Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer

Purpose

Several cases have been reported in which central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) resistant to gefitinib were improved by erlotinib. However, there has been no study in which cerebrospinal fluid (CSF) concentrations of gefitinib and erlotinib are directly compared. Thus, we aimed to compare them.

Methods

We examined 15 Japanese patients with NSCLC and CNS metastases with epidermal growth factor receptor gene mutations who received CSF examinations during epidermal growth factor receptor-tyrosine kinase inhibitors treatment (250?mg daily gefitinib or 150?mg daily erlotinib). Plasma and CSF concentrations were determined using high-performance liquid chromatography with tandem mass spectrometry.

Results

The concentration and penetration rate of gefitinib (mean?±?standard deviation) in the CSF were 3.7?±?1.9?ng/mL (8.2?±?4.3?nM) and 1.13?±?0.36?%, respectively. The concentration and penetration rate of erlotinib in the CSF were 28.7?±?16.8?ng/mL (66.9?±?39.0?nM) and 2.77?±?0.45?%, respectively. The CSF concentration and penetration rate of erlotinib were significantly higher than those of gefitinib (P?=?0.0008 and <0.0001, respectively). The CNS response rates of patients with erlotinib treatment were preferentially (but not significantly) higher than those with gefitinib treatment. (1/3 vs. 4/7, respectively). Leptomeningeal metastases in one patient, which were refractory to gefitinib, dramatically responded to erlotinib.

Conclusions

This study suggested that higher CSF concentration could be achieved with erlotinib and that erlotinib could be more effective for the treatment for CNS metastases, especially leptomeningeal metastases, than gefitinib.     

非小细胞肺癌脑转移厄洛替尼和吉非替尼治疗临床比较

目的比较和评价厄洛替尼和吉非替尼靶向治疗非小细胞肺癌脑转移的疗效。方法回顾性分析2009-01-01-2012-11-25广州医科大学附属第一医院81例晚期NSCLC初诊有脑转移患者和111例晚期NSCLC初诊无脑转移患者,192例患者均为肺腺癌合并EGFR基因突变,分为吉非替尼和厄洛替尼治疗组,生存分析采用Kaplan-Meier法统计,组间生存率比较采用Log-rank检验。结果初诊有脑转移患者颅内病灶,客观有效率为45.68%(37/81),疾病控制率为90.12%(73/81)。吉非替尼、厄洛替尼治疗的无进展生存期(progression-free survival,PFS)分别为9.5和9.0个月,P=0.344;不同EGFR突变类型(19外显子序列缺失突变、21外显子突变)PFS比较分别为10.4和8.6个月,P=0.408。初诊无脑转移患者PFS分别为14.0和15.0个月,P=0.369;不同EGFR突变类型的PFS分别为14.0和15.0个月,P=0.408。结论厄洛替尼和吉非替尼一线治疗肺癌EGFR突变脑转移效果无显著性差异。     

Three-arm randomised controlled phase 2 study comparing pemetrexed and erlotinib to either pemetrexed or erlotinib alone as second-line treatment for never-smokers with non-squamous non-small cell lung cancer

