Herceptin® In The Adjuvant Setting


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  • CSK: adjuvant Adjuvant Breast cancer: primary
  • Herceptin® In The Adjuvant Setting

    1. 1. Herceptin ® in the adjuvant setting
    2. 2. Herceptin ® in the adjuvant setting: rationale <ul><li>HER2 overexpression is an early event in breast cancer </li></ul><ul><li>development and is associated with aggressive disease </li></ul><ul><li>Herceptin ® offers </li></ul><ul><li>A new mechanism of antitumour activity </li></ul><ul><li>Proven clinical benefits in the metastatic setting, including increased survival when used in combination with chemotherapy </li></ul><ul><li>Greater benefit when used earlier in metastatic disease </li></ul><ul><li>A favourable safety profile and good tolerability </li></ul>
    3. 3. Four major ongoing Herceptin ® adjuvant trials <ul><li>The extensive Herceptin ® adjuvant trial programme will </li></ul><ul><ul><li>investigate complementary strategies </li></ul></ul><ul><ul><li>establish the efficacy and role of Herceptin ® in the adjuvant setting </li></ul></ul><ul><ul><li>establish the safety profile of Herceptin ® </li></ul></ul><ul><ul><li>determine the optimal duration of adjuvant Herceptin ® therapy </li></ul></ul>
    4. 4. Herceptin  in the adjuvant setting: major trials <ul><li>Four main trials are currently investigating </li></ul><ul><li>Herceptin ® in the adjuvant setting </li></ul><ul><li>HERA ( Her ceptin ® A djuvant) Trial </li></ul><ul><li>NSABP (National Surgical Adjuvant Breast Project) trial B31 </li></ul><ul><li>Intergroup trial N9831 </li></ul><ul><li>BCIRG (Breast Cancer International Research Group) trial 006 </li></ul>
    5. 5. HERA TRIAL: study design *Observation group to receive the same follow-up as the Herceptin ® treatment groups Herceptin ® q3w x 1 year Herceptin ® q3w x 2 years Observation* Stratification Randomisation Primary management (surgery, [neo]adjuvant chemotherapy ± adjuvant radiotherapy)
    6. 6. HERA TRIAL: primary objectives <ul><li>Compare disease-free survival (DFS) in patients with HER2-overexpressing breast cancer who received Herceptin ® versus those who did not receive Herceptin ® </li></ul><ul><ul><li>in patients treated for 1 year </li></ul></ul><ul><ul><li>and those treated for 2 years </li></ul></ul>
    7. 7. HERA TRIAL: secondary objectives <ul><li>Overall survival, relapse-free survival and distant DFS </li></ul><ul><ul><li>1 year of Herceptin ® versus observation </li></ul></ul><ul><ul><li>2 years of Herceptin ® versus observation </li></ul></ul><ul><li>Safety and tolerability – Herceptin ® versus observation </li></ul><ul><li>Incidence of cardiac dysfunction – Herceptin ® versus observation </li></ul><ul><li>Treatment duration (efficacy and safety) – 1 year versus 2 years of Herceptin ® </li></ul>
    8. 8. HERA TRIAL: substudies <ul><li>To study PK of Herceptin ® : </li></ul><ul><li>in the a djuvant setting </li></ul><ul><li>a fter 1 year versus 2 years of treatment </li></ul><ul><li>with 3-weekly regimen </li></ul>Correlate levels of natriuretic peptides and other markers with LVEF/CHF and outcomes Pharmacokinetic (PK) substudy Cardiac marker substudy TransHERA substudy To establish a tissue bank to enable translational research
    9. 9. HERA TRIAL: study size and duration <ul><li>Number of centres: ~600 </li></ul><ul><li>Sample size: 3,192 (1,064 per arm) </li></ul><ul><li>Target population: women with HER2-positive primary breast cancer (IHC 3+ or FISH positive) </li></ul><ul><li>Study duration </li></ul><ul><ul><li>recruitment 48 months </li></ul></ul><ul><ul><li>follow-up until 10 years after last patient enrolled </li></ul></ul>
    10. 10. HERA TRIAL: planned duration Interim safety analyses Enrolment complete Main efficacy analysis Enrolment starts Interim efficacy analysis 10-year follow-up complete Enrolment Follow-up 2003 2004 2005 2006 2007 2002 2016 2008
    11. 11. HERA TRIAL: key inclusion criteria <ul><li>Invasive, non-metastatic, operable primary breast cancer –histologically confirmed and adequately excised </li></ul><ul><li>Axillary node positive, or node negative with tumour size >1cm </li></ul><ul><li>Known hormone receptor status (ER/PgR or ER alone) </li></ul><ul><li>Completed  4 cycles of approved (neo)adjuvant chemotherapy </li></ul><ul><li>Baseline LVEF >55% (echocardiography or MUGA scan) </li></ul><ul><li>Completed radiotherapy if indicated </li></ul><ul><li>Centrally confirmed HER2 overexpression (IHC 3+ or FISH positive) in invasive component of primary tumour </li></ul>
