依維莫司為晚期乳腺癌治療

1、mTOR抑制劑：依維莫司為HR+晚期乳腺癌患者治療開啟新時代,新藥的不斷面世為乳腺癌患者帶來更多獲益mBC的生存時間隨著治療進展而不斷延長,Figure adapted from Chia S, et al. Cancer. 2007;110(5):973-979.mBC = metastatic breast cancer..,一項來自英國的統(tǒng)計顯示，mBC患者自診斷起的生存時間不斷延長 1991-2001,N = 2,15

2、0,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,1.0,1999-2001,1997-1998,1994

3、-1995,1991-1992,,0.8,Overall Survival,,0.6,,0.4,,0.2,,0,1,,,,,,,2,,3,Time, years,,4,,5,,0,,Cohorts 3 & 4:P ≤ .01,4 組,當前NCCN指南推薦HR+ mBC患者若無明顯癥狀內(nèi)臟轉(zhuǎn)移，應使用內(nèi)分泌治療,NCCN Clinical Practice Guidelines in Oncology. Breast Canc

4、er. Version 2.2011.,不論HR+mBC患者的HER2及月經(jīng)狀態(tài)如何，只要無明顯癥狀的內(nèi)臟轉(zhuǎn)移，均應使用內(nèi)分泌治療,常用內(nèi)分泌藥物匯總,內(nèi)分泌治療通過剝奪雌激素對腫瘤的影響而起作用1選擇性雌激素受體調(diào)節(jié)劑通過與雌激素受體結合和減少雌激素與受體結合，從而阻礙雌激素起作用代表藥物 他莫西芬(Novaldex®), 托瑞米芬(Fareston®)芳香化酶抑制劑抑制雄激素轉(zhuǎn)化為雌激素從而降低雌激

5、素對腫瘤的作用代表藥物 阿那曲唑(Arimidex®), 來曲唑(Femara®), 依西美坦 (Aromasin®)選擇性雌激素受體下調(diào)劑通過減少有效ER數(shù)量而阻礙雌激素發(fā)揮作用代表藥物 氟維司群(Faslodex®),1Bilynskyj BT. ExpOncol2010; 32(3): 190–194; 2Slamon DJ, et al. N EnglJ Med 2001;344

6、:783–792; 3Vogel CL, et al. J ClinOncol2002; 20:719–726; 4Miller K, et al. N EnglJ Med 2007; 357:2666–2676;5Geyer CE, et al.N EnglJ Med2006;356:2733–2743.,對于HR+ mBC患者，LET較TAM療效顯著,Mouridsen H, et al. J Clin Oncol. 2003;21

7、:2101-2109.,,,Abbreviation: MBC, metastatic breast cancer.,期待新的藥物能進一步提高內(nèi)分泌療效與AI相比，氟維司群單藥并不能顯著改善HR+ mBC患者的療效,Trial 20 & Trial 21研究N=451+400接受過內(nèi)分泌治療（主要為TAM）的絕經(jīng)后晚期乳腺癌患者,EFECT研究N=693接受過非甾體類AI治療的絕經(jīng)后晚期乳腺癌患者,1.Robertso

8、n JF, et al, Cancer, 2003;98; 2.Chia S, et al, J Clin Onco, 2008; 26(10);,未接受過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間2004.6-2009.6主要研究終點：PFS次要研究終點：OS及安全性,期待新的藥物能進一步提高內(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過TAM治療的HR+ mBC患者的療效,內(nèi)

9、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,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-l

10、ike growth factor-1 receptor; mTOR, mammalian target of rapamycin.,芳香化酶抑制劑：ER+乳腺癌,內(nèi)分泌治療耐藥與腫瘤細胞信號傳導通路的改變有關,在雌激素剝奪后的ER+乳腺癌細胞中觀察到PI3K/AKT mTOR通路活化1,1. Santen RJ, et al. Endocr Relat Cancer. 2005;12 suppl 1:S61-S73; 2. Boul

11、ay A, et al. Clin Cancer Res. 2005;11:5319-5328.,ER+的腫瘤細胞中觀察到依維莫司和來曲唑具有協(xié)同作用2,***P<.001, 2-way ANOVA using Tukey’s test for pairwise comparisons (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,***,***,***,***,Abb

12、reviations: ANOVA, analysis of variance; ER, estrogen receptor; mTOR, mammalian target of rapamycin; PFS, progression-free survival.,依維莫司 (Everolimus),口服mTOR抑制劑已獲批用于轉(zhuǎn)移性腎細胞癌，神經(jīng)內(nèi)分泌腫瘤及室管膜下巨細胞星狀細胞瘤體外試驗肯定了其對于內(nèi)分泌抵抗的乳腺癌細胞有效1

