landscape of personalized therapy in non-small-cell lung cancer (NSCLC), emphasizing how advances in molecular biology and precision medicine have reshaped clinical management. NSCLC remains the leading cause of cancer-related deaths worldwide, and effective treatment increasingly depends on the tumor’s molecular profile. Approximately 15–20% of newly diagnosed NSCLC patients harbor actionable oncogenic drivers, necessitating comprehensive molecular testing to guide targeted therapies. For patients without known drivers, immune checkpoint inhibitors (alone or with chemotherapy) are standard; however, molecular characterization remains important due to variable immunotherapy responsiveness and the influence of certain mutations. The piece outlines current practice, emerging technologies (liquid biopsy, AI), and strategic frameworks (molecular tumor boards) that enable personalized care, and highlights future directions including resistance profiling and expansion of targeted therapies into earlier disease stages.

The editorial synthesizes key literature illustrating: (1) the rapid expansion of next-generation sequencing (NGS) for detecting established and uncommon actionable alterations in NSCLC; (2) evidence that major oncogenic drivers (e.g., EGFR, ALK) correlate with poor response to immune checkpoint inhibitors, underscoring the need for accurate upfront genotyping; (3) the growing relevance of mutations such as KEAP1 and STK11 and tumor microenvironment features as modulators of immunotherapy efficacy; (4) extension of targeted therapy into localized disease, exemplified by the ADAURA trial showing improved outcomes with adjuvant osimertinib; (5) the role and structure of molecular tumor boards in navigating complex and rare molecular findings; (6) the importance of elucidating acquired resistance mechanisms (e.g., MET alterations after EGFR inhibitors) to inform next-line strategies; (7) the maturation of liquid biopsy for serial, minimally invasive, longitudinal monitoring, while acknowledging current constraints relative to tissue assessment (e.g., histologic transformation detection); and (8) emerging applications of artificial intelligence in digital pathology and radiomics for predicting histomolecular features, including EGFR mutation status from imaging.

- Molecular profiling is central to NSCLC care: around 15–20% of newly diagnosed patients harbor actionable drivers that guide targeted therapy. - Patients with major oncogenic drivers (e.g., EGFR, ALK) generally have poor responses to immune checkpoint inhibitors, making precise identification crucial to avoid suboptimal outcomes. - Additional alterations (e.g., KEAP1, STK11) and tumor microenvironment factors may affect immunotherapy efficacy and are under active investigation with potential clinical relevance. - Targeted therapy is moving into earlier-stage disease; the ADAURA study demonstrated improved outcomes with adjuvant osimertinib in EGFR-mutant resected NSCLC. - Continuous improvements in detection technologies (broader, more sensitive NGS) reveal uncommon mutations and novel targets, but availability of matching therapies varies by regulatory region. - Molecular tumor boards can help interpret complex profiles, prioritize therapies, and manage access to treatments, especially for uncommon alterations. - Understanding and identifying resistance mechanisms to targeted therapies are essential for guiding subsequent treatments (e.g., MET-mediated resistance after EGFR inhibition) and for designing prevention strategies. - Liquid biopsy enables noninvasive, repeatable, longitudinal molecular monitoring and may better capture tumor heterogeneity than single-site tissue biopsy, but cannot replace histology for tasks like histotype diagnosis or detecting morphologic transformation (e.g., small-cell transformation). - AI-driven digital pathology and radiomics can extract subvisual features from slides and imaging to predict molecular profiles, potentially streamlining personalized care once validated and integrated into practice.

The editorial articulates how comprehensive molecular characterization, alongside evolving technologies, directly advances the goal of personalized NSCLC therapy. By aligning treatment to specific oncogenic drivers and resistance mechanisms, patient outcomes improve compared with non-stratified approaches. It emphasizes that precision in identifying actionable alterations avoids ineffective immunotherapy exposures in driver-positive tumors and supports timely deployment of targeted agents. The discussion highlights the clinical significance of integrating liquid biopsy for ongoing disease monitoring and recharacterization at progression, addressing both tumor heterogeneity and patient convenience. Moreover, the piece situates AI as an enabling tool to augment histomolecular prediction from routine pathology and imaging, potentially expediting and broadening access to precision care. Organizational innovations like molecular tumor boards are presented as critical to translating complex genomic data into practical decisions, particularly in the face of regulatory and access heterogeneity.

Precision oncology has transformed NSCLC management, yielding notable survival gains through molecularly guided therapies. Despite this progress, substantial opportunities remain: expanding the catalog of clinically actionable alterations, refining strategies to prevent and treat acquired resistance, extending targeted and immunomodulatory approaches into earlier stages, and operationalizing scalable tools such as liquid biopsy and AI. Continued multidisciplinary collaboration, infrastructure development (including molecular tumor boards), and equitable drug access will be key to fully realizing personalized therapy in NSCLC.

As an editorial, this work does not present original data or a systematic methodology. The author notes practical constraints that affect generalizability and implementation: variability in therapy availability across regulatory jurisdictions; limited evidence for uncommon mutations and novel targets; the need for continual upgrades and training in molecular diagnostics; challenges of re-biopsy at progression; and current limitations of liquid biopsy, which cannot replace histology for diagnostic classification or detection of morphologic transformation.