BCIRG 0062006年SABCS乳腺癌

1、Phase III Trial Comparing AC-T with AC-TH and with TCHin the Adjuvant Treatment ofHER2 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, Vale

2、ro 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 GenentechBCIRG 006Slamon D., SABCS 2006After the presentation these slides will be available at:www.

3、 The HER2 AlterationIHCSouthernNorthern WesternSlamon et al. Science 1987,1989BCIRG 006Slamon D., SABCS 2006Global Project CoordinatorValerie Bee4 x AC60/600 mg/m24 x Docetaxel100 mg/m26 x Docetaxel and Carboplatin75 mg/m2AUC 61 Year TrastuzumabSlamon D., SABCS 2006N=3,222Strati

4、fied by Nodes and Hormonal Receptor Status1 Year TrastuzumabAC TAC THTCHHer 2+(Central FISH)N+or high risk N-4 x AC60/600 mg/m24 x Docetaxel100 mg/m2BCIRG 006EndpointsBCIRG 006Slamon D., SABCS 2006PrimaryDisease-free SurvivalSecondaryOverall SurvivalToxicityPathologic & Molecular MarkersPatient

5、characteristics%6361515279AC-TH n=1,074606351606350Mastectomy Radiotherapy Hormonotherapy54805280Age 105438557%AC-TH n=1,0745454ER and/or PR +%Number of nodes +%Tumor Size (cm)4054641536? 2 2 and ? 5 5TCH n=1,075AC-T n=1,073Randomized (n=3,222)BCIRG 006Slamon D., SABCS 2006CrossoverBCIRG 006Slamon D

6、., SABCS 2006After the trastuzumab efficacy results were announced in April 05, to date: A total of 17 patients (1.6%) of 1,073 randomized to the the ITT control arm (AC-T) crossed-over to receive trastuzumab Leaving 98.4% of the control arm enrollment intact for subsequent DFS, OS and safety compar

7、ison analysesFirst/Second Interim Efficacy AnalysisBCIRG 006Slamon D., SABCS 2006(cutoff date June 30, 2005/November 01, 2006)Median follow-up time = 23 /36 months322 /462DFS Events Breast Cancer Relapse Second Primary Malignancy Death84 /185 DeathsDisease Free Survival 1stinterim analysis% Disease

8、Free0123Year from randomization4577%73%Patients EventsBCIRG 006Slamon D., SABCS 200686%80%84%80%86%93%91%1073147AC-T107477AC-TH HR (AC-TH vs AC-T) = 0.49 0.37;0.65 PT) = 0.61 0.47;0.79 P=0.0002Disease Free Survival - 2ndInterim AnalysisAbsolute DFS benefits (from years 2 to 4):AC-T

9、H vs AC-T: 6% TCH vs AC-T: 5% Disease Free0123Year from randomization4577%Patients Events1073192 AC-TAC-TH HR (AC-TH vs AC-T) = 0.61 0.48;0.76 PT) = 0.67 0.54;0.83 P=0.00031074128107514281%87%86%83%82%87%93%92%BCIRG 006Slamon D., SABCS 2006p-values at Interim Efficacy Analysesat 1s

10、t interim analysisat 2nd interim analysis147 / 19277 / 128p=0.0000005 / 0.000011p=0.00015 / 0.00028p=0.16 / 0.42AC-TH n=1,07498 / 142Patients with eventAC-T n=1,073TCH n=1,07567 / 9852 / 93113 / 143Metastatic eventsHR at 1st interim analysis0.610.49AC-THTCH01.00.4HR at 2nd interim analysis0

11、.67BCIRG 006Slamon D., SABCS 20060.61TCHAC-TH01.00.4Overall Survival 2nd Interim Analysis1.080AC-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% Survival0.80.901Patients Events10731074107597%BCIRG 006Slamon D., SABCS 2006Year

12、from randomization99%98%93%97%95%92%91%86%Deaths at Interim Efficacy Analyses20 / 49AC-TH n=1,07428 / 5636 / 80Total number of deaths from any causeAC-T n=1,073TCH n=1,07521 / 4719 / 4433 / 69Breast Cancer Deathsat 1st interim analysisat 2nd interim analysisBCIRG 006Slamon D., SABCS 2006p=0.004p=0.0

