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Combatting acquired resistance to osimertinib in EGFR-mutant lung cancer
Jiyun Lee1, Zofia Piotrowska2, Ross Soo3
1Lung cancer Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
Abstract:
The discovery of activating mutations in epidermal growth factor receptor (EGFR) in non-small-cell lung cancer transformed the care and prognosis of patients and heralded the era of 'personalized medicine' in thoracic oncology. Osimertinib, a third-generation EGFR inhibitor, has been established as the preferred EGFR inhibitor for newly diagnosed patients which urged the need to develop treatment options for patients progressing on first-line osimertinib. However, acquired resistance invariably emerges and numerous efforts have been attempted to delay or overcome acquired resistance. In this article, we thoroughly reviewed the current understanding of osimertinib resistance mechanisms and explored the established and emerging treatment options. Newer treatment strategies targeting EGFR-dependent or -independent resistance mechanisms, novel approaches using bispecific antibodies and antibody-drug conjugates will be discussed. Moreover, what to do with brain only progression, and how to incorporate immunotherapy in EGFR-mutant lung cancer will be discussed. Lastly, future perspectives on the ongoing clinical trials and combination of front-line therapy will be introduced.
Insights
Acquired resistance to osimertinib, a targeted therapy for EGFR-mutant non-small-cell lung cancer, necessitates new treatment strategies. This review explores resistance mechanisms and emerging therapies, including bispecific antibodies and immunotherapy, to improve patient outcomes.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Activating mutations in epidermal growth factor receptor (EGFR) drive non-small-cell lung cancer (NSCLC) and personalized medicine.
- Osimertinib, a third-generation EGFR inhibitor, is a preferred first-line treatment for EGFR-mutant NSCLC.
- Acquired resistance to osimertinib is a significant clinical challenge, necessitating the development of alternative treatment options.
Purpose of the Study:
- To review current understanding of osimertinib resistance mechanisms in NSCLC.
- To explore established and emerging treatment strategies for patients progressing on first-line osimertinib.
- To discuss novel approaches, including bispecific antibodies, antibody-drug conjugates, immunotherapy, and management of brain metastases.
Main Methods:
- Comprehensive literature review of osimertinib resistance mechanisms.
- Analysis of current and emerging treatment strategies for EGFR-mutant NSCLC.
- Discussion of clinical trials and future perspectives in combination therapies.
Main Results:
- Multiple EGFR-dependent and -independent mechanisms contribute to osimertinib resistance.
- Emerging strategies include targeting resistance pathways, novel antibody-based therapies, and immunotherapy integration.
- Management of specific scenarios like isolated brain progression requires tailored approaches.
Conclusions:
- Understanding resistance mechanisms is crucial for developing effective treatment strategies.
- Combination therapies and novel agents show promise in overcoming osimertinib resistance.
- Future research and clinical trials are essential to optimize treatment for EGFR-mutant NSCLC.
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