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Should clinicians routinely recommend trastuzumab (Herceptin) as part of the adjuvant therapy for all patients with Her2 positive early breast cancer? A review of recent data, and reflections on how these results relate to the use of Adjuvant!. Details Of Use Of These Slides

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    1. Should clinicians routinely recommend trastuzumab (Herceptin) as part of the adjuvant therapy for all patients with Her2 positive early breast cancer? A review of recent data, and reflections on how these results relate to the use of Adjuvant!

    2. Details Of Use Of These Slides For many of the slides there is additional information available in the text area of the slide. This information can be accessed by selection of the “View” on the top bar and the selecting “Normal”. Below the slide area in the “normal” view the additional text can be viewed.

    3. An Interpretation of Adjuvant Herceptin Results Presented at ASCO May 2005 1) Romond EH, Perez EA, Bryant J, et al. Doxorubicin and Cyclophosphamide Followed by Paclitaxel with or without Trastuzumab as Adjuvant Therapy for Patients with HER-2 Positive Operable Breast Cancer: Combined Analysis of NSABP B31/NCCTG-N9831 2) Perez EA, Suman VJ, Davidson N, et al. NCCTG N9831 May 2005 Update 3) Piccart MJ First Results Of The HERA Trial

    4. NSABP B-31 Arm 1 Arm 2 NCCTG N9831 Arm A Arm B Arm C HERA (Randomization after chemotherapy) Arm A No Herceptin Arm B (1 yr) Arm C (2 yr) AC q 3 wk * 4 = paclitaxel q 1 wk * 12 = paclitaxel q 3 wk * 4 = trastuzumab q 1 w = trastuzumab q 3 w

    5. Combined analysis of B31 / N9831 Control Arm 1 (B31) Arm A (N9831) Herceptin Arm 2 (B31) Arm C (N9831) Combined: n = 3,351; median follow-up 2.0 yr NSABP B-31: n = 1,736; median follow-up 2.4 yr N9831: n = 1,615; median follow-up 1.5 yr

    6. Eligibility NSABP B-31 / N9841 • Definitively resected primary adenocarcinoma of the breast. • Axillary node positive (N9841 was amended to allow high risk node negative). • No locally advanced or metastatic disease. • Normal hematologic, hepatic, and renal function. • No prior anthracycline or taxane therapy. • No significant sensory or motor neuropathy. • No past or current cardiac history. • Normal LVEF. • Her2 IHC +++ or FISH + (N9831 by central lab, B31 by approved reference laboratory).

    7. Patient / Tumor: Characteristics No Imbalances Between Treatment Arms (numbers shown are % of total) Age < 50 51 50 - 59 33 > 59 16 Nodes N0 6 NP (1-3) 53 NP (4-9) 27 NP (> 9) 14 Tumor Size T < 2cm 39 T 2.1-4.0 cm 45 T > 4 cm 15 ER and PgR Status ER + 52 ER - 48 PgR + 40 PgR - 59

    8. Combined Analysis for DFS of NSABP B-31 / NCCTG – N9831 ACTH 87% 85% ACT 75% % 67% N Events ACT 1679 261 ACTH 1672 134 HR=0.48, 2P=3x10-12 Years From Randomization

    9. Combined Analysis for DFS of NSABP B-31 / NCCTG – N9831 Subset Analysis For DFS Herceptin Benefit In all age subsets In all tumor size subsets In all nodal subsets (NN CI very broad) In ER positive and negative subsets In both N9831 and B31

    10. Forest Plot For DFS: B31/N9831 ALL DATA Age ≥60 50-59 40-49 ≤39 Positive Negative Hormone Receptor ≥ 4.1cm 2.1- 4.0 cm <2.0 cm Tumor Size No. Positive Nodes 10+ 4-9 1-3 0 Protocol N9831 NSABP B-31 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Hazard Ratio

    11. Combined Analysis for DDFS of NSABP B-31 / NCCTG – N9831 100 ACTH AC->T+H 90% 90% 90% 90% 90% 90% 90 ACT AC->T 80 81% 81% 81% % 74% 74% 74% 70 N Events N Events ACTH 1672 96 ACT 1679 194 AC->T 1679 194 60 AC->T+H 1672 96 HR=0.47, 2P=8x10-10 HR=0.47, 2P=8x10-10 50 0 1 2 3 4 5 Years From Randomization

    12. Annual Hazard of Distant Recurrence 120 100 ACT 80 Rate per 1000 Women /Yr 60 40 ACTH 20 0 0 1 2 3 4 Years From Randomization

    13. Combined Analysis for OS of NSABP B-31 / NCCTG – N9831 ACTH 94% 91% ACT 92% 87% N Deaths ACT 1679 92 ACTH 1672 62 HR=0.67, 2P=0.015 Years From Randomization B31/N9831

    14. Cardiac Monitoring ~ 20% of the patients discontinued Herceptin because of symptomatic or asymptomatic heart problems Herceptin * 12 mns AC * 4 Taxol * 4 3 mns 6 mns 9 mns 15 mns 18 mns Baseline 7.7% 10.1% 2.1% % stopping Herceptin by time period ~ 4 % of patients never got Herceptin because of developing a low LVEF post AC * 4. LVEF measurements This analysis from B31data alone.

