Second-line treatment of EGFR T790M-negative non-small cell lung cancer patients

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.

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Real-world mutational profiling of Chinese non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) uncommon mutations acquired resistant to icotinib using next generation sequencing: A multicenter study.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21557 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21557-e21557

Author(s):

Wen xian Wang ◽

Chunwei Xu ◽

Lei Lei ◽

You-cai Zhu ◽

Jinluan Li ◽

...

Keyword(s):

Lung Cancer ◽

Next Generation Sequencing ◽

Acquired Resistance ◽

Small Cell ◽

Small Cell Lung ◽

Egfr Amplification ◽

Nsclc Patients ◽

Ctnnb1 Mutation ◽

Generation Sequencing ◽

Egfr T790m

e21557 Background: Just like classical EGFR mutations, EGFR uncommon mutations non-small cell lung cancer (NSCLC) will still have acquired resistant problem to icotinib. The mechanism of icotinib resistance in such uncommon EGFR mutant patients has also risen to be a difficult question in lung cancer research. In order to explore the resistance mechanism in EGFR uncommon mutant NSCLC patients treated by icotinib, it is necessary to first identify the resistant gene profiles and clinic-pathologic characteristics of those patients. As far as we know that there is no large cohort of EGFR uncommon mutant NSCLC study in evaluating the efficacy and resistant genomic profiling of icotinib. Methods: We screened 3279 patients with NSCLC for EGFR uncommon mutations. Among them, 106 patients received icotinib treatment, and a total of 69 patients with stage IIIb-IV EGFR uncommon mutations NSCLC were undergoing tumor biopsies or blood withdrawing by the time of primary or acquiring to icotinib, in including formalin-fixed paraffin-embedded (FFPE) samples, serum samples and serous effusions. We used targeted next-generation sequencing to detect genes status of patients. Results: Among 69 patients treated with icotinib, 69.57% (48/69) developed acquired resistance, and 30.43% (21/69) had primary resistance. Using the specimens at the baseline, there were 39(81.25%) patients with EGFR T790M (including 7 patients with EGFR T790M, 32 patients with EGFR T790M plus EGFR amplification), 3(36.25%) patients with EGFR amplification, 1(2.08%) patient with BRAF mutation, 1(2.08%) patient with PIK3CA mutation, 1(2.08%) patient with CTNNB1 mutation, 1(2.08%) patient with ALK fusion, 1(2.08%) patient with ROS1 fusion, and 1(2.08%) patient with unknown status. Conclusions: EGFR T790M, EGFR amplification, BRAF mutation, PI3K-AKT-mTOR signaling pathway (PIK3CA mutations), CTNNB1 mutation, ALK fusion or ROS1 fusion might contribute to molecular mechanisms of acquired resistance to icotinib in EGFR uncommon mutations NSCLC. Our study uncovered EGFR uncommon mutational profiles of NSCLC patients with icotinib resistance with potential therapeutic implications.

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