ASCO乳腺癌内分泌治疗与骨保护进展陈占红.pptx

6 6月1 1日9 9个口头大会报告LBA500LBA500：NSABP B-35NSABP B-35关于绝经后DCISDCIS采取“肿块切除+放疗”常规治疗基础上，内分泌治疗选择TAMTAM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期临床研究；LBA502LBA502：PALOMA3PALOMA3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500mg500mg基础加或不加CDK4/6CDK4/6抑制剂palbociclibpalbociclib的期临床研究；A503-504A503-504：早期乳腺癌辅助双膦酸盐或地诺单抗（denosumabdenosumab）治疗期临床研究(S0307(S0307和ABCSG-18);ABCSG-18);A505A505：Her-2Her-2阳性乳腺癌“多西他赛和/或曲妥珠单抗和/或pertuzumabpertuzumab”新辅助治疗期临床研究(NeoSphere)5(NeoSphere)5年随访结果；A506A506：ER+/PR+/HER-2+ER+/PR+/HER-2+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期临床研究；A507A507：Her-2Her-2阳性乳腺癌一线选择T-DM1T-DM1 pertuzumabpertuzumab对曲妥珠单抗紫杉类随机期临床研究(MARIANNE(MARIANNE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NeratinibNeratinib安慰剂对照、随机期临床研究（NxteNETNxteNET）HER-2/ER专场第1页/共67页内容 LBA500LBA500：NSABP B-35NSABP B-35关于绝经后DCISDCIS采取“肿块切除+放疗”常规治疗基础上，内分泌治疗选择TAMTAM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线选择来曲唑单药或联合贝伐单抗的期临床研究；234LBA502LBA502：PALOMA3PALOMA3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500mg500mg基础加或不加CDK4/6CDK4/6抑制剂palbociclibpalbociclib的期临床研究；A503-504A503-504：早期乳腺癌辅助双膦酸盐或地诺单抗（denosumabdenosumab）治疗期临床研究(S0307(S0307和ABCSG-ABCSG-18);18);第2页/共67页S l i d e 3 5Presented By Eric Winer at 2015 ASCO Annual Meeting第3页/共67页S l i d e 3 7Presented By Eric Winer at 2015 ASCO Annual Meeting主要研究终点：BCFI第4页/共67页S l i d e 3 8Presented By Eric Winer at 2015 ASCO Annual Meeting分层分析第5页/共67页S l i d e 3 9Presented By Eric Winer at 2015 ASCO Annual Meeting次要研究终点：OS第6页/共67页S e r i o u s C o m p l i c a t i o n sPresented By Eric Winer at 2015 ASCO Annual Meeting第7页/共67页N S A B P B-3 5 S u m m a r yPresented By Eric Winer at 2015 ASCO Annual Meeting第8页/共67页内容 LBA500LBA500：NSABP B-35NSABP B-35关于绝经后DCISDCIS采取“肿块切除+放疗”常规治疗基础上，内分泌治疗选择TAMTAM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线选择来曲唑单药或联合贝伐单抗的期临床研究；234LBA502LBA502：PALOMA3PALOMA3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500mg500mg基础加或不加CDK4/6CDK4/6抑制剂palbociclibpalbociclib的期临床研究；A503-504A503-504：早期乳腺癌辅助双膦酸盐或地诺单抗（denosumabdenosumab）治疗期临床研究(S0307(S0307和ABCSG-ABCSG-18);18);第9页/共67页C A L G B 4 0 5 0 3 (A l l i a n c e)/C T S U 4 0 5 0 3/N C T 0 0 6 0 1 9 0 0 P h a s e I I I T r i a l E v a l u a t i n g t h e A d d i t i o n o f B e v a c i z u m a b t o L e t r o z o l e A s F i r s t-l i n e E n d o c r i n e T h e r a p y f o r T r e a t m e n t o f H o r m o n e-r e c e p t o r P o s i t i v e (H R+)A d v a n c e d B r e a s t C a n c e rPresented By Maura Dickler at 2015 ASCO Annual Meeting第10页/共67页B e v a c i z u m a b p l u s c h e m o t h e r a p y a s f i r s t-l i n e t h e r a p y i n H E R 2-n e g a t i v e m e t a s t a t i c b r e a s t c a n c e rPresented By Joseph Sparano at 2015 ASCO Annual Meeting第11页/共67页研究设计分层：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+/-贝伐单抗第12页/共67页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第13页/共67页B a s e l i n e P a t i e n t C h a r a c t e r i s t i c s (1)Presented By Maura Dickler at 2015 ASCO Annual Meeting基线特征（1）第14页/共67页B a s e l i n e P a t i e n t C h a r a c t e r i s t i c s (2)Presented By Maura Dickler at 2015 ASCO Annual Meeting基线特征（2）第15页/共67页P r o g r e s s i o n-F r e e S u r v i v a l C A L G B (A l l i a n c e)4 0 5 0 3Presented 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）第16页/共67页P r o g r e s s i o n-F r e e S u r v i v a l B y S u b g r o u p A n a l y s i sPresented By Maura Dickler at 2015 ASCO Annual