乳腺癌的分子靶向治療課件

1、 乳腺癌的分子靶向治療惡性腫瘤的發(fā)生發(fā)展,侵襲轉(zhuǎn)移和腫瘤血管生成，是多數(shù)腫瘤共同的生物學過程,其間涉及許多細胞和分子學機制.對惡性腫瘤的細胞和分子生物學機制的研究，推動乳腺癌的基礎(chǔ)和臨床研究以及分子靶向藥物研發(fā).分子靶向藥物已經(jīng)成為抗腫瘤藥物的新興門類，已經(jīng)并進一步對腫瘤治療產(chǎn)生日益重要的影響。惡性腫瘤發(fā)生的細胞和分子學機制自我生長促進對生長抑制信號敏感性下降逃避凋亡和死亡侵襲和轉(zhuǎn)移腫瘤血管生長分子靶向藥物的研究抗HER2的研究抗腫瘤血管生成研究PARP 抑制劑抗骨轉(zhuǎn)移的研究M-TOR三陰乳腺癌中抗EGFRHER2陽性乳腺癌Her2/neu是4個表皮生長因子受體家族成員之一，與細胞的生長，分化

2、生存重要相關(guān)。Her2蛋白的過渡表達或基因擴增的乳腺癌約占1/4,是腫瘤惡性程度高，預后差 的標志。Trastuzumab(Herceptin,赫賽汀)是人源化單克隆抗體，針對Her2受體細胞外功能簇。單藥或者與化療聯(lián)合應(yīng)用，治療Her2陽性MBC改善療效。1998年FDA批準治療Her2陽性MBC，與紫杉類聯(lián)合成為標準一線方案。輔助性治療的 臨床研究也已經(jīng)完成，并在2006年獲得FDA批準。NCCN 和 St.gallen 2007 HER2成為風險分級和治療分組的指標。曲妥珠單抗治療HER2陽性乳腺癌MBC1st lineHO648gM77001 US OncologyBCIRG 007C

3、HATTAnDEMRHEA 2nd+ linesGBG-26BO17929EGF104900Numerous Phase II studies曲妥珠單抗治療HER2陽性乳腺癌EBCAdjuvant:HERANSABP B-31NCCTG N9831BCIRG 006PACS 04Neo Adjuvant:NOAHMDACCGeparQuattro曲妥珠單抗 in EBC Trial 無病生存期 (ITT分析): 4-年中位隨訪時間1008060402000612182430483642隨機分組后月1698170315641619144015521363148512971414124013527

4、12854118012809921020No. at risk事件數(shù)4583694-年DFS72.278.6風險系數(shù)0.7695% 可信區(qū)間0.66, 0.87p 值0.00011-年赫賽汀組觀察組6.4%患者(%)新輔助治療顯著提高病理完全緩解率(pCR)MDACC:PCR: H + (P FEC) vs P + FEC alone (65.2% vs 26.3%)NOAHPCR: 43% vs 23%tPCR: 38% VS 20%MDACC研究：2/3的患者獲病理學完全緩解解26.3%n=1965.2%n=2395% CI(4384%)p=0.016(n=42)pCR (%)P + FE

5、C aloneH + (P FEC)Buzdar A, et al. Proc ASCO 2007NOAH: 更高臨床緩解率ORR, %CR, %PR, %SD, %PD, %+ H(n=115)80.960.020.90.94.3- H(n=113)73.451.322.15.36.265.725.240.410.110.1HER2 positiveHER2 negative(n=99)Gianni et al ASCO 2007, poster 532ORR, overall response rate; CR, complete response; PR, partial respons

6、e; SD, stable disease; PD, progressive disease NOAH：顯著提高病理學完全緩解率(pCR) 01020304050+ H- HHER2 negative+ H- HHER2 negativePatients(%)HER2 positiveHER2 positivepCRtpCR43%23%17%38%20%16%p=0.29p=0.002p=0.003p=0.43pCR, pathological complete response; tpCR, total pathological complete response in breast and

7、 nodesGianni et al ASCO 2007, poster 532NOAH: tumour response赫賽汀聯(lián)合化療:新輔助治療的pCR率pCR (%)PDPAC PVD + cisplatinD + HD + VX + DAC P CMFDP FEC-75P FECStudyHerceptinLapatinibpCR, pathological complete response; AC, doxorubicin, cyclophosphamide; E, epirubicin; L, lapatinib; V, vinorelbine; X, Xeloda; FEC,

