乳腺癌分子靶向药物治疗进展课件

1、 乳腺癌分子靶向药物治疗进展 张清媛哈尔滨医科大学附属肿瘤医院ChemotherapyEndocrine therapyTargeted therapiesTreatmentofBCHIGHLIGHTS IN BREAST CANCER DISEASE BIOLOGY针对HER2受体的靶向药物针对表皮生长因子受体(EGFR)的靶向治疗针对肿瘤血管生成的分子靶向药物其他信号通路抑制剂mTOR，Ras， MEK等乳腺癌分子靶向药物治疗中位生存期的缩短HER2 扩增/过度表达3 年HER2 正常表达6 - 7 年HER2 受体过度表达HER2 原癌基因扩增HER2在约20% 30%的乳腺癌组织中过度

2、表达Slamon DJ et al. Science 1987;235:17782HER2阳性与内分泌治疗及部分化疗耐药密切相关，是重要的预后指标HER2成为乳腺癌治疗的理想靶点，是预测赫赛汀疗效的重要指标赫赛汀(曲妥珠单抗): 人源化抗HER2单克隆抗体高度亲和性 (Kd=0.1nM) 和特异性95% 人源化, 5% 鼠抗，显著降低免疫原性(HAMA)全球第一种治疗实体瘤的单克隆抗体Inhibition of HER2-mediated signallingActivation of ADCC赫赛汀的作用机制Additional mechanismsPrevents formation of

3、 truncated HER2 (p95)Inhibition of HER2-regulated angiogenesisADCC, antibody-dependent cellular cytotoxicity赫赛汀已成为HER2阳性乳腺癌的基础治疗1st lineHO648gM77001 US OncologyBCIRG 007CHATTAnDEMRHEARelapse2nd+ linesGBG-26BO17929EGF104900Numerous Phase II studiesMBCProgressionHERANSABP B-31NCCTG N9831BCIRG 006Adjuv

4、antNOAHMDACCGeparQuattroNumerous Phase II studiesNeoEBCHER2, human epidermal growth factor receptor 2 EBC, early breast cancer; MBC, metastatic breast cancer13,000 患者入组的赫赛汀四大辅助临床研究Piccart-Gebhart et al 2019 Romond et al 2019; Slamon et al 2019NCCTG N9831 (USA)HERA (ex-USA)BCIRG 006 (global)NSABP B-3

5、1 (USA)IHC / FISH (n=5,090)Observation1 year2 yearsIHC / FISH (n=3,505)1 year1 yearFISH(n=3,222)1 year1 yearIHC / FISH (n=2,030)1 yearDocetaxelDocetaxel + carboplatinDoxorubicin + cyclophosphamideHerceptinStandard CTxPaclitaxelIHC, immunohistochemistry FISH, fluorescence in situ hybridisation CTx, c

6、hemotherapy赫赛汀可减少三分之一的死亡风险012B-31 / N9831 ACPH 3HERA CTxH 1 year2Median follow-up, yearsOverall survival benefitBCIRG 006 ACDH3BCIRG 006 DCarboH3FavoursHerceptinFavours noHerceptinHRSlamon et al 2019 Perez et al 2019; Smith et al 2019H, Herceptin; AC, doxorubicin, cyclophosphamide P, paclitaxel; D,

7、docetaxel; Carbo, carboplatin HR, hazard ratioSize of square represents sample size; horizontal bars indicate 95% confidence intervals无论肿瘤大小，赫赛汀均显示DFS获益Slamon et al 2019 Perez et al 2019; Smith et al 20192-5 cmBCIRG 0062-5 cm5 cm0.01.52.00-2 cmN9831 / B-310-2 cm5 cmACDH2 cmDCarboH10+ nodesD

8、CarboHN-N+N+BCIRG 006N-ACDHN-HERAHRSlamon et al 2019 Perez et al 2019; Smith et al 2019无论年龄大小，赫赛汀均显示DFS获益35-49 years0.01.52.0HERA35 years50-59 years60 yearsN9831 / B-3140 years60 years40-49 years50-59 yearsFavours HerceptinFavours no HerceptinHRPerez et al 2019; Smith et al 2019赫赛汀的新辅助治疗研究进

