Initial Treatment of Aumolertinib in Combination with Bevacizumab for Advanced NSCLC with Primary EGFR T790M Mutation: A Report of Three Cases and Literature Review / 中国肺癌杂志

With the development of sequencing technology, the detection rate of non-small cell lung cancer (NSCLC) with primary epidermal growth factor receptor (EGFR) T790M mutation is increasing. However, the first-line treatment for primary EGFR T790M-mutated NSCLC still lacks standard recommendations. Here, we reported three advanced NSCLC cases with EGFR-activating mutation and primary T790M mutation. The patients were initially treated with Aumolertinib combination with Bevacizumab; among which, one case was discontinued Bevacizumab due to bleeding risk after treatment for three months. Treatment was switched to Osimertinib after ten months of treatment. Another case switched to Osimertinib and discontinued Bevacizumab after thirteen months of treatment. The best effect response in all three cases was partial response (PR) after initial treatment. Two cases progressed after first-line treatment and progression-free survival (PFS) was eleven months and seven months respectively. The other one patient had persistent response after treatment, and the treatment duration has reached nineteen months. Two cases had multiple brain metastases before administration and the best response to intracranial lesions was PR. The intracranial PFS was fourteen months and not reached (16+ months), respectively. There were no new adverse events (AEs), and no AEs of grade three or above were reported. In addition, we summarized the research progress of Osimertinib in the treatment of NSCLC with primary EGFR T790M mutation. In conclusion, Aumolertinib combined with Bevacizumab in the treatment of advanced NSCLC with primary EGFR T790M mutation has a high objective response rate (ORR) and control ability of intracranial lesions, which can be used as one of the initial options for first-line advanced NSCLC with primary EGFR T790M mutation.
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Ideal sequencing in Stage IV epidermal growth factor receptor mutant Non朣mall?Cell Lung Cancer

Evidence from several studies has shown improved progression?free survival (PFS) with first? or second?generation epidermal growth factor receptor (EGFR)杢yrosine kinase inhibitors (TKIs) compared with chemotherapy for advanced NSCLC patients. But resistance to first or second?generation TKI therapies after 9 to 12 months of treatment initiation is a concern. Osimertinib is a third?generation, irreversible, oral EGFR?TKI that potently and selectively inhibits both EGFRm (epidermal growth factor receptor mutated) and EGFR T790M and has demonstrated efficacy in NSCLC central nervous system (CNS) metastases. Trials have reported significantly longer PFS and higher median duration of response with osimertinib compared with first?generation EGFR?TKIs (erlotinib, gefitinib) and chemotherapy, respectively. And relatively lower rates of discontinuation due to adverse events (AEs). Significant improvement in overall survival was also observed when used as first?line treatment. Because EGFR?mutated tumors are highly dependent on EGFR signaling, optimal sequence of available TKIs � erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib � is necessary. The sequencing of EGFR?TKIs has changed over the past decade and depends on factors such as expected efficacy, CNS activity, tolerability, and options available after progression. Third?generation TKI may be the preferred first?line treatment because patients may not opt for or die before the start of second?line therapy, and it is difficult to predict which patients will eventually develop T790M mutation. The favorable tolerability profile alongside a longer time to disease progression makes osimertinib a preferred first?line treatment. Though clinical practice guidelines do not provide clear consensus on the most preferred EGFR?TKI, recent updates recommend osimertinib as a first?line treatment for advanced NSCLC patients. Also, improved patient selection incorporating clinical and molecular characteristics will help translate to better survival outcomes and improved quality of life. This review aims to determine the optimal sequence of administration of the EGFR?TKIs considering toxicity, quality of life, and survival outcomes among advanced NSCLC patients.

