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HERCEPTIN

HERCEPTIN. Herceptin [ trastuzumab ] 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 Efficacy is consistent across tumor size and nodal status.

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HERCEPTIN

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  1. HERCEPTIN Herceptin [trastuzumab] 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 Efficacy is consistent across tumor size and nodal status

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

  3. 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 Marla 2008 Slamon 1989 Slamon 1987 Penault-Llorca 2005

  4. HER2 = Important therapeutic target Spector 2009

  5. 5 mechanisms of action + + + + Action 1 Action 2 Action 3 Action 4 Action 5 t t t t t Herceptin inhibits proliferation and induces apoptosis of HER2+ tumor cells Spector 2009

  6. Herceptin : Expertise in all stages of Breast Cancer EBC MBC Surgery Relapse Progression Neoadjuvant 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 104900 Numerous Phase II studies EBC: Early Breast Cancer MBC: Metastatic Breast Cancer

  7. 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 1. van der Hage et al. 2007; 2. Fisher et al. 19983. van der Hage et al. 2001; 4. Connolly and Stearns 20105. von Minckwitz et al. 2008; 6. Kaufmnann et al. 20077. von Minckwitz et al. 2010; 8. Symanns et al. 2007

  8. 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) 80 Overall Survival (%) non-pCR (n=1889) 60 40 4 5 6 7 0 1 2 3 Years after surgery Bear et al. 2006

  9. NOAH: Study design HER2-positive(IHC 3+ or FISH+) HER2-negative(IHC 0/1+) n=118 n=117 n=99 H + ATq3w x 3 cycles ATq3w x 3 cycles ATq3w x 3 cycles H + T q3w x 4 cycles Tq3w x 4 cycles Tq3w x 4 cycles H q3w x 4 cycles+ CMF q4w x 3 cycles CMFq4w x 3 cycles CMFq4w x 3 cycles Surgery followed by radiotherapy Surgery followed by radiotherapy Surgery followed by radiotherapy H continued q3wto 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

  10. 50 p=0.0007 43% 40 43% 30 Patients with pCR, % 22% 20 10 n=118 n=117 0 WithHerceptin WithoutHerceptin NOAH: Herceptin almost doubles pCR rates Median follow-up = 3 years pCR =pathological Complete Response Gianni 2010

  11. n Events 51 36 118 117 NOAH: Herceptin extends event-free survival 1.00 0.75 Probability, event-free survival 0.50 3-year EFS (%) HR 95% CI p valuea 0.25 CTxHerceptin + CTx 0.013 56 71 0.59 0.38-0.90 0.00 0 6 12 18 24 30 36 42 Months Median follow-up = 3 years a Unadjusted for stratification variables CTx: chemotherapy Gianni 2010

  12. NOAH : Herceptin is well tolerated with acceptable cardiac safety WithoutHerceptin n=113 3 4 2 0 0 1 2 4 0 4 WithHerceptin n=115 0 1 2 0 2 1 1 3 1 1 Selected grade ¾adverse events (%) Arthralgia Diarrhea Febrile neutropenia Infection LVEF decline Myalgia Neuropathy peripheral Neutropenia Pneumonia Stomatitis Gianni 2010

  13. TECHNO Trial : PCR after NeoAdjuvant Chemotherapy predicts survival

  14. Geparquinto : pCR with Herceptin is statistically better than with lapatinib. 60% 50.4% 50% 35.2% 40% 30% P<0.05 20% 10% 0 EC + Doc + Herceptin EC + Doc + lapatinib (noinvasive/ non-invasive residual in breast & nodes ) Untch M, et al. SABCS 2010;#S3-1

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

  16. NeoAltto StudyPathological Complete Response 60% 51.3% 50% 40% 29.5% % Response 30% 24.7 20% 10% 0 Herceptin + lapatinib lapatinib Herceptin Baselga J, et al. SABCS 2010;#S3-3

  17. Herceptin : Expertise in all stages of Breast Cancer EBC MBC Surgery Relapse Progression Neoadjuvant 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 104900 Numerous Phase II studies EBC: Early Breast Cancer MBC: Metastatic Breast Cancer

  18. Key trastuzumab studies in HER2-positive EBC 1. Gianni L, et al. 2011; 2. Slamon D, et al. 2009; 3. Perez EA, et al. 2011 Extensive clinical programme involving >12,000 patients *Chemotherapy selected from a list of approved regimens consisting of ≥4 cycles