13、 早期臨床試驗肯定了其療效2,3新輔助治療試驗（2222試驗）更證實了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

14、J, et al. J Clin Oncol. 2009;27:2630-2637.,Abbreviation: mTOR, mammalian target of rapamycin.,n = 138,n = 132,Tumor biopsies (surgery),,,16 wk,Surgery,,Tumor biopsies(pretreatment),,Tumor biopsies (2 wk),,,,,,,,,,Basel

15、ga 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/dayEverolimus 10 mg/day,Letrozole 2.5 mg/dayPlacebo,SCREEN,Abbreviation

16、: ER, estrogen receptor.,依維莫司組的患者中57%Ki67表達降低 (一種細胞增殖的標記物) ，而對照組僅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,

17、TAMRAD 方案,隨機，II期臨床研究接受過AI治療的HR+,HER2-的轉(zhuǎn)移性乳腺癌患者分層因素: 原發(fā)/繼發(fā)內(nèi)分泌耐藥原發(fā): AI治療時發(fā)生復發(fā)轉(zhuǎn)移，或AI治療后6個月內(nèi)繼發(fā): 復發(fā)轉(zhuǎn)移(≥6 mo) 或針對轉(zhuǎn)移性病灶應用AI后出現(xiàn)進一步的疾病進展不允許交叉換藥,Bachelot T, et al. Breast Cancer Res Treat. 2010;100 suppl 1; SABCS 2

18、010, abstract S1-6.,Abbreviation: TAM, tamoxifen.,14,患者人群特征,Bourgier， Abstract, ESMO,2011,臨床獲益率及至疾病進展時間(TTP),15,臨床獲益率P = 0.045 (exploratory analysis),,,,,,,,,,,,,,,,0,10,20,30,40,50,60,70,TAM,TAM + EVE,CBR, % of Patient

19、s (95% CI),42.1%(29.1-55.9),61.1%(46.9-74.1),至疾病進展時間TAM: 4.5 monthsTAM + EVE: 8.6 monthsHR (95% CI) = 0.54 (0.36-0.81) P = 0.0021 (exploratory analysis),0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,2,4,6,8,10,12,1

20、4,16,18,20,22,24,26,28,30,32,34,隨訪時間，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,Bo

21、urgier， Abstract, ESMO,2011,16,總生存,,TAM,,TAM + EVE,Bourgier， Abstract, ESMO,2011,根據(jù)內(nèi)分泌耐藥情況分析至疾病進展時間,17,原發(fā)性耐藥TAM: 3.8 monthsTAM + EVE: 5.4 monthsHR = 0.70 (0.40-1.21)P = NS (exploratory analysis),繼發(fā)性耐藥TAM: 5.5 months

22、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,根據(jù)內(nèi)分泌耐藥情況分析總生存,原發(fā)性耐藥N (%) of eventsTAM: 15 (54%)TAM + EVE: 12 (46%)HR = 0.73 (0.34-1.

23、55)P = 0.41 (exploratory analysis),繼發(fā)性耐藥N (%) of eventsTAM: 16 (55%)TAM + EVE: 4 (15%)HR = 0.21 (0.07-0.63)P = 0.002 (exploratory analysis),Bourgier， Abstract, ESMO,2011,副反應分析,Bourgier， Abstract, ESMO,2011,20,TAMR

24、AD 小結,在這項mTOR抑制劑和抗雌激素藥物聯(lián)合應用的隨機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: HR = 0.54; 95% CI, 0.36-0.81總生存: HR = 0.45; 95% CI, 0.24-0.81對于繼發(fā)性耐藥患者，臨床獲益更大副反應可管理，與既往研究相一致,Bourgier， Abstract, E

25、SMO,2011,正在進行的II期臨床研究ER+且AI治療失敗的轉(zhuǎn)移性乳腺癌患者應用Fulvestrant 和Everolimus,11 例AI治療6個月內(nèi)出現(xiàn)復發(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 thereafterEverolimus 5 mg/day in the first mo

26、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-

27、02-05.,Abbreviations: AE, adverse event; AI, aromatase inhibitor; CR, complete response; ER, estrogen receptor; MBC, metastatic breast cancer; PR, partial response; SD, stable disease.,依西美坦 ± 依維莫司 治療晚期乳腺癌患者(III期),,,

28、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：主要: PFS （當?shù)丶爸醒朐u估）次要: OS, ORR, 至ECOG體能狀態(tài)評分下降時間, 安全性, 生活質(zhì)量變化,.,2:1,直到疾病進展或出現(xiàn)嚴重毒性反應,N = 705絕經(jīng)后 ER+不可切除的局部晚期或轉(zhuǎn)移性乳腺癌 來曲唑或阿那曲唑治療后疾

