HERCEPTIN Herceptin [trastuzumab] Herceptin Small Tumor

HERCEPTIN Herceptin [trastuzumab] Herceptin Small Tumor
Foundation of care in women with HER2-positive breast cancer Update 2010 Herceptin Small Tumor Efficacy is consistent across tumor size and nodal status Herceptin KIT MBC Ref: Marla SABCS 2008; poster 3159 Slamon DJ et Science 1989;244: Slamon DJ Science 1987;235: Penault-Llorca F et al. J Clin Oncol 2005;23:16s,abstract 764

Herceptin® (trastuzumab)
Foundation of care in women with HER2-positive breast cancer Update 2010 This document contains information outside of the indications of Herceptin

HER2: role in breast cancer
Human epidermal growth factor receptor 2 (HER2) is a transmembrane protein and part of the HER family of 4 growth factor receptors (HER1/EGFR to HER4) Overexpression of HER2 and / or amplification of the HER2 gene occurs in up to 15% of breast cancers HER2 positivity is associated with aggressive disease a high risk of relapse poor survival Ref: Marla SABCS 2008; poster 3159 Slamon DJ et Science 1989;244: Slamon DJ Science 1987;235: Penault-Llorca F et al. J Clin Oncol 2005;23:16s,abstract 764 Marla 2008 Slamon 1989 Slamon 1987 Penault-Llorca 2005

HER2 = Important therapeutic target
Ref: Spector J Clin Oncol 2009;27: Spector 2009

5 mechanisms of action Herceptin inhibits proliferation and
Ref: Spector J Clin Oncol 2009;27: t Action 1 + t Action 2 + t Action 3 + t Action 4 + t Action 5 Herceptin inhibits proliferation and induces apoptosis of HER2+ tumor cells Spector 2009

Herceptin : Expertise in all stages of Breast Cancer
EBC MBC Neoadjuvant Surgery Relapse Progression Adjuvant 1st line 2nd+ lines TECHNO NOAH GeparQuinto NeoAltto NeoSphere HERA NSABP-B31 NCCTG N9831 BCIRG 006 FinHer PACS-04 HO648g M77001 BCIRG 007 CHAT TAnDEM RHEA GBG-26 EGF Numerous Phase II studies EBC: Early Breast Cancer MBC: Metastatic Breast Cancer 6

Why do we give neoadjuvant therapy to patients with HER2-positive breast cancer?
Decrease primary tumor size Surgical removal of previously inoperable tumor1 Increase chance of breast-conserving surgery2,3 Assess chemoresponsiveness of tumor4-6 Predict outcome by assessment of tumor response5,7 Decrease residual cancer burden8 Improve long-term outcome4,8 Reduce micrometastases4 van der Hage JA, van de Velde CJ, Mieog JS, Preoperative chemotherapy for women with operable breast cancer. Cochrane Database Syst Rev Apr 18;(2):CD Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, Wickerham DL, Begovic M, DeCillis A, Robidoux A, Margolese RG, Cruz AB Jr, Hoehn JL, Lees AW, Dimitrov NV, Bear HD. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol Aug;16(8): van der Hage JA, van de Velde CJ, Julien JP, Tubiana-Hulin M, Vandervelden C, Duchateau L. Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial J Clin Oncol Nov 15;19(22): Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, Buzdar AU, Singletary SE, Hortobagyi GN, Pusztai L. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol Oct 1;25(28): Epub 2007 Sep 4. Connolly R, Stearns V. A multidisciplinary approach to neoadjuvant therapy for primary operable breast cancer. Challenges and opportunities. Oncology (Williston Park) Feb;24(2): von Minckwitz G, Untch M, Nüesch E, Loibl S, Kaufmann M, Kümmel S, Fasching PA, Eiermann W, Blohmer JU, Costa SD, Mehta K, Hilfrich J, Jackisch C, Gerber B, du Bois A, Huober J, Hanusch C, Konecny G, Fett W, Stickeler E, Harbeck N, Müller V, Jüni P. Impact of treatment characteristics on response of different breast cancer phenotypes: pooled analysis of the German neo-adjuvant chemotherapy trials. Breast Cancer Res Treat Nov 3. [Epub ahead of print] von Minckwitz G. Preoperative therapy: what, when and for whom? Ann Oncol Jul;19 Suppl 5:v113-6. Kaufmann M, von Minckwitz G, Bear HD, Buzdar A, McGale P, Bonnefoi H, Colleoni M, Denkert C, Eiermann W, Jackesz R, Makris A, Miller W, Pierga JY, Semiglazov V, Schneeweiss A, Souchon R, Stearns V, Untch M, Loibl S. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives Ann Oncol Dec;18(12): Epub 2007 Nov 12. 1. van der Hage et al. 2007; 2. Fisher et al van der Hage et al. 2001; 4. Connolly and Stearns von Minckwitz et al. 2008; 6. Kaufmnann et al von Minckwitz et al. 2010; 8. Symanns et al. 2007

Assessing response: pathological complete response as surrogate for survival (NSABP-B27)
2411 patients with primary operable breast cancer Primary endpoint: OS and DFS pCR was a significant predictor of OS, regardless of treatment (hazard ratio = 0.33; 95% CI: 0.23–0.47; P<0.0001) 100 pCR (n=410) Bear HD, Anderson S, Smith RE, Geyer CE Jr, Mamounas EP, Fisher B, Brown AM, Robidoux A, Margolese R, Kahlenberg MS, Paik S, Soran A, Wickerham DL, Wolmark N. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer:National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol May 1;24(13): Epub 2006 Apr 10. 80 Overall Survival (%) non-pCR (n=1889) 60 40 1 2 3 4 5 6 7 Years after surgery Bear et al. 2006

NOAH: Study design 9 HER2-positive (IHC 3+ or FISH+)
HER2-negative (IHC 0/1+) n=118 n=117 n=99 AT q3w x 3 cycles H + AT q3w x 3 cycles AT q3w x 3 cycles T q3w x 4 cycles H + T q3w x 4 cycles T q3w x 4 cycles CMF q4w x 3 cycles H q3w x 4 cycles + CMF q4w x 3 cycles CMF q4w x 3 cycles Surgery followed by radiotherapy Ref: Gianni Lancet 2010;375: Surgery followed by radiotherapy Surgery followed by radiotherapy H continued q3w to Week 52 Median follow-up = 3 years H, trastuzumab (8 mg/kg loading dose then 6 mg/kg); AT, doxorubicin (60 mg/m2), paclitaxel (150 mg/m2); q3w, every 3 weeks; T, paclitaxel (175 mg/m2); q4w, every 4 weeks CMF: Cyclophosphamide (600mg/m2), Methotrexate (40mg/m2), Fluorouracil (600mg/m2) Gianni 2010 9

NOAH: Herceptin almost doubles pCR rates
10 20 30 40 50 Without Herceptin With Herceptin Patients with pCR, % p=0.0007 43% n=117 n=118 22% Ref: Gianni Lancet 2010;375: Median follow-up = 3 years pCR = pathological Complete Response Gianni 2010 10

NOAH: Herceptin extends event-free survival
1.00 0.75 Probability, event-free survival 0.50 3-year EFS (%) 0.25 n Events HR 95% CI p valuea Ref: Gianni Lancet 2010;375: CTx Herceptin + CTx 0.59 0.013 0.00 6 12 18 24 30 36 42 Months Median follow-up = 3 years a Unadjusted for stratification variables CTx: chemotherapy Gianni 2010

NOAH : Herceptin is well tolerated with acceptable cardiac safety
Without Herceptin n=113 3 4 2 1 With Herceptin n=115 1 2 3 Selected grade ¾ adverse events (%) Arthralgia Diarrhea Febrile neutropenia Infection LVEF decline Myalgia Neuropathy peripheral Neutropenia Pneumonia Stomatitis Ref: Gianni Lancet 2010;375: Gianni 2010

TECHNO Trial : PCR after NeoAdjuvant Chemotherapy predicts survival

(no invasive/ non-invasive residual in breast & nodes )
Geparquinto : pCR with Herceptin is statistically better than with lapatinib. 60% 50.4% 50% 40% 35.2% 30% P<0.05 20% 10% Marty et al Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer administered as first-line treatment: the M77001 study group J.Clin.Oncol. 2005; 23 (19): EC + Doc + Herceptin EC + Doc + lapatinib (no invasive/ non-invasive residual in breast & nodes ) Untch M, et al. SABCS 2010;#S3-1 14

NeoSphere : pCR % Response Gianni L, et al. SABCS 2010;#S3-2 60% 45.8
50% 40% 29,0 % Response 30% 24.0% 20% 16.8% 10% Herceptin + Doecetaxel Herceptin + Pertuzumab + Docetaxel Herceptin + Pertuzumab Pertuzumab + Docetaxel Gianni L, et al. SABCS 2010;#S3-2

NeoAltto Study Pathological Complete Response
60% 51.3% 50% 40% 29.5% % Response 30% 24.7 20% 10% lapatinib Herceptin Herceptin + lapatinib Baselga J, et al. SABCS 2010;#S3-3

EBC MBC Neoadjuvant Surgery Relapse Progression Adjuvant 1st line 2nd+ lines NOAH MDACC GeparQuattro Numerous Phase II studies HERA NSABP-B31 NCCTG N9831 BCIRG 006 FinHer PACS-04 HO648g M77001 BCIRG 007 CHAT TAnDEM RHEA GBG-26 EGF Numerous Phase II studies EBC: Early Breast Cancer MBC: Metastatic Breast Cancer

Key trastuzumab studies in HER2-positive EBC
Extensive clinical programme involving >12,000 patients Study N Treatment arms Follow-up (yrs) HERA1 5102 CT* ± RT  observation CT* ± RT  trastuzumab 1 year CT* ± RT  trastuzumab 2 years 4 BCIRG 0062 3222 AC  docetaxel AC  docetaxel+trastuzumab  trastuzumab Docetaxel+carboplatin+trastuzumab  trastuzumab 5 NCCTG N98313 2614 AC  paclitaxel AC  paclitaxel  trastuzumab AC  paclitaxel+trastuzumab  trastuzumab NSABP B-313 2043 References Gianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244. Slamon D, Eiermann W, Robert N, et al. BCIRG 006 phase III trial comparing AC→T with AC→TH and with TCH in the adjuvant treatment of HER2-amplified early breast cancer patients: Third planned efficacy analysis. Oral presentation at the 32nd San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 1013 December 2009 (Abstract 62). Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373. *Chemotherapy selected from a list of approved regimens consisting of ≥4 cycles 1. Gianni L, et al. 2011; 2. Slamon D, et al. 2009; 3. Perez EA, et al. 2011

Pivotal adjuvant trials all now published
Conclusions Pivotal adjuvant trials all now published HERA Joint Analysis BCIRG-006

HERA (BO16348) HERceptin Adjuvant (HERA): A randomised three-arm multicentre comparison of 1 year and 2 years of trastuzumab versus no trastuzumab in women with HER2-positive primary breast cancer who have completed adjuvant chemotherapy

