Lung cancer remains one of the leading causes of cancer-related deaths worldwide. Among its types, non-small cell lung cancer (NSCLC) constitutes approximately 85%, posing significant challenges for patients and healthcare professionals, especially due to its late-stage diagnosis and complex treatment processes. However, the last decade has witnessed transformative advancements in molecular biology and drug development, changing the grim outlook of lung cancer treatment. Central to this transformation has been the role of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).
EGFR-TKIs have emerged as a beacon of hope, especially for patients with NSCLC harboring EGFR mutations. Among these, osimertinib, a third-generation EGFR-TKI, has gained prominence by targeting the EGFR’s T790M mutation, offering effective treatment options. Initially approved for patients with EGFR T790M mutations, osimertinib has now become the dominant first-line targeted therapy for the majority of EGFR mutant lung cancers.
The effectiveness of osimertinib in both first and second-line treatments is noteworthy. However, the emergence of resistance during treatment poses significant limitations to its long-term efficacy. Studies have shown that NSCLC patients typically develop resistance to osimertinib within an average of 19 months in first-line treatment and 11 months in second-line treatment. The mechanisms of resistance are complex and multifaceted, involving both EGFR-dependent and independent pathways.
Understanding and overcoming these resistance mechanisms present substantial challenges for both basic and clinical researchers. The C797S mutation in EGFR’s exon 20 is one of the most commonly known mutations leading to resistance against osimertinib treatment. Additionally, other mutations in exon 20 are also linked to resistance. The loss of the T790M mutation, a consequence of continuous use of third-generation EGFR-TKIs, also contributes to osimertinib resistance. Moreover, mutations in the L718 and G719 regions of EGFR’s exon 18 can also lead to resistance against osimertinib.
To overcome these resistance mechanisms, new treatment strategies are being developed, including the exploration of fourth-generation TKIs. Brigatinib, a fourth-generation TKI developed to overcome the C797S mutation, has shown promising therapeutic effects in NSCLC patients with this mutation.
Large-scale clinical trials, like the ORCHARD trial, are necessary to evaluate the effectiveness of various treatment options against these resistance mechanisms. Current treatment modalities also include chemotherapy and immunotherapy. Notably, immunotherapy agents like PD-1 and PD-L1 have opened new horizons in the treatment of EGFR mutation-driven NSCLC. Additionally, chimeric antigen receptor T cell (CAR-T) immunotherapy has emerged as a novel idea in NSCLC treatment, although its efficacy in patients with EGFR mutations needs further research and case studies.
As osimertinib continues to play a central role in the treatment of NSCLC with EGFR mutations, understanding resistance mechanisms and developing corresponding strategies is of utmost importance. Progress in this field continues to offer new hopes and opportunities in lung cancer treatment.
Reference
Li, Yufeng, et al. “Toward the next generation EGFR inhibitors: an overview of osimertinib resistance mediated by EGFR mutations in non-small cell lung cancer.” Cell Communication and Signaling 21.1 (2023): 71
