晚期非小細(xì)胞肺癌個體化治療現(xiàn)狀困境希望

1、1晚期非小細(xì)胞肺癌個體化治療晚期非小細(xì)胞肺癌個體化治療現(xiàn)狀、困境與希望現(xiàn)狀、困境與希望 王王 潔潔 北京大學(xué)腫瘤醫(yī)院北京大學(xué)腫瘤醫(yī)院 2BSC25 monthsSingle-agent platinum68 monthsPlatinum-based doublets810 monthsMedian survival (months)Schiller, et al. NEJM 2002Sandler, et al. NEJM 200602468101224+2000s1990s1980s1970s Platinum-based doublet + Avastin for non-SQC12.3

2、months EGFR-TKI therapy improves outcome of Advanced NSCLC patients with EGFR mutation: BSC = best supportive careTKI Therapy as first-line for the patients with EGFR mutation3困境一困境一:僅僅根據(jù)病理組織學(xué)類型選擇治療僅僅根據(jù)病理組織學(xué)類型選擇治療:新的瓶頸？新的瓶頸？4培美曲塞多西他賽隨機N=571OS培美曲塞安慰劑隨機N=663OS培美曲塞順鉑吉西他濱順鉑隨機N=1725OSJMEI二線治療二線治療JMEN維持治療

3、維持治療JMDB一線治療一線治療培美曲塞治療非鱗癌的培美曲塞治療非鱗癌的NSCLC患者更為有效：患者更為有效：來自三項大型、來自三項大型、III期、隨機研究的薈萃分析期、隨機研究的薈萃分析5結(jié)果結(jié)果JMEIJMDB *JMEN類型*培美曲塞多西他賽培美曲塞順鉑吉西他濱順鉑培美曲塞安慰劑非鱗癌205194618634325156MST (月)9.38.011.010.1*15.510.3經(jīng)調(diào)整的HR0.780.840.7095%CI0.61-1.000.74-0.960.56-0.88P0.0480.0110.002鱗癌789424422911666MST (月)6.27.49.410.89.9

4、10.8經(jīng)調(diào)整的HR1.561.231.0795%CI1.08-2.261.00-1.510.77-1.50P0.0180.0500.678*:PFS:5.1個月個月6組織學(xué)與組織學(xué)與TS腺癌腺癌鱗癌鱗癌BAC腺鱗癌 S E N S I T I V E R E S I S T A N T理想的生物標(biāo)記物理想的生物標(biāo)記物腺癌小細(xì)胞分化程度7JMEN： ：鱗鱗癌和癌和東亞東亞裔裔亞組顯亞組顯示培美曲塞示培美曲塞 維維持治持治療療不如安慰不如安慰劑劑的的趨勢趨勢Cappuzzo F et al, ASCO 2009; Abstract No:8001.Belani CP et al, ASCO 20

5、09; Abstract CRA:8000.安慰劑有利0.00.20.40.60.81.01.21.41.61.8培美曲塞有利腺癌腺癌 (n=328)鱗癌鱗癌 (n=182)高加索裔高加索裔 (n=428)東亞裔東亞裔 (n=154)其他種族其他種族 (n=81)總生存總生存在東亞人群中培美曲塞維持治療未見優(yōu)勢在東亞人群中培美曲塞維持治療未見優(yōu)勢, ,原因何在原因何在? ?藥物基因組學(xué)差異藥物基因組學(xué)差異(TS)?.(TS)?.8ECOG1594:組織學(xué)類型與生存期方案鱗癌腺癌大細(xì)胞癌其他PMST (月)順鉑紫杉醇6.95.3-9.49.17.9-10.96.12.9-63.9-9.10.09

6、順鉑吉西他濱9.45.7-15.68.16.8-9.89.74.5-17.17.96.3-11.30.63順鉑多西他賽8.15.5-11.27.76.5-9.46.85.9-11.78.25.6-12.40.91卡鉑紫杉醇9.37.3-12.17.66.6-9.88.33.6-16.76.94.9-11.60.37P0.180.390.390.829根據(jù)病理組織學(xué)類型選擇治療方案新的瓶頸？縱觀此三組研究: 培美曲賽提高了非鱗非小細(xì)胞肺癌一、二線治療的中位生存期，但仍徘徊于1年左右. 鱗癌的治療并無突破 維持治療研究中培美曲賽對腺癌中位生存期雖提高幅度較大（5個月），但與之相對應(yīng)的是安慰劑對照組

