scholarly journals EGFR Exon 20 Insertion in Metastatic Non-Small-Cell Lung Cancer: Survival and Clinical Efficacy of EGFR Tyrosine-Kinase Inhibitor and Chemotherapy

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5132
Author(s):  
Samy Chelabi ◽  
Xavier Mignard ◽  
Karen Leroy ◽  
Isabelle Monnet ◽  
Solenn Brosseau ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tumor Response ◽  
Genetic Alterations ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Egfr Tyrosine Kinase ◽  
Significant Difference ◽  
Exon 20 ◽  
Egfr Tkis

EGFR exon 20 insertions are rare genetic alterations in non-small-cell lung cancers (NSCLCs) that are usually unresponsive to approved EGFR tyrosine kinase inhibitors (TKIs). In this paper, we describe the clinical characteristics, efficacy of EFGR TKIs and chemotherapy, and resulting survival in this population. We retrospectively collected patients with EGFR exon 20 insertions (Exon20ins) from 11 French genetic platforms and paired them (1:2 ratio) with classic Exon 19/21 EGFR mutation patients (controls). Between 2012 and 2017, 35 Exon20ins patients were included. These patients were younger at diagnosis than the controls. All Exon20ins patients who were treated with first-line EGFR TKIs (n = 6) showed progressive disease as the best tumor response. There was no significant difference in the tumor response or the disease control rate with first-line platinum-based chemotherapy between the two groups. A trend towards shorter overall survival was observed in Exon20ins vs. controls (17 months (14—not reach(NR) 95% confidence interval(CI) vs. 29 months (17–NR 95%CI), p = 0.09), respectively. A significant heterogeneity in amino acid insertion in EGFR exon 20 was observed. EGFR exon 20 insertions are heterogeneous molecular alterations in NSCLC that are resistant to classic EGFR TKIs, which contraindicates their use as a first-line treatment.

Circulating Endothelial Cells for Evaluation of Tumor Response in Non-Small Cell lung cancer patients receiving first-line chemotherapy

2015 ◽  
Vol 30 (4) ◽  
pp. 374-381
Author(s):  
Fadi Najjar ◽  
Ghassan Al-Massarani ◽  
Israa Banat ◽  
Moosheer Alammar
Keyword(s):  
Advanced Nsclc ◽  
Tumor Response ◽  
Small Cell ◽  
Percentage Change ◽  
Circulating Endothelial Cells ◽  
Small Cell Lung ◽  
First Line ◽  
Significant Difference ◽  
Nsclc Patients ◽  
Line Chemotherapy

Background Circulating endothelial cells (CECs) reflect the neovascularization in the tumor mass. We therefore investigated the potential role of CEC kinetics after first-line chemotherapy in advanced non-small cell lung cancer (NSCLC) patients. Methods Peripheral blood samples were obtained from 45 healthy subjects and 51 naïve patients with advanced NSCLC. Quantification of CD146+ CECs was performed using immunomagnetic separation (IMS). Results Pretreatment and posttreatment CEC levels in NSCLC patients were significantly higher than in healthy subjects (p<0.0001). An objective response was achieved after chemotherapy with partial response (PR) or stable disease (SD) in 26 patients, whereas the remaining 25 patients had progressive disease (PD). Baseline CEC levels were significantly higher in PR/SD patients than in PD patients (p = 0.039). After chemotherapy, CEC count significantly decreased in PR/SD patients (p = 0.014) and increased in patients with PD (p = 0.019). Moreover, there was a significant difference in the percentage change of CEC counts between the 2 groups (p = 0.0016). No significant difference in the median progression-free survival and overall survival (OS) was observed between patients with high baseline CEC counts and those with low baseline CEC levels. However, patients with high percentage change in CEC count had longer OS than those with low percentage change after chemotherapy (p = 0.05). Conclusions Changes in CEC counts after chemotherapy reflect tumor response in advanced NSCLC patients. Moreover, high percentage changes in CEC counts after chemotherapy may predict longer OS in advanced NSCLC. High baseline CEC levels might be an indicator of tumor response in advanced NSCLC patients after first-line chemotherapy.