    12. 12. HERA TRIAL: key exclusion criteria <ul><li>Clinical T4 tumour, including inflammatory breast cancer </li></ul><ul><li>Cumulative dose of doxorubicin >360mg/m 2 or epirubicin >720mg/m 2 </li></ul><ul><li>(Neo)adjuvant chemotherapy with peripheral blood/bone marrow stem cell support </li></ul><ul><li>Supraclavicular lymph node involvement </li></ul><ul><li>Any prior malignant neoplasms (including primary invasive breast cancer), except </li></ul><ul><ul><li>curatively treated basal/squamous cell carcinoma of skin </li></ul></ul><ul><ul><li>curatively treated in-situ cervical carcinoma </li></ul></ul>
    13. 13. HERA TRIAL: unique features <ul><li>Investigating the role of Herceptin ® independently from chemotherapy regimen </li></ul><ul><li>Investigating 2 years of Herceptin ® treatment </li></ul><ul><li>3-weekly schedule from the start </li></ul><ul><ul><li>more convenient </li></ul></ul><ul><ul><li>gives similar exposure to Herceptin ® as weekly administration of lower doses </li></ul></ul><ul><li>New model of partnership between academia and pharmaceutical industry </li></ul>
    14. 14. NSABP trial B-31: study design *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 ®
    15. 15. NSABP trial B31: treatment plan <ul><li>Doxorubicin 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
    16. 16. NSABP trial B31: primary objectives <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>
    17. 17. NSABP trial B31: secondary objectives <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-phosphorylated receptor, ECD level or HER2 overexpression upon relapse </li></ul>
    18. 18. NSABP trial B31: key inclusion criteria <ul><li>Histologically/cytologically proven invasive adenocarcinoma of the breast </li></ul><ul><li>At least one positive axillary node </li></ul><ul><li>Axillary dissection AND either total mastectomy OR lumpectomy </li></ul><ul><li>HER2 overexpression (IHC 3+ or FISH positive) </li></ul><ul><li>Known hormone receptor status (ER/PgR) </li></ul><ul><li>No more than 84 days since prior surgery for breast cancer </li></ul><ul><li>No prior chemotherapy, radiotherapy or hormonal therapy for breast cancer </li></ul><ul><li>Normal cardiac, renal and hepatic function </li></ul>
    19. 19. NSABP trial B31: patient accrual 1,200 1,000 800 600 400 200 0 0 4 8 12 16 20 24 Months Number of patients Actual Projected
    20. 20. NSABP trial B31: overall toxicity 50 40 30 20 10 0 Percentage of patients 2 3 4 5 Grade of overall toxicity P (n=251) P + H (n=245)
    21. 21. NSABP trial B31: toxicity (paclitaxel versus paclitaxel plus Herceptin ® ) Neutropenic infection Febrile neutropenia 0 1 2 Percentage of patients Grade 3 Grade 4 P P + H P
    22. 22. NSABP trial B31: toxicity (paclitaxel versus paclitaxel plus Herceptin ® ) 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
    23. 23. Intergroup trial N9831: study design Operable breast cancer HER2-positive tumour Node positive Randomisation AC q3w x 4 Paclitaxel x 12 + Herceptin ® x 12 Herceptin ® x 40 AC q3w x 4 Paclitaxel x 12 AC q3w x 4 Paclitaxel x 12 + Herceptin ® x 52
    24. 24. Intergroup trial N9831: treatment plan <ul><li>Herceptin ® </li></ul><ul><ul><li>4mg/kg loading dose (90 minutes i.v. infusion) followed by 4mg/kg weekly (90 minutes i.v. infusion or 30 minutes i.v. infusion based on toxicity) </li></ul></ul><ul><li>Doxorubicin 60mg/m 2 every 3 weeks </li></ul><ul><li>Cyclophosphamide 600mg/m 2 every 3 weeks </li></ul><ul><li>Paclitaxel 80mg/m 2 weekly </li></ul>
    25. 25. Intergroup trial N9831: objectives <ul><li>Primary </li></ul><ul><ul><li>disease-free survival </li></ul></ul><ul><ul><li>cardiotoxicity </li></ul></ul><ul><li>Secondary </li></ul><ul><ul><li>overall survival </li></ul></ul><ul><ul><li>evaluation of whether sHER1 or sHER2 levels at baseline are prognostic for disease-free and overall survival </li></ul></ul><ul><ul><li>concordance of IHC (HercepTest ® ) with FISH (Vysis TM ); disease-free survival; and overall survival </li></ul></ul>
    26. 26. Intergroup trial N9831: inclusion criteria <ul><li>Operable, histologically confirmed adenocarcinoma of the breast </li></ul><ul><li>Node-positive disease </li></ul><ul><li>Hormonal status known (ER/PgR) </li></ul><ul><li>HER2 overexpression (IHC 3+ or FISH positive) </li></ul><ul><li>No prior chemotherapy </li></ul><ul><ul><li>hormonal therapy allowed for up to 4 weeks but discontinued prior to enrolment </li></ul></ul><ul><li>No more than 84 days from mastectomy or axillary node dissection </li></ul><ul><li>LVEF normal </li></ul>
    27. 27. Intergroup trial N9831: exclusion criteria <ul><li>Locally advanced tumours </li></ul><ul><li>Prior history of breast cancer </li></ul><ul><li>Prior chemotherapy or radiotherapy for breast cancer </li></ul><ul><li>Cardiac disease including: </li></ul><ul><ul><li>myocardial infarction </li></ul></ul><ul><ul><li>history of congestive heart failure </li></ul></ul><ul><ul><li>medication for arrythmia or angina pectoris </li></ul></ul><ul><li>Prior anthracycline or taxane therapy for any malignancy </li></ul>
    28. 28. Intergroup trial N9831: cardiotoxicity <ul><li>Arm 3 suspended due to a few cardiotoxic events </li></ul><ul><li>This arm was reopened following the first interim safety analysis in June 2002 and patient accrual continues </li></ul><ul><li>At first interim analysis cardiotoxicity remained within acceptable limits based on review Data Monitoring Committee </li></ul>Intergroup trial N9831 NSABP trial B31 Arm 3: AC x 4   paclitaxel 80mg/m 2 qw x 12 with weekly Herceptin ® Arm 2: AC x 4  paclitaxel 175mg/m 2 q3w x 4 with weekly Herceptin ®
    29. 29. BCIRG trial 006: study design AC x 4 Docetaxel + cisplatin or carboplatin x 6 + Herceptin ® weekly  3-weekly Herceptin ® for 1 year from date of first administration Docetaxel x 4 Operable node-positive, HER2-positive (FISH) breast cancer AC x 4 Docetaxel x 4 + Herceptin ® weekly  3-weekly Herceptin ® for 1 year from date of first administration Randomisation
    30. 30. BCIRG trial 006: treatment plan <ul><li>Doxorubicin 60mg/m 2 </li></ul><ul><li>Cyclophosphamide 600mg/m 2 </li></ul><ul><li>Docetaxel 100mg/m 2 </li></ul><ul><li>Platinum salt </li></ul><ul><ul><li>carboplatin AUC 6 </li></ul></ul><ul><ul><li>cisplatin 75mg/m 2 </li></ul></ul><ul><li>Herceptin ® </li></ul><ul><ul><li>6mg/kg every 3 weeks </li></ul></ul>
    31. 31. BCIRG trial 006: objectives <ul><li>Primary </li></ul><ul><ul><li>disease-free survival </li></ul></ul><ul><li>Secondary </li></ul><ul><ul><li>overall survival </li></ul></ul><ul><ul><li>safety </li></ul></ul><ul><ul><li>cardiac toxicity </li></ul></ul><ul><ul><li>quality of life </li></ul></ul><ul><ul><li>prognostic value of HER2 overexpression </li></ul></ul>
    32. 32. BCIRG trial 006: key inclusion criteria <ul><li>Histologically proven breast cancer </li></ul><ul><li>Definitive surgical treatment </li></ul><ul><li>Node-positive/negative disease </li></ul><ul><li>HER2 overexpression (FISH positive) </li></ul><ul><li>Normal renal, hepatic and cardiac function </li></ul><ul><li>No prior systemic therapy or radiotherapy for breast cancer </li></ul>
    33. 33. Comparison of the four large Herceptin ® adjuvant trials OS = overall survival DFS = disease-free survival
    34. 34. Other Herceptin ® adjuvant trials: ECOG trial E2198 234 anthracycline-naive patients IHC 2+/3+ Paclitaxel + Herceptin ® AC  observation Paclitaxel + Herceptin ® Sledge G, et al. Breast Cancer Res Treat 2001;69:209 (Abstract 4) AC  Herceptin ®
    35. 35. ECOG trial E2198: inclusion criteria <ul><li>Histologically confirmed stage II or IIIa adenocarcinoma of the breast </li></ul><ul><li>HER2 overexpression (IHC 2+/3+) </li></ul><ul><li>Axillary node dissection AND mastectomy or lumpectomy within 12 weeks prior to enrolment </li></ul><ul><li>No prior chemotherapy, hormonal therapy (at least one year since tamoxifen therapy) or radiotherapy </li></ul><ul><li>No history of cardiac disease </li></ul>
    36. 36. ECOG trial E2198: objectives <ul><li>Evaluate the incidence of cardiotoxicity associated with paclitaxel plus Herceptin ® in women with HER2-positive breast cancer </li></ul><ul><li>Assess the long-term safety of Herceptin ® in this patient population </li></ul>
    37. 37. ECOG trial E2198: cardiotoxicity Sledge G, et al. Breast Cancer Res Treat 2001;69:209 (Abstract 4)
    38. 38. Other Herceptin ® adjuvant trials: PACS 04 Second randomisation n=2,600 (HER2 positive/negative) First randomisation FEC100 x 6 Epirubicin + docetaxel x 6 1-year Herceptin ® monotherapy Observation n=520 (HER2 positive)
    39. 39. Herceptin ® in the adjuvant setting: conclusions <ul><li>The extensive Herceptin ® adjuvant trial programme will enable the role of Herceptin ® in the adjuvant setting to be defined </li></ul><ul><li>Using Herceptin ® in the adjuvant setting may lower the risk of treatment failure and improve survival in women with HER2-positive disease </li></ul>