P-81 Therapeutic efficacy comparison of second-generation EGFR-TKI (afatinib) and first-generation EGFR-TKIs (gefitinib/erlotinib) in Advanced EGFR-positive Non-Small-cell Lung Cancer in the real world

강래형,윤성훈,서현택,옥혜성,변기섭,전두수 대한결핵 및 호흡기학회 2017 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.124 No.-

Objective: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are routinely used to treat non small cell lung cancer (NSCLC) in patients with activating mutations of the EGFR gene. The aim of the study was to compare the efficacies of second-generation EGFR-TKI (afatinib) and first-generation EGFR-TKIs (gefitinib/erlotinib) in the real world. Method: A retrospective analysis of 93 NSCLC patients treated with second-generation EGFR-TKI (afatinib, n=53) and first-generation EGFR-TKIs (gefitinib/erlotinib, n=42) was performed. EGFR mutations were analyzed using PNA clamp. We assessed the response of tumor and progression-free survival with the type of EGFR gene mutation. Result: Second-generation EGFR-TKI (afatinib) versus First-generation EGFR-TKIs (gefitinib/erlotinib) showed that the objective response rates were 73% versus 63% (p=0.962) and median progression-free survival (PFS) was 11 versus 13.6 months (p= 0.385). Discontinuation rate due to drug-related adverse events was 7 patient (16%) versus 4 patient (8%). The type of EGFR mutation had no impact on median PFS and response rate. Demographic and clinical factors had no impact on PFS or response rate in patients treated with EGFR TKIs. Conclusion: Second-generation EGFR-TKI (afatinib) and first-generation EGFR-TKIs (gefitinib/erlotinib) showed similar efficacies based on treatment response, median PFS (regardless of the type of EGFR gene mutation).

MDR1/ABCB1 gene polymorphisms in patients with chronic myeloid leukemia

Mabel Lardo,Marcelo Castro,Beatriz Moiraghi,Francisca Rojas,Natalia Borda,Jorge A Rey,Alberto Lazarowski 대한혈액학회 2015 Blood Research Vol.50 No.3

BackgroundTyrosine kinase inhibitors (TKIs) are the recommended treatment for patients with chronic myeloid leukemia (CML). The MDR1/ABCB1 gene plays a role in resistance to a wide spec-trum of drugs, including TKIs. However, the association of MDR1/ABCB1 gene poly-morphisms (SNPs) such as C1236T, G2677T/A, and C3435T with the clinical therapeutic evolution of CML has been poorly studied. We investigated these gene polymorphisms in CML-patients treated with imatinib, nilotinib and/or dasatinib.MethodsABCB1-SNPs were studied in 22 CML-patients in the chronic phase (CP) and 2 CML-pa-tients in blast crisis (BC), all of whom were treated with TKIs, and compared with 25 healthy controls using nested-PCR and sequencing techniques.ResultsSeventeen different haplotypes were identified: 7 only in controls, 6 only in CML-patients, and the remaining 4 in both groups. The distribution ratios of homozygous TT-variants present on each exon between controls and CML-patients were 2.9 for exon 12, and 0.32 for the other 2 exons. Heterozygous T-variants were observed in all controls (100%) and 75% of CML-patients. Wt-haplotype (CC-GG-CC) was observed in 6 CML-patients (25%). In this wt-group, two were treated with nilotinib and reached a major molecular response. The remaining 4 cases had either a minimal or null molecular response, or developed bone marrow aplasia.ConclusionOur results suggest that SNPs of the MDR1/ABCB1 gene could help to characterize the prognosis and the clinical-therapeutic evolution of CML-patients treated with TKIs. Wt-haplotype could be associated with a higher risk of developing CML, and a worse clin-ical-therapeutic evolution.

