《肺癌内科治疗进展》

1、非小细胞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编辑课件化疗进展化疗进展 早期术后辅助化疗：个体化？早期术后辅助化疗：个体化？ 局部晚期局部晚期 同步化放疗，同步化放疗，AP未超越未超越EP 鳞癌：白蛋白紫杉醇鳞癌：白蛋白紫杉醇普通紫杉醇普通紫杉醇;ND优于优于DP 非鳞癌非鳞癌 分子靶向治疗分子靶向治疗 贝伐单化疗优于化疗贝伐单化疗优于化疗 培美优于健择培美优于健择 连续维持治疗改善总体生存连续维持治疗改善总体生存 免疫治疗免疫治疗编辑课件辅助治疗的必要性编辑课件辅助化疗辅助化疗 是淋巴结阳性完全切除早期是淋巴结阳性完全切除早期NSCLC的标准治疗的标准治疗

2、在淋巴结阴性病人在淋巴结阴性病人,仍存在争议仍存在争议 顺铂为基础方案是标准顺铂为基础方案是标准 卡铂为基础方案未得到批准卡铂为基础方案未得到批准,但经常使用但经常使用 证据最多的是证据最多的是NP ECOG1505允许所有未批准的方案允许所有未批准的方案编辑课件BRCA1水平和含铂药物化疗的相关性Yang Y et al.J Exp Clin Cancer Res,2013编辑课件Customized BRCA1 Adjuvant Treatment in Stage II-II NSCLC (SCAT)Presented By Mark Socinski at 2015 ASCO Annu

3、al MeetingResectedNSCLC R0pN1 / pN21.3CONTROLEXPERIMENTALDocetaxel/CisT1 BRCA1T2 BRCA1T3 BRCA1Gem/CisDocetaxel/CisDocetaxelEudract: 2007-000067-15NCTgov:00478699Statification factors:-Stage: N1 vs. N2-Age 65 vs 65 y-Histology: Non-SCC vs. SCC-Type of resection: Lobectomy vs PneumonectomyPlanned numb

4、er of patients : 432 (amended)CT should be started before 8 weeks after surgeryPORT in N2 patientsSLIDES ARE THE PROPERTY OF THE AUTHOR.PERMISSION REQUIRED FOR REUSE.编辑课件Presented By Mark Socinski at 2015 ASCO Annual MeetingCustomized BRCA1 Adjuvant Treatment in Stage II-II NSCLC (SCAT)ResectedNSCLC

5、 R0pN1 / pN21.3CONTROLEXPERIMENTALDocetaxel/CisT1 BRCA1T2 BRCA1T3 BRCA1Gem/CisDocetaxel/CisDocetaxelEudract: 2007-000067-15NCTgov:00478699Primary Endpoint: OS5 yr OS 45% 65%SLIDES ARE THE PROPERTY OF THE AUTHOR.PERMISSION REQUIRED FOR REUSE.编辑课件实验组的OSBRCA1低水平低水平BRCA1中等水平中等水平BRCA1高水平高水平1.00.80.60.40.

6、20.001020304050607080时间时间 ( (月月) )OSHR低水平低水平 vs 高水平：高水平：0.84中等水平中等水平 vs 高水平：高水平：0.95编辑课件Massuti B, et al. 2015 ASCO Abstract 7507.BRCA1高水平患者DFS和OS1.00.80.60.40.20.001020304050607080试验试验组组对照组对照组HR=1.87 (0.83-4.19)时间时间 (月月)DFS1.00.80.60.40.20.001020304050607080试验组试验组对照组对照组HR=1.24 (0.59-2.59)时间时间 (月月)O

7、SBRCA1高表达者未显示顺铂耐药。高表达者未显示顺铂耐药。编辑课件Massuti B, et al. 2015 ASCO Abstract 7507.BRCA1低表达患者DFS和OS1.00.80.60.40.20.0010203040506070801.00.80.60.40.20.001020304050607080试验试验组组对照组对照组HR=0.64 (0.38-1.09)试验试验组组对照组对照组HR=0.50 (0.28-0.88)P=0.016时间时间 ( (月月) )DFS时间时间 ( (月月) )OSBRCA1低表达者多见于腺癌、非吸烟和女性患者。低表达者多见于腺癌、非吸烟和

8、女性患者。编辑课件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：无进展生存主要终点：无进展生存AQUA测定测定RRM1及及ERCC1 随机分组随机分组低低RRM140.5高高RRM1低低RRM140.5

9、高高RRM1低低ERCC166.0吉西他滨吉西他滨+卡铂卡铂多西他赛多西他赛+卡铂卡铂低低ERCC166.0吉西他滨吉西他滨+卡铂卡铂高高ERCC1吉西他滨吉西他滨+多西他赛多西他赛多西他赛多西他赛+长春瑞滨长春瑞滨高高ERCC12 : 1N=275编辑课件研究结果：PFS和OS1.00.80.60.40.20.00612182430 3642对照组对照组 (n=92)中位中位PFS：6.9个月个月6个月个月PFS：56.5%研究组研究组 (n=183)中位中位PFS：6.1个月个月6个月个月PFS：52.0%Log-rank P=0.181PFS时间时间 (月月)1.00.80.60.40.