HERA study design Women with locally determined HER2-positive invasive early breast cancer Surgery + (neo)adjuvant CTx ± RT Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55% Randomisation Observation 1 year Herceptin 8 mg/kg mg/kg 3-weekly schedule 2 years Herceptin 8 mg/kg 6 mg/kg 3-weekly schedule Ref: Gianni et al. Oral presentation 25 at the 11th International Conference on the Primary Therapy of Early Breast Cancer, St Gallen, Switzerland, March 2009 After ASCO 2005, option of crossover to Herceptin CTx: chemotherapy RT: radiotherapy Gianni 2009 21

HERA: Key inclusion criteria
Histologically confirmed, completely excised, invasive breast cancer Centrally confirmed HER2 overexpression (IHC 3+) or amplification (FISH+) Node-positive or (sentinel) node-negative with >T1c Completed >4 cycles of approved adjuvant or neoadjuvant CT Baseline LVEF >55% (ECHO or MUGA scan) after completion of (neo)adjuvant CT and RT Known hormone receptor status Reference Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer N Engl J Med 2005; 353:16591672. Piccart-Gebhart MJ, et al. 2005 22

HERA: Endpoints Primary endpoint DFS Trastuzumab 1 year vs observation
Trastuzumab 2 years vs observation Secondary endpoints OS, TTR, TTDR, cardiac safety Trastuzumab 1 year vs trastuzumab 2 years References Gianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244. Smith I, Procter M, Gelber RD, et al; HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 369:2936. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer N Engl J Med 2005; 353:16591672. Gianni L, et al. 2011; Smith I, et al. 2007; Piccart-Gebhart MJ, et al. 2005 23 23 23

HERA: Cardiac safety endpoints
Assessment of specific cardiac events Severe CHF Symptomatic CHF Significant LVEF drop Confirmed significant LVEF drop Three interim analyses of cardiac endpoints after n=300, n=600 and n=900 patients treated/followed for 6 months Stopping guideline: ≥4% absolute increase in pre-defined cardiac events Reference Suter TM, Procter M, van Veldhuisen DJ, et al. Trastuzumab-associated cardiac adverse effects in the Herceptin adjuvant trial. J Clin Oncol 2007; 25:38593865. Suter TM, et al. 2007 24 24

HERA: Study timeline 1st interim analysis (n=475 DFS events)
2-year follow-up (n=539 DFS events) 4-year follow-up (n=827 DFS events) Anticipated release of 2-year data* 2005 2006 2007 2008 2009 2010 2011 Q3/4 2012 References Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer N Engl J Med 2005; 353:16591672. Smith I, Procter M, Gelber RD, et al; HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 369:2936. Gianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244. DFS data: ASCO NEJM1 OS data: ASCO OS data: Lancet2 4-year data: St Gallen 4-year data: Lancet Oncol3 *Event-driven analysis: 725 OS events required 1. Piccart-Gebhart MJ, et al. 2005; 2. Smith I, et al. 2007;3. Gianni L, et al. 2011

HERA: Patient characteristics (1)
Patients, % Observation (n=1698) Trastuzumab 1 year (n=1703) Age, years <35 7 8 35−49 44 50−59 32 ≥60 16 Prior (neo)adjuvant CT No anthracyclines 6 Anthracyclines, no taxanes 68 Anthracyclines + taxanes 26 Reference Gianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244. Gianni L, et al. 2011 26 26

HERA: Patient characteristics (2)
Patients, % Observation (n=1698) Trastuzumab 1 year (n=1703) Menopausal status* Premenopausal 14 15 Postmenopausal 45 Uncertain 41 40 Hormone receptor status Negative 50 Positive Nodal status Neoadjuvant CT 10 11 33 32 13 29 ≥4 28 Reference Gianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244. *Status at randomisation Gianni L, et al. 2011 27

Interim analysis and IDMC recommendations
As specified in the protocol, an interim analysis of 1-year vs 2-year Herceptin was performed in Q3 2008 The IDMC reviewed the interim analysis on 20 October 2008 and recommended that: no information on the 1-year vs 2-year Herceptin be released updated information on the 1-year Herceptin vs observation be presented and published Ref: Gianni et al. Oral presentation 25 at the 11th International Conference on the Primary Therapy of Early Breast Cancer, St Gallen, Switzerland, March 2009 IDMC: Independent Data Monitoring Committee Gianni 2009

HERA study design Women with locally determined HER2-positive invasive early breast cancer Surgery + (neo)adjuvant CTx ± RT Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55% Randomisation Observation 1 year Herceptin 8 mg/kg mg/kg 3-weekly schedule 2 years Herceptin 8 mg/kg mg/kg 3-weekly schedule Ref: Gianni et al. Oral presentation 25 at the 11th International Conference on the Primary Therapy of Early Breast Cancer, St Gallen, Switzerland, March 2009 After ASCO 2005, option of crossover to Herceptin CTx: chemotherapy RT: radiotherapy Gianni 2009 29

Months from randomisation
Sustained DFS Benefit 100 1-year Herceptin +8.4% +6.3% +6.4% 80 Observation p<0.0001 p<0.0001 p<0.0001 60 Patients (%) 40 4-year DFS Events HR 0.76 95%Cl 0.66, 0.87 p value <0.0001 20 Ref: Gianni et al. Oral presentation 25 at the 11th International Conference on the Primary Therapy of Early Breast Cancer, St Gallen, Switzerland, March 2009 Piccart et al. N Engl J Med 2005;353: Smith et al. Lancet 2007;369:29-36 6 12 18 24 30 36 42 48 Months from randomisation No. at risk Gianni 2009 Piccart 2005 Smith 2007

HERA: DFS at all timepoints
Consistent DFS benefit for trastuzumab vs observation Median follow-up Number of DFS events Trastuzumab vs observation DFS benefit 127 vs 220 P<0.0001 1 year1 218 vs 321 P<0.0001 2 years2 References Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer N Engl J Med 2005; 353:16591672. Smith I, Procter M, Gelber RD, et al; HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 369:2936. Gianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244. 369 vs 458 P<0.0001 4 years3 Favours trastuzumab 1 Favours no trastuzumab 2 HR (95% CI) 1. Piccart-Gebhart MJ, et al. 2005; 2. Smith I, et al. 2007; 3. Gianni L, et al. 2011 31

HERA: Exploratory analysis of DFS by subgroup (1)
Consistent DFS benefit for trastuzumab across subgroups Number of events trastuzumab vs observation Subgroup (number of patients) HR (95% CI) Age at randomisation <35 years (253) 19 vs 31 0.57 (0.32‒1.01) 35‒49 years (1508) 89 vs 150 0.54 (0.42‒0.70) 50‒59 years (1096) 71 vs 97 0.71 (0.52‒0.97) ≥60 years (544) 39 vs 43 0.91 (0.59‒1.41) Menopausal status at randomisation Premenopausal (491) 43 vs 49 0.80 (0.53‒1.21) Uncertain (1373) 70 vs 135 0.48 (0.36‒0.64) Postmenopausal (1535) 105 vs 137 0.75 (0.58‒0.97) Reference Smith I, Procter M, Gelber RD, et al; HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 369:2936. Nodal status Not assessed (372) 39 vs 50 0.66 (0.43‒1.00) Negative (1099) 34 vs 58 0.59 (0.39‒0.91) 1‒3 positive nodes (976) 50 vs 80 0.61 (0.43‒0.87) ≥4 positive nodes (953) 95 vs 132 0.64 (0.49‒0.83) All patients (3401) 218 vs 321 0.64 (0.54‒0.76) 0.0 0.5 1.0 1.5 HR Smith I, et al. 2007

HERA: Exploratory analysis of DFS by subgroup (2)
Consistent DFS benefit for trastuzumab across subgroups Number of events trastuzumab vs observation Subgroup (number of patients) HR (95% CI) Pathological tumour size Any (neoadjuvant chemo) (372) 39 vs 50 0.66 (0.43‒1.00) 0‒2 cm (1351) 61 vs 95 0.65 (0.47‒0.90) >2‒5 cm (1482) 97 vs 150 0.55 (0.43‒0.71) >5 cm (171) 20 vs 25 1.14 (0.63‒2.06) Hormone receptor status ER-negative/PgR-negative (1627) 126 vs 190 0.63 (0.50‒0.78) ER-negative/PgR-positive (172) 12 vs 12 0.77 (0.34‒1.74) ER-positive/PgR-negative (460) 26 vs 39 0.82 (0.50‒1.34) ER-positive/PgR-positive (984) 46 vs 61 0.63 (0.43‒0.93) Reference Smith I, Procter M, Gelber RD, et al; HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 369:2936. Previous radiotherapy Yes (2606) 183 vs 265 0.64 (0.53‒0.77) No (795) 35 vs 56 0.64 (0.42‒0.98) Type of (neo)adjuvant chemo No anthracyclines (202) 12 vs 15 0.76 (0.35‒1.62) Anthracyclines, no taxanes (2310) 132 vs 221 0.57 (0.46‒0.71) Anthracyclines and taxanes (889) 74 vs 85 0.80 (0.59‒1.10) All patients (3401) 218 vs 321 0.64 (0.54‒0.76) 0.0 0.5 1.0 1.5 HR Smith I, et al. 2007

HERA: Patient crossover to trastuzumab
Proportion of patients crossing over increased over time 0.6 Switched to trastuzumab 0.5 0.4 885/1354 eligible patients (65%) crossed over to trastuzumab Probability of crossover to trastuzumab 0.3 0.2 Reference Gianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244. 0.1 0.0 6 12 18 24 30 36 42 48 Time from randomisation (months) No. at risk 1698 1557 1359 1040 722 432 194 65 19 Gianni L, et al. 2011

HERA: DFS at 4 years, censored for crossover
Censored analysis reinforces long-term DFS benefits 100 Trastuzumab 1 year 80 6.9% Observation* 60 Alive and disease free (%) 40 4-year DFS HR 0.69 95% CI 0.59–0.79 P value <0.0001 Reference Gianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244. 20 6 12 18 24 30 36 42 48 Months from randomisation No. at risk *Excludes data from patients randomised to observation who crossed over to trastuzumab (n=885) Gianni L, et al. 2011

HERA: OS at 4 years, censored for crossover
Censored analysis suggests OS benefit of trastuzumab for 1 year 100 Trastuzumab 1 year 80 7.8% Observation* 60 Alive (%) 40 4-year DFS HR 0.53 95% CI 0.44–0.65 P value <0.0001 Reference Gianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244. 20 6 12 18 24 30 36 42 48 Months from randomisation No. at risk *Excludes data from patients randomised to observation who crossed over to trastuzumab (n=885) Gianni L, et al. 2011

HERA: Impact of crossover on DFS
Improvement in DFS even for late introduction of trastuzumab 100 80 60 Alive and disease free (%) 40 Reference Gianni L, Goldhirsch A, Gelber RD, et al. Update of the HERA trial and the role of 1 year trastuzumab as adjuvant therapy for breast cancer. Oral presentation at the 11th International Conference on the Primary Therapy of Breast Cancer, St. Gallen, Switzerland, 1114 March 2009 (Abstract S25). 20 Selective crossover to trastuzumab No crossover 6 12 18 24 30 36 42 48 Months from randomisation No. at risk 885 885 884 878 870 851 822 690 480 469 468 455 438 408 388 358 302 232 Gianni L, et al. 2009