13、17p=0.58DFS Lymph Node Negative2nd Interim Analysis% Disease Free012345PatientsEvents92%99%97%88%95%94%86%94%93%BCIRG 006Slamon D., SABCS 2006Year from randomization30935AC-T31012AC-TH HR (AC-TH vs AC-T) = 0.32 0.17;0.62 P=0.000730917TCHHR (TCH vs AC-T) = 0.47 0.26;0.83 P=0.0096Ove

14、rall Survival Lymph Node Negative2nd Interim Analysis% Survival012345Patients Events100%100%99%98%98%96%93%97%98%BCIRG 006Slamon D., SABCS 2006Year from randomization30712AC-T3092AC-THHR (AC-TH vs AC-T) = 0.16 0.04;0.73P=0.0183075TCHHR (TCH vs AC-T) = 0.42 0.15;1.2 P=0.106DFS Subpo

15、pulations1.00.02.0AC-THbetterAC-TbetterAC-TH vs AC-TSubgroupNode neg Node posHR - HR +Tsize2cm Tsize=2cm1.00.02.0SubgroupBCIRG 006Slamon D., SABCS 2006Node neg Node posHR - HR +Tsize2cm Tsize=2cmTCH vs AC-TTCHbetterAC-TbetterOverall Survival Subpopulations1.00.02.0AC-THbetterAC-TbetterAC-TH vs AC-TT

16、CH vs AC-TSubgroupSubgroupNode neg Node posHR - HR +Tsize2cm Tsize=2cm1.00.02.0Node neg Node posHR - HR +Tsize 30)214242234Hypertension177177190Radiotherapy (# of Pts)662656671After chemotherapyTo left chest346320333Cardiac Deaths and CHFas per Independent Review Panelfirst interim analysissecond in

17、terim analysisP = 0.0015AC-T n=1,050AC-TH n=1,068TCH n=1,056Cardiac related death0 / 00 / 00 / 0Cardiac left ventricular function (CHF) Grade 3 / 43 / 417 / 204 / 4Patients with 10% relative LVEF declinefirst interim analysissecond interim analysisP = 0.002 P 0.0001 P 0.0001 P T(N=1012)300400Days500

18、600700800LVEFAC-TH (N=1040)TCH(N=1029)AC-TTCHAC-TH605958Mean LVEF - All Observations2nd Interim Analysis6162636466650LVEF points %100200AC-T (N=1014)AC-TH (N=1042)3004005006007008009001000Time since randomization (days)AC-TTCH(N=1030)BCIRG 006Slamon D., SABCS 2006TCHAC-THHER2 and TOPO II in BCIRG 00

19、62120 of 3222 patients analyzed2990 of 3222 patients analyzed17 q 1217 q 21.117 q 21.2BCIRG 006Slamon D., SABCS 2006HER2Core region1285 pts (60%)1788 pts (60%)91 pts (4%)145 pts (5%)N=2120N=2990Topo II NonCo-AmplifiedNormalAmplifiedDeletionTOPO IIregion744 pts (35%)1057 pts (35%)Co-Amplifiedfirst in

20、terim analysissecond interim analysisTOPO IIa (not HER2) Amplificationas a Predictor of Anthracycline Response in Breast CancerBCIRG 006Slamon D., SABCS 2006Since 2002, at least 6 studies have been published demonstrating the association between topo II alpha amplification and improved anthracyline

21、response.StudyYrNPark et al.2006284Tanner et al.2006525Knoop at al.2005805Park et al.2003188Coon et al.200235Di Leo et al.2002354DFS Topo II Co-Amplified vs Non Co-AmplifiedAll Patients (1st interim analysis)1376191Non Co-amplified0.8% Disease Free0.91.00Year from randomizationBCIRG 006Slam

22、on D., SABCS 200612345Logrank P0.001Co-AmplifiedNon Co-amplifiedPatientsEvents Topo II74457Co-AmplifiedDFS Topo II Co-Amplified vs Non Co-Amplified All Patients (2nd interim analysis)% Disease Free012345Patients Events Topo II94%88%88%82%84%78%Non Co-amplifiedCo-AmplifiedYear from

23、randomizationBCIRG 006Slamon D., SABCS 20061044 119Co-Amplified1904 325Non Co-amplifiedHR (Co-Amp vs Non Co-Amp) = 1.44 1.16;1.78 PT AC-TH TCHLogrank P= 0.24AC-THAC-TTCHYear from randomizationBCIRG 006Slamon D., SABCS 2006DFS Co-Amplified Topo II by Arm(2nd Interim Analysis)% Disease Free0.