10、20.00612182430364248对照组对照组 (n=92)中位中位OS：11.3个月个月12个月个月OS：46.6%研究组研究组 (n=183)中位中位OS：11.0个月个月12个月个月OS：46.1%Log-rank P=0.656时间时间 (月月)OSBepler G, et al. 2013 ASCO Abstract 8001.OS编辑课件So what can we conclude from this study and what are the issues?Presented By Mark Socinski at 2015 ASCO Annual Meeting BR

11、CA1 does not appear to be a robust biomarker in this small 4-arm trial RT-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 factors Raises the hypothe

12、sis that different cisplatin-based doublets may have differing effects in different subsets Compliance to therapy important (but reasons for non-compliance not delineated)编辑课件化疗进展化疗进展 早期术后辅助化疗：个体化？早期术后辅助化疗：个体化？ 局部晚期局部晚期 同步化放疗，同步化放疗，AP未超越未超越EP 鳞癌：白蛋白紫杉醇鳞癌：白蛋白紫杉醇普通紫杉醇普通紫杉醇;ND优于优于DP 非鳞癌非鳞癌 分子靶向治疗分子靶向治疗

13、 贝伐单化疗优于化疗贝伐单化疗优于化疗 培美优于健择培美优于健择 连续维持治疗改善总体生存连续维持治疗改善总体生存 免疫治疗免疫治疗编辑课件Unresectable Stage III NSCLCPresented By Mark Socinski at 2015 ASCO Annual Meeting Chemoradiation established as the standard of care over a decade ago Concurrent superior to sequential chemoradiation Optimal chemotherapy regimen/

14、strategy still unclear Full-dose as well as low-dose strategies accepted as a standard of care Common full-dose regimens - cisplatin + etoposide, vinorelbine, vinblastine, docetaxel Common low-dose regimen weekly carboplatin/paclitaxel编辑课件除了EP同步化放为2B证据外，其他都为2A级证据。编辑课件不可手术的III期NSCLC过去10年,III期临床研究所致力解

15、决的问题: 诱导治疗的作用； 巩固治疗的作用； 新药新药 vs. 老老药药； 放疗的剂量（60 vs. 74Gy); Cetuximab的作用； Tecemotide的作用；编辑课件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 RT 11 ph I trials with either cisplatin or carboplati

16、n 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 months AII ph I/II trials used systemic doses Ph II trials reported rates of gr 3-4 esophagitis and pnemonitis of 0-16% and 3-23%, respectively编辑课件PROCLAIM: Study De

17、signPresented By Mark Socinski at 2015 ASCO Annual MeetingPrimary 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=

18、thoracic radiotherapy.Previouslyuntreatedstage IIIA-IIIB*nonsquamousNSCLCPS 0/1RPemetrexed: 500 mg/m2 Cisplatin: 75 mg/m2 ,q3wTRT: 66 Gy, 2 Gy/fx daily3 CYCLESEtoposide: 50 mg/m2 D1-5,q4wCisplatin: 50 mg/m2 D1.8,q4wTRT: 66 Gy, 2 Gy/fx daily2 CYCLESPemetrexed: 500 mg/m2 ,q3w 4 CYCLESInvestigators cho

19、ice:Etoposide-Cisplatin: (same dosing/schedule)orVinorelbine-Cisplatin: Vin:30 mg/m2 iv,D1.8,q3wCis:75 mg/m2 D1,q3worPaclitaxel-Carboplatin: Pac:200 mg/m2 iv,q3wCar.AUC=6iv,q3w 2 CYCLESArm AArm BPR/CR/SDPerRECISTConcurrent PhaseRecovery Period(3-5 wks)Consolidation PhaseTwo variables编辑课件Presented By

20、 Mark Socinski at 2015 ASCO Annual MeetingPrimary 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 radioth