MDR1/ABCB1 gene polymorphisms in patients with chronic myeloid leukemia

Mabel Lardo,Marcelo Castro,Beatriz Moiraghi,Francisca Rojas,Natalia Borda,Jorge A Rey,Alberto Lazarowski 대한혈액학회 2015 Blood Research Vol.50 No.3

BackgroundTyrosine kinase inhibitors (TKIs) are the recommended treatment for patients with chronic myeloid leukemia (CML). The MDR1/ABCB1 gene plays a role in resistance to a wide spec-trum of drugs, including TKIs. However, the association of MDR1/ABCB1 gene poly-morphisms (SNPs) such as C1236T, G2677T/A, and C3435T with the clinical therapeutic evolution of CML has been poorly studied. We investigated these gene polymorphisms in CML-patients treated with imatinib, nilotinib and/or dasatinib.MethodsABCB1-SNPs were studied in 22 CML-patients in the chronic phase (CP) and 2 CML-pa-tients in blast crisis (BC), all of whom were treated with TKIs, and compared with 25 healthy controls using nested-PCR and sequencing techniques.ResultsSeventeen different haplotypes were identified: 7 only in controls, 6 only in CML-patients, and the remaining 4 in both groups. The distribution ratios of homozygous TT-variants present on each exon between controls and CML-patients were 2.9 for exon 12, and 0.32 for the other 2 exons. Heterozygous T-variants were observed in all controls (100%) and 75% of CML-patients. Wt-haplotype (CC-GG-CC) was observed in 6 CML-patients (25%). In this wt-group, two were treated with nilotinib and reached a major molecular response. The remaining 4 cases had either a minimal or null molecular response, or developed bone marrow aplasia.ConclusionOur results suggest that SNPs of the MDR1/ABCB1 gene could help to characterize the prognosis and the clinical-therapeutic evolution of CML-patients treated with TKIs. Wt-haplotype could be associated with a higher risk of developing CML, and a worse clin-ical-therapeutic evolution.

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Versus Placebo as Maintenance Therapy for Advanced Non-small-cell Lung Cancer: A Meta-analysis of Randomized Controlled Trials

Alimujiang, S.,Zhang, Tao,Han, Zhi-Gang,Yuan, Shuai-Fei,Wang, Qiang,Yu, Ting-Ting,Shan, Li Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.4

Background: Use of epidermal growth factor receptor inhibitors (EGFR-TKIs ) is now standard for non-small-cell lung cancer (NSCLC). However, the effects of EGFR-TKIs in maintenance therapy for advanced NSCLC patients are still unclear. The preent meta-analysis was performed to examine pooled data of randomized control trials (RCT) where EGFR-TKIs were compared against placebo in maintenance regimens for patients with advanced NCSLC to quantify potential benefits and determine safety. Methods: Several data bases were searched, including PubMed, EMBASE and CENTRAL, and we performed an internet search of conference literature. The endpoints were objective response rates (ORR), progression-free survival (PFS) and overall survival (OS). We performed a meta-analysis of the published data, using Comprehensive Meta Analysis software (Version 2.0). with a fixed effects model and an additional random effects model, when applicable. The results of the meta-analysis are expressed as hazard ratios (HRs) or risk ratios (RRs), with their corresponding 95% confidence intervals (95%CIs). Results: The final analysis included six trials, covering 3,758 patients. Compared with placebo, EGFR-TKIs maintenance therapy improved ORR and PFS for patients with advanced NSCLC, the difference being statistically significant (P<0.05), but proved unable to prolong patients' OS. The main adverse reactions were diarrhea and rashes. Conclusion: EGFR-TKIs demonstrated encouraging efficacy, safety and survival when delivered as maintenance therapy for patients with advanced NSCLC after first-line chemotherapy, especially for the patients who had adenocarcinomas, were female, non-smokers and patients with EGFR gene mutations.

F-145 Cumulative smoking dose affects the clinical outcomes of EGFR-mutated lung adenocarcinoma patients treated with EGFR-TKIs

김인애,김희정,이종식,김완섭,이계영 대한결핵 및 호흡기학회 2017 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.124 No.-