Advances in the research and clinical application of the third generation EGFR TKIs in the treatment of non-small cell lung cancer / 中国临床药理学与治疗学

Epidermal growth factor receptor (EGFR) is one of the most common targeted oncogenes in non-small cell lung cancer (NSCLC). The third-generation EGFR tyrosine kinase inhibitors (TKIs) have become the standard treatment for metastatic or recurrent NSCLC patients harboring EGFR positive or concomitant T790M mutations. However, the inevitable emergence of acquired resistance markedly limits their prolonged clinical benefits, although the third-generation EGFR TKIs have shown potent clinical outcomes in initial several months. This paper firstly reviews the characEpidermal growth factor receptor (EGFR) is one of the most common targeted oncogenes in non-small cell lung cancer (NSCLC). The third-generation EGFR tyrosine kinase inhibitors (TKIs) have become the standard treatment for metastatic or recurrent NSCLC patients harboring EGFR positive or concomitant T790M mutations. However, the inevitable emergence of acquired resistance markedly limits their prolonged clinical benefits, although the third-generation EGFR TKIs have shown potent clinical outcomes in initial several months. This paper firstly reviews the characteristics and clinical efficacy of the third-generation EGFR TKIs in the market or in the clinical development. Then this article summarizes the detailed mechanisms behind the acquired drug resistance of third-generation EGFR TKIs，and further expounds the current treatment strategies to overcome the resistance. Collectively, this review could provide more information for the development and clinical application of drugs targeting EGFR.

Identification of Candidate Biomarkers for EGFR-T790M Drug-resistant Gene Mutation in Advanced Lung Adenocarcinoma / 中国肺癌杂志

BACKGROUND@#Osimertinib is approved by Food and Drug Administration for patients with advanced non-small cell lung cancer carrying EGFR-T790M mutations. Osimertinib therapy was missed in many patients who were unable to perform biopsy due to occult lesion progression or weak body. In this study. We hope that some proteins associated with predicting EGFR-T790M resistance could be screened from the serum to provide help for clinical medication. The aim of this study is to explore the protein associated with EGFR-T790M drug resistance gene and provide help for clinical medication.@*METHODS@#In this study, 36 patients with advanced lung adenocarcinoma treated by gefitinib were included. After the disease progression of the patients, biopsy was performed. 18 patients in the EGFR-T790M mutation group and 18 patients in the non-EGFR-T790M mutation group were detected by the ARMS method. Serum of patients with drug resistance was collected, and proteins related to EGFR-T790M resistance were screened by isotopic marker relative and absolute quantitative marker combined with two-dimensional liquid chromatography tandem mass spectrometry proteomics technology.@*RESULTS@#Seventeen different proteins were screened out, including 6 up-regulated proteins and 11 down-regulated proteins associated with EGFR-T790M gene mutation, which were mainly involved in 31 biological processes, 7 cell components and 26 molecular functions. Twelve enrichment pathways were identified, among which the highest enrichment index was the coagulation cascade pathway.@*CONCLUSIONS@#Seventeen proteins associated with EGFR-T790M resistance were found, and proteins involved in the coagulation cascade pathway are expected to be biomarkers associated with predicting EGFR-T790M resistance mutations.

Acquired Drug Resistance Mechanism of Osimertinib in the Targeted Therapy of Non-small Cell Lung Cancer / 中国肺癌杂志

While treating cancer, epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) still faces inevitable drug resistance. Investigations into the mechanisms which foster resistance to EGFR-TKI has led to the discovery of novel biomarkers and drug targets, and in turn has enabled the development of third-generation TKIs and proposals for rational therapeutic combinations. The threonine-to-methionine substitution mutation at position 790 (T790M) is clinically validated to engender refractoriness to first- and second-generation TKI, and is a standard-of-care predictive biomarker used in therapeutic stratification. For patients who are T790M-negative, cytotoxic chemotherapy or protracted EGFR-TKI treatment are acceptable treatment standards after disease progression, although combinations of targeted therapies and checkpoint blockade immunotherapy may offer promising alternatives in the future. Among T790M-positive patients, the third-generation EGFR-TKI, osimertinib, has shown superiority over both platinum-doublet chemotherapy and first-generation EGFR-TKI in randomized clinical trials. This article appraises the key literature on the contemporary management of non-small cell lung cancer patients with acquired resistance to EGFR-TKIs, and envisions future directions in translational and clinical research.

