Next-generation sequencing based mutation profiling reveals heterogeneity of clinical response and resistance to osimertinib

Zhao, Jun; Lin, Gen; Zhuo, Minglei; Zhang, Fan; Miao, Liyun; Chen, Likun; Zeng, Aiping; Yin, Rong; Ou, Yangming; Shi, Zhihui; Yin, Jie; Gao, Wen; Chen, Jianhua; Zhou, Xiangdong; Zeng, Yong; Xiang, Liu; Xu, Huamin; Chen, Rongrong; Xia, Xuefeng; Carbone, David P.

doi:10.1016/j.lungcan.2019.10.021

Cited by 34 publications

(33 citation statements)

References 10 publications

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“…In addition to TP53 mutation, maintained T790M mutation was also associated with heterogeneous mechanisms of resistance (PI3KCA mutation and PTEN loss). This finding indicated that subclones with T790M mutants can be found alongside subclones with specific mechanisms related to resistance (Zhao et al, 2020). In this case, targeting T790M alone is unlikely to result in clinical benefit.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Combination Treatment With Apatinib and Osimertinib After Osimertinib Resistance in Epidermal Growth Factor Receptor-Mutant Non-small Cell Lung Carcinoma—A Retrospective Analysis of a Multicenter Clinical Study

Yang

Xia

et al. 2021

Front. Mol. Biosci.

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Currently, there are limited treatment options for patients who developed resistance to osimertinib, a third-generation epidermal growth factor receptor (EGFR) inhibitor. Resistance to EGFR inhibitors is frequently associated with enhanced vascular endothelial growth factor (VEGF) levels. This multicenter, retrospective study aimed to evaluate the efficacy of the combination treatment with apatinib and osimertinib in 39 patients with EGFR-mutant non-small cell lung carcinoma (NSCLC) who developed osimertinib resistance. The patients received the combination of oral apatinib 250 mg qd and osimertinib 80 mg qd. The efficacy was evaluated after the first month then every 2 months thereafter. The primary endpoint was progression-free survival (PFS). The overall response rate (ORR) and the disease control rate (DCR) of the combination of apatinib and osimertinib was 12.8% (5/39) and 79.5% (31/39), respectively. The median PFS was 4 months [95% confidence interval (CI): 3.5–4.5 months]. Fourteen patients were administered with at least 6 months of combination therapy, and 11 of them remained on treatment programs. The 6-month PFS rate was 38%. Nine patients underwent biopsies after failing osimertinib treatment, and five of six patients with TP53 mutations had PFS of less than 3 months. The spectrum of resistance to osimertinib mechanisms included c-mesenchymal-epithelial transition factor (c-Met) amplification, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gain-of-function mutation, phosphatase and tensin homolog (PTEN) loss-of-function mutation, Erb-B2 receptor tyrosine kinase 2 (ERBB2) amplification, and insulin-like growth factor 1 receptor (IGF1R) mutation. The most common adverse events were hypertension (30.7%, 12/39), diarrhea (15.4%, 6/39), and proteinuria (12.8%, 5/39). The combination of apatinib and osimertinib improved the ORR and the DCR of patients with osimertinib-refractory EGFR-positive NSCLC, thus making it a reasonable treatment choice after the development of osimertinib resistance.

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Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Combination Treatment With Apatinib and Osimertinib After Osimertinib Resistance in Epidermal Growth Factor Receptor-Mutant Non-small Cell Lung Carcinoma—A Retrospective Analysis of a Multicenter Clinical Study

Yang

Xia

et al. 2021

Front. Mol. Biosci.

