OPTIMIZING NONANTHRACYLINES FOR EARLY BREAST CANCER. Stephen E. Jones, M.D. US Oncology Research, McKesson Specialty Health The Woodlands, Tx

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1 OPTIMIZING NONANTHRACYLINES FOR EARLY BREAST CANCER Stephen E. Jones, M.D. US Oncology Research, McKesson Specialty Health The Woodlands, Tx

2 ANTHRACYCLINES AND TAXANES ARE COMMONLY USED USED IN MOST REGIMENS LEVEL I EVIDENCE IN TRIALS AROUND THE WORLD OXFORD OVERVIEW CONFIRMS THE VALUE OF BOTH BUT ONLY A SMALL FRACTION OF PTS BENEFIT FROM ANTHRACYCLINES (HER2+)

3 WHAT DO ANTHRACYCLINES DO FOR YOU? Significant cardiac toxicity, some of it appearing late Increased nausea and vomiting, some delayed Rare, but real, risk of leukemia or MDS

4 BCIRG Trial Design n= countries 112 centers T A C Docetaxel 75 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2 R Every 3 weeks for 6 cycles Stratification Nodal status Center F A C Fluorouracil 500 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2 Dexamethasone premedication, 8 mg bid, 3 days Prophylactic ciprofloxacin 500 mg bid, days 5 14 No primary G-CSF prophylaxis was allowed San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December

5 Disease-free survival probability DFS at a Median 10-year Follow-up (ITT) TAC: 76% 0.60 HR= %CI: Log-rank P=0.001 FAC: 69% 0.40 HR= %CI: Log-rank P= Number at Risk Disease-free survival time (months) TAC FAC San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December

6 Overall survival probability OS at a Median 10-year Follow-up (ITT) 1.00 TAC: 87% 0.80 HR= %CI: Log-rank P=0.008 FAC: 81% HR= %CI: Log-rank P= Survival time (months) Number at Risk TAC FAC deaths: 188 TAC; 241 FAC San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December

7 Probability of CHF Cumulative Incidence of CHF TAC (n=744) FAC (n=736) Number of CHF events Reported in the first 55 months of follow-up 13 5 Reported in months 55 to 120 of follow-up TAC FAC Time from randomization to CHF event (months) Number at Risk TAC FAC San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December

8 Conclusions CHF was reported in 3.5% and 2.3% of patients treated with TAC and FAC, Most CHF cases were grade 3 CHF was fatal in 2 TAC patients and 4 FAC patients Significant LVEF decreases (>20%) were similar between treatment groups (TAC 17%, FAC 15%) Hematological malignancies (leukemia or MDS) were reported in 9 patients (0.6% or 1 in 200) San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December

9 E2197 Study Design and Results #1021 Study Design Patient Characteristics AC Doxorubicin 60 mg/m2 Cyclophosphamide 600 mg/m2 Every 3 weeks x 4 cycles Tamoxifen x 5 years If HR-Positive (Amended to Allow A.I.s) Plus RT if Indicated PRESENTED BY: Hope S. Rugo Operable Breast Cancer 0-3 Positive Nodes T > 1 cm if Node Negative N=2885 Eligible Patients AT Doxorubicin 60 mg/m2 Docetaxel 60 mg/m2 Every 3 weeks x 4 cycles Tamoxifen x 5 years If HR-Positive (Amended to Allow A.I.s) Plus RT if Indicated AML/MDS: 17 cases ( 0.5%) 68% ER positive 65% LN negative Grade 48% low or intermediate Median T-size 2.0 cm Results At 5 years: DFS (85%) and OS (92%) identical between the 2 arms RS predicted recurrence Now: Median follow-up 11.5 yrs DFS (77%) and OS (84%) still identical No difference based on hormone receptor status

10 THE TWO NON-ANTHRACYCLINE ALTERNATIVES TC (Docetaxel/Cyclophosphamide) TCH (Docetaxel/Carboplatin/Trastuzumab)

11 US Oncology 9735: Study Design N= % ER+ 48% N R 4 x TC q3w Docetaxel (75 mg/m 2 ) Cyclophosphamide (600 mg/m 2 ) n=506 4 x AC q3w Doxorubicin (60 mg/m 2 ) Cyclophosphamide (600 mg/m 2 ) n=510 Eligibility: Stage I, II, or III disease Median follow up: 5.5 years Chemotherapy doses based on actual BSA (no cap) Chemotherapy given prior to radiation Tamoxifen for all ER+ patients after chemotherapy +/- radiation Jones et al. J Clin Oncol. 2006;24:

12 USO 9735: Effectiveness of TC Over AC Single study robust outcome Worked in 65+ years (subset analysis) 26% DFS 31% OS Jones et al, 2009.

13 WHAT HAS CHANGED WITH TC? Practice patterns around the world Should we use paclitaxel instead? Number of cycles of TC? Should growth factors be used with TC? What if TC was combined with trastuzumab? Finally for the nonbelievers, a study.