Case Report of Non-small Cell Lung Cancer Patient with EGFR T790M Mutation Treated with Th ird Generation Inhibitor

Lung cancer treatment based on the molecular classifi cation of the tumor has paved the way for multiple lines of targeted treatment, even though the development of resistance remains a major cause of concern. Epidermal growth factor receptor (EGFR) remains the poster boy for the use of targeted therapy, and the presence/absence of mutations in this gene has led to the development of inhibitors targeting specifi c mutations. We present the case of an advanced non-small cell lung cancer patient with EGFR T790M mutation treated with Osimertinib, a third-generation inhibitor.

Provisional Guideline Recommendation for EGFR Gene Mutation Testing in Liquid Samples of Lung Cancer Patients: A Proposal by the Korean Cardiopulmonary Pathology Study Group

Liquid biopsy for detection of mutation from circulating tumor DNA is a new technology which is attractive in that it is non-invasive. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is an effective first line drug for advanced non-small cell lung cancer patients who harbor activating EGFR mutation. During the course of treatment, resistance against TKI arises which can be contributed to EGFR T790M mutation in about 50–60% of patients. Third generation TKI may overcome the resistance. In patients who cannot undergo tissue biopsy due to variable reasons, liquid biopsy is an excellent alternative for the detection of EGFR T790M mutation. However, this relatively novel method requires standardization and vigorous quality insurance. Thus, a standard set of guideline recommendations for liquid biopsy for EGFR mutation testing suitable for the Korean medical community is necessary. In this article, we propose a set of provisional guideline recommendations that was discussed and approved by the Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists.

A Phase II Trial of Osimertinib in the Second-Line Treatment of Non-small Cell Lung Cancer with the EGFR T790M Mutation, Detected from Circulating Tumor DNA: LiquidLung-O-Cohort 2 / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Administering the best treatment after failure of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy requires knowledge of resistance status. In this trial, treatment efficacy of osimertinib was assessed in patients with non-small cell lung carcinoma (NSCLC) harboring the T790M resistance mutation, detected from circulating tumor DNA (ctDNA) with unknown tumor mutation status. MATERIALS AND METHODS: To extract ctDNA from plasma, 15 mL of peripheral blood was withdrawn and centrifuged immediately before storage. Cobas ver. 2 and PANA Mutyper were used for ctDNA genotyping. Patients with T790M, detected from ctDNA, were enrolled and they received a once-daily administration of osimertinib 80 mg. The primary endpoint was objective response rate (ORR), and secondary endpoints were ctDNA test sensitivity, progression-free survival (PFS), duration of response (DoR), and safety. RESULTS: Eighty patients with acquired resistance to prior EGFR-TKI therapies were screened. ctDNA of 21 patients showed T790M positivity, and 19 patients were enrolled. In the response-evaluable population (n=15), ORR was 66.7% (10/15). Median PFS was 8.3 months (95% confidence interval [CI], 7.9 to 8.7) and median DoR was 6.8 months (95% CI, 5.3 to 8.3) in the intent-to-treat population (n=19). No subject experienced drug-related adverse event of grades ≥ 3 or required dose reduction. The sensitivity of the ctDNA tests was 56.8% using both methods and 45.9% with either method from the estimated T790M-positive cases. CONCLUSION: Osimertinib has favorable efficacy in patients with NSCLC harboring T790M, detected from ctDNA with unknown tumor mutation status, in whom disease had progressed during prior EGFR-TKI therapy.

Real-World Analysis of the Efficacy of Rebiopsy and EGFR Mutation Test of Tissue and Plasma Samples in Drug-Resistant Non-Small Cell Lung Cancer