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“…Through mutation studies, EGFR C797S mutation, EGFR L718Q mutation, KRAS G12S mutation, CMET amplification and HER2 amplification were identified to be responsible for this acquired resistance [14][15][16][17][18]. Recently, Zhao et al identified recurrent EGFR V834L mutation might also contribute to resistance mechanisms of osimertinib [19]. Besides, ERBB2, PIKECA, RB1 and KRAS were also reported to be involved in osimertinib resistance development [20].…”

Section: Introductionmentioning

confidence: 99%

Exosomal long non-coding RNA MSTRG.292666.16 is associated with osimertinib (AZD9291) resistance in non-small cell lung cancer

Deng

Fang

Xie

et al. 2020

Aging

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Acquired resistance of osimertinib is encountered in clinic treatment of non-small cell lung cancer (NSCLC). However, the molecular mechanisms of osimertinib resistance are not fully revealed. This study aimed to investigate the roles of exosomes in delivering osimertinib resistance in NSCLC. Exosomes were successfully isolated. LncRNA sequencing identified a total of 123 differentially expressed lncRNAs, including 45 upregulated lncRNAs and 78 downregulated lncRNAs. The relative expression level of lncRNA MSTRG.292666.16 was significantly upregulated in osimertinibresistant plasma, osimertinib-resistant H1975R cells and their derived exosomes, compared with those in osimertinib-sensitive plasma, H1975 cells and exosomes (P < 0.05). Besides, osimertinib-resistant exosomes could regulate gene expressions induced by osimertinib, including miRNA-21, miRNA-125b, TGFβ, ARF6 and c-Kit. Osimertinib-resistant exosomes could be taken up by osimertinib-sensitive H1975 cells and resulting in osimertinibresistance in vivo. Knockdown of lncRNA MSTRG.292666.16 decreased osimertinib resistance of H1975R cells. Our results suggest that exosomal lncRNA MSTRG.292666.16 might be associated with osimertinib resistance in NSCLC.

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“…Of note, those patients develop cerebral metastases more often than patients with an EGFR mutation and unmutated TP53. In a retrospective multicenter study of lung cancer patients who had developed resistance to osimertinib, Zhao et al (2020) show that pathogenic mutations of TP53 were negatively related to the efficacy of osimertinib. 5 The mutations reported in our patient (p.L833V and p. H835F) have already been described in coexistence with a third mutation (E709K) in a 70-year-old male former smoker (30 pack-years) who quit smoking 26 years before the diagnosis of lung cancer was made.…”

Section: Discussionmentioning

confidence: 99%

Response to Osimertinib in a Patient With Non-Small Cell Lung Cancer and Two Uncommon EGFR mutations

Astaras¹,

Bettini²,

Prof³

2020

healthbook TIMES Onco Hema

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In advanced non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) mutations are one of the most frequent oncogenic drivers. They confer a favorable prognosis and strongly predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Over the last decades, several EGFR genetic alterations, common and uncommon mutations, have been described in exons 18−21. Common mutations are exon 19 deletions (most frequently E746-A750) and exon 21 L858R substitution. Uncommon mutations include exon 18 G719X, exon 20 S768l, exon 21 L861Q and many other rare ones. This report describes the case of a 55-year-old woman with a newly diagnosed metastatic lung adenocarcinoma harboring two rare EGFR mutations and showing sustained response to osimertinib.

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Next-generation sequencing based mutation profiling reveals heterogeneity of clinical response and resistance to osimertinib

Cited by 34 publications

References 10 publications

Efficacy and Safety of Combination Treatment With Apatinib and Osimertinib After Osimertinib Resistance in Epidermal Growth Factor Receptor-Mutant Non-small Cell Lung Carcinoma—A Retrospective Analysis of a Multicenter Clinical Study

Efficacy and Safety of Combination Treatment With Apatinib and Osimertinib After Osimertinib Resistance in Epidermal Growth Factor Receptor-Mutant Non-small Cell Lung Carcinoma—A Retrospective Analysis of a Multicenter Clinical Study

Exosomal long non-coding RNA MSTRG.292666.16 is associated with osimertinib (AZD9291) resistance in non-small cell lung cancer

Response to Osimertinib in a Patient With Non-Small Cell Lung Cancer and Two Uncommon EGFR mutations

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