HERA: Adverse events and cardiac endpoints
Low incidence of cardiac adverse events with trastuzumab Adverse event, n (%) Observation* (n=1719) Trastuzumab 1 year (n=1677) Patients with ≥1 Grade 3/4 AE 131 (8) 239 (14) Patients with ≥1 SAE 129 (8) 199 (12) Fatal adverse events 6 (0) 12 (1) Treatment withdrawals  176 (11) Cardiac endpoints Cardiac death 1 (0) Symptomatic CHF (II, III and IV)† 2 (0) 33 (2)‡ Confirmed significant LVEF drop§ 13 (1) 62 (4) Trastuzumab discontinued due to cardiac problems 87 (5) Any type of cardiac endpoint 14 (1) 75 (5) Reference Gianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244. Notes Fatal adverse events in the observation group were cardiac failure, suicide, pulmonary sepsis, pancreatic carcinoma, myocardial infarction and pulmonary embolism. Fatal adverse events in the trastuzumab group were cerebral haemorrhage, cerebrovascular accident, sudden death, appendicitis, unknown cause following road accident, malignant melanoma, meningioma, metastatic renal-cell carcinoma, uterine cancer, congestive cardiac failure, rectal cancer and one unknown. *Crossover patients were censored from the date of starting trastuzumab; †Not including cardiac death ‡20 New York Heart Association II and 13 New York Heart Association III and IV § Asymptomatic or mildly symptomatic Gianni L, et al. 2011 38

HERA: Adverse event profile in crossover patients
Crossover to trastuzumab does not affect tolerability Adverse event, n (%) No selective crossover* (n=469) Selective crossover† (n=865) Patients with ≥1 Grade 3/4 AE 19 (4) 80 (9) Patients with ≥1 SAE 79 (9) Fatal adverse events 2‡ (0) 1§ (0) Treatment withdrawals  103 (12) Cardiac endpoints Cardiac death Symptomatic CHF (II, III and IV) ** 1 (0) 9 (1) Confirmed significant LVEF drop†† 5‡‡ (1) 26 (3) Trastuzumab discontinued due to cardiac problems 43 (5) Any type of cardiac endpoint 5 (1) Reference Gianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244. *After 15 May 2005; †After crossover to trastuzumab; ‡Myocardial infarction and pulmonary embolism § Haemorrhagic stroke; **Not including cardiac death; ††Symptomatic or mildly symptomatic ‡‡For 3 patients, LVEF drop happened soon after the release of trial results Gianni L, et al. 2011

HERA: Risk of cardiac death, or severe or symptomatic CHF
Low incidence of cardiac events at long-term follow-up 0.15 Trastuzumab for 1 year Observation 0.10 Probability of a cardiac event 0.05 Reference Procter M, Suter TM, de Azambuja E, et al. Longer-term assessment of Trastuzumab-related cardiac adverse events in the Herceptin Adjuvant (HERA) Trial. J Clin Oncol 2010; 28:34223428. 6 12 18 24 30 36 42 48 Time (months) Procter M, et al. 2010

NCCTG N9831 and NSABP B-31 NCCTG N9831: Phase III trial of doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel with or without trastuzumab as adjuvant treatment for women with HER2 overexpressing node-positive or high-risk node-negative breast cancer NSABP B-31: A randomised trial comparing the safety and efficacy of adriamycin and cyclophosphamide followed by paclitaxel (ACT) to that of adriamycin and cyclophosphamide followed by paclitaxel plus trastuzumab (ACTH) in node-positive breast cancer patients who have tumours that overexpress HER2 41 41

Paclitaxel (qw x 12) + trastuzumab (qw x 52)
NCCTG N9831: Study design Arm A RANDOMI SAT ION AC (q3w x 4) Paclitaxel (qw x 12) n=819 HER2-positive EBC N=2614 Arm B AC (q3w x 4) Paclitaxel (qw x 12) Trastuzumab (qw x 52) n=981 Reference Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:16731684. Arm C AC (q3w x 4) Paclitaxel (qw x 12) + trastuzumab (qw x 52) n=814 AC = doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4; Paclitaxel 80 mg/m2/wk × 12) Trastuzumab 4 mg/kg loading dose then 2 mg/kg qw × 52 Note: Sequential arm (B) was excluded from the joint analysis with NSABP B-31 Romond EH, et al. 2005

NSABP B-31: Study design RANDOMI SAT ION Group 1
AC (q3w x 4) Paclitaxel (q3w x 4 or qw x 12) n=1024 HER2-positive EBC N=2043 Group 2 AC (q3w x 4) Paclitaxel (q3w x 4 or qw x 12) + trastuzumab (qw x 52) Reference Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:16731684. n=1019 AC = doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4 Paclitaxel 175 mg/m2 q3w × 4 or 80 mg/m2 qw × 12 Trastuzumab 4 mg/kg loading dose then 2 mg/kg qw × 52 Romond EH, et al. 2005

Combined analysis: Rationale
Treatment arms broadly comparable 52 weeks of trastuzumab added to anthracycline → paclitaxel Trastuzumab administered concurrently with paclitaxel for 12 weeks, then 40 weeks alone RT or hormonal therapy initiated after completion of 12-week regimen of trastuzumab + paclitaxel Joint efficacy analysis Primary endpoint: DFS Secondary endpoint: OS Reference Perez EA, Romond EH, Suman VJ, et al. Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patients with HER2-positive breast cancer. Oral presentation at the 43rd American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, USA, 15 June 2007 (Abstract 512). Perez EA, et al. 2007

Combined analysis: Study design
Concurrent administration of trastuzumab with paclitaxel Control group (n=2017): ACT AC T NCCTG N9831 Arm A (n=971) AC T NSABP B-31 Group 1 (n=1046) Trastuzumab group (n=2028): ACTH AC T NCCTG N9831 Arm C (n=973) References Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373. H AC T NSABP B-31 Group 2 (n=1055) H = AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4) = T (paclitaxel 80 mg/m2/wk × 12) = T (paclitaxel 175 mg/m2 q3w × 4 or 80 mg/m2 qw × 12) = H (trastuzumab 4 mg/kg loading dose then 2 mg/kg qw × 52) Perez EA, et al. 2011

Combined analysis: Key inclusion criteria
Resected invasive HER2-positive breast cancer NCCTG N9831: Node-positive; amended to allow high-risk node-negative disease >1.0 cm if ER-negative or >2.0 cm if ER-positive NSABP B-31: Node-positive Adequate haematological, hepatic and renal function No significant sensory or motor neuropathy No significant past or active cardiac disease LVEF ≥ radiology facility’s lower limit of normal Reference Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373. Perez EA, et al. 2011 46

Combined analysis: Endpoints and analyses
Primary DFS Local/regional/distant recurrence Contralateral breast disease (including DCIS) 2nd primary invasive cancers Death due to any cause Secondary OS TTDR 1st interim efficacy analysis after 355 DFS events1 2nd interim efficacy analysis after 619 DFS events2 References Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:16731684. Perez EA, Romond EH, Suman VJ, et al. Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patients with HER2-positive breast cancer. Oral presentation at the 43rd American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, USA, 15 June 2007 (Abstract 512). Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373. 3rd interim efficacy analysis after 779 DFS events3 1. Romond EH, et al. 2005; 2. Perez EA, et al. 2007; 3. Perez EA, et al. 2011 47 47

Combined analysis: Patient characteristics (1)
NCCTG N9831 NSABP B-31 Patients, % ACT n=971 ACTH n=973 n=1046 n=1055 Age, years <40 4049 5059 ≥6069 16.8 33.4 33.8 16.1 15.4 31.9 18.9 16.3 33.6 33.9 34.8 32.5 16.4 Tumour size, cm ≤ 5.0 ≥5.0 Not stated 40.4 52.4 7.1 0.1 38.0 53.6 8.4 40.3 50.4 7.6 1.7 50.1 10.6 1.3 Nodal involvement 0 13 49 ≥10 47.0 24.3 13.3 13.7 48.9 24.7 12.7 57.5 29.1 13.5 57.9 28.6 Tumour grade 12 3 Not stated 27.4 71.4 1.2 28.0 70.3 1.6 65.3 2.2 29.6 68.6 1.8 ER+ PgR+ 51.4 39.4 49.7 37.9 52.3 52.0 38.9 Reference Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373. Perez EA, et al. 2011 48

Combined analysis: Patient characteristics (2)
NCCTG N9831 NSABP B-31 Patients, % ACT n=971 ACTH n=973 n=1046 ACTH n=1055 Extent of surgery Mastectomy Breast conserving 60.5 39.4 62.0 38.0 60.0 38.9 60.7 38.7 Paclitaxel Weekly Every 3 weeks 100.0 0.0 16.1 83.9 RT Yes No Unknown 65.0 25.3 9.7 67.3 26.3 6.4 76.5 24.5 76.9 24.1 Hormonal therapy (First) 51.3 47.5 1.2 51.0 48.3 0.7 55.9 44.1 56.0 44.0 Reference Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373. Perez EA, et al. 2011 49

Combined analysis: DFS at 4 years of follow-up
Significant DFS benefit of trastuzumab at all timepoints 20 40 60 80 100 1 2 3 4 5 92.4% 88.0% 85.7% ACTH 86.8% 79.0% ACT 73.7% Alive and disease-free (%) Reference Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373. Stratified HR at 4 years = 0.52 (95% CI: 0.45‒0.60); P<0.001 Factors: nodes, hormone receptor status, paclitaxel schedule, study 1952 1756 1300 891 495 No. at risk 1881 1652 1132 702 395 Perez EA, et al. 2011 Follow-up (years) 50

Combined analysis: OS at 4 years of follow-up
Significant OS benefit of trastuzumab at long-term follow-up 20 40 60 80 100 1 2 3 4 5 97.7% 95.1% 93.0% 96.1% ACTH 92.7% 85.6% ACT Alive (%) Reference Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373. Stratified HR at 4 years = 0.61 (95% CI: 0.50‒0.75); P<0.001 Factors: nodes, hormone receptor status, paclitaxel schedule, study 1991 1875 1420 976 554 No. at risk 1960 1816 1375 886 503 Follow-up (years) Perez EA, et al. 2011 51

Combined analysis: Independent adjudication of cardiac events
Incidence of symptomatic cardiac events with trastuzumab is very low at 2.0%, and most patients recover with treatment Confirmed cardiac events, n (%) ACT (n=1755) ACTH (n=1799) Total events 8 (0.5) 36 (2.0) Symptomatic CHF 7 (0.4) 34 (1.9) Probable cardiac death 1 (0.1) 2 (0.1) Hospitalised 5 (0.3) 11 (0.6) Recovery 7 36 Reference Russell SD, Blackwell KL, Lawrence J, et al. Independent adjudication of symptomatic heart failure with the use of doxorubicin and cyclophosphamide followed by trastuzumab adjuvant therapy: A combined review of cardiac data from the National Surgical Adjuvant Breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 clinical trials. J Clin Oncol 2010; 28:34163421. Russell SD, et al. 2010

NCCTG N9831: DFS with sequential trastuzumab
DFS benefit observed with sequential treatment 100 85.2% 80.1% 80 AC→T→H 79.7% AC→T 71.9% 60 Alive and disease-free (%) 40 Reference Perez EA, Suman VJ, Davidson NE, et al. Results of chemotherapy alone, with sequential or concurrent addition of 52 weeks of trastuzumab in the NCCTG N9831 HER2-positive adjuvant breast cancer trial. Oral presentation at the 32nd San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 1013 December 2009 (Abstract 80). Note This slide is from the presentation at SABCS Please note that the number of events shown here for the sequential arm (n=164) and the % DFS and HR are not consistent with that shown for the comparison between sequential and concurrent treatment on the next slide. n Events HR 0.67 P value 0.0005 95% CI 0.55−0.82 20 Years from randomisation 1 2 3 4 5 No. at risk 1097 1087 735 728 675 643 624 581 586 529 513 447 Perez EA, et al. 2009 53 53

NCCTG N9831: DFS for sequential vs concurrent trastuzumab
Non-significant* DFS benefit for concurrent treatment 100 89.1% 84.2% AC→TH 80 85.7% AC→T→H 79.8% 60 Alive and disease-free (%) 40 Reference Perez EA, Suman VJ, Davidson NE, et al. Results of chemotherapy alone, with sequential or concurrent addition of 52 weeks of trastuzumab in the NCCTG N9831 HER2-positive adjuvant breast cancer trial. Oral presentation at the 32nd San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 1013 December 2009 (Abstract 80). Note This slide is from the presentation at SABCS Please note that the number of events shown here for the sequential arm (n=174) and the % DFS and HR are not consistent with that shown for the comparison between sequential and concurrent treatment on the previous slide. n Events HR 0.75 P value* 0.0190 95% CI 0.60−0.94 20 Years from randomisation 1 2 3 4 5 No. at risk 949 954 837 830 788 766 740 705 676 641 456 418 Perez EA, et al. 2009 *Significant P value pre-defined as P= 54 54

NCCTG N9831 and NSABP B31: Conclusions
Trastuzumab for 1 year provides long-term benefits during concurrent or sequential administration with paclitaxel In this analysis of more than 4000 patients, 1 year of trastuzumab provided a consistent long-term survival advantage after 4 years of follow-up 48% relative reduction in DFS event rate 39% relative reduction in death rate Trastuzumab was associated with a low incidence of cardiac events, with no evidence of an increase over time Reference Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373. Perez EA, et al. 2011

BCIRG 006 Multicentre Phase III randomised trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC→T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) and with docetaxel, carboplatin and trastuzumab (TCH) in the treatment of node-positive and high-risk node-negative adjuvant patients

BCIRG 006: Study design → → AC→T AC→TH TCH 57 57 57 4 x AC 4 x T
HER2-positive Node-positive or high-risk node-negative EBC N=3222 Stratified by nodes and hormone-receptor status → 4 x AC 4 x T AC→TH 1 year of trastuzumab 6 x T + C Reference Slamon D, Eiermann W, Robert N, et al. BCIRG 006 phase III trial comparing AC→T with AC→TH and with TCH in the adjuvant treatment of HER2-amplified early breast cancer patients: Third planned efficacy analysis. Oral presentation at the 32nd San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 1013 December 2009 (Abstract 62). TCH 1 year of trastuzumab AC: Doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 q3w x 4 T: Docetaxel 100 mg/m2 q3w x 4 (75 mg/m2 q3w x 6 when combined with carboplatin) C: Carboplatin AUC 6 q3w x 6 H: Trastuzumab was administered weekly during chemotherapy (4 mg/kg loading dose, then 2 mg/kg qw), followed by 6 mg/kg q3w as monotherapy for a total treatment duration of 12 months Slamon D, et al. 2011 57 57 57

BCIRG 006: Key inclusion criteria
Histologically confirmed breast cancer Definitive surgical treatment within 60 days of registration Stage T 1‒3, N0 or N1, M0 1/6 resected nodes positive for tumour or 0/6 resected nodes positive for tumour and negative sentinel node biopsy AND at least one of the following risk factors Tumour size >2 cm ER and PgR negative Histologic and/or nuclear grade 23 Age <35 years HER2-positive by FISH Age 1870 years Karnofsky performance status >80% No prior systemic therapy or RT for breast cancer Reference Slamon D, et al. 2011

BCIRG 006: Endpoints and analyses
Primary DFS Local/regional/distant recurrence 2nd primary invasive cancers Death due to any cause Secondary OS Safety Pathological and molecular markers for predicting efficacy 1st interim efficacy analysis after 322 DFS events (23 months)1 2nd interim efficacy analysis after 462 DFS events (36 months)2 References Slamon D, Eiermann W, Robert N, et al. Phase III trial comparing AC-T with AC-TH and with TCH in the adjuvant treatment of HER2 positive early breast cancer patients: First interim efficacy analysis. Oral presentation at the 28th SABCS, San Antonio, Texas, USA, 811 December 2005 (Abstract 30). Slamon D, Eiermann W, Robert N, et al. 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 Oral presentation at the 29th San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 1417 December 2006 (Abstract 52). Slamon D, Eiermann W, Robert N, et al. BCIRG 006 phase III trial comparing AC→T with AC→TH and with TCH in the adjuvant treatment of HER2-amplified early breast cancer patients: Third planned efficacy analysis. Oral presentation at the 32nd San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 1013 December 2009 (Abstract 62). 3rd interim efficacy analysis after 656 DFS events (65 months)3 1. Slamon D, et al. 2005; 2. Slamon D, et al. 2006; 3. Slamon D, et al. 2011 59 59 59

BCIRG 006: Patient characteristics (1)
Patients, % AC→T (n=1073) AC→TH (n=1074) TCH (n=1075) Age <50 years 52 54 Karnofsky performance status of 100 80 79 Mastectomy 59 63 60 RT 67 68 Hormonal therapy 49 50 Reference Slamon D, Eiermann W, Robert N, et al. BCIRG 006 phase III trial comparing AC→T with AC→TH and with TCH in the adjuvant treatment of HER2-amplified early breast cancer patients: Third planned efficacy analysis. Oral presentation at the 32nd San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 1013 December 2009 (Abstract 62). Slamon D, et al. 2011 60 60

BCIRG 006: Patient characteristics (2)
Patients, % AC→T (n=1073) AC→TH (n=1074) TCH (n=1075) Number of positive nodes 29 28 13 38 39 410 22 24 23 >10 11 9 10 Tumour size, cm ≤2 41 40 >2 and ≤5 53 55 >5 6 7 ER+ and/or PgR+ 54 Reference Slamon D, Eiermann W, Robert N, et al. BCIRG 006 phase III trial comparing AC→T with AC→TH and with TCH in the adjuvant treatment of HER2-amplified early breast cancer patients: Third planned efficacy analysis. Oral presentation at the 32nd San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 1013 December 2009 (Abstract 62). Slamon D, et al. 2011 61 61

BCIRG 006: Patient crossover
After the trastuzumab efficacy results were announced in April 2005, patients were permitted to cross over to receive trastuzumab 23/1073 patients (2.1%) randomised to AC→T crossed over to receive trastuzumab 1050/1073 patients (97.9%) remained in the AC→T arm for subsequent DFS, OS and safety comparisons Reference Slamon D, Eiermann W, Robert N, et al. BCIRG 006 phase III trial comparing AC→T with AC→TH and with TCH in the adjuvant treatment of HER2-amplified early breast cancer patients: Third planned efficacy analysis. Oral presentation at the 32nd San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 1013 December 2009 (Abstract 62). Slamon D, et al. 2011

DFS: Median follow-up 5,4 years
BCIRG006 Significant DFS benefit with trastuzumab in both regimens 1 0.9 84% 0.8 81% % alive and Disease-Free 75% 0.7 0.6 Patients Events HR (95% C.I.) p Ref: Slamon et al. Oral presentation 62 at the 32nd SABCS, San Antonio, Texas, USA, December 2009 AC-T100 1073 257 1 (reference) 0.5 AC-T100Herceptin 1074 185 0.64 ( ) <0.001 T75CbHerceptin 1075 214 0.75 ( ) 0.04 0.4 12 24 36 48 60 72 Time (months) A: doxorubicin, 60 mg/m2; C: cyclophosphamide, 600 mg/m2; T100: docetaxel, 100 mg/m2 ; T75: docetaxel, 75 mg/m2 ; Cb: carboplatin AUC 6 Slamon 2009

BCIRG 006: OS at 5 years of follow-up
Significant OS benefit with trastuzumab at long-term follow-up 20 40 60 80 100 1 2 3 4 6 5 ACTH TCH ACT Alive (%) Reference Slamon D, Eiermann W, Robert N, et al. BCIRG 006 phase III trial comparing AC→T with AC→TH and with TCH in the adjuvant treatment of HER2-amplified early breast cancer patients: Third planned efficacy analysis. Oral presentation at the 32nd San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 1013 December 2009 (Abstract 62). n Events HR (ref) 95% CI 0.48‒ ‒0.99 − P value < − ACTH TCH ACT Years from randomisation Slamon D, et al. 2011 64 64

BCIRG 006: Summary of efficacy endpoints at 5 year follow-up
Consistent efficacy benefit of trastuzumab with anthracycline-based and non-anthracycline-based regimens No. events Trastuzumab vs observation HR (95% CI) AC→TH 185 vs 257 0.64 (0.530.78) DFS TCH 214 vs 257 0.75 (0.630.90) AC→TH 94 vs 141 0.63 (0.480.81) Reference Slamon D, Eiermann W, Robert N, et al. BCIRG 006 phase III trial comparing AC→T with AC→TH and with TCH in the adjuvant treatment of HER2-amplified early breast cancer patients: Third planned efficacy analysis. Oral presentation at the 32nd San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 1013 December 2009 (Abstract 62). OS TCH 113 vs 141 0.77 (0.600.99) 0.0 0.5 1.0 1.5 HR (95% CI) Favours trastuzumab Favours observation Slamon D, et al. 2011 65 65

BCIRG 006: Grade 3/4 non-haematological adverse events
Low incidence of Grade 3/4 non-haematological AEs across treatment groups at 5 years of follow-up Events, % AC→T n=1050 AC→TH n=1068 TCH n=1056 Arthralgia 3.2 3.3 1.4* Myalgia 5.2 1.8* Fatigue 7.0 7.2 Hand-foot syndrome 1.9 0.0* Stomatitis 3.5 2.9 Diarrhoea 3.0 5.6 5.4 Nausea 5.9 5.7 4.8 Vomiting 6.2 6.7 3.5* Irregular menses 27.0 24.3 26.5 Reference Slamon D, Eiermann W, Robert N, et al. BCIRG 006 phase III trial comparing AC→T with AC→TH and with TCH in the adjuvant treatment of HER2-amplified early breast cancer patients: Third planned efficacy analysis. Oral presentation at the 32nd San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 1013 December 2009 (Abstract 62). *Statistically significantly fewer events Slamon D, et al. 2011

BCIRG 006: Grade 3/4 haematological adverse events
Similar incidence of Grade 3/4 haematological AEs across treatment groups at 5 years of follow-up Events, % AC→T n=1050 AC→TH n=1068 TCH n=1056 Neutropenia 63.3 71.5 65.9* Leucopenia 51.8 60.3 48.2* Febrile neutropenia 9.3 10.9 9.6 Neutropenic infection 11.1 11.9 11.2 Anaemia 2.4 3.1* 5.8 Thrombocytopenia 1.6 2.1* 6.1 Reference Slamon D, Eiermann W, Robert N, et al. BCIRG 006 phase III trial comparing AC→T with AC→TH and with TCH in the adjuvant treatment of HER2-amplified early breast cancer patients: Third planned efficacy analysis. Oral presentation at the 32nd San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 1013 December 2009 (Abstract 62). *Statistically significantly fewer events Slamon D, et al. 2011

BCIRG 006: Cardiac deaths and CHF (independently adjudicated)
Stable CHF rates at long-term follow-up Events, n AC→T n=1050 AC→TH n=1068 TCH n=1056 Cardiac-related death First analysis (23 months) Second analysis (36 months) Third analysis (65 months) Cardiac left ventricular function (CHF) Grade 3/4 3 17 4 20 7 21 Reference Slamon D, Eiermann W, Robert N, et al. BCIRG 006 phase III trial comparing AC→T with AC→TH and with TCH in the adjuvant treatment of HER2-amplified early breast cancer patients: Third planned efficacy analysis. Oral presentation at the 32nd San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 1013 December 2009 (Abstract 62). P=0.0121 P<0.001 Slamon D, et al. 2009; Slamon D, et al. 2011

BCIRG 006: Mean LVEF (all observations)
LVEF >50% maintained long term in both Herceptin arms with good recovery of function in TCH arm 66 TCH (n=1030) 65 64 AC→T (n=1014) 63 LVEF points (%) 62 AC→TH (n=1042) 61 Reference Slamon D, Eiermann W, Robert N, et al. BCIRG 006 phase III trial comparing AC→T with AC→TH and with TCH in the adjuvant treatment of HER2-amplified early breast cancer patients: Third planned efficacy analysis. Oral presentation at the 32nd San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 1013 December 2009 (Abstract 62). 60 59 58 12 24 36 48 60 Time (months) Slamon D, et al. 2011

BCIRG 006: Conclusions Trastuzumab for 1 year provides significant clinical benefits which are maintained over 5 years of follow-up Significant DFS and OS benefits maintained over the long-term Concurrent administration of trastuzumab with docetaxel was effective and well tolerated Consistent benefit of trastuzumab when used with either anthracycline-based or non-anthracycline-based chemotherapy Both combinations were well tolerated Lower incidence of adverse events (including cardiovascular) with non-anthracycline-based chemotherapy Reference Slamon D, Eiermann W, Robert N, et al. BCIRG 006 phase III trial comparing AC→T with AC→TH and with TCH in the adjuvant treatment of HER2-amplified early breast cancer patients: Third planned efficacy analysis. Oral presentation at the 32nd San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 1013 December 2009 (Abstract 62). Slamon D, et al. 2011

Cardiac safety profile with trastuzumab is maintained with long-term follow-up
B-31 AC THerceptin (n=947) 10 N9831 AC THerceptin (n=570) Anthracycline-containing BCIRG 006 AC THerceptin (n=1068) 8 N9831 AC T Herceptin (n=710) HERA CTx Herceptin (n=1682) 6 Cumulative incidence Congestive heart failure (Gr3/4) and cardiac death (%) Anthracycline-free BCIRG TCbHerceptin (n=1056) 4 3.8% 3.3% Ref: Rastogi et al. Oral presentation LBA513 at the 43rd ASCO annual meeting, Chicago, Illinois, USA, 2-5 June 2007 Perez et al. J Clin Oncol 2008;26: Slamon et al. Oral presentation 62 at the 32nd SABCS, San Antonio, Texas, USA, December 2009 Gianni et al. Oral presentation 25 at the 11th International Conference of the Primary Therapy of Early Breast Cancer, St Gallen, Switzerland, March 2009 Procter et al. JCO 2010;28(21): 2.8% 2 2% 0.8% 0.4% 1 2 3 4 5 Rastogi 2007 Perez 2008 Slamon 2009 Gianni 2009 Procter 2010 Time (years) A: doxorubicin, 60 mg/m2; C: cyclophosphamide, 600 mg/m2; T100: docetaxel, 100 mg/m2 ; T75: docetaxel, 75 mg/m2 ; Cb: carboplatin AUC 6

1-year Herceptin increases Disease Free Survival
Trials 2184 3401 3387 3968 2147 n Treatment DFS benefit N9831 HERA N9831/B31 BCIRG006 AC T H CTx H AC TH H 0.0005 <0.0001 < <0.001 P Median Follow-up (years) 5.5 4 2 1 2.9 5.4 0.67 0.76 0.64 0.54 0.48 0.64 Ref : Perez et al. Oral presentation 80 at the 32nd SABCS, San Antonio, Texas, USA, December 2009 Gianni et al. Oral presentation 25 at the 11th International Conference on the Primary Therapy of Early Breast Cancer, St Gallen, Switzerland, March 2009 Piccart et al. N Engl J Med 2005;353: Smith et al. Lancet 2007;369:29-36 Perez et al. J Clin Oncol 2007; 25(18S suppl.):512 Slamon et al. Oral presentation 62 at the 32nd SABCS, San Antonio, Texas, USA, December 2009 2 Herceptin Favours no Herceptin Favours 1 HR Risk of Relapse is reduced by up to 52% Perez 2008; Gianni 2009; Smith 2007; Piccart 2005; Perez 2007; Slamon 2009

1-year Herceptin extends Overall Survival in Early Breast Cancer
Trials 2184 3401 3968 2147 n Treatment OS benefit P N9831 HERA N9831/B31 BCIRG006 AC T H CTx H AC TH H 0.281 0.1087 0.0115 0.0007 <0.001 Median Follow-up (years) 5.5 4 2 2.9 5.4 0.86 0.85 0.66 0.65 0.63 Confounded by crossover Confounded by crossover Ref: Perez et al. Oral presentation 80 at the 32nd SABCS, San Antonio, Texas, USA, 11th International Conference on the Primary Therapy of Early Breast Cancer, St Gallen, Switzerland, March 2009 Gianni et al. Oral presentation 25 at the 11th International Conference of the Primary Therapy of Early Breast Cancer, St Gallen, Switzerland, March 2009 Piccart et al. N Engl J Med 2005;353: Smith et al. Lancet 2007;369:29-36 Perez et al. J Clin Oncol 2007; 25(18S suppl.):512 Slamon et al. Oral presentation 62 at the 32nd SABCS, San Antonio, Texas, USA, December 2009 2 Herceptin Favours no Herceptin Favours 1 HR Risk of Death is reduced by up to 37% Perez 2009 ; Gianni 2009; Smith 2007; Piccart 2005; Perez 2007; Slamon 2009

Adjuvant Herceptin is changing the epidemiology of the disease
20.000 Projected MBC patients 18.000 Impact of Herceptin 16.000 14.000 27.727 12.000 Number of patients with MBC in 5 EU countries 10.000 8.000 Ref: Weisgerber-Kriegl et al. Poster 6589 presented at the 44th ASCO annual meeting, Chicago, Illinois, USA, 30 May – 3 June 2008 6.000 4.000 2.000 2000 2005 2010 2015 2020 Weisgerber-Kriegl 2008

Herceptin therapy is unilaterally recommended for HER2-positive disease
NCCN consider Herceptin for ESMO use Herceptin for St Gallen use Herceptin for Node- & 0.6-1cm Hormone receptor- use Herceptin for ≥ 1cm OR Node+ ≥ 1cm OR Node+ Node- & 0.6-1cm Hormone receptor- (if grade>1 & unfavorable features) Ref: NCCN Clinical Practice Guidelines in Oncology – Breast Cancer v – Kataja et al. Ann Oncol 2009;20(supplement 4):iv10-iv14 Goldhirsch et al. Ann Oncol 2009;20: OR >1cm OR Node+ NCCN 2010; Kataja 2009; Goldhirsch 2009

Conclusions 1-year adjuvant Herceptin extends Overall Survival
Herceptin delivers high cure rates for women with HER2-positive early breast cancer Herceptin is well tolerated with acceptable cardiac safety Herceptin is the foundation of care in women with HER2-positive early breast cancer Ref: De Vita et al Nat Clin Pract Oncol 2006;3(2):59 Smith et al Lancet 2007;369:29-36 Romond et al. N Engl J Med 2005;353(16): Marty et al. J Clin Oncol 2005;23(19): Spector et al. J Clin Oncol 2009;27(34): Procter et al. JCO 2010;28(21): De Vita 2006 Smith 2007 Romond 2005 Marty 2005 Spector 2009 Procter 2010

EBC MBC Neoadjuvant Surgery Relapse Progression Adjuvant 1st line 2nd+ lines NOAH MDACC GeparQuattro Numerous Phase II studies HERA NSABP-B31 NCCTG N9831 BCIRG 006 FinHer PACS-04 HO648g M77001 BCIRG 007 CHAT TAnDEM RHEA GBG-26 EGF Numerous Phase II studies EBC: Early Breast Cancer MBC: Metastatic Breast Cancer 77

Study design H0648g HER2-positive MBC (IHC 2+ or IHC 3+) No prior chemotherapy for MBC Paclitaxel 175mg/m2 n=96 Paclitaxel 175mg/m2 + Herceptin 2 mg/kg/week (4mg/kg loading dose) n=92 Anthracycline + Cyclophosphamide n=138 Anthracycline + Cyclophosphamide + Herceptin n=143 Ref: Slamon et al. N Engl J Med 2001;344: Slamon 2001

Study design M77001 HER2-positive MBC (IHC 3+ and / or FISH+)
No prior chemotherapy for MBC Baseline LVEF>50% n=188 Docetaxel 100 mg/m2 q3w x 6 cycles n=94a Docetaxel 100 mg/m2 q3w x 6 cycles + Herceptin 4 mg/kg loading dose, then 2 mg/kg qw until disease progression n=92b Ref: Marty et al. J Clin Oncol 2005;23: a Additional cycles of docetaxel administered at investigator’s discretion. Patients progressing on docetaxel alone could cross over to receive Herceptin b 2 patients did not receive study medication FISH, fluorescence in situ hybridisation; LVEF, left ventricular ejection fraction Marty 2005

Anastrozole 1mg/day + Herceptin 2 mg/kg/week
Study design TAnDEM Postmenopaused women with HER2-positive (ICH 3+ or FISH+) & hormone receptor-positive (ERpositive and/or PgR positive) MBC Anastrozole 1mg/day n=104 Anastrozole 1mg/day + Herceptin 2 mg/kg/week (4mg/kg loading dose) n=103 Ref: Kaufman et al. J Clin Oncol 2009;27: Kaufman 2009

