【作者】 王婷；

【导师】 王秀问； 郝静；

【作者基本信息】 山东大学 ， 肿瘤学（专业学位）， 2021， 硕士

【摘要】 研究目的:肺癌目前是全世界最常见的恶性肿瘤,在我国发生率、死亡率也居恶性肿瘤之首。其中非小细胞肺癌占绝大多数(约85%),多数患者就诊时已为中晚期(ⅢB/Ⅳ期)。对于晚期转移性驱动基因阴性的非小细胞肺癌(NSCLC)且无免疫检查点抑制剂禁忌症的患者,一线化疗联合免疫治疗已成为目前优先推荐的治疗策略,但耐药之后的治疗模式仍需要深入探索。对于一线仅接受传统含铂化疗方案的晚期NSCLC患者,多西他赛等单药治疗和免疫治疗成为NSCLC的二线标准治疗。其中多西他赛单药有效率(RR)仅10%左右,中位无进展生存期(mPFS)2～4个月,中位生存期(mOS)5.5～12.5个月。2018年6月15日纳武利尤单抗获中国国家药品监督管理局批准,用于表皮生长因子受体(EGFR)、间变性淋巴瘤激酶(ALK)阴性,既往接受过含铂方案化疗后进展的局部晚期或转移性NSCLC患者。尽管二线免疫检查点抑制剂治疗与多西他赛单药相比,无论有效率、PFS还是OS均显著提高,分别为14～30%,2.3～4.0个月和9.2～13.8个月,但免疫治疗其原发、继发耐药,缺乏有效的疗效预测标志物,治疗相关不良事件和价格高昂、未纳入医保等问题亟待解决,限制了其在国内患者中的广泛应用。分析过去十年内国内二线治疗晚期NSCLC的方案选择变迁,研究在单药化疗的基础上如何提高二线治疗疗效,改善生存仍然具有重要的现实意义。本研究目的:(1)回顾性分析山东大学齐鲁医院肿瘤中心驱动基因阴性的晚期非小细胞肺癌患者二线治疗方案的组成及比例变化;(2)本研究回顾性分析接受替吉奥联合非铂类方案二线治疗晚期NSCLC的疗效与安全性,旨在为晚期NSCLC患者二线治疗策略的优化提供证据,同时为未来免疫检查点抑制剂联合替吉奥及非铂类治疗的可行性研究打下基础。方法:(1)回顾性分析山东大学齐鲁医院肿瘤中心2011年1月-2020年12月十年期间收治的晚期非小细胞肺癌患者二线治疗方案的组成及比例变化。入组标准包括国际肺癌研究协会(IASLC)第七版肺癌TNM分期系统不可手术或根治性放化疗的ⅢB/Ⅳ期肺癌;病理类型为非小细胞肺癌,鳞癌或非鳞癌;EGFR/ALK阴性或未知;既往接受含铂双药一线化疗失败。排除标准包括混合小细胞或大细胞神经内分泌癌成分;EGFR/ALK阳性;合并其他恶性肿瘤。收集二线治疗方案,并归类为单药化疗、含铂双药化疗、非铂双药化疗(不含替吉奥)、替吉奥联合非铂类双药化疗、单药化疗联合抗血管生成治疗、双药化疗联合抗血管生成治疗、免疫治疗、免疫联合抗血管生成治疗共八类。将二线治疗方案的十年变迁根据替吉奥联合非铂类临床研究开始时间(2015年1月)、纳武利尤单抗获中国国家药品监督管理局批准时间(2018年6月)划分为三个时间段,第一阶段(2011年1月-2014年12月)、第二阶段(2015年1月-2018年6月)、第三阶段(2018年6月-2020年12月)。(2)接受替吉奥联合非铂类方案二线治疗晚期NSCLC的疗效与安全性分析:回顾性分析了 2015.1-2020.5期间在山东大学齐鲁医院、山东大学齐鲁医院青岛分院、山东省肿瘤医院、淄博市第一人民医院、章丘市人民医院、临沂市人民医院、济南市第四人民医院接受该研究方案的晚期非小细胞肺癌患者,入选标准:非小细胞肺癌;根据IASLC的第七版肺癌TNM分期系统不可手术或根治性放化疗的ⅢB/Ⅳ期肺癌;年龄≥18岁,≤75岁,根据美国东部肿瘤协作组(ECOG)体能状况评分,治疗前ECOG评分均在0-1分;EGFR/ALK阴性或未知,或者驱动基因阳性,经靶向药物(TKI)治疗后耐药;只接受过一线含铂双药化疗后方案进展;根据实体瘤的疗效评价标准(RECIST):至少要有一个可以精确测量最大径的可测量目标病灶,病灶的最大径要≥10mm。排除标准:症状性脑转移。生存随访截止日期为2020年10月31日。研究方案为多西他赛联合替吉奥或吉西他滨联合替吉奥,剂量范围为:替吉奥:40～60mg,bid,连服14日,休7日;多西他赛:60～75mg/m2,dl;吉西他滨:1000mg/m2,dl,d8。主要研究终点:无进展生存期;次要研究终点:近期有效率、总生存期、安全性。统计学方法:患者的一般人口学及疾病特征采用描述性统计分析,正态分布的计量资料采用均值±标准差表示,偏态分布的计量资料采用中位数(四分位间距)表示,计数资料采用例数(百分比)表示。采用Kaplan-Meier法绘制生存曲线并采用Log-rank检验进行组间比较,95%置信区间采用log-log法估计。采用Cox回归进行多因素分析,采用后退法筛选危险因素。全部统计学分析应用R3.5.0和SAS 9.4软件进行,双侧检验,检验水准α=0.05。设定历史对照多西他赛近期有效率为10%,Fisher确切概率法用于与历史对照比较,单侧检验p<0.025认为有统计学意义。使用匹配调整间接比较方法,通过加权后的平衡人群比较替吉奥联合非铂类方案和多西他赛的疗效(PFS与OS)。安全性分析按照CACTE标准收集分析该研究方案不良事件。电话随访或查阅病历资料获得后续治疗信息。本临床研究经过山东大学齐鲁医院医学伦理会批准(伦申第2015040)。结果:(1)山东大学齐鲁医院晚期非小细胞肺癌二线治疗方案的组成及比例变化:符合标准患者452例,其中接受含铂双药化疗方案的患者共228例(50.44%),为最常用的二线治疗方案。接受单药化疗的患者比例在三个阶段呈下降趋势,分别为18.13%、7.74%、5.64%;含铂双药化疗的比例同样呈现下降趋势,分别为75.63%、42.86%、28.23%;替吉奥联合非铂类方案的比例分别为1.25%,42.86%,16.93%,第二阶段接受率最高;联合抗血管生成治疗比例在三个阶段呈上升趋势,为3.12%、6.54%、37.10%,而免疫治疗比例在第三阶段达12.10%。(2)本研究最终纳入87例进行安全性分析,83例进行生存分析,76例进行无进展生存期分析,mPFS为5.23个月[95%可信区间(CI):4.40～7.90个月],中位生存期(mOS)为14.40个月(95%CI:12.53～17.40个月)。有效率为22.89%,与设定历史对照10%相比(p<0.001);匹配加权法将本研究与多西他赛的疗效(PFS、OS)间接调整比较,替吉奥联合非铂类方案加权后mPFS为7.90个月,mOS为19.37个月,均显著高于多西他赛的历史对照研究。