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Moving forward: Herceptin ®  in the adjuvant setting – Trials in which Herceptin ®  is combined with chemotherapy Elizabet...
NSABP B-31 *Tamoxifen for ER+ or PgR+; tamoxifen optional for ER– and PgR– patients   50 years old Operable breast cancer...
NSABP B-31 stratification Operable breast cancer HER2-positive tumour Pathologically positive axillary nodes <ul><li>Strat...
Primary aim <ul><li>Stage I: (n=1,000) </li></ul><ul><ul><li>evaluation of cardiac safety </li></ul></ul><ul><li>Stage II:...
Eligibility <ul><li>Node positive </li></ul><ul><li>HER2 positive: IHC 3+ or FISH+ </li></ul><ul><li>Normal MUGA </li></ul...
Drug dose <ul><li>Adriamycin 60mg/m 2 </li></ul><ul><li>Cyclophosphamide 600mg/m 2 </li></ul><ul><li>Paclitaxel 175mg/m 2 ...
MUGA schedule Arm I AC Paclitaxel 18 months 6 months 9 months 3 months 0 months 0 months 18 months 6 months 9 months 3 mon...
Post-AC left ventricular ejection fraction (LVEF) in asymptomatic patients *LLN = lower limit of normal
Herceptin ®  management in  asymptomatic patients *Repeat MUGA after 4 weeks
Secondary aim <ul><li>Tissue-block collection </li></ul><ul><ul><li>primary tumour </li></ul></ul><ul><ul><li>involved lym...
Secondary aim (cont’d) <ul><li>Prognostic and predictive value of phosphorylated HER2 receptor  </li></ul><ul><li>Prognost...
B-31 accrual 1,200 1,000 800 600 400 200 0 0 4 8 12 16 20 24 Months Number of patients Projected Actual
Patient characteristics Age (years)  Race  No. of positive  nodes  39 40–49 50–59  60 White Black Other 1–3 4–9 10+ 100 ...
Pathological tumour size (cm)  1.0 1.1–2.0 2.1–3.0 3.1–4.0 4.1–5.0  5.1 AC    P (mean 2.9cm) AC   P + H (mean 2.8cm)...
Patient characteristics Operation and radiotherapy Tamoxifen treatment AC   P AC    P + H Mastectomy + no radiotherapy...
Overall toxicity 50 40 30 20 10 0 Percentage of patients 2 3 4 5 Grade of overall toxicity AC (n=615)
Overall toxicity (cont’d) 50 40 30 20 10 0 Percentage of patients 2 3 4 5 Grade of overall toxicity P (n=251) P + H (n=245)
Toxicity in patients receiving paclitaxel (n=251) versus paclitaxel plus Herceptin ®  (n=245) Neutropenic infection Febril...
Toxicity in patients receiving paclitaxel (n=251) versus paclitaxel plus Herceptin ®  (n=245) Sensory neuropathy Arthralgi...
Cardiac toxicity assessments <ul><li>Three formal interim statistical comparisons  per arm : </li></ul><ul><ul><li>1) afte...
NSABP B-31: cardiac monitoring <ul><li>At its first interim analysis, the cardiotoxicity (LV dysfunction) remains within a...
HER2 retesting at control reference laboratory (Lab Corp): initial test done at  large volume *  laboratories *More than 1...
HER2 retesting at control reference laboratory (Lab Corp): initial test done at  smaller volume *  laboratories *Less than...
Central FISH  (PathVysion TM ): correlation between reference laboratory (Lab Corp) and NSABP pathology laboratory retesti...
NSABP B-31 amendment <ul><li>HER2 assays by IHC must be done at an NSABP-approved reference laboratory </li></ul><ul><li>H...
Herceptin ®  adjuvant therapy:  summary of ongoing trials *H q3w at 6mg/kg NSABP B-31 Paclitaxel   q3w  x 4 Paclitaxel   q...
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Herceptin

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  • SOTA II February 2002 E. Tan-Chiu
  • Transcript of "Herceptin"

    1. 1. Moving forward: Herceptin ® in the adjuvant setting – Trials in which Herceptin ® is combined with chemotherapy Elizabeth Tan-Chiu Medical Oversight NSABP Operations Office Pittsburgh, Pennsylvania, USA
    2. 2. NSABP B-31 *Tamoxifen for ER+ or PgR+; tamoxifen optional for ER– and PgR– patients  50 years old Operable breast cancer HER2-positive tumour Pathologically positive axillary nodes Randomisation AC x 4* Paclitaxel x 4 AC x 4* Paclitaxel x 4 + Herceptin ®
    3. 3. NSABP B-31 stratification Operable breast cancer HER2-positive tumour Pathologically positive axillary nodes <ul><li>Stratification </li></ul><ul><li>Number of positive nodes </li></ul><ul><li>Type of surgery </li></ul><ul><li>Tamoxifen administration </li></ul><ul><li>Type of radiation therapy </li></ul>
    4. 4. Primary aim <ul><li>Stage I: (n=1,000) </li></ul><ul><ul><li>evaluation of cardiac safety </li></ul></ul><ul><li>Stage II: (n=1,700; total=2,700) </li></ul><ul><ul><li>evaluation of efficacy </li></ul></ul><ul><ul><ul><li>survival: primary endpoint </li></ul></ul></ul><ul><ul><ul><li>disease-free survival (DFS): secondary endpoint </li></ul></ul></ul>
    5. 5. Eligibility <ul><li>Node positive </li></ul><ul><li>HER2 positive: IHC 3+ or FISH+ </li></ul><ul><li>Normal MUGA </li></ul><ul><li>No previous history of significant cardiac disease </li></ul>