    15. Cardiac Monitoring Rules for action for asymptomatic patients * Repeat LVEF assessment in 4 weeks If criteria for continuation met restart If 2 consecutive holds of a total of 3 holds, discontinue Herceptin

    16. Cardiac Safety Age and Post AC LVEF were predictors of the risk of developing CHF In both age groups about 10% of the patients had a LVEF of 50-54, about 50% of the patients had a LVEF of 55-64, and 35% had a LVEF of > 65%. Average risk of early CHF for patient younger than 50 is 2 % and older than 50 is ~ 5% This analysis from B31data alone.

    17. Risk of Cardiac Events (no strong evidence of an major delayed toxicity) End of Herceptin treatment period The only cardiac death that occurred during this study occurred in a control patient. This analysis from B31 data alone.

    18. NSABP B-31 Cardiac Safety Analysis For First 1000 Patients Baseline all patients normal LVEF (median 63%) After 3 months of AC LVEF median 61% (lower, p<0.001) 4.2% of patients with LVEF < 50% Total symptomatic cardiac events during Herceptin 4.28 % in Herceptin group 0.78 % in Control group Patients with low LVEF did not go on to get Herceptin. of these 33% had LVEF < 30%, 52% LVEF 30-39%

    19. NSABP B-31 Cardiac Safety Analysis For First 1000 Patients Herceptin Related Fall In LVEF Was Largely Reversible In Patients With A Cardiac Event (n=27) ~ 68% of the patients had symptoms resolve within 6 months

    20. Analysis of Three Arms of N9831 NCCTG N9831 Arm A Arm B Arm C n = 2,804; median follow-up 1.5 yr

    21. N9831 Disease-Free Survival Control vs Concurrent AC → T + H → H 100 90 80 70 60 50 40 30 20 10 0 AC → T % Hazard ratio = 0.55 Stratified logrank 2P = 0.0005 0 1 2 3 4 Years

    22. N9831 Disease-Free Survival Control vs Sequential AC → T → H 100 90 80 70 60 50 40 30 20 10 0 AC → T % Hazard ratio = 0.87 Stratified logrank 2P = 0.29 0 1 2 3 4 Years

    23. N9831 Disease-Free Survival Sequential vs Concurrent AC → T + H → H 100 90 80 70 60 50 40 30 20 10 0 AC → T → H % Hazard ratio = 0.64 Stratified logrank 2P = 0.0114 0 1 2 3 4 Years

    24. Cardiac Safety in 9831 • Difference in the incidence of cardiac events (CHF and cardiac deaths) between non-H and H arms is < 4% • 9 month (post finishing AC * 4) analysis; 500 per arm with normal LVEF or LVEF decrease  15% from baseline (after AC) • 0.0% with events (95% CI,0.0-0.7%) for control • 2.2% with events (95% CI,1.1-3.8%) for control vs sequential • 3.3% with events (95% CI,2.0-5.1%) for control vs concurrent* therapy with paclitaxel * at month 9, concurrent pts have received 3 additional months of Herceptin compared to sequential

    25. HERA Trial HERA (Randomization after chemotherapy) Arm A No Herceptin Arm B (1 yr) Arm C (2 yr) Only Arms 1 and 2 analyzed in this interim analysis n = 3,307, median follow-up ~ 1 year

    26. Eligibility HERA Trial • Definitively resected primary adenocarcinoma of the breast. • Received and completed neoadjuvant and/or adjuvant chemotherapy. Chemotherapy must have been at least 4 cycles of an approved regimen. • If node negative tumor size must have been T1c or larger (for adjuvant patients). • Normal LVEF by MUGA or echo of > 55%. • Her2 IHC +++ or FISH + by central lab. • Known (and centrally reviewed ER status).