(3)PFS与OS单因素和多因素COX回归分析:单因素分析显示替吉奥联合非铂类方案二线治疗的PFS与年龄、性别、ECOG评分、吸烟、分期、组织学类型、是否合并脑转移均无关;一线化疗PFS>9个月的患者,较PFS≤9个月的患者,接受该方案的二线PFS有延长的趋势,分别为8.7个月vs 5.0个月(p=0.058);二线治疗后的总生存与二线化疗近期疗效密切相关,PR、SD、PD患者中位生存分别为23.5个月,14.9个月和4.9个月(p<0.001),而与年龄、性别、ECOG评分、吸烟、分期、组织学类型、是否合并脑转移、一线化疗疗效等因素无关。多因素COX分析同样显示替吉奥联合非铂类方案二线治疗的PFS与一线化疗的PFS密切相关(p=0.049),OS与二线化疗的RR密切相关(p<0.001)。(4)本研究不良事件发生率88.51%,3-4级不良事件发生率20.69%,最常见的药物不良反应贫血(60.92%)、恶心(55.17%)和白细胞降低(33.33%),最常见的3-4级严重不良反应为中性粒细胞降低(14.94%);剂量下调的患者10例,因严重不良事件中断治疗4例,剂量下调率11.49%,中断治疗率4.60%。(5)在随访到后续治疗的77例患者中,接受后续系统治疗的患者63例(81.82%),更换化疗药物方案占32.47%,抗血管生成治疗单药或联合化疗药物占28.57%,接受免疫治疗PD-1单抗患者占6.49%。结论:(1)2011～2020年期间晚期NSCLC常用的二线化疗方案依次为,含铂双药化疗、替吉奥联合非铂类化疗、抗血管生成药物联合化疗、单药化疗、免疫治疗(PD-1单抗)等;含铂双药化疗及单药化疗方案随时间呈现下降趋势,替吉奥联合非铂类方案在2015～2018年期间处方率最高;联合抗血管生成治疗及免疫治疗比例在2018～2020年呈迅速上升趋势。(2)替吉奥联合非铂类方案与标准二线历史对照多西他赛单药相较,有效率显著升高,无进展生存期和总生存期较历史对照均明显延长,不良反应可耐受,证实替吉奥联合非铂类方案二线治疗晚期NSCLC安全有效,也为未来联合免疫检查点抑制剂或抗血管生成治疗打下良好的基础。更多还原

【Abstract】 PurposeLung cancer is currently the most common malignant tumor around the world,both in incidence and death rate in my country and non-small cell lung cancer(NSCLC)accounts for the majority of lung cancer,about 85%of it.Most of these patients were diagnosed as advanced(stage ⅢB/Ⅳ).For advanced metastatic NSCLC patients who have negative driver genes without contraindications to immune checkpoint inhibitors(ICIs),first-line chemotherapy combined with immunotherapy has become the preferred treatment strategy now,but the treatment mode after drug resistance still needs to be further explored.For advanced NSCLC patients who only receive the traditional platinum-based chemotherapy in the first line,monotherapy such as docetaxel and immunotherapy has become the standard second-line treatment for NSCLC.The response rate(RR)of docetaxel was just about 10%,the median progression-free survival(mPFS)and median overall survival(mOS)were 2～4 months and 5.5～12.5months,respectively.Nivolumab was approved by the National Medical Products Administration of China on June 15,2018 for using in patients with locally advanced or metastatic NSCLC who are negative for EGFR or ALK and who have progressed after previous platinum-based chemotherapy.Although ICIs as second-line therapy showed significant improvements in RR,PFS,and OS compared with docetaxel monotherapy,with rates of 14 to 30%,2.3～4.0 months,and 9.2～13.8 months,respectively,some problems exist to be addressed,such as primary and acquired resistance,the lack of effective and prognostic bio-markers,treatment-related adverse events,the high cost and not covered by Health Care.Therefore,these restrict its wide application in domestic patients.It is still of great practical significance to analyze the changes of second-line treatment for advanced NSCLC patients in China in the past 10 years,and to study how to improve second-line treatment efficacy and survival on the basis of monotherapy.Purposes of this study:(1)To retrospectively analyze the composition and proportion of second-line