9、展1st lineHO648gM77001 US OncologyBCIRG 007CHATTAnDEMRHEARelapse2nd+ linesGBG-26BO17929EGF104900Numerous Phase II studiesMBCProgressionHERANSABP B-31NCCTG N9831BCIRG 006AdjuvantNOAHMDACCGeparQuattroNumerous Phase II studiesNeoEBCNOAH study: neoadjuvant Herceptin for LABCaHormone receptor-positive pat

10、ients receive adjuvant tamoxifen AP, doxorubicin 60 mg/m2, paclitaxel 150 mg/m2; H, Herceptin 8 mg/kg loading then 6 mg/kg P, paclitaxel 175 mg/m2; CMF, cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, 5-fluorouracil 600 mg/m2 LABC, locally advanced breast cancer; q3w, every 3 weeks; q4w, every 4

11、weeksHER2-positive LABC(IHC 3+ and/or FISH+)n=113H + APq3w x 3H + Pq3w x 4H q3w x 4 + CMF q4w x 3Surgery followed byradiotherapyaH continued q3wto Week 52n=115Pq3w x 4CMFq4w x 3Surgery followed byradiotherapyaAPq3w x 3APq3w x 3Pq3w x 4CMFq4w x 3Surgery followed byradiotherapyan=99HER2-negative LABC(

12、IHC 0/1+)p=0.002p=0.004pCR (%)Baselga et al 2019; Gianni et al 2019HER2 positive (n=228)HER2 positive(n=62)NOAH研究中赫赛汀新辅助显著提高了pCR率Without HerceptinWith Herceptin9080706050403020100HER2 negative (n=99)HER2 negative(n=14)234317195529Total populationIBC populationpCR, pathological complete response in t

13、he breastIBC, inflammatory breast cancer新辅助化疗中加入赫赛汀明显提高疗效(16个相关研究, 1,226例患者入组)aX was given either concurrently or sequentially with D + HEC, epirubicin, cyclophosphamide; FEC, 5-fluorouracil, epirubicin, cyclophosphamide My, Myocet; X, Xeloda0102030405060708090100pCR (%)Antn et al 2019, n=26My + P +

14、 HaUntch et al 2019, n=452EC + H D + H X HCoudert et al 2019, n=70D + HMarty et al 2019, n=30EC D + HLimentani et al 2019, n=31D + V + H (including IBC)Bines et al 2019, n=32D + HBurstein et al 2019, n=40P + H (including IBC)Kelly et al 2019, n=37AC P + H (including IBC)Harris et al 2019, n=40V + H

15、(including IBC)Hurley et al 2019, n=48D + cisplatin + H (including IBC)Tripathy et al 2019, n=28P + X + HLybaert et al 2019, n=25X + D + HBuzdar et al 2019, n=45P FEC + HPernas et al 2019, n=33P FEC + HGianni et al 2019, n=115AP P CMF + H (including IBC)Untch et al 2019, n=174EC P + H赫赛汀已成为HER2阳性乳腺癌

16、的基础治疗1st lineHO648gM77001 US OncologyBCIRG 007CHATTAnDEMRHEARelapse2nd+ linesGBG-26BO17929EGF104900Numerous Phase II studiesMBCProgressionHER2, human epidermal growth factor receptor 2 EBC, early breast cancer; MBC, metastatic breast cancer EBCHERANSABP B-31NCCTG N9831BCIRG 006AdjuvantNOAHMDACCGepar

17、QuattroNumerous Phase II studiesNeo一线赫赛汀治疗显著延长患者的生存时间Median survival (months)IHC, immunohistochemistry; P, paclitaxel H, Herceptin; D, docetaxel; Carbo, carboplatinH0648g(IHC 3+)M77001BCIRG 007US Oncology(IHC 3+)Smith et al 2019; Marty et al 2019 Robert et al 2019; Pegram et al 2019TAnDEM-赫赛汀联合阿那曲唑治

