ASCO乳腺癌内分泌治疗进展.ppt

1、2015ASCO 乳腺癌内分泌治疗进展,6月1日9个口头大会报告,LBA500：NSABP B-35关于绝经后DCIS采取“肿块切除+放疗” 常规治疗基础上，内分泌治疗选择TAM和阿那曲唑何者更优？ A501：CALGB40503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； LBA502：PALOMA3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择氟维司群500mg基础加或不加CDK4/6抑制剂palbociclib的期临床研究； A503-504：早期乳腺癌辅助双膦酸盐或地诺单抗（denosumab）治疗期临床研究(S0307和ABCSG-18

2、); A505：Her-2阳性乳腺癌“多西他赛和/或曲妥珠单抗和/或pertuzumab”新辅助治疗期临床研究(NeoSphere)5年随访结果； A506：ER+/PR+/HER-2+早期乳腺癌新辅助治疗T-DM1基础上加或不加内分泌治疗期临床研究； A507：Her-2阳性乳腺癌一线选择T-DM1pertuzumab对曲妥珠单抗紫杉类随机期临床研究(MARIANNE研究); A508：Her-2阳性早期乳腺癌曲妥珠单抗辅助治疗基础上序贯Neratinib安慰剂对照、随机期临床研究（NxteNET）,HER-2/ER专场,内容,LBA502：PALOMA3是对于激素受体阳性晚期乳腺癌内分泌解

3、救选择氟维司群500mg基础加或不加CDK4/6抑制剂palbociclib的期临床研究；,A503-504：早期乳腺癌辅助双膦酸盐或地诺单抗（denosumab）治疗期临床研究(S0307和ABCSG-18);,Slide 35,Presented By Eric Winer at 2015 ASCO Annual Meeting,Slide 37,Presented By Eric Winer at 2015 ASCO Annual Meeting,主要研究终点：BCFI,Slide 38,Presented By Eric Winer at 2015 ASCO Annual Meetin

4、g,分层分析,Slide 39,Presented By Eric Winer at 2015 ASCO Annual Meeting,次要研究终点：OS,Serious Complications,Presented By Eric Winer at 2015 ASCO Annual Meeting,NSABP B-35 Summary,Presented By Eric Winer at 2015 ASCO Annual Meeting,内容,LBA502：PALOMA3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500mg基础加或不加CDK4/6抑制剂palbociclib的期临床

5、研究；,A503-504：早期乳腺癌辅助双膦酸盐或地诺单抗（denosumab）治疗期临床研究(S0307和ABCSG-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 Cancer,Presented By Maura

6、Dickler at 2015 ASCO Annual Meeting,Bevacizumab plus chemotherapy as first-line therapy in HER2-negative metastatic breast cancer,Presented 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

7、组条件,绝经后女性患者（允许使用LHRH激动剂） 局部进展或晚期转移性乳腺癌 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1,Baseline 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

8、at 2015 ASCO Annual Meeting,基线特征（2）,Progression-Free SurvivalCALGB (Alliance) 40503,Presented By Maura Dickler at 2015 ASCO Annual Meeting,PFS：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 Analysis,Presented By Maura Dickler at 2015 ASCO Annual Meeting,亚

9、组分析,Overall Survival CALGB (Alliance) 40503,Presented By Maura Dickler at 2015 ASCO Annual Meeting,次要研究终点：OS,Tumor Response,Presented By Maura Dickler at 2015 ASCO Annual Meeting,Patient Disposition,Presented By Maura Dickler at 2015 ASCO Annual Meeting,Adverse Events Grade 3* With Treatment Attribu

10、tionMaximum Grade By Patient,Presented By Maura Dickler at 2015 ASCO Annual Meeting,Treatment-related Toxicity Grade 3* Events of Special Interest,Presented 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)

11、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1,2 PFS获益而OS未获益与既往贝伐单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,LBA502：PALOMA3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500mg基础加或不加CDK4/6抑制剂palbociclib的期临

12、床研究；,A503-504：早期乳腺癌辅助双膦酸盐或地诺单抗（denosumab）治疗期临床研究(S0307和ABCSG-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(