BackgroundThis randomised controlled phase 2 study compared pemetrexed and erlotinib in combination with either agent alone in terms of efficacy and safety as second-line treatment in a clinically selected population of never-smokers with non-squamous non-small cell lung cancer (NSCLC).MethodsPatients who had failed only one prior chemotherapy regimen and had Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ?2 were randomised to either: pemetrexed 500 mg/m² on day 1 plus erlotinib 150 mg daily on days 2–14; erlotinib 150 mg daily; or pemetrexed 500 mg/m² on day 1 of a 21-day cycle until discontinuation criteria were met. The primary endpoint, progression-free survival (PFS), was analysed using a multivariate Cox model. Firstly, a global comparison across the three arms was performed. If the global null hypothesis was rejected at a two-sided 0.2 significance level, pairwise comparisons of pemetrexed–erlotinib versus erlotinib or pemetrexed were then conducted using the same model. Statistical significance was claimed only if both global and pairwise null hypotheses were rejected at a two-sided 0.05 significance level.FindingsA total of 240 patients (male, 35%; East Asian, 55%; ECOG PS 0–1, 93%) were included. A statistically significant difference in PFS was found across the three arms (global p = 0.003), with pemetrexed–erlotinib significantly better than either single agent: HR = 0.57, 95% confidence interval (CI): 0.40–0.81, p = 0.002 versus erlotinib; HR = 0.58, 95% CI: 0.39–0.85, p = 0.005 versus pemetrexed. Median PFS (95% CI) was 7.4 (4.4, 12.9) months in pemetrexed–erlotinib, 3.8 (2.7, 6.3) months in erlotinib and 4.4 (3.0, 6.0) months in pemetrexed. Safety analyses showed a higher incidence of drug-related grade 3/4 toxicity in pemetrexed–erlotinib (60.0%) than in pemetrexed (28.9%) or erlotinib (12.0%); the majority being neutropenia, anaemia, rash and diarrhoea.InterpretationPemetrexed–erlotinib significantly improved PFS compared to either drug alone in this clinically selected population. The combination had more toxicity, but was clinically manageable.     

吉非替尼与厄洛替尼治疗非小细胞肺癌脑转移的临床观察

目的 探讨吉非替尼与厄洛替尼治疗非小细胞肺癌脑转移的疗效。方法 回顾性分析67例EGFR突变阳性的肺腺癌脑转移患者的病历资料,患者均口服吉非替尼250 mg/天（吉非替尼组,n=38）或厄洛替尼150 mg/天（厄洛替尼组,n=29）,直至发生颅内病变进展、死亡或不可耐受的不良反应。疗效分析采用RECIST 1.1版标准,生存分析采用Kaplan-Meier法并行Log-rank检验。结果 全组颅内病变的有效率（RR）和疾病控制率（DCR）分别为44.8％和92.5％,吉非替尼组和厄洛替尼组分别为42.1％、92.1％和48.3％、93.1％（P=0.881）。颅外病变的RR和DCR分别为53.7％和95.5％,吉非替尼组和厄洛替尼组分别为52.6％、94.7％和55.2％、96.6％（P=0.932）。全组患者的中位无进展生存期（PFS）和总生存期（OS）分别为10.8个月和15.3个月,吉非替尼组和厄洛替尼组分别为10.6个月、14.8个月和11.7个月、15.7个月（P=0.720,P=0.569）。结论 吉非替尼和厄洛替尼对EGFR突变阳性的非小细胞肺癌脑转移具有较好的疗效,可以作为脑转移患者的治疗选择,两种药物在脑转移瘤的疗效及患者的预后等方面无差异。     

组蛋白去乙酰化酶6在非小细胞肺癌组织中的表达及意义

目的 探讨组蛋白去乙酰化酶6 (HDAC6)在非小细胞肺癌(NSCLC)组织中的表达及其临床意义.方法 应用免疫组织化学SP法检测HDAC6在70例NSCLC组织和18例正常肺组织中的表达.结果 在NSCLC组织中HDAC6阳性率为58.57％,显著高于正常肺组织的16.67％ (P ＜0.01);NSCLC组织中HD...     

Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib.