1st line Herceptin increases Progression Free Survival
14 11.7 months 12 (TTP) 10 6.9 months 8 (TTP) Months 4.8 months 6 +5.6 months p=0.0001 (PFS) 4 2 +3.9 months p<0.001 +2.4 months p=0.0016 Ref: Slamon et al. N Engl J Med 2001;344: Marty et al. J Clin Oncol 2005;23: Kaufman et al. J Clin Oncol 2009;27: paclitaxel paclitaxel Herceptin docetaxel docetaxel Herceptin anastrozole anastrozole Herceptin n=188 H0648g n=186 M77001 Slamon 2001 Marty 2005 Kaufman 2009 n=207 TAnDEM

1st line Herceptin extends Overall Survival
35 31.2 months 28.5 months 30 25 22.1 months +8.5 months p=0.0325 20 +4.6 months p=0.325** Months 15 +3.7 months p=0.17%* 10 5 Ref: Slamon et al. N Engl J Med 2001;344: Marty et al. J Clin Oncol 2005;23: Kaufman et al. J Clin Oncol 2009;27: docetaxel Herceptin paclitaxel paclitaxel Herceptin docetaxel anastrozole anastrozole Herceptin n=188 H0648g n=186 M77001 n=207 TAnDEM * Subgroup analysis limited to 188 patients (total population = 469) ** 70% of patients in the anastrozole alone arm crossed over to receive Herceptin after progression on anastrozole alone Slamon 2001 Marty 2005 Kaufman 2009

Herceptin in MBC considerably improves the prognosis of HER2-positive disease
100 HER2 negative (n=1782) HER2 positive, no Herceptin (n=118) 80 HER2 positive, Herceptin (n=191) 60 Probability of survival (%) 40 Ref: Dawood et al. J Clin Oncol 2010;28:92-98 20 12 24 36 48 60 Months from diagnosis Dawood 2010

EBC MBC Neoadjuvant Surgery Relapse Progression Adjuvant 1st line 2nd+ lines NOAH MDACC GeparQuattro Numerous Phase II studies HERA NSABP-B31 NCCTG N9831 BCIRG 006 FinHer PACS-04 HO648g M77001 BCIRG 007 CHAT TAnDEM RHEA GBG-26 EGF Numerous Phase II studies EBC: early breast cancer MBC: metastatic breast cancer 84

GBG-26 is the 1st randomised Phase III study to investigate continuation of Herceptin beyond progression Progression under Herceptin-based 1st line therapya (monotherapy or with taxane- or with non taxane-chemotherapy) RANDOMIZATION Xeloda 1,250 mg/m2 bid d1-14 q21d n=78 Xeloda 1,250 mg/m2 bid d1-14 q21d + continuation of Herceptin 6 mg/kg q3w n=78 Ref: von Minckwitz et al. J Clin Oncol 2009;27: a Includes 3 patients who received adjuvant Herceptin + taxane von Minckwitz 2009

Continuation of Herceptin improves response rate
80 Xeloda (n=68) 70 75 Herceptin + Xeloda (n=75) 60 p=0.01 50 54 Patients (%) 40 48 30 20 27 10 Ref: von Minckwitz et al. J Clin Oncol 2009;27: CR + PR CBR Median follow-up 15.6 months CR: Complete Response PR: Partial Response CBR: CR+PR or SD > 24 weeks von Minckwitz 2009

Continuation of Herceptin prolongs median Time to Progression
Xeloda (n=78) Herceptin + Xeloda (n=78) 1.0 0.8 HR=0.69 (p=0.034) Probability 0.6 0.4 0.2 Ref: von Minckwitz et al. J Clin Oncol 2009;27: 5.6 8.2 0.0 10 20 30 40 Time from 1st progression (months) Median follow-up 15.6 months von Minckwitz 2009

Continuation of Herceptin extends Overall Survival
Xeloda (n=78) Herceptin + Xeloda (n=78) 1.0 0.8 HR=0.76 (p=0.26) Probability 0.6 0.4 0.2 Ref: von Minckwitz et al. J Clin Oncol 2009;27: 20.4 25.5 0.0 10 20 30 40 Time from 1st progression (months) Median follow-up 15.6 months von Minckwitz 2009

Continuation of Herceptin beyond progression was not associated with increased toxicity
Grade ¾ adverse events (%) Xeloda Herceptin + Xeloda Anemia Cardiovascular disorder Diarrhea Dyspnea Edema Fatigue Febrile neutropenia Fever Infection Mucositis Nail changes Neutropenia Sensory neuropathy Skin changes* Thrombocytopenia Vomiting 2.78 2.7 18.9 6.8 1.4 5.4 8.1 4.4 24.3 1.39 4.1 5.2 15.6 2.6 3.9 1.3 5.3 32.5 Ref: von Minckwitz et al. J Clin Oncol 2009;27: * includes hand-foot syndrome von Minckwitz 2009 89

EGF104900 study: Lapatinib ± Herceptin in progressing MBC
HER2-positive MBC (FISH+ or IHC 3+) n=296 Lapatinib 1500 mg qd n=148 Lapatinib 1000 mg qd + Herceptin mg/kg qw n=148 Ref: Blackwell et al. Oral presentation 61 at the 32nd SABCS, San Antonio, Texas, USA, 10-13 December 2009 Blackwell et al. J Clin Oncol 2010;28: Crossover if Progressive Disease Blackwell 2009 Blackwell 2010

Heavily pretreated population
Study Arms ITT Population Lapatinib n=148 Lapatinib + Herceptin n=148 Median prior chemotherapy regimens % patients ≥ 6 prior regimens Median prior Herceptin regimens for MBC 4 28 3 5 34 3 Ref: Blackwell et al. Oral presentation 61 at the 32nd SABCS, San Antonio, Texas, USA, December 2009 Blackwell et al. J Clin Oncol 2010;28: Blackwell 2009 Blackwell 2010 91

Herceptin + lapatinib is superior to lapatinib alone
Lapatinib n = 145 Lapatinib + Herceptin n = 146 5 10 15 20 25 30 ORR CBR 60 p=0.026 p=0.01 50 60.2 24.7 40 (%) 40.9 (weeks) p=0.46 30 12.4 12.4 20 p=0.008 10.3 Ref: Blackwell et al. Oral presentation 61 at the 32nd SABCS, San Antonio, Texas, USA, December 2009 Blackwell et al. J Clin Oncol 2010;28: 6.9 10 12.0 8.1 PFS OS ORR, overall response rate CBR, clinical benefit rate PFS, progression-free survival OS, overall survival Blackwell 2009 Blackwell 2010

Cardiac & safety events
Study Arms ITT Population Lapatinib n=146 Lapatinib + Herceptin n=149 Total # patients with event1 Grade 3/4 Serious events2 Event related to study drug(s) Fatal3 3 1 2 111 3 10 1 Ref: Blackwell et al. Oral presentation 61 at the 32nd SABCS, San Antonio, Texas, USA, December 2009 Blackwell et al. J Clin Oncol 2010;28: 1 Two patients experienced 2 events (other event was Grade 1/2) 2 Serious events defined as LV dysfunction ≥ Grade 3 or LVEF decrease ≥ 20% relative to baseline + below institutions LLN 3 Cardiac failure; cause of death: pulmonary thromboembolism Blackwell 2009 Blackwell 2010 93

Adverse events All grades (% patients)
Lapatinib n=146 10 48 19 9 28 29 18 Lapatinib + Herceptin n=149 11 5 60 12 21 10 28 22 14 adverse event (incidence ≥ 10%) Anorexia Cough Dermatitis acneiform Diarrhea Dyspnea Fatigue Headache Nausea Rash Vomiting Ref: Blackwell et al. Oral presentation 61 at the 32nd SABCS, San Antonio, Texas, USA, December 2009 Blackwell et al. J Clin Oncol 2010;28: Blackwell 2009 Blackwell 2010 94

Herceptin given in 2nd line or beyond increases Progression Free Survival
8.2 months 9 (TTP) 8 7 6 +2.6 months p=0.0338* 5 Months 4 2.7 months 3 (PFS) 2 1 +0.9 months p=0.008** Ref: Von Minckwitz et al. J Clin Oncol 2009;27: Blackwell et al. Oral presentation 61 at the 32nd SABCS, San Antonio, Texas, USA, December 2009 Blackwell et al. J Clin Oncol 2010;28: Xeloda Xeloda + Herceptin lapatnib lapatinib + Herceptin n=156 GBG-26 n=291 EGF104900 Von Minckwitz 2009 Blackwell 2009 Blackwell 2010 * HR = 0.69; 95% Cl, 0.48 to 0.97; p = ** HR = 0.73; 95% Cl, 0.57 to 0.93; p = 0.008 95

Herceptin given in 2nd line or beyond extends Overall Survival
30 25.5 months 25 20 Months +5.1 months p=0.257* 14 months 15 10 +4.5 months p=0.026** 5 Ref: Von Minckwitz et al. J Clin Oncol 2009;27: Blackwell et al. Oral presentation 61 at the 32nd SABCS, San Antonio, Texas, USA, December 2009 Blackwell et al. J Clin Oncol 2010;28: Xeloda Xeloda + Herceptin lapatnib lapatinib + Herceptin n=156 GBG-26 n=296 EGF104900 Von Minckwitz 2009 Blackwell 2009 Blackwell 2010 * HR = 0.76; two-sided; p = 0.257 ** HR = 0.74; 95% Cl, 0.57 to 0.97; p = 0.026 96

Conclusions Herceptin improves Overall Survival in 1st line MBC
Benefit of continuing Herceptin beyond progression has been confirmed in phase III trial Herceptin is well tolerated with an acceptable cardiac safety profile Herceptin is the foundation of any treatment regimen in HER2-positive breast cancer Ref: Slamon et al. N Engl J Med 2001;344: Marty et al. J Clin Oncol 2005;23: Kaufman et al. J Clin Oncol 2009;27: von Minckwitz et al. J Clin Oncol 2009;27: Blackwell et al. Oral presentation 61 at the 32nd SABCS, San Antonio, Texas, USA, December 2009 Blackwell et al. J Clin Oncol 2010;28: Slamon 2001 Marty 2005 Kaufman 2009 von Minckwitz 2009 Blackwell 2009 Blackwell 2010

Update on CNS metastases in HER2-positive breast cancer
Prevention Delay Overall Survival increase Quality of Life

Median time to CNS metastases (months)
Herceptin given in 1st Line MBC delays the occurrence of CNS metastases P<0.001 20 19 18 p=0.0008 16 14 13.1 12 Median time to CNS metastases (months) 10 8 7 6 Ref: Dawood et al. Ann Oncol 2008;19: Park et al. Ann Oncol 2009;20:56-62 4 2.1 2 Not treated with Herceptin n=80 Treated with Herceptin n=100 Not treated with Herceptin n=11 Treated with Herceptin n=38 Dawood 2008 Park 2009

Herceptin delays the progression of CNS metastases
10 9 8 7.8 7 6 Median TTP of intracranial tumors (months) 5 4 2.9 3 2 Ref: Park et al. Ann Oncol 2009;20:56-62 1 Not treated with Herceptin n=11 Treated with Herceptin after BM n=29 Park 2009

