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(xué)過(guò)程,其間涉及許多細(xì)胞和分子學(xué)機(jī)制.對(duì)惡性腫瘤的細(xì)胞和分子生物學(xué)機(jī)制的研究，推動(dòng)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(mén)類，已經(jīng)并進(jìn)一步對(duì)腫瘤治療產(chǎn)生日益重要的影響。惡性腫瘤發(fā)生的細(xì)胞和分子學(xué)機(jī)制自我生長(zhǎng)促進(jìn)對(duì)生長(zhǎng)抑制信號(hào)敏感性下降逃避凋亡和死亡侵襲和轉(zhuǎn)移腫瘤血管生長(zhǎng)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(yáng)性乳腺癌Her2/neu是4個(gè)表皮生長(zhǎng)因子受體家族成員之一，與細(xì)胞的生長(zhǎng)，分化

2、生存重要相關(guān)。Her2蛋白的過(guò)渡表達(dá)或基因擴(kuò)增的乳腺癌約占1/4,是腫瘤惡性程度高，預(yù)后差 的標(biāo)志。Trastuzumab(Herceptin,赫賽汀)是人源化單克隆抗體，針對(duì)Her2受體細(xì)胞外功能簇。單藥或者與化療聯(lián)合應(yīng)用，治療Her2陽(yáng)性MBC改善療效。1998年FDA批準(zhǔn)治療Her2陽(yáng)性MBC，與紫杉類聯(lián)合成為標(biāo)準(zhǔn)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(zhǔn)。NCCN 和 St.gallen 2007 HER2成為風(fēng)險(xiǎn)分級(jí)和治療分組的指標(biāo)。曲妥珠單抗治療HER2陽(yáng)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(yáng)性乳腺癌EBCAdjuvant:HERANSABP B-31NCCTG N9831BCIRG 006PACS 04Neo Adjuvant:NOAHMDACCGeparQuattro曲妥珠單抗 in EBC Trial 無(wú)病生存期 (ITT分析): 4-年中位隨訪時(shí)間1008060402000612182430483642隨機(jī)分組后月1698170315641619144015521363148512971414124013527

4、12854118012809921020No. at risk事件數(shù)4583694-年DFS72.278.6風(fēng)險(xiǎn)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(xué)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(xué)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(zhǔn)上市與卡培他濱聯(lián)合，用于既往曾接受過(guò)蒽環(huán)類、紫杉醇類和曲妥珠單抗治療的ErbB2過(guò)表達(dá)的轉(zhuǎn)移性乳腺癌AktLapatinib 作用機(jī)制RasRafMAPKPSosShcGrb2ATPAktMAPKPI3KLapatinib增

9、生通路生存通路通過(guò)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(duì)突變的ErbB-1 和頂端缺失的 ErbB-2有活性配體的濃度不會(huì)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(wú)活性配體的飽和會(huì)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(jī)、III期研究進(jìn)展、HER2+轉(zhuǎn)移性乳腺癌或LABC 曾接受過(guò)蒽環(huán)類、紫杉類和曲妥珠單抗治療*未接受過(guò)卡培他濱治療患者接受治療直至疾病進(jìn)展或出現(xiàn)不可耐受的毒性并進(jìn)行生存期隨訪N=528 隨機(jī)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(fù)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(guò)表達(dá)？治療主要終點(diǎn)EGF20002II期N=78含曲妥珠單抗治療后進(jìn)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(jìn)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(jìn)

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(gè)以上療程治療后疾病進(jìn)展是Lapatinib +/-曲妥珠單抗TTP, RRHER2陽(yáng)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(jìn)展，并且已經(jīng)用過(guò)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(dá)到PR,1例聯(lián)合Ca

14、pecitabin又達(dá)到PR.20例單藥Lapa達(dá)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(jī)對(duì)照試驗(yàn)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(jì)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(zhǔn)的用藥列表中選擇)LVEF 50%Max 6 w當(dāng)?shù)貙?shí)驗(yàn)室確定的 HER2陽(yáng)性浸潤(rùn)性乳腺癌中心實(shí)驗(yàn)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(gè)臨床試驗(yàn)中1126名使用lapatinib的患者： 50%出現(xiàn)腹瀉 分級(jí)54%為1級(jí) (輕度)30%為2級(jí) (中度)15%為3級(jí) (重度)1%為4級(jí) (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(kāi)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(gè)臨床試驗(yàn)中1126名使用lapatinib的患者，46%報(bào)告有皮疹(所有級(jí)別)*重度皮疹罕見(jiàn); 4%的患者出現(xiàn)3級(jí)皮疹，沒(méi)有4級(jí)皮疹的報(bào)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(wú)需干預(yù)、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(qiáng)。61例三線治療的安全性報(bào)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(duì)心臟功能影響很小，2例33例可評(píng)價(jià)療效，ORR 18.2%, CB 39.4%，進(jìn)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(pán)生長(zhǎng)因子PIGFVEGF-AVEGF-BVEGF-CVEGF-DBevacizumab (重組人抗VEGF單克隆抗體 )貝伐單抗:針對(duì)VEGF的人源化單克隆抗體 (93% human, 7% murine),能夠識(shí)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(diǎn)貝伐單抗治療晚期乳腺癌I/II期臨床研究75例化療過(guò)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(shí)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(dú)立評(píng)估委員會(huì)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(yàn))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(zhǎng)程N(yùn)SABP 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(diǎn)治療藥物抗VEGF 貝伐單抗VEGF Trap（可溶性受體,已經(jīng)進(jìn)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(jìn)行中。 阿那曲唑+/-Sorafenib（ER+ 和/或PR+MBC）AxitinibPazopanib 選擇性更強(qiáng)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