埃克替尼一线治疗134例EGFR突变阳性的晚期肺腺癌的疗效分析

摘 要：［目的］ 观察埃克替尼一线治疗EGFR突变阳性的晚期肺腺癌患者的疗效及不良反应。［方法］ 对134例Ⅲb/Ⅳ期EGFR突变阳性的晚期肺腺癌患者应用埃克替尼125mg 每天三次治疗,直至疾病进展或出现不可耐受的不良反应。［结果］ 134例EGFR基因突变阳性晚期肺腺癌患者中,完全缓解(CR)6例（4.5%）,部分缓解(PR)90例（67.2%）,疾病稳定（SD）32例（23.9%）,疾病进展（PD）6例（4.5%)。客观缓解率（ORR)为71.6%(96/134),疾病控制率(DCR)为95.5%（128/134）。中位无进展时间（mPFS）为11.2个月(95%CI：9.8～12.5个月）,OS尚未获得。19外显子缺失突变的ORR 为81.8%,DCR为93.5%,mPFS为11.8个月。21外显子L858R突变患者ORR 为 57.9%,DCR为94.7%,mPFS为10.2个月。19外显子缺失突变的ORR明显优于21外显子L858R突变（81.8% vs 57.9%,P=0.002)。不吸烟患者的ORR优于吸烟患者（77.4% vs 58.5%,P=0.025)。不同性别、年龄、肺癌分期、EGFR突变类型、吸烟状态对mPFS和DCR的影响无统计学差异。主要不良反应为Ⅰ～Ⅱ度的皮疹（44.8%）和腹泻（25.3%）,经对症处理后,患者多可耐受。［结论］ 埃克替尼一线治疗EGFR突变阳性的晚期肺腺癌患者取得了很好的疗效,不良反应的发生率低,且患者多可耐受。     

二线吉非替尼对不同表皮生长因子受体突变点位晚期非小细胞肺癌患者疗效及生存情况的影响

目的 探讨二线吉非替尼对不同表皮生长因子受体(EGFR)突变点位晚期非小细胞肺癌(NSCLC)患者疗效及生存情况的影响.方法 选取72例晚期NSCLC患者,按照不同EGFR突变点位分为两组,EGFR19外显子缺失35例为观察组,EGFR21外显子缺失37例为对照组,比较两组患者二线吉非替尼治疗的临床疗效、不良反应及生存情况.结果 观察组患者疾病控制率(DCR)、客观缓解率(ORR)分别为62.86％(22/35)、60.00％(21/35),均高于对照组的37.84％(14/37)、35.14％(13/37),差异均有统计学意义(χ2=4.504、4.462,P=0.034、0.035).两组患者不良反应发生率比较,差异均无统计学意义(P>0.05).观察组患者中位无进展生存期(PFS)为28.00个月(95％CI:17.60～38.40),优于对照组的13.00个月(95％CI:8.25～17.75),差异有统计学意义(χ2=4.033,P=0.045);观察组患者的中位总生存期(OS)为28.00个月(95％CI:20.55～35.45),优于对照组的15.00个月(95％CI:10.23～19.77),差异有统计学意义(χ2=4.419,P=0.036).结论 二线吉非替尼治疗晚期NSCLC的疗效显著,与EG-FR21外显子缺失相比,EGFR19外显子缺失治疗表现出更高的敏感性,OS、PFS更优.EGFR突变状态有助于预测晚期NSCLC接受吉非替尼治疗的效果及生存情况.     

盐酸埃克替尼治疗晚期非小细胞肺癌的临床观察

目的:观察盐酸埃克替尼治疗晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）的疗效、安全性及其影响因素。方法:回顾性分析云南省肿瘤医院2013年11月-2016年2月收治的接受盐酸埃克替尼治疗的晚期NSCLC患者56例,对患者疗效、生存期及毒副反应进行评价。结果:56例患者均可评价疗效,客观有效率（objective response rate,ORR）为30.4%,疾病控制率（disease control rate,DCR）为83.9%,中位无进展生存期（progression free survival,PFS）为9个月。腺癌患者的DCR、PFS均优于鳞癌患者（P＜0.05）。12例患者进行EGFR基因检测,均为突变阳性,EGFR突变患者的ORR为58.3%,DCR为100%,PFS为9个月。EGFR突变患者的ORR优于EGFR状态未知患者（P＜0.05）。毒副反应主要为轻度的皮肤毒性和腹泻。结论:盐酸埃克替尼是治疗晚期NSCLC的有效药物,毒副反应较轻,腺癌患者能获得较好的疗效,EGFR突变患者的疗效更好。     

