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  • CSK: adjuvant Adjuvant Breast cancer: primary

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  • 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