24、80.91.0012345Patients Events32835735942AC-T35AC-TH P=0.33642TCH92%95%87%89%87%85%83%83%Year from randomizationBCIRG 006Slamon D., SABCS 2006P=0.64894DFS Non Co-Amplified Topo II by Arm(1st Interim Analysis)% Disease Free012345PatientsEventsYear from randomizationBCIRG 006Slamon D., SABCS 20

25、06AC-THTCH0.545892AC-T47245AC-THLogrank P= T44654TCHDFS Non Co-Amplified Topo II by Arm(2nd Interim Analysis)% Disease Free012345Patients Events643643618146 AC-T87 AC-TH92 TCH83%91%90%85%83%78%71%84%81%P0.001 P AC-THTCH 0In addition, 23 pts with bona fide HER2 amplification who wer

26、e randomized to the AC-TH arm never got trastuzumab due to unacceptable declines in LVEF before receiving the antibody OSAC-TH -49TCH 56 Br Ca DeathsAC-TH -44TCH 47Critical QuestionBCIRG 006Slamon D., SABCS 2006Considering: The recently published data from US Oncology showing a highly statistically

27、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, nei

28、ther 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 anthrac

29、yclinesin the adjuvant treatment of breast cancer?AcknowledgementsBCIRG 006Slamon D., SABCS 2006All 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 HinestrosaBCI

30、RG 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 LindsayGiacomi Martinez MickiewiczAUSTRALIA/NZAbdbi BegbieBeith Byard Chan* ChirgwinClingan CraftDalley Dewar Ganju Green Grimes Harvey Isaacs Jameson Kan

31、nourakis Koczwara Kotasek LewisLinks Ransom RichardsonDovalBCIRG 006Slamon D., SABCS 2006Sullivan Walpole White Young AUSTRIADittrich Sevelda BELGIUMCocquyt Demol Dirix Verhoeven Vermorken BOSNIABeslijaBRAZILFerrari LagoSchwartsmannBULGARIABeslija Timcheva Tzekova CANADADorreen Dufresne Klimo Latrei

32、lle LopezProvencher Roy SehdevSmylie*Wilson Zibdawi COLOMBIAGomez Sanchez Vargas CROATIAGrgicMarkulin-Grgic Mrsic-Krmpotic Vrdoljak CYPRUSAdamouCZECH REPUBLICPetruzelka Vyzula EGYPTAzimEl KhodaryESTONIAPadrik Valvere FRANCEAchille BonneterreCarola Colin Dalivoust Dutel Gligorov Guastalla Jaubert Kha

33、yat Levy PriouTournigand Valenza Vannetzel GERMANYBreitbach Brunnert Carstensen Christensen Clemens Conrad Dubois Eiermann*Feltz-Sussenbach HempelHenschen Hilfrich Jonat Kettner KlareLichtenegger Lrmann Meerpohl Meinerz PrellScharl Schmidt Schweppe Souchon TessenVon MinkwitzWeist Winzer Wolf Zedeliu

34、s GREECEGeorgouliasHONG KONGChowHUNGARYBaki Dank Pinter*Gupta Julka Ranade Szanto INDIAAdvaniGrogan Keane Kennedy* McCaffrey ISRAELBarakBen BaruchGeffen Goldberg Kaufman Rizel Steiner ITALYBarone BonettiGamucciGasparini Geminiani Iaffaioli MarangoloNardi Pollera Ravaioli LEBANONAbi Gerges Chahine Gh

35、osn SaghirPrincipal Investigators involved in the study (I)* Highest recruitersARGENTINASchwarzMackey*BressacKretzschmarIRELANDFeinStewartPotvinCalsKullmerCrown*POLANDBorowska KarnickaPawlicki * Pienkowski * Wojtukiewicz Zaluski ROMANIABadulescu Ghilezan RomanRUSSIAGarinGorbunova SemiglazovSLOVAKIAKoza SpanikSLOVENIACufer TakacSOUTH AFRICAMoodley Pienarr Rapoport SlabberSOUTH KOREABangIm Kim RoBCIRG 006Slamon D., SABCS 2006* Hi