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1、2015ASCO乳腺癌内分泌治疗进展6 6月月1 1日日9 9个个口头大会报告口头大会报告LBA500LBA500：NSABP B-35NSABP B-35关于绝经后关于绝经后DCISDCIS采取采取“肿块切除肿块切除+放疗放疗”常规治疗基础上，内分泌治常规治疗基础上，内分泌治疗选择疗选择TAMTAM和阿那曲唑何者更优？和阿那曲唑何者更优？A501A501：CALGB40503CALGB40503关于绝经后激素受体阳性乳腺癌一线选择来曲唑单药或联合贝伐单抗的关于绝经后激素受体阳性乳腺癌一线选择来曲唑单药或联合贝伐单抗的期临床研究；期临床研究；LBA502LBA502：PALOMA3PALOMA
2、3是最为关注的是最为关注的期临床研究，对于激素受体阳性晚期乳腺癌内分泌解救选期临床研究，对于激素受体阳性晚期乳腺癌内分泌解救选择氟维司群择氟维司群500mg500mg基础加或不加基础加或不加CDK4/6CDK4/6抑制剂抑制剂palbociclibpalbociclib的的期临床研究；期临床研究；A503-504A503-504：早期乳腺癌辅助双膦酸盐或地诺单抗（早期乳腺癌辅助双膦酸盐或地诺单抗（denosumabdenosumab）治疗）治疗期临床研究期临床研究(S0307(S0307和和ABCSG-18);ABCSG-18);A505A505：Her-2Her-2阳性乳腺癌阳性乳腺癌“多西
3、他赛和多西他赛和/或曲妥珠单抗和或曲妥珠单抗和/或或pertuzumabpertuzumab”新辅助治疗新辅助治疗期临期临床研究床研究(NeoSphere)5(NeoSphere)5年随访结果；年随访结果；A506A506：ER+/PR+/HER-2+ER+/PR+/HER-2+早期乳腺癌新辅助治疗早期乳腺癌新辅助治疗T-DM1T-DM1基础上加或不加内分泌治疗基础上加或不加内分泌治疗期临期临床研究；床研究；A507A507：Her-2Her-2阳性乳腺癌一线选择阳性乳腺癌一线选择T-DM1T-DM1 pertuzumabpertuzumab对曲妥珠单抗紫杉类随机对曲妥珠单抗紫杉类随机期临床期
4、临床研究研究(MARIANNE(MARIANNE研究研究););A508A508：Her-2Her-2阳性早期乳腺癌曲妥珠单抗辅助治疗基础上序贯阳性早期乳腺癌曲妥珠单抗辅助治疗基础上序贯NeratinibNeratinib安慰剂对照、随机安慰剂对照、随机期临床研究（期临床研究（NxteNETNxteNET）HER-2/ER专场专场Slide 38Presented By Eric Winer at 2015 ASCO Annual Meeting分层分析Slide 39Presented By Eric Winer at 2015 ASCO Annual Meeting次要研究终点：OSSer
5、ious ComplicationsPresented By Eric Winer at 2015 ASCO Annual MeetingNSABP B-35 SummaryPresented By Eric Winer at 2015 ASCO Annual Meeting内容内容 LBA500LBA500：NSABP B-35NSABP B-35关于绝经后关于绝经后DCISDCIS采取采取“肿块切除肿块切除+放疗放疗”常规治疗基础上，内分泌治疗选择常规治疗基础上，内分泌治疗选择TAMTAM和阿那曲唑何者更优？和阿那曲唑何者更优？1 A501A501：CALGB40503CALGB40503
6、关于绝经后激素受体阳性乳腺癌一关于绝经后激素受体阳性乳腺癌一线选择来曲唑单药或联合贝伐单抗的线选择来曲唑单药或联合贝伐单抗的期临床研究；期临床研究；234LBA502LBA502：PALOMA3PALOMA3是对于激素受体阳性晚期乳腺癌内分是对于激素受体阳性晚期乳腺癌内分泌解救选择氟维司群泌解救选择氟维司群500mg500mg基础加或不加基础加或不加CDK4/6CDK4/6抑制剂抑制剂palbociclibpalbociclib的的期临床研究；期临床研究；A503-504A503-504：早期乳腺癌辅助双膦酸盐或地诺单抗早期乳腺癌辅助双膦酸盐或地诺单抗（denosumabdenosumab）治
7、疗）治疗期临床研究期临床研究(S0307(S0307和和ABCSG-ABCSG-18);18);CALGB 40503(Alliance)/CTSU 40503/NCT00601900Phase III Trial Evaluating the Addition of Bevacizumab to Letrozole As First-line Endocrine Therapy for Treatment of Hormone-receptor Positive(HR+)Advanced Breast CancerPresented By Maura Dickler at 2015 ASCO
