肺癌内科治疗进展

非小细胞肺癌内科治疗进展,周彩存同济大学附属上海市肺科医院,化疗进展,早期术后辅助化疗：个体化？局部晚期 同步化放疗，AP未超越EP鳞癌：白蛋白紫杉醇普通紫杉醇;ND优于DP非鳞癌 分子靶向治疗 贝伐单化疗优于化疗 培美优于健择 连续维持治疗改善总体生存免疫治疗,辅助治疗的必要性,辅助化疗,是淋巴结阳性完全切除早期NSCLC的标准治疗在淋巴结阴性病人,仍存在争议顺铂为基础方案是标准卡铂为基础方案未得到批准,但经常使用证据最多的是NPECOG1505允许所有未批准的方案,BRCA1水平和含铂药物化疗的相关性,Yang Y et al.J Exp Clin Cancer Res,2013,Customized BRCA1 Adjuvant Treatment in Stage II-II NSCLC (SCAT),Presented By Mark Socinski at 2015 ASCO Annual Meeting,Presented By Mark Socinski at 2015 ASCO Annual Meeting,Customized BRCA1 Adjuvant Treatment in Stage II-II NSCLC (SCAT),SLIDES ARE THE PROPERTY OF THE AUTHOR.PERMISSION REQUIRED FOR REUSE.,实验组的OS,Massuti B, et al. 2015 ASCO Abstract 7507.,BRCA1高水平患者DFS和OS,BRCA1高表达者未显示顺铂耐药。,Massuti B, et al. 2015 ASCO Abstract 7507.,BRCA1低表达患者DFS和OS,BRCA1低表达者多见于腺癌、非吸烟和女性患者。,分子学分析指导下的晚期NSCLC患者全球III期研究：研究设计,分层因素：PS、性别、既往(新)辅助治疗治疗：6周期、无维持治疗、无贝伐单抗主要入组条件：IIIB(湿性)/IV期NSCLC，PS 0-1，可测量疾病，FFPE组织块并有蛋白表达数据计划入组：267例 (254个事件),Bepler G, et al. 2013 ASCO Abstract 8001.,招募：运输组织块，筛选符合条件受试者,主要终点：无进展生存,2 : 1,N=275,研究结果：PFS和OS,Bepler G, et al. 2013 ASCO Abstract 8001.,OS,So what can we conclude from this study and what are the issues?,Presented By Mark Socinski at 2015 ASCO Annual Meeting,BRCA1 does not appear to be a robust biomarker in this small 4-arm trialRT-PCR - is it a valid method to quantitate BRCA1 function?Three different treatments given - how do you separate the treatment effects from the biology? Terciles were not balanced for known prognostic factorsRaises the hypothesis that different cisplatin-based doublets may have differing effects in different subsetsCompliance to therapy important (but reasons for non-compliance not delineated),化疗进展,早期术后辅助化疗：个体化？局部晚期 同步化放疗，AP未超越EP鳞癌：白蛋白紫杉醇普通紫杉醇;ND优于DP非鳞癌 分子靶向治疗 贝伐单化疗优于化疗 培美优于健择 连续维持治疗改善总体生存免疫治疗,Unresectable Stage III NSCLC,Presented By Mark Socinski at 2015 ASCO Annual Meeting,Chemoradiation established as the standard of care over a decade agoConcurrent superior to sequential chemoradiationOptimal chemotherapy regimen/strategy still unclearFull-dose as well as low-dose strategies accepted as a standard of careCommon full-dose regimens - cisplatin + etoposide, vinorelbine, vinblastine, docetaxelCommon low-dose regimen weekly carboplatin/paclitaxel,除了EP同步化放为2B证据外，其他都为2A级证据。,不可手术的III期NSCLC,过去10年,III期临床研究所致力解决的问题:诱导治疗的作用；巩固治疗的作用；新药 vs. 老药；放疗的剂量（60 vs. 74Gy);Cetuximab的作用；Tecemotide的作用；,Is CisPem “worthy” of a Phase III Trial in stage III NSCLC?,Presented By Mark Socinski at 2015 ASCO Annual Meeting,Pre-clinical synergism of pemetrexed with RT11 ph I trials with either cisplatin or carboplatin all using RT doses of 40-70 Gy (most common 66 Gy)8 ph II trials of various strategies showed high ORR (46-86%) and med OS of 18-34 monthsAII ph I/II trials used systemic dosesPh II trials reported rates of gr 3-4 esophagitis and pnemonitis of 0-16% and 3-23%, respectively,PROCLAIM: Study Design,Presented By Mark Socinski at 2015 ASCO Annual Meeting,Primary Endpoint: OS (superiority)*Stratified for. ECOG PS (0 vs 1);PET scan staging(yes vs no);gender, and disease stage(IIIA vs IIIB).AJCC Cancer Staging Manual(ed 6),2002.Folic acid, vitamin B12,and dexamethasone administered in Arm A TRT=thoracic radiotherapy.,Presented By Mark Socinski at 2015 ASCO Annual Meeting,Primary Endpoint: OS (superiority)*Stratified for. ECOG PS (0 vs 1);PET scan staging(yes vs no);gender, and disease stage(IIIA vs IIIB).AJCC Cancer Staging Manual(ed 6),2002.Folic acid, vitamin B12,and dexamethasone administered in Arm A TRT=thoracic radiotherapy.,PROCLAIM: Study Design,PROCLAIM: Primary Endpoint, OS,Presented By Mark Socinski at 2015 ASCO Annual Meeting,HR(95% CI): 0.98(0.79,1.20)Lag-rank p=0.831Median OS (95% CI),mosPem-Cis: 26.8 (20.4,30.9)Eto-Cis: 25.0 (22.2,29.8)Median follow-up times(mosrange)All patients:Pem-Cis,22.2(0.1-66.6)Eto-Cis,22.6 (0.0-71.4)Patients alive: Pem-Cis,32.9(0.1-66.6)Eto-Cis, 35.7(0.0-71.4)Total events:357Pem-Cis:177 events/301 patientsEto-Cis: 180 events/297patients,PROCLAIM in the wake of RTOG 0617,Presented By Mark Socinski at 2015 ASCO Annual Meeting,*p普通紫杉醇;ND优于DP非鳞癌 分子靶向治疗 贝伐单化疗优于化疗 培美优于健择 连续维持治疗改善总体生存免疫治疗,WJOG5208L: Study design,Presented By Takehito Shukuya at 2015 ASCO Annual Meeting,主要终点：OS;次人终点: PFS, RR, AEs初期样本大小250例； 修改后样本350例，power 由80%变为90%,WJOC 5208L: 比较nedaplatin与顺铂联合多烯紫杉醇一线治疗晚期或复发肺鳞癌,Chemo-naive PS 0-1 Age 20-74Stage IIIb/IV orrecurrent SqLCN:350,Docetaxel 60 mg/m2 dlNedaplatin 100 mg/m2 dlq3w,4-6 cyclesN=175,Docetaxel 60 mg/m2 dlCisplatin 80 mg/m2 dlq3w,4-6 cyclesN=175,1:1,Stratification factors:Stage(IIIb, IV or recurrent)GenderInstitutions,Baseline characteristics,Presented By Takehito Shukuya at 2015 ASCO Annual Meeting,Primary endpoint: Overall survival,Presented By Takehito Shukuya at 2015 ASCO Annual Meeting,Progression-free survival,Presented By Takehito Shukuya at 2015 ASCO Annual Meeting,Objective tumor response,Presented By Takehito Shukuya at 2015 ASCO Annual Meeting,RECIST ver. 1.1,*Fishers exact test,Treatment exposure,Presented By Takehito Shukuya at 2015 ASCO Annual Meeting,*One and 2 patients withdrew before study treatment in ND and CD, respectively,Post-Study Systemic Therapy,Presented By Takehito Shukuya at 2015 ASCO Annual Meeting,CA031试验设计,初次化疗PS 0-1b/ 期NSCLCN=1,050,1：1,白蛋白结合型紫杉醇： 100mg/m2 ，第1、8、15天卡铂：AUC 6，第1天无预处理N=525,溶剂型紫杉醇： 200mg/m2 ，第1天卡铂：AUC 6，第1天地塞米松+抗组胺药预处理N=525,分层因素：分期(b或 期)年龄(70或70)性别组织学(鳞状细胞非鳞状细胞)区域,三周重复,Abstract # LBA7511, 2010 ASCO,主要终点ORR-所有组织学类型,RR = 1.31(1.082-1.593)P = 0.005,33%,25%,缓解率,独立影像学评价,Nab-P/C (n=521),P/C (n=531),37%,30%,研究者评价,RR = 1.26(1.060-1.496)P = 0.008,Abstract # LBA7511, 2010 ASCO,主要终点ORR-组织学分层,鳞癌,Nab-P/C,P/C,非鳞癌,Abstract # LBA7511, 2010 ASCO,41%,24%,26%,25%,P0.001,P=0.808,n=228,n=221,n=292,n=310,独立影像学评价,缓解率,化疗方案的选择,JMDB研究：力比泰/顺铂对非鳞癌患者的疗效更优,Scagliotti GV, et al. J Clin Oncol. 2008;26(21): 3543-51,OS(非鳞癌),OS(鳞癌),化疗方案的选择,Pujol JL, et al. Oral abstract presented at 2012 ESMO. Vienna, Austria.,患者(%),恶心P=0.004,呕吐p=1.0,脱水(任何分级)P=0.075,脱发(任何分级)P0.001,疲乏P=0.143,发热性中性粒细胞减少P=0.002,患者(%),3/4级非血液学毒性反应,3/4级血液学毒性反应,力比泰/顺铂一线治疗非鳞癌耐受性优势显著,化疗方案的选择,晚期NSCLC非鳞癌（尤其EGFR突变状态未知）患者：优选力比泰,*非鳞癌包括：腺癌、大细胞癌和其他未确定类型的NSCLC,Scagliotti G. et al. J Thorac Oncol.2011; 6(1): 64-70.,PARAMOUNT研究：力比泰同药维持治疗显著延长非鳞癌(EGFR突变状态未知)患者PFS,力比泰同药维持：显著降低患者疾病进展风险40%,Paz-Ares L, et al. J Clin Oncol.2013 Aug 10;31(23):2895-902. Scagliotti GV, et al. Lung Cancer. 2014 Sep;85(3):408-14.,PFS（维持治疗阶段）,PFS（自诱导开始）,HR=0.60 (0.50-0.73)p普通紫杉醇;ND优于DP非鳞癌 分子靶向治疗 贝伐单化疗优于化疗 培美优于健择 连续维持治疗改善总体生存免疫治疗,Mutational heterogeneity in cancer,Presented By Laura Chow at 2014 ASCO Annual Meeting,适应性免疫应答可