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Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
Herceptin® In The Adjuvant Setting
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Herceptin® In The Adjuvant Setting

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  • CSK: adjuvant Adjuvant Breast cancer: primary
  • Transcript

    • 1. Herceptin ® in the adjuvant setting
    • 2. Herceptin ® in the adjuvant setting: rationale
      • HER2 overexpression is an early event in breast cancer
      • development and is associated with aggressive disease
      • Herceptin ® offers
      • A new mechanism of antitumour activity
      • Proven clinical benefits in the metastatic setting, including increased survival when used in combination with chemotherapy
      • Greater benefit when used earlier in metastatic disease
      • A favourable safety profile and good tolerability
    • 3. Four major ongoing Herceptin ® adjuvant trials
      • The extensive Herceptin ® adjuvant trial programme will
        • investigate complementary strategies
        • establish the efficacy and role of Herceptin ® in the adjuvant setting
        • establish the safety profile of Herceptin ®
        • determine the optimal duration of adjuvant Herceptin ® therapy
    • 4. Herceptin  in the adjuvant setting: major trials
      • Four main trials are currently investigating
      • Herceptin ® in the adjuvant setting
      • HERA ( Her ceptin ® A djuvant) Trial
      • NSABP (National Surgical Adjuvant Breast Project) trial B31
      • Intergroup trial N9831
      • BCIRG (Breast Cancer International Research Group) trial 006
    • 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. HERA TRIAL: primary objectives
      • Compare disease-free survival (DFS) in patients with HER2-overexpressing breast cancer who received Herceptin ® versus those who did not receive Herceptin ®
        • in patients treated for 1 year
        • and those treated for 2 years
    • 7. HERA TRIAL: secondary objectives
      • Overall survival, relapse-free survival and distant DFS
        • 1 year of Herceptin ® versus observation
        • 2 years of Herceptin ® versus observation
      • Safety and tolerability – Herceptin ® versus observation
      • Incidence of cardiac dysfunction – Herceptin ® versus observation
      • Treatment duration (efficacy and safety) – 1 year versus 2 years of Herceptin ®
    • 8. HERA TRIAL: substudies
      • To study PK of Herceptin ® :
      • in the a djuvant setting
      • a fter 1 year versus 2 years of treatment
      • with 3-weekly regimen
      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. HERA TRIAL: study size and duration
      • Number of centres: ~600
      • Sample size: 3,192 (1,064 per arm)
      • Target population: women with HER2-positive primary breast cancer (IHC 3+ or FISH positive)
      • Study duration
        • recruitment 48 months
        • follow-up until 10 years after last patient enrolled
    • 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. HERA TRIAL: key inclusion criteria
      • Invasive, non-metastatic, operable primary breast cancer –histologically confirmed and adequately excised
      • Axillary node positive, or node negative with tumour size >1cm
      • Known hormone receptor status (ER/PgR or ER alone)
      • Completed  4 cycles of approved (neo)adjuvant chemotherapy
      • Baseline LVEF >55% (echocardiography or MUGA scan)
      • Completed radiotherapy if indicated
      • Centrally confirmed HER2 overexpression (IHC 3+ or FISH positive) in invasive component of primary tumour
    • 12. HERA TRIAL: key exclusion criteria
      • Clinical T4 tumour, including inflammatory breast cancer
      • Cumulative dose of doxorubicin >360mg/m 2 or epirubicin >720mg/m 2
      • (Neo)adjuvant chemotherapy with peripheral blood/bone marrow stem cell support
      • Supraclavicular lymph node involvement
      • Any prior malignant neoplasms (including primary invasive breast cancer), except
        • curatively treated basal/squamous cell carcinoma of skin
        • curatively treated in-situ cervical carcinoma
    • 13. HERA TRIAL: unique features
      • Investigating the role of Herceptin ® independently from chemotherapy regimen
      • Investigating 2 years of Herceptin ® treatment
      • 3-weekly schedule from the start
        • more convenient
        • gives similar exposure to Herceptin ® as weekly administration of lower doses
      • New model of partnership between academia and pharmaceutical industry
    • 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. NSABP trial B31: treatment plan
      • Doxorubicin 60mg/m 2
      • Cyclophosphamide 600mg/m 2
      • Paclitaxel 175mg/m 2 q3w
      • Herceptin ®
        • loading dose 4mg/kg on week 1
        • maintenance dose 2mg/kg x 51 weeks
      AC
    • 16. NSABP trial B31: primary objectives
      • Stage I: (n=1,000)
        • evaluation of cardiac safety
      • Stage II: (n=1,700; total=2,700)
        • evaluation of efficacy
          • survival: primary endpoint
          • disease-free survival (DFS): secondary endpoint
    • 17. NSABP trial B31: secondary objectives
      • Prognostic and predictive value of phosphorylated HER2 receptor