PURPOSE: Standard treatment for cases of non-small cell lung cancer (NSCLC) exhibiting acquired drug resistance includes tumor rebiopsy, epidermal growth factor receptor (EGFR) mutation testing (e.g., for T790M mutations), and the subsequent administration of third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, rebiopsies are typically invasive, costly, and occasionally not feasible. Therefore, the present study aimed to assess rebiopsy procedures by analyzing real-world data collected by the ASTRIS study of patients with resistant NSCLC. MATERIALS AND METHODS: The present study used statistical models to evaluate data collected by the ASTRIS trial (NCT02474355) conducted at Yonsei Cancer Center, including the rebiopsy success rate, incidence of T790M mutations in collected tissue and plasma samples, and association of administered osimertinib treatment efficacy. RESULTS: In a total of 188 screened patients, 112 underwent rebiopsy. An adequate tumor specimen was obtained in 95 of these patients, the greatest majority of whom (43.8%) were subjected to bronchoscopy. T790M mutations were detected in 53.3% of successfully EGFR-tested rebiopsy samples. A total of 88 patients received osimertinib treatment, and the objective response rate and median progression-free survival time was 44.3% and 32.7 weeks, respectively, among the treated patients overall, but 57.8% and 45.0 weeks, and 35.2% and 20.4 weeks among patients who exhibited T790M-positive tissue (n=45) and plasma (n=54) samples, respectively. CONCLUSION: Approximately 60% of patients in the analyzed real-world cohort were eligible for tissue rebiopsy upon NSCLC progression. Osimertinib activity was higher in patients in whom T790M mutations were detected in tissues rather than in plasma samples.

Analysis of related factors for long-term results and prognosis of personalized treatment in T790M-positive lung adenocarcinoma patients with bone metastasis / 中国肿瘤生物治疗杂志

@# Objective: To explore the related factors for efficacy and prognosis of personalized comprehensive treatment for T790Mpositive lung adenocarcinoma patients with bone metastasis. Methods: The clinical data of 68 patients undergoing personalized comprehensive treatment for T790M-positive lung adenocarcinoma with bone metastasis were retrospectively reviewed; chemotherapy, radiotherapy, molecule-targeted agents, Bevacizumab, bisphosphonate and other therapies were chosen for the patients, and the efficacy and prognosis were observed to explore the related factors. Results: Effective rate of personalized comprehensive treatment was 60.3% (41/ 68), with a median survival time of 23 months. Multiple factors showed significant effects on long-term efficacy, such as no radiotherapy, T790M mutation but no KRAS mutation, adjuvant scheme+rescue scheme in prior chemotherapy treatment, N1 stage, isolated bone metastasis, alternative treatment of osimertinib with chemotherapy, less metastasized organs and ECOG scores<2 (P<0.05). Multivariate analysis revealed that T790M mutation but no KRAS mutation (P=0.012), number of metastasized organs =0 or 1 (P=0.000), alternative treatment of osimertinib with chemotherapy (P=0.020), and isolated bone metastasis (P=0.006) were independent protective factors for long-term results of personalized comprehensive treatment for T790M-positive lung adenocarcinoma patients with bone metastasis. Conclusion: Chemotherapy combined with osimertinib, agents of bisphosphonate and other personalized comprehensive treatment prolongs survival time in T790M-positive lung adenocarcinoma patients without KRAS mutation, providing a potential therapeutic model for those patients.

Advanced Research on Non-small Cell Lung Cancer with De Novo T790M Mutation / 中国肺癌杂志