8、5-fluorouracil, epirubicin, cyclophosphamide; CMF, cyclophosphamide, methotrexate, 5-fluorouracil; D, docetaxel 拉帕替尼（Lapatinib）酪氨酸激酶抑制劑有效的選擇性ErbB1 (EGFR)和ErbB2 (HER2) 的雙重抑制劑2007年3月13日FDA批準上市與卡培他濱聯(lián)合，用于既往曾接受過蒽環(huán)類、紫杉醇類和曲妥珠單抗治療的ErbB2過表達的轉(zhuǎn)移性乳腺癌AktLapatinib 作用機制RasRafMAPKPSosShcGrb2ATPAktMAPKPI3KLapatinib增

9、生通路生存通路通過ATP的正?；罨疞apatinib阻斷其活化生存通路增生通路Xia W, et al. Oncogene 2002;21:6255-63.Rusnak DW, et al. Mol Cancer Ther 2001;1:85-94.單克隆抗體與小分子TKI的比較抑制激酶的胞內(nèi)區(qū)對突變的ErbB-1 和頂端缺失的 ErbB-2有活性配體的濃度不會影響其抑制活性與受體的胞外區(qū)結(jié)合不能與突變和頂端缺失的受體結(jié)合-無活性配體的飽和會影響其療效小分子酪氨酸激酶抑制劑單克隆抗體MBC單藥療效5.1%， (SD 40%)難治性MBC單藥療效1.4%，(SD 33%)難治性晚期或轉(zhuǎn)移性乳腺癌

10、應(yīng)用Lapatinib 卡培他濱 VS 卡培他濱單藥治療的隨機、III期研究進展、HER2+轉(zhuǎn)移性乳腺癌或LABC 曾接受過蒽環(huán)類、紫杉類和曲妥珠單抗治療*未接受過卡培他濱治療患者接受治療直至疾病進展或出現(xiàn)不可耐受的毒性并進行生存期隨訪N=528 隨機卡培他濱2500 mg/m2/d po days 1-14 q 3 wkLapatinib 1250 mg po qd + 卡培他濱2000 mg/m2/d po days 1-14 q 3 wk *Trastuzumab must have been administered for metastatic disease Presented b

11、y C.E. Geyer et al, ASCO 2006Lapatinib+Capecitabine vs CapecitabinePhase III 復治的MBC（ITT） Time (weeks)010203040506070Cumulative Progression-Free Survival, %01020304050607080901000.001P-value (log-rank, 1-sided)73 (45%)45 (28%)Progressed or died0.49 (0.34, 0.71)Hazard ratio (95% CI)4.48.4Median PFS, m

12、os161160No. of ptsCapecitabineLapatinib + capecitabineGeyer et al, NEJM 2006; 355: 2733-43 Lapatinib在難治性晚期/轉(zhuǎn)移性乳腺癌患者人群是否ErbB-2過表達？治療主要終點EGF20002II期N=78含曲妥珠單抗治療后進展的女性是LapatinibORR 5,1%(SD 40%)EGF20008II期N=229含蒽環(huán)類、紫杉醇類、卡培他濱曲妥珠單抗治療后進展的女性是/否LapatinibORR 1.4%(SD 33%)EGF100151 III期N= 399含蒽環(huán)類、紫杉醇類及曲妥珠單抗治療后進

13、展的女性是卡培他濱 lapatinibTTP, RREGF104383III期一線是紫杉醇+曲妥珠單抗+/- lapatinibTTP, RREGF104535*III期一線是紫杉醇+/- lapatinib臨床受益率EGF104900III期曲妥珠單抗2個以上療程治療后疾病進展是Lapatinib +/-曲妥珠單抗TTP, RRHER2陽性乳腺癌腦轉(zhuǎn)移Lapatinib單藥治療腦轉(zhuǎn)移有效，51例Lapatinib治療腦放療后進展，并且已經(jīng)用過Lapatinib治療的患者，聯(lián)合Capecitabin腫瘤縮小20%，占37%腫瘤縮小50%，占20%5例單藥Lapatinib達到PR,1例聯(lián)合Ca

