scholarly journals Patterns and Treatment Strategies of Osimertinib Resistance in T790M-Positive Non-Small Cell Lung Cancer: A Pooled Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Chunsheng Wang ◽  
Kewei Zhao ◽  
Shanliang Hu ◽  
Minghuan Li ◽  
Yipeng Song
Keyword(s):  
Lung Cancer ◽  
Clinical Characteristics ◽  
Egfr Mutation ◽  
Treatment Strategies ◽  
Pooled Analysis ◽  
Small Cell ◽  
Resistance Pattern ◽  
Small Cell Lung ◽  
Nsclc Patients ◽  
Egfr Tki

IntroductionOsimertinib resistance is inevitable. The purpose of this study was to explore the predictive value of pretreatment clinical characteristics in T790M-positive non-small cell lung cancer NSCLC patients for the resistance pattern of osimertinib during tumor progression as well as the treatment strategy.MethodsWe performed a literature search in the NCBI PubMed database to identify relevant articles and completed a pooled analysis based on 29 related published studies. The relationship between clinical characteristics, EGFR mutation type, previous treatment history and the gene mutation pattern at resistance to osimertinib was analyzed.ResultsA total of 38 patients were included in the pooled analysis. Patients with an initial epidermal growth factor receptor EGFR mutation status of 19 deletions were more likely to have T790M loss (HR: 12.187, 95% CI: 2.186–67.945, p = 0.004). Patients with an initial EGFR mutation of L858R were more likely to have C797S mutations (HR: 0.063, 95% CI: 0.011–0.377, p = 0.002). The other factors (age, gender, ethnicity, smoking history, previous EGFR-TKI targeted therapy history, history of radiotherapy and chemotherapy) were not associated with the resistance pattern of osimertinib (all p > 0.05).ConclusionsThe type of EFGR mutation in T790M-positive NSCLC patients prior to treatment can predict the resistance pattern to osimertinib. This finding plays a vital role and theoretical basis in guiding clinicians to formulate treatment strategies at the early stage of treatment and rationally combine drugs to overcome EGFR-TKI resistance.

ERK Inhibitor ASN007 Effectively Overcomes Acquired Resistance to EGFR Inhibitor in Non-small Cell Lung Cancer

2021 ◽  
Author(s):  
Bo Mi Ku ◽  
Jae Yeong Heo ◽  
Jinchul Kim ◽  
Jong-Mu Sun ◽  
Se-Hoon Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Acquired Resistance ◽  
Small Cell ◽  
Erk Signaling ◽  
Small Cell Lung ◽  
Nsclc Patients ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract The emergence of acquired resistance limits the long-term efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Thus, development of effective strategies to overcome resistance to EGFR-TKI is urgently needed. Multiple mechanisms to reactivate ERK signaling have been successfully demonstrated in acquired resistance models. We found that in EGFR mutant non-small cell lung cancer (NSCLC) patients, acquired resistance to EGFR-TKIs was accompanied by increased activation of ERK. Increased ERK activation was also found in in vitro models of acquired EGFR-TKI resistance. ASN007 is a potent selective ERK1/2 inhibitor with promising antitumor activity in cancers with BRAF and RAS mutations. ASN007 treatment impeded tumor cell growth and the cell cycle in EGFR-TKI-resistant cells. In addition, combination treatment with ASN007 and EGFR-TKIs synergistically decreased the survival of resistant cells, enhanced induction of apoptosis, and effectively inhibited the growth of erlotinib-resistant xenografts, providing the preclinical rationale for testing combinations of ASN007 and EGFR-TKIs in EGFR-mutated NSCLC patients. This study emphasizes the importance of targeting ERK signaling in maintaining the long-term benefits of EGFR-TKIs by overcoming acquired resistance.

scholarly journals Small cell lung cancer transformation during antitumor therapies: A systematic review

Open Medicine ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. 1160-1167
Author(s):  
Xing Chai ◽  
Xinru Zhang ◽  
Wenqian Li ◽  
Jin Chai
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Treatment Strategies ◽  
Small Cell ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
Histological Transformation ◽  
Nsclc Patients

Abstract Lung cancer is the most common cause of cancer-related death. Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are the two major histological categories of lung cancers. Drug resistance is a great challenge for cancer treatment, and histological transformation from NSCLC to SCLC is one of the mechanisms underlying drug resistance in NSCLC patients. SCLC-transformed patients show combined characteristics of NSCLC and SCLC; however, they lack timely diagnoses and effective treatment strategies. Thus, we reviewed the clinical characteristics of SCLC transformation patients with a literature search to enhance clinical consciousness, diagnosis, and personalized treatment for patients with it.

scholarly journals Efficacy and Acquired Resistance of EGFR-TKI Combined with Chemotherapy as First-Line Treatment for Chinese Patients with Advanced Non-Small Cell Lung Cancer in a Real-world Setting

2020 ◽  
Author(s):  
Qianqian Wang ◽  
Wen Gao ◽  
Fangyan Gao ◽  
Shidai Jin ◽  
Tianyu Qu ◽  
...  
Keyword(s):  
Egfr Mutation ◽  
Advanced Nsclc ◽  
Acquired Resistance ◽  
Small Cell ◽  
Combination Group ◽  
Monotherapy Group ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Nsclc Patients ◽  
Egfr Tki