14 Decline in the Use of Anthracyclines for Breast Cancer Sharon H. Giordano, Yu-Li Lin, Yong-Fang Kuo, Gabriel N. Hortobagyi, and James S. Goodwin The University of Texas MD Anderson Cancer Center, The University of Texas Medical Branch at Galveston JCO 30: , 2012

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16 Changes in adjuvant breast cancer chemotherapy regimens over time in the community. Patt D et al: ASCO abstract 6109,

17 ASCO abstract 6109,

18 WHY NOT USE PACLITAXEL? CALGB 40101* 2 X 2 FACTORIAL DESIGN TESTED 4 v 6 CYCLES OF AC OR PACLITAXEL 6 WAS NOT BETTER PACLITAXEL WAS INFERIOR 5 yr RFS AC 91% v paclitaxel 88% AML/MDS OCCURRED ON AC ARMS * Shulman L et al, ASCO abstract 1007, 2013

19 NUMBER OF CYCLES OF TC? Original trial: 4 cycles BCIRG 005 and NSABP B30 node + TAC6 or AC/docetaxel (8) 4 of TAC was inferior B38 compared 6 TAC with ddac/paclitaxel and ddac/paclitaxel and gemcitibine No difference in outcome What if the anthracycline does not matter?

20 FEBRILE NEUTROPENIA WITH TC: ARE WBC GROWTH FACTORS NEEDED? USON 9735: FN 5% (OLDER: 8%) SABCS 2011 MORE DATA Kaiser Permanente data USON data

21 FEBRILE NEUTROPENIA WITH TC: ARE WBC GROWTH FACTORS NEEDED? USON 9735: FN 5% (OLDER: 8%) Kaiser data* Prophylaxis 128 pts: FN 8.6% No prophylaxis 204 pts: FN 24.5% Captured ER and hospitalization data in an integrated health care system *Lee, J et al, SABCS 2011

22 FEBRILE NEUTROPENIA WITH TC: ARE WBC GROWTH FACTORS NEEDED? USON 9735: FN 5% (OLDER: 8%) USON TC v TAC* 593 pts received TC; 70% of cases of FN occurred with the first course of treatment 214 received prophylaxis: FN 2.5% 379 no prophylaxis: FN 7.4% *Jones, S et al, SABCS 2011

23 FEBRILE NEUTROPENIA WITH TC: ARE WBC GROWTH FACTORS NEEDED? USON 9735: FN 5% (OLDER: 8%) Kaiser Permanente data 2011 USON data 2011 Other reports with high rates of FN but no randomized data Many oncologists use growth factors

24 WHAT ABOUT TC IN HER2+EARLY BC? USON STUDY 06038: HER TC Presented at SABCS 2011 Submitted for publication 2013 Single arm phase II trial of 4 TC combined with trastuzumab for 1 year

25 San Antonio Breast Cancer Symposium-Cancer Therapy and Research Center at UT Health Science Center, December 6-10, 2011 Results No. Patients DFS (%) 2-Year DFS (%) 3-Year OS (%) 2-Year OS (%) 3-Year 486 safety population node positive node negative <1.0-cm node-ve In 486 patients, there were 14 cases of recurrent breast cancer (local 5, or local/distant 9), which resulted in a 3-year disease-free survival of 96.3%. This presentation is the intellectual property of the author/presenter. Contact them at steve.jones@usoncology.com for permission to reprint and/or distribute.

26 Disease-free Probability San Antonio Breast Cancer Symposium-Cancer Therapy and Research Center at UT Health Science Center, December 6-10, 2011 DFS by Nodal Status Node negativee Node positive Event indicator Months This presentation is the intellectual property of the author/presenter. Contact them at steve.jones@usoncology.com for permission to reprint and/or distribute.

27 Survival Probability San Antonio Breast Cancer Symposium-Cancer Therapy and Research Center at UT Health Science Center, December 6-10, 2011 OS by Nodal Status Node negative Node positive Event indicator Months This presentation is the intellectual property of the author/presenter. Contact them at steve.jones@usoncology.com for permission to reprint and/or distribute.

28 US Oncology Node-Positive, High Risk Node Negative, HER2 Negative Breast Cancer STRATIFICATION Stage (IA, IIA, IIB, IIIA, IIIB, IIIC) TC x 6 TAC x 6 Accrual goal patients DFS - Primary endpoint Study stopped at 1200 pts.

29 B-46 USOR R TAC TC TCB N=3900; 3y DFS; HR.75 TCB USON TC v TAC closed (N=1200) Total TC v TAC N=3600 non inferiority

30 B-49 (CTEP) R Dox-based TC N=1843 (4200 with B-46I and TicTacToe); Median 4+ yr IDFS; 80% Power for Non-Inferiority (HR <1.18) Accrual opened 4/4/2012

31 NO TO ANTHRACYCLINES Very small benefit to use of anthracyclines and this benefit is almost entirely in the HER2+ population TC, TCH and HER TC represent real world options for many patients Results from the anthracycline question trials should finally settle the debate

32 THANK YOU