18、疗HER-2 ( + ）激素敏感性转移性乳腺癌临床研究结果（2019年圣安东尼奥）H+AIAIORR20.3%6.8%CBR42.7%27.9%PFS4.8 月2.4月TTP4.8 月2.4月OS28.5月23.9月 2019年3月欧洲推荐赫赛汀联合芳香化酶抑制剂治疗HER2与激素受体阳性转移性乳癌疾病进展后如何合理选择赫赛汀个体化治疗方案1st lineHO648gM77001 US OncologyBCIRG 007CHATTAnDEMRHEARelapse2nd+ linesGBG-26BO17929EGF104900Numerous Phase II studiesMBCProgres

19、sionEBCHERANSABP B-31NCCTG N9831BCIRG 006AdjuvantNOAHMDACCGeparQuattroNumerous Phase II studiesNeoHerceptin improves OS if continued beyond progressionOS (months)Continued HerceptinDiscontinued HerceptinExtra et al 2019Jackisch et al 2019; Menard et al 2019p0.0001p50 (5.1%-5.4%)Use of hypertensive m

20、edications (6.8%)Baseline LVEF 50-54 (12.9%)Rastogi et al. Abstract LBA513 ASCO 2019考虑到心脏不良反应事件，临床上不建议Trastuzumab与蒽环类药物联合。Trastuzumab可以在AC方案后与紫杉醇联合使用或者在化疗完成后序贯使用。目前Trastuzumab治疗疗程为1年，建议每三个月一次进行心功检查。心功能监测LVEF低于50%恢复至50%以上不恢复、或继续恶化终止Herceptin治疗继续用药暂停Herceptin治疗，观察或对症处理 赫赛汀临床应用2019年NCCN复发或IV期乳腺癌指南HR阴性，

21、HER2阳性具有内脏危象复发或IV期乳腺癌曲妥珠单抗化疗赫赛汀联合辅助化疗方案AC THAC DHTCH化疗HDH FEC用法： 每周方案 首剂4mg/kg，维持2mg/kg 三周方案 首剂8mg/kg，维持6mg/kg帕妥珠单抗Pertuzumab(2C4): anti HER2 agent 以HER-2为靶位的人源化单克隆抗体与HER-2 受体胞外结构域区结合，抑制二聚体的形成抑制HER2 与 EGFR 和 HER3形成二聚体。 Herceptin + pertuzumab provides clinical benefit to patients progressing on Herce

22、ptinGelmon et al 2019ResponseCRPRORRSD for 6 months ( Cycle 8)CBRPDMedian PFSn (%)n=665 (7.6)11 (16.7) 16 (24.2) 17 (25.8)33 (50.0)33 (50.0)24 weeksHerceptin + pertuzumab is a well-tolerated combinationPatients (%)Adverse events, all gradesAdverse events, grades 3/4Gelmon et al 2019针对HER2受体的靶向药物针对表皮

23、生长因子受体(EGFR)的靶向治疗针对肿瘤血管生成的分子靶向药物其他信号通路抑制剂mTOR，Ras， MEK等针对EGFR的靶向治疗小分子酪氨酸激酶抑制剂 (SMTKIs)EGFR单克隆抗体(MAbs)多靶点抗肿瘤抑制剂酪氨酸激酶抑制剂拉帕替尼（Lapatinib，Tykerb） 吉非替尼（ZD1839，Iressa，Gefitinib，易瑞沙） 埃罗替尼（Tarceva，erlotinib）Lapatinib (Tykerb)口服的TKI双重抑制剂:EGFR 和HER-2 Geyer CE, et al. ASCO 2019. Clinical Science Symposium.EGF10

24、0151: Lapatinib + Capecitabine in Advanced Breast CancerRefractory, progressive metastatic or locally advanced HER2+ breast cancer previously treated with anthracycline, taxane, or trastuzumab(N = 528 planned*)Lapatinib 1250 mg daily +Capecitabine 2000 mg/m2 dailyfor Days 1-14, 3-week cycles(n = 160

25、)Capecitabine 2500 mg/m2 dailyfor Days 1-14, 3-week cycles(n = 161)Follow-up:until progressionor unacceptabletoxicity*Study enrollment terminated early by IDMC due to superiority of combination arm in primary endpoint.EGF100151: Lapatinib + Capecitabine in Advanced Breast Cancer (contd)Longer time t

