Observational Study of Re-Biopsy in EGFR-TKI-Resistant Patients with EGFR Mutation-Positive Advanced NSCLC

Abstract Identification of acquired resistant mutation has been essential in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) active mutations. Re-biopsy plays a pivotal role to select the optimal treatment for patients who develop resistance to initial EGFR-tyrosine kinase inhibitors (EGFR-TKIs). This multicenter, observational study was conducted to investigate the details of re-biopsy in Japanese clinical practice.The primary endpoints were the implementation rate of re-biopsy and the concordance rate for the T790M mutation detection between histology and cytology specimens using the Cobas ® EGFR mutation test v2. 194 patients with EGFR-mutant NSCLC were enrolled and 120 patients developed acquired resistance to EGFR-TKIs. The median age was 68 years (range 20-87), and 52.5% of the patients were women. Re-biopsy was performed on 109 patients with the implementation rate of re-biopsy was 90.8%. The success rate of re-biopsy in total/histology/cytology/liquid biopsy population was 78.0%, 94.9%, 83.3% and 43.8%, respectively. The positive percent agreement and the negative percent agreement in the detection of T790M mutations between the histology and cytology specimens was both of 90.9%. Aggressive obtaining histological or cytological tissue samples at re-biopsy may contribute to improvement of the detection rate of T790M mutation. (trial registration number: UMIN000026019)

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High expression of hypoxia inducible factor 1α related with acquired resistant to EGFR tyrosine kinase inhibitors in NSCLC

Scientific Reports ◽

10.1038/s41598-020-79801-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Qian Jin ◽

Feihua Huang ◽

Xianrong Xu ◽

Haidong He ◽

Yingqing Zhang

Keyword(s):

First Generation ◽

Kinase Inhibitors ◽

Acquired Resistance ◽

Hypoxia Inducible Factor ◽

High Expression ◽

Normal Lung ◽

Nsclc Tissue ◽

T790m Mutation ◽

Level Group ◽

Egfr Tkis

AbstractThe acquired resistance of the first generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is a main factor leading to poor prognosis of non-small cell lung cancer (NSCLC), so we researched whether the high expression of hypoxia-inducible factor-1α (HIF-1α) in EGFR-TKIs sensitive NSCLC tissue tends to induce the acquired resistance. We detected the HIF-1α in normal lung tissue, EGFR-TKIs sensitive NSCLC tissue, the first generation EGFR-TKIs acquired resistant NSCLC tissue and acquired EGFR T790M mutation NSCLC tissue with the method of immunohistochemistry. Then, we compared the expression of HIF-1α in these tissues, and evaluate the effect of HIF-1α expression to the occurrence of acquired resistance. The expression of HIF-1α was much higher in the EGFR-TKIs sensitive NSCLC tissue than that in normal lung tissue. HIF-1α level became higher after the occurrence acquired resistance. There was negative correlation between HIF-1α level before receiving treatment and the time of acquired resistance occurring as well as the acquired EGFR T790M mutation occurring. As the treatment going on, EGFR-TKIs sensitivity rate of low HIF-1α level group was much higher than that of high level group. The high expression of HIF-1α related with the acquired resistance of the first generation EGFR-TKIs, and HIF-1α can be a biomarker to predict the early occurrence of acquired resistance.

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

Future Oncology ◽

10.2217/fon-2020-0203 ◽

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)

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The Journey of an EGFR-Mutant Lung Adenocarcinoma through Erlotinib, Osimertinib and ABCP Immunotherapy Regimens: Sensitivity and Resistance

Case Reports in Oncology ◽

10.1159/000503417 ◽

2019 ◽

Vol 12 (3) ◽

pp. 765-776 ◽

Cited By ~ 4

Author(s):

Albina Kibirova ◽

Malcolm D. Mattes ◽

Matthew Smolkin ◽

Patrick C. Ma

Keyword(s):

Kinase Inhibitors ◽

Egfr Mutation ◽

Tumor Response ◽

Checkpoint Inhibitors ◽

Acquired Resistance ◽

Growth Factor Receptor ◽

Epidermal Growth ◽

Egfr Mutant ◽

Egfr Tkis ◽

Guided Therapy

Patients with epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC) have several EGFR targeting tyrosine kinase inhibitors (TKIs) available in frontline management. However, the disease will inevitably progress over time due to acquired resistance. Longitudinal tumor profiling for genomics guided therapy is indicated upon disease progression. It is a common scenario yet, when after failure of EGFR-TKIs, potentially actionable genomic alterations are lacking. Management of such patient is challenging with very limited options available. Combination of chemotherapy, anti-vascular/anti-angiogenic and immune-checkpoint inhibitors may become a salvage option for such patients. Here we describe a case of TKI refractory EGFR-mutant NSCLC successfully treated with carboplatin, paclitaxel, atezolizumab and bevacizumab combination with remarkable prompt tumor response.