Abstract Background To compare the benefits and explore the cause of acquired resistance of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and its combination with chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients harboring EGFR mutation in a real-life setting.Methods This retrospective analysis included 117 advanced NSCLC patients with EGFR mutation who underwent next-generation sequencing (NGS) prior to treatment. The combination group included 50 patients who received the regimen of EGFR-TKI combined with chemotherapy, while the EGFR-TKI monotherapy group included 67 patients treated with TKI only. The primary endpoint of this study was progression-free survival (PFS); the secondary endpoints were overall survival (OS), response rate, and toxicity.Results The median PFS was significantly longer in the combination group than in the EGFR-TKI monotherapy group (19.00 months [95% CI, 14.674-23.326] vs. 11.70 months [95% CI, 10.807-12.593], p = 0.000). Subgroup analysis showed a similar trend of results. The median OS was not reached in the combination group and was 38.50 (95% CI, 35.300-41.700) months in the EGFR-TKI monotherapy group (p = 0.586). Patients in the combination group were more likely to experience adverse events, most of which showed the severity of grade 1 or 2. T790M mutation remains the main reason for acquired resistance, and the frequency of T790M mutation was similar between the two groups (p = 0.898). Conclusions Compared with EGFR-TKI monotherapy, EGFR-TKI combined with chemotherapy significantly improved PFS in advanced NSCLC patients with EGFR mutation, with acceptable toxicity.

scholarly journals Adjuvant treatment with EGFR TKI in resected non-small cell lung cancer with EGFR mutation: all that glitters is not gold!

2020 ◽  
Vol 8 (18) ◽  
pp. 1199-1199
Author(s):  
Alfonso Fiorelli ◽  
Fabiana Vitiello ◽  
Floriana Morgillo ◽  
Rosa Maria Di Crescenzo ◽  
Andrea Bianco ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Adjuvant Treatment ◽  
Egfr Mutation ◽  
Small Cell ◽  
Small Cell Lung ◽  
Egfr Tki

Integrated genomic analysis of EGFR-mutant non-small cell lung cancer immediately following erlotinib initiation in patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11067-11067
Author(s):  
Trever Grant Bivona ◽  
Petros Giannikopoulos ◽  
Carlota Costa ◽  
Niki Karachaliou ◽  
Santiago Viteri ◽  
...  
Keyword(s):  
Lung Cancer ◽  
High Resolution ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Genomic Analysis ◽  
Small Cell ◽  
Small Cell Lung ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
Egfr Tki

11067 Background: Major obstacles limiting the clinical success of EGFR TKI therapy in non-small cell lung cancer (NSCLC) patients are heterogeneity and variability in the initial anti-tumor response to treatment. The underlying molecular basis for this heterogeneity has not been explored in patients immediately after initiation of therapy. Methods: We conducted CT-guided core needle biopsies immediately prior to erlotinib treatment initiation and at 6 days post erlotinib initiation in a patient with histologically confirmed NSCLC harboring an established activating mutation in EGFR. DNA from the paired frozen biopsies and matched normal tissue was analyzed by whole exome sequencing and RNA from the biopsies was analyzed by whole transcriptome sequencing. High-resolution CT images were obtained at the time of each biopsy to compare the degree of molecular and radiographic response observed. Results: Two established activating somatic mutations were identified in EGFR (p.G719A and p. R776H). Selective depletion of each EGFR mutant allele, but not the EGFR wild type allele, was observed upon erlotinib treatment. Gene expression analysis of the paired transcriptomes revealed that erlotinib treatment resulted in significant upregulation of proapoptotic genes including BAD, BAX, BID, CASP3 and growth inhibitory genes including CDKN1A, GADD45B, GADD45G and downregulation of growth-promoting genes including CCNB1 and CCND3. Several unexpected and novel molecular biomarkers were identified by transcriptome analysis and the complete dataset will be presented. High-resolution CT scans revealed no interval radiographic changes in the target lesion and no clinical complications were encountered. Conclusions: This study is the first reported integrated genomic analysis of EGFR-mutant NSCLC immediately following EGFR TKI initiation. We documented the feasibility, safety and utility of this strategy to establish initial drug efficacy at the molecular level prior to any radiographic evidence of response. Additional, serial integrated genomic analysis is ongoing in the index patient and others on therapy to enhance the management of NSCLC patients on targeted therapy.