treatment for advanced NSCLC patients with negative driver genes in Qilu Hospital Cancer Center,(2)This study was an retrospective analysis of the efficacy and safety of second-line treatment of advanced NSCLC with S-1 combined with non-platinum-based chemotherapy,so as to provide evidence for the optimization of second-line treatment strategies for patients with advanced NSCLC and to lay a foundation for future feasibility studies of ICIs combined with S-1 or non-platinum-based chemotherapy.Methods(1)Retrospectively analysis of the composition and proportion of second-line treatment for patients with advanced NSCLC patients admitted to Qilu Hospital Cancer Center from January 2011 to December 2020.Inclusion criteria included staging IIIB/IV lung cancer by the International Association for the Study of Lung Cancer(IASLC)7th Edition of TNM Staging with inoperable or non-definitive chemoradiotherapy;the pathological types were NSCLC,squamous carcinoma or non-squamous carcinoma;negative EGFR/ALK or unknown;previously treated with platinum-based chemotherapy.Exclusion criteria included mixed small-cell or large-cell neuroendocrine carcinoma;positive EGFR/ALK;complicated with other malignant tumors.Second-line treatment regimens were collected and classified as monotherapy,platinum-based chemotherapy,non-platinum dual-drug chemotherapy(excluding S-I);S-1 combined with non-platinum-based chemotherapy,monotherapy combined with antiangiogenic therapy,dual drug chemotherapy combined with antiangiogenic therapy;immunotherapy;immunotherapy combined with antiangiogenic therapy.According to the start date of this study and the time of approval of Nivolumab by the National Medical Products Administration of C hina,second-line treatment regimens over 10 years were divided into the first phase(January 2011-December 2014),the second stage(January 2015-June 2018)and the third stage(on June 6,2018-December 2020).(2)The analysis of the efficacy and safety of second-line treatment of advanced NSCLC with S-1 combined with non-platinum-based chemotherapy:This study retrospectively analyzed advanced NSCLC patients receiving this chemotherapy from 2015.1to2020.5 in Qilu Hospital,Qingdao branch of Qilu Hospital,Shandong Cancer Hospital,The First People’s Hospital of Zibo,The People’s Hospital of Zhangqiu,Linyi People’s Hospital and Jinan Fourth People’s Hospital.The inclusion criteria included NSCLC;staging ⅢB/Ⅳ lung cancer according to the IASLC 7th Edition of TNM Staging with inoperable or non-definitive chemoradiotherapy;and age≥18 years,≤75 years,Eastern Cooperative Oncology Group performance status ≤1;negative EGFR/ALK or unknown,or patients with positive driver genes and resistant to targeted therapy(TKI);and previously only treated with platinum-based chemotherapy;according to RECIST of solid tumor:there should be at least one