Factors affecting treatment selection and overall survival for first-line EGFR-tyrosine kinase inhibitor therapy in non-small-cell lung cancer

2021 ◽  
Vol 10 (3) ◽  
pp. 193-206
Author(s):  
Yong-Jin Kim ◽  
Mark Oremus ◽  
Helen H Chen ◽  
Thomas McFarlane ◽  
Danielle Fearon ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Treatment Selection ◽  
Small Cell Lung ◽  
First Line ◽  
Egfr Tkis

Aim: To investigate the factors associated with treatment selection and overall survival for first-line EGFR-tyrosine kinase inhibitors (EGFR-TKIs) therapy among patients with non-small-cell lung cancer. Materials & methods: We conducted a retrospective cohort study of linked administrative health databases in Ontario, Canada. Results: A total of 1011 patients received an EGFR-TKI as first-line therapy. Treatment selection and overall survival associated with these treatments were affected by age, sex, geographical residency, comorbidities and different sites of metastasis. Conclusion: Though recent approval of osimertinib offers a potential new standard of care in the first-line setting, earlier generation TKIs remain pillars in treatment of non-small-cell lung cancer therapeutic armamentarium. Our findings may contribute to optimizing treatment sequencing of EGFR-TKIs to maximize clinical benefits.

scholarly journals The Presence of Concomitant Mutations Affects the Activity of EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) Patients

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 341 ◽  
Author(s):  
Anna Rachiglio ◽  
Francesca Fenizia ◽  
Maria Piccirillo ◽  
Domenico Galetta ◽  
Lucio Crinò ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Driver Mutations ◽  
Small Cell Lung ◽  
First Line ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Mutant ◽  
Egfr Tkis

Recent findings suggest that a fraction of EGFR-mutant non-small-cell lung cancers (NSCLC) carry additional driver mutations that could potentially affect the activity of EGFR tyrosine kinase inhibitors (TKIs). We investigated the role of concomitant KRAS, NRAS, BRAF, PIK3CA, MET and ERBB2 mutations (other mutations) on the outcome of 133 EGFR mutant patients, who received first-line therapy with EGFR TKIs between June 2008 and December 2014. Analysis of genomic DNA by Next Generation Sequencing (NGS) revealed the presence of hotspot mutations in genes other than the EGFR, including KRAS, NRAS, BRAF, ERBB2, PIK3CA, or MET, in 29/133 cases (21.8%). A p.T790M mutation was found in 9/133 tumour samples (6.8%). The progression free survival (PFS) of patients without other mutations was 11.3 months vs. 7 months in patients with other mutations (log-rank test univariate: p = 0.047). In a multivariate Cox regression model including the presence of other mutations, age, performance status, smoking status, and the presence of p.T790M mutations, the presence of other mutations was the only factor significantly associated with PFS (Hazard Ratio 1.63, 95% CI 1.04–2.58; p = 0.035). In contrast, no correlation was found between TP53 mutations and patients’ outcome. These data suggest that a subgroup of EGFR mutant tumours have concomitant driver mutations that might affect the activity of first-line EGFR TKIs.

scholarly journals Therapies after first-line afatinib in patients with EGFRm+ NSCLC in Japan: retrospective analysis of LUX-Lung 3

2020 ◽  
Vol 16 (4) ◽  
pp. 49-60
Author(s):  
Hiroshige Yoshioka ◽  
Terufumi Kato ◽  
Isamu Okamoto ◽  
Hiroshi Tanaka ◽  
Toyoaki Hida ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Japanese Patients ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
First Line ◽  
Egfr Tyrosine Kinase

Aim: Acquired resistance to EGFR tyrosine kinase inhibitors is inevitable in non-small-cell lung cancer. To inform subsequent treatment decisions, we retrospectively assessed therapies following afatinib in Japanese patients from LUX-Lung 3. Patients & methods: LUX-Lung 3 was a randomized, open-label, Phase III study of afatinib versus cisplatin/pemetrexed in treatment-naive patients with EGFR mutation-positive ( EGFRm+) advanced lung adenocarcinoma. Results: Among 47 Japanese patients who discontinued first-line afatinib, 91/81/62% received ≥one/two/three subsequent therapies. The most common second-line therapies were platinum-based chemotherapy (38%) and a first-generation EGFR tyrosine kinase inhibitor (17%). Median overall survival (afatinib vs cisplatin/pemetrexed) was 47.8 versus 35.0 months (not significant). Conclusion: First-line afatinib does not appear to diminish suitability for subsequent therapies in EGFRm+ non-small-cell lung cancer.