21、erapy.Previouslyuntreatedstage IIIA-IIIB*nonsquamousNSCLCPS 0/1RPemetrexed: 500 mg/m2 Cisplatin: 75 mg/m2 ,q3wTRT: 66 Gy, 2 Gy/fx daily3 CYCLESEtoposide: 50 mg/m2 D1-5,q4wCisplatin: 50 mg/m2 D1.8,q4wTRT: 66 Gy, 2 Gy/fx daily2 CYCLESPemetrexed: 500 mg/m2 ,q3w 4 CYCLESInvestigators choice:Etoposide-Ci

22、splatin: (same dosing/schedule)orVinorelbine-Cisplatin: Vin:30 mg/m2 iv,D1.8,q3wCis:75 mg/m2 D1,q3worPaclitaxel-Carboplatin: Pac:200 mg/m2 iv,q3wCar.AUC=6iv,q3w 2 CYCLESArm AArm BPR/CR/SDPerRECISTConcurrent PhaseRecovery Period(3-5 wks)Consolidation Phase 24 weeks 15 weeksPROCLAIM: Study Design编辑课件P

23、ROCLAIM: Primary Endpoint, OSPresented By Mark Socinski at 2015 ASCO Annual MeetingHR(95% CI): 0.98(0.79,1.20)Median OS (95% CI),mosPem-Cis: 26.8 (20.4,30.9)Eto-Cis: 25.0 (22.2,29.8)Median follow-up times(mos-range)All patients:Pem-Cis,22.2(0.1-66.6)Eto-Cis,22.6 (0.0-71.4)Patients alive: Pem-Cis,32.

24、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编辑课件PROCLAIM in the wake of RTOG 0617Presented By Mark Socinski at 2015 ASCO Annual MeetingEP(n=297)CisPem(n=301)CbP/60 Gy*(n=217)Med OS, mos25.026.828.72-yr OS,%525257.6Med PFS, mos9.811.

25、411.8Infield failure45.837.330.7Distant failure45.85046.6Gr 3-4 esophagitis (%)18.815.57Gr 3-4 F/N, (%)5.39.6NRAll gr pneumonitis,(%)10.71710*p普通紫杉醇普通紫杉醇;ND优于优于DP 非鳞癌非鳞癌 分子靶向治疗分子靶向治疗 贝伐单化疗优于化疗贝伐单化疗优于化疗 培美优于健择培美优于健择 连续维持治疗改善总体生存连续维持治疗改善总体生存 免疫治疗免疫治疗编辑课件WJOG5208L: Study designPresented By Takehito Shu

26、kuya at 2015 ASCO Annual Meeting主要终点：主要终点：OS;次人终点次人终点: PFS, RR, AEs初期样本大小初期样本大小250例；例； 修改后样本修改后样本350例，例，power 由由80%变为变为90%WJOC 5208L: 比较比较nedaplatin与顺铂联合多烯紫杉醇一线治疗晚期或复发肺鳞与顺铂联合多烯紫杉醇一线治疗晚期或复发肺鳞癌癌Chemo-naive PS 0-1 Age 20-74Stage IIIb/IV orrecurrent SqLCN:350Docetaxel 60 mg/m2 dlNedaplatin 100 mg/m2 dlq

27、3w,4-6 cyclesN=175 Docetaxel 60 mg/m2 dlCisplatin 80 mg/m2 dlq3w,4-6 cyclesN=1751:1Stratification factors:Stage(IIIb, IV or recurrent)GenderInstitutions编辑课件Baseline characteristicsPresented By Takehito Shukuya at 2015 ASCO Annual MeetingND(N=177)CD(N=172)AgeMedian(years)Range(years)70 years70 years6

28、4.037-7433(18.6%)144(81.4%)65.041-7431(18.0%)141(82.0%)GenderMaleFemale157(88.7%)20(11.3%)153(89.0%)19(11.0%)Smoking statusNever smokerCurrent or former smoker5(2.8%)172(97.2%)10(5.8%)162(94.2%)PS0181(45.8%)96(54.2%)63(36.6%)109(63.4%)Stage at screeningIIIBIVPostoperative recurrence56(31.6%)107(60.5

29、%)14(7.9%)56(32.6%)106(61.6%)10(5.8%)编辑课件Primary endpoint: Overall survivalPresented By Takehito Shukuya at 2015 ASCO Annual MeetingND(N=177)CD(N=172)Median, months13.611.41 year, %55.943.52 year, %27.118.1HR (90%CI)0.81(0.67-0.98)p*0.037编辑课件Progression-free survivalPresented By Takehito Shukuya at

30、2015 ASCO Annual MeetingND(N=177)CD(N=172)Median, months4.94.56 months, %35.627.9HR (90%CI)0.83(0.69-1.00)p*0.050编辑课件Objective tumor responsePresented By Takehito Shukuya at 2015 ASCO Annual MeetingND(N=172)CD(N=168)*p valueCR3(1.7%)1(0.6%)_PR93(54.1%)88(52.4%)_SD50(29.1%)47(28.0%)_PD24(14.0%)27(16.