measurable target lesion that can accurately measure the maximum diameter and the maximum diameter of the lesion should be≥10mm.Exclusion criteria is symptomatic brain metastasis.The cutoff date for survival follow-up was October 3 1,2020.The study chemotherapy regimens were Docetaxel combined with S-1 or Gemcitabine combined with S-1.The dose range was:S-1:40-60mg,bid;Docetaxel:60-75mg/m2,d1;Gemcitabine:1000mg/m2,d1,d8.The primary endpoint is PFS.Secondary endpoints were RR,OS and safety.Statistical analysis:The demographics and disease characteristics of patients were analyzed by descriptive statistics.The measurement data of normal distribution was expressed as mean±standard deviation,the measurement data of skewed distribution was expressed as median(interquartile range),and the count data was expressed as number(%).Survival curves were estimated using the Kaplan-Meier method and Log-rank test.The 95%confidence interval was estimated using the log-log method.COX regression analysis was used for multivariate analysis and regression method was used to screen risk factors.All statistical analyses were carried out using R 3.5.0 and SAS 9.4 software,and perform two-sided test(α=0.05).The response rate of Docetaxel was set as 10%in historical control.Fisher’s exact probability method was used to compare with historical control.p<0.025 in unilateral test was considered statistically significant.Matching-adjusted indirect comparisons were used to compare the efficacy of S-1 in combination with non-platinum-based chemotherapy and Docetaxel in a weighted balanced population.Safety analysis was estimated according to the CTCAE standard.The subsequent treatment information was available by telephone or medical records.Results(1)The composition and proportion of second-line treatment for patients with advanced NSCLC patients admitted to Qilu Hospital Cancer Center:452 patients were enrolled,among which 228 patients(50.44%)received the platinum-based chemotherapy,which was the most commonly used second-line treatment.The proportion of patients receiving single drug chemotherapy showed a decreasing trend in three stages,which were 18.13%,7.74%,5.64%,respectively.The proportion of platinum-based chemotherapy also showed a decreasing trend,which were 75.63%,42.86%,28.23%,respectively.The proportion of S-1 combined with non-platinum chemotherapy were 1.25%,42.86%,16.93%,respectively,with the highest acceptance rate in the second stage.The proportion of combined antiangiogenic therapy increased in three stages,which were 3.12%,6.54%,3 7.10%,while the proportion of immunotherapy reached 12.10%in the third stage.