BCIRG 006 2006年SABCS乳腺癌

Phase III Trial Comparing AC-T with AC-TH and with TCHin the Adjuvant Treatment of,HER2 positive Early Breast Cancer Patients: Second Interim Efficacy AnalysisSlamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Pawlicki M, Chan A, Smylie M, Liu M, Falkson C, Pinter T, Fornander T, Shiftan T, Valero V, Von Minckwitz G, Mackey J, Tabah-Fisch I, Buyse M, Lindsay MA, Riva A, Bee V, Pegram M, Press M, Crown J, on behalf of the BCIRG 006 Investigators.,Study sponsored by Sanofi-Aventis Support from Genentech,BCIRG 006Slamon D., SABCS 2006,After the presentation these slides will be available at: ,The HER2 Alteration,IHC,SouthernNorthern Western,Slamon et al. Science 1987,1989,BCIRG 006Slamon D., SABCS 2006,Global Project Coordinator,Valerie Bee,4 x AC60/600 mg/m2,4 x Docetaxel100 mg/m2,6 x Docetaxel and Carboplatin75 mg/m2AUC 6,1 Year TrastuzumabSlamon D., SABCS 2006,N=3,222Stratified by Nodes and Hormonal Receptor Status,1 Year Trastuzumab,ACT,ACTH,TCH,Her 2+(Central FISH),N+or high risk N-,4 x AC60/600 mg/m2,4 x Docetaxel100 mg/m2,BCIRG 006,Endpoints,BCIRG 006Slamon D., SABCS 2006,PrimaryDisease-free SurvivalSecondaryOverall SurvivalToxicityPathologic & Molecular Markers,Patient characteristics,%,%,%,636151,5279,AC-TH n=1,074,606351,606350,Mastectomy Radiotherapy Hormonotherapy,5480,5280,Age 10,54,38557,%,%,AC-TH n=1,074,54,54,ER and/or PR +,%,%,Number of nodes +,%,%,Tumor Size (cm),40546,41536, 2 2 and 5 5,TCH n=1,075,AC-T n=1,073,Randomized (n=3,222),BCIRG 006Slamon D., SABCS 2006,Crossover,BCIRG 006Slamon D., SABCS 2006,After the trastuzumab efficacy results were announced in April05, to date:A totalof 17 patients (1.6%) of 1,073 randomized to the the ITT control arm (AC-T) crossed-over to receive trastuzumabLeaving 98.4% of the control arm enrollment intact for subsequent DFS, OS and safety comparison analyses,First/Second Interim Efficacy Analysis,BCIRG 006Slamon D., SABCS 2006,(cutoff date June 30, 2005/November 01, 2006),Median follow-up time = 23 /36 months,322 /462,DFS Events, Breast Cancer Relapse Second Primary Malignancy Death84 /185 Deaths,Disease Free Survival 1stinterim analysis,% Disease Free,0.5,0.6,0.7,0.8,0.9,1.0,0,1,23Year from randomization,4,5,77%73%,Patients Events,BCIRG 006Slamon D., SABCS 2006,86%,80%,84%80%,86%,93%,91%,Disease Free Survival - 2ndInterim Analysis,Absolute DFS benefits (from years 2 to 4):,AC-TH vs AC-T: 6% TCH vs AC-T: 5%,% Disease Free,0.5,0.6,0.7,0.8,0.9,1.0,0,1,23Year from randomization,4,5,77%Patients Events,1073192,AC-TAC-TH HR (AC-TH vs AC-T) = 0.61 0.48;0.76 PT) = 0.67 0.54;0.83 P=0.0003,10741281075142,81%,87%,86%,83%,82%,87%,93%,92%,BCIRG 006Slamon D., SABCS 2006,p-values at Interim Efficacy Analyses,at 1st interim analysisat 2nd interim analysis,147 / 19277 / 128p=0.0000005 / 0.000011,p=0.00015 / 0.00028p=0.16 / 0.42,AC-TH n=1,074,98 / 142,Patients with event,AC-T n=1,073,TCH n=1,075,67 / 98,52 / 93,113 / 143,Metastatic events,HR at 1st interim analysis,0.61,0.49,AC-TH,TCH,0,0.2,0.6,0.8,1.0,0.4,HR at 2nd interim analysis,0.67,BCIRG 006Slamon D., SABCS 2006,0.61,TCH,AC-TH,0,0.2,0.6,0.8,1.0,0.4,Overall Survival 2nd Interim Analysis,0.5,0.6,0.7,1.0,80AC-T49AC-TH HR (AC-TH vs AC-T) = 0.59 0.42;0.85 P=0.00456TCHHR (TCH vs AC-T) = 0.66 