26、o progression36.9 vs 19.7 wks (P = .00016)Longer progression-free survival36.9 vs 17.9 wks (P = .000045)Fewer progressions or deaths38% vs 48%Response (independent review)Overall: 22.5% vs 14.3% (P = .113)Geyer CE, et al. ASCO 2019. Clinical Science Symposium.Progression-Free Survival (%)Time (Wks)2

27、040608001001020304050CapecitabineLapatinib + capecitabineITT population 2019.3 FDA批准 拉帕替尼联合卡培他滨治疗HER2过度表达且经蒽环类、紫杉类药物和曲妥珠单抗治疗后复发的晚期或者转移性乳腺癌 39 patients (38 patients progression after radiothrapy) New/progressive measurable ( 1 cm) brain metastasesTreatment: Lapatinib 750 mg po BIDResult2 patients PR

28、158d and 347d5 patients SD 16 weeks Median TTP 3.2 months MST 6.57 months1 patient had response, but did not meet RECISTLapatinib成为Trastuzumab耐药或脑转移患者新选择 Lapatinib for Brain Metastases in Her2+ Cancer Lin et al. ASCO 2019; NCI-CTEP 6969 trialLapatinib+Trastuzumab for Trastuzumab progressing on Her2+

29、 Cancer ASCO 2019Progression-Free SurvivalOverall Survival in ITT Population0200DaysGefitinib-表皮生长因子受体酪氨酸激酶抑制剂1306090120150400600800100012001400Tumour volume(mm3)Massarweh et al. Breast Cancer Res Treat 2019FulvestrantFulvestrant + gefitinibOestradiolFulvestrant plus gefitinib delays resistance in M

30、CF-7 / HER2 tumours in vivo Phase II Trial of Gefitinib in Advanced Breast Cancer Partial responseStable diseaseClinical benefitProgressive disease15 6 (66%)3ER-positive(n=9)ER-negative (n=18)11 2 (11%)16Robertson et al. ASCO Proc. 2019Acquired resistance to TAM (n=27) or ER-negative tumours (n=27)

31、Gefitinib LD 1000 mg (D1) Daily dose 500 mg/day until disease progression or unacceptable toxicityErlotinib-小分子EGFR 酪氨酸激酶抑制剂 previous therapy with either an anthracycline or a taxane for MBC Erlotinib （150 mg orally daily ） +gemcitabine （ 1000 mg/m2 ,Days 1、8, 3-week cycles ）A partial response (PR)

32、rate of 17% has been reported (ASCO 2019) N0234 ：Erlotinib + GemcitabineN0234 ：Erlotinib + GemcitabineResultTNNON-TN PPR25%14%0.30CBR25%22%0.75PFS72d98d0.13OS227d738d0.0002TN*=ER ( - ) /PR( - ) /HER-2 ( - )三阴 ASCO 2019西妥昔单抗(Cetuximab， erbitux， C225，爱必妥)Cetuximab是针对HER-1的特异性单克隆抗体动物试验显示，Cetuximab可有效抑制

33、乳腺癌细胞增殖和生长，现有不少研究机构开始应用Cetuximab单药或与化疗药物联合治疗EGFR 阳性乳腺癌。泰欣生是一个针对EGFR的单抗药物，通过与EGFR胞外区3A表位结合，竞争性抑制配体与EGFR的结合，使受体失去活性：IgG1型单克隆抗体，分子量为150KD95人源化激发ADCC和CDC效应抑制肿瘤细胞比内源性配体亲合力更高（Kd=10-9）泰欣生（尼妥珠单抗, Nimotuzumab） 古巴：泰欣生联合新辅助化疗治疗乳腺癌研究终点评估尼妥珠单抗联合化疗药物治疗局部晚期乳腺癌患者新辅助化疗的安全性、药代动力学及疗效。期初治乳腺癌患者泰欣生（50/100/200/400mg，qw）阿霉

34、素（60mg/m2 ，q3w ）环磷酰胺（600mg/m2 ，q3w ）J.Soriano, N.Batista, et al. European Journal of Cancer Supplements, Vol 5 No 4, Page 116 1 7 8 15 22 28 29 36 43 49 50 57 64 70RANDOMIZATIONSURGERYNimotuzumab AC用药方案J.Soriano, N.Batista, et al. European Journal of Cancer Supplements, Vol 5 No 4, Page 116疾病控制情况疾病控

