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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.

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Presentation on theme: "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."— Presentation transcript:

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 036912151821 ACP ACD PTX DTX Pts with BCS received RT. Pts with ER(+) BC received TAM or an AI for 5 yrs. weeks ADM 60 mg/m 2 CPA 600 mg/m 2 Paclitaxel 175 mg/m 2 Docetaxel 75 mg/m 2 RANDOMIZE

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)  =0.05; 1-sided (non-inferiority); power (1-  ) = 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 Patients randomly assigned (n=1060) ACP 263 ACD 265 PTX 267 DTX 265 Patients eligible for this trial (n=1060) ACP 263 ACD 265 PTX 267 DTX 265 Patients analyzed for safety and efficacy (n=1044) ACP 260 ACD 262 PTX 263 DTX 259 Patients completed protocol therapy (n=902) ACP 227 ACD 226 PTX 228 DTX 221 Did not receive protocol therapy (n=16) ACP 3 ACD 3 PTX 4 DTX 6 Did not complete protocol therapy (n=142) ACP 33 ACD 36 PTX 35 DTX 38

10 Patient characteristics (1) ACP (n=260) ACD (n=262) PTX (n=263) DTX (n=259) Age ( mean±sd ) 52.8±8.352.7±9.552.4±8.751.9±8.6 Stage I42182935 II A95115102103 II B8510610997 III A3823 24 Pathological tumor size <3 cm 168167 165 ≥3 cm 92959694 Number of positive lymph nodes 1 - 3 154158156154 4 - 9 63 61 64 10 - 43 41

11 Patient characteristics (2) ACPACDPTXDTX Estrogen Receptor positive147144147144 negative110116111112 not tested3253 Progesterone Receptor positive 107122109113 negative 149138147142 unknown 4254 Type of surgery Breast conserving surgery121 122121 Mastectomy135140139136 Others 4 1 2 2 HER2 (HercepTest ® ) 0 85 77 91 90 1+ 76 68 63 61 2+ 24 26 29 27 3+ 35 36 35 34 unknown 40 55 45 47

12 Grade ¾ adverse events (%) (1) ACPACDPTXDTX Neutropenia 171826 Leukopenia 3502 Thrombocytopenia 0000 Anemia 0000 Febrile neutropenia 51108 Elevated AST or ALT 2120 Elevated bilirubin 0000 Edema 01011 Pleural effusion 0000 Ascites 0000 Body weight gain 0000 Hair loss 0000 Phlebitis (injection site) 0000 Nail changes 0000

13 Grade ¾ adverse events (%) (2) ACPACDPTXDTX Stomatitis 1100 Nausea 5301 Vomiting 3301 Constipation 1100 Diarrhea 0102 Urinary urgency 0000 Hematuria 0000 Fatigue 3322 Lacrimation 0000 Rash, desquamation 2101 Sensory neuropathy 4064 Motor neuropathy 2111 Joint pain (arthralgia) 6482 Muscle pain (myalgia) 4351

14 Disease-free Survival Time from randomization ( years ) 100 90 80 70 60 50 0 01234 : ACP : ACD : PTX : DTX ~~~~~~ Percent probability

15 Disease-free Survival Summary of events (disease-free survival) ACPACDPTXDTX No. of pts258255261257 Hypothesis 1: A taxane alone is not inferior to AC + a taxane Hazard ratio (AC + a taxane as standard) 1.26 99% CI0.92 - 1.72 90% CI1.03 - 1.53 p value0.67 Hypothesis 2: Whether PTX or DTX is more effective Hazard ratio (PTX as standard) 0.81 99.5% CI0.57 - 1.14 95% CI0.64 - 1.03 p value0.08 ・ 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 Time from randomization ( years ) 100 90 80 70 60 50 0 01234 : AC –> Taxane : Taxane ~~~~~~ Percent probability Hazard ratio (99%CI) : 1.26(0.92 – 1.72) Time from randomization ( years ) 100 90 80 70 60 50 0 01234 : ACD+DTX : ACP+PTX ~~~~~~ Hazard ratio (99.5%CI) : 0.81(0.57 – 1.14)

17 AC  Taxane vs. Taxane Subset according to HER2 Time from randomization ( years ) 100 90 80 70 60 50 0 01234 : AC  Taxane : Taxane ~~~~~~ Percent probability Hazard ratio (95% CI): 1.63(1.05 – 2.54) HER2 positive Time from randomization ( years ) 100 90 80 70 60 50 0 01234 : AC  Taxane : Taxane ~~~~~~ Hazard ratio (95% CI): 1.13(0.85 – 1.50) HER2 negative/unknown ・ Interactions between the response to AC and HER-2 positive/HER-2 negative/unknown status, P=0.17

18 AC  Taxane vs. Taxane Subset according to ER ER positive ER negative 100 90 80 70 60 50 0 01234 Percent probability ~~~~ Hazard ratio (95%CI) : 1.32(0.90 – 1.95) : AC  Taxane : Taxane Time from randomization ( years ) 100 90 80 70 60 50 0 01234 : AC  Taxane : Taxane ~~~~~~ Hazard ratio (95%CI) : 1.22(0.90 – 1.66) 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/m 2 ) is superior to paclitaxel (175 mg/m 2 ) 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 vomiting were higher with AC (x4)  a taxane (x4) than with taxane (x8). –Edema and febrile neutropenia were higher with docetaxel (75 mg/m 2 ) than with paclitaxel (175 mg/m 2 ). –Sensory neuropathy was higher with paclitaxel (175 mg/m 2 ) than with docetaxel (75 mg/m 2 ).

21 Conclusions AC can be omitted in certain subsets of patients with postoperative breast cancer. When given every 3 weeks, docetaxel (75 mg/m 2 ) improves DFS in women with node-positive breast cancer as compared with paclitaxel (175 mg/m 2 ). The expression of HER2 may be associated with a benefit from the addition of AC.


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