asco乳腺癌內(nèi)分泌治療進展

1、2015ASCO乳腺癌內(nèi)分泌治療進展,6月1日9個口頭大會報告,LBA500：NSABP B-35關于絕經(jīng)后DCIS采取“腫塊切除+放療” 常規(guī)治療基礎上，內(nèi)分泌治療選擇TAM和阿那曲唑何者更優(yōu)？A501：CALGB40503關于絕經(jīng)后激素受體陽性乳腺癌一線選擇來曲唑單藥或聯(lián)合貝伐單抗的Ⅲ期臨床研究；LBA502：PALOMA3是最為關注的Ⅲ期臨床研究，對于激素受體陽性晚期乳腺癌內(nèi)分泌解救選擇氟維司群500mg基礎加或不加CD

2、K4/6抑制劑palbociclib的Ⅲ期臨床研究；A503-504：早期乳腺癌輔助雙膦酸鹽或地諾單抗（denosumab）治療Ⅲ期臨床研究(S0307和ABCSG-18);A505：Her-2陽性乳腺癌“多西他賽和/或曲妥珠單抗和/或pertuzumab”新輔助治療Ⅱ期臨床研究(NeoSphere)5年隨訪結(jié)果；A506：ER+/PR+/HER-2+早期乳腺癌新輔助治療T-DM1基礎上加或不加內(nèi)分泌治療Ⅱ期臨床研究；A

3、507：Her-2陽性乳腺癌一線選擇T-DM1±pertuzumab對曲妥珠單抗紫杉類隨機Ⅲ期臨床研究(MARIANNE研究);A508：Her-2陽性早期乳腺癌曲妥珠單抗輔助治療基礎上序貫Neratinib安慰劑對照、隨機Ⅲ期臨床研究（NxteNET）,HER-2/ER專場,內(nèi)容,LBA502：PALOMA3是對于激素受體陽性晚期乳腺癌內(nèi)分泌解救選擇氟維司群500mg基礎加或不加CDK4/6抑制劑palbociclib的

4、Ⅲ期臨床研究；,A503-504：早期乳腺癌輔助雙膦酸鹽或地諾單抗（denosumab）治療Ⅲ期臨床研究(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,主要研究終點：BCFI,Slide 38,Present

5、ed By Eric Winer at 2015 ASCO Annual Meeting,分層分析,Slide 39,Presented By Eric Winer at 2015 ASCO Annual Meeting,次要研究終點：OS,Serious Complications,Presented By Eric Winer at 2015 ASCO Annual Meeting,NSABP B-35 Summary,Presen

6、ted By Eric Winer at 2015 ASCO Annual Meeting,內(nèi)容,LBA502：PALOMA3是對于激素受體陽性晚期乳腺癌內(nèi)分泌解救選擇氟維司群500mg基礎加或不加CDK4/6抑制劑palbociclib的Ⅲ期臨床研究；,A503-504：早期乳腺癌輔助雙膦酸鹽或地諾單抗（denosumab）治療Ⅲ期臨床研究(S0307和ABCSG-18);,CALGB 40503 (Alliance)/CTSU 40

7、503/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 Dickler at 2015

8、 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,研究設計,分層：1.可測量病灶（有/無）2. 無病間隔（≤24月/＞24月）主要研究終點：PFS

9、次要研究終點：OS，ORR，CBR，治療相關毒性事件,隨機，開放，多中心，III期臨床評估晚期一線乳腺癌使用來曲唑+/-貝伐單抗,入組條件,絕經(jīng)后女性患者（允許使用LHRH激動劑）局部進展或晚期轉(zhuǎn)移性乳腺癌ER和/或PR+（≥1%），不論HER2狀態(tài)≤一線針對晚期乳腺癌的化療方案允許輔助或新輔助化療或包含AI或Tam的輔助內(nèi)分泌治療良好的骨髓和臟器功能沒有已知的腦轉(zhuǎn)移ECOG PS 0或1,Baseline Patien

10、t Characteristics (1),Presented By Maura Dickler at 2015 ASCO Annual Meeting,,基線特征（1）,Baseline Patient Characteristics (2),Presented By Maura Dickler at 2015 ASCO Annual Meeting,,基線特征（2）,Progression-Free SurvivalCALGB (A

11、lliance) 40503,Presented By Maura Dickler at 2015 ASCO Annual Meeting,PFS：從入組研究至首次疾病進展或任何原因的死亡,,主要研究終點：PFS,中位隨訪時間：39月（范圍0.8-70月）,Progression-Free Survival By Subgroup Analysis,Presented By Maura Dickler at 2015 ASCO Annu

12、al Meeting,,亞組分析,Overall Survival CALGB (Alliance) 40503,Presented By Maura Dickler at 2015 ASCO Annual Meeting,,次要研究終點：OS,Tumor Response,Presented By Maura Dickler at 2015 ASCO Annual Meeting,Patient Disposition,Present

13、ed By Maura Dickler at 2015 ASCO Annual Meeting,Adverse Events ≥ Grade 3* With Treatment AttributionMaximum Grade By Patient,Presented By Maura Dickler at 2015 ASCO Annual Meeting,Treatment-related Toxicity ≥ Grade 3* Ev

14、ents of Special Interest,Presented By Maura Dickler at 2015 ASCO Annual Meeting,結(jié)論,在晚期乳腺癌一線來曲唑治療方案中加入貝伐單抗： 1. 延長PFS 4月（HR=0.75，p=0.016），改善ORR及CBR 2. 截止目前未獲得OS獲益(HR 0.87,p=0.188) 3. 3級不良事件明顯升高，尤其是高血壓和蛋白尿?qū)φ战M來曲唑單

15、藥較以往Ⅲ期臨床試驗顯示了更長的PFS時間，達到16月1,2PFS獲益而OS未獲益與既往貝伐單抗在晚期乳腺癌的臨床試驗結(jié)果相一致，但這種PFS獲益需要權(quán)衡藥物的費用及毒性作用下一步工作需要研究可識別治療是否有效及耐藥的潛在生物標志物，包括PIK3CA突變、CTC、luminal亞型的分析等，同樣也等待CALGB40503與LEA研究（來曲唑/氟維斯群聯(lián)合貝伐單抗研究）的聯(lián)合分析,內(nèi)容,LBA502：PALOMA3是對于激素受體陽

16、性晚期乳腺癌內(nèi)分泌解救選擇氟維司群500mg基礎加或不加CDK4/6抑制劑palbociclib的Ⅲ期臨床研究；,A503-504：早期乳腺癌輔助雙膦酸鹽或地諾單抗（denosumab）治療Ⅲ期臨床研究(S0307和ABCSG-18);,Abstract LBA502 A Double Blind Phase 3 Trial of Fulvestrant With or Without Palbociclib in Pre- and

17、Post-menopausal Women With Hormone Receptor-positive, HER2-negative Advanced Breast Cancer That Progressed on Prior Endocrine Therapy(PALOMA3 Study),Presented By Nicholas Turner at 2015 ASCO Annual Meeting,Slide 2,Presen

18、ted By Nicholas Turner at 2015 ASCO Annual Meeting,,內(nèi)分泌耐藥問題仍然是臨床難題及挑戰(zhàn)HR+乳腺癌的生長依賴細胞周期蛋白D1，它是ER的直接轉(zhuǎn)錄靶點細胞周期蛋白D1激活CDK4/6，導致G1期向S期轉(zhuǎn)化，進入細胞周期內(nèi)分泌耐藥的細胞系模型生長仍然依賴細胞周期蛋白D1和CDK4/6,Palbociclib,Palbociclib是一種口服CDK4/6抑制劑，作用是通過阻止細胞周期G

19、1期向S期轉(zhuǎn)化而抑制細胞增殖和DNA合成。1對內(nèi)分泌耐藥細胞系研究發(fā)現(xiàn)，Palbociclib有效并且與氟維司群有協(xié)同作用。2在一項II期研究中顯示Palbociclib+來曲唑?qū)Ρ葋砬騿嗡幹委熜略\斷的晚期HR+乳腺癌能明顯提高PFS。3,CDK=cyclin-dependent kinase,PALOMA3 Study Design,Presented By Nicholas Turner at 2015 ASCO Annual