29、病進展,22,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.,23,BOLERO-2: 前期治療,LET: let

30、rozole, ANA: anastrozole,Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.,24,BOLERO-2 (隨訪12個月): PFS當?shù)卦u估,,0,20,40,60,80,100,0,6,12,18,24,30,36

31、,42,48,54,60,66,72,78,84,90,96,Time (weeks),Probability (%) of Event,,,HR = 0.44 (95% CI: 0.36-0.53)Log rank P value: <1 x 10-16EVE + EXE: 7.4 monthsPBO + EXE: 3.2 months,EVE + EXE (E/N = 267/485),PBO + EXE (E/N =

32、 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,Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7),BOLERO-2

33、 (隨訪12個月): PFS中央評估,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,

34、,0,20,40,60,80,100,0,6,12,18,24,30,36,42,48,54,60,66,72,78,84,90,96,Probability (%) of Event,,,HR = 0.36 (95% CI: 0.28-0.45)Log rank P value: <1 x 10-16EVE + EXE: 11.0 monthsPBO + EXE: 4.1 months,EVE + EXE (E/N =

35、 155/485),PBO + EXE (E/N = 127/239),Time (weeks),Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7),BOLERO-2 (隨訪12個月): PFS亞組分析,Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7),BOLERO-2 (隨訪12個月): 反應率 & 臨床獲益率,P < 0.

36、0001,Percent,反應率,臨床獲益率,Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7),BOLERO-2 (隨訪12個月): 總生存,截止2011年7月8日：共137例患者死亡17.2% 在依維莫司組22.7% 在安慰機組OS 最終分析需392例死亡事件80%把握度，預估風險下降25%,29,OS = overall survival; PFS = progressio

37、n-free survival.Hortobagyi G et al. SABCS 2011 (Abstract #S3-7),BOLERO-2 (長期隨訪數(shù)據(jù)): QOLQoL 分級評分: 至評分惡化≥5%的時間,Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7),,0,20,40,60,80,100,0,6,12,18,24,30,36,42,48,54,60,66,72,78,8

38、4,90,96,Time (weeks),Probability (%) of Event,HR = 0.81 (97.5% CI: 0.62-1.06)Log rank p value: 0.0396EVE + EXE: 7.0 monthsPBO + EXE: 5.6 months,EVE + EXE (E/N = 246/485),PBO + EXE (E/N = 106/239),Everolimus,Placebo,

39、Number of patients still at risk,485,425,299,239,187,149,109,75,56,33,25,14,11,8,2,1,0,239,200,115,82,60,44,27,17,9,7,4,4,1,0,0,0,0,,,QOL evaluated using the EORTC-QLQ-30 scale,BOLERO-2 (隨訪12個月): 骨標記物,EVE = everolimus; E

40、XE = 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,-0.4,20.9,35.5,29.5,18.1,40.7,40.3,-40,-30,-20,-10,0,10,20,30,40,50,BSAP,P1NP,

41、CTX,BSAP,P1NP,CTX,6 周,12 周,,EVE + EXE,,PBO + EXE,Δ27%,Δ56%,Δ36%,Δ22%,Δ67%,Δ41%,BOLERO-2: 安全性分析,Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LB

42、A.,AE: Adverse Event; AST: Aspartate aminotransferase,32,BOLERO-2 小結,對于非甾體類芳香化酶抑制劑治療失敗的ER+，HER2-的晚期乳腺癌患者，依維莫司聯(lián)合依西美坦可有效逆轉(zhuǎn)內(nèi)分泌耐藥依西美坦組骨吸收和骨形成標記物均升高，聯(lián)合組則均降低依維莫司有望改變晚期乳腺癌患者的治療模式,33,總結,臨床前和臨床證據(jù)證實EGFR/HER2和mTOR信號傳導通路在轉(zhuǎn)移性乳腺癌內(nèi)

43、分泌耐藥過程中起了重要作用HR+ HER2+ 的轉(zhuǎn)移性乳腺癌一線治療中AI + HER2抑制劑優(yōu)于單用AI在TAMRAD研究中AI治療過的轉(zhuǎn)移性乳腺癌患者聯(lián)用依維莫司和TAM現(xiàn)實了很好的療效和可管理的安全性特征BOLERO-2研究進一步證實了依維莫司可為內(nèi)分泌治療失敗的ER+乳腺癌患者帶來臨床獲益,Abbreviations: AI, aromatase inhibitor; EGFR, epidermal growth fact