35、制情况共有13例患者入组，12例患者可评估：9例PR，3例SD。PatientsDoseAgeRaceTNMStageDiagnoseNGERHER-2015045WT4bN0M0IIIBIDC3NegNeg025040WT3N1M0IIIAILC3Neg3 +035044WT3N1M0IIIAIDC3Pos2 +0510059BT4bN1M0IIIBIDC3NegNeg0610063BT4bN1M0IIIBIDC2NegNeg1310046BT3N1M0IIIAIDC1PosNeg0720064WT4bN1M0IIIBIDC3NegNeg0820042WT3N1M0IIIAIDC3PosNe

36、g0920042WT4aN1M0IIIBIDC3Neg3 +1040058WT4bN0M0IIIBIDC2PosNeg1140059BT4bN1M0IIIBIDC3Neg3 +1240034WT3N1M0IIIAIDC1PosNegJ.Soriano, N.Batista, et al. European Journal of Cancer Supplements, Vol 5 No 4, Page 116安全性：在50、100、200和400mg中，未见剂量限制性毒性临床未见心脏毒性；联合治疗安全性高，患者耐受性良好常见不良反应为：皮疹、皮肤反应、恶心、呕吐；红斑,丘疹及色素沉着较常见，通常

37、发生在面部及上肢上部，能自行缓解初步结论： 泰欣生治疗乳腺癌有效，联合治疗在50，100，200和400mg 剂量下是安全的，有很好的耐受性 结 论J.Soriano, N.Batista, et al. European Journal of Cancer Supplements, Vol 5 No 4, Page 116苏尼替尼（Sunitinib）-小分子多靶点酪氨酸激酶抑制剂 NHONHH3CCH3NHONCH3CH3Selective inhibitor of: PDGFR VEGFR2 (KDR) KIT FLT32019年1 月美国FDA 批准上市, 用于治疗晚期肾细胞癌和胃肠道

38、间质瘤。 Sunitinib in Breast Cancer Patients multicentric phase II study with 64 patients*One PR not yet confirmed.N=64Partial Response*7 (11%)Stable Disease 6 months3 (5%)Overall Clinical Benefit10 (16%)patients had received 3.5 different chemotherapies（anthracycline or taxane）85% of patients had recei

39、ved adjuvant chemotherapysunitinib 50 mg/d 多激酶抑制剂：丝氨酸/苏氨酸：C-Raf (Raf-1)和B-Raf1酪氨酸激酶受体：VEGFR-2、 VEGFR-3、 PDGFR-b、 FLT-3和 c-KIT Wilhelm S et al. Clin Cancer Res. 2019;64:7099-7109.索拉非尼( sorafenib)：口服信号转导抑制剂,在Raf激酶水平和受体酪氨酸激酶VEGFR-2和PDGFR-阻断Raf/MEK/ERK途径,抗肿瘤血管生成及肿瘤细胞增殖Sofitinib phase II in MBC针对HER2受体的靶

40、向药物针对表皮生长因子受体(EGFR)的靶向治疗针对肿瘤血管生成的分子靶向药物其他信号通路抑制剂mTOR，Ras， MEK等Angiogenesis is involved throughout tumour formation, growth and metastasisAdapted from Poon RT, et al. J Clin Oncol 2019;19:120725Stages at which angiogenesis plays a role in tumour progressionPremalignantstageMalignanttumourTumourgrowth

41、VascularinvasionDormantmicrometastasisOvertmetastasis(Avasculartumour)(Angiogenicswitch)(Vascularisedtumour)(Tumour cellintravasation)(Seeding indistant organs)(Secondaryangiogenesis)血管生成的双向调节机制ActivatorInhibitorAngiostatinEndostatinThrombospondin-1VEGFbFGFPDGFBevacizumab (Monoclonal Antibody to VEGF)Humanized to avoid immunogenicity (93% human, 7% murine)Recognizes all isoforms of vascular endothelial growth factor, Kd=8 x 10-10MTerminal half life 17-21 days715 cases Stratify: DFI 24 os. 3 metastatic sites Adjuvant chemotherapy yes vs. no ER+ vs. ER- vs. ER unknownage