scholarly journals Current Therapeutic Strategies and Prospects for EGFR Mutation-Positive Lung Cancer Based on the Mechanisms Underlying Drug Resistance

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3192
Author(s):  
Yukari Tsubata ◽  
Ryosuke Tanino ◽  
Takeshi Isobe
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Egfr Mutations ◽  
Radical Cure ◽  
Primary Therapy ◽  
T790m Mutation ◽  
Acquired Drug Resistance ◽  
Egfr Tkis

The discovery of activating mutations in the epidermal growth factor receptor (EGFR) gene and the development of EGFR tyrosine kinase inhibitors (TKIs) have led to a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). EGFR mutation-positive NSCLC is common in East Asia, and approximately 50% of adenocarcinomas harbor EGFR mutations. Undoubtedly, EGFR-TKIs, with their promising efficacy, are the mainstay of primary therapy. However, even if tumor shrinkage is achieved, most patients become resistant to EGFR-TKIs and relapse; hence, EGFR-TKIs do not achieve a radical cure. The problem of the development of resistance to targeted drugs has been a persistent challenge. After the role of EGFR T790M mutation in acquired drug resistance was reported, osimertinib, a third-generation irreversible EGFR-TKI, was designed to overcome the resistance conferred by T790M mutation. In addition, some studies have reported the mechanism of drug resistance caused by mutations other than the T790M mutation and strategies to overcome them. Elucidating the mechanism underlying drug resistance development and combining therapeutic approaches are expected to further improve NSCLC prognosis.

scholarly journals The role of EGFR mutation testing in the choice for surgical tactics in NSCLC treatment

2021 ◽  
Vol 67 (3) ◽  
pp. 315-322
Author(s):  
Evgeniy Slugin ◽  
Evgeniy Levchenko ◽  
Evgeniy Imyanitov ◽  
Olga Lopushanskaya
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Resistance Mechanisms ◽  
Egfr Mutations ◽  
Choice Of Treatment ◽  
Surgical Tactics ◽  
Key Aspects ◽  
Egfr Tkis

Lung cancer is the most commonly diagnosed cancer in the world, and currently the mortality rate from this disease is one of the highest. The detection of EGFR mutation plays an important role in the choice of treatment in clinical practice. As already known, over the past decade, EGFR mutations have been a predictive factor for the prescription of tyrosine kinase inhibitors (EGFR TKIs) in patients with advanced non-small cell lung cancer (NSCLC). The role of EGFR mutation as a prognostic factor for patients undergoing surgery and the possibility of using surgery to overcome the resistance mechanisms that develop in response to EGFR TKIs remain unexplored. This literature review examines key aspects of the EGFR mutation as a factor that can influence the treatment and using the surgical method.

scholarly journals Real-world osimertinib for EGFR mutation-positive non-small-cell lung cancer with acquired T790M mutation

2020 ◽  
Vol 16 (21) ◽  
pp. 1537-1547
Author(s):  
Fumio Imamura ◽  
Madoka Kimura ◽  
Yukihiro Yano ◽  
Masahide Mori ◽  
Hidekazu Suzuki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Acquired Resistance ◽  
Small Cell ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Clinical Trial Registration

Aim: Osimertinib is a key drug for EGFR mutation-positive non-small-cell lung cancer (NSCLC). As the hazards ratio of overall survival in comparison with first-generation EGFR-tyrosine kinase inhibitors was almost similar between FLAURA and ARCHER 1050, salvage use of osimertinib is still a treatment option. Patients & methods: We retrospectively analyzed the clinical courses of EGFR mutation-positive NSCLC patients who were potential candidates for salvage osimertinib. Results: Among 524 patients enrolled from five hospitals, 302 patients underwent biopsy, with 52.6% detection rate of T790M. Osimertinib was administered in 93.6% of the T790M-positive patients. The overall response rate and median progression-free survival time of osimertinib were calculated with 147 patients, to be 55.6% and 17.2 months, respectively. Conclusion: Osimertinib is active for T790M-driven acquired resistance in EGFR-mutant NSCLC, but the detection of T790M was unsatisfactory. Clinical Trial Registration: UMIN000028989 (UMIN Clinical Trials Registry)