13、PALOMA3 Study),Presented By Nicholas Turner at 2015 ASCO Annual Meeting,Slide 2,Presented 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CDK4/6,Palbociclib,Palbociclib是一种口服CDK4/6抑制剂，作用是通过阻止

14、细胞周期G1期向S期转化而抑制细胞增殖和DNA合成。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。3,CDK=cyclin-dependent kinase,PALOMA3 Study Design,Presented By Nicholas Turner at 2015 ASCO Annual Meeting,HR+ 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

15、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/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，QoL,Demographics and Baseline Tumor Characteristics,Presented By Nicholas Turner at 2015 ASCO Annual Meeting,基线肿瘤特征,Tumor Characteristics and Prior Treatment,Presented By Nicholas Turner at 201

16、5 ASCO Annual Meeting,肿瘤特征和前期治疗,Treatment Summary,Presented By Nicholas Turner at 2015 ASCO Annual Meeting,治疗情况汇总,Primary Endpoint: PFS (ITT Population),Presented By Nicholas Turner at 2015 ASCO Annual Meeting,Slide 16,Presented By Nicholas Turner at 2015 ASCO Annual Meeting,Summary of Key Secondary

17、 Efficacy Endpoints,Presented By Nicholas Turner at 2015 ASCO Annual Meeting,次要疗效终点汇总,Adverse EventsAll Cause,Presented By Nicholas Turner at 2015 ASCO Annual Meeting,不良反应,Summary of Adverse Events,Presented By Nicholas Turner at 2015 ASCO Annual Meeting,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

18、展的HR+/ HER2-晚期乳腺癌的PFS HR=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,LBA502：PALOMA3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500mg基础加或不加CDK4/6抑制剂palbociclib的期临床研究；,A503-504：早期乳腺癌辅助双膦酸盐或地诺单抗（denosumab）治疗期临床研究(S0307和ABCSG-18);,Role of Adjuvant Bisphosphon

19、ates In Early Breast Cancer,Presented By Robert Coleman at 2015 ASCO Annual Meeting,Aromatase Inhibitors Result In Increased Bone Loss and Poorer Quality Bone,Presented By Robert Coleman at 2015 ASCO Annual Meeting,Aromatase Inhibitors Are Associated With An Increased Rate of Fractures,Presented By

20、Robert Coleman at 2015 ASCO Annual Meeting,EBCTCG Bisphosphonate Meta-analysis Fracture Data,Presented By Robert Coleman at 2015 ASCO Annual Meeting,Outline,Presented By Robert Coleman at 2015 ASCO Annual Meeting,Slide 7,Presented By Robert Coleman at 2015 ASCO Annual Meeting,ABCSG 18 Study Design,P

21、resented By Robert Coleman at 2015 ASCO Annual Meeting,Slide 13,Presented By Michael Gnant at 2015 ASCO Annual Meeting,Slide 14,Presented By Michael Gnant at 2015 ASCO Annual Meeting,Slide 15,Presented By Michael Gnant at 2015 ASCO Annual Meeting,Risk of Fractures By Baseline BMD,Presented By Robert

22、 Coleman at 2015 ASCO Annual Meeting,ABCSG 18 Bone Mineral Density Changes,Presented By Robert Coleman at 2015 ASCO Annual Meeting,Slide 11,Presented By Michael Gnant at 2015 ASCO Annual Meeting,Phase III trial of bisphosphonates as adjuvant therapy in primary breast cancer: SWOG/Alliance/ECOG-ACRIN

23、/NCIC Clinical Trials Group/NRG Oncology study S0307,Presented By Robert Coleman at 2015 ASCO Annual Meeting,S0307: Study Design,Presented By Robert Coleman at 2015 ASCO Annual Meeting,I-III 期乳腺癌,S0307 Primary Endpoint:Disease-Free Survival,Presented By Robert Coleman at 2015 ASCO Annual Meeting,S0307: DFS Analysis by Tumor Subtype,Presented By Julie Gralow at 2015 ASCO An