7、而非延遲的培美曲賽治療組，這是迄今幾項維持治療研究（包括SATURN試驗）揮之不去的陰影! 其它三代藥物如多西紫杉醇、 吉西它濱等并未發(fā)現(xiàn)與病理組織亞型的關(guān)系10困境二困境二:化化療療相關(guān)的相關(guān)的藥藥物靶基因物靶基因:能否常能否常規(guī)應(yīng)規(guī)應(yīng)用指用指導(dǎo)臨導(dǎo)臨床床實實踐？踐？1112Excision Repair Cross Complementing 1 (ERCC1): A Predictor of Chemotherapy Benefit ?13Lord et al. 2002. CCR 8:2286-91ERCC1 levels higher in SCC than in adenocarc

8、inoma (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=56ERCC1 表達與NSCLC的生存 吉西他濱-順鉑14M Cobo et al, JCO 200715M Cobo et al, JCO 2007161718困境三困境三:維維持治持治療療怎怎樣選擇樣選擇病人？病人？19SATURN研究:E

9、rlotinibVs 安慰劑作為晚期非小細(xì)胞肺癌一線治療后的維持治療的國際、隨機、多中心臨床研究20OS subgroup analyses for EGFR IHC and EGFR mutationsAllEGFR IHC+EGFR IHC-*EGFR mutation+ EGFR wild-type0.40.60.81.01.2FavourserlotinibFavoursplaceboHR1.61.41.82.0HR (95% CI)n0.81 (0.700.95)889 0.77 (0.640.93)6210.91 (0.591.38)1210.83 (0.342.02) 490.7

10、7 (0.610.97)38867% of patients with EGFR mutation+ disease in the placebo arm received a second-line EGFR TKI21%Erlotinib(n=436)Placebo(n=445)p-valueResponse (CR/PR) 11.9 5.40.0006Stable disease* (SD) 48.645.4NSDisease control rate (DCR=CR+PR+SD) 60.650.80.0035SATURN: Best Overall Response*Stable di

11、sease 6 weeksCR + PR + SD 12 weeksPatients (%)50250ErlotinibPlacebo (n=436) (n=445)p0.000140.8%27.4%40.8%27.4%Disease control rate 12 weeks近近40%Tarceva40%Tarceva維持治療組維持治療組患者疾病仍有進展患者疾病仍有進展近近50%50%安慰劑治療者安慰劑治療者仍處于仍處于疾病控制中疾病控制中22困境四困境四:EGFR突突變變患者患者:一一線線TKI化化療療與一與一 線線化化療療二二線線TKI治治療療哪種策略更好哪種策略更好?2324Media

12、nOSHR n (months)(95% CI)21727.022.731.3SLOG Study: Survival in patients with EGFR mutation+ disease1.00.80.60.40.20Probability of PFS012243648Time (months)MedianPFSHR n (months)(95% CI)21714.011.316.71.00.80.60.40.20Probability of OS012243648Time (months)14.027.0Rosell R, et al. N Eng J Med 2009;361

13、:95867IPASS9.8 mnIPASSNot Mature25Randomized Study on Japanese Population with EGFR Mutation: NEJGSG002Maemondo M, et al. NEJM, 2010.GefitinibN=98P/CN=100CR40PR6929SD1350PD815NE46緩解率緩解率73 (74.5%)29(29%)P0.001HR=0.357 95% CI: 0.252-0.507, P0.00126DocetaxelCisplatinGefitinibChemotherapy- nave stage II

14、Ib/IV NSCLC; EGFR mutation (Exon 19 or 21); PS 02; Age 18y;Progression Free Survival R A N D O M I S E1:1lPrimary endpoint: PFSlSecondary endpoint: OS; ORR; QOL; SafetyWJTOG 3405Progression Free SurvivalOverall SurvivalMItsudomi T, et al. Lancet Oncol,200927OPTIMAL study design Erlotinib 150mg/dayl

15、Chemonavel Stage IIIB/IV NSCLCl EGFR 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 Cooperative Oncology Group; PS = performance status; HRQoL = heal

16、th-related quality of life; FACT-L = Functional Assessment of Cancer Therapy-Lung; LCSS = lung cancer symptom scale1:1Primary endpointProgression-free survival (PFS)Secondary endpointsOverall survival (OS), objective response rate (ORR), time to disease progression, duration of response, safety, HRQ

17、oL (FACT-L, LCSS), exploratory biomarker analysesStratification factorsMutation typeHistologySmoking statusEfficacy assessmentEvery 6 weeks28PFS: updated analysisPFS Probability1.00.80.60.40.20HR=0.16 (0.100.26)Log-rank p0.0001Time (months)05101520Patients at riskGem/7226400Erlotinib 827051202Gem/ca

18、rbo (n=72)Erlotinib (n=82)13.14.6carbo29Subgroup analysis of PFSOverallStage IV Stage IIIBFemaleMaleAge 65Age 65PS 01PS 2Never smokerCurrent/former smokerAdenocarcinomaNon-adenocarcinoma00.51.01.50.16 (0.100.26)1540.18 (0.110.28)138 0.27 (0.061.16)160.13 (0.070.24)910.26 (0.140.50)630.17 (0.070.43)3

19、80.19 (0.110.31)1160.16 (0.100.26)1440.21 (0.041.28)100.14 (0.080.25)1090.21 (0.090.49)450.17 (0.110.28)1340.22 (0.060.73)20HR (95% Cl)nHRFavours erlotinibFavours gem/carboTo be redrawn on logarithmic scale30NEJGSG002WJTOG 340595%左右的患者后左右的患者后續(xù)續(xù)治治療療兩兩組組交替交替31TORCH：International multicenter randomized

20、 phase III study of first-line erlotinib (E) followed by second-line cisplatin plus gemcitabine (CG) versus first-line CG followed by second-line E in advanced non-small cell lung cancer (aNSCLC) 31ASCO 2010 C. Gridelli, et al., Abstract # 7508試驗組試驗組厄洛替尼厄洛替尼150mg/d,至至PD順鉑順鉑80mg/m2 D1吉西他濱吉西他濱1200mg/m

21、2D1/8, q3w, 6個周期個周期標(biāo)準(zhǔn)組標(biāo)準(zhǔn)組順鉑順鉑+吉西他濱吉西他濱順鉑順鉑80mg/m2 D1吉西他濱吉西他濱1200mg/m2D1/8, q3w, 6個個周期周期厄洛替尼厄洛替尼150mg/d 細(xì)胞學(xué)或組織學(xué)確細(xì)胞學(xué)或組織學(xué)確診的診的IIIB*與與IV期期NSCLC ECOG PS 0-1 分層因素分層因素 組織學(xué)組織學(xué) 吸煙狀態(tài)吸煙狀態(tài) 性別性別 國家國家 年齡年齡 種族種族 既往未用化療既往未用化療(既往既往輔助化療可入組，輔助化療可入組，但需不含吉西他濱但需不含吉西他濱方案且一年后復(fù)發(fā)方案且一年后復(fù)發(fā))RPDPD*鎖骨上淋巴結(jié)轉(zhuǎn)移或胸腔積液鎖骨上淋巴結(jié)轉(zhuǎn)移或胸腔積液E-GPG

22、P-E首要終點：首要終點： OS次要終點：次要終點： 毒性毒性(NCI-CTCAE v3),RR(RECIST) PFS,QOL*,藥物經(jīng)濟學(xué)分藥物經(jīng)濟學(xué)分析析* 腫瘤和血液生物標(biāo)志物分腫瘤和血液生物標(biāo)志物分析析*32TORCH：GP-E治療組的OS/PFS優(yōu)于E-GP組 中期評估時兩組的中期評估時兩組的OS32ASCO 2010 C. Gridelli, et al., Abstract # 7508 PFS33SLCG III期臨床研究特羅凱治療伴EGFR突變的NSCLC患者 研究中心：N=67 計劃入組：N=146 主要終點：PFS 次要終點 OS，ORR，1YS，安全性, QoL 分層

23、因素 PS評分 突變類型 血清 vs. 腫瘤組織隨機分組入選條件 既往未經(jīng)放療 IIIB/ IV期 有EGFR突變 ECOG PS 0-2PD后可交換治療方案特羅凱 150mg/d含鉑的化療PI: Dr. Rafael Rosell34困境五困境五:EGFR突突變變在二在二線線TKI治治療療中扮中扮演的角色？演的角色？35BR21:Biomarker and SurvivalChang-Qi Zhu et al. J Clin Oncol 26.200836總體人群亞裔人群N=106N=19 N=19N=123N=9N=5N=13N=15Data on file37JCO 201038二二線線

24、治治療療需否需否EGFR突突變檢測變檢測? No! 無論EGFR突變與否,二線TKI治療OS至少不差于化療. Yes! 有突變者給予TKI治療療效及PFS顯著優(yōu)于化療(PFS:7.1 Vs 4.0, HR0.16)一線治療前標(biāo)本檢測能反映二線一線治療前標(biāo)本檢測能反映二線時時EGFREGFR突變的即時狀態(tài)嗎突變的即時狀態(tài)嗎? ?39療前療前44%化療前后化療前后EGFR突變的改變突變的改變-來自北來自北京腫瘤醫(yī)院的報道京腫瘤醫(yī)院的報道療后療后28%療前療前35.7%療后療后28.6%40困境六困境六:組織標(biāo)組織標(biāo)本本EGFR突突變變的異的異質(zhì)質(zhì)性性對對治治療療的影響的影響?41 Heterogeneity Between Primary and Metastatic TumorsDiscordant rate of EGFR mutation between primary and metastatic tumor reached 27% 25% (7/30)ca