Chitosan-derived Nanoparticles Impede Signal Transduction for T790M Lung Cancer Therapy

2021 ◽  
Author(s):  
Guojun Huang ◽  
Qi Chen ◽  
Jiawei Hu ◽  
Jianming Mao ◽  
Yunhong He ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
T790m Mutation ◽  
Develop Disease Progression ◽  
Lung Cancer Therapy ◽  
Epidermal Growth ◽  
Egfr Tkis ◽  
Receptor Tyrosine Kinase Inhibitors

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treated patients ultimately develop disease progression, about 50% of which involved in the emergence of a T790M mutation acquiring drug resistance. In...

scholarly journals Clinical Characteristics of Osimertinib Responder in Non-Small Cell Lung Cancer Patients with EGFR-T790M Mutation

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 365 ◽  
Author(s):  
Akihiro Yoshimura ◽  
Tadaaki Yamada ◽  
Naoko Okura ◽  
Takayuki Takeda ◽  
Kazuki Hirose ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Nsclc Patients ◽  
Egfr T790m ◽  
Egfr Tkis

Osimertinib is a mutant-selective EGFR inhibitor that is effective against non-small cell lung cancer (NSCLC) in patients with the EGFR-T790M mutation, who are resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the factors affecting response to osimertinib treatment are unknown. In this retrospective study, 27 NSCLC patients with the EGFR-T790M mutation were enrolled at five institutions in Japan. Among several parameters tested, the progression-free survival (PFS) associated with the initial EGFR-TKIs was positively correlated with the PFS after osimertinib treatment (p = 0.021). The median PFS following osimertinib treatment and the overall survival (OS) were longer in patients who responded to osimertinib than in those who did not (17.7 months versus 3.5 months, p = 0.009 and 24.2 months versus 13.5 months, p = 0.021, respectively). A multivariate analysis demonstrated that the PFS with initial EGFR-TKIs was significantly related to the PFS with osimertinib treatment (p = 0.035), whereas osimertinib response was significantly related to the PFS and OS with osimertinib treatment (p = 0.016 and p = 0.006, respectively). Our retrospective observations indicate that PFS following the initial EGFR-TKI treatment and the response rate to osimertinib might be promising predictors for effective osimertinib treatment in NSCLC patients with the EGFR-T790M mutation.

Rebiopsy of patients (pts) with acquired resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8025-8025 ◽  
Author(s):  
M. E. Arcila ◽  
G. J. Riely ◽  
M. F. Zakowski ◽  
M. G. Kris ◽  
M. Ladanyi ◽  
...  
Keyword(s):  
Median Time ◽  
Progressive Disease ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Acquired Resistance ◽  
Egfr Mutations ◽  
Met Amplification ◽  
Metastatic Sites ◽  
Egfr Tki ◽  
Egfr Tkis

8025 Background: The EGFR-TKIs erlotinib and gefitinib produce dramatic regressions of tumor in ∼ 70% of NSCLC patients with activating mutations in the EGFR-TK domain. After a median time to progression of ∼1 year, most pts have progressive disease. We undertook this study to search for mechanisms of “acquired resistance” to EGFR-TKIs, to determine the spectrum and frequency of secondary EGFR mutations which arose, and to determine the feasibility of rebiopsy in this setting. Methods: All pts had metastatic or recurrent NSCLC and prior treatment with EGFR-TKI and progressive disease while on EGFR-TKI. Pts must also have had an activating EGFR mutation OR radiographic response (RECIST or WHO) to EGFR-TKI OR significant and durable improvement in cancer-related symptoms as judged by patient's physician. Core biopsies were performed and studied for EGFR mutation (exons 18–21 including PCR-based test for T790M) and MET amplification. Results: From 8/04–12/08 98 pts were consented for rebiopsy and 85 underwent the procedure. Demographics Female/Male=59/39; median age 62 (range 28–88); smoking: never=59, former/current=39. Primary EGFR mutation was exon 19 del-39; exon 21 L858R-11, other/WT-28, pending-7. Median time on EGFR-TKI before biopsy was 12 months (7–28 months). Secondary EGFR mutations: T790M-33, other-2, none detected-31, indeterminate-10, pending-9. MET amplification in 2/16 studied to date. Conclusions: 1) Rebiopsy of patients with NSCLC and acquired resistance to EGFR TKIs is feasible and well-received by pts. 2) Knowledge of EGFR genotype including EGFR T790M and MET status can inform clinical trials of targeted therapies in this population 3) More complete annotation of MET status and exploratory analyses of profiles of specimens by metastatic sites and prior EGFR-TKI versus chemo and EGFR-TKI is ongoing. Supported by the Doris Duke Foundation, the LaBrecque Foundation, Steps for Breath, NIH, and an anonymous donor. No significant financial relationships to disclose.

