Optimizing Osimertinib for NSCLC: Targeting Resistance and Exploring Combination Therapeutics

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.

Keywords: combination therapy; non-small-cell lung cancer; osimertinib resistance.

Figure 1

Key mechanisms of off-target resistance to osimertinib in NSCLC. Resistance arises from both on-target mechanisms involving EGFR and off-target pathways. Off-target resistance is driven by alternative signaling pathways such as MAPK (RAS-RAF-MEK-ERK) and PI3K/AKT/mTOR, activated by EGFR mutations, HER2 amplification, HER3 upregulation, MET amplification, AXL overexpression, abnormalities in other receptor tyrosine kinases (RTKs, such as FGFR1, IGF1R), BCL-2 dysregulation, cell cycle alterations (CDK4/6), histologic transformation, and epithelial-to-mesenchymal transition (EMT). Together, these mechanisms promote tumor survival, proliferation, and metastasis and reduce the efficacy of osimertinib. This figure was created using BioRender (https://BioRender.com, accessed on 20 January 2025) under a paid license.