Brain radiotherapy makes blood-brain barrier more permeable
cerebrospinal fluid (ng/mL) Herceptin in 100 200 300 400 Before radiotherapy 226ng/ml After Ref: Stemmler et al. Anti-cancer Drugs 2007;18(1):23-28 After radiotherapy for brain metastases, Herceptin levels in brain (n = 6) Stemmler 2007

Disruption of the blood-brain barrier occurs at the site of brain metastases
Ref: Dijkers et al. Clinical Pharmacology & Therapeutics Advance – 2010 May;87(5): MRI PET HER2-positive brain lesion revealed by 89 Zr-Herceptin PET imaging and confirmed by MRI Dijkers 2010

Herceptin: the only anti-HER2 treatment improving Overall Survival of patients with CNS metastases
25 21 months 20 15 13.6 months 11.9 months Months (0S) 11.6 months 10 +12 months p<0.001 5 +5.5 months p=0.03 +8.1 months p<0.001 +8.9 months p=0.05 Ref: Church et al. Am J Clin Oncol 2008;31: Bartsch et al. J Neuro Oncol 2007;85: Dawood et al. Ann Oncol 2008;19: Park et al. Ann Oncol 2009;20:56-62 * After BM +Herceptin* +Herceptin** +Herceptin* +Herceptin*** ** After WBRT *** Before or at time of BM diagnosis Church n=26 Bartsch n=38 Dawood n=254 Park n=40 Church 2008 Bartsch 2007 Dawood 2008 Park 2009

Anti-HER2 targeted therapy: the future…

Dimerisation domain of HER2
Pertuzumab and trastuzumab bind to different regions on HER2 and have synergistic activity HER2 receptor Trastuzumab Pertuzumab Subdomain IV of HER2 Dimerisation domain of HER2 Ref: Baselga et al. Nat Rev Cancer 2009;9: Preferentially inhibits ligand-independent HER2 signalling Prevents shedding of HER2 ECD Flags cells for destruction by the immune system Inhibits HER2 forming dimer pairs Suppresses multiple HER signalling pathways, leading to a more comprehensive blockade of HER signalling Flags cells for destruction by the immune system Baselga 2009

BO17929: a Phase II trial of pertuzumab + trastuzumab in HER2-positive MBC patients progressing during trastuzumab-based therapy HER2-positive MBC progressing on trastuzumab + chemotherapy (Cohort 1, n=24; Cohort 2, n=42) Pertuzumab + trastuzumab Cohorts 1 and 2 HER2-positive MBC progressing on trastuzumab + chemotherapy (n=29) Pertuzumab 16 patients received pertuzumab + trastuzumab PD Cohort 3 Ref: Baselga et al. J Clin Oncol 2010;28: Baselga et al. Poster 5114 presented at the 32nd SABCS, San Antonio, Texas, USA, 10-13 December 2009 Primary objective: efficacy (ORR and/or SD> 6 months) Secondary objectives: safety profile of the combination, duration of response, time to response, TTP, PFS (evaluate safety of combined antibody treatment) efficacy (response rate + stabilisation of disease = CBR) Heavily pretreated population median 3 prior lines of therapy in the metastatic setting MBC: Metastatic Breast Cancer CBR: Clinical Benefit Rate Baselga 2010 Baselga 2009

Pertuzumab / trastuzumab combination therapy more active than treatment with either agent alone
Cohorts 1 and 2 (P + T) n=66 Cohort 3 (P) n=27a 0.0 3.4 6.9 10.3 not available Cohort 3 (P  P + T) n=14b 0.0 21.4 42.8 57.1 CR, % PR, % ORR, % SD ≥ 6 months, % CBR, % (CR + PR + SD ≥ 6 months) PD, % 7.6 16.7 24.2 25.8 50.0 Ref: Baselga et al. J Clin Oncol 2010;28: Baselga et al. Poster 5114 presented at the 32nd SABCS, San Antonio, Texas, USA, 10-13 December 2009 a: only 27 patients evaluable: 1 patient did not progress on pertuzumab monotherapy before moving onto combination therapy and 1 patient’s tumour was unassessable after cycle 2 b: n=14 as at data cut-off, 1 patient had not reached overall best response end point (8 cycles of assessment during this phase) and 1 patient died before efficacy assessment P, pertuzumab monotherapy; P + T, pertuzumab / trastuzumab combination therapy; CR: Complete Response; PR: Partial Response; ORR: Overall Response Rate; SD: Stable Disease; PD: Progressive Disease Baselga 2010 Baselga 2009

Pertuzumab / trastuzumab combination safety profile comparable to pertuzumab monotherapy
BO17929 Cohort 3 Pertuzumab monotherapy n=29 BO17929 Cohort 3 Pertuzumab + trastuzumab n=16 AEs Asthenia Back pain Chills Diarrhoea Fatigue Nausea Rash Vomiting Weight decrease Any grade, % 17 48 34 10 24 Grade 3/4, % 3 Any grade, % 13 19 31 25 Grade 3/4, % 6 Ref: Baselga et al. Poster 5114 presented at the 32nd SABCS, San Antonio, Texas, USA, 10-13 December 2009 AEs: Adverse Events Baselga 2009

BO17929: pertuzumab + trastuzumab has a similar cardiac safety profile to trastuzumab
No significant changes in LVEF over the treatment period Only 3 patients in the trial had a decrease in LVEF of ≥10% points and <50% absolute value but all were asymptomatic No additional cardiac safety signals were observed Ref: Baselga et al. J Clin Oncol 2010;28: Baselga et al. Poster 5114 presented at the 32nd SABCS, San Antonio, Texas, USA, 10-13 December 2009 LVEF: Left Ventricular Ejection Fraction Baselga 2010 Baselga 2009

CLEOPATRA: a Phase III trial of trastuzumab + pertuzumab in the 1st line setting
Docetaxel + trastuzumab + placebo HER2-positive MBC (n=800a) 1:1 1:1 Docetaxel + trastuzumab + pertuzumab An international, Phase III, randomised, double-blind, placebo-controlled study (~250 sites worldwide) End points PFS and OS (cardiac) Safety

PHEREXA: a Phase II trial of trastuzumab + capecitabine with or without pertuzumab
HER2-positive MBC (n=450a) 1:1 1:1 Trastuzumab + capecitabine + pertuzumab An international, Phase II, randomised study in patients with HER2-positive MBC that has progressed after 1st line of trastuzumab-based therapy in the metastatic setting aRecruitment started Jan 2010

T-DM1: 1st-in-class HER2 antibody-drug conjugate (ADC)
Target expression: HER2 Monoclonal antibody: trastuzumab Cytotoxic agent: DM1 Highly potent chemotherapy (maytansine derivative) Ref: Baselga et al. Poster 5114 presented at the 32nd SABCS, San Antonio, Texas, USA, 10-13 December 2009 Baselga et al. Nat Rev Cancer 2009;9: T-DM1 Linker Systemically stable Breaks down in target cancer cell Baselga 2009

T-DM1 selectively delivers a highly toxic payload to HER2-positive tumour cells
T-DM1 binds to the HER2 protein on cancer cells Ref: Baselga et al. Poster 5114 presented at the 32nd SABCS, San Antonio, Texas, USA, 10-13 December 2009 Baselga 2009

Receptor-T-DM1 complex is internalised into HER2-positive cancer cell Ref: Baselga et al. Poster 5114 presented at the 32nd SABCS, San Antonio, Texas, USA, 10-13 December 2009 Baselga et al. Nat Rev Cancer 2009;9: Baselga 2009

Potent antimicrotubule agent is released once inside the HER2-positive tumour cell Ref: Baselga et al. Poster 5114 presented at the 32nd SABCS, San Antonio, Texas, USA, 10-13 December 2009 Baselga et al. Nat Rev Cancer 2009;9: Baselga 2009

Single-agent T-DM1 Phase II studies in pretreated HER2-positive MBC
Phase II (TDM4258g) n=112 Single-arm study of single-agent T-DM1 (3.6 mg/kg iv q3w) HER2-positive MBC patients who have progressed on HER2 therapy Previously received trastuzumab and ≥ 1 line of chemotherapy for MBC Phase II (TDM4374g) n=110 Single-arm study of single-agent T-DM1 (3.6 mg/kg i.v. q3w) for HER2-positive MBC patients who have been pretreated with lapatinib, trastuzumab, capecitabine, anthracyclines and taxanes Two HER2-directed regimens in the metastatic setting PD on last regimen received Ref: Vogel et al. Oral presentation 1017 at the 45th ASCO annual meeting, Orlando, Florida, 29 May – 2 June, 2009 Krop et al. Poster 1003 at the 45th ASCO annual meeting, Orlando, Florida, Krop et al. Oral presentation 710 at the 32nd SABCS, San Antonio, Texas, USA, December 2009 Vogel 2009 Krop 2009

TDM4258g: encouraging efficacy demonstrated for single-agent T-DM1
Population All efficacy evaluable patients 112 38.4 25.0 4.9 Lapatinib pretreated patients 67 35.8 23.9 na Patients with centrally confirmed HER2-positive disease 75 48 32.0 na n ORR, % Investigator assessed Independent review PFS, months After 9.5 months’ follow-up Ref: Vogel et al. Oral presentation 1017 at the 45th ASCO annual meeting, Orlando, Florida, 29 May – 2 June, 2009 Heavily pretreated population median 3 prior chemotherapy agents in the metastatic setting na: not available Vogel 2009

TDM4374g: a Phase II trial of T-DM1 in HER2-positive MBC patients progressing during HER2-targeted therapy Patients with HER2-positive MBC (n=110) Prior exposure to anthracycline, taxane, capecitabine, lapatinib and trastuzumab (median 7 prior agents of therapy in the metastatic setting) PD on last regimen received T-DM1 3.6 mg/kg q3w Ref: Krop et al. Poster 1003 at the 45th ASCO annual meeting, Orlando, Florida, 29 May – 2 June, 2009 Krop et al. Oral presentation 710 at the 32nd SABCS, San Antonio, Texas, USA, December 2009 Krop 2009

Investigator assessed n=110
Substantial clinical benefit seen with T-DM1 in a heavily pretreated population Independent review n=110 32.7 (24.1, 42.1) 46.4 18.2 1.8 0.9 44.5 (35.1, 54.3) 7.3 (0-11.7) Investigator assessed n=110 30.0 (22.0, 39.4) 1.8 28.2 52.7 13.6 0.9 2.7 40.0 (31.1, 49.3) n/a Tumour response ORR, % (95% CI) CR PR SDa PD Unevaluable Missing CBR, % (95% CI) Median PFS, months (range) Ref: Krop et al. Poster 1003 at the 45th ASCO annual meeting, Orlando, Florida, 29 May – 2 June, 2009 Krop et al. Oral presentation 710 at the 32nd SABCS, San Antonio, Texas, USA, December 2009 aIncluding unconfirmed PRs CI, confidence interval; n/a, not assessed Krop 2009