14、pecitabin又達到PR.20例單藥Lapa達SD,加上Capecitabin3例PR,10例SD.輔助治療臨床研究EGF105485 III期 Lapa vs PlaceboALLTO Study III期 4組 隨機對照試驗52WEEKSLapatinib Lapatinib+曲妥珠單抗每3周方案共40周Lapatinib+曲妥珠單抗每周方案共12周曲妥珠單抗每周方案共12周Lapatinib52周曲妥珠單抗每3周方案共40周Lapatinib34 周紫杉醇每周方案共12周+/-放射治療6周清洗期曲妥珠單抗每周方案共12周 在完成任何蒽環(huán)類為主的（新-）輔助化療后，計劃靶向治療與紫杉醇

15、聯(lián)合使用手術(shù)、 完成（新）輔助化療 (在批準的用藥列表中選擇)LVEF 50%Max 6 w當?shù)貙嶒炇掖_定的 HER2陽性浸潤性乳腺癌中心實驗室確定 HER2+; ER and PgR紫杉醇每周方案共12周+/-放射治療紫杉醇每周方案共12周+/-放射治療紫杉醇每周方案共12周+/-放射治療ALLTO StudyLapatinib 腹瀉8個臨床試驗中1126名使用lapatinib的患者： 50%出現(xiàn)腹瀉 分級54%為1級 (輕度)30%為2級 (中度)15%為3級 (重度)1%為4級 (威脅生命) 發(fā)作及周期44%的患者在最初6天內(nèi)出現(xiàn)22%的患者在開始治療28天后出現(xiàn)每次發(fā)作平均持續(xù)5天D

16、ata on File, GlaxoSmithKline.Lapatinib皮膚事件8個臨床試驗中1126名使用lapatinib的患者，46%報告有皮疹(所有級別)*重度皮疹罕見; 4%的患者出現(xiàn)3級皮疹，沒有4級皮疹的報告多數(shù)皮膚事件出現(xiàn)較早，在治療前14天內(nèi)出現(xiàn)中位數(shù)周期為29天85%的事件無需干預、劑量調(diào)整或治療中斷1%由于皮膚事件終止治療* Excluding PPE Data on File, GlaxoSmithKline.其它新的抗HER2藥物Pertuzumab阻斷異源性二聚體，效力可能比Herceptin更強。61例三線治療的安全性報告了該抗體相關(guān)的毒性：59%腹瀉（G3/

17、4 僅2%），其他G3/4 AE：DV血栓1例，皮疹1例。對心臟功能影響很小，2例33例可評價療效，ORR 18.2%, CB 39.4%，進行中研究：聯(lián)合Herceptin一線MBC.其他新型抗HER2藥物(續(xù))HKI-272, 不可逆的全HER2 TKI。N=42 MBCPR 13, SD 20%1例 G3/4腹瀉。Trastuzumab-DM1 HER2+MBCN=16 PR26%貝伐單抗在乳腺癌的臨床研究-抗腫瘤血管生成治療 VEGF 家族和受體Neufeld G, et al. FASEB J. 1999;13:9-22.VEGFR-3(Flt-4)VEGFR-2(Flk-1/KDR

18、)VEGFR-1(Flt-1)AngiogenesisLymphangiogenesisAngiogenesisLymphangiogenesis胎盤生長因子PIGFVEGF-AVEGF-BVEGF-CVEGF-DBevacizumab (重組人抗VEGF單克隆抗體 )貝伐單抗:針對VEGF的人源化單克隆抗體 (93% human, 7% murine),能夠識別所有VEGF亞型( Kd=8 x 10-10M),終末半衰期17-21 天.抗血管生成治療靶點貝伐單抗治療晚期乳腺癌I/II期臨床研究75例化療過的晚期乳腺癌接受不同劑量貝伐單抗療效分析:療效 3mg/kg(18) 10mg/kg(4

19、1) 20mg/kg(16) CR(%) 0 1(2.4) 0PR(%) 1(5.6) 4(9.8) 1(6.8)22周臨床獲益(5) 2(11) 7(17) 3(19)中位有效時間(M) 3.1 5.6 8.0 Cobleigh MA, et al. Semin Oncol 2003;30, 117-24TumorStudyComparisonBev DoseDFSOSBreast 2nd lineMiller et al4zCapecitabine vs Cape + Bev15 mg/kg Q3W=Breast 1st lineE21005Paclitaxel vs Pac + Bev1

20、0 mg/kg D1, 15?Breast 1st lineAVADODocetaxel vs Doce + Bev7.5-15 mg/kg Q3w? Breast 1st line RIBBON-1CT+Bev vs CT + Place15 mg/kg Q3W= Breast 2st line RIBBON-2CT+Bev vs CT + Place15 mg/kg Q3WNANA1 2. Kabbinavar F, et al. J Clin Oncol. 2003;21:60-65. 3. Giantonio B, et al. ASCO 2005. Abstract 2. 4. Mi