With the development of sequencing technology, the detection rate of de novo T790M mutation is increasing. The emergence of the third generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) provide treatment opportunities. Secondary T790M mutation is often emphasized in clinic, but de novo T790M mutation is neglected. This review found that the incidence of de novo T790M mutation fluctuated greatly, which was mainly affected by sequencing techniques. The de novo T790M mutation is mainly low in mutation abundance, easy to combine with other gene changes, a poor predictor and prognostic factor and the efficacy of the first and second generation EGFR-TKIs is limited. The therapeutic value of osimertinib needs to be studied.
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The Association of Acquired T790M Mutation with Clinical Characteristics after Resistance to First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Lung Adenocarcinoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The main objective of this study was to investigate the relationship among the clinical characteristics and the frequency of T790M mutation in advanced epidermal growth factor receptor (EGFR)–mutant lung adenocarcinoma patients with acquired resistance after firstline EGFR–tyrosine kinase inhibitor (TKI) treatment. MATERIALS AND METHODS: We enrolled EGFR-mutant stage IIIB-IV lung adenocarcinoma patients, who had progressed to prior EGFR-TKI therapy, and evaluated their rebiopsy EGFR mutation status. RESULTS: A total of 205 patients were enrolled for analysis. The overall T790M mutation rate of rebiopsy was 46.3%. The T790M mutation rates among patients with exon 19 deletion mutation, exon 21 L858R point mutation, and other mutations were 55.0%, 37.3%, and 27.3%, respectively. Baseline exon 19 deletion was associated with a significantly higher frequency of T790M mutation (adjusted odds ratio, 2.14; 95% confidence interval [CI], 1.20 to 3.83; p=0.010). In the exon 19 deletion subgroup, there was a greater prevalence of T790M mutation than other exon 19 deletion subtypes in patients with the Del E746-A750 mutation (61.6% vs. 40.6%; odds ratio, 2.35; 95% CI, 1.01 to 5.49; p=0.049). The progression-free survival (PFS) of first-line TKI treatment > 11 months was also associated with a higher T790M mutation rate (54.1% vs. 39.3%; adjusted odds ratio, 1.82; 95% CI, 1.02 to 3.25; p=0.044). Patients who underwent rebiopsy at metastatic sites had more chance to harbor T790M mutation (52.6% vs. 33.8%; adjusted odds ratio, 1.97; 95% CI, 1.06 to 3.67; p=0.032). CONCLUSION: PFS of first-line EGFR-TKI, rebiopsy site, EGFR exon 19 deletion and its subtype Del E746-A750 mutation are associated with the frequency of T790M mutation.

Monitoring EGFR T790M mutations by Blocker PCR in plasma of advanced non-small-cell lung cancer patients with EGFR-TKI acquired resistance / 复旦学报（医学版）

Objective To evaluate the feasibility of Blocker PCR assays in monitoring T790M mutations in plasma of non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) acquired resistance.Methods Blocker PCR assays were employed to identify mutations in plasma for 127 advanced NSCLC with acquired EGFR-TKI resistance.In addition,the paired tumor re-biopsy or PE samples were obtained to analyze EGFR mutations.Meanwhile,we evaluated the detection accuracy of Blocker PCR assays in comparison with the next generation sequencing (NGS).Results Among the 127 patients,40.15％ (51/127) EGFR T790M was detected in the plasma,78.44％ (40/51) coexisted with an EGFR activating mutation.Additionally,54.54 ％ (6/11) EGFR T790M was identified in re-biopsy tissues,while 43.75 ％ (14/32) were detected in the plasma.Furthermore,the concordance rate of Blocker PCR and NGS in identifying EGFR sensitizing mutations and EGFR T790M mutations was 100％.Conclusions Blocker PCR is a highly sensitive and reliable method in monitoring EGFR T790M mutations in the plasma of NSCLC patients with EGFR-TKI acquired resistance.

Influence of Different Therapies on EGFR Mutants by Circulating Cell-free DNA of Lung Adenocarcinoma and Prognosis / 中国肺癌杂志