Lung adenocarcinoma with activating epidermal growth factor receptor(EGFR) mutations is mostly found in never smoker but one third of the patients are ever smokers. The aim of this study is to investigate whether cumulative smoking dose(CSD) affects the clinical outcomes such as progression-free survival(PFS) and overall survival(OS) in EGFR-mutated lung adenocarcinoma patients treated with EGFR-TKIs. We retrospectively analyzed 142 advanced or recurrent lung adenocarcinoma patients who harbored activating EGFR mutations and had received gefitinib, erlotinib or afatinib. The patients were classified into 4 groups by CSD (never smoker, light smoker (≤10 pack-years(PYs), moderate smoker (11-30 PYs) and heavy smoker (> 30 PYs)). PFS and OS were analyzed according to smoking subgroups by Kaplan- Meier curves Among 142 EGFR-mutated patients, 91(64.1%) were never-smokers, 12(8.5%) were light smokers, 22(15.5%) were moderate smokers and 17(12%) were heavy smokers. CSD was inversely associated with median PFS in dose-dependent manner with statistical significance. (11.8 months, 10.9 months, 7.4 months, 3.9 months. p < 0.05). Statistically significant negative association between CSD and median OS was also observed.(33.6months, 26.3months, 20months, 8.9months: p<0.001) In the multivariate analysis adjusted for age, sex, performance status, stage, and the timing of EGFR-TKIs, CSD was an independent negative predictive factor for the disease progression (hazard ratio, 2.98; 95% confidence interval(CI), 1.74-5.01 p = 0.012) and OS(HR 3.9,p<0.001)to EGFR-TKIs.

Subsequent Treatment Choices for Patients with Acquired Resistance to EGFR-TKIs in Non-small Cell Lung Cancer: Restore after a Drug Holiday or Switch to another EGFR-TKI?

Song, Tao,Yu, Wei,Wu, Shi-Xiu Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.1

The outcomes of first-generation EGFR-TKIs (Gefitnib and Erlotinib) have shown great advantages over traditional treatment strategies in patients with non-small cell lung cancer (NSCLC), but unfortunately we have to face the situation that most patients still fail to respond in the long term despite initially good control. Up to now, the mechanism of acquired resistance to EGFR-TKIs has not been fully clarified. Herein, we sought to compile the available clinical reports in the hope to better understanding the subsequent treatment choices, particularly on whether restoring after a drug holiday or switching to another EGFR-TKI is the better option after failure of one kind of EGFR-TKI.

Chronicles of EGFR Tyrosine Kinase Inhibitors: Targeting EGFR C797S Containing Triple Mutations

( Krishna Babu Duggirala ),( Yujin Lee ),( Kwangho Lee ) 한국응용약물학회 2022 Biomolecules & Therapeutics(구 응용약물학회지) Vol.30 No.1

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase widely expressed in many cancers such as non-small cell lung cancer (NSCLC), pancreatic cancer, breast cancer, and head and neck cancer. Mutations such as L858R in exon 21, exon 19 truncation (Del19), exon 20 insertions, and others are responsible for aberrant activation of EGFR in NSCLC. First-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have clinical benefits for EGFR-sensitive (L858R and Del19) NSCLC patients. However, after 10-12 months of treatment with these inhibitors, a secondary T790M mutation at the gatekeeper position in the kinase domain of EGFR was identified, which limited the clinical benefits. Second-generation EGFR irreversible inhibitors (afatinib and dacomitinib) were developed to overcome this T790M mutation. However, their lack of selectivity toward wild-type EGFR compromised their clinical benefits due to serious adverse events. Recently developed third-generation irreversible EGFR TKIs (osimertinib and lazertinib) are selective toward driving mutations and the T790M mutation, while sparing wildtype EGFR activity. The latest studies have concluded that their efficacy was also compromised by additional acquired mutations, including C797S, the key residue cysteine that forms covalent bonds with irreversible inhibitors. Because second- and thirdgeneration EGFR TKIs are irreversible inhibitors, they are not effective against C797S containing EGFR triple mutations (Del19/ T790M/C797S and L858R/T790M/C797S). Therefore, there is an urgent unmet medical need to develop next-generation EGFR TKIs that selectively inhibit EGFR triple mutations via a non-irreversible mechanism.

Nicotinamide in Combination with EGFR-TKIs for the Treatment of Stage IV Lung Adenocarcinoma with EGFR Mutations: A Randomized Double Blind (Phase IIb) Trial

( Hyung-joo Oh ),( Young-chul Kim ),( Suk-chul Bae ),( In-jae Oh ),( Cheol-kyu Park ),( Kyoung-mi Jung ),( Da-mi Kim ),( Chang Kyun Kang ),( Il Yeong Park ) 대한결핵 및 호흡기학회 2023 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.136 No.0

Novel EGFR-TK Inhibitor EKB-569 Inhibits Hepatocellular Carcinoma Cell Proliferation by AKT and MAPK Pathways

