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Study sponsored by Sanofi-Aventis Support from Genentech

Phase III Trial Comparing AC-T with AC-TH and with TCH in the Adjuvant Treatment of HER2 positive Early Breast Cancer Patients: Second Interim Efficacy Analysis.

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Study sponsored by Sanofi-Aventis Support from Genentech

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  1. 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 Analysis Slamon 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

  2. After the presentation these slides will be available at:www.sabcs.orgwww.cirg.org

  3. The HER2 Alteration Southern Northern Western IHC Slamon et al. Science 1987,1989

  4. Global Project Coordinator Valerie Bee

  5. BCIRG 006 4 x Docetaxel 100 mg/m2 4 x AC60/600 mg/m2 ACT Her 2+ (Central FISH) N+ or high riskN- 4 x Docetaxel 100 mg/m2 4 x AC60/600 mg/m2 ACTH 1 Year Trastuzumab 6 xDocetaxel and Carboplatin 75 mg/m2 AUC 6 N=3,222 TCH Stratified by Nodes and Hormonal Receptor Status 1 Year Trastuzumab Slamon D., SABCS 2006

  6. Endpoints Primary • Disease-free Survival Secondary • Overall Survival • Toxicity • Pathologic & Molecular Markers

  7. Patient characteristics Enrollment: April 2001 to March 2004

  8. Tumor Characteristics

  9. Crossover After 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 toreceive trastuzumab • Leaving98.4%of the control arm enrollment intact for subsequent DFS, OS and safety comparison analyses

  10. First Interim Efficacy Analysis(cutoff date June 30, 2005 ) /Second /November 01, 2006 /36 /462 /185 • Median follow-up time = 23 months • 322 DFS Events • Breast Cancer Relapse • Second Primary Malignancy • Death • 84 Deaths

  11. Disease Free Survival – 1st interim analysis 1.0 93% 0.9 91% 86% 84% 86% 80% 80% 0.8 77% % Disease Free 73% 0.7 Patients Events 0.6 1073 147 AC->T HR (AC->TH vs AC->T) = 0.49 [0.37;0.65] P<0.0001 1074 77 AC->TH 1075 98 TCH HR (TCH vs AC->T) = 0.61 [0.47;0.79] P=0.0002 0.5 0 1 2 3 4 5 Year from randomization

  12. Disease Free Survival - 2nd Interim Analysis Absolute DFS benefits (from years 2 to 4): ACTH vs ACT: 6% TCH vs ACT: 5% 1.0 93% 0.9 87% 92% 83% 86% 87% 82% 0.8 81% % Disease Free 77% 0.7 Patients Events 1073 192 AC->T 0.6 HR (AC->TH vs AC->T) =0.61 [0.48;0.76]P<0.0001 1074 128 AC->TH HR (TCH vs AC->T) =0.67 [0.54;0.83]P=0.0003 1075 142 TCH 0.5 0 1 2 3 4 5 Year from randomization

  13. p-values at Interim Efficacy Analyses / 192 / 128 / 142 / 0.000011 at 2nd interim analysis / 0.00028 / 0.42 HR at 1st interim analysis HR at 2nd interim analysis TCH 0.61 TCH 0.67 AC-TH 0.61 0.49 AC-TH 0 0.2 0.4 0.6 0.8 1.0 0 0.2 0.4 0.6 0.8 1.0 at 1st interim analysis p=0.0000005 p=0.00015 p=0.16

  14. Overall Survival – 2nd Interim Analysis 1.0 99% 97% 98% 97% 95% 92% 93% 0.9 91% 86% % Survival 0.8 0.7 Patients Events 0.6 1073 80 AC->T HR (AC->TH vs AC->T) =0.59 [0.42;0.85]P=0.004 1074 49 AC->TH HR (TCH vs AC->T) =0.66 [0.47;0.93]P=0.017 1075 56 TCH 0.5 1 0 2 3 4 5 Year from randomization

  15. Deaths at Interim Efficacy Analyses / 80 / 49 / 56 p=0.004 at 2nd interim analysis p=0.017 p=0.58 at 1st interim analysis

  16. DFS Lymph Node Negative2nd Interim Analysis 99% 1.0 95% 94% 97% 94% 93% 0.9 92% 88% 86% 0.8 % Disease Free 0.7 Patients Events 0.6 309 35 AC->T 310 12 AC->TH HR (AC->TH vs AC->T) =0.32 [0.17;0.62] P=0.0007 309 17 TCH HR (TCH vs AC->T) =0.47 [0.26;0.83] P=0.0096 0.5 0 1 2 3 4 5 Year from randomization