BACKGROUND@#Epidermal growth factor receptor (EGFR) gene mutation is closely related to the EGFR-TKI target treatment and prognosis of lung adenocarcinoma patients. The mutation status of EGFR is limited by tissue detection. The purpose of this study was to investigate the difference of EGFR mutants in plasmacirculating cell-free DNA (cfDNA) obtained from patients with non-small cell lung cancer (NSCLC) in three groups: pre-therapy, after traditional chemotherapy and targeted therapy. The aim of this study was to analyze whether the plasma cfDNA could effectively determine the EGFR mutations and monitor the drug resistant gene T790M, as well as its prognostic prediction value in patients with targeted therapy.@*METHODS@#ARMS (amplification refractory mutation system)-PCR was used to detect EGFR mutations in 107 (50 of pre-therapy, 29 after traditional chemotherapy and 28 after targeted therapy) cases of paired plasma and tumor tissue specimens, followed by comparing their concordance. The sensitivity, specificity and the prognostic value of plasma cfDNA detection were also observed.@*RESULTS@#The total rate of EGFR mutation was 56% (60/107) in all plasma samples and 77.6% (83/107) in corresponding tumor tissues. Completely the same mutants and wild-type EGFR were found in 68.2% cases of paired specimens. The sensitivity of plasma cfDNA detection was 72.3% and the specificity was up to 100%. Patients were sub-categorized according to therapy. The results showed that the highest consistent rate of cfDNA and tumor tissues was found in the group of pre-therapy (74%, 37/50). Whereas, the lowest consistent rate was observed in the targeted therapy group (57.1%, 16/28). It indicated that the targeted treatment could change the EGFR status in plasma cfDNA. Further analyses on inconsistent cases in this group revealed that 50% of them were compound EGFR mutations with T790M. Thereby, it suggested that targeted therapy might induce the emergence of drug resistance gene T790M. This speculation was confirmed by survival analyses. Based on plasma cfDNA results, patients with T790M mutant had significantly worse progression-free survival (PFS) and overall survival (OS).@*CONCLUSIONS@#For EGFR testing, ARMS-PCR on plasma cfDNA is a promising methodology with the highest specificity and effective sensitivity. It is useful for EGFR testing in patients before treatment, especially the late-stage patients. Simultaneously, plasma cfDNA could be used to monitor the drug resistant mutation, T790M status and predict prognosis after targeted therapy.

Evaluation of Consistency in detection of epidermal growth factor receptor gene T790M mutation in plasma and tumor specimens of patients with lung adenocarcinoma / 中华肿瘤杂志

Objective@#To evaluate the consistency in detection of T790M mutation of epidermal growth factor receptor gene (EGFR) in plasma and tumor samples of patients with lung adenocarcinoma.@*Methods@#The tumor tissues or cytological specimens of 12 patients with operable lung adenocarcinoma(stage Ⅰ-ⅢA) and 100 patients with advanced stage ⅢB-Ⅳ lung adenocarcinoma were collected, among which 11 patients showed acquired resistance for gefitinib (11/100). In the same period, peripheral blood samples were collected from all patients and 50 healthy volunteers. Amplification refractory mutation system (ARMS) was used to detect EGFR mutations in tumor specimens. Next Generation Sequencing(NGS) based circulating single-molecule amplification and resequencing technology (cSMART)was performed to quantitatively detect the EGFR mutations in circulating tumor DNA (ctDNA) from plasma specimens.@*Results@#The sensitivity, specificity and concordance rate of EGFR T790M mutation between plasma and tissue specimens from 100 advanced stage patients were 50.0%, 72.9% and 72.0%, respectively. For L858R mutation and exon 19 deletion mutations, the above mentioned sensitivity, specificity and concordance rate were 91.7%, 100.0%, and 98.0%, as well as 79.2%, 100.0% and 95.0%, respectively. The L858R mutation and exon 19 deletion mutations were not detected in plasma of 50 healthy volunteers, whereasT790M mutation(1.0±0.0 copies) was found in 7 individuals(7/50, 14.0%). Similarly, in 12 resectable patients, 4 (4/12, 33.3%) T790M mutations were found in plasma (1.2±0.2 copies), but no L858R mutation and 19 exon deletion mutations. In comparison, 28.0% of patients with advanced lung adenocarcinoma (28/100)had detectable T790M mutation in plasma with copy numbers (34.0±22.7 copies). Furthermore, the copy numbers of T790M were 268.2±119.9 in plasma of 5 cases with acquired gefitinib-resistance.@*Conclusions@#In patients with advanced stages of lung adenocarcinoma, the detection of T790M mutation in plasma and tumor specimens is low. The T790M mutation also exists in the plasma of some healthy controls, suggesting that T790M mutation participates in EGFR signaling pathway and it might function in healthy population.