Treatment in EGFR-mutated Non-small Cell Lung Cancer: How to Block the Receptor and overcome Resistance Mechanisms

2017 ◽  
Vol 103 (4) ◽  
pp. 325-337 ◽  
Author(s):  
Claudia Proto ◽  
Giuseppe Lo Russo ◽  
Giulia Corrao ◽  
Monica Ganzinelli ◽  
Francesco Facchinetti ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Factor Receptor ◽  
Resistance Mechanisms ◽  
Small Cell ◽  
Third Generation ◽  
Small Cell Lung ◽  
Epidermal Growth ◽  
Exon 20 ◽  
Egfr Mutated ◽  
Egfr Tkis

In non-small cell lung cancer (NSCLC), the identification of epidermal growth factor receptor (EGFR) mutations and the parallel development of EGFR tyrosine kinase inhibitors (TKIs) have radically changed the therapeutic management strategies. Currently, erlotinib, gefitinib, and afatinib are all approved as standard first-line treatment in EGFR-mutated NSCLC. However, despite the proven efficacy, some EGFR-mutated NSCLCs do not respond to EGFR TKIs, while some patients, after a favorable and prolonged response to EGFR TKIs, inevitably progress within about 10-14 months. Epidermal growth factor receptor-dependent mechanisms, activation of alternative pathways, or phenotypic transformation can cause the resistance to EGFR TKIs. The exon 20 p.Thr790Met point mutation (T790M) is responsible for about 60% of cases of resistance when progression occurs. A third-generation TKI, osimertinib, improved outcome in patients harboring T790M after first- and second-generation TKI treatment. However, resistance develops even after treatment with third-generation drugs. To date, the Cys797Ser (C797S) mutation in exon 20 of EGFR is the most well-known resistance mutation after osimertinib. Fourth-generation TKIs are already under development. Nevertheless, additional information is needed to better understand and effectively overcome resistance. The aim of this review is to report recent advances and future perspectives in the treatment of EGFR-mutated NSCLC, highlighting the resistance mechanisms that underlie disease progression.

scholarly journals ELF3 Is a Target That Promotes Therapeutic Efficiency in EGFR Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer Cells via Inhibiting PKCί

2021 ◽  
Vol 22 (22) ◽  
pp. 12287
Author(s):  
Jeon-Soo Lee ◽  
Young Eun Choi ◽  
Sunshin Kim ◽  
Ji-Youn Han ◽  
Sung-Ho Goh
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Small Cell ◽  
Lung Cancer Cells ◽  
Therapeutic Effects ◽  
Small Cell Lung ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tki

(1) Background: Mutations in epidermal growth factor receptor (EGFR) proteins account for many non-small cell lung cancers (NSCLCs), and EGFR tyrosine kinase inhibitors (TKIs) are being used as targeted therapeutics. However, resistance to TKIs continues to increase owing to additional mutations in more than half of the patients receiving EGFR TKI therapy. In addition to targeting new mutations with next-generation therapeutics, it is necessary to find an alternative target to overcome the challenges associated with resistance. (2) Methods: To identify potential alternative targets in patients with NSCLC undergoing targeted therapy, putative targets were identified by transcriptome profiling and validated for their biological and therapeutic effects in vitro and in vivo. (3) Results: ELF3 was found to be differentially expressed in NSCLC, and ELF3 knockdown significantly increased cell death in K-Ras mutant as well as in EGFR L858R/T790M mutation harboring lung cancer cells. We also found that auranofin, an inhibitor of protein kinase C iota (PKCί), a protein upstream of ELF3, effectively induced cell death. (4) Conclusions: Our study suggests that blocking ELF3 is an effective way to induce cell death in NSCLC with K-Ras and EGFR T790M/L858R mutations and thus advocates the use of auranofin as an effective alternative drug to overcome EGFR TKI resistance.

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