21、ller KD, et al. J Clin Oncol. 2005;23:792-799. 5. Miller KD. SABCS 2005. Abstract 3. 6. Sandler AB, et al. ASCO 2005. Abstract LBA4. 7. Kindler HL, et al. ASCO GI 2007. Abstract 108. 8. Available at: .Bevacizumab Phase III Trials MBCCapecitabine vs. Capecitabine + Beva 治療晚期乳腺癌Adverse Event, %Capetab

22、ine(230)Avast+Cape(232)P valueORR研究者19.130.20.006獨立評估委員會9.119.20.001中位PFS, 月4.24.9NS中位生存14.515.1NS KD Miller. J Clin Oncol, 2005Capecitabine vs. Capecitabine + Beva 不良反應(yīng)不良事件 Capetabine(215)Avast+Cape(229)高血壓0.517.9蛋白尿00.9血栓3.75.6手足綜合癥24.227.5出血0.50.419.2CHF/心肌病13惡心1.92.6 KD Miller. J Clin Oncol, 200

23、5No grade 4Best response (%)Phase III trial of bevacizumab plus paclitaxelin first-line mBC (E2100): 有效率All patientsPatients withmeasurable disease49.2%25.2%21.2%36.9%PaclitaxelBevacizumab + paclitaxelCR + PRp0.001CR + PRp0.001CR = complete responsePR = partial responseMiller, et al. NEJM 2007605040

24、302010011.4061218243036PFS estimateHR=0.48Paclitaxel (n=354)Bevacizumab + paclitaxel (n=368)PFS by investigator 5.811.3HR=0.42PFS by IRF*5.8Months1.00.80.60.40.20*Scans available for 90% of patients Phase III trial of bevacizumab plus paclitaxel in first-line mBC (E2100): PFSAdapted from Cameron. EJ

25、C Suppl. 2008 withpermission from Elsevier; Avastin SmPC 2008AVADO: response (patients with measurable disease), %Placebo+ docetaxel(n=207)Bev 7.5 + docetaxel (n=201)Bev 15 + docetaxel (n=206)Overall response rate p value (vs control)44550.0295630.0001Best responseCRPRSD PD 1443912 35235 5 16225 4mg

26、/kg q3wMiles, et al. ASCO 2008 (Abstract LBA1011)Bev 15 +docetaxel (n=247)HR + 95% CI (unstratified)Bev 7.5 +docetaxel (n=248)1.00.80.60.40.20MonthsPFS estimate061218MonthsPFS estimate1.00.80.60.40.20061218AVADO: progression-free survival(ITT population)*Data censored for non-protocol therapy before

27、 PD; mg/kg q3wHR + 95% CI (stratified*)0.69 (0.540.89)p=0.00350.79 (0.630.98)p=0.0318Placebo +docetaxel (n=241)Median8.78.0HR + 95% CI (stratified*)0.61 (0.480.78)p0.0001Median8.88.00.72 (0.570.90)p=0.0099HR + 95% CI (unstratified)Placebo +docetaxel (n=241)Miles, et al. ASCO 2008 (Abstract LBA1011)4

28、3RIBBON-1: Study DesignPreviously untreated MBC (n=1237)Stratification factors: Disease-free interval Previous adjuvant chemotherapy Number of metastatic sites Cape., T or Anthra.Capecitabineor TaxaneorAnthracyclineChemo +Bevacizumabq3wChemo +placeboq3wTreatuntilPDOptional2nd-line chemo+ bevacizumab

29、21CHOICE OF CHEMORobert et al. ASCO 2009. Abstract 1005.Primary endpoint: PFS as assessed by investigatorSecondary endpoints: Overall Survival (OS) & 1-year OS rate Objective response rate (ORR); PFS by independent review committee (IRC); SafetyCapecitabine (1000 mg/m2 BID x 14d)Taxane (docetaxel or

30、 protein- bound paclitaxel)Anthracycline-based chemotherapy (AC, EC, FAC, FEC)Placebo or bevacizumab (15 mg/kg)4444RIBBON-1: Patient CharacteristicsCapecitabineTaxane/AnthracyclinePL (n=206)BV (n=409)PL (n=207)BV (n=415)Median age, years ECOG PS 05753565355535553HR positive Triple negative7425772277