  17. Overall Survival Lymph Node Negative2nd Interim Analysis 100% 100% 1.0 98% 99% 98% 97% 98% 96% 93% 0.9 % Survival 0.8 0.7 Patients Events 307 12 AC->T 0.6 HR (AC->TH vs AC->T) =0.16 [0.04;0.73]P=0.018 309 2 AC->TH 307 5 TCH HR (TCH vs AC->T) =0.42 [0.15;1.2]P=0.106 0.5 0 1 2 3 4 5 Year from randomization

  18. DFS Subpopulations AC-TH vs AC-T TCH vs AC-T Subgroup Subgroup Node neg Node neg Node pos Node pos HR - HR - HR + HR + Tsize<2cm Tsize<2cm Tsize≥2cm Tsize≥2cm 0.0 1.0 2.0 0.0 1.0 2.0 AC-TH better AC-T better TCH better AC-T better

  19. Overall Survival Subpopulations AC-TH vs AC-T TCH vs AC-T Subgroup Subgroup Node neg Node neg Node pos Node pos HR - HR - HR + HR + Tsize<2cm Tsize<2cm Tsize≥2cm Tsize≥2cm 0.0 1.0 2.0 0.0 1.0 2.0 AC-TH better AC-T better TCH better AC-T better

  20. Safety Results

  21. Grade 3/4 Non-Hematological toxicity * * * * * Yellow = numerically less events AC-TH or TCH *Statistically significant AC-TH or TCH

  22. Specific non-hematological toxicity (all grades) * * * * Yellow = numerically less events AC-TH or TCH *Statistically significant AC-TH or TCH

  23. Grade 3/4 Hematological Toxicity * * * * Yellow = numerically less events AC-TH or TCH *Statistically significant AC-TH or TCH

  24. CARDIAC TOXICITY

  25. Cardiovascular risk factors

  26. Cardiac Deaths and CHF as per Independent Review Panel / 0 / 0 / 0 / 4 / 4 / 20 P = 0.0015 second interim analysis first interim analysis

  27. Patients with >10% relative LVEF decline /1014 /1042 /1030 /189 /89 /102 /10 /18 /8.6 P <0.0001 P <0.0001 P = 0.5 second interim analysis P <0.0001 P = 0.002 first interim analysis P = 0.5

  28. Mean LVEF - All Observations1st Interim Analysis 66 65 TCH 64 63 LVEF AC->T 62 AC->TH 61 60 59 0 100 200 300 400 500 600 700 800 AC->T(N=1012) Days AC->TH(N=1040) TCH (N=1029)

  29. Mean LVEF - All Observations2nd Interim Analysis 66 65 TCH 64 AC->T 63 62 LVEF points % AC->TH 61 60 59 58 0 100 200 300 400 500 600 700 800 900 1000 AC->T (N=1014) Time since randomization (days) AC->TH (N=1042) TCH (N=1030)

  30. Normal Amplified Deletion 2990 of 3222 patients analyzed TOPO II region N=2990 Topo II NonCo-Amplified 1788 pts (60%) 145 pts (5%) Co-Amplified 744 pts (35%) 1057 pts (35%) second interim analysis HER2 and TOPO II in BCIRG 006 2120 of 3222 patients analyzed 17 q 12 17 q 21.1 17 q 21.2 HER2 Core region N=2120 1285 pts (60%) 91 pts (4%) first interim analysis

  31. TOPO IIa (not HER2) Amplification as a Predictor of Anthracycline Response in Breast Cancer Since 2002, at least 6 studies have been published demonstrating the association between topo II alpha amplification and improved anthracyline response.

  32. DFS Topo II Co-Amplified vs Non Co-Amplified All Patients (1st interim analysis) 1.0 0.9 Co-Amplified % Disease Free 0.8 Non Co-amplified 0.7 Patients Events Topo II 744 57 Co-Amplified Logrank P<0.001 1376 191 Non Co-amplified 0.6 0.5 1 2 3 4 5 0 Year from randomization

  33. DFS Topo II Co-Amplified vs Non Co-Amplified All Patients (2nd interim analysis) 1.0 94% 0.9 88% 88% 84% Co-Amplified 0.8 82% % Disease Free 78% Non Co-amplified 0.7 Patients Events Topo II 0.6 Co-Amplified 1044 119 Non Co-amplified HR (Co-Amp vs Non Co-Amp) =1.44 [1.16;1.78]P<0.001 1904 325 0.5 0 1 2 3 4 5 Year from randomization