31、1%)_NE2(1.2%)5(3.0%)_ORR55.8%53.0%0.663DCR84.9%81.0%0.387*Fishers exact test编辑课件Treatment exposurePresented By Takehito Shukuya at 2015 ASCO Annual MeetingND(N=177)*CD(N=172)*Cycles received 3 4 5 6 median,(range)48(27.1%)68(38.4%)20(11.3%)40(22.6%)4(1-6)64(37.2%)72(41.9%)11(6.4%)23(13.4%)4(1-6)Rela

32、tive dose intensity (%),median Nedaplatin Cisplatin Docetaxel93.393.892.3 94.6*One and 2 patients withdrew before study treatment in ND and CD, respectively编辑课件Post-Study Systemic TherapyPresented By Takehito Shukuya at 2015 ASCO Annual MeetingND(N=177) (%)CD(N=172) (%)2nd line therapy Gemcitabine S

33、-1 Carboplatin + paclitaxel Gemcitabine + vinorelbine Gemcitabine + S-1 Carboplatin + gemcitabine Carboplatin + S-1 Docetaxel Vinorelbine Erlotinib Others78.013.614.711.94.05.62.83.44.51.11.714.776.714.012.26.47.02.35.23.52.33.52.917.43rd line therapy53.740.14th line therapy27.725.0编辑课件CA031试验设计试验设计

34、初次化疗初次化疗PS 0-1b/ 期期NSCLCN=1,0501：1白蛋白结合型紫杉醇：白蛋白结合型紫杉醇： 100mg/m2 ，第，第1、8、15天天卡铂：卡铂：AUC 6，第，第1天天无预处理无预处理N=525溶剂型紫杉醇：溶剂型紫杉醇： 200mg/m2 ，第，第1天天卡铂：卡铂：AUC 6，第，第1天天地塞米松地塞米松+抗组胺药预处理抗组胺药预处理N=525分层因素：分层因素：分期分期(b或或 期期)年龄年龄(70或或70)性别性别组织学组织学(鳞状细胞鳞状细胞非鳞状细胞非鳞状细胞)区域区域三周重复三周重复Abstract # LBA7511, 2010 ASCO编辑课件主要终点主要终

35、点ORR-所有组织学类型所有组织学类型RR = 1.31(1.082-1.593)10%20%30%40%33%25%缓缓解解率率独立影像学评价独立影像学评价Nab-P/C (n=521)P/C (n=531)37%30%研究者评价研究者评价RR = 1.26(1.060-1.496)Abstract # LBA7511, 2010 ASCO编辑课件主要终点主要终点ORR-组织学分层组织学分层10%20%30%40%鳞癌鳞癌Nab-P/C P/C非鳞癌非鳞癌Abstract # LBA7511, 2010 ASCO41%24%26%25%n=228n=221n=292n=310独立影像学评价独

36、立影像学评价缓缓解解率率编辑课件化疗方案的选择化疗方案的选择 JMDB研究：力比泰研究：力比泰/顺铂对非鳞癌患者的疗效更优顺铂对非鳞癌患者的疗效更优Scagliotti GV, et al. J Clin Oncol. 2008;26(21): 3543-51OS(非鳞癌非鳞癌)OS(鳞癌鳞癌)编辑课件化疗方案的选择化疗方案的选择15.15.64.14.826.79.912.77.6051015202530 力比泰力比泰/顺铂顺铂(n=830)健择健择/顺铂顺铂(n=830)Pujol JL, et al. Oral abstract presented at 2012 ESMO. Vienn

37、a, Austria.中性粒细中性粒细胞减少胞减少p0.001贫血贫血(血红蛋白血红蛋白)P=0.001血小板减少血小板减少(血小板血小板)P0.001白细胞白细胞减少减少P=0.019患者患者(%)7.26.13.611.96.71.33.96.1221.44.93.7051015202530 力比泰力比泰/顺铂顺铂(n=830)健择健择/顺铂顺铂(n=830)恶心恶心呕吐呕吐脱水脱水(任何分级任何分级)脱发脱发(任何分级任何分级)疲乏疲乏发热性中性发热性中性粒细胞减少粒细胞减少患者患者(%)3/4级非级非血液学毒性反应血液学毒性反应3/4级级血液学毒性反应血液学毒性反应 力比泰力比泰/顺铂

38、一线治疗非鳞癌耐受性优势显著顺铂一线治疗非鳞癌耐受性优势显著编辑课件化疗方案的选择化疗方案的选择 晚期晚期NSCLC非鳞癌（尤其非鳞癌（尤其EGFR突变状态未知）患者：优选突变状态未知）患者：优选力比泰力比泰NSCLC组织学分组组织学分组一线治疗一线治疗Pem/Cis vs. Gem/Cis维持治疗维持治疗Pem vs. Placebo二线治疗二线治疗Pem vs. DocPem+CisGem+CisPemPlaceboPemDoc非鳞癌非鳞癌*N=618N=634N=325N=156N=205N=194 mOS(月月)11.010.115.510.39.38.0 校对的校对的HR(95% C

39、I) P值值0.84(0.74, 0.96)0.0110.70(0.56, 0.88)0.0020.78(0.61, 1.00)0.048鳞癌鳞癌N=244N=229N=116N=66N=78N=94 mOS(月月)9.410.89.910.86.27.4 校对的校对的HR(95% CI) P值值1.23(1.00, 1.51)0.0501.07(0.77, 1.50)0.6781.56(1.08, 2.26)0.018*非鳞癌包括：腺癌、大细胞癌和其他未确定类型的非鳞癌包括：腺癌、大细胞癌和其他未确定类型的NSCLCScagliotti G. et al. J Thorac Oncol.20

40、11; 6(1): 64-70.编辑课件PARAMOUNT研究：力比泰同药维持治疗显著研究：力比泰同药维持治疗显著延长非鳞癌延长非鳞癌(EGFR突变状态未知突变状态未知)患者患者PFS 力比泰同药维持：显著降低患者疾病进展风险力比泰同药维持：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. HR=0.60 (0.50-0.73)pmedian1310.220.340.53P25

41、660.20.460.83P25-P50650.180.361.71P50-P75690.17 0.330.64P75650.22 0.390.72VEGFR-2 median1370.26 0.400.62P25690.180.340.63P25-P50680.230.400.71P50-P75660.16 0.300.56P75680.250.460.830.20.40.61LowerUpperCategorySubgroupNlimitEst.limitconfidenceconfidenceHazard RatioOSAllAll2740.500.680.93Baseline medi

42、an1310.410.641.00VEGF-A median1310.400.620.96P25660.270.531.03P25-P50650.490.891.60P50-P75690.28 0.531.01P75650.41 0.761.39Baseline median1370.42 0.640.97VEGFR-2 median1370.40 0.630.98P25690.300.530.94P25-P50680.420.771.41P50-P75660.25 0.480.91P75680.38 0.711.350.20.4 0.6123LowerUpperCategorySubgrou

43、pNlimitEst.limitconfidenceconfidenceHazard Ratio编辑课件化疗进展化疗进展 早期术后辅助化疗：个体化？早期术后辅助化疗：个体化？ 局部晚期局部晚期 同步化放疗，同步化放疗，AP未超越未超越EP 鳞癌：白蛋白紫杉醇鳞癌：白蛋白紫杉醇普通紫杉醇普通紫杉醇;ND优于优于DP 非鳞癌非鳞癌 分子靶向治疗分子靶向治疗 贝伐单化疗优于化疗贝伐单化疗优于化疗 培美优于健择培美优于健择 连续维持治疗改善总体生存连续维持治疗改善总体生存 免疫治疗免疫治疗编辑课件Mutational heterogeneity in cancerPresented By Laura

44、Chow at 2014 ASCO Annual Meeting编辑课件适应性免疫应答可以预测预后适应性免疫应答可以预测预后Galon J, et.al, Science,2006,313:1960-1964编辑课件克服免疫逃逸的根本克服免疫逃逸的根本 解除解除T细胞细胞的抑制的抑制 T细胞效应功能受到宿主和肿瘤微环境的影响而抑制 - 对于Treg细胞增多的患者，抗CTLA-4和PD-1是一种有效的方式 - 阻断T细胞正常表达的CTLA-4，PD-L1，或LAG3可减少它们的抗原应答 - 仅仅通过抑制CTLA-4和PD-1对CD8+T细胞增殖和生存是不够的，加入LAG3抑制剂可进一步增强T细胞的增殖和激活 - 对于具有MDSCs或调节性B细胞表型的患者，或肿瘤微环境相关的先天性免疫应答缺陷的患者，另一种免疫检测点抑制剂可能有效，比如OX40或ICOSLucas CL, et al. Blood.2011;117:5532-5540Tw