0.47;0.93 P=0.0172345,% Survival0.8,0.9,0,1,Patients,Events,107310741075,97%,BCIRG 006Slamon D., SABCS 2006,Year from randomization,99%,98%,93%,97%,95%,92%,91%,86%,Deaths at Interim Efficacy Analyses,20 / 49,AC-TH n=1,074,28 / 56,36 / 80,Total number of deaths from any cause,AC-T n=1,073,TCH n=1,075,21 / 47,19 / 44,33 / 69,Breast Cancer Deaths,at 1st interim analysisat 2nd interim analysis,BCIRG 006Slamon D., SABCS 2006,p=0.004,p=0.017,p=0.58,DFS Lymph Node Negative,2nd Interim Analysis,% Disease Free,0.5,0.6,0.7,0.8,0.9,1.0,0,1,2,3,4,5,Patients,Events,92%,99%,97%,88%,95%,94%,86%,94%,93%,BCIRG 006Slamon D., SABCS 2006,Year from randomization,Overall Survival Lymph Node Negative,2nd Interim Analysis,% Survival0.8,0.5,0.6,0.7,0.9,1.0,0,1,2,3,4,5,Patients Events,100%100%99%98%,98%,96%,93%,97%,98%,BCIRG 006Slamon D., SABCS 2006,Year from randomization,DFS Subpopulations,1.0,0.0,2.0,AC-THbetter,AC-Tbetter,AC-TH vs AC-TSubgroup,Node neg Node pos,HR - HR +,Tsize2cm Tsize=2cm,1.0,0.0,2.0,Subgroup,BCIRG 006Slamon D., SABCS 2006,Node neg Node pos,HR - HR +,Tsize2cm Tsize=2cm,TCH vs AC-T,TCHbetter,AC-Tbetter,Overall Survival Subpopulations,1.0,0.0,2.0,AC-THbetter,AC-Tbetter,AC-TH vs AC-TTCH vs AC-TSubgroupSubgroup,Node neg Node pos,HR - HR +,Tsize2cm Tsize=2cm,1.0,0.0,2.0,Node neg Node pos,HR - HR +,Tsize10% relative LVEF decline,first interim analysissecond interim analysis,P = 0.002 P 0.0001 P 0.0001 P T(N=1012),300,400Days,500,600,700,800,LVEF,AC-TH (N=1040)TCH(N=1029),AC-T,TCH,AC-TH,605958,Mean LVEF - All Observations2nd Interim Analysis,61,62,63,64,6665,0,LVEF points %,100200AC-T (N=1014)AC-TH (N=1042),300,400,500,600,700,800,900,1000,Time since randomization (days),AC-T,TCH,(N=1030),BCIRG 006Slamon D., SABCS 2006,TCH,AC-TH,HER2 and TOPO II in BCIRG 006,2120 of 3222 patients analyzed2990 of 3222 patients analyzed17 q 1217 q 21.117 q 21.2,BCIRG 006Slamon D., SABCS 2006,HER2Core region,1285 pts (60%)1788 pts (60%)91 pts (4%)145 pts (5%),N=2120N=2990,Topo II NonCo-Amplified,Normal,Amplified,Deletion,TOPO IIregion,744 pts (35%)1057 pts (35%),Co-Amplified,first interim analysissecond interim analysis,TOPO IIa (not HER2) Amplificationas a Predictor of Anthracycline Response in Breast Cancer,BCIRG 006Slamon D., SABCS 2006,Since 2002, at least 6 studies have been published demonstrating the association between topo II alpha amplification and improved anthracyline response.,DFS Topo II Co-Amplified vs Non Co-Amplified,All Patients (1st interim analysis),1376,191Non Co-amplified,0.8% Disease Free,0.5,0.6,0.7,0.9,1.0,0,Year from randomization,BCIRG 006Slamon D., SABCS 2006,1,2,3,4,5,Logrank PT AC-TH TCH,Logrank P= 0.24,AC-THAC-TTCH,Year from randomization,BCIRG 006Slamon D., SABCS 2006,DFS Co-Amplified Topo II by Arm(2nd Interim Analysis),% Disease Free,0.5,0.6,0.7,0.8,0.9,1.0,0,1,2,3,4,5,Patients Events,328357359,42AC-T,35AC-TH P=0.336,42TCH,92%,95%,%,87%,89%,87%,85%83%83%,Year from randomization,BCIRG 006Slamon D., SABCS 2006,P=0.648,DFS Non Co-Amplified Topo II by Arm(1st Interim Analysis),% Disease Free0.8,0.6,1.0,0,1,2,3,4,5,Patients,Events,Year from randomization,BCIRG 006Slamon D., SABCS 2006,AC-THTCH,0.5,DFS Non Co-Amplified Topo II by Arm(2nd Interim Analysis),% Disease