Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related deaths globally. The high incidence and mortality rates underscore the urgent need for effective therapies. Significant advancements in molecular biology have revolutionized NSCLC treatment, shifting the paradigm towards precision medicine. The current therapeutic landscape is complex, demanding a detailed molecular characterization of each tumor to guide treatment decisions. Approximately 15-20% of newly diagnosed NSCLC patients harbor an actionable oncogenic driver, necessitating targeted therapies. Even in patients without actionable drivers, who are typically treated with immune checkpoint inhibitors (ICIs) or combinations with chemotherapy, molecular profiling remains crucial. Major oncogenic drivers like EGFR and ALK are associated with poor ICI responses, highlighting the importance of identifying these alterations. Furthermore, research is increasingly focusing on mutations like KEAP1 or STK11, which, while not considered drivers, may impact ICI efficacy. The role of molecular characterization is expanding beyond advanced-stage NSCLC, with clinical trials exploring targeted therapies in localized disease, exemplified by the ADAURA study demonstrating the benefit of adjuvant osimertinib. This complex landscape necessitates continuous updates to therapeutic algorithms and requires a multidisciplinary approach.

The editorial cites numerous studies supporting the need for precision medicine in NSCLC. Several papers focus on next-generation sequencing (NGS) and its application in identifying various oncogenic drivers and other relevant mutations. Studies examining the role of immune checkpoint inhibitors in patients with or without oncogenic drivers are also reviewed, emphasizing the importance of biomarker-driven treatment strategies. Furthermore, the literature review includes studies exploring emerging targets, resistance mechanisms to targeted therapies, the use of liquid biopsy, and the applications of artificial intelligence in NSCLC diagnostics and treatment.

This editorial does not present original research with a specific methodology. Instead, it synthesizes existing literature and expert knowledge to provide an overview of the current state and future directions of personalized therapy in NSCLC. The author's approach relies on a comprehensive review of relevant publications in the field, including clinical trials, systematic reviews, and other scientific articles to support the presented arguments and recommendations.

Key findings summarized from the referenced literature highlight the following: 1) The rapid and continuous improvement of molecular alteration detection technologies, including improved sensitivity in identifying both known and novel mutations. 2) The increasing availability of targeted therapies, although with variations in regulatory approval across different agencies. 3) The challenges faced by pathologists and medical oncologists in keeping up with these advancements and managing patients with uncommon molecular alterations for which limited data exist. 4) The emerging role of molecular tumor boards in optimizing the management of patients with complex molecular profiles. 5) The importance of understanding and addressing resistance mechanisms to targeted therapies, including the potential of liquid biopsy for repeated molecular characterization to monitor disease progression and identify new actionable mutations. 6) The promising applications of artificial intelligence (AI) in digital pathology and radiomics for aiding in histomolecular diagnosis and predicting molecular profiles. 7) The limitations of liquid biopsy compared to traditional biopsy, specifically in histotype diagnosis and detection of morphological shifts. The editorial stresses that despite the progress, there is significant potential for future improvements.

The editorial emphasizes that while precision medicine has significantly advanced NSCLC treatment, substantial room for improvement remains. The ongoing research into emerging molecular alterations and the development of novel therapies to target oncogenic drivers are crucial for improving patient outcomes. The discussion highlights the interdisciplinary nature of this field, requiring collaboration between pathologists, molecular biologists, medical oncologists, and other specialists. The need for continuous training and updates in laboratory tools and clinical decision-making is underscored. The integration of AI and liquid biopsy holds great promise in improving diagnostic accuracy and monitoring treatment response. The editorial concludes that continued research efforts and collaborations will be essential in further personalizing NSCLC therapies.

The rapid advancements in molecular oncology and precision medicine have dramatically improved survival rates for NSCLC patients. However, significant challenges remain, particularly in managing uncommon molecular alterations and developing strategies to overcome treatment resistance. Future research should focus on identifying novel biomarkers, developing targeted therapies against these emerging targets, and refining the use of liquid biopsy and AI to optimize patient care.

The editorial's primary limitation is its inherent nature as a review article—it does not present original data but rather synthesizes existing knowledge. The author's perspective may be influenced by their experience and expertise. Also, the focus is primarily on advancements in the Western context, with potential limitations in generalizability to settings with varying access to resources and technologies.