    27. HERA Trial: Patient / Tumor: Characteristics No Imbalances Between Treatment Arms (numbers shown are % of total) Age < 50 51 50 - 59 32 > 59 16 Nodes N0 33 NP (1-3) 29 NP > 4 28 NeoAdj 11 Adjuvant Regimen Anthracyclines 68 Anathra + Taxane 26 No A or Taxane 6 ER and PgR Status ER + 51 ER - 49

    28. DFS: HERA Trial Trastuzumab 1 yr % alive and disease free 100 90 80 Observation 70 60 50 2-yrDFS % 40 Events HR [95% CI] p value 30 127 85.8 0.54 [0.43, 0.67] <0.0001 20 220 77.4 10 0 0 5 10 15 20 25 Months from randomization No. at risk 1694 1472 1067 629 303 102 1693 1428 994 580 280 87

    29. DFS In Patient Subsets: HERA Trial Hazard Hazard ratio ratio n n All All 3387 3387 0.54 0.54 Nodal Nodal status status Any, neo Any, neo - - adjuvant chemotherapy adjuvant chemotherapy 358 358 0.53 0.53 0 pos, no neo 0 pos, no neo - - adjuvant chemotherapy adjuvant chemotherapy 1100 1100 0.52 0.52 1 1 - - 3 pos, no neo 3 pos, no neo - - adjuvant chemotherapy adjuvant chemotherapy 972 972 0.51 0.51 ³ ³ 4 pos, no neo 4 pos, no neo - - adjuvant chemotherapy adjuvant chemotherapy 953 953 0.53 0.53 Adjuvant chemotherapy regimen Adjuvant chemotherapy regimen No anthracycline or taxane No anthracycline or taxane 203 203 0.64 0.64 Anthracycline, no taxane Anthracycline, no taxane 2307 2307 0.43 0.43 Anthracycline + taxane Anthracycline + taxane 872 872 0.77 0.77 Receptor status/endocrine therapy Receptor status/endocrine therapy Negative Negative 1674 1674 0.51 0.51 Pos + no endocrine therapy Pos + no endocrine therapy 467 467 0.49 0.49 1234 1234 0.68 0.68 Pos + endocrine therapy Pos + endocrine therapy Age group <35 yrs <35 yrs 251 251 0.47 0.47 35 35 - - 49 yrs 49 yrs 1490 1490 0.52 0.52 50 50 - - 59 yrs 59 yrs 1091 1091 0.53 0.53 ³ ³ 60 yrs 60 yrs 549 549 0.70 0.70 Trastuzumab Better Observation Better 0 1 2

    30. Cardiac Safety in HERA (very early 1 year median follow-up report)

    31. BCIRG 006 (n ~ 3000) Will Arm 3 (a non-anthracycline adjuvant regimen) be the answer ? BCIRG 006 Arm 1 Arm 2 Arm 3 Expected efficacy report SABCS December 2005 Current reported cases of Grade 3/4 CHF Arm 1 / Arm 2 / Arm 3 = 1, 18, 1 Current reported cases LVEF 15% < LLN Arm 1 / Arm 2 / Arm 3 = 6, 25, 4 AC q 3 wk * 4 = docetaxel/platinum q 3 wk * 6 = docetaxel q 3 wk * 4 = trastuzumab q 1 w = trastuzumab q 1 w

    32. So Is Adjuvant Herceptin For All Breast Cancer Patients? Informed Speculation ! 60 Year Old Women. ER +, Her2 +, average comorbidity. Competeing mortality about 8%. To Get Tam + CA * 4, T * 4q3w. Her2 FISH +. Additional RR conferred by Her2 1.5. Risk of developing CHF 5%, 2/3 have symptoms resolve in 6 months. Cardiac status at 10 years??

    33. CA * 4 then T * 4 Results of 9344, 9741, and B-31 /N9831 No major difference in outcome of this arm between trials.

    34. Early Results Triumphs and Cautionary Tales Tam vs Obs Her vs Obs (Overview) (B31/N9831) Proportional risk reductions at 2 Years for DFS 53 % 52% Proportional risk reductions at 10 years for DFS 39 % ??? Durable but Durable ? Late Toxicity Late Toxicity ?

    35. Early Results Do Not Always Reflect Late Results In Adjuvant Therapy Poly Chemotherapy Tamoxifen (5 yrs) Proportional Risk Reduction During Time Interval Time Periods (yrs) Time Periods (yrs) Recurrence Breast Cancer Specific Mortality

    36. NSABP/Intergroup Recommendations For Control Patients The recommendations were covered in letters to the patients and clinicians. The recommendations were complex because the letter had to deal with the spectrum of possible treatment points that the patient might be at. Of special relevance to patients who were not trial participants were the following: Patients in the control (non-trastuzumab) arms with adequate cardiac function, and within 6 months of finishing chemotherapy were offered trastuzumab. The NSABP suggested that trial patients who had not yet started the paclitaxel/trastuzumab, who were > 50 years old and who had a post AC *4 LVEF of 50-54%, consider the option of starting the trastuzumab only after completing the paclitaxel.

    37. Should clinicians routinely recommend trastuzumab (Herceptin) as part of the adjuvant therapy for all patients with Her2 positive early breast cancer? Adjuvant Herceptin should only recommended as a part of a process that includes both information about the early gains and warns the patient that she faces some increased risk of developing CHF. Although early results are very encouraging, information about long term benefits and risks is not yet available.