8、 Annual MeetingBevacizumab plus chemotherapy as first-line therapy in HER2-negative metastatic breast cancerPresented By Joseph Sparano at 2015 ASCO Annual Meeting研究设计分层：1.可测量病灶（有/无）2.无病间隔（24月/24月）主要研究终点：PFS次要研究终点：OS，ORR，CBR，治疗相关毒性事件随机，开放，多中心，III期临床评估晚期一线乳腺癌使用来曲唑+/-贝伐单抗入组条件绝经后女性患者（允许使用LHRH激动剂）局部进展或晚
9、期转移性乳腺癌ER和/或PR+（1%），不论HER2状态一线针对晚期乳腺癌的化疗方案允许辅助或新辅助化疗或包含AI或Tam的辅助内分泌治疗良好的骨髓和脏器功能没有已知的脑转移ECOG PS 0或1Baseline Patient Characteristics(1)Presented By Maura Dickler at 2015 ASCO Annual Meeting基线特征（1）Baseline Patient Characteristics(2)Presented By Maura Dickler at 2015 ASCO Annual Meeting基线特征（2）Progressio
10、n-Free SurvivalCALGB(Alliance)40503Presented By Maura Dickler at 2015 ASCO Annual MeetingPFS：从入组研究至首次疾病进展或任何原因的死亡主要研究终点：PFS中位随访时间：39月（范围0.8-70月）Progression-Free Survival By Subgroup AnalysisPresented By Maura Dickler at 2015 ASCO Annual Meeting亚组分析Overall Survival CALGB(Alliance)40503Presented By Ma
11、ura Dickler at 2015 ASCO Annual Meeting次要研究终点：OSTumor ResponsePresented By Maura Dickler at 2015 ASCO Annual MeetingPatient DispositionPresented By Maura Dickler at 2015 ASCO Annual MeetingAdverse Events Grade 3*With Treatment AttributionMaximum Grade By PatientPresented By Maura Dickler at 2015 ASC
12、O Annual MeetingTreatment-related Toxicity Grade 3*Events of Special InterestPresented By Maura Dickler at 2015 ASCO Annual Meeting结论在晚期乳腺癌一线来曲唑治疗方案中加入贝伐单抗：1.延长PFS 4月（HR=0.75，p=0.016），改善ORR及CBR 2.截止目前未获得OS获益(HR 0.87,p=0.188)3.3级不良事件明显升高，尤其是高血压和蛋白尿对照组来曲唑单药较以往期临床试验显示了更长的PFS时间，达到16月1,2PFS获益而OS未获益与既往贝伐单
13、抗在晚期乳腺癌的临床试验结果相一致，但这种PFS获益需要权衡药物的费用及毒性作用下一步工作需要研究可识别治疗是否有效及耐药的潜在生物标志物，包括PIK3CA突变、CTC、luminal亚型的分析等，同样也等待CALGB40503与LEA研究（来曲唑/氟维斯群联合贝伐单抗研究）的联合分析内容内容 LBA500LBA500：NSABP B-35NSABP B-35关于绝经后关于绝经后DCISDCIS采取采取“肿块切除肿块切除+放疗放疗”常规治疗基础上，内分泌治疗选择常规治疗基础上，内分泌治疗选择TAMTAM和阿那曲唑何者更优？和阿那曲唑何者更优？1 A501A501：CALGB40503CALGB
14、40503关于绝经后激素受体阳性乳腺癌一关于绝经后激素受体阳性乳腺癌一线选择来曲唑单药或联合贝伐单抗的线选择来曲唑单药或联合贝伐单抗的期临床研究；期临床研究；234LBA502LBA502：PALOMA3PALOMA3是对于激素受体阳性晚期乳腺癌内分是对于激素受体阳性晚期乳腺癌内分泌解救选择氟维司群泌解救选择氟维司群500mg500mg基础加或不加基础加或不加CDK4/6CDK4/6抑制剂抑制剂palbociclibpalbociclib的的期临床研究；期临床研究；A503-504A503-504：早期乳腺癌辅助双膦酸盐或地诺单抗早期乳腺癌辅助双膦酸盐或地诺单抗（denosumabdenosu
15、mab）治疗）治疗期临床研究期临床研究(S0307(S0307和和ABCSG-ABCSG-18);18);Abstract LBA502 A Double Blind Phase 3 Trial of Fulvestrant With or Without Palbociclib in Pre-and Post-menopausal Women With Hormone Receptor-positive,HER2-negative Advanced Breast Cancer That Progressed on Prior Endocrine Therapy(PALOMA3 Study)P
