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NCCTG N9831 May 2005 Update

NCCTG N9831 May 2005 Update. Perez EA, Suman VJ, Davidson N, Martino S, Kaufman P, on Behalf of NCCTG, ECOG, SWOG, CALGB. NCCTG N9831 Schema. Paclitaxel qw x 12. AC q3w x 4. Arm A:. RANDOMI Z E. Paclitaxel qw x 12. Arm B:. AC q3w x 4. H qw x 52. Paclitaxel qw x 12 + H qw x 12.

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NCCTG N9831 May 2005 Update

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  1. NCCTG N9831May 2005 Update Perez EA, Suman VJ, Davidson N, Martino S, Kaufman P, on Behalf of NCCTG, ECOG, SWOG, CALGB

  2. NCCTG N9831 Schema Paclitaxel qw x 12 AC q3w x 4 Arm A: RANDOMIZE Paclitaxel qw x 12 Arm B: AC q3w x 4 H qw x 52 Paclitaxel qw x 12 + H qw x 12 Arm C: H qw x 40 AC q3w x 4 Radiation and/or hormonal therapy as indicated Perez E. Protocol NCCTG-N9831. H=trastuzumab (4mg/kg loading dose, followedby 2mg/kg); doxorubicin dose 60mg/m2;cyclophosphamide, 600mg/m2; paclitaxel, 80mg/m2 q3w=every 3 weeks; qw=weekly

  3. Statistical PlanAddition of H to AC  T • Two pairwise comparisons • Goal • To detect a 33% increase in median DFSfrom 6.3 to 8.4 years • Final analysis • At 663 events for A vs Ccomparison • At 789 events for A vs B comparison Sequential AC  T H Control: AC  T vs Concurrent AC  T + H  H Control: AC  T vs T=paclitaxel; DFS=disease free survival

  4. Statistical Plan Timing of H Initiation • Pairwise comparison • Goal • To detect a 29% increase in median DFSfrom 7.3 to 9.4 years • Final analysis • At 590 events for B vs C comparison Sequential AC  T H Concurrent AC  T + H  H vs

  5. Cardiac Testing  RANDOMIZE Paclitaxel Arm A: AC x 4   Arm B: AC x 4 Paclitaxel H   Arm C: AC x 4 H Paclitaxel + H Time (months) 6 0 3 9 18–21 LVEF measurement No H if symptoms or LVEF ↓ >15% or ↓ to <LLN Pre-AC Post-AC LVEF=left ventricular ejection fraction; LLN=lower limit of normal

  6. Impact of Joint Analysis on N9831 April 2005 • Joint analysis with B-31: Concurrent approach • DMC asked for an unplanned interim analysis comparing Arm B (sequential) vs Arm C (concurrent) to assist in patient management AC  T + HHsignificantly improves disease-free and overall survival vs control: AC  T DMC=data monitoring committee

  7. Patient/Event Status at Time of Joint Analysis April 2005 • Patients • Enrollment goals met (n: >3300) • 700 patients on chemotherapy • 2701 patients entered prior to 1/1/2005 • Median follow up: 1.5 years • Total disease-free survival events • A and B: 220 (of 789 needed) • B and C: 147 (of 590 needed)

  8. Results Disease-Free Survival Joint Analysis *Stratified – nodal status and receptor status N9831 Analysis A B B C *Stratified – nodal status and receptor status **for patients randomized before 1/1/2005

  9. Disease-Free Survival: A vs BN9831 AC → T → HEvents=103 100 90 80 70 60 50 40 30 20 10 0 AC → TEvents=117 % Hazard ratio=0.87 Stratified logrank 2P=0.2936 0 1 2 3 4 Years Number of patients followed A 979 629 353 168 15 B 985 637 403 169 20

  10. Disease-Free Survival: B vs CN9831 AC → T + H → HEvents=53 100 90 80 70 60 50 40 30 20 10 0 AC → T → HEvents=84 % Hazard ratio=0.64 Stratified logrank 2P=0.0114 0 1 2 3 4 Years Number of patients followed B 842 501 285 162 20 C 840 520 285 178 17

  11. Overall Survival Joint Analysis Results *Stratified – nodal status and receptor status N9831 Analysis Results A B B C *Stratified – nodal status and receptor status

  12. Other Relevant Factorsfor Patient Management • HER2 testing • Cardiac tolerability comparisons based on planned analyses

  13. HER2 Testing in N9831 • Modest level of concordance between local and central laboratories for both IHC and FISH • With HercepTest™: 81% (78-83%) • With FISH: 87% (84-90%) • High level of agreement between central and reference laboratory results for HER2 • 94.5% for IHC (0, 1+, 2+) • 95.1% for FISH (not amplified) • Accurate HER2 testing is critical given the degree of trastuzumab benefit as a component of adjuvant therapy Updated from Perez EA, et al. ASCO 2004 (abstract 567)

  14. Cardiac Monitoring Plan • Monthly formal review of LVEF, clinical data • Interim analyses after 100, 300, and 500 patients per arm • completed AC and followed at least 6 months • ~ 9 months from registration Perez EA, et al. ASCO 2005 (abstract 556)

  15. Effect of the Introduction of H on Cardiac Tolerability • Difference in the incidence of cardiac events (CHF and cardiac deaths) between non-H and H arms is <4% • 9 month analysis; 500 per arm with nl LVEF or LVEF decrease  15% from baseline (after AC) • 0.0% (95% CI,0.0-0.7%) for control • 2.2% (95% CI,1.1-3.8%) for control vs sequential • 3.3% (95% CI,2.0-5.1%) for control vs concurrent* therapy with paclitaxel * at month 9, concurrent pts have received 3 additional months of H compared to sequential Perez EA, et al. ASCO 2005 (abstract 556)

  16. Effect of Introduction of H on Disease RecurrenceConclusions • 52% decreased recurrence with concurrentvs control treatment (P=3X10-12) (joint analysis finding) • 13% decreased recurrence with sequential vs control treatment (P=0.2936) • 36% decreased recurrence with concurrent vs sequential treatment (P=0.0114) • More follow up is needed to determine whether this trend continues

  17. NCCTG N9831Next Steps • Pre-specified interim analyses at 50%, 67%, and 75% of events still planned • Continued exploration of predictive factors for cardiac toxicity • Continued patient follow up

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