Analysis of epidermal growth factor receptor gene T790M mutation in plasmatic ctDNA samples of pa-tients with non-small cell lung cancer / 实用医学杂志

Objective To investigate epidermal growth factor receptor(EGFR)gene T790M mutation in plasmatic ctDNA samples from 171 patients with non-small cell lung cancer and analyze the relationship between EGFR T790M mutation and the clinical factors. Methods The EGFR T790M mutation was detected in 171 cases by super amplification refractory mutation system(Super ARMS)in this paper. Rusults The EGFR gene T790M mutation was identified in 7.60%(13/171)plasmatic ctDNA samples which mostly came from patients withⅢb~Ⅳstages of lung cancer. The EGFR T790M mutation rate was identified in 2.05%(3/146)plasmatic samples of pa-tients who did not received treatment of EGFR-TKIs,which was lower than 40.00%(10/25,P<0.05)plasmatic samples of patients who received treatment of first generational EGFR-TKIs. The EGFR T790M mutation rate was identified in 75.00%(3/4) and 60.00%(6/10) plasmatic samples of patients who have received TKI for 6 to 10 months and more than 10 months,which was higher than 9.10%(1/11,P < 0.05)plasmatic samples of patients who have received TKIs for less than 6 months. Conclusions This article demonstrated that EGFRT790M muta-tion was more common in lately NSCLC patients who have received TKIs treatmentover 6 months,meanwhile the EGFR T790M mutation dynamical detective technology will effectively guide the clinic treatment.

Analysis of epidermal growth factor receptor gene T790M mutation in plasmatic ctDNA samples of pa-tients with non-small cell lung cancer / 实用医学杂志

Objective To investigate epidermal growth factor receptor(EGFR)gene T790M mutation in plasmatic ctDNA samples from 171 patients with non-small cell lung cancer and analyze the relationship between EGFR T790M mutation and the clinical factors. Methods The EGFR T790M mutation was detected in 171 cases by super amplification refractory mutation system(Super ARMS)in this paper. Rusults The EGFR gene T790M mutation was identified in 7.60%(13/171)plasmatic ctDNA samples which mostly came from patients withⅢb~Ⅳstages of lung cancer. The EGFR T790M mutation rate was identified in 2.05%(3/146)plasmatic samples of pa-tients who did not received treatment of EGFR-TKIs,which was lower than 40.00%(10/25,P<0.05)plasmatic samples of patients who received treatment of first generational EGFR-TKIs. The EGFR T790M mutation rate was identified in 75.00%(3/4) and 60.00%(6/10) plasmatic samples of patients who have received TKI for 6 to 10 months and more than 10 months,which was higher than 9.10%(1/11,P < 0.05)plasmatic samples of patients who have received TKIs for less than 6 months. Conclusions This article demonstrated that EGFRT790M muta-tion was more common in lately NSCLC patients who have received TKIs treatmentover 6 months,meanwhile the EGFR T790M mutation dynamical detective technology will effectively guide the clinic treatment.

Mechanism and clinical efficacy of third-generation epidermal growth factor receptor tyrosine kinase inhibitor in non-small cell lung cancer / 中华肿瘤杂志

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, most of patients will develop resistance to TKIs treatment due to the emergence of the T790M mutation. The third-generation EGFR-TKI is highly selective and efficient for activating mutants (EGFR sensitive mutations) and resistance mutant (T790M+ ). This review summarizes the mechanism and clinical efficacy of the third-generation EGFR-TKI in NSCLC patients.