Free,0.5,0.6,0.7,0.8,0.9,1.0,0,1,2,3,4,5,Patients,Events,643643618,146AC-T87AC-TH92TCH,83%,91%90%85%83%,78%71%,84%,81%,P0.001 P AC-TH,TCH 0,In addition, 23 pts with bona fide HER2 amplification who were randomized to the AC-TH arm never got trastuzumab due to unacceptable declines in LVEF before receiving the antibody,Critical Question,BCIRG 006Slamon D., SABCS 2006,Considering: The recently published data from US Oncology showing a highly statistically significant superiority of docetaxel-cyclophospamide (TC) over adriamycin-cyclophosphamide (AC) in terms of breast cancer efficacy (Jones, S. JCO 24:5381, 2006). The 006 update for HER2 positive malignancies shows the difference in number of DFS events and breast cancer deaths in favor of AC-TH, neither of which are statistically significant, is now exceeded by the number of critical adverse events. These include grade III/IV CHF and AC- related leukemia as well as a small AND sustained loss of LVEF for 18% (189 pts) both of which are highly statistically significantWhat is the role of anthracyclinesin the adjuvant treatment of breast cancer?,Acknowledgements,BCIRG 006Slamon D., SABCS 2006,All participating Investigators and PatientsIDMC (Chair, S Swain) and Independent Cardiac PanelCentral laboratories:M Press (USC), G Sauter(Basel)IDDI: M. BuyseNBCC: Fran Visco and Carolina HinestrosaBCIRG Central Team:V Bee, D Cabaribere, T Kiskartalyi, T Smith,L Lallaoui, H Taupin, K Afenjar, P Drevot, L Andersen, H Fung, J Mortimer, A Riva, MA Lindsay,Giacomi Martinez MickiewiczAUSTRALIA/NZAbdbi BegbieBeith Byard Chan* ChirgwinClingan CraftDalley Dewar Ganju Green Grimes Harvey Isaacs Jameson Kannourakis Koczwara Kotasek LewisLinks Ransom Richardson,Doval,BCIRG 006Slamon D., SABCS 2006,Sullivan Walpole White Young AUSTRIADittrich Sevelda BELGIUMCocquyt Demol Dirix Verhoeven Vermorken BOSNIABeslijaBRAZILFerrari LagoSchwartsmannBULGARIABeslija Timcheva Tzekova CANADADorreen Dufresne Klimo Latreille Lopez,Provencher Roy SehdevSmylie*Wilson Zibdawi COLOMBIAGomez Sanchez Vargas CROATIAGrgicMarkulin-Grgic Mrsic-Krmpotic Vrdoljak CYPRUSAdamouCZECH REPUBLICPetruzelka Vyzula EGYPTAzimEl KhodaryESTONIAPadrik Valvere FRANCEAchille Bonneterre,Carola Colin Dalivoust Dutel Gligorov Guastalla Jaubert Khayat Levy PriouTournigand Valenza Vannetzel GERMANYBreitbach Brunnert Carstensen Christensen Clemens Conrad Dubois Eiermann*Feltz-Sussenbach HempelHenschen Hilfrich Jonat Kettner Klare,Lichtenegger Lrmann Meerpohl Meinerz PrellScharl Schmidt Schweppe Souchon TessenVon MinkwitzWeist Winzer Wolf Zedelius GREECEGeorgouliasHONG KONGChowHUNGARYBaki Dank Pinter*Gupta Julka Ranade Szanto INDIA,Advani,Grogan Keane Kennedy* McCaffrey ISRAELBarakBen BaruchGeffen Goldberg Kaufman Rizel Steiner ITALYBarone BonettiGamucciGasparini Geminiani Iaffaioli MarangoloNardi Pollera Ravaioli LEBANONAbi Gerges Chahine Ghosn Saghir,Principal Investigators involved in the study (I),* Highest recruiters,POLANDBorowska KarnickaPawlicki * Pienkowski * Wojtukiewicz Zaluski ROMANIABadulescu Ghilezan RomanRUSSIAGarinGorbunova SemiglazovSLOVAKIAKoza SpanikSLOVENIACufer TakacSOUTH AFRICAMoodley Pienarr Rapoport SlabberSOUTH KOREABangIm Kim Ro,BCIRG 006Slamon D., SABCS 2006,* Highest recruiters,SPAINAdrover Alba ConejoAlonso Romero AlvarezAles MartinezAranda ArcusaBaena Canad