Targeted Adjuvant Systemic Therapy of Breast Cancer Current
Targeted Adjuvant Systemic Therapy of Breast Cancer Current & Future Role of Trastuzumab NSABP Annual Group Meeting 9/ 17/ 05 Peter A. Kaufman MD Norris Cotton Cancer Center Dartmouth-Hitchcock Medical Center CALGB
Doxorubicin and Cyclophosphamide Followed by Weekly Paclitaxel +/- Trastuzumab as Adjuvant Treatment for Women with HER-2/neu Overexpressing Node (+) or High Risk Node (-) Breast Cancer NCCTG N 9831 May 2005 Update Perez EA, Suman VJ, Davidson N, Martino S, Kaufman PA on Behalf of NCCTG, ECOG, SWOG, & CALGB
Clinical Research Goals • Evaluate whether trastuzumab adds to the benefit of adjuvant AC paclitaxel in resected HER-2 (+) breast cancer • Evaluate impact of trastuzumab schedule – Sequential to paclitaxel – Concurrent with paclitaxel • Evaluate cardiac safety AC=doxorubicin & cyclophosphamide
Study Schema Arm A: AC q 3 w x 4 R A N D O M I Z E Arm B: AC q 3 w x 4 Arm C: AC q 3 w x 4 Paclitaxel qw x 12 H qw x 52 Paclitaxel qw x 12 + H qw x 12 H qw x 40 Radiation and/or hormonal therapy as indicated Perez E et al. Protocol NCCTG-N 9831. H=trastuzumab (4 mg/kg loading dose, followed by 2 mg/kg); doxorubicin dose 60 mg/m 2; cyclophosphamide, 600 mg/m 2; paclitaxel, 80 mg/m 2 q 3 w=every 3 weeks; qw=weekly
Eligibility • • • Resected invasive breast cancer Node (+) High risk node (-) – >1. 0 cm if ER (-) or >2. 0 cm if ER (+) • HER-2 (+) by central testing – Protein overexpression (IHC 3+) – Gene amplification (FISH+) • Cardiac eligibility – Normal left ventricular ejection fraction – No prior MI or CHF ER=estrogen receptor; HER 2=human epidermal growth factor 2; IHC=immunohistochemistry; FISH=fluorescence in situ hybridization; MI=myocardial infarction; CHF=congestive heart failure
Clinical Endpoints • Disease-free survival – Local/regional/distant recurrence – Contralateral breast disease (including DCIS*) – Second primary invasive cancers – Death due to any cause • Overall survival * DCIS=ductal carcinoma in situ
Statistical Plan Addition of H to AC T • Two pairwise comparisons Sequential AC T H Concurrent AC T + H H • Control: AC T vs Control: AC T Goal – • vs To detect a 33% increase in median DFS from 6. 3 to 8. 4 years Final analysis – – At 663 events for A vs C comparison At 789 events for A vs B comparison T=paclitaxel; DFS=disease free survival
Statistical Plan Timing of H Initiation • Pairwise comparison Sequential AC T H vs Concurrent AC T + H H • Goal – To detect a 29% increase in median DFS from 7. 3 to 9. 4 years • Final analysis – At 590 events for B vs C comparison
Cardiac Testing R A N D O M I Z E Arm A: AC x 4 Paclitaxel Arm B: AC x 4 Paclitaxel H Arm C: AC x 4 Paclitaxel + H H Time (months) 0 LVEF measurement Pre-AC 6 3 No H if symptoms or LVEF ↓ >15% or ↓ to <LLN Post-AC LVEF=left ventricular ejection fraction; LLN=lower limit of normal 9 18– 21
Impact of Joint Analysis on N 9831 (April 2005) • Joint analysis with B-31: Concurrent approach AC T + H H significantly improves disease-free and overall survival vs control: AC T • DMC asked for an unplanned interim analysis comparing Arm B (sequential) vs Arm C (concurrent) DMC=data monitoring committee
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)
