B-31/N9831 First Interim Joint Analysis NSABP Meeting Baltimore MD 17 September 2005 Edward H. Romond, M.D.

NSABP B-31 NCCTG N9831 Control: ACT Arm 1 Arm 2 Arm A Arm B Arm C Investigational: ACT+H Arm B Arm C = doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4 = paclitaxel (T) 175 mg/m2 q 3 wk x 4 = paclitaxel (T) 80 mg/m2/wk x 12 = trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51

Joint Analysis Flow Diagram Trial Number Registered1 Treatment Arm Number Randomized Accepted / Refused Protocol Therapy (follow-up pending)4 Number with follow-up4 Total per arm with follow-up Joint Analysis Cohort B-31 2043 N9831 2766 1006 (142) 864 18 (10) 8 1015 (152) 863 4 (3) 1 806 (3) 803 13 (9) 4 809 (1) 808 5 (5) 1 1024 2 1019 A 819 (A′)2 (152) (B)3 (981) C 814 / / / / 872 864 807 808 1679 1672 Group 1: ACPTX Group 2: ACPTX+H Total in Intent-to-Treat Comparison 3351 1 B-31: as of 2/15/2005; N9831: as of 11/1/2004 2 (A′): Randomized to Arm A 2/1/1002—9/3/2002 while Arm C was closed to accrual; excluded from joint analysis 3 (B): Excluded from joint analysis 4 B-31: as of 2/15/2005; N9831: as of 3/15/2005

Patient and Tumor Characteristics (%) AC  Paclitaxel + Trastuzumab 872 B-31 807 N9831 864 808 Age <50 50-59 ≥60 52 34 15 51 32 16 50 18 No. Pos Nodes 1-3 4-9 10+ 57 29 14 13 48 25 11 Hormone Receptors ER+ ER- PR+ PR- 53 47 41 58 46 39 60 Tumor Size ≤2.0 cm. 2.1-4.0 cm. >4.0 cm. 43 40 37 44 17 38

Disease-Free Survival ACTH 87% 85% ACT 75% % 67% N Events ACT 1679 261 ACTH 1672 134 HR=0.48, 2P=3x10-12 Years From Randomization B31/N9831

Forest Plot For Disease-Free Survival ALL DATA Age ≥60 50-59 40-49 ≤39 Hormone Receptor Positive Negative Tumor Size ≥ 4.1cm 2.1- 4.0 cm <2.0 cm No. Positive Nodes 10+ 4-9 1-3 Protocol N9831 NSABP B-31 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Hazard Ratio

N9831/B-31 Disease Free Survival By Age

N9831/B-31 DSF By HR Status 1 2 3 4 5 50 70 90 A. Negative B. Positive

B-31/N9831 Disease Free Survival By Path Tumor Size A: <= 2.0cm B: 2.1-4.0cm 90 90 70 70 50 50 1 2 3 4 5 1 2 3 4 5 C: >= 4.1cm 90 70 50 1 2 3 4 5

B-31/N9831 Disease Free Survival By Nodal Status

Disease-Free Survival 1 2 3 4 5 50 60 70 80 90 100 B-31 N9831 ACTH ACTH 87% 87% 85% ACT 86% ACT 78% 74% % 66% 68% N Events N Events ACT 807 90 ACT 872 171 ACTH 808 51 ACTH 864 83 HR=0.45, 2P=1x10-9 HR=0.55, 2P=0.0005 Years From Randomization

Time to First Distant Recurrence 100 ACTH AC->T+H 90% 90% 90% 90% 90% 90% 90 ACT AC->T 80 81% 81% 81% % 74% 70 74% 74% N Events N Events ACTH 1672 96 ACT 1679 194 AC->T 1679 194 60 AC->T+H 1672 96 HR=0.47, 2P=8x10-10 HR=0.47, 2P=8x10-10 50 1 2 3 4 5 Years From Randomization B31/N9831

Hazard of Distant Recurrence 120 100 ACT 80 Rate per 1000 Women /Yr 60 40 ACTH 20 1 2 3 4 Years From Randomization B31/N9831

B-31/N9831 Survival HR=0.67, 2P=0.015 ACTH 94% 91% ACT 92% 87% N Deaths ACT 1679 92 ACTH 1672 62 HR=0.67, 2P=0.015 Years From Randomization B31/N9831

B-31 : HER-2 Retesting at Control Reference Lab (Lab Corp) Initial Test Done at Smaller Volume* Labs Initial Submitted Result Central Herceptest not 3+ Central Path Vysion FISH Neg. Both Central Assays Neg. Herceptest 3+ Other IHC pos. 10/52 11/23 12/52 9/23 10/52 (19%) 8/23 (35%) Total 21/75 18/75 (24%) *Less than 100 assays/month Paik et al.: J Natl Cancer Inst 94:852-854, 2002

Central Herceptest not 3+ Both Central Assays Neg. HER-2 Retesting at Control Reference Lab (Lab Corp) Initial Test Done at Large Volume* Labs Initial Submitted Result Central Herceptest not 3+ Central FISH (PathVysion) Neg Both Central Assays Neg. Herceptest 3+ Other IHC pos. 1/28 0/1 1/28 (4%) 0/1 (0%) Total 1/29 1/29 (3%) *More than 100 assays/month Paik et al.: J Natl Cancer Inst 94:852-854, 2002

B-31Central Review of Cases Entered by FISH * 26/27 cases by PathVysion, 1/27 case by Inform test

Central Review of Cases Entered After Amendment (N=240) * two cases with increase in both HER2 and CEP17 signals were regarded as amplified since both PathVysion and Inform HER2 test were allowed for eligibility Paik, et al.: Breast Cancer Res Treat 2002; 76(suppl 1): S31 (abstr 9)

Genentech: Pamela Klein B-31 N9831 Edward Romond John Bryant Charles Geyer Elizabeth Tan-Chiu Soon Paik Sandra Swain Louis Fehrenbacher Victor Vogel Greg Yothers Ann Brown Terry Mamounas Norman Wolmark Edith Perez Vera Suman Nancy Davidson Silvana Martino Peter Kaufman Thomas Pisansky Leila Kutteh Daniel Visscher Robert Jenkins Shakir Dakhil Wilma Lingle James Ingle Genentech: Pamela Klein