PURPOSE: Somatic mutations in the epidermal growth factor receptor (EGFR) have been detected in patients with non-small cell lung cancer (NSCLC) and are associated with sensitivity to treatment with gefitinib or erlotinib. Our study explored the relationship between the two most common types of somatic EGFR mutations, exon 19 deletions and the L858R point mutation, and outcomes of patients following treatment with gefitinib or erlotinib. EXPERIMENTAL DESIGN: Tumor specimens obtained before treatment with gefitinib or erlotinib were analyzed for EGFR mutations. Patients with exon 19 deletion or L858R mutations were identified. The response rate, time to progression, and overall survival were determined for the two groups. RESULTS: We identified 36 patients with NSCLC and an EGFR mutation who were treated with gefitinib or erlotinib. Patients with an exon 19 deletion had a significantly longer overall survival compared with patients with an L858R mutation (38 versus 17 months; P = 0.04). There were also trends toward higher response rate (73% versus 50%) and improved time to progression (24 versus 10 months) for the patients with an exon 19 deletion, although these were not independently significant in a multivariate analysis. A difference in response rate for patients treated with gefitinib compared with erlotinib was also noted [18 of 23 (78%) versus 3 of 9 (33%); P = 0.04]. No obvious difference in time to progression or overall survival was noted between gefitinib- and erlotinib-treated patients. CONCLUSIONS: Patients with NSCLC and EGFR exon 19 deletions have a longer survival following treatment with gefitinib or erlotinib compared with those with the L858R mutation. Pooling of greater numbers of patients and completion of prospective trials are needed to further define the predictive and prognostic roles of different EGFR mutations with respect to treatment with gefitinib, erlotinib, and other EGFR inhibitors.     

Recurrent responses to non-small cell lung cancer brain metastases with erlotinib

We report the case of a Caucasian female never smoker with erlotinib sensitive metastatic non-small cell lung cancer in the brain. Having progressed after receiving whole brain radiotherapy, her brain metastases responded both initially and on re-treatment with erlotinib. However, her extra-cranial disease remained erlotinib-resistant throughout. This case demonstrates that brain metastases may be sensitive to erlotinib and also highlights the oligoclonal nature of non-small cell lung cancer reflected by differential tyrosine kinase inhibitor tumour sensitivity. On the basis of this case we suggest that erlotinib should be considered in the treatment paradigm for patients with intra-cranial disease and propose further study into the continued use of this drug in the situation where there is a differential response.     

First-line systemic treatment with gefitinib in stage IV non-small cell lung cancer

Lung cancer has a high mortality rate and is often diagnosed in locally advanced or metastatic stages. A new therapeutic option for patients with non-small cell lung cancer (NSCLC) in these stages with progress or relapse after platinum-based chemotherapy exists in the inhibitors of the epidermal growth factor receptor (EGFR) tyrosine-kinase. EGFR tyrosine-kinase inhibitor treatment might also be an option for patients ineligible for surgery and conventional chemotherapy. We present a case of a 53-year-old woman who was diagnosed due to pain from multiple bone metastases of a lung adenocarcinoma. She refused cytotoxic chemotherapy, and we administered first-line systemic treatment with gefitinib subsequent to radiotherapy of metastatic bone disease. The patient responded well to gefitinib treatment and achieved a partial response after 3 weeks. No relevant side effects occurred, and the patient experienced an 8-month remission of disease. With a follow-up of 10 months, the patient is still alive. Retrospectively, we found a mutation of the EGF receptor in tumor cells of the patient, which is associated with sensitivity to gefitinib. EGFR tyrosine-kinase inhibitors (TKI) can be an alternative first-line systemic treatment option for selected patients with metastatic NSCLC.     

吉非替尼与厄洛替尼二线治疗EGFR基因敏感突变晚期NSCLC患者的疗效观察

目的 探讨吉非替尼与厄洛替尼二线治疗EGFR基因敏感突变非小细胞肺癌（non-small cell lung cancer,NSCLC）患者的临床疗效和安全性。方法 选择我院2013年3月至2015年2月收治的一线化疗失败的EGFR基因敏感突变晚期NSCLC患者50例,按随机数字表法平均分为两组,一组接受吉非替尼（吉非替尼组）250 mg/d治疗,另一组接受厄洛替尼（厄洛替尼组）150 mg/d治疗,观察无进展生存时间（PFS）、总有效率（ORR）、疾病控制率 （DCR）和药物的毒副反应。结果 吉非替尼组和厄洛替尼组的中位PFS、ORR、DCR分别为（6.5±1.2）个月、60%、92%和（7.2±0.9）个月、56%、88%,差异均无统计学意义（P＞0.05）。吉非替尼组和厄洛替尼组的毒副反应发生率分别为32%和60%,差异具有统计学意义（P＜0.05）。结论 吉非替尼和厄洛替尼均能有效地二线治疗EGFR基因敏感突变晚期NSCLC患者,疗效相当,但吉非替尼治疗的毒副反应发生率明显低于厄洛替尼。     