阿美替尼治疗EGFR突变晚期非小细胞肺癌疗效及安全性分析

摘 要：［目的］ 评价阿美替尼在真实世界中治疗晚期非小细胞肺癌NSCLC患者的疗效与安全性。［方法］ 回顾性分析河南省肿瘤医院于2020年4月至2021年4月收治的100例接受阿美替尼治疗的EGFR突变晚期NSCLC患者的临床资料,采用Kaplan-Meier生存曲线分析无进展生存期(progression free survival,PFS)和总生存期(overall survival,OS),采用Cox回归模型进行多因素分析和预后因素评估。［结果］ 一线接受阿美替尼治疗患者(n=45)的客观缓解率(objective response rate,ORR)为71%,中位PFS为16.7个月,中位OS未达到。 既往第一、二代EGFR-TKI治疗进展后接受阿美替尼治疗的患者(n=55)中,T790M(+)患者(n=12)的ORR为50.0%,mPFS为11.9个月,中位OS未达到;T790M(-)患者(n=35)的ORR为25.6%,中位PFS为10.8个月,中位OS未达到,差异均无统计学意义(P均>0.05)。患者出现的不良反应主要为肌酸激酶升高(28%)、皮疹(12%)、肝功能损伤(8%)、皮肤瘙痒(8%)、白细胞降低(7%)、贫血(6%)、腹泻(6%)和口腔炎(3%),其中3级及以上不良反应发生率仅2%,均集中在血液学毒性。多因素Cox回归分析显示,肌酸激酶升高是中位PFS延长的重要预测因素(HR=0.176,P=0.001)。［结论］ 阿美替尼在EGFR突变NSCLC脑转移患者中表现出良好的疗效和安全性。既往EGFR-TKI进展后T790M(-)的患者如果拒绝化疗或化疗疗效较差,可以考虑将阿美替尼作为后续治疗选择之一。肌酸激酶升高是接受阿美替尼治疗的患者中位PFS延长的重要预测因素。     

埃克替尼治疗98例复治EGFR突变阳性的晚期肺腺癌的疗效分析

目的:观察埃克替尼治疗复治表皮生长因子受体(epidermal growth factor receptor,EGFR）敏感突变的晚期肺腺癌患者的疗效及不良反应。方法:收集2011年11月至2016年7月期间一线或多线化疗进展的98例EGFR 敏感突变的晚期肺腺癌患者应用埃克替尼治疗的疗效、不良反应及生存资料。结果:98例既往化疗失败的EGFR基因敏感突变晚期肺腺癌患者中,达到完全缓解（CR）1例（1.0%）,部分缓解（PR）66例（67.3%）,疾病稳定（SD）20例（20.4%）,疾病进展（PD）11例（11.2%）;客观缓解率（ORR）为68.4%（67/98),疾病控制率（DCR）为88.8%（87/98）,中位无进展时间（mPFS）为8.8个月（95%CI:7.1～10.5个月）,中位生存时间（mOS）为15.5个月（95%CI:11.8～19.2个月）。亚组分析中,19外显子缺失突变患者的ORR（82.0% vs 54.2%,P=0.003）、mPFS（11.0个月 vs 6.0个月,P=0.008）及mOS（20.0个月 vs 12.6个月,P=0.016）均优于21外显子L858R突变患者;非脑转移患者的mOS优于脑转移患者（16.0个月 vs 8.0个月,P=0.039）;不吸烟患者的ORR 优于吸烟患者（76.7% vs 55.3%,P=0.023）;不同性别、年龄、肺癌分期、治疗线数、转移器官数对预后的影响均未见差异有统计学意义。不良反应以皮疹、腹泻、肝功能异常为主,经对症处理后症状均可明显缓解。结论:埃克替尼治疗既往化疗失败的EGFR突变阳性的晚期肺腺癌患者取得了确切的疗效,且不良反应发生率低。     

EGFR-TKI治疗后缓慢进展的晚期NSCLC患者原药维持联合阿帕替尼的疗效及安全性

目的:观察一代EGFR-TKI治疗后缓慢进展的晚期NSCLC患者继续原药联合阿帕替尼的疗效及安全性。方法:收集2016年9月至2018年7月于大连医科大学附属第二医院肿瘤内科就诊的29例经一代EGFR-TKI单药治疗后缓慢进展（疾病控制≥6个月，与以往评估相比，肿瘤负荷较前轻度增加 2分，症状评分 1分），继续原药维持联合阿帕替尼(250 mg／日1次)的晚期NSCLC患者的病例资料，观察客观缓解率（ORR）、疾病控制率（DCR）、中位无进展生存期（mPFS）及不良反应情况。结果:29例患者中，ORR为13.8%，DCR为86.2%，mPFS为5.470个月（95%CI 4.367~6.573个月）；常见的药物相关毒性反应是高血压、乏力和蛋白尿，经治疗后症状改善；其中4例经联合治疗一段时间后，临床症状稳定，出现病灶增大，但未达到疾病进展的患者，未换其他治疗方案，而是将阿帕替尼的用量加至500 mg／日1次，病灶再次稳定或缩小；L858R突变患者的mPFS比19号外显子缺失者显著延长，差异有统计学意义（P=0.011）。结论:一代EGFR-TKI治疗后缓慢进展的晚期NSCLC患者原药维持联合阿帕替尼治疗有效，且具有可接受可控的毒副作用。     

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。     

吉非替尼对比培美曲塞二线治疗晚期非鳞型非小细胞肺癌的随机对照临床研究

背景与目的吉非替尼和培美曲塞均是晚期非小细胞肺癌(non-smallcelllungcancer,NSCLC)二线治疗的药物,但直接对比两者二线治疗的研究数据有限。本研究旨在比较吉非替尼和培美曲塞二线治疗晚期非鳞型NSCLC的疗效、安全性及对生活质量的影响。方法将46例一线含铂双药化疗方案(不含培美曲塞)治疗失败的晚期非鳞型NSCLC患者随机分为两组,每组23例,分别给予吉非替尼口服(吉非替尼组),或静脉滴注培美曲塞(培美曲塞组),比较两组的疗效和安全性及治疗对生活质量的影响。结果培美曲塞组的客观缓解率(objectiveresponserate,ORR)为13.0%(3/23),疾病控制率(diseasecontrolrate,DCR)为30.4%(7/23),中位无进展生存时间(medianprogression-freesurvival,mPFS)为3.1个月;吉非替尼组的ORR17.3%(4/23),DCR39.1%(9/23),mPFS4.4个月;两组的ORR、DCR和mPFS均未见统计学差异(P>0.05)。培美曲塞最常见的不良反应为中性粒细胞减少(n=9,39.13%)和乏力(n=8,34.78%);吉非替尼最常见的不良反应为皮疹(n=8,34.78%)和腹泻(n=4,17.39%)。和治疗前基线相比,培美曲塞组和吉非替尼组治疗后生活质量评分均有不同程度的改善,吉非替尼组在情绪,活动能力及肺癌附加关注的其它因素方面较培美曲塞组改善更明显(P<0.05)。结论吉非替尼和培美曲塞二线治疗晚期非鳞型NSCLC的疗效相似,不良反应各异;两者均能改善患者的生活质量,但是吉非替尼改善更明显。     

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。     

EGFR T790M突变丰度对奥希替尼治疗晚期非小细胞肺癌疗效的影响

摘 要：［目的］ 分析奥希替尼治疗晚期非小细胞肺癌疗效,并探索ddPCR方法外周血检测表皮生长因子（epidermal growth factor,EGFR）T790M突变的丰度与奥希替尼疗效之间的关系。［方法］ 回顾性分析104例接受奥希替尼治疗的Ⅲb~Ⅳ期非小细胞癌肺癌患者,采用ddPCR法测定外周血T790M突变丰度,采用Kaplan-Meier法和Cox模型进行生存预后分析,并探索疗效相关T790M突变丰度的界值。［结果］ 外周血EGFR T790M突变丰度中位值为0.89%（0.02%~35.10%）。将突变丰度分为＜5.00%和≥5.00%两组,客观缓解率分别为46.5%和88.9%（P=0.001）,中位无进展生存期分别为8.80个月和21.83个月（P=0.039）。Cox回归分析显示,初治时基因类型（EGFR 19外显子缺失和21外显子L858R突变）、PS评分、外周血EGFR T790M突变丰度分组（＜5.00%和≥5.00%）是奥希替尼治疗患者PFS的独立影响因素。［结论］ EGFR T790M突变丰度可能可预测奥希替尼治疗的晚期EGFR T790M突变NSCLC患者的有效率和无进展生存期。     