31、237624Disease-free 3 metastatic sitesMeasurable diagnosis4579438045864583All data as %, unless otherwise noted.Robert et al. ASCO 2009. Abstract 1005.45RIBBON-1: Objective Response RatePLBVPLBV23.635.437.951.3Capecitabinep=0.0097Taxane/Anthracyclinep=0.0054%Measurable*Disease, %79808683*Includes onl

32、y patients with measurable disease at baselineCRPRRobert et al. ASCO 2009. Abstract 1005.45th Asco 200946RIBBON-1: Exploratory Secondary Endpoint:PFS by Chemotherapy SubgroupsTaxaneAnthracyclinePL (n=104)BV (n=203)PL (n=103)BV (n=212)mPFS, mo8.29.27.99.2HR (95% CI)P-value0.75 (0.56-1.01)0.05470.55 (

33、0.40-0.74)3 AEsCapecitabineTaxaneAnthracyclinePL (n=201)BV (n=404)PL (n=102)BV (n=203)PL (n=100)BV (n=210)Bleeding eventsFebrile neutropeniaGI perforationHypertensionLV systolic dysfunctionNeutropeniaProteinuriaSensory neuropathyVTE0.5001.00.51.000.53.50.2009.41.01.22.23.04.802.01.02.004.908.84.95.4

34、8.42.58.92.09.43.48.42.000.50004.0001.003.8010.02.94.31.90.52.9VTE=Venous ThromboEmbolismRobert et al. ASCO 2009. Abstract 1005.49RIBBON-1: Authors Summary For the pre-specified capecitabine and taxane/anthracycline cohorts, the addition of bevacizumab led to a statistically significant improvement

35、in:PFS (by investigator)PFS (by IRC)ORR No difference was noted in OSSafety:Incidence of bevacizumab-related adverse events consistent with prior studiesNo new bevacizumab-related safety signals in each of the chemotherapy groupsRobert et al. ASCO 2009. Abstract 1005.貝伐單抗臨床研究方向 (III期臨床試驗)轉(zhuǎn)移性乳腺癌: 一線R

36、IBBON1: 化療+/-貝伐單抗, (1239例)AVEREL: Docetaxel+Herceptin+/- 貝伐單抗 (462例)輔助治療:BEATRICE(三陰): 輔化+/-貝伐單抗, (2530例)BETH（NSABP B-44）: HER2+: 輔化/Herceptin+/-貝伐單抗 (5400例)E5103:AC-T+/-B,BEVA 短程.長程NSABP B-46 1 TAC/TC/ TC+B新輔助化療:NSABP B40: AC/TX/DG+貝伐單抗(1200例)研究中的抗血管生成新靶點治療藥物抗VEGF 貝伐單抗VEGF Trap（可溶性受體,已經(jīng)進入3期臨床）小分子配體

37、阻斷劑TKISutent單藥臨床獲益16%，與Taxan聯(lián)合進行中。 阿那曲唑+/-Sorafenib（ER+ 和/或PR+MBC）AxitinibPazopanib 選擇性更強的VEGF抑制劑?？筕EGFRAxitinib治療晚期乳腺癌Axitinib+Docetaxel vs Docetaxel N=168例M-TTP: 8.2m vs 7.0mORR: 40% vs 23%AE(G3/4):ADDFN (16%/7%)Stomatitis(13%/2%)Diarrhea(11%/0%)Hypertension(5%/2%)受體酪氨酸激酶抑制劑Sunitinib Phase III Tri

38、al MBCSUN 1064 Doce+/-Sunitinib in her2- MBC(一線)SUN 1094 Pacli+beva vs Pacli+Sunitinib LA/MBCSUN 1099 Xelo+/-Sunitinib in her2+ MBC(hercep or lapa treated)EBC HER2陰性乳腺癌新輔助化療后：SUN vs PLACEBO 1年其他新型分子靶向治療以及研究 PARP1 Olaparib AZD2281口服PARP 1 抑制劑 I期 Inhibitor BSI-201 NF-kB受體活化因子的配體（RANKL）抑制劑Denosumab抑制RANKL的活性，減少骨吸收。Addition of PARP1 Inhibitor BSI-201 to Gemcitabine/Carboplatin Improves Outcomes in Metastatic TNBCRandomized, multicenter, open-label phase II trial Poly (ADP-ribose) polymerase-1 (P