20、 Meeting,HR+ HER2- 晚期乳腺癌絕經(jīng)前，圍絕經(jīng)*，絕經(jīng)后之前內(nèi)分泌治療進展輔助期間或者結(jié)束12個內(nèi)晚期乳腺癌治療期間≤1線的針對晚期腫瘤的化療*絕經(jīng)前圍絕經(jīng)均使用戈舍瑞林,內(nèi)臟轉(zhuǎn)移之前治療的敏感性絕技前/圍絕經(jīng) vs 絕經(jīng)后,絕經(jīng)后患者必須是之前AI治療進展的患者首要終點： PFS 次要終點：CBR，ORR，OS，安全性，標記物，QoL,Demographics and Baseline Tumor

21、 Characteristics,Presented By Nicholas Turner at 2015 ASCO Annual Meeting,基線腫瘤特征,,,Tumor Characteristics and Prior Treatment,Presented By Nicholas Turner at 2015 ASCO Annual Meeting,腫瘤特征和前期治療,,Treatment Summary,Presented

22、 By Nicholas Turner at 2015 ASCO Annual Meeting,治療情況匯總,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,Sum

23、mary of Key Secondary Efficacy Endpoints,Presented By Nicholas Turner at 2015 ASCO Annual Meeting,次要療效終點匯總,,Adverse Events—All Cause,Presented By Nicholas Turner at 2015 ASCO Annual Meeting,不良反應,Summary of Adverse Events

24、,Presented By Nicholas Turner at 2015 ASCO Annual Meeting,總結(jié),Palbociclib聯(lián)合氟維司群較安慰劑聯(lián)合氟維司群治療能明顯提高之前內(nèi)分泌治療進展的HR+/ HER2-晚期乳腺癌的PFSHR=0.422 （95% CI， 0.318 到 0.560；P＜0.000001）在所有提前預設的亞組均能看到獲益安全性能耐受Palbociclib聯(lián)合氟維司群是治療之前內(nèi)分泌治療

25、進展的患者的有效的治療方式,內(nèi)容,LBA502：PALOMA3是對于激素受體陽性晚期乳腺癌內(nèi)分泌解救選擇氟維司群500mg基礎加或不加CDK4/6抑制劑palbociclib的Ⅲ期臨床研究；,A503-504：早期乳腺癌輔助雙膦酸鹽或地諾單抗（denosumab）治療Ⅲ期臨床研究(S0307和ABCSG-18);,Role of Adjuvant Bisphosphonates In Early Breast Cancer,Presen

26、ted 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 Wit

27、h An Increased Rate of Fractures,Presented By 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 Ro

28、bert Coleman at 2015 ASCO Annual Meeting,Slide 7,Presented By Robert Coleman at 2015 ASCO Annual Meeting,ABCSG 18 – Study Design,Presented By Robert Coleman at 2015 ASCO Annual Meeting,Slide 13,Presented By Michael Gnant

29、 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 Coleman a

30、t 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 bisphosphonate

31、s 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 Meeting,S0307: Study Design,Presented By Robe

32、rt 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 201

33、5 ASCO Annual Meeting,S0307: DFS Analysis by Age,Presented By Julie Gralow at 2015 ASCO Annual Meeting,S0307: Overall Survival,Presented By Julie Gralow at 2015 ASCO Annual Meeting,S0307: Grade 3, 4 Toxicities,Presented

34、By Julie Gralow at 2015 ASCO Annual Meeting,S0307: Osteonecrosis of the Jaw (ONJ),Presented By Julie Gralow at 2015 ASCO Annual Meeting,S0307: Fractures,Presented By Julie Gralow at 2015 ASCO Annual Meeting,Conclusions,P

35、resented By Robert Coleman at 2015 ASCO Annual Meeting,總結(jié),LBA502：PALOMA3 對于激素受體陽性晚期乳腺癌內(nèi)分泌解救治療：氟維司群500mg結(jié)合palbociclib的方案是一種非常有效的治療選擇；,A503-504：早期乳腺癌輔助治療不同類型雙膦酸鹽無顯著差異，地諾單抗可顯著降低接受 AI 治療的絕經(jīng)后乳腺癌患者的骨折次數(shù)并提高患者骨密度且安全性良好。,A501：CAL