依維莫司為晚期乳腺癌治療PPT演示幻燈片

1、1,mTOR抑制劑：依維莫司為HR+晚期乳腺癌患者治療開(kāi)啟新時(shí)代,2,新藥的不斷面世為乳腺癌患者帶來(lái)更多獲益mBC的生存時(shí)間隨著治療進(jìn)展而不斷延長(zhǎng),Figure adapted from Chia S, et al. Cancer. 2007;110(5):973-979. mBC = metastatic breast cancer. .,一項(xiàng)來(lái)自英國(guó)的統(tǒng)計(jì)顯示，mBC患者自診斷起的生存時(shí)間不斷延長(zhǎng) 1991-2001,N = 2,150,1.0,1999-2001,1997-1998,1994-1995,1991-1992,0.8,Overall Survival,0.6,0.4,0.2,

2、0,1,2,3,Time, years,4,5,0,Cohorts 3 32(3): 190194; 2Slamon DJ, et al. N EnglJ Med 2001;344:783792; 3Vogel CL, et al. J ClinOncol2002; 20:719726; 4Miller K, et al. N EnglJ Med 2007; 357:26662676;5Geyer CE, et al.N EnglJ Med2006;356:27332743.,5,對(duì)于HR+ mBC患者，LET較TAM療效顯著,Mouridsen H, et al. J Clin Oncol.

3、 2003;21:2101-2109.,Abbreviation: MBC, metastatic breast cancer.,6,期待新的藥物能進(jìn)一步提高內(nèi)分泌療效 與AI相比，氟維司群?jiǎn)嗡幉⒉荒茱@著改善HR+ mBC患者的療效,Trial 20 98; 2.Chia S, et al, J Clin Onco, 2008; 26(10);,7,未接受過(guò)TAM治療的患者(n=414),治療期間不允許接受其他類型的內(nèi)分泌治療和化療 入組時(shí)間2004.6-2009.6 主要研究終點(diǎn)：PFS 次要研究終點(diǎn)：OS及安全性,期待新的藥物能進(jìn)一步提高內(nèi)分泌療效 氟維司群聯(lián)合AI并不能顯著改善既往未接受

4、過(guò)TAM治療的HR+ mBC患者的療效,8,內(nèi)分泌作用通路與其他通路之間的CROSS-TALKPI3K/Akt/mTOR通路的激活與內(nèi)分泌耐藥相關(guān),Yue W, et al. J Steroid Biochem Mol Biol. 2007;106:102-110.,Abbreviations: E, estrogen; EGFR, epidermal growth factor receptor; ER, estrogen receptor; IGF-1R, insulin-like growth factor-1 receptor; mTOR, mammalian target of ra

5、pamycin.,芳香化酶抑制劑： ER+乳腺癌,內(nèi)分泌治療耐藥與腫瘤細(xì)胞信號(hào)傳導(dǎo)通路的改變有關(guān),9,在雌激素剝奪后的ER+乳腺癌細(xì)胞中觀察到PI3K/AKT mTOR通路活化1,1. Santen RJ, et al. Endocr Relat Cancer. 2005;12 suppl 1:S61-S73; 2. Boulay A, et al. Clin Cancer Res. 2005;11:5319-5328.,ER+的腫瘤細(xì)胞中觀察到依維莫司和來(lái)曲唑具有協(xié)同作用2,*P.001, 2-way ANOVA using Tukeys test for pairwise comparis

6、ons (synergistic drug interaction),臨床前數(shù)據(jù)支持mTOR抑制劑與內(nèi)分泌治療聯(lián)用,*,*,*,*,Abbreviations: ANOVA, analysis of variance; ER, estrogen receptor; mTOR, mammalian target of rapamycin; PFS, progression-free survival.,10,依維莫司 (Everolimus),口服mTOR抑制劑 已獲批用于轉(zhuǎn)移性腎細(xì)胞癌，神經(jīng)內(nèi)分泌腫瘤及室管膜下巨細(xì)胞星狀細(xì)胞瘤 體外試驗(yàn)肯定了其對(duì)于內(nèi)分泌抵抗的乳腺癌細(xì)胞有效1 早期臨床試驗(yàn)肯定

7、了其療效2,3 新輔助治療試驗(yàn)（2222試驗(yàn)）更證實(shí)了LET+EVE的療效4,1. Boulay A, et al. Clin Cancer Res. 2005; 11:5319-5328; 2. Ellard SL, et al. J Clin Oncol. 2009;27:4536-4541; 3. Awada A, et al. Eur J Cancer. 2008;44:84-91; 4. Baselga J, et al. J Clin Oncol. 2009;27:2630-2637.,Abbreviation: mTOR, mammalian target of rapamyci

