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Background

516 (32723) Phase III trial comparing AC (x4) t axane (x4) with taxane (x8) as adjuvant therapy for node-positive breast cancer: Results of N-SAS-BC02 trial (Japan). T. Watanabe, M. Kuranami, K. Inoue, N. Masuda, K. Aogi, H. Iwata, H. Mukai, S. Tanaka, T. Yamaguchi, Y. Ohashi. Background.

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  1. 516 (32723)Phase III trial comparing AC (x4)taxane (x4) with taxane (x8) as adjuvant therapy for node-positive breast cancer:Results of N-SAS-BC02 trial (Japan) T. Watanabe, M. Kuranami, K. Inoue, N. Masuda, K. Aogi, H. Iwata, H. Mukai, S. Tanaka, T. Yamaguchi, Y. Ohashi

  2. Background • Doxorubicin and cyclophosphamide (AC) x 4  paclitaxel x 4 is a standard regimen for postoperative chemotherapy. • Rare but serious side effects (e.g., cardiac failure, secondary leukemia) are major concerns with AC. • AC cannot be used in some patients. • Relative efficacy of docetaxel to that of paclitaxel needs to be clarified.

  3. Trial Design ACP ADM 60 mg/m2 CPA 600 mg/m2 R A N D O M I Z E ACD Paclitaxel 175 mg/m2 PTX Docetaxel 75 mg/m2 DTX • Pts with BCS received RT. • Pts with ER(+) BC received TAM or an AI for 5 yrs. 0 3 6 9 12 15 18 21 weeks

  4. Primary objectives • To compare disease-free survival (DFS) with AC (x4)taxane (x4) vs. taxane (x8) • To compare DFS with paclitaxel (x8) vs. docetaxel (x8) in node-positive breast cancer

  5. Exploratory analyses • To find subsets of patients who benefit from additional treatment with AC • Subsets: • HER2 positive vs. HER2 negative or unknown • ER positive vs. ER negative or unknown

  6. Inclusion Criteria • Stage I to IIIA invasive breast cancer • Histologically involved axillary lymph nodes • Age 18-75 years • PS (ECOG) 0, 1 • No prior chemotherapy or endocrine therapy • Adequate organ functions • Written informed consent

  7. Statistical Considerations Hypothesis 1: A taxane (x8) is not inferior to AC (x4)  a taxane (x4) Hypothesis 2: One of the taxanes is superior or equivalent to the other. Planned N = 1200 (based on planned events (≥320) in hypothesis 1) a=0.05; 1-sided (non-inferiority); power (1-b) = 0.80

  8. Patient accrual • Between December 2001 and April 2006, 1060 patients were randomized at 84 institutions in Japan. • Date of first analysis: June 15, 2008

  9. Patient Disposition

  10. Patient characteristics (1)

  11. Patient characteristics (2)

  12. Grade ¾ adverse events (%) (1)

  13. Grade ¾ adverse events (%) (2)

  14. Disease-free Survival 100 90 Percent probability 80 70 60 50 ：ACP ：ACD ：PTX ：DTX ～ ～ ～ 0 0 1 2 3 4 Time from randomization （years）

  15. Disease-free Survival ・Two confidence intervals are calculated for each endpoint, taking into account multiplicity due to interim analysis. ・Final analysis will be planned number of events (>=320) are observed.

  16. Disease-free Survival 100 100 90 90 Percent probability 80 80 70 70 60 60 ： AC –>Taxane ： Taxane ：ACD+DTX ：ACP+PTX 50 50 Hazard ratio (99.5%CI)：0.81(0.57 – 1.14) Hazard ratio (99%CI)：1.26(0.92 – 1.72) ～ ～ ～ ～ ～ ～ 0 0 0 1 2 3 4 0 1 2 3 4 Time from randomization （years） Time from randomization （years）

  17. AC Taxane vs. TaxaneSubset according to HER2 HER2 positive HER2 negative/unknown 100 100 90 90 Percent probability 80 80 70 70 60 60 ： AC Taxane ： Taxane ： AC Taxane ： Taxane 50 50 Hazard ratio (95% CI): 1.63(1.05 – 2.54) Hazard ratio (95% CI): 1.13(0.85 – 1.50) ～ ～ ～ ～ ～ ～ 0 0 0 1 2 3 4 0 1 2 3 4 Time from randomization（years） Time from randomization （years） ・Interactions between the response to AC and HER-2 positive/HER-2 negative/unknown status, P=0.17

  18. AC Taxane vs. TaxaneSubset according to ER ER negative ER positive 100 100 90 90 Percent probability 80 80 70 70 60 60 ：AC Taxane ：Taxane ：AC Taxane ：Taxane 50 50 Hazard ratio (95%CI)：1.32(0.90 – 1.95) ～ ～ ～ Hazard ratio (95%CI)：1.22(0.90 – 1.66) ～ ～ 0 0 0 1 2 3 4 0 1 2 3 4 Time from randomization （years） Time from randomization （years）

  19. Summary (1) • Taxane (x8) is not demonstrated to be non-inferior to AC (x4)  a taxane (x4) in the study group as a whole in terms of DFS. • Docetaxel (75 mg/m2) is superior to paclitaxel (175 mg/m2) when given every 3 weeks in terms of DFS. • In the subset of HER2-positive patients, AC (x4)  a taxane (x4) produced superior DFS than did a taxane (x8). This result was not obtained in patients with HER2-negative or unknown tumors. • For ER, there was no interaction with the addition of AC.

  20. Summary (2) • Regarding the incidences of adverse events: • Nausea and vomitingwere higher with AC (x4)  a taxane (x4) than with taxane (x8) . • Edema and febrile neutropeniawere higher with docetaxel (75 mg/m2) than with paclitaxel (175 mg/m2) . • Sensory neuropathywas higher with paclitaxel (175 mg/m2) than with docetaxel (75 mg/m2) . 

  21. Conclusions • AC can be omitted in certain subsets of patients with postoperative breast cancer. • When given every 3 weeks, docetaxel (75 mg/m2) improves DFS in women with node-positive breast cancer as compared with paclitaxel (175 mg/m2) . • The expression of HER2 may be associated with a benefit from the addition of AC.

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