    6. 6. Drug dose <ul><li>Adriamycin 60mg/m 2 </li></ul><ul><li>Cyclophosphamide 600mg/m 2 </li></ul><ul><li>Paclitaxel 175mg/m 2 q3w </li></ul><ul><li>Herceptin ® </li></ul><ul><ul><li>loading dose 4mg/kg on week 1 </li></ul></ul><ul><ul><li>maintenance dose 2mg/kg x 51 weeks </li></ul></ul>AC
    7. 7. MUGA schedule Arm I AC Paclitaxel 18 months 6 months 9 months 3 months 0 months 0 months 18 months 6 months 9 months 3 months Arm II AC Paclitaxel + Herceptin ®
    8. 8. Post-AC left ventricular ejection fraction (LVEF) in asymptomatic patients *LLN = lower limit of normal
    9. 9. Herceptin ® management in asymptomatic patients *Repeat MUGA after 4 weeks
    10. 10. Secondary aim <ul><li>Tissue-block collection </li></ul><ul><ul><li>primary tumour </li></ul></ul><ul><ul><li>involved lymph node </li></ul></ul><ul><ul><li>relapse tissue, if biopsied </li></ul></ul><ul><li>Serum collection </li></ul><ul><ul><li>at entry </li></ul></ul><ul><ul><li>at relapse </li></ul></ul>
    11. 11. Secondary aim (cont’d) <ul><li>Prognostic and predictive value of phosphorylated HER2 receptor </li></ul><ul><li>Prognostic and predictive value of shed extracellular domain (ECD) </li></ul><ul><li>Concordance between different HER2 assays, i.e. IHC versus FISH </li></ul><ul><li>Change in HER2 receptor phosphorylation, ECD level or HER2 overexpression upon relapse </li></ul>
    12. 12. B-31 accrual 1,200 1,000 800 600 400 200 0 0 4 8 12 16 20 24 Months Number of patients Projected Actual
    13. 13. Patient characteristics Age (years) Race No. of positive nodes  39 40–49 50–59  60 White Black Other 1–3 4–9 10+ 100 80 60 40 20 0 Percentage of patients AC = anthracycline/cyclophosphamide; P = paclitaxel; H = Herceptin ® AC   P AC  P + H
    14. 14. Pathological tumour size (cm)  1.0 1.1–2.0 2.1–3.0 3.1–4.0 4.1–5.0  5.1 AC   P (mean 2.9cm) AC  P + H (mean 2.8cm) 100 80 60 40 20 0 Percentage of patients
    15. 15. Patient characteristics Operation and radiotherapy Tamoxifen treatment AC  P AC   P + H Mastectomy + no radiotherapy Mastectomy + left and/or right radiotherapy Lumpectomy + left radiotherapy Lumpectomy + left and right radiotherapy No tamoxifen Received tamoxifen 100 80 60 40 20 0 Percentage of patients
    16. 16. Overall toxicity 50 40 30 20 10 0 Percentage of patients 2 3 4 5 Grade of overall toxicity AC (n=615)
    17. 17. Overall toxicity (cont’d) 50 40 30 20 10 0 Percentage of patients 2 3 4 5 Grade of overall toxicity P (n=251) P + H (n=245)
    18. 18. Toxicity in patients receiving paclitaxel (n=251) versus paclitaxel plus Herceptin ® (n=245) Neutropenic infection Febrile neutropenia 0 1 2 Percentage of patients Grade 3 Grade 4 P P + H P
    19. 19. Toxicity in patients receiving paclitaxel (n=251) versus paclitaxel plus Herceptin ® (n=245) Sensory neuropathy Arthralgia Myalgia Fatigue 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 P P + H Grade 2 Grade 3 Percentage of patients P P + H P P + H P P + H
    20. 20. Cardiac toxicity assessments <ul><li>Three formal interim statistical comparisons per arm : </li></ul><ul><ul><li>1) after 100 evaluable patients </li></ul></ul><ul><ul><li>2) after 300 evaluable patients </li></ul></ul><ul><ul><li>3) after 500 evaluable patients </li></ul></ul><ul><ul><li>treated and followed for at least </li></ul></ul><ul><ul><li>6 months after start of Herceptin ® </li></ul></ul>
    21. 21. NSABP B-31: cardiac monitoring <ul><li>At its first interim analysis, the cardiotoxicity (LV dysfunction) remains within acceptable limits as reviewed by the Data Monitoring Committee (DMC) </li></ul>
    22. 22. HER2 retesting at control reference laboratory (Lab Corp): initial test done at large volume * laboratories *More than 100 assays/month
    23. 23. HER2 retesting at control reference laboratory (Lab Corp): initial test done at smaller volume * laboratories *Less than 100 assays/month
    24. 24. Central FISH (PathVysion TM ): correlation between reference laboratory (Lab Corp) and NSABP pathology laboratory retesting 77/81 = 95% correlation
    25. 25. NSABP B-31 amendment <ul><li>HER2 assays by IHC must be done at an NSABP-approved reference laboratory </li></ul><ul><li>HER2 by FISH may be done at any laboratory </li></ul>
    26. 26. Herceptin ® adjuvant therapy: summary of ongoing trials *H q3w at 6mg/kg NSABP B-31 Paclitaxel q3w x 4 Paclitaxel q3w x 4 + H AC x 4 HERA Trial H q3w* x 12 months H q3w* x 24 months Observation Any CT and/or RT Intergroup N9831 Paclitaxel qw x 12 Paclitaxel qw x 12 Paclitaxel qw x 12 + H AC x 4 BCIRG 006 Docetaxel q3w x 4 AC x 4 AC x 4 Docetaxel q3w x 4 + H Carboplatin + docetaxel q3w x 6 + H H
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