Meeting亚组分析第17页/共67页O v e r a l l S u r v i v a l C A L G B (A l l i a n c e)4 0 5 0 3Presented By Maura Dickler at 2015 ASCO Annual Meeting次要研究终点：OS第18页/共67页T u m o r R e s p o n s ePresented By Maura Dickler at 2015 ASCO Annual Meeting第19页/共67页P a t i e n t D i s p o s i t i o nPresented By Maura Dickler at 2015 ASCO Annual Meeting第20页/共67页A d v e r s e E v e n t s G r a d e 3*W i t h T r e a t m e n t A t t r i b u t i o n M a x i m u m G r a d e B y P a t i e n tPresented By Maura Dickler at 2015 ASCO Annual Meeting第21页/共67页T r e a t m e n t-r e l a t e d T o x i c i t y G r a d e 3*E v e n t s o f S p e c i a l I n t e r e s tPresented By Maura Dickler at 2015 ASCO Annual Meeting第22页/共67页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）的联合分析第23页/共67页内容 LBA500LBA500：NSABP B-35NSABP B-35关于绝经后DCISDCIS采取“肿块切除+放疗”常规治疗基础上，内分泌治疗选择TAMTAM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线选择来曲唑单药或联合贝伐单抗的期临床研究；234LBA502LBA502：PALOMA3PALOMA3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500mg500mg基础加或不加CDK4/6CDK4/6抑制剂palbociclibpalbociclib的期临床研究；A503-504A503-504：早期乳腺癌辅助双膦酸盐或地诺单抗（denosumabdenosumab）治疗期临床研究(S0307(S0307和ABCSG-ABCSG-18);18);第24页/共67页A b s t r a c t L B A 5 0 2 A D o u b l e B l i n d P h a s e 3 T r i a l o f F u l v e s t r a n t W i t h o r W i t h o u t P a l b o c i c l i b i n P r e-a n d P o s t-m e n o p a u s a l W o m e n W i t h H o r m o n e R e c e p t o r-p o s i t i v e,H E R 2-n e g a t i v e A d v a n c e d B r e a s t C a n c e r T h a t P r o g r e s s e d o n P r i o r E n d o c r i n e T h e r a p y (P A L O M A 3 S t u d y)Presented By Nicholas Turner at 2015 ASCO Annual Meeting第25页/共67页S l i d e 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CDK4/6第26页/共67页PalbociclibPalbociclib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 kinase第27页/共67页P A L O M A 3 S t u d y D e s i g nPresented 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/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第28页/共67页D e m o g r a p h i c s a n d B a s e l i n e T u m o r C h a r a c t e r i s t i c s Presented By Nicholas Turner at 2015 ASCO Annual Meeting基线肿瘤特征第29页/共67页T u m o r C h a r a c t e r i s t i c s a n d P r i o r T r e a t m e n tPresented By Nicholas Turner at 2015 ASCO Annual Meeting肿瘤特征和前期治疗第30页/共67页P r i m a r y E n d p o i n t:P F S (I T T P o p u l a t i o n)Presented By Nicholas Turner at 2015 ASCO Annual Meeting第32页/共67页S l i d e 1 6Presented By Nicholas Turner at 2015 ASCO Annual Meeting第33页/共67页S u m m a r y o f K e y S e c o n d a r y E f f i c a c y E n d p o i n t sPresented By Nicholas Turner at 2015 ASCO Annual Meeting次要疗效终点汇总第34页/共67页A d v e r s e E v e n t s A l l C a u s e Presented By Nicholas Turner at 2015 ASCO Annual Meeting不良反应第35页/共67页总结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第37页/共67页内容 LBA500LBA500：NSABP B-35NSABP B-35关于绝经后DCISDCIS采取“肿块切除+放疗”常规治疗基础上，内分泌治疗选择TAMTAM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线选择来曲唑单药或联合贝伐单抗的期临床研究；234LBA502LBA502：PALOMA3PALOMA3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500mg500mg基础加或不加CDK4/6CDK4/6抑制剂palbociclibpalbociclib的期临床研究；A503-504A503-504：早期乳腺癌辅助双膦酸盐或地诺单抗（denosumabdenosumab）治疗期临床研究(S0307(S0307和ABCSG-ABCSG-18);18);第38页/共67页R o l e o f A d j u v a n t B i s p h o s p h o n a t e s I n E a r l y B r e a s t C a n c e rPresented By Robert Coleman at 2015 ASCO Annual Meeting第39页/共67页A r o m a t a s e I n h i b i t o r s R e s u l t I n I n c r e a s e d B o n e L o s s a