A practical decision-making strategy based on clinical triple features for EGFR-TKIs to treat advanced non-small cell lung cancer patients with unknown EGFR mutation status.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19082-e19082
Author(s):  
Di Zheng ◽  
Jiying Wang ◽  
Bing Lu
Keyword(s):  
Lung Cancer ◽  
Salvage Therapy ◽  
Egfr Mutation ◽  
Response Rate ◽  
Small Cell ◽  
Smoking History ◽  
Small Cell Lung ◽  
Mutation Status ◽  
Egfr Tki ◽  
Egfr Tkis

e19082 Background: EGFR mutated lung cancers are strongly associated with clinical characteristics of never- smoking history and adenocarcinoma histology type, and tended to develop multiple pulmonary metastases.Whether multiple pulmonary metastatic lung adenocarcinomas with never-smoking history would respond to EGFR-TKIs as those harboring EGFR active mutation remains unclear. Methods: 223 consecutive metastatic non-small cell lung cancer (NSCLC) patients with unknown EGFR status who received EGFR-TKIs as salvage therapy after failure of previous platinum-based chemotherapy in Shanghai Pulmonary hospital between 2009 and 2011 were included to the study. Available CT scans, routinely performed at baseline and one month after the start of EGFR-TKIs therapy, were reviewed independently by two investigators. For the purposes of this study, diffuse pulmonary metastatic nodules were defined as multiple nodules distributed diffusely throughout the whole lung with at least 20 nodules within the unilateral lung field. Paraffin embedded tissues were available for 45 of 223 patients for EGFR gene mutation test. Results: Of 134 never-smokers with lung adenocarcinoma,70 patients responded to EGFR-TKIs with an objective response rate (ORR) of 52.2% (70/134), and the ORR for the 62 patients with diffuse pulmonary metastatic nodules was 79% (49/62). Among the 20 patients with confirmed EGFR mutation (based on the available 45 archived specimen), the ORR was 75% (15/20). The multivariate analyses showed that the presence of diffused multiple pulmonary metastatic nodules, activating EGFR mutation and female are independent predictive factors of the response to EGFR-TKIs. Conclusions: Patient selection based on specific clinical features to recieve EGFR-TKI treatment yield high response rate comparable to that selected by EGFR mutation status. It is practical to consider EGFR-TKI as salvage therapy in non-smoking patients with lung adenocarcinoma characterized by diffuse pulmonary nodules when EGFR mutation testing is a challenge.

Prediction of EGFR-TKI efficacy in non-small cell lung cancer patients by metabolomics and genomics.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20627-e20627
Author(s):  
Lei Zhang ◽  
Rongrong Luo ◽  
Lin Wang ◽  
Jiarui Yao ◽  
Di Wu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Prediction Model ◽  
Small Cell Lung Cancer ◽  
Somatic Mutations ◽  
Small Cell ◽  
Joint Analysis ◽  
Small Cell Lung ◽  
Ffpe Samples ◽  
Nsclc Patients ◽  
Egfr Tki

e20627 Background: Metabolites and somatic mutations involved in EGFR-TKI efficacy remains unclear in non-small cell lung cancer (NSCLC) patients with EGFR sensitizing mutation (EGFRsm+). Here we performed a joint analysis of metabolomics and genomics data to identify metabolites and somatic mutations as biomarkers for EGFR-TKI efficacy. Methods: Metabolomic profiling of plasma samples (n = 43) from NSCLC patients with EGFRsm+, consisting of cohort A (n = 30) and B (n = 13), was conducted using UPLC or rapid separation LC-MS/MS. The 13 matched FFPE samples in cohort B were also used in the targeted sequencing below. FFPE samples (n = 18) from NSCLC patients with EGFRsm+ were subjected to targeted sequencing. According to progression free survival (PFS), all patients were assigned a status of poor (PFS≤42 weeks) and good responders (PFS > 42 weeks). A joint analysis of metabolomics and genomics data was adopted to identify biomarkers for EGFR-TKI efficacy. Results: The partial least squares discrimination analysis mothod was performed to establish a prediction model responsible for separation of good and poor responders in cohort A, comprising 27 metabolites with variable importance in projection score (VIP) > 1.5. Based on the prediction model, the ROC analysis demonstrated the sensitivity of 0.8, the specificity of 0.75, and the area under the ROC curve (AUC) of 0.7 in cohort B. The Welch’s t test method identified 15 significant metabolites ( P < 0.05) in cohort A. With the criteria of VIP > 1.5 and P < 0.05, four metabolites, 3-Methyl-L-Histidine, LysoPE(18:2(9Z,12Z)/0:0), Histamine, and SM(d18:1/16:0), were detected as potential biomarkers. To further validate them, associations of these metabolites and somatic mutations were explored in 13 patients with both metabolomics and genomics data available using the Welch’s t test. The results revealed patients with either CTCF R415X or PTK2B G491X had significantly lower Histamine level compared with those without either mutation (both P < 0.05), and significantly increased level of SM(d18:1/16:0) was observed in patients with either GATA2 P250A or MAGI1 S763X (both P < 0.05). Intriguingly, worse PFS was showed in patients with any mutation of GATA2 P250A ( P = 0.02), CTCF R415X ( P = 0.002), PTK2B G491X ( P = 0.002), and MAGI1 S763X ( P = 0.0007). Conclusions: Our joint analysis identified two plasma metabolites and four somatic mutations as biomarkers for EGFR-TKI efficacy. The present findings may provide insights into molecular mechanisms of EGFR-TKI efficacy. Further validation in prospective studies was warranted.

Sign in / Sign up

Export Citation Format

Share Document