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Optimizing Osimertinib for NSCLC: Targeting Resistance and Exploring Combination Therapeutics
1
Department of Medicine, National Taiwan University College of Medicine, Taipei 100233, Taiwan
2
Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei 100233, Taiwan
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(3), 459; https://doi.org/10.3390/cancers17030459
Submission received: 25 December 2024
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Revised: 24 January 2025
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Accepted: 27 January 2025
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Published: 29 January 2025
(This article belongs to the Special Issue Targeted Therapies for EGFR in Non-Small Cell Lung Cancer)
Simple Summary
Osimertinib has revolutionized EGFR-mutant NSCLC therapy by specifically targeting the T790M mutation, yet acquired resistance remains inevitable. Mechanisms include tertiary EGFR mutations such as C797S, bypass pathway activation (MET, HER2, HER3), and histologic transformations. Emerging combination strategies that integrate osimertinib with chemotherapy, angiogenesis inhibitors, MET-targeting agents, immunotherapies, and other molecularly tailored drugs show the potential to circumvent resistance and prolong clinical benefits. Real-time molecular monitoring, including liquid biopsy and single-cell analyses, is crucial for the early detection of resistant clones and guiding therapeutic adjustments. While ongoing clinical trials will clarify optimal combinations and sequencing, a personalized approach that incorporates biomarker-driven patient selection and adaptive treatment paradigms remains essential. By harnessing diverse strategies against parallel signaling pathways and immune evasion, these regimens aim to extend survival and preserve quality of life. Continued collaboration among researchers, clinicians, and patients will accelerate the translation of these advances into practice.
Abstract
Non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, with epidermal growth factor receptor (EGFR) mutations present in a substantial proportion of patients. Third-generation EGFR tyrosine kinase inhibitors (EGFR TKI), exemplified by osimertinib, have dramatically improved outcomes by effectively targeting the T790M mutation—a primary driver of acquired resistance to earlier-generation EGFR TKI. Despite these successes, resistance to third-generation EGFR TKIs inevitably emerges. Mechanisms include on-target mutations such as C797S, activation of alternative pathways like MET amplification, histologic transformations, and intricate tumor microenvironment (TME) alterations. These resistance pathways are compounded by challenges in tolerability, adverse events, and tumor heterogeneity. In light of these hurdles, this review examines the evolving landscape of combination therapies designed to enhance or prolong the effectiveness of third-generation EGFR TKIs. We explore key strategies that pair osimertinib with radiotherapy, anti-angiogenic agents, immune checkpoint inhibitors, and other molecularly targeted drugs, and we discuss the biological rationale, preclinical evidence, and clinical trial data supporting these approaches. Emphasis is placed on how these combinations may circumvent diverse resistance mechanisms, improve survival, and maintain a favorable safety profile. By integrating the latest findings, this review aims to guide clinicians and researchers toward more individualized and durable treatment options, ultimately enhancing both survival and quality of life for patients with EGFR-mutated NSCLC.
