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1、晚期非小细胞肺癌个体化治疗 现状、困境与希望王 洁 北京大学肿瘤医院 1BSC 25 monthsSingle-agent platinum 68 monthsPlatinum-based doublets 810 monthsMedian survival (months)Schiller, et al. NEJM 2002 Sandler, et al. NEJM 200602468101224+2000s1990s1980s1970sPlatinum-based doublet + Avastin for non-SQC 12.3 months EGFR-TKI therapy impr
2、oves outcome of Advanced NSCLC patients with EGFR mutation: BSC = best supportive careTKI Therapy as first-line for the patients with EGFR mutation2困境一:仅仅根据病理组织学类型选择治疗: 新的瓶颈？3培美曲塞多西他赛随机 N=571OS培美曲塞安慰剂随机 N=663OS培美曲塞顺铂吉西他滨顺铂随机 N=1725OSJMEI二线治疗JMEN维持治疗JMDB一线治疗培美曲塞治疗非鳞癌的NSCLC患者更为有效： 来自三项大型、III期、随机研究的荟萃分
3、析4结果JMEIJMDB *JMEN类型*培美曲塞多西他赛培美曲塞顺 铂吉西他滨顺 铂培美曲塞安慰剂非鳞癌205194618634325156MST (月)9.38.011.010.1*15.510.3经调整的 HR0.780.840.7095%CI0.61-1.000.74-0.960.56-0.88P0.0480.0110.002鳞癌789424422911666MST (月)6.27.49.410.89.910.8经调整的 HR1.561.231.0795%CI1.08-2.261.00-1.510.77-1.50P0.0180.0500.678 *:PFS:5.1个月5组织学与TS腺癌
4、鳞癌BAC腺鳞癌S E N S I T I V E R E S I S T A N T理想的生物标记物腺癌小细胞分化程度6JMEN：鳞鳞癌和东亚东亚裔亚组显亚组显示培美曲塞维维持治疗疗不如安慰剂剂的趋势趋势Cappuzzo F et al, ASCO 2009; Abstract No:8001.Belani CP et al, ASCO 2009; Abstract CRA:8000.安慰剂有利0.00.20.40.60.81.01.21.41.61.8培美曲塞有利腺癌 (n=328) 鳞癌 (n=182)高加索裔 (n=428) 东亚裔 (n=154) 其他种族 (n=81)总生存在东亚人
5、群中培美曲塞维持治疗未见优势,原因何在?药物基因组学差异(TS)?7ECOG1594:组织学类型与生存期方案鳞癌腺癌大细胞癌其他PMST (月)顺铂紫杉醇6.9 5.3-9.49.1 7.9-10.96.1 2.9-6 3.9-9.10.09顺铂吉西他滨9.4 5.7-15.68.1 6.8-9.89.7 4.5-17.17.9 6.3-11.30.63顺铂多西他赛8.1 5.5-11.27.7 6.5-9.46.8 5.9-11.78.2 5.6-12.40.91卡铂紫杉醇9.3 7.3-12.17.6 6.6-9.88.3 3.6-16.76.9 4.9-11.60.37P0.180.39
6、0.390.828根据病理组织学类型选择治疗方 案新的瓶颈？纵观此三组研究: 培美曲赛提高了非鳞非小细胞肺癌一、二线治疗的中 位生存期，但仍徘徊于1年左右. 鳞癌的治疗并无突破 维持治疗研究中培美曲赛对腺癌中位生存期虽提高幅 度较大（5个月），但与之相对应的是安慰剂对照组而 非延迟的培美曲赛治疗组，这是迄今几项维持治疗研 究（包括SATURN试验）挥之不去的阴影! 其它三代药物如多西紫杉醇、 吉西它滨等并未发现与 病理组织亚型的关系9困境二:化疗疗相关的药药物靶基因: 能否常规应规应用指导临导临床实实践？1011Excision Repair Cross Complementing 1 (ER
7、CC1): A Predictor of Chemotherapy Benefit ?12Lord et al. 2002. CCR 8:2286-91ERCC1 levels higher in SCC than in adenocarcinoma (P=0.01)Overall Survival (weeks)120100806040200Cumulative Survival1.0.8.6.4.2ERCC1 mRNA median (6.7) MS=5 monthsERCC1 mRNA median (6.7) MS= 15 monthsp=0.009 (Log rank test)n=
8、56ERCC1 表达与NSCLC的生存 吉西他滨-顺铂13M Cobo et al, JCO 200714M Cobo et al, JCO 2007151617困境三:维维持治疗疗怎样选择样选择病人？18SATURN研究:ErlotinibVs 安慰剂作为晚期 非小细胞肺癌一线治疗后的维持治疗的国 际、随机、多中心临床研究19OS subgroup analyses for EGFR IHC and EGFR mutationsAllEGFR IHC+EGFR IHC-*EGFR mutation+EGFR wild-type0.40.60.81.01.2Favours erlotinibF
