Second-line treatment of EGFR T790M-negative non-small cell lung cancer patients
Bin-Chi Liao1, Sebastian Griesing1, James Chih-Hsin Yang2
1Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan, Republic of China.
Abstract:
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the currently recommended treatment for advanced EGFR mutation-positive non-small cell lung cancer (NSCLC). Acquired resistance inevitably develops, with the EGFR T790M mutation comprising approximately 55% of the mechanisms of resistance following first- or second-generation EGFR-TKI therapy (e.g. gefitinib, erlotinib, afatinib, and dacomitinib). Patients without T790M are a heterogeneous group for whom platinum-based chemotherapy is currently recommended as a second-line treatment. In addition to secondary mutations in EGFR (e.g. T790M), the currently known resistance mechanisms can be classified into the following three categories: bypass pathways, downstream signaling pathways, and histologic transformations. Given the evolving knowledge and convenience of diagnosing acquired resistance mechanisms by next-generation sequencing and liquid biopsy, exploratory studies targeting these resistance mechanisms and incorporating immunotherapy into the treatment paradigm have become the mainstream of future development. This review focuses on acquired resistance mechanisms other than T790M that develop after first- or second-generation EGFR-TKI therapy. Exploratory second-line treatments targeting resistance mechanisms as well as combination immunotherapy and chemotherapy in ongoing clinical trials are reviewed here. We also highlight the recent development of next-generation sequencing and liquid biopsy in this field.
Insights
Acquired resistance to EGFR-TKIs in non-small cell lung cancer (NSCLC) is common. This review explores resistance mechanisms beyond T790M mutations and discusses emerging treatments including immunotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are standard for EGFR mutation-positive non-small cell lung cancer (NSCLC).
- Acquired resistance, particularly the EGFR T790M mutation, limits long-term efficacy.
- Understanding diverse resistance mechanisms is crucial for advancing NSCLC treatment.
Purpose of the Study:
- To review acquired resistance mechanisms to first- and second-generation EGFR-TKIs in NSCLC, excluding the T790M mutation.
- To discuss novel second-line treatment strategies targeting these resistance mechanisms.
- To highlight the role of next-generation sequencing and liquid biopsy in diagnosing resistance.
Main Methods:
- Literature review focusing on acquired resistance mechanisms in EGFR-TKI treated NSCLC.
- Analysis of current clinical trials investigating targeted therapies and immunotherapy combinations.
- Emphasis on advancements in diagnostic technologies like next-generation sequencing and liquid biopsy.
Main Results:
- Resistance to EGFR-TKIs involves bypass pathways, downstream signaling alterations, and histologic transformations, besides T790M.
- Next-generation sequencing and liquid biopsy facilitate comprehensive diagnosis of resistance mechanisms.
- Emerging treatments include targeted therapies and immunotherapy combinations showing promise in clinical trials.
Conclusions:
- Resistance mechanisms beyond T790M are critical targets for overcoming EGFR-TKI failure in NSCLC.
- Advanced diagnostics and novel therapeutic strategies, including immunotherapy, are reshaping the treatment landscape.
- Further research into these resistance mechanisms and combination therapies is essential for improving patient outcomes.
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