n d P o o r e r Q u a l i t y B o n ePresented By Robert Coleman at 2015 ASCO Annual Meeting第40页/共67页A r o m a t a s e I n h i b i t o r s A r e A s s o c i a t e d W i t h A n I n c r e a s e d R a t e o f F r a c t u r e sPresented By Robert Coleman at 2015 ASCO Annual Meeting第41页/共67页E B C T C G B i s p h o s p h o n a t e M e t a-a n a l y s i s F r a c t u r e D a t aPresented By Robert Coleman at 2015 ASCO Annual Meeting第42页/共67页O u t l i n ePresented By Robert Coleman at 2015 ASCO Annual Meeting第43页/共67页S l i d e 7Presented By Robert Coleman at 2015 ASCO Annual Meeting第44页/共67页A B C S G 1 8 S t u d y D e s i g nPresented By Robert Coleman at 2015 ASCO Annual Meeting第45页/共67页S l i d e 1 3Presented By Michael Gnant at 2015 ASCO Annual Meeting第46页/共67页S l i d e 1 4Presented By Michael Gnant at 2015 ASCO Annual Meeting第47页/共67页S l i d e 1 5Presented By Michael Gnant at 2015 ASCO Annual Meeting第48页/共67页R i s k o f F r a c t u r e s B y B a s e l i n e B M DPresented By Robert Coleman at 2015 ASCO Annual Meeting第49页/共67页A B C S G 1 8 B o n e M i n e r a l D e n s i t y C h a n g e sPresented By Robert Coleman at 2015 ASCO Annual Meeting第50页/共67页S l i d e 1 1Presented By Michael Gnant at 2015 ASCO Annual Meeting第51页/共67页P h a s e I I I t r i a l o f b i s p h o s p h o n a t e s a s a d j u v a n t t h e r a p y i n p r i m a r y b r e a s t c a n c e r:S W O G/A l l i a n c e/E C O G-A C R I N/N C I C C l i n i c a l T r i a l s G r o u p/N R G O n c o l o g y s t u d y S 0 3 0 7 Presented By Robert Coleman at 2015 ASCO Annual Meeting第52页/共67页S 0 3 0 7:S t u d y D e s i g nPresented By Robert Coleman at 2015 ASCO Annual MeetingI-III 期乳腺癌第53页/共67页S 0 3 0 7 P r i m a r y E n d p o i n t:D i s e a s e-F r e e S u r v i v a lPresented By Robert Coleman at 2015 ASCO Annual Meeting第54页/共67页S 0 3 0 7:D F S A n a l y s i s b y T u m o r S u b t y p ePresented By Julie Gralow at 2015 ASCO Annual Meeting第55页/共67页S 0 3 0 7:D F S A n a l y s i s b y A g ePresented By Julie Gralow at 2015 ASCO Annual Meeting第56页/共67页S 0 3 0 7:O v e r a l l S u r v i v a lPresented By Julie Gralow at 2015 ASCO Annual Meeting第57页/共67页S 0 3 0 7:G r a d e 3,4 T o x i c i t i e sPresented By Julie Gralow at 2015 ASCO Annual Meeting第58页/共67页S 0 3 0 7:O s t e o n e c r o s i s o f t h e J a w (O N J)Presented By Julie Gralow at 2015 ASCO Annual Meeting第59页/共67页S 0 3 0 7:F r a c t u r e sPresented By Julie Gralow at 2015 ASCO Annual Meeting第60页/共67页C o n c l u s i o n sPresented By Robert Coleman at 2015 ASCO Annual Meeting第61页/共67页总结 1 234LBA502：PALOMA3 对于激素受体阳性晚期乳腺癌内分泌解救治疗：氟维司群500mg结合palbociclib的方案是一种非常有效的治疗选择；A503-504：早期乳腺癌辅助治疗不同类型双膦酸盐无显著差异，地诺单抗可显著降低接受 AI 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。A501：CALGB40503 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可改善 PFS，但增加贝伐单抗相关的毒性；LBA500LBA500：NSABP B-35NSABP B-35关于绝经后DCISDCIS采取“肿块切除+放疗”常规治疗基础上，内分泌治疗选择阿那曲唑更优；第62页/共67页谢谢您的关注！陈占红陈占红 2012015 5.6.21.6.21第63页/共67页P h a s e I I I T r i a l s E n d o c r i n e T h e r a p y +/-B e v a c i z u m a b (o p e n-l a b e l)Presented By Joseph Sparano at 2015 ASCO Annual Meeting第64页/共67页主要数据截止期后，进展由研究者确定氟维司群 500mgn=102阿那曲唑 1mgn=103进展患者数（%）63(61.8)79(76.7)中位时间（月）23.413.106121824303642480.00.20.40.60.81.0 无进展存活患者比例时间（月）1027465524534206 0103695539302182 0氟维司群 500mg阿那曲唑 1mgHR=0.6695%CI(0.47,0.92)p=0.01氟维司群 500 mg阿那曲唑 1 mg风险患者数：65012184248 月3630246至进展时间（TTP 随访分析）Robertson et al.Breast Cancer Res Treat 2012第65页/共67页第66页/共67页感谢您的观看。第67页/共67页