共突变基因与晚期非小细胞肺癌靶向治疗预后生存的相关性分析

目的:进一步验证晚期表皮生长因子受体（epidermal growth factor receptor,EGFR）突变非小细胞肺癌(non-small cell lung cancer,NSCLC)靶向治疗预后生存情况,探讨共突变基因与患者预后生存的相关性。方法:回顾性分析2016年01月至2019年12月我院经病理确诊为晚期NSCLC,二代测序（next-generation sequencing,NGS）为EGFR突变阳性,且使用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）一代药物作为一线治疗的102例患者的病历和随访资料。收集其临床病理特征、治疗前的检验结果、基因检测报告、共突变基因和随访信息。采用Cox回归模型分析共突变基因与无疾病进展生存期（progression-free survival,PFS）的相关性。通过基因表达谱数据动态分析（Gene Expression Profiling Interactive Analysis,GEPIA）公共数据库分析磷脂酞肌醇-3-激酶催化亚单位α基因（phosphoinositide-3-kinase catalytic alpha polypeptide gene,PIK3CA）、人类表皮生长因子受体2（human epidermal growth factor receptor 2,HER-2）、间质表皮转化因子（mesenchymal-epithelial transition factor,MET）三种共突变基因与肺癌总生存期（overall survival,OS）和无病生存期（disease-free survival,DFS）的相关性。结果:102例一线靶向治疗的晚期NSCLC患者中位PFS为10个月。单因素分析表明,EGFR突变合并PIK3CA突变的患者一线靶向治疗的中位PFS为8个月,不合并PIK3CA突变患者的中位PFS为11个月,差异有统计学意义（P=0.037）;EGFR突变合并T790M突变患者的中位PFS为6个月,不合并T790M突变患者中位PFS为10个月,差异有统计学意义（P=0.043）;EGFR突变合并HER-2扩增的患者中位PFS为7个月,不合并HER-2扩增的患者中位PFS为10个月,差异有统计学意义（P=0.048）;EGFR突变合并MET扩增的患者中位PFS为3个月,不合并MET扩增的患者中位PFS为10个月,差异有统计学意义（P=0.001）。多因素分析显示,合并PIK3CA突变（HR=0.536,95%CI:0.302~0.951,P=0.033）、HER-2扩增（HR=0.359,95%CI:0.142~0.909,P=0.031）、MET扩增（HR=0.139,95%CI:0.042~0.464,P=0.001）是PFS的独立预后因素。PIK3CA基因与晚期NSCLC的DFS有相关性（P<0.05）。结论:晚期NSCLC靶向治疗前合并PIK3CA突变、HER-2扩增、MET扩增是患者PFS的独立影响因素。     

安罗替尼联合替吉奥治疗三线及以上晚期非小细胞肺癌的安全性和有效性

目的:前瞻性应用安罗替尼联合替吉奥治疗三线及以上晚期非小细胞肺癌,观察临床疗效和药物的安全性。方法:均经组织病理或细胞学明确诊断晚期非小细胞肺癌,且二线化疗治疗后疾病进展。口服安罗替尼胶囊8 mg/d,d1~14联合替吉奥胶囊60 mg/m2 bid d1~14,21天为一个周期。治疗终止时间为疾病进展或出现不可接受的毒副反应。结果:本研究结果显示,总体客观缓解率（ORR）可达到26.8%,总体疾病控制率（DCR）可达到80.5%,中位无进展生存期（mPFS）达到5.2个月（95%CI:3.9~6.6个月）。单因素分析,脑转移组患者mPFS（4.8个月）对比无脑转移组患者mPFS（5.9个月）,两组差异具有统计学意义（P=0.039）。多变量回归分析显示,ECOG评分(P=0.002)、治疗线数（P=0.015）和疗效(P=0.014)是PFS的独立影响因素。最常见毒副反应为高血压、蛋白尿、骨髓抑制、胃肠道反应、疲乏和口腔黏膜炎。结论:安罗替尼联合替吉奥胶囊在晚期非小细胞肺癌三线及以上治疗中,其总体的疗效确切且药物毒副反应可控。     

Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients

Aim

Non-small cell lung cancer (NSCLC)-patients with an epidermal growth factor receptor (EGFR)-mutation have median progression-free survival (PFS) of 12 months on tyrosine kinase inhibitors (TKIs). Resistance is mediated by the EGFR T790M-mutation in the majority of patients. Longitudinal follow-up data are lacking. We retrospectively evaluated EGFR-mutated NSCLC-patients who were rebiopsied after TKI-treatment. A subgroup was sequentially rebiopsied along the course of the disease.

Patients and methods

Advanced EGFR-mutated NSCLC-patients who had both a pre-TKI biopsy and post-TKI biopsy available were included. Information on treatments and (re)biopsies was collected chronologically. Primary endpoint was the incidence of the T790M-mutation.

Results

Sixty-six patients fulfilled the inclusion criteria. In first post-TKI biopsies, T790M-mutation was detected in 34 patients (52%) of patients. Twenty-seven patients had subsequent post-TKI rebiopsies with mutation analysis available; in 10 patients (37%) the T790M-status in subsequent post-TKI rebiopsies was not consistent with the T790M-status of the first post-TKI biopsy. Progression free survival (PFS) on TKI-treatment was 12.0 months. Objective response rate on TKI-treatment was 81%. Patients developing T790M-mutation at post-TKI biopsy had longer median PFS compared to T790M-negative patients (14.2 versus 11.1 months respectively (P = 0.034)) and longer overall survival (45.9 months versus 29.8 months respectively (P = 0.213)). Transformation to SCLC was detected in 1 patient (2%).

Conclusion

Incidence of T790M-mutation at first post-TKI biopsy in this cohort of EGFR-mutated NSCLC-patients was 52%. Detection of T790M-mutation was not consistent over time; some patients who were T790M-positive at first post-TKI biopsy became T790M-negative in later post-TKI rebiopsies and vice versa. T790M-positive patients showed longer PFS than T790M-negative patients. Whether the low incidence of transformation to SCLC is justifying post-TKI rebiopsy in EGFR-mutated NSCLC-patients with acquired TKI-resistance in regular clinical practice is debatable.     

Activity of the EGFR-HER2 Dual Inhibitor Afatinib in EGFR-Mutant Lung Cancer Patients With Acquired Resistance to Reversible EGFR Tyrosine Kinase Inhibitors

BackgroundThe purpose of this study was to evaluate the efficacy of afatinib in EGFR-mutant metastatic NSCLC patients with acquired resistance to erlotinib or gefitinib.Materials and MethodsWe retrospectively analyzed the outcome of patients with EGFR-mutant advanced NSCLC treated with afatinib after failure of chemotherapy and EGFR TKIs.ResultsA total of 96 individuals were included in the study. According to EGFR status, most patients (n = 63; 65.6%) harbored a deletion in exon 19, and de novo T790M mutation was detected in 2 cases (T790M and exon 19). Twenty-four (25%) patients underwent repeated biopsy immediately before starting afatinib and secondary T790M was detected in 8 (33%) samples. Among the 86 patients evaluable for efficacy, response rate was 11.6%, with a median progression free-survival (PFS) and overall survival (OS) of 3.9 and 7.3 months, respectively. No significant difference in PFS and OS was observed according to type of last therapy received before afatinib, type of EGFR mutation or adherence to Jackman criteria, and patients benefiting from afatinib therapy had longer PFS and OS (P < .001). Outcome results for repeated biopsy patients were similar to the whole population, with no evidence of response in T790M-positive patients. All patients were evaluable for toxicity, and 81% experienced an AE of any grade, with grade 3 to 4 AEs, mainly diarrhea and skin toxicity, occurring in 19 (20%) patients.ConclusionOur results showed that afatinib has only modest efficacy in a real life population of EGFR mutant NSCLC patients with acquired resistance to erlotinib or gefitinib.     

Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment

BackgroundThe efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.Patients and methodsWe identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).ResultsIn cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively (P = 0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20–1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of ≥1% or <1%, respectively (P = 0.084; hazard ratio of 0.37, 95% confidence interval of 0.10–1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of ≥10% and ≥50%. The proportion of tumors with a PD-L1 level of ≥10% or ≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8⁺ TIL density and nonsynonymous mutation burden.ConclusionT790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.     

一代EGFR-TKI联合同步放疗治疗EGFR-TKI耐药晚期肺腺癌患者的有效性和安全性

目的:探索第一代EGFR酪氨酸激酶抑制剂（EGFR-TKI）耐药后继续口服EGFR-TKI并联合局部放疗治疗晚期肺腺癌的有效性和安全性。方法:回顾性纳入2014年1月至2017年7月期间本中心符合纳入标准的、接受第一代EGFR-TKI联合局部放疗治疗的晚期肺腺癌患者,分析其疗效及不良事件发生情况。结果:研究纳入了64例符合纳入标准及排除标准的患者,继续口服原EGFR-TKIs并联合局部放疗的平均PFS为（5.48±3.85）个月。PFS与患者进展病灶不同数量相关,出现1、2、3个病灶进展患者的无进展生存期分别为6.60个月、5.17个月和 2.82个月,组间比较有显著统计学差异（P=0.006）。继续口服原EGFR-TKIs并联合局部放疗总体3-4级不良事件发生率为10.9%。结论:第一代EGFR-TKI联合局部放疗是EGFR-TKI治疗晚期肺腺癌后局部进展的有效治疗方式之一。     

Safety,Efficacy, and Pharmacokinetics of Almonertinib (HS-10296) in Pretreated Patients With EGFR-Mutated Advanced NSCLC: A Multicenter,Open-label,Phase 1 Trial

IntroductionAlmonertinib (HS-10296) is a novel, third-generation EGFR tyrosine kinase inhibitor (EGFR TKI) that targets both EGFR-sensitizing and T790M resistance mutations. This first-in-human trial aimed to evaluate the safety, efficacy, and pharmacokinetics of almonertinib in patients with locally advanced or metastatic EGFR mutation-positive NSCLC that had progressed after pevious EGFR TKI therapy.MethodsThis phase 1, open-label, multicenter clinical trial (NCT0298110) included dose-escalation (55, 110, 220, and 260 mg) and dose-expansion cohorts (55, 110, and 220 mg) with once daily oral administration of almonertinib. In each expansion cohort, tumor biopsies were obtained for the determination of EGFR T790M status. The safety, tolerability, antitumor activity, and pharmacokinetics of almonertinib were evaluated.ResultsA total of 120 patients (26 patients in the dose-escalation cohort and 94 patients in the dose-expansion cohort) were enrolled. The maximum tolerated dose was not defined in the dose-escalation phase; the 260 mg regimen was not further evaluated in the dose-expansion phase owing to safety concerns and saturation of exposure. The most common treatment-related grade greater than or equal to 3 adverse events were increased blood creatine phosphokinase (10%) and increased alanine aminotransferase (3%). Among 94 patients with the EGFR T790M mutation in the dose-expansion cohort, the investigator-assessed objective response rate and disease control rate were 52% (95% confidence interval [CI]: 42–63) and 92% (95% CI: 84–96), respectively. Median progression-free survival was 11.0 months (95% CI: 9.5–not reached) months.ConclusionsAlmonertinib is safe, tolerable and effective for patients with locally advanced or metastatic NSCLC harboring the EGFR T790M mutation who were pretreated with EGFR TKIs.     

Characterization of Liver Metastasis and Its Effect on Targeted Therapy in EGFR-mutant NSCLC: A Multicenter Study

Background

The risk factors for liver metastasis (LM) in patients with non–small-cell lung cancer (NSCLC) remain unknown. Whether LM predicts for the effect of first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutant NSCLC needs to be explored.