(2)This study enrolled in 87 patients of security analysis,83 patients of survival analysis and 76 patients of progression-free survival analysis.The m.PFS was 5.23 months[95%confidence interval(CI)4.40-7.90 months],the mOS was 14.40months(95%CI:12.53-17.40 months),RR was 22.89%,compared with 10%for the historical control(p<0.001).The PFS and OS of this study indirectly adjusted by matching weighting was compared with those of docetaxel.The weighted mPFS(7.90 months)and mOS(19.37 months)of S-1 combined with non-platinum-based chemotherapy were significantly higher than those of the historical control study.(3)Univariate and multivariate Cox regression analysis of PFS and OS:Univariate analysis showed that no correlation was observed between age,sex,ECOG score,smoking,TNM stage,histological type,brain metastasis or not and PFS.Patients whose PFS>9m in first-line,compared with patients whose PFS≤9m,showed a tendency of prolongation in PFS(p=0.058).The OS was closely related to the short-term efficacy of second-line chemotherapy(p<0.001),but not related to other factors.Multivariate Cox analysis also showed that PFS of this study was closely correlated with PFS of first-line chemotherapy(p=0.049),and OS was closely correlated with RR of second-line chemotherapy(p<0.001)(4)The incidence of adverse events in this study was 88.51%,and the incidence of grade 3-4 adverse events was 20.69%.The most common adverse drug reactions of were anemia(60.92%),nausea(55.17%)and leukocytopenia(33.33%),and the most common grade 3/4 severe adverse drug reactions were neutropenia(14.94%).The dose reduction rate was 11.49%,and the treatment discontinuation rate was 4.60%.(5)Among the 77 patients who were followed up subsequent treatment,63 patients(81.82%)received subsequent systematic treatment,of which chemotherapy accounted for 32.47%.Antiangiogenic therapy accounted for 28.57%as monotherapy or in combination.6.49%of patients received PD-1 immunotherapy.Conclusion(1)From 2011 to 2020,the commonly used second-line chemotherapy for advanced NSCLC were,in order,platinum-based chemotherapy,S-l combined with non-platinum-based chemotherapy,antiangiogenic therapy combined with chemotherapy,monotherapy,immunotherapy(PD-l monoclonal antibody),etc.The platinum-based chemotherapy and monotherapy showed a decreasing trend over time,and the prescription rate of S-1 combined with non-platinum-based chemotherapy was the highest from 2015 to 2018.The proportion of combined antiangiogenic therapy and immunotherapy showed a rapidly increasing trend from 2018 to 2020.(2)Compared with docetaxel monotherapy as the standard second-line,the response rate was significantly increased,the progression-free survival and overall survival were significantly longer than those of the historical control,and the adverse reactions were tolerable,confirming the safety and efficacy of the combination of S-1 and non-platinum-based chemotherapy as second-line treatment for advanced NSCLC,and also lays a good foundation for feasibility studies of S-1 combined with ICIs or antiangiogenic therapies.更多还原