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

  20. 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

  21. 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 6 mg/kg 3-weekly schedule 2 years Herceptin 8 mg/kg 6 mg/kg 3-weekly schedule After ASCO 2005, option of crossover to Herceptin CTx: chemotherapy RT: radiotherapy Gianni 2009

  22. 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 Piccart-Gebhart MJ, et al. 2005

  23. 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 observation Trastuzumab 2 years vs observation Trastuzumab 1 year vs trastuzumab 2 years Gianni L, et al. 2011; Smith I, et al. 2007; Piccart-Gebhart MJ, et al. 2005

  24. 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 Suter TM, et al. 2007

  25. HERA: Study timeline Anticipatedrelease of 2-year data* 1st interimanalysis(n=475DFS events) 2-year follow-up(n=539DFS events) 4-year follow-up(n=827DFS events) Q3/4 2012 2009 2010 2011 2007 2008 2005 2006 • 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

  26. HERA: Patient characteristics (1) Gianni L, et al. 2011

  27. HERA: Patient characteristics (2) *Status at randomisation Gianni L, et al. 2011

  28. 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 IDMC: Independent Data Monitoring Committee Gianni 2009

  29. 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 6 mg/kg 3-weekly schedule 2 years Herceptin 8 mg/kg 6 mg/kg 3-weekly schedule After ASCO 2005, option of crossover to Herceptin CTx: chemotherapy RT: radiotherapy Gianni 2009

  30. No. at risk 1703 1698 1619 1564 1552 1440 1485 1363 1414 1297 1352 1240 1280 1180 1020 992 854 712 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-yearDFS 78.672.2 HR 0.76 95%Cl 0.66, 0.87 p value <0.0001 Events 369458 20 0 0 6 12 18 24 30 36 42 48 Months from randomisation Gianni 2009 Piccart 2005 Smith 2007

  31. HERA: DFS at all timepoints Consistent DFS benefit for trastuzumab vs observation Medianfollow-up Number of DFS events Trastuzumabvs observation DFS benefit 127 vs 220P<0.0001 1 year1 218 vs 321P<0.0001 2 years2 369 vs 458P<0.0001 4 years3 0 1 2 Favourstrastuzumab Favours notrastuzumab HR (95% CI) 1. Piccart-Gebhart MJ, et al. 2005; 2. Smith I, et al. 2007; 3. Gianni L, et al. 2011

  32. HERA: Exploratory analysisof DFS by subgroup (1) Consistent DFS benefit for trastuzumab across subgroups Number of eventstrastuzumab vs observation Subgroup (number of patients) HR (95% CI) Age at randomisation 19 vs 31 <35 years (253) 0.57 (0.32‒1.01) 35‒49 years (1508) 89 vs 150 0.54 (0.42‒0.70) 71 vs 97 0.71 (0.52‒0.97) 50‒59 years (1096) 39 vs 43 ≥60 years (544) 0.91 (0.59‒1.41) Menopausal status at randomisation Premenopausal (491) 0.80 (0.53‒1.21) 43 vs 49 70 vs 135 0.48 (0.36‒0.64) Uncertain (1373) Postmenopausal (1535) 105 vs 137 0.75 (0.58‒0.97) 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) 0.61 (0.43‒0.87) 50 vs 80 ≥4 positive nodes (953) 0.64 (0.49‒0.83) 95 vs 132 All patients (3401) 218 vs 321 0.64 (0.54‒0.76) 1.0 0.0 0.5 1.5 HR Smith I, et al. 2007

  33. HERA: Exploratory analysisof DFS by subgroup (2) Consistent DFS benefit for trastuzumab across subgroups Number of eventstrastuzumab vs observation Subgroup (number of patients) HR (95% CI) Pathological tumour size 39 vs 50 0.66 (0.43‒1.00) Any (neoadjuvant chemo) (372) 61 vs 95 0.65 (0.47‒0.90) 0‒2 cm (1351) >2‒5 cm (1482) 97 vs 150 0.55 (0.43‒0.71) 20 vs 25 >5 cm (171) 1.14 (0.63‒2.06) Hormone receptor status 126 vs 190 0.63 (0.50‒0.78) ER-negative/PgR-negative (1627) 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) 0.63 (0.43‒0.93) 46 vs 61 Previous radiotherapy 0.64 (0.53‒0.77) 183 vs 265 Yes (2606) 0.64 (0.42‒0.98) 35 vs 56 No (795) Type of (neo)adjuvant chemo 12 vs 15 0.76 (0.35‒1.62) No anthracyclines (202) Anthracyclines, no taxanes (2310) 0.57 (0.46‒0.71) 132 vs 221 Anthracyclines and taxanes (889) 0.80 (0.59‒1.10) 74 vs 85 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