9、avours placeboHR1.61.41.82.0HR (95% CI)n 0.81 (0.700.95)8890.77 (0.640.93)6210.91 (0.591.38)1210.83 (0.342.02) 490.77 (0.610.97)38867% of patients with EGFR mutation+ disease in the placebo arm received a second-line EGFR TKI20%Erlotinib (n=436)Placebo (n=445)p- valueResponse (CR/PR)11.9 5.40.000 6S
10、table disease* (SD)48.645.4NSDisease control rate (DCR=CR+ PR+SD)60.650.80.003 5SATURN: Best Overall Response*Stable disease 6 weeks CR + PR + SD 12 weeksPatients (%)50250 ErlotinibPlacebo(n=436) (n=445)p0.000140. 8%27. 4%40.8%27.4%Disease control rate 12 weeks近40%Tarceva维持治疗组患者疾病仍有进展近50%安慰剂治疗者仍处于疾病
11、控制中21困境四:EGFR突变变患者:一线线TKI化疗疗与一 线线化疗疗二线线TKI治疗疗哪种策略更好?2223Median OSHRn (months)(95% CI)21727.022.731.3SLOG Study: Survival in patients with EGFR mutation+ disease1.00.80.60.40.20Probability of PFS012243648Time (months)Median PFSHRn (months)(95% CI)21714.011.316.71.00.80.60.40.20Probability of OS012243
12、648Time (months)14.027.0Rosell R, et al. N Eng J Med 2009;361:95867IPASS 9.8 mnIPASS Not Mature24Randomized Study on Japanese Population with EGFR Mutation: NEJGSG002Maemondo M, et al. NEJM, 2010.Gefitinib N=98P/C N=100 CR40 PR6929 SD1350 PD815 NE46 缓解率73 (74.5%)29(29%) P0.001HR=0.357 95% CI: 0.252-
13、0.507, P0.00125Docetaxel CisplatinGefitinibChemotherapy- nave stage IIIb/IV NSCLC; EGFR mutation (Exon 19 or 21); PS 02; Age 18y;Progression Free SurvivalRANDOMISE1:1lPrimary endpoint: PFSlSecondary endpoint: OS; ORR; QOL; SafetyWJTOG 3405Progression Free SurvivalOverall SurvivalMItsudomi T, et al.
14、Lancet Oncol,200926OPTIMAL study design Erlotinib 150mg/dayl Chemonavel Stage IIIB/IV NSCLClEGFR Act Mut+ (exon 19 deletion or exon 21 L858R mutation) l ECOG PS 02l (n=165)Gemcitabine (1000 mg/m2 d1,8) Carboplatin (AUC5 d1) q 3 wks, up to 4 cyclesRAct Mut+ = activating mutations; ECOG = Eastern Coop
15、erative Oncology Group; PS = performance status; HRQoL = health-related quality of life; FACT-L = Functional Assessment of Cancer Therapy-Lung; LCSS = lung cancer symptom scale1:1Primary endpoint Progression-free survival (PFS)Secondary endpoints Overall survival (OS), objective response rate (ORR),
16、 time to disease progression, duration of response, safety, HRQoL (FACT-L, LCSS), exploratory biomarker analysesStratification factors Mutation type Histology Smoking statusEfficacy assessment Every 6 weeks27PFS: updated analysisPFS Probability1.00.80.60.40.20HR=0.16 (0.100.26) Log-rank p0.0001Time (months)05101520Patients at riskGem/7226400E