김희수,임호영 대한의학회 2011 Journal of Korean medical science Vol.26 No.12

Epidermal growth factor receptor (EGFR)–targeted therapies have been effective in some cancers, but not in hepatocellular carcinoma (HCC). The aim of this study was to investigate the drug potential to overcome multi-drug resistance in HCC cells. Thirteen drug-sensitive HCC cells were assessed using the CCK-8 assay. G_0-G_1 arrest was measured by FACS. Western blot analysis was used to detect the key enzymes in both the Ras/Raf and PI3K pathways. When establishing the IC_50 of HCC to several drugs, including EKB-569, sorafenib, erlotinib, gefitinib, pazopanib, and brivanib, SK-Hep1 cells treated with EKB-569 have shown the highest (72.8%-86.4%) G_0-G_1 arrest and decreased the phosphorylation of AKT and ERK at the protein level. We found that EKB-569 had higher efficacy in HCC, compared to first generation, reversible EGFR-TK inhibitors. Furthermore,the combination of sorafenib and EKB-569 showed a synergistic effect to inhibit proliferation of SNU-475, previously the most resistant cell to EGFR-TKIs. Therefore, novel EKB-569 in combination with sorafenib may be able to overcome HCC resistance to EGFR-TK inhibitors.

관광통계시스템 품질이 신뢰, 이용자 만족, 충성도에 미치는 영향 : DeLone과 McLean의 수정된 정보시스템(Information Systems: IS) 성공 모델의 적용

이진희(Lee, Jinhee),홍순기(Hong, Soonki) 대한관광경영학회 2020 觀光硏究 Vol.35 No.3

최근 관광통계는 집계에 대한 문제가 발생하여 신뢰를 잃고 있으나, 관광학 분야에서 이 문제를 다루는 연구는 미비한 실정이다. 따라서 통계의 신뢰성 확보와 이용자의 지속 이용을 유도하기 위해서는 통계의 어떠한 품질을 향상시켜야 하는지에 대한 연구가 이루어질 필요가 있다. 이에 본 연구에서는 관광통계시스템 품질이 신뢰, 이용자 만족, 충성도에 미치는 영향을 파악하고자 한다. 이를 위하여 설문조사는 최근 6개월 내 관광지식정보시스템을 이용한 경험이 있는 내국인을 대상으로 진행하였으며 371개의 유효 표본으로 분석을 실시하였다. 분석결과, 정보시스템 품질인 시스템 품질, 정보 품질, 서비스 품질은 신뢰에 유의한 영향을 미치는 것으로 나타났다. 정보시스템 품질 중 정보 품질과 서비스 품질은 이용자 만족에 유의한 영향을 미치는 것으로 나타난 반면, 시스템 품질은 유의한 영향을 미치지 않는 것으로 밝혀졌다. 마지막으로, 신뢰는 만족에 유의한 영향을 미쳤으며 신뢰와 만족은 충성도에 유의한 영향을 미치는 것으로 나타났다. 대부분의 관광통계나 정보시스템 관련 선행연구가 행동 관련 변수에 초점을 맞추어 이루어진 반면, 본 연구는 정보시스템 성공 이론을 바탕으로 신뢰 변수를 추가하여 연구하였다는 점에서 기존 이론을 뒷받침하고 일반화하는 데 많은 도움이 될 것이라 예상된다. 또한, 본 연구의 연구결과는 향상된 품질의 통계의 생산 및 관리와 관련한 정책수립에 기초 자료로 이용될 수 있을 것이라 판단된다. Recently, tourism statistics arose losing trust from various counted problems, however, it could not be tackled with this phenomenon to research in tourism. Furthermore, it is necessary to develop the quality of statistics for sustainable use and credibility. The purpose of this study analyzes relationships with the quality for Tourism statistical system, trust, users’ satisfaction, and loyalty. The survey of Koreans who had used TKIS within the last six months was conducted to be based on 371 valid responses. In this result, information system qualities which were system quality, information quality and service quality had a relevant effect on trust. Among information system quality, it was found that information quality and service quality had a significant impact on users’ satisfaction, by contrast, system quality had a non-significant effect. Also, trust had a sinificant influence on satisfaction, trust and satisfaction had a significant influence on loyalty. While ordinary research in tourism statistics and information systems were focused on behavior factors, this research would help to support the theories which were based on the theory of information system, what it studied adding trust factors. The results of this study could contribute fundamental data to set policies, which improve the quality of statistics and management.