16、resented By Nicholas Turner at 2015 ASCO Annual MeetingSlide 2Presented By Nicholas Turner at 2015 ASCO Annual Meeting内分泌耐药问题仍然是临床难题及挑战HR+乳腺癌的生长依赖细胞周期蛋白D1，它是ER的直接转录靶点细胞周期蛋白D1激活CDK4/6，导致G1期向S期转化，进入细胞周期内分泌耐药的细胞系模型生长仍然依赖细胞周期蛋白D1和CDK4/6PalbociclibPalbociclib是一种口服CDK4/6抑制剂，作用是通过阻止细胞周期G1期向S期转化而抑制细胞增殖和DNA合
17、成。1对内分泌耐药细胞系研究发现，Palbociclib有效并且与氟维司群有协同作用。2在一项II期研究中显示Palbociclib+来曲唑对比来曲唑单药治疗新诊断的晚期HR+乳腺癌能明显提高PFS。3CDK=cyclin-dependent kinasePALOMA3 Study DesignPresented By Nicholas Turner at 2015 ASCO Annual MeetingHR+HER2-晚期乳腺癌绝经前，围绝经*，绝经后之前内分泌治疗进展辅助期间或者结束12个内晚期乳腺癌治疗期间1线的针对晚期肿瘤的化疗*绝经前围绝经均使用戈舍瑞林内脏转移之前治疗的敏感性绝技前
18、/围绝经 vs 绝经后绝经后患者必须是之前AI治疗进展的患者首要终点：PFS 次要终点：CBR，ORR，OS，安全性，标记物，QoLDemographics and Baseline Tumor Characteristics Presented By Nicholas Turner at 2015 ASCO Annual Meeting基线肿瘤特征Tumor Characteristics and Prior TreatmentPresented By Nicholas Turner at 2015 ASCO Annual Meeting肿瘤特征和前期治疗Primary Endpoint:P
19、FS(ITT Population)Presented By Nicholas Turner at 2015 ASCO Annual MeetingSlide 16Presented By Nicholas Turner at 2015 ASCO Annual MeetingSummary of Key Secondary Efficacy EndpointsPresented By Nicholas Turner at 2015 ASCO Annual Meeting次要疗效终点汇总Adverse EventsAll Cause Presented By Nicholas Turner at
20、 2015 ASCO Annual Meeting不良反应总结Palbociclib联合氟维司群较安慰剂联合氟维司群治疗能明显提高之前内分泌治疗进展的HR+/HER2-晚期乳腺癌的PFSHR=0.422（95%CI，0.318 到 0.560；P0.000001）在所有提前预设的亚组均能看到获益安全性能耐受Palbociclib联合氟维司群是治疗之前内分泌治疗进展的患者的有效的治疗方式内容内容 LBA500LBA500：NSABP B-35NSABP B-35关于绝经后关于绝经后DCISDCIS采取采取“肿块切除肿块切除+放疗放疗”常规治疗基础上，内分泌治疗选择常规治疗基础上，内分泌治疗选择T
21、AMTAM和阿那曲唑何者更优？和阿那曲唑何者更优？1 A501A501：CALGB40503CALGB40503关于绝经后激素受体阳性乳腺癌一关于绝经后激素受体阳性乳腺癌一线选择来曲唑单药或联合贝伐单抗的线选择来曲唑单药或联合贝伐单抗的期临床研究；期临床研究；234LBA502LBA502：PALOMA3PALOMA3是对于激素受体阳性晚期乳腺癌内分是对于激素受体阳性晚期乳腺癌内分泌解救选择氟维司群泌解救选择氟维司群500mg500mg基础加或不加基础加或不加CDK4/6CDK4/6抑制剂抑制剂palbociclibpalbociclib的的期临床研究；期临床研究；A503-504A503-5
22、04：早期乳腺癌辅助双膦酸盐或地诺单抗早期乳腺癌辅助双膦酸盐或地诺单抗（denosumabdenosumab）治疗）治疗期临床研究期临床研究(S0307(S0307和和ABCSG-ABCSG-18);18);Role of Adjuvant Bisphosphonates In Early Breast CancerPresented By Robert Coleman at 2015 ASCO Annual MeetingAromatase Inhibitors Result In Increased Bone Loss and Poorer Quality BonePresented By