T-DM1 is well tolerated with no new safety signals observed
Grade 1, % 11 17 30 26 13 Grade 2, % 11 3 4 26 10 8 13 Grade 3, % 3 1 4 Grade 4, % 2 All grades, % 25 21 20 59 37 22 29 AST increased Constipation Dry mouth Fatigue Headache Nausea Pyrexia Thrombocytopenia Ref: Krop et al. Poster 1003 at the 45th ASCO annual meeting, Orlando, Florida, 29 May – 2 June, 2009 Krop et al. Oral presentation 710 at the 32nd SABCS, San Antonio, Texas, USA, December 2009 Only 6 (5.5%) patients discontinued due to AEs AST: aspartate aminotransferase Krop 2009

T-DM1: potential future clinical benefit for heavily pretreated patients with HER2-positive MBC
T-DM1 has shown robust single-agent activity in heavily pretreated patient groups substantial clinical benefit observed in patients with PD during prior HER2-targeted therapy T-DM1 is well tolerated with no dose-limiting cardiac events observed Further investigation of T-DM1 is ongoing Ref: Krop et al. Poster 1003 at the 45th ASCO annual meeting, Orlando, Florida, 29 May – 2 June, 2009 Krop et al. Oral presentation 710 at the 32nd SABCS, San Antonio, Texas, USA, December 2009 Krop 2009

Capecitabine + lapatinib
EMILIA: ongoing Phase III study of T-DM1 vs capecitabine + lapatinib in the 2nd-line setting HER2-positive incurable locally advanced breast cancer or MBC Prior trastuzumab and taxane n=580 1:1 T-DM1 3.6 mg/kg q3w Capecitabine + lapatinib n=221 as of 16 March 2010

Trastuzumab + docetaxel
TDM4450g: ongoing Phase II study of T-DM1 vs trastuzumab + docetaxel in 1st-line HER2-positive MBC HER2-positive locally advanced or MBC No prior chemotherapy for metastatic disease n=120 T-DM1 Trastuzumab + docetaxel Study start date July 2008 Fully recruited

Trastuzumab + docetaxel
TDM4788g / BO22589: Phase III study of T-DM1 + pertuzumab vs trastuzumab + docetaxel in 1st-line HER2-positive MBC HER2-positive locally advanced or MBC No prior chemotherapy for metastatic disease n=1092 T-DM1 + placebo T-DM1 + pertuzumab Trastuzumab + docetaxel

Summary: pertuzumab and T-DM1 are promising new therapeutic agents for HER2-positive MBC
1st HER2 dimerisation inhibitor Has demonstrated encouraging clinical efficacy and tolerability in combination with trastuzumab Offers a more comprehensive approach to blocking HER2-driven signalling than trastuzumab alone T-DM1 1st HER2-directed ADC delivering cytotoxic drug specifically to HER2-positive tumour cells while retaining the biological activity of trastuzumab Has demonstrated encouraging clinical efficacy and tolerability in heavily pretreated patients Clinical trials of both agents are ongoing, including pertuzumab and T-DM1 in combination

Outlook Small or Node negative HER2 positive tumors : should you botHER? HER2-positive cancers have a distinct biology and an aggressive behaviour Do we have a cure? 18 Infusions of Herceptin deliver high cure rates for women with HER2-positive early breast cancer Is Herceptin efficient at all HER2 positive tumors? Herceptin efficacy is consistent across tumor size and nodal status What do the international guidelines recommend? St Gallen 2011 guidelines recommend : Herceptin when tumor size >0,5 cm CHAPTER 2 : Herceptin efficacy is consistent across tumor size and nodal status 126 126

HER2-positive cancers have a distinct biology and an aggressive behaviour(1,5)
Ref: von Minckwitz et al. J Clin Oncol 2009;27: 1 Oakman at al;Annals of oncology 21, 2010 (Supplement 7);vii112-vii119 2 Gonzalez-Angulo et al. J Clin Oncol 2009;27; 3 Chia et al, Journal of Clinical Oncology, 2008, p 4 Tovey et al, British Journal of Cancer, 2009,1-4 5 Banerjee et al, Lancet Oncol 2010; 11: 1193–99

Small HER2-positive tumors have a high risk of relapse(1)
0.2 0.4 0.6 0.8 1.0 1 2 3 4 5 HER2-negative 93,7% Reccurrence-Free Survival [proposition] HER2-negative 51 Gonzalez-Angulo et al.j clin Oncol 2009;27; n=965T1a,bN0MO tumors P<0,0001 Time since diagnosis (years) 128 128

Small HER2-positive tumors have a high risk of relapse(1)
0.2 0.4 0.6 0.8 1.0 1 2 3 4 5 HER2-negative 77,1% HER2-positive 93,7% Reccurrence-Free Survival [proposition] HER2-negative 51 Gonzalez-Angulo et al.j clin Oncol 2009;27; n=965T1a,bN0MO tumors P<0,0001 Time since diagnosis (years) 129 129

Distant Disease-Free Survival
Small HER2-positive tumors have a high risk of relapse(1) Finnish population based study(2) HER2-negative 20 40 60 80 100 1 2 3 4 5 HER2-positive Distant Disease-Free Survival CISH HER2-negative (n=167) CISH HER2-positive (n=17) 1 Gonzalez-Angulo et al. J Clin Oncol 2009;27; 2 Joensuu et al, Clin Cancer Res 2003;9: 1-10 mmn Node negative P<0,0001 Joensuu(2) Years of folluw-up 130 130

Small tumors were defined in these studies as tumors of 1 cm or less(1,2)
Breast Cancer Classification(3)* T1mi : Tumor ≤ 1 mm T1a : Tumor >1mm but ≤ 5mm T1b : Tumor >5mm but ≤ 10 mm T1c : Tumor > 10 mm but ≤ 20 mm T2 : Tumor > 20 mm but ≤ 50 mm T3 : Tumor > 50 mm T4 : Tumor of any size with direct extension to the chest wall and/or the skin 1 Gonzalez-Angulo et al. J Clin Oncol 2009;27; 2 Joensuu et al, Clin Cancer Res 2003;9: 3 American Joint Committee on Cancer, Cancer staging handbook, 7th edition * In greatest dimension

Breast Cancer-Specific Survival (probability)
Even for node negative patients, HER2 positivity doubles the 10-year risk of dying from breas cancer HER2-negative 0.2 0.4 0.6 0.8 1.0 2 4 6 8 10 Breast Cancer-Specific Survival (probability) CISH HER2-negative (n=167) * Node negative cohort did not receive any adjuvant systemic treatment 1 Chia et al, Journal of Clinical Oncology, 2008, p5697 – 5704 n=1420 P<0,001 Chia*(1) Time (years) 132 132

Breast Cancer-Specific Survival (probability)
Even for node negative patients, HER2 positivity doubles the 10-year risk of dying from breas cancer 0.2 0.4 0.6 0.8 1.0 2 4 6 8 10 HER2-negative HER2-positive Breast Cancer-Specific Survival (probability) HER2-negative HER2-positive * Node negative cohort did not receive any adjuvant systemic treatment 1 Chia et al, Journal of Clinical Oncology, 2008, p5697 – 5704 n=1420 P<0,001 Chia*(1) Time (years) 133 133

Breast Cancer-Specific Survival
Poor survival outcomes in HER2-positive breast cancer patients with low-grade, node-negative tumours(2) 0.2 0.4 0.6 0.8 1.0 2 4 6 8 10 HER2-negative HER2-positive Breast Cancer-Specific Survival HER2-negative (n=240) HER2-positive (n=22) * Node negative cohort did not receive any adjuvant systemic treatment 1 Chia et al, Journal of Clinical Oncology, 2008, p5697 – 5704 P<0,001 1 3 5 7 9 Tovey(2) Follow-up (years) 134 134

Herceptin significantly improves Overall Survival Relatives reduction in the risk of death of 37%
100 ___ 92% ACTH 90 ACT 87% 80 70 % Alive 1 De Vita-Nat Clin Pract Oncol 2006;3(2):59 2 Slamon at al.Oral presentation during 2009 SABC, San Antonio, Texas, Dec2009 Perez et al. JCO, 2007 vol 25:N0185:512 60 ACT + Herceptin (n=1.074) ACT (n=1.073) 50 HR=0,63 (95%CI,0.48_- 0.81) P<0.001 40 Time (years) 1 2 3 4 5 6 BCIRG 006 136 136

Alive and disease-free (%)
Over 85% of women live without disease progression 4 years after the start of adjuvant treatment with Herceptin(3) 100 80 92.3% AC-TH 87.9% 85.9% 86.4% 60 77.6% 73.1% Alive and disease-free (%) AC-T ACT-T+ Herceptin 40 AC-T HR* adj=0,48 (95%CI,0.41_- 0.57) 20 1 De Vita-Nat Clin Pract Oncol 2006;3(2):59 3 Perez et al. JCO, 2007 vol 25:NO185:512 P<0.001 Follow-up (years) 1 2 3 4 5 6 Number at risk AC-TH (n=1.989) AC-T (n=1.979) 1.854 1.800 1.347 1.235 868 753 522 460 202 168 4 8 Joint analysis of N9831 and NSABP B31 trials *Nodes, receptor status, paclitaxel schedule, protocol 137 137

Combined analysis of N9831/B31 and N981 trials, 4 year FU(2)
1 Oakman at al; Annals of oncology 21 (Supplement 7);vii112-vii119,2010 2 Perez et al ; JCO, 2011, p1-9 139 139

Combined analysis of N9831/B31 and N981 trials, 4 year FU(2) Disease Free Survival Rate
1 Oakman at al; Annals of oncology 21 (Supplement 7);vii112-vii119,2010 2 Perez et al ; JCO, 2011, p1-9 140 140

Adjuvant Herceptin decreases the recurrence or death rate
Adjuvant Herceptin decreases the recurrence or death rate* for patient with small tumors ≤1cm * Calculated based on invasive DFS (1), on RFS (2) and on DFS (3) ** Defined as invasive disease - free survival *** Cross-Trial comparison 1 Wasserman et al, ASCO 2011, Abstract 557 2 McArthur et al, Cancer, 2011 p1-8 3 Dall et al, ASCO 2011, Abstract 607 141 141

Adjuvant Herceptin significantly improves DFS for patients with small tumors ≤1cm(1)
1 Slamon et al, N Engl. J Med 2011;365: 142 142

HERA: Disease Free Survival at 2 year median follow-up(2)
1 Oakman at all; Annals of oncology 21 (Supplement 7);vii112-vii119,2010 2 Untch et al, Annals Oncol 19 (Suppl 6) : 1090 – 1096 143 143

Herceptin overall survival benefit for node negative tumors is confirmed after a median follow-up of more than 5 years * AC-TH versus AC-T 3 Supplement to : Slamon et al ; NEJM 2011 ;365 : 144 144

Adjuvant Herceptin plus Chemotherapy results in consistent benefits for node-negative patients(1)
1 Oakman at all; Annals of oncology 21 (Supplement 7);vii112-vii119,2010 2 Untch et al, Annals Oncol 19 (Suppl 6) : 1090 – 1096 145 145

HERCEPTIN Herceptin [trastuzumab] Herceptin Small Tumor

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HERCEPTIN Herceptin [trastuzumab] Herceptin Small Tumor

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