A Phase II Study of Poziotinib in Patients with Epidermal Growth Factor Receptor (EGFR)-Mutant Lung Adenocarcinoma Who Have Acquired Resistance to EGFR–Tyrosine Kinase Inhibitors / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: We examined the efficacy of poziotinib, a second-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) in patients with lung adenocarcinoma with activating EGFR mutations, who developed acquired resistance (AR) to EGFR-TKIs. MATERIALS AND METHODS: This single-arm phase II study included EGFR-mutant lung adenocarcinoma with AR to erlotinib or gefitinib based on the Jackman criteria. Patients received poziotinib 16 mg orally once daily in a 28-day cycle. The primary endpoint was progression-free survival (PFS). Prestudy tumor biopsies and blood samples were obtained to determine resistance mechanisms. RESULTS: Thirty-nine patients were treated. Tumor genotyping was determined in 37 patients; 19 EGFR T790M mutations and two PIK3CA mutations were detected in the prestudy tumors, and seven T790M mutations were detected in the plasma assay. Three (8%; 95% confidence interval [CI], 2 to 21) and 17 (44%; 95% CI, 28 to 60) patients had partial response and stable disease, respectively. The median PFS and overall survival were 2.7 months (95% CI, 1.8 to 3.7) and 15.0 months (95% CI, 9.5 to not estimable), respectively. A longer PFS was observed for patients without T790M or PIK3CA mutations in tumor or plasma compared to those with these mutations (5.5 months vs. 1.8 months, p=0.003). The most frequent grade 3 adverse events were rash (59%), mucosal inflammation (26%), and stomatitis (18%). Most patients required one (n=15) or two (n=15) dose reductions. CONCLUSION: Low activity of poziotinib was detected in patients with EGFR-mutant non-small cell lung cancer who developed AR to gefitinib or erlotinib, potentially because of severe-toxicityimposed dose limitation.

The research on the change of chemosensitivity of geiftinib-resistant lung adenocarcinoma cell caused byEGFR-T790M mutation / 中国癌症杂志

Background and purpose:Chemotherapy is an alternative treatment option, which could still get a therapeutic effect, when the EGFR-TKI treatment of non-small cell lung cancer failed. Studies have shown that RR, TYMS, ERCC1 and TUBB3 have respectively relationship with chemosensitivity of gemcitabine, pemetrexed, platinum-based drugs and microtubule-based chemotherapy drugs.The expression levels of these molecular markers can predict the sensitivity of these chemotherapy drugs. The patients with RRMI, TS, ERCC1 and TUBB3 higher expression have reduced chemosensitivity, and lower expression have increased sensitivity. The purpose of this study was to explore the sensitivity of tumor cell lines with acquired resistance to geiftinib caused byEGFR-T790M mutation to cisplatin, gemcitabine, pemetrexed, vinorelbine, paclitaxel and docetaxel.Methods:MTT assay was used to detect the IC50 values of cisplatin, gemcitabine, vinorelbine, paclitaxel and docetaxel, pemetrexed to PC9 and PC9/GR cells, and to explore the chemosensitivity of lung adenocarcinoma cells to these chemotherapy drugs; Luminex method was used respectively to detect the expression levels of ERCC1 mRNA, TUBB3 mRNA, TS mRNA, and RRM1 mRNA in PC9 and PC9/GR cells. Western blot was used to detect the protein expression levels of ERCC1, TUBB3, TS and RRM1 in PC9 and PC9/GR cells.Results: The IC50 values of cisplatin, gemcitabine and pemetrexed to PC9/GR cells were signiifcantly higher than those to PC9 cells (P<0.05), while the IC50 values of vinorelbine, paclitaxe and docetaxel to PC9/GR cells were signiifcantly decreased (P<0.05). Luminex method showed the expressions of ERCC1 mRNA, TS mRNA and RRM1 mRNA in PC9/GR cells were signiifcantly increased than those in PC9 cells (P<0.05), while the expression of TUBB3 mRNA was signiifcantly decreased (P<0.05). Western blot method showed the expressions of TUBB3, TS and RRM1 protein in PC9/GR cells were signiifcantly increased than those in PC9 cells (P<0.05), while TUBB3 protein expression in PC9/GR cells was signiifcantly decreased (P<0.05). Western blot method analysis result showed that the expressions of TUBB3, TS and RRM1 protein in PC9/GR cells were significantly increased than those in PC9 cells (P<0.05), while TUBB3 protein expression in PC9/GR cells was signiifcantly decreased (P<0.05). Conclusion:The chemosensitivity of lung adenocarcinoma with EGFR-T790M mutation is changed. It has decreased sensitivity to cisplatin, gemcitabine, pemetrexed and increased sensitivity to vinorelbine, paclitaxel and docetaxel. The reason of the change of chemosensitivity of geiftinib-resistant lung adenocarcinoma cell maybe related to the changes of ERCC1 mRNA, RRM1 mRNA and TS mRNA and their protein expressions.