8、n.,11,n = 138,n = 132,Tumor biopsies (surgery),16 wk,Surgery,Tumor biopsies (pretreatment),Tumor biopsies (2 wk),Baselga J, et al. J Clin Oncol. 2009;27:2630-2637.,新輔助 Letrozole Everolimus的II期臨床研究,新診斷, 未治療的ER+ 乳腺癌 觸診腫瘤大小: 2 cm,RANDOMIZE,Letrozole 2.5 mg/day Everolimus 10 mg/day,Letrozole 2.5 mg/day

9、Placebo,SCREEN,Abbreviation: ER, estrogen receptor.,12,依維莫司組的患者中57%Ki67表達(dá)降低 (一種細(xì)胞增殖的標(biāo)記物) ，而對(duì)照組僅30%,Baselga J, et al. J Clin Oncol. 2009;27:2630-2637.,Abbreviations: CR, complete response; PR, partial response.,新輔助 Letrozole Everolimus的II期臨床研究,13,TAMRAD 方案,隨機(jī)，II期臨床研究 接受過(guò)AI治療的HR+,HER2-的轉(zhuǎn)移性乳腺癌患者 分層因素:

10、原發(fā)/繼發(fā)內(nèi)分泌耐藥 原發(fā): AI治療時(shí)發(fā)生復(fù)發(fā)轉(zhuǎn)移，或AI治療后6個(gè)月內(nèi) 繼發(fā): 復(fù)發(fā)轉(zhuǎn)移(6 mo) 或針對(duì)轉(zhuǎn)移性病灶應(yīng)用AI后出現(xiàn)進(jìn)一步的疾病進(jìn)展 不允許交叉換藥,Bachelot T, et al. Breast Cancer Res Treat.2010;100 suppl 1; SABCS 2010, abstract S1-6.,Abbreviation: TAM, tamoxifen.,14,患者人群特征,Bourgier， Abstract, ESMO,2011,15,臨床獲益率及至疾病進(jìn)展時(shí)間(TTP),臨床獲益率 P = 0.045 (exploratory analys

11、is),0,10,20,30,40,50,60,70,TAM,TAM + EVE,CBR, % of Patients (95% CI),42.1% (29.1-55.9),61.1% (46.9-74.1),至疾病進(jìn)展時(shí)間 TAM: 4.5 months TAM + EVE: 8.6 months HR (95% CI) = 0.54 (0.36-0.81) P = 0.0021 (exploratory analysis),0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,2,4,6,8,10,12,14,16,18,20,22,24,26,28,

12、30,32,34,隨訪時(shí)間，月,TTP Probability,TAM,At risk,57,54,45,39,34,28,26,25,20,19,17,14,10,3,3,2,1,44,30,24,22,16,13,11,7,6,4,2,2,1,0,0,TAM + EVE,Bourgier， Abstract, ESMO,2011,16,總生存,TAM,TAM + EVE,Bourgier， Abstract, ESMO,2011,17,根據(jù)內(nèi)分泌耐藥情況分析至疾病進(jìn)展時(shí)間,原發(fā)性耐藥 TAM: 3.8 months TAM + EVE: 5.4 months HR = 0.70 (0.40

13、-1.21) P = NS (exploratory analysis),繼發(fā)性耐藥 TAM: 5.5 months TAM + EVE: 14.8 months HR = 0.46 (0.26-0.83) P = 0.0087 (exploratory analysis),Bourgier， Abstract, ESMO,2011,TAM,TAM + EVE,18,18,根據(jù)內(nèi)分泌耐藥情況分析總生存,原發(fā)性耐藥 N (%) of events TAM: 15 (54%) TAM + EVE: 12 (46%) HR = 0.73 (0.34-1.55) P = 0.41 (explorato

14、ry analysis),繼發(fā)性耐藥 N (%) of events TAM: 16 (55%) TAM + EVE: 4 (15%) HR = 0.21 (0.07-0.63) P = 0.002 (exploratory analysis),Bourgier， Abstract, ESMO,2011,19,副反應(yīng)分析,Bourgier， Abstract, ESMO,2011,20,TAMRAD 小結(jié),在這項(xiàng)mTOR抑制劑和抗雌激素藥物聯(lián)合應(yīng)用的隨機(jī)II期臨床研究中： 與他莫西芬單藥治療相比，他莫西芬聯(lián)合依維莫司能有效提高患者CBR, TTP及總生存 CBR: 61 vs 42 % TTP

15、: HR = 0.54; 95% CI, 0.36-0.81 總生存: HR = 0.45; 95% CI, 0.24-0.81 對(duì)于繼發(fā)性耐藥患者，臨床獲益更大 副反應(yīng)可管理，與既往研究相一致,Bourgier， Abstract, ESMO,2011,21,正在進(jìn)行的II期臨床研究ER+且AI治療失敗的轉(zhuǎn)移性乳腺癌患者應(yīng)用Fulvestrant 和Everolimus,11 例AI治療6個(gè)月內(nèi)出現(xiàn)復(fù)發(fā)轉(zhuǎn)移的ER+轉(zhuǎn)移性乳腺癌 Fulvestrant 500 mg on day 1, then 250 mg on days 14 and 28, and then monthly therea