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3075 Association between clinical outcome of first EGFR-TKIs and T790M mutation in NSCLC patients harboring EGFR mutation with acquired resistance to EGFR-TKIs

European Journal of Cancer ◽

10.1016/s0959-8049(16)31716-6 ◽

2015 ◽

Vol 51 ◽

pp. S622

Author(s):

Y. Oya

Keyword(s):

Clinical Outcome ◽

Egfr Mutation ◽

Acquired Resistance ◽

T790m Mutation ◽

Nsclc Patients ◽

Egfr Tkis

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

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.8025 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 8025-8025 ◽

Cited By ~ 3

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.

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Rebiopsy of non-small cell lung cancer patients with acquired resistance to EGFR-TKI: Comparison between T790M mutation-positive and -negative populations.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.7528 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 7528-7528 ◽

Cited By ~ 3

Author(s):

Akito Hata ◽

Nobuyuki Katakami ◽

Hiroshige Yoshioka ◽

Jumpei Takeshita ◽

Kosuke Tanaka ◽

...

Keyword(s):

Nucleic Acid ◽

Kinase Inhibitors ◽

Egfr Mutation ◽

Performance Status ◽

Acquired Resistance ◽

Locked Nucleic Acid ◽

Smoking History ◽

Continuous Administration ◽

T790m Mutation ◽

Mutation Site

7528 Background: The secondary epidermal growth factor receptor (EGFR) mutation T790M accounts for approximately half of acquired resistances to EGFR-tyrosine kinase inhibitors (TKI). A recent report has demonstrated the presence of T790M predicts a favorable prognosis and indolent progression, compared to the absence of T790M after TKI failure. However, rebiopsy to confirm T790M status can be challenging due to limited tissue availability and procedural feasibility, and little is known regarding the differences among patients with or without T790M. Methods: We investigated 73 patients harboring EGFR sensitive mutations who had undergone rebiopsy to confirm the emergence of T790M after TKI failure. The peptide nucleic acid-locked nucleic acid PCR clamp method was used in EGFR mutational analyses. Patient characteristics (age, gender, smoking history, performance status, EGFR mutation site, initial TKI, response to initial TKI, line of initial TKI, progression-free survival with initial TKI, and biopsy site) and postprogression survivals (PPS) after initial TKI failure, were retrospectively compared in patients with and without T790M. Results: We identified T790M in 2 (10%) of 21 central nervous system (CNS) (19 cerebrospinal fluid and 2 brain tissue) specimens, and in 20 (38%) of 52 other lesions (25 lung tissue, 24 pleural effusion, and 3 lymph node) (p = 0.0225). Other characteristics had no statistical association with the detection of T790M. Median PPS in patients with T790M was 34.0 months, and in those without T790M, 14.5 months (p = 0.0038). Although none of our patients received TKIs continuously after initial failure, 56 (77%) patients were re-administered TKIs. Regardless of T790M status, PPS in patients with TKI re-administration (23.4 months) was significantly longer than without re-administration (10.4 months) (p = 0.0085). Conclusions: The emergence of T790M in CNS is rare compared with other lesions. Patients with T790M after TKI failure have significantly better prognosis than those without T790M. The effectiveness of TKI re-administration or continuous administration beyond progression is suggested after initial TKI failure.

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

Cells ◽

10.3390/cells10113192 ◽

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.

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

Biomedical Research and Therapy ◽

10.15419/bmrat.v4is.243 ◽

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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Temporal Heterogeneity of ROS1 Fusion and Braf Fusion Conferred Resistance to First-and Third-generation EGFR Tkis: a Case Report.

10.21203/rs.3.rs-32711/v1 ◽

2020 ◽

Author(s):

Meng Zhang ◽

Yihua Huang ◽

Baorong Chen ◽

Yuna Peng ◽

Jing Lin ◽

...

Keyword(s):

Kinase Inhibitors ◽

Acquired Resistance ◽

Progression Free Survival ◽

Temporal Heterogeneity ◽

T790m Mutation ◽

Free Survival ◽

First Case ◽

Exon 19 Deletion ◽

Braf Fusion ◽

Egfr Tkis

Abstract Background: The development of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized the treatment paradigms for non-small cell lung cancer (NSCLC) patients. However, acquired resistance inevitably develops with a median progression-free survival (PFS) less than a year. The advancements in sequencing technologies have significantly promoted the identification of potential resistant mechanisms to targeted therapies.Case presentation: A 39-year-old Chinese male was diagnosed stage IVB NSCLC with EGFR exon 19 deletion (EGFR 19del) and received icotinib but got primary EGFR-TKI resistance caused by ROS1 fusion one month later. Then he received icotinib plus crizotinib and achieved partial response with a profession free survival of 4.8 months. Then he switched to osimertinib plus crizotinib due to the emergence of EGFR T790M mutation. TRIM24-BRAF fusion was detected after osimertinib failure, which might be potential resistant mechanism to osimertinib.Conclusions: This is the first case to confirm crizotinib plus icotinib in patients harboring both EGFR 19del and ROS1 fusion. This case displays the temporal heterogeneity of different resistant mechanisms emerging during disease course, highlighting the importance of dynamic genetic monitoring for better clinical managements.

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