Audit of Molecular Mechanisms of Primary and Secondary Resistance to Various Generations of Tyrosine Kinase Inhibitors in Known Epidermal Growth Factor Receptor-Mutant Non-small Cell Lung Cancer Patients in a Tertiary Centre

AimsPresently, three generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are approved against oncogene addicted EGFR-mutant non-small cell lung cancer (NSCLC). Patients with actionable EGFR mutations invariably develop resistance. This resistance can be intrinsic (primary) or acquired (secondary).Materials and methodsThis was a retrospective study carried out between January 2016 and April 2021 analysing 486 samples of NSCLC for primary and secondary resistance to first- (erlotinib, gefitinb), second- (afatinib) and/or third-generation (osimertinib) TKIs in EGFR-mutant NSCLCs by next generation sequencing (NGS). Tissue NGS was carried out using the Thermofischer Ion Torrent? Oncomine? Focus 52 gene assay; liquid biopsy NGS was carried out using the Oncomine Lung Cell-Free Total Nucleic Acid assay. All cases were previously tested for a single EGFR gene with the Therascreen® EGFR RGQ PCR kit.ResultsThe results were divided into four groups: (i) group 1: primary resistance to first- and/or second-generation TKIs. This group, with 21 cases, showed EGFR exon 20 insertions, dual, complex mutations and variant of unknown significance, de novo MET gene amplification besides other mutations. (ii) Group 2: primary resistance to third-generation TKIs. This group showed two cases, with one showing dual EGFR mutation (L858R and E709A) and EGFR gene amplification. (iii) Group 3: secondary resistance to first- and second-generation TKIs. This group had 27 cases, which were previously reported negative for EGFR T790M by single gene testing. Significant findings were MET gene amplification in four cases, with one also showing MET exon 14 skipping mutation. Three cases showed small cell change and one showed loss of primary mutation. (iv) Group 4: secondary resistance to third-generation TKIs. The latter group was further subgrouped into group 4A: secondary resistance to osimertinib (third-generation TKI) when offered as second-line therapy after first- and second-generation TKIs on detection of T790M mutation. This group had 15 cases. EGFR T790M mutation was lost in 10 (10/15; 67%) cases and was retained in five cases. Patients with T790M loss experienced early resistance (6.9 months versus 12.6 months mean, P = 0.0024) compared with cases that retained T790M. Two cases gained MET amplification as the resistance mechanisms. Other mutations that were found when EGFR T790M was lost were in FGFR3, KRAS, PIK3CA, CTNNB1, BRAF genes. One case had EML4-ALK translocation. Two cases showed driver EGFR deletion 19, retained T790M and C797S mutation in Cis form. Group 4B: secondary resistance to osimertinib (when given as first-line therapy) in EGFR-mutant NSCLC. This group had three cases. The duration of osimertinib treatment ranged from 11 to 17 months. Two patients showed additional C797S mutation along with primary EGFR mutation.ConclusionThis study shows the wide spectrum of primary and secondary EGFR resistance mechanisms to first, second and third generation of TKIs and helps us to identify newer therapeutic targets that could carry forward the initial advantage offered by EGFR TKIs.     

吉非替尼联合培美曲塞和顺铂治疗晚期非小细胞肺癌的安全性和有效性

目的:比较单用培美曲塞/顺铂化疗或吉非替尼联合培美曲塞/顺铂化疗治疗晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）的临床疗效及安全性,为临床应用提供参考。方法:选择标准一线化疗后复发的晚期NSCLC患者112例,其中联合治疗组52例接受培美曲塞/顺铂及吉非替尼治疗,化疗组60例仅采用培美曲塞和顺铂化疗,评价两组患者的临床疗效及不良反应。结果:联合组客观有效率（objective response rate,ORR）为36.5%,高于化疗组的18.3%（P=0.030）;两组疾病控制率（disease control rate,DCR）分别为71.2%和55.0%（P=0.035）;两组患者的中位无进展生存期（progression free survival,PFS）分别为8.7个月和6.7个月,差别有统计学意义（P=0.047）,但两组患者的中位总生存期（overall survival,OS）差别无统计学意义（P=0.265）。与治疗前相比,两组患者的肿瘤标志物均明显下降,但联合组的CEA和CYFRA21-1水平比化疗组更低（P<0.05）。联合组皮疹和腹泻的发生率高于化疗组（P<0.05）,两组之间其它不良反应的发生率无明显差别（P>0.05）。结论:晚期NSCLC患者一线化疗失败后,采用培美曲塞/顺铂化疗联合吉非替尼靶向治疗较单用化疗显示出更高的ORR和中位PFS,且不良反应可以耐受,值得临床推广运用。