  34. DFS Co-Amplified Topo II by Arm (1st Interim Analysis) 1.0 AC->TH AC->T 0.8 % Disease Free TCH Patients Events AC->T 227 23 0.6 Logrank P= 0.24 265 13 AC->TH 252 21 TCH 0.5 0 1 2 3 4 5 Year from randomization

  35. DFS Co-Amplified Topo II by Arm (2nd Interim Analysis) 1.0 95% 94% 89% 0.9 92% 87% % Disease Free 87% 85% 83% 0.8 83% 0.7 Patients Events 0.6 328 42 AC->T 357 35 AC->TH P=0.336 359 42 TCH P=0.648 0.5 0 1 2 3 4 5 Year from randomization

  36. DFS Non Co-Amplified Topo II by Arm (1st Interim Analysis) 1.0 0.8 % Disease Free AC->TH TCH Patients Events 0.6 458 92 AC->T 472 45 AC->TH Logrank P= <0.001 AC->T 446 54 TCH 0.5 0 1 2 3 4 5 Year from randomization

  37. DFS Non Co-Amplified Topo II by Arm (2nd Interim Analysis) 1.0 91% 0.9 90% 85% % Disease Free 83% 84% 83% 0.8 81% 78% 71% 0.7 Patients Events 0.6 643 146 AC->T P<0.001 643 87 AC->TH 618 92 TCH P<0.001 0.5 0 1 2 3 4 5 Year from randomization

  38. Therapeutic Index – Most Recent Data • Difference in DFS, OS and BC death events (ITT) between the 2 Herceptin-containing arms • DFS AC-TH - 128 TCH – 142 • OS AC-TH - 49 TCH – 56 • Br Ca Deaths AC-TH - 44 TCH – 47 • Difference in critical adverse events between anthracycline and non-anthracycline containing arms • Grade 3/4 CHF • AC-T - 5 AC-TH - 20TCH - 4 • Leukemia • Anthracycline-Based Arms - 4 TCH – 0 • Global safety TCH > AC-TH • 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

  39. Critical Question • 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 significant… What is the role of anthracyclines in the adjuvant treatment of breast cancer?

  40. Acknowledgements • All participating Investigators and Patients • IDMC (Chair, S Swain) and Independent Cardiac Panel • Central laboratories: M Press (USC), G Sauter (Basel) • IDDI: M. Buyse • NBCC: Fran Visco and Carolina Hinestrosa • BCIRG 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

  41. Principal Investigators involved in the study (I) * Highest recruiters

  42. Principal Investigators involved in the study (II) POLAND SPAIN Tezcan Touroutouglou Borowska Adrover Valero* Karnicka Alba Conejo Vaughn Pawlicki * Alonso Romero Vogel Alvarez Pienkowski * Ales Martinez Waintraub Wojtukiewicz Aranda Waisman Zaluski Arcusa Walker ROMANIA Baena Canada Wallmark Badulescu Calvo Martinez Yost Ghilezan Crespo Young Roman Dominguez Yunus RUSSIA Garcia Estevez VENEZUELA Garin Florian Gerico De Joghn Gorbunova Jara Vera Semiglazov Margeli SLOVAKIA Martin* Koza Martin Lorente Spanik Mel Lorenzo SLOVENIA Oltra Ferrando Cufer Pelegri Takac SWEDEN SOUTH AFRICA Fornander* Moodley SWITZERLAND Pienarr Aapro Rapoport TAIWAN Slabber Chao SOUTH KOREA Liu * Bang TUNISIA Im Kim Mezlini Ro Frikha Fesen TURKEY Nair Goodman Aydiner Neel Greenwald Nicholls Baltali Grosbach Olopade UK Hajdenberg Orlowski Chan Osborn Houston sherwin Page Jhangiani Wardley Patel Jones URUGUAY Patton Justice Rodriguez Petruska Juturi Krygier Philip Kalman USA Polikoff Kennedy Abukabr Polikoff (network) Kerr Adler Posada Kincaid Rahman Appelbaum Koneky Rangineni Ansari Laufman Reich Arena Lemon Reiling Beall Lewis Rinaldi Berdeaux Limentani Robert (USO)* Beattie Link Rodriguez Bianco Lower Rubin Boros Mac Andrew Russell Brufsky Malamud Schwatzberg Burris Mc Croskey Shaffer Carroll Shiftan* McKeen Chakrabarti Mena Silvermann Chitneni Mills Slamon * Chowhan Modiano Sparano Chuu Moore Sylvester Cobb Tang Moroose Dreisbach Tansino Moss Falkson* Tchekmedyian * Highest recruiters

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