吉非替尼靶向治疗非小细胞肺癌

吉非替尼(gefitinib)是用于靶向治疗非小细胞肺癌(NSCLC)的二线或三线药物,是表皮生长因子受体(EGFR)酪氨酸激酶(PTK)抑制剂,能选择性阻断EGFR的PTK,有效地"切断"EGFR向细胞内发出信号.gefitinib具有减慢和降低癌细胞增殖的作用,虽不能完全治愈NSCLC,但可以长期使用,能有效延缓病情恶化,减少并发症,改善患者的生活质量,延长患者生存期,为NSCLC患者提供了一种重要的新型治疗方法.现综述gefitinib的作用机制及其临床应用.     

CT findings in non-small-cell lung cancer patients treated with gefitinib or erlotinib

Purpose: We performed this study to explore the association of computed tomography (CT) findings with outcomes of patients with non-small-cell lung cancer (NSCLC) treated with tyrosin kinase inhibitor (TKI) such as gefitinib or erlotinib. Materials and Methods: We analyzed outcomes for 240 patients according to primary tumor (T), regional nodal (N) staging and diffuse small pulmonary metastases (DSPM) at the initial presentation. Tests for epidermal growth factor receptor (EGFR) mutation were performed in 92 patients. Results: On multivariate analysis for tumor response, the N3 stage was predictive of a poor response (P < 0.001), whereas DSPM was a favorable factor (P = 0.007). Multivariate analysis for progression-free survival showed that the T3-4 stage (hazard ratio [HR]: 2.5, P < 0.001), in addition to the N3 stage (HR: 2.1, P < 0.001), was predictive of a poor outcome, whereas DSPM (HR: 0.6, P = 0.006) was a favorable factor. Notably, the multivariate model that included the EGFR mutational status revealed that the T3-4 stage predicted poor progression-free survival (HR: 2.2, P = 0.017) and poor overall survival (HR: 4.1, P < 0.001). Conclusion: Our data suggest that, in addition to EGFR mutational status, T-stage based on CT is predictive of outcomes of TKI-treated NSCLC patients.     

244-MPT overcomes gefitinib resistance in non-small cell lung cancer cells

The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer(NSCLC). Several EGFR tyrosine kinase inhibitors(TKIs), such as gefitinib, have been used as effective clinical therapies for patients with NSCLC. Unfortunately, acquired resistance to gefitinib commonly occurs after 6–12 months of treatment. The resistance is associated with the appearance of the L858R/T790M double mutation of the EGFR. In our present study, we discovered a compound,referred to as 244-MPT, which could suppress either gefitinib-sensitive or -resistant lung cancer cell growth and colony formation, and also suppressed the kinase activity of both wildtype and double mutant (L858R/T790M) EGFR. The underlying mechanism reveals that 244-MPT could interact with either the wildtype or double-mutant EGFR in an ATP-competitive manner and inhibit activity. Treatment with 244-MPT could substantially reduce the phosphorylation of EGFR and its downstream signaling pathways, including Akt and ERK1/2 in gefitinib-sensitive and -resistant cell lines. It was equally effective in suppressing EGFR phosphorylation and downstream signaling in NL20 cells transfected with wildtype, single-mutant (L858R) or mutant (L858R/T790M) EGFR. 244-MPT could also induce apoptosis in a gefitinib-resistant cell line and strongly suppress gefitinib-resistant NSCLC tumor growth in a xenograft mouse model. In addition, 244-MPT could effectively reduce the size of tumors in a gefitinib-resistant NSCLC patient-derived xenograft (PDX) SCID mouse model. Overall, 244-MPT could overcome gefitinib-resistance by directly targeting the EGFR.     