A phase II trial of durvalumab (MEDI4736) and tremelimumab with chemotherapy in metastatic EGFR mutant non-squamous non-small cell lung cancer (NSCLC) following progression on EGFR tyrosine kinase inhibitors (TKIs) (ILLUMINATE).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS9631-TPS9631
Author(s):  
Chee Khoon Lee ◽  
Shalini Subramaniam ◽  
Antony Mersiades ◽  
Jenna Mitchell ◽  
Hannora Jurkovic ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitor ◽  
Small Cell ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Mutant ◽  
Egfr Tkis

TPS9631 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have proven remarkably effective in the treatment of advanced EGFR mutant non-small cell lung cancer (NSCLC). However, drug resistance is inevitable and outcomes with subsequent platinum-pemetrexed chemotherapy are poor. The role of immune-checkpoint inhibitor monotherapy in EGFR mutant NSCLC remains uncertain with trials demonstrating inferior survival outcomes compared to chemotherapy. However, a recent randomised study with combination checkpoint inhibitor-chemotherapy demonstrated improved survival over chemotherapy alone in this patient population. This study aims to evaluate the efficacy and tolerability of combination dual immune-checkpoint blockade, durvalumab and tremelimumab, with platinum-pemetrexed chemotherapy in metastatic EGFR mutant NSCLC following progression on EGFR-TKIs. Methods: This international phase II cohort study will recruit 100 participants from Australia and Taiwan with advanced EGFR mutant NSCLC following disease progression with EGFR-TKIs [Cohort 1 (n=50): T790M mutation negative on tissue and plasma; Cohort 2 (n=50): T790M mutation positive on tissue and/or plasma, and progression on3rd generation TKIs]. Participants will receive 4 cycles of induction durvalumab 1500mg and tremelimumab 75mg with platinum-pemetrexed chemotherapy every 3 weeks, followed by maintenance durvalumab 1500mg and pemetrexed 500mg/m2 every 4 weeks until disease progression. Response will be assessed at 6 and 12 weeks, then 8-weekly during the first year, and 12-weekly thereafter. Major endpoints include objective tumour response rate (OTRR; RECIST1.1; primary), disease control rate, OTRR (iRECIST), progression-free survival, overall survival, and adverse events. Correlative studies include biomarker assessment as potential predictive/prognostic factors. ILLUMINATE is a collaboration between the Australasian Lung Cancer Trials Group, National Health Research Institutes (Taiwan) and the NHMRC Clinical Trials Centre, University of Sydney. As of 6/2/2020, 11 of planned 100 participants have been recruited. Clinical trial information: NCT03994393 .