      • Prognostic and predictive value of shed extracellular domain (ECD)
      • Concordance between different HER2 assays, i.e. IHC versus FISH
      • Change in HER2-phosphorylated receptor, ECD level or HER2 overexpression upon relapse
    • 18. NSABP trial B31: key inclusion criteria
      • Histologically/cytologically proven invasive adenocarcinoma of the breast
      • At least one positive axillary node
      • Axillary dissection AND either total mastectomy OR lumpectomy
      • HER2 overexpression (IHC 3+ or FISH positive)
      • Known hormone receptor status (ER/PgR)
      • No more than 84 days since prior surgery for breast cancer
      • No prior chemotherapy, radiotherapy or hormonal therapy for breast cancer
      • Normal cardiac, renal and hepatic function
    • 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. 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. 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. 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. 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. Intergroup trial N9831: treatment plan
      • Herceptin ®
        • 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)
      • Doxorubicin 60mg/m 2 every 3 weeks
      • Cyclophosphamide 600mg/m 2 every 3 weeks
      • Paclitaxel 80mg/m 2 weekly
    • 25. Intergroup trial N9831: objectives
      • Primary
        • disease-free survival
        • cardiotoxicity
      • Secondary
        • overall survival
        • evaluation of whether sHER1 or sHER2 levels at baseline are prognostic for disease-free and overall survival
        • concordance of IHC (HercepTest ® ) with FISH (Vysis TM ); disease-free survival; and overall survival
    • 26. Intergroup trial N9831: inclusion criteria
      • Operable, histologically confirmed adenocarcinoma of the breast
      • Node-positive disease
      • Hormonal status known (ER/PgR)
      • HER2 overexpression (IHC 3+ or FISH positive)
      • No prior chemotherapy
        • hormonal therapy allowed for up to 4 weeks but discontinued prior to enrolment
      • No more than 84 days from mastectomy or axillary node dissection
      • LVEF normal
    • 27. Intergroup trial N9831: exclusion criteria
      • Locally advanced tumours
      • Prior history of breast cancer
      • Prior chemotherapy or radiotherapy for breast cancer
      • Cardiac disease including:
        • myocardial infarction
        • history of congestive heart failure
        • medication for arrythmia or angina pectoris
      • Prior anthracycline or taxane therapy for any malignancy
    • 28. Intergroup trial N9831: cardiotoxicity
      • Arm 3 suspended due to a few cardiotoxic events
      • This arm was reopened following the first interim safety analysis in June 2002 and patient accrual continues
      • At first interim analysis cardiotoxicity remained within acceptable limits based on review Data Monitoring Committee
      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. 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. BCIRG trial 006: treatment plan
      • Doxorubicin 60mg/m 2
      • Cyclophosphamide 600mg/m 2
      • Docetaxel 100mg/m 2
      • Platinum salt
        • carboplatin AUC 6
        • cisplatin 75mg/m 2
      • Herceptin ®
        • 6mg/kg every 3 weeks
    • 31. BCIRG trial 006: objectives
      • Primary
        • disease-free survival
      • Secondary
        • overall survival
        • safety
        • cardiac toxicity
        • quality of life
        • prognostic value of HER2 overexpression
    • 32. BCIRG trial 006: key inclusion criteria
      • Histologically proven breast cancer
      • Definitive surgical treatment
      • Node-positive/negative disease
      • HER2 overexpression (FISH positive)
      • Normal renal, hepatic and cardiac function
      • No prior systemic therapy or radiotherapy for breast cancer
    • 33. Comparison of the four large Herceptin ® adjuvant trials OS = overall survival DFS = disease-free survival
    • 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. ECOG trial E2198: inclusion criteria
      • Histologically confirmed stage II or IIIa adenocarcinoma of the breast
      • HER2 overexpression (IHC 2+/3+)
      • Axillary node dissection AND mastectomy or lumpectomy within 12 weeks prior to enrolment
      • No prior chemotherapy, hormonal therapy (at least one year since tamoxifen therapy) or radiotherapy
      • No history of cardiac disease
    • 36. ECOG trial E2198: objectives
      • Evaluate the incidence of cardiotoxicity associated with paclitaxel plus Herceptin ® in women with HER2-positive breast cancer
      • Assess the long-term safety of Herceptin ® in this patient population
    • 37. ECOG trial E2198: cardiotoxicity Sledge G, et al. Breast Cancer Res Treat 2001;69:209 (Abstract 4)
    • 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. Herceptin ® in the adjuvant setting: conclusions
      • The extensive Herceptin ® adjuvant trial programme will enable the role of Herceptin ® in the adjuvant setting to be defined
      • Using Herceptin ® in the adjuvant setting may lower the risk of treatment failure and improve survival in women with HER2-positive disease

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