Patient and Tumor Characteristics Race Caucasian African American Other Age <40 40ミ 49 50ミ 59 60+ Nodal Status N 0 1ミ 3 4ミ 9 10+ ER- and/or Pg. R-positive Tumor イ 2 cm AC > T, % (n=979) AC > T> H, % (n=985) AC > T + H > H, % (n=840) 85 6 9 86 7 7 83 6 11 17 34 34 15 19 32 32 16 16 34 32 18 11 47 27 15 11 47 28 14 12 50 25 13 54 34 55 31
Results Disease-Free Survival Joint Analysis Pairwise Comparison A C Number of events AC > T vs AC > T + H > H 395 Log rank p-value* ミ 12 3 x 10 HR* (95% CI) 0. 48 (0. 39 -0. 60) *Stratified – nodal status and receptor status N 9831 Analysis Pairwise Comparison Number of events Log rank p-value* HR* (95% CI) AC > T 220 0. 2936 0. 87 (0. 67 -1. 13) AC > T > H 137 0. 0114 0. 64 (0. 46 -0. 91) A vs AC > T > H B (n=1964)** B vs AC > T + H > H C (n=1682)** *Stratified – nodal status and receptor status **for patients randomized before 1/1/2005
Disease-Free Survival: A vs C From the Joint Analysis 100 90 80 70 60 % 50 40 30 20 10 0 AC > T + H > H Events=134 AC > T Events=261 Hazard ratio=0. 48 Stratified logrank 2 P=3 x 10 -12 0 1 Number of patients followed A 1162 689 C 1217 766 2 Years 374 427 3 193 238 4 59 74
Disease-Free Survival: A vs B N 9831 100 90 80 70 60 % 50 40 30 20 10 0 AC >T >H Events=103 AC > T Events=117 Hazard ratio=0. 87 Stratified logrank 2 P=0. 2936 0 1 Number of patients followed A 979 629 B 985 637 2 Years 3 4 353 403 168 169 15 20
Disease-Free Survival: B vs C N 9831 100 90 80 70 60 % 50 40 30 20 10 0 AC > T + H > H Events=53 AC > T > H Events=84 Hazard ratio=0. 64 Stratified logrank 2 P=0. 0114 0 1 Number of patients followed B 842 501 C 840 520 2 Years 3 4 285 162 178 20 17
Overall Survival Joint Analysis Results Pairwise Comparison Number of events Log rank p-value* HR* (95% CI) A AC > T C vs AC > T + H > H 154 0. 015 0. 67 (0. 48 -0. 93) Number of events Log rank p-value* HR* (95% CI) *Stratified – nodal status and receptor status N 9831 Analysis Results Pairwise Comparison A B AC > T vs AC > T > H 79 0. 4752 0. 85 (0. 55 -1. 33) B C AC > T > H vs AC > T + H > H 56 0. 2696 0. 74 (0. 43 -1. 26) *Stratified – nodal status and receptor status
Other Relevant Factors for Patient Management • HER 2 testing • Cardiac tolerability comparisons based on planned analyses
HER 2 Testing in N 9831 • Modest level of concordance between local and central laboratories for both IHC and FISH – With IHP: 81% (78 -83%) – With FISH: 87% (84 -90%) • High level of agreement between central and reference laboratory results for HER 2 – 94. 5% for IHC (0, 1+, 2+) – 95. 1% for FISH (not amplified) • Accurate HER 2 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)
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)
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 sequential therapy – 3. 3% (95% CI, 2. 0 -5. 1%) for 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)
Effect of Introduction of Traztusumab on Disease Recurrence • 52% decreased recurrence with concurrent vs control treatment (P=3 X 10 -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
N 9831 -- Future Plans • 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
NCCTG N 9831 Collaborative Team • Co-investigators – NCCTG, ECOG, SWOG, CALGB – Personnel from Operations Offices of Cooperative Groups • NCI • Genentech • Breast Cancer Research Foundation • Advocates and our Patients PI: Edith A. Perez
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