Identification of RET fusion as mechanisms of resistance to EGFR tyrosine-kinase inhibitors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21074-e21074
Author(s):  
Zhongxing Bing ◽  
Weiran Wang ◽  
Danhua Wang ◽  
Tonghui Ma
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Next Generation Sequencing Data ◽  
Egfr Mutations ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Tki ◽  
Egfr Tkis

e21074 Background: Responses to EGFR-targeted therapy are generally temporary, due to inevitable drug resistance. Although RET fusions have been identified in resistant EGFR-mutant non–small cell lung cancer (NSCLC), their characteristics acquired resistance to EGFR tyrosine-kinase inhibitors (TKIs) are rarely investigated. Methods: We retrospectively reviewed next-generation sequencing data of EGFR+ lung cancer patients, and 8 patients were identified coexisting of EGFR mutations and RET fusion. Their treatment history was collected. Results: The co-occurrence of RET fusion with EGFR oncogenic variations was observed in eight patients, and all of the 8 patients have received previous EGFR-TKI treatment. EGFR mutations were including 4 L858R mutations, 4 exon 19 deletions, and 6 T790M mutations. And the partner genes of RET identified by NGS were including TRIM33 (2/8), GPRC6A (1/8), TLN1 (1/8), KIAA1598 (1/8), SPECC1 (1/8), TRIM24 (1/8) and CCDC6 (1/8). The allelic fractions (AFs) of first-generation EGFR-TKI sensitizing mutations were higher than AFs of EGFR T790M mutations as well as AFs of RET fusion. These RET fusions are fused with rare partner genes, rather than the most common KIF5B in lung cancer. Conclusions: This study extended the knowledge of RET fusion as resistance mechanism to EGFR TKIs in lung cancer. The detection of RET fusions may uncover potential resistance mechanisms of EGFR TKIs, which might inform therapeutic strategies, such as combination-therapy approaches.[Table: see text]

scholarly journals EGFR tyrosine kinase inhibitors for EGFR mutation-positive non-small-cell lung cancer: outcomes in Asian populations

2021 ◽  
Author(s):  
Edward S Kim ◽  
Barbara Melosky ◽  
Keunchil Park ◽  
Nobuyuki Yamamoto ◽  
James C-H Yang
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Small Cell ◽  
Third Generation ◽  
Small Cell Lung ◽  
Asian Populations ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Tkis

Few data are available that have compared outcomes with different EGFR tyrosine kinase inhibitors (TKIs) specifically in Asian patients with EGFR mutation-positive non-small-cell lung cancer. In this narrative review, we have collated available data from prospective studies that have assessed first-, second- and third-generation EGFR TKIs in Asian populations, including subanalyses in individual countries (China and Japan). These data indicate that outcomes with first- and second-generation TKIs are broadly similar in Asian and non-Asian populations. However, while the third-generation EGFR TKI, osimertinib, confers significant overall survival benefit over erlotinib/gefitinib in non-Asians, this is not apparent in Asians, particularly in countries like Japan with well-resourced healthcare. Head-to-head comparisons of second- and third-generation EGFR TKIs, with OS as a primary end point, should be considered in Asia.

scholarly journals ID3021 Acquired resistance to with EGFR tyrosine kinase inhibitors by the EGFR T790M mutation in non-small cell lung cancer

2017 ◽  
Vol 4 (S) ◽  
pp. 33
Author(s):  
Van Thanh Ta
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Small Cell ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Tkis

Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene respond well to treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) including gefitinib and erlotinib in non-small cell lung cancer (NSCLC). Detection of these mutations has an important role for therapeutic decision-making in NSCLC treatment. However, all patients who experienced marked improvements with these drugs eventually developed disease progression after 10-20 months of treatment due to the acquisition of drug resistance. Approximately half of the cases with acquired resistance to EGFR-TKIs can be accounted for by a second-site mutation in exon 20 of the EGFR kinase domain T790M. In this study, 40 patients with advanced NSCLC who developed acquired resistance to EGFR-TKIs were selected. The diagnosis was defined based on the Jackman criteria for acquired resistance to EGFR-TKIs in lung cancers. Re-biopsy were performed at National cancer hospital and Oncology hospitals at Ha Noi and Ho Chi Minh City. Scorpion ARMS method was used to detect EGFR mutation status. In all, 40% (16/40) of the patients carried T790M mutation after the failure of EGFR-TKIs. The study demonstrated a critical role of molecular diagnostics for TKI acquired resistance through re-biopsies at the time of disease progression.

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