23、 Robert Coleman at 2015 ASCO Annual MeetingAromatase Inhibitors Are Associated With An Increased Rate of FracturesPresented By Robert Coleman at 2015 ASCO Annual MeetingEBCTCG Bisphosphonate Meta-analysis Fracture DataPresented By Robert Coleman at 2015 ASCO Annual MeetingOutlinePresented By Robert
24、Coleman at 2015 ASCO Annual MeetingSlide 7Presented By Robert Coleman at 2015 ASCO Annual MeetingABCSG 18 Study DesignPresented By Robert Coleman at 2015 ASCO Annual MeetingSlide 13Presented By Michael Gnant at 2015 ASCO Annual MeetingSlide 14Presented By Michael Gnant at 2015 ASCO Annual MeetingSli
25、de 15Presented By Michael Gnant at 2015 ASCO Annual MeetingRisk of Fractures By Baseline BMDPresented By Robert Coleman at 2015 ASCO Annual MeetingABCSG 18 Bone Mineral Density ChangesPresented By Robert Coleman at 2015 ASCO Annual MeetingSlide 11Presented By Michael Gnant at 2015 ASCO Annual Meetin
26、gPhase III trial of bisphosphonates as adjuvant therapy in primary breast cancer:SWOG/Alliance/ECOG-ACRIN/NCIC Clinical Trials Group/NRG Oncology study S0307 Presented By Robert Coleman at 2015 ASCO Annual MeetingS0307:Study DesignPresented By Robert Coleman at 2015 ASCO Annual MeetingI-III 期乳腺癌S030
27、7 Primary Endpoint:Disease-Free SurvivalPresented By Robert Coleman at 2015 ASCO Annual MeetingS0307:DFS Analysis by Tumor SubtypePresented By Julie Gralow at 2015 ASCO Annual MeetingS0307:DFS Analysis by AgePresented By Julie Gralow at 2015 ASCO Annual MeetingS0307:Overall SurvivalPresented By Juli
28、e Gralow at 2015 ASCO Annual MeetingS0307:Grade 3,4 ToxicitiesPresented By Julie Gralow at 2015 ASCO Annual MeetingS0307:Osteonecrosis of the Jaw(ONJ)Presented By Julie Gralow at 2015 ASCO Annual MeetingS0307:FracturesPresented By Julie Gralow at 2015 ASCO Annual MeetingConclusionsPresented By Rober
29、t Coleman at 2015 ASCO Annual Meeting总结总结 1 234LBA502LBA502：PALOMA3 PALOMA3 对于激素受体阳性晚期乳腺癌内分泌解救对于激素受体阳性晚期乳腺癌内分泌解救治治疗：疗：氟维司群氟维司群500mg500mg结合结合palbociclib的方案的方案是是一种非常有效的治一种非常有效的治疗选择；疗选择；A503-504A503-504：早期乳腺癌辅助治疗早期乳腺癌辅助治疗不同类型不同类型双膦酸盐双膦酸盐无显著差异，无显著差异，地诺单抗地诺单抗可显著降低接受可显著降低接受 AI 治疗的绝经后乳腺癌患者的骨折次治疗的绝经后乳腺癌患者的骨折次数并提高患者骨密度且安全性良好。数并提高患者骨密度且安全性良好。A501A501：CALGB40503 CALGB40503 绝经后激素受体阳性乳腺癌一线选择来曲唑绝经后激素受体阳性乳腺癌一线选择来曲唑联合贝伐单抗联合贝伐单抗可改善可改善 PFS，但增加贝伐单抗相关的毒性；，但增加贝伐单抗相关的毒性；LBA500LBA500：NSABP B-35NSABP B-35关于绝经后关于绝经后DCISDCIS采取采取“肿块切除肿块切除+放放疗疗”常规治疗基础上，内分泌治疗选择阿那曲唑更优常规治疗基础上，内分泌治疗选择阿那曲唑更优；谢谢您的关注！