吉非替尼、厄洛替尼与埃克替尼治疗EGFR基因敏感突变晚期NSCLC患者的疗效观察

目的:观察吉非替尼、厄洛替尼与埃克替尼在EGFR基因敏感突变晚期非小细胞肺癌(NSCLC)患者一线治疗中的疗效差异。方法:收集2013年5月—2014年12月间在我院接受治疗的76例EGFR基因突变的晚期NSCLC患者,随机分为三组,A组接受吉非替尼治疗,250 mg,1次/d,空腹口服;B组接受厄洛替尼治疗,150 mg,1次/d,餐前1 h口服;C组接受埃克替尼治疗,125 mg,3次/d,评价疗效及安全性。结果:吉非替尼组、厄洛替尼组和埃克替尼组的客观有效率（ORR）分别为26.9%、34.6%和45.8%;疾病控制率（DCR）分别为61.5%、73.0%和79.2%。三组之间的有效率和疾病控制率差异无统计学意义(P＞0.05）。三组的无进展生存时间（PFS）分别为9.5个月、10个月和9.5个月;19号外显子缺失突变型患者中,三组的PFS分别为8.5个月、12个月和9个月;21号外显子L858R错义突变型患者中,PFS分别为9.5个月、8.5个月和7个月,三组之间无统计学差异(P＞0.05）。结论:吉非替尼、厄洛替尼与埃克替尼治疗EGFR基因突变的晚期NSCLC疗效相似,但在19号外显子缺失突变型患者中,厄洛替尼略显优势。     

组蛋白去乙酰化酶5在非小细胞肺癌迁移中的作用研究

背景与目的:组蛋白乙酰化状态受组蛋白去乙酰化酶(histone deacetylases,HDACs)和组蛋白乙酰化酶(histone acetyltransferases,HATs)调节,进而调控基因转录.HDACs和HATs失衡是肿瘤发生发展的重要分子机制.组蛋白去乙酰化酶5(histone deacetylase 5,HDAC5)在多数肿瘤中表达降低,然而其在非小细胞肺癌细胞迁移中的作用尚未见报道.本研究旨在检测HDAC5基因在非小细胞肺癌中的差异性表达,研究HDAC5基因过表达对肺腺痛NCI-H1299细胞迁移的影响.方法:采用real time RT-PCR、Western blot检测28例非小细胞肺癌手术标本中HDAC5 mRNA和蛋白表达;将野生型HDAC5(HDAC5wt)基因转染到NCI-H1299细胞中,将细胞分为转染HDAC5wt基因的实验组(HDAC5wt)、未转染任何质粒的正常对照组(control)、转染空质粒的阴性对照组(vector).通过MTT方法比较3组细胞的生长情况;利用划痕、Transwell方法检测HDAC5基因过表达对细胞迁移能力的影响.结果:对照组相比,约71.4%(20/28)非小细胞肺癌患者手术标本中HDAC5 mRNA和蛋白表达明显降低;MTT结果显示在第2～5天,实验组D490值显著性低于正常对照组及阴性对照组,而在24 h时,3组细胞增殖差异无统计学意义;Transwell迁移实验结果显示实验组跨膜细胞的数目为158.3±19.4,较正常对照组(247.0±12.1)及阴性对照组(236.0±14.9)均显著减少(P<0.05);划痕实验结果显示HDAC5基因过表达后,H1299细胞划痕愈合程度明显降低.结论:HDAC5基因在非小细胞肺癌中低表达;体外过表达HDAC5基因可抑制NCI-H1299细胞迁移.