ABC Trials Joint Analysis: TC vs TaxAC in High-Risk, HER2-Negative Early Breast Cancer CCO Independent Conference Coverage* of the 2016 ASCO Annual Meeting, June 3-7, 2016 *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. ABC, anthracyclines in early breast cancer; TC, docetaxel/cyclophosphamide; TaxAC, anthracycline/taxane-based chemotherapy. This activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.

ABC Joint Analysis of TC vs TaxAC in HER2- Breast Cancer: Background 2011 EBCTCG meta-analysis[1] 10-yr BC mortality similar with std doses of anthracyclines; reduced with higher cumulative doses of anthracyclines vs CMF 8-yr BC mortality further reduced by adding taxanes to anthracyclines (TaxAC) 10-yr BC mortality reduced by 1/3 with TaxAC vs no chemotherapy Cardiac mortality increased with anthracyclines vs CMF or nil USOR trial showed superior OS for TC vs AC (HR: 0.69; P = .032)[2] Pooled analysis undertaken to determine if 6 cycles of TC is noninferior to TaxAC in women with resected, high-risk, HER2- negative breast cancer[3] ABC, anthracyclines in early breast cancer; AC, doxorubicin/cyclophosphamide; CMF, cyclophosphamide/methotrexate/fluorouracil; EBCTCG; Early Breast Cancer Trialists' Collaborative Group; TC, docetaxel/cyclophosphamide; TaxAC, anthracycline/taxane-based chemotherapy. 1. EBCTCG, et al. Lancet. 2012;379:432-444. 2. Jones S, et al. J Clin Oncol. 2009;27:1177-1183. 3. Blum JL, et al. ASCO 2016. Abstract 1000. Slide credit: clinicaloptions.com

TC vs TaxAC in HER2- Breast Cancer (ABC Joint Analysis): Timeline, Accrual, Tx Data from 3 clinical trials of anthracyclines in early breast cancer (ABC trials) prospectively pooled for analysis Pts received same general regimens across trials TaxAC arms: concurrent TAC or sequential AC followed by paclitaxel (only in NSABP B-49) Other arms: TC ER+ or PgR+ pts: ≥ 5 yrs endocrine therapy Trial Accrual, n Dates of Accrual Median Follow-up, Yrs USOR 06-090 1295 May 2007 - June 2009 6.3 NASBP B-461 USOR 07132 1077 May 2009 - Jan 2012 4.8 NSABP B-49 1870 April 2012 - Nov 2013 2.2 ABC, anthracyclines in early breast cancer; AC, doxorubicin/cyclophosphamide; ER, estrogen receptor; PgR, progesterone receptor; TAC, docetaxel/doxorubicin/cyclophosphamide; TC, docetaxel/cyclophosphamide; TaxAC, anthracycline/taxane-based chemotherapy; Tx, treatment. Slide credit: clinicaloptions.com Blum JL, et al. ASCO 2016. Abstract 1000.

TC vs TaxAC in HER2- Breast Cancer: Eligibility Criteria HER2-negative breast cancer De novo disease LVEF ≥ 50% Node positive or high-risk node negative; pathology includes 1 of the following pT1-3 if PN1, pN2a, pN3a, pN3b pT2-3 if pN0 pT1c if pN0 and either: ER and PgR negative ER+ or PgR+ and either grade 3 or Oncotype DX recurrence score ≥ 31 (for USOR 06-090) or ≥ 25 (for B-46I/07132 and B-49) ER, estrogen receptor; LVEF, left ventricular ejection fraction; PgR, progesterone receptor; TC, docetaxel/cyclophosphamide; TaxAC, anthracycline/taxane-based chemotherapy; Slide credit: clinicaloptions.com Blum JL, et al. ASCO 2016. Abstract 1000.

TC vs TaxAC in HER2- Breast Cancer: Statistical Plan Primary objective: determine if iDFS with TC noninferior to TaxAC Inferiority predefined as HR ≥ 1.18 stratified by parent trial, nodal status, and hormone receptor status Observed HR with 668 events would need to be significantly < 1.18 to establish noninferiority 1 interim analysis planned for futility at 334 iDFS events Secondary objectives: RFI, OS, toxicity Prespecified subset analyses Cox models testing association between primary endpoint and stratification variables (parent trial, nodal status, ER/PgR positivity) Tests for treatment by covariate interactions Formal subgroup analyses if interactions significant at P < .01 ER, estrogen receptor; iDFS, invasive disease-free survival; PgR, progesterone receptor; RFI, recurrