非小细胞肺癌患者外周血表皮生长因子受体T790M检测与奥希替尼疗效的相关性研究

摘 要：［目的］ 评估非小细胞肺癌患者第一代表皮生长因子受体-酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI）获得性耐药后外周血EGFR T790M突变的阳性率和用外周血T790M检测结果预测奥希替尼疗效的可靠性。［方法］ 回顾性分析2017 年3月至2018年6月经第一代EGFR-TKI治疗后获得性耐药且使用超级扩增阻滞突变系统(ultra-amplification refractory mutation system,Ultra-ARMS )进行外周血EGFR T790M检测的原发性非小细胞肺癌患者。评估血T790M阳性患者使用奥希替尼的疗效。［结果］共有103例符合标准的第一代EGFR-TKI获得性耐药患者,其中28例（27.2%,28/103）血T790M阳性,75例（72.8%,75/103）血T790M阴性。血T790M阳性患者中,接受奥希替尼治疗有23例：部分缓解（partial response,PR） 15例,疾病稳定（stable disease,SD）6例,疾病进展（progression of disease,PD） 2例。疾病控制率(disease control rate,DCR) 91.3%,客观有效率（objective response rate,ORR)65.2%。奥希替尼治疗的中位无进展生存时间（progression free survival,PFS） 12.5个月（95%CI：11.2~13.8）。有9例血T790M阴性患者后续进行了组织检测,3例在组织中检测到T790M突变。有6例血T790M阴性的患者虽未再行组织检测,但要求试用奥希替尼靶向治疗,1例患者获得了PR,1例SD（PFS超过5个月）。［结论］对第一代EGFR-TKI获得性耐药后未能再次行组织活检的非小细胞肺癌患者,Ultra-ARMS方法检测血T790M阳性可预测奥希替尼疗效。血T790M检测阴性的患者建议再次取组织进行T790M检测以排除假阴性。组织检测是T790M检测的金标准,血T790M检测可作为补充。     

一线EGFR-TKIs联合血管生成抑制剂治疗晚期EGFR突变非小细胞肺癌的疗效分析

目的:比较一线表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors, EGFR-TKIs)联合血管生成抑制剂对比EGFR-TKIs单药治疗晚期EGFR突变非小细胞肺癌(non-small cell lung cancer, NSCLC)的疗效和安全性。方法:对PubMed、Embase、Web of Science和Cochrane Library数据库以及欧洲医学肿瘤学会(ESMO)、美国临床肿瘤学会(ASCO)中会议摘要进行了全面的文献检索。检索时间截止至2020年11月13日。使用STATA V.14.0对相关数据进行统计分析。结果:本meta共纳入6个II/III期RCTs(11篇文章),包括1 537例符合分析条件的NSCLC患者。结果表明,与EGFR-TKIs单药组相比,联合血管生成抑制剂组患者的无进展生存期(progression-free survival, PFS)显著延长(HR=0.62,95%CI 0.54～0.70,P<0.001)。然而,联合治疗并不能改善...     

非小细胞肺癌EGFR突变类型与TKIs疗效关系的研究进展

摘 要：表皮生长因子受体(epidermal growth factor receptor,EGFR)基因突变状态的检测以及表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）的应用开创了晚期非小细胞肺癌患者个体化分子靶向治疗的新纪元。本文就EGFR的不同突变类型与TKIs临床疗效的关系进行综述,为临床上EGFR突变——尤其是少见EGFR突变类型的晚期非小细胞肺癌患者个体化治疗方案的选择提供理论依据。     

吉非替尼、培美曲塞和贝伐珠单抗一线治疗EGFR突变晚期肺腺癌的有效性和安全性

目的探讨吉非替尼、培美曲塞和贝伐珠单抗一线治疗表皮生长因子受体(EGFR)突变晚期肺腺癌的疗效和安全性。方法选择2020年4月21日至2021年4月22日山东省肿瘤医院收治的35例初治EGFR突变晚期肺腺癌患者, 一线给予吉非替尼250 mg、培美曲塞500 mg/m2和贝伐珠单抗7.5～10.0 mg/kg, 21 d为1个周期。4个周期后给予吉非替尼联合培美曲塞维持治疗。分析患者的客观缓解率(ORR)、疾病控制率(DCR), 12个月、18个月无进展生存(PFS)率以及不良反应发生率。结果 35例EGFR突变晚期肺腺癌患者ORR为85.7%(30/35), DCR为100%(35/35);EGFR 19del、L858R、L861Q患者的客观缓解例数分别为16、12、2例, 疾病控制例数分别为19、14、2例;ⅢB～ⅢC期、Ⅳ期患者的客观缓解例数分别为10、20例, 疾病控制例数分别为10、25例;美国东部肿瘤协作组评分0～1分、2分患者的客观缓解例数分别为18、12例, 疾病控制例数分别为20、15例。35例EGFR突变晚期肺腺癌患者12个月PFS率为80.0%(95%CI为63...     

EGFR-TKIs联合贝伐珠单抗治疗非小细胞肺癌疗效及安全性的Meta分析

目的:系统评价第一代EGFR-TKIs联合贝伐珠单抗治疗不可切除局部晚期及转移性EGFR敏感突变非小细胞肺癌的疗效及安全性。方法:计算机检索Pubmed、Cochrane Library、EMbase、CBM、CKNI、万方数据库等数据库,检索时间为建库至2019年09月,按照严格的纳入和排除标准筛选文献和提取资料后,采用RevMan 5.3软件进行Meta分析。结果:最终纳入9篇文献,包括1 482名患者。这项研究终点是中位无进展生存期、客观缓解率、疾病控制率及安全性。Meta分析结果显示,第一代EGFR-TKIs联合贝伐珠单抗较EGFR-TKIs单药能有效改善不可切除局部晚期及转移性EGFR敏感突变非小细胞肺癌疾病控制率(disease control rate,DCR)［比值比（odds ratio,OR）=1.86,95%可信区间（confidence interval,CI）(1.40,2.46),P<0.000 1］、客观缓解率（objective response rate,ORR）［OR=1.90,95%CI(1.46,2.48),P<0.000 01］、中位无进展生存期（median progression free survival,mPFS）［风险比（hazard ratio,HR）=0.62,95%CI(0.54,0.71),P<0.000 01］,差异有统计学意义。安全性方面:Ⅲ级及以上不良反应,联合治疗组皮疹［OR=1.64,95%CI(1.20,2.24),P=0.002］、高血压［OR=6.50,95%CI(4.07,10.39),P<0.000 01］、蛋白尿［OR=9.87,95%CI(2.97,32.81),P=0.000 2］发生率高于EGFR-TKIs单药组,差异有统计学意义;腹泻［OR=1.09,95%CI(0.54,2.17),P=0.82］、出血事件［OR=1.74,95%CI(0.74,4.09),P=0.21］发生率差异无统计学意义。结论:在治疗不可切除局部晚期及转移性EGFR敏感突变非小细胞肺癌时,第一代EGFR-TKIs联合贝伐珠单抗与EGFR-TKIs单药相比能有效改善疾病控制率、客观缓解率及中位无进展生存期,不良反应主要有皮疹、高血压、蛋白尿,试验组发生率高于对照组,差异有统计学意义。     

厄洛替尼与西妥昔单抗联合应用治疗吉非替尼耐药NSCLC的疗效

本研究通过EGFR-TKI和EGFR单克隆抗体联合应用探讨治疗EGFR突变阴性和EGFR T790M突变继发性耐药的NSCLC的疗效。方法：应用EGFR突变阴性和EGFR T790M突变继发性耐药的NSCLL细胞原代培养及药敏技术检验EGFR-TKI和EGFR单克隆抗体联合应用的疗效。结果：检测厄洛替尼和西妥昔单抗联合处理对于15例EGFR突变阴性和8例T790M突变阳性的继发性耐药的NSCLC患者原代细胞的影响,应用浓度分别为50 μg/mL西妥昔单抗和1 μM厄洛替尼作用于EGFR突变阴性的NSCLC患者原代细胞,结果显示这三组间T/C值无显著性差异（P>0.05）,对于T790M突变阳性的继发性耐药的NSCLC原代细胞这三组间T/C值有显著性差异（P<0.05）,联合用药组疗效明显高于单药组。结论：进一步验证了厄洛替尼和西妥昔单抗联合应用对于EGFR突变阴性的NSCLC患者无效,但对于T790M突变阳性的继发性耐药的NSCLC患者有效。     

吉非替尼对EGFR敏感突变肺腺癌脑转移患者的预后影响

摘 要：［目的］ 了解吉非替尼在EGFR敏感突变肺腺癌脑转移患者中的生存情况,进一步分析临床、影像及药物动力学等因素对预后有无影响。［方法］ 37例初治EGFR 敏感突变肺腺癌脑转移患者口服吉非替尼250mg/d,服用吉非替尼一月后检测血药及脑脊液药物浓度,病情进展后联合化疗或全脑放疗。［结果］ 8例患者病情稳定,29例肿瘤进展;无进展生存期为2.1~16月,中位无进展生存期6.2月;总生存期为2.1~21.9月,中位生存期8.7月。吉非替尼血药浓度、脑脊液浓度及脑脊液通透率与无进展生存期、总生存期均有正相关性,其中脑脊液浓度的相关性最大。在多种预后因素中,颅内病灶能否控制对无进展生存期及总生存期的影响具有统计学意义。［结论］ 吉非替尼明显改善了EGFR敏感突变肺腺癌脑转移患者的无进展生存期及总生存期,颅内病灶有效控制是改善患者预后的重要因素。     

奥西替尼二线治疗EGFR突变型晚期非小细胞肺癌的疗效观察

目的 评价奥西替尼二线治疗表皮生长因子受体(EGFR)突变型晚期非小细胞肺癌(NSCLC)的疗效,对治疗前转移部位、耐药后进展部位与疗效间的关系进行探讨.方法 收集2017年1月1日至2019年1月1日67例经1～2代EGFR-酪氨酸激酶抑制剂(EGFR-TKI)治疗和50例一线化疗后进展的晚期NSCLC患者.全组患者...     

阿帕替尼联合EGFR-TKI一线治疗EGFR敏感突变的晚期非鳞非小细胞肺癌的疗效和安全性分析

目的 观察阿帕替尼联合表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)一线治疗EGFR敏感突变的晚期非鳞非小细胞肺癌(nsNSCLC)的疗效及不良反应.方法 拟计划入组2016年8月至2018年8月本院初治伴EGFR敏感突变的Ⅲb～Ⅳ期nsNSCLC患者20例,给予甲磺酸阿帕替尼联合EGFR-TKI治疗直至疾病进展...     

EGFR mutation testing in NSCLC: Patterns of care and outcomes in Western Australia

Aims:   This study evaluated the EGFR mutation status, administration of gefitinib or erlotinib and outcomes of patients assessed for EGFR mutations since the commencement of testing in Western Australia.
Methods:   A retrospective study identified patients with NSCLC who undergone EGFR mutation testing in the Department of Anatomical Pathology, Royal Perth Hospital, Western Australia from March 2005 until May 2007. Patient characteristics, cancer history, treatment, outcomes and survival were collected from the medical records and pathology reports.
Results:   Tumor samples from 64 patients were sequenced for mutations in exons 18–21 EGFR and, of these, 53 patients with NSCLC were included in the analysis. The mean age at diagnosis was 61 years (range 19–80) and most of the tumor samples tested were from female patients (76%). Overall 36% of patients tested were mutation-positive with 95% of mutations occurring in exons 19 or 21. A total of 63% of mutation-positive and 18% of mutation-negative patients were treated with gefitinib or erlotinib. Of these, 83% of patients whose tumors had an EGFR mutation had a favorable response following treatment, compared to 17% of mutation-negative patients. The duration of treatment was longer in mutation-positive patients (mean 30 weeks vs 9 weeks).
Conclusion:   EGFR mutation testing is not routinely performed in NSCLC in Western Australia. Referral for testing is at the discretion of the treating physician, accounting for the high proportion of women and adenocarcinoma histology. Selection of mutation-positive tumors for treatment with gefitinib or erlotinib is associated with good responses to treatment. This study supports the use of gefitinib or erlotinib in routine clinical practice in patients with NSCLC carrying an EGFR mutation.     

EGFR-TKI治疗对NSCLC患者血清CEA的影响

目的 探讨表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)治疗对非小细胞肺癌(NSCLC)患者血清癌胚抗原(CEA)的影响.方法 选取NSCLC患者81例,均接受EGFR-TKI治疗,监测患者治疗前后的CEA水平.结果 完全缓解(CR)+部分缓解(PR)患者治疗后的CEA水平低于治疗前(P﹤0.05);进展(PD)患者治疗后的CEA水平高于治疗前(P﹤0.05);稳定(SD)患者治疗前后的CEA水平比较,差异无统计学意义(P﹥0.05);CR+PR患者治疗前的CEA水平高于SD和PD患者(P﹤0.05);不同年龄、性别、吸烟史、组织类型、临床分期和治疗药物的NSCLC患者的近期疗效比较,差异无统计学意义(P﹥0.05);基线CEA≥5 ng/ml患者的近期疗效优于基线CEA﹤5 ng/ml的患者(P﹤0.05);基线CEA≥5 ng/ml组患者的中位无疾病进展时间为16.61个月(95%CI:12.22~20.43个月),长于基线CEA﹤5 ng/ml组患者的9.82个月(95%CI:5.21~14.40个月)(P﹤0.05).结论 血清CEA监测有助于判断NSCLC患者EGFR-TKI治疗效果,CEA治疗前高水平可能预示靶向药物治疗效果好.     

T790M突变与EGFR-TKI耐药后治疗策略

表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI）治疗非小细胞肺癌已获得较好的疗效,患者生活质量明显改善。但EGFR-TKI耐药似乎成为了靶向治疗的瓶颈,耐药的产生可能存在多种机制,包括T790M突变、K-ras基因突变、C-Met基因扩增、BRAF基因突变、BIM多态性缺失、EML4-ALK融合基因突变及上皮间充质转化等,其中最常见的是T790M基因突变。目前研究表明,T790M基因还可能具有一定预测疗效和预后的作用。本文将简要介绍T790M基因的发现、起源、作用机制及预后,并主要针对EGFR-TKIs耐药后的治疗策略进行综述。     

Osimertinib in Japanese patients with EGFR T790M mutation‐positive advanced non‐small‐cell lung cancer: AURA3 trial

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the first‐line treatment for patients with EGFR mutant non‐small‐cell lung cancer (NSCLC). However, most patients become resistant to these drugs, so their disease progresses. Osimertinib, a third‐generation EGFR‐TKI that can inhibit the kinase even when the common resistance‐conferring Thr790Met (T790M) mutation is present, is a promising therapeutic option for patients whose disease has progressed after first‐line EGFR‐TKI treatment. AURA3 was a randomized (2:1), open‐label, phase III study comparing the efficacy of osimertinib (80 mg/d) with platinum‐based therapy plus pemetrexed (500 mg/m²) in 419 patients with advanced NSCLC with the EGFR T790M mutation in whom disease had progressed after first‐line EGFR‐TKI treatment. This subanalysis evaluated the safety and efficacy of osimertinib specifically in 63 Japanese patients enrolled in AURA3. The primary end‐point was progression‐free survival (PFS) based on investigator assessment. Improvement in PFS was clinically meaningful in the osimertinib group (n = 41) vs the platinum‐pemetrexed group (n = 22; hazard ratio 0.27; 95% confidence interval, 0.13‐0.56). The median PFS was 12.5 and 4.3 months in the osimertinib and platinum‐pemetrexed groups, respectively. Grade ≥3 adverse events determined to be related to treatment occurred in 5 patients (12.2%) treated with osimertinib and 12 patients (54.5%) treated with platinum‐pemetrexed. The safety and efficacy results in this subanalysis are consistent with the results of the overall AURA3 study, and support the use of osimertinib in Japanese patients with EGFR T790M mutation‐positive NSCLC whose disease has progressed following first‐line EGFR‐TKI treatment. (ClinicalTrials.gov trial registration no. NCT02151981.)     

Reversed mutation rates of KRAS and EGFR genes in adenocarcinoma of the lung in Taiwan and their implications

BACKGROUND.

In western countries, the Kirsten ras oncogene homolog gene (KRAS) mutation rate is high in patients with nonsmall cell lung cancer (NSCLC), especially in those with adenocarcinoma (30%‐50%), but the epidermal growth factor receptor gene (EGFR) mutation rate is very low (3%‐8%). In addition, KRAS mutations reportedly were associated with EGFR tyrosine kinase inhibitor (EGFR‐TKI) resistance. In Taiwan, high EGFR mutation rates associated with high EGFR‐TKI response rates in patients with NSCLC have been reported; however, KRAS mutation data are limited and have not been correlated with TKI response.

METHODS.

KRAS mutation analysis was performed on 237 NSCLC specimens, and the results were correlated with clinicopathologic features. All but 2 tumors also underwent EGFR mutation analysis.

RESULTS.

KRAS mutations were identified in only 9 of 237 patients (3.80%). Five patients were women who were nonsmokers, and 4 patients were men who were ever‐smokers. The mutation rate was 5.03% in patients with adenocarcinoma (8 of 159 patients) and 1.56% in patients with squamous cell carcinoma (1 of 64 patients). Four mutations were G12V, 3 mutations were G12D, 1 mutation was L19F, and 1 was the duplication insertion mutation dupT50_M72. In contrast, EGFR mutations were detected in 96 of 235 patients (40.8%) and in 90 of 157 adenocarcinomas (57.3%). None of the KRAS mutations coexisted with EGFR mutations. KRAS mutations were not associated significantly with any clinicopathologic characteristics, including smoking status. Among the 53 patients who had received TKI monotreatment, only 1 patient had a KRAS mutation and had progressive disease.

CONCLUSIONS.

The KRAS mutation rate was too low to play a significant role in TKI resistance or tumorigenesis among Taiwanese patients with NSCLC, which was the complete reverse of the results reported in western countries. Cancer 2008. © 2008 American Cancer Society.     

转化性小细胞肺癌1例分析

我国肺癌发病率及死亡率在恶性肿瘤中居首位[1].肺癌分为小细胞肺癌( small cell lung cancer,SCLC)和非小细胞肺癌(non -small cell lung cancer,NSCLC)[2].NSCLC 包括腺癌、鳞癌及大细胞肺癌.最常见的组织学分类是腺癌,其次是小细胞癌,鳞状细胞癌或神经内分...     

Clinical activity of ASP8273 in Asian patients with non‐small‐cell lung cancer with EGFR activating and T790M mutations

Epidermal growth factor receptor (EGFR)‐activating mutations confer sensitivity to tyrosine kinase inhibitor (TKI) treatment for non‐small‐cell lung cancer (NSCLC). ASP8273 is a highly specific, irreversible, once‐daily, oral, EGFR TKI that inhibits both activating and resistance mutations. This ASP8273 dose‐escalation/dose‐expansion study (NCT02192697) was undertaken in two phases. In phase I, Japanese patients (aged ≥20 years) with NSCLC previously treated with ≥1 EGFR TKI received escalating ASP8273 doses (25‐600 mg) to assess safety/tolerability and to determine the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D) by the Bayesian Continual Reassessment Method. In phase II, adult patients with T790M‐positive NSCLC in Japan, Korea, and Taiwan received ASP8273 at RP2D to further assess safety/tolerability and determine antitumor activity, which was evaluated according to Simon's two‐stage design (threshold response = 30%, expected response = 50%, α = 0.05, β = 0.1). Overall, 121 (n = 45 [33W/12M] phase I, n = 76 [48W/28M]) phase 2) patients received ≥1 dose of ASP8273. In phase I, RP2D and MTD were established as 300 and 400 mg, respectively. As 27 of the 63 patients treated with ASP8273 300 mg achieved a clinical response, ASP8273 was determined to have antitumor activity. The overall response rate at week 24 in all patients was 42% (n = 32/76; 95% confidence interval, 30.9‐54.0). Median duration of progression‐free survival was 8.1 months (95% confidence interval, 5.6, upper bound not reached). The most commonly reported treatment‐related adverse event in phase II was diarrhea (57%, n = 43/76). ASP8273 300 mg was generally well tolerated and showed antitumor activity in Asian patients with both EGFR‐activating and T790M mutations.     

Lamellarin 14, a derivative of marine alkaloids,inhibits the T790M/C797S mutant epidermal growth factor receptor

The emergence of acquired resistance is a major concern associated with molecularly targeted kinase inhibitors. The C797S mutation in the epidermal growth factor receptor (EGFR) confers resistance to osimertinib, a third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI). We report that the derivatization of the marine alkaloid topoisomerase inhibitor lamellarin N provides a structurally new class of EGFR-TKIs. One of these, lamellarin 14, is effective against the C797S mutant EGFR. Bioinformatic analyses revealed that the derivatization transformed the topoisomerase inhibitor-like biological activity of lamellarin N into kinase inhibitor-like activity. Ba/F3 and PC-9 cells expressing the EGFR in-frame deletion within exon 19 (del ex19)/T790M/C797S triple-mutant were sensitive to lamellarin 14 in a dose range similar to the effective dose for cells expressing EGFR del ex19 or del ex19/T790M. Lamellarin 14 decreased the autophosphorylation of EGFR and the downstream signaling in the triple-mutant EGFR PC-9 cells. Furthermore, intraperitoneal administration of 10 mg/kg lamellarin 14 for 17 days suppressed tumor growth of the triple-mutant EGFR PC-9 cells in a mouse xenograft model using BALB/c nu/nu mice. Thus, lamellarin 14 serves as a novel structural backbone for an EGFR-TKI that prevents the development of cross-resistance against known drugs in this class.     

非小细胞肺癌EGFR不同突变状态的脑转移发生特点及治疗

目的 有研究显示,表皮生长因子受体(epidermal growth factor receptor,EGFR)的突变状态,与非小细胞肺癌(non-small cell lung cancer,NSCLC)脑转移存在相关性.本研究进一步探讨EGFR不同突变状态的NSCLC患者,脑转移发生的特点以及相应的治疗.方法 选取2009-04-01-2014-12-01中国人民解放军火箭军总医院肿瘤科病理确诊断的231例NSCLC患者的临床资料,进行回顾性研究.并应用实时定量PCR方法,检测上述患者的EGFR突变状态.利用x2检验比较EGFR不同突变状态的患者,脑转移特点的差异.Kaplan-Meier法进行生存分析.结果 EGFR检测结果示野生型119例,18、19、20、21号外显子及19/21双突变的分别有3例、58例、5例、42例和4例.19号外显子突变患者的脑转移发生率(55.2％)显著高于野生型患者(41.2％),P=0.04.伴21号外显子突变＞3个脑转移病灶患者(47.6％)的比例显著高于野生型患者(28.6％),P＜0.01.此外,伴21号外显子突变患者的中位脑转移年龄(63岁)也显著高于野生型患者(52岁),P=0.02.对于伴有EGFR突变的脑转移患者,脑转移后接受过酪氨酸激酶抑制剂(tyro-sine kinase inhibitors,TKIs)的患者,其中位脑转移后生存期显著长于接受常规化疗的患者(未达到vs 9个月),P=0.01.结论 伴EGFR特定位点突变的患者有更高的脑转移发生率、脑转移数目及脑转移时年龄.TKIs可改善伴EG-FR突变脑转移患者的预后.