  34. HERA: Patient crossoverto trastuzumab Proportion of patients crossing over increased over time 0.6 Switched totrastuzumab 0.5 0.4 885/1354 eligible patients (65%) crossed over to trastuzumab Probability of crossover to trastuzumab 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 Time from randomisation (months) No.at risk 1359 1040 722 432 194 19 65 1698 1557 Gianni L, et al. 2011

  35. 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-yearDFS 78.671.7 HR 0.69 95% CI 0.59–0.79 P value <0.0001 20 0 0 6 12 18 24 30 36 42 48 Months from randomisation 17031698 16191557 15521364 14851089 1414836 1352620 1280448 1020324 854234 No. at risk *Excludes data from patients randomised to observation who crossed over to trastuzumab (n=885) Gianni L, et al. 2011

  36. HERA: OS at 4 years, censoredfor crossover Censored analysis suggests OS benefit of trastuzumab for 1 year 100 Trastuzumab 1 year 7.8% 80 Observation* 60 Alive (%) 40 4-yearDFS 89.381.5 HR 0.53 95% CI 0.44–0.65 P value <0.0001 20 0 0 6 12 18 24 30 36 42 48 Months from randomisation 16401524 15771047 17031698 16601635 16151287 1524827 1447636 1149479 953331 No. at risk *Excludes data from patients randomised to observation who crossed over to trastuzumab (n=885) Gianni L, et al. 2011

  37. HERA: Impact of crossover on DFS Improvement in DFS even for late introduction of trastuzumab 100 80 60 Alive and disease free (%) 40 20 Selective crossover to trastuzumab No crossover 0 0 6 12 18 24 30 36 42 48 Months from randomisation 885 885 884 878 870 851 822 690 480 No. at risk 469 468 455 438 408 388 358 302 232 Gianni L, et al. 2009

  38. HERA: Adverse events and cardiac endpoints Low incidence of cardiac adverse events with trastuzumab *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

  39. HERA: Adverse event profilein crossover patients Crossover to trastuzumab does not affect tolerability *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

  40. 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 0 0 6 12 18 24 30 36 42 48 Time (months) Procter M, et al. 2010

  41. 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

  42. NCCTG N9831: Study design Arm A RANDOMISATION Paclitaxel(qw x 12) AC (q3w x 4) n=819 HER2-positiveEBC N=2614 Arm B AC (q3w x 4) Trastuzumab(qw x 52) Paclitaxel(qw x 12) n=981 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

  43. NSABP B-31: Study design RANDOMISATION Group 1 Paclitaxel(q3w x 4 or qw x 12) AC (q3w x 4) n=1024 HER2-positiveEBC N=2043 Group 2 AC (q3w x 4) Paclitaxel(q3w x 4 or qw x 12) + trastuzumab (qw x 52) n=1019 AC = doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4Paclitaxel 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

  44. 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 completionof 12-week regimen of trastuzumab + paclitaxel • Joint efficacy analysis • Primary endpoint: DFS • Secondary endpoint: OS Perez EA, et al. 2007

  45. 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) 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

  46. 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 Perez EA, et al. 2011

  47. Primary DFS Local/regional/distant recurrence Contralateral breast disease (including DCIS) 2nd primary invasive cancers Death due to any cause Secondary OS TTDR Combined analysis: Endpoints and analyses 1st interim efficacyanalysis after 355 DFS events1 2nd interim efficacyanalysis after 619 DFS events2 3rd interim efficacyanalysis after 779 DFS events3 1. Romond EH, et al. 2005; 2. Perez EA, et al. 2007; 3. Perez EA, et al. 2011

  48. Combined analysis: Patient characteristics (1) Perez EA, et al. 2011

  49. Combined analysis: Patient characteristics (2) Perez EA, et al. 2011

  50. 100 80 60 40 20 0 0 1 2 3 4 5 Combined analysis: DFS at 4 years of follow-up Significant DFS benefit of trastuzumab at all timepoints 92.4% 88.0% 85.7% ACTH 86.8% 79.0% ACT 73.7% Alive and disease-free (%) 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 Follow-up (years) Perez EA, et al. 2011

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