16、fter Everolimus 5 mg/day in the first mo in first 5 patients then 10 mg/day afterward; 10 mg/day for subsequent patients 療效分析 平均TTP: 8.6 mo 臨床獲益率(CR + PR + SD 24 wk): 55%,Badin F, et al. Breast Cancer Res Treat.2010;100 suppl 1; SABCS 2010, abstract P4-02-05.,Abbreviations: AE, adverse event; AI, ar

17、omatase inhibitor; CR, complete response; ER, estrogen receptor; MBC, metastatic breast cancer; PR, partial response; SD, stable disease.,22,依西美坦 依維莫司 治療晚期乳腺癌患者(III期),依維莫司 10 mg PO qd + 依西美坦 25 mg PO qd (n= 485),安慰劑 PO qd + EXE 25 mg PO qd (n= 239),R,研究終點(diǎn)： 主要: PFS （當(dāng)?shù)丶爸醒朐u(píng)估） 次要: OS, ORR, 至ECOG體能狀態(tài)評(píng)分下

18、降時(shí)間, 安全性, 生活質(zhì)量變化,.,2:1,直到疾病進(jìn)展或出現(xiàn)嚴(yán)重毒性反應(yīng),N = 705 絕經(jīng)后 ER+ 不可切除的局部晚期或轉(zhuǎn)移性乳腺癌 來(lái)曲唑或阿那曲唑治療后疾病進(jìn)展,22,23,BOLERO-2: 患者基線特征,a All other patients had 1 bone lesion.,Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.,24,BOLERO-2: 前期治療,LET

19、: letrozole, ANA: anastrozole,Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.,25,BOLERO-2 (隨訪12個(gè)月): PFS當(dāng)?shù)卦u(píng)估,0,20,40,60,80,100,0,6,12,18,24,30,36,42,48,54,60,66,72,78,84,90,96,Time (weeks),Probability (%) of Event,HR = 0.

20、44 (95% CI: 0.36-0.53) Log rank P value: 1 x 10-16 EVE + EXE: 7.4 months PBO + EXE: 3.2 months,EVE + EXE (E/N = 267/485),PBO + EXE (E/N = 190/239),Everolimus,Placebo,Number of patients still at risk,485,436,365,303,246,188,136,96,64,45,34,21,13,9,2,2,0,239,190,131,95,63,45,29,19,12,8,6,6,4,2,0,0,0,H

21、ortobagyi G. et al, SABCS 2011 (Abstract #S3-7),26,BOLERO-2 (隨訪12個(gè)月): PFS中央評(píng)估,Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7),Everolimus,Placebo,Number of patients still at risk,485,422,351,284,224,176,119,86,57,38,32,22,12,7,2,2,0,239,179,112,74,56,36,23,18,8,5,4,4,3,1,0,0,0,0,20,40,60,80,100,0,6,

22、12,18,24,30,36,42,48,54,60,66,72,78,84,90,96,Probability (%) of Event,HR = 0.36 (95% CI: 0.28-0.45) Log rank P value: 1 x 10-16 EVE + EXE: 11.0 months PBO + EXE: 4.1 months,EVE + EXE (E/N = 155/485),PBO + EXE (E/N = 127/239),Time (weeks),Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7),27,BOLERO-2 (

23、隨訪12個(gè)月): PFS亞組分析,Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7),28,BOLERO-2 (隨訪12個(gè)月): 反應(yīng)率 PFS = progression-free survival. Hortobagyi G et al. SABCS 2011 (Abstract #S3-7),30,BOLERO-2 (長(zhǎng)期隨訪數(shù)據(jù)): QOLQoL 分級(jí)評(píng)分: 至評(píng)分惡化5%的時(shí)間,Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7),0,20,40,60,80,100,0,6,12,18,24,3

24、0,36,42,48,54,60,66,72,78,84,90,96,Time (weeks),Probability (%) of Event,HR = 0.81 (97.5% CI: 0.62-1.06) Log rank p value: 0.0396 EVE + EXE: 7.0 months PBO + EXE: 5.6 months,EVE + EXE (E/N = 246/485),PBO + EXE (E/N = 106/239),Everolimus,Placebo,Number of patients still at risk,485,425,299,239,187,14

25、9,109,75,56,33,25,14,11,8,2,1,0,239,200,115,82,60,44,27,17,9,7,4,4,1,0,0,0,0,QOL evaluated using the EORTC-QLQ-30 scale,31,BOLERO-2 (隨訪12個(gè)月): 骨標(biāo)記物,EVE = everolimus; EXE = exemestane; PBO = placebo. Hortobagyi G et al. SABCS 2011 (Abstract #S3-7),% Change From Baseline,-5.6,-20.3,-6.3,-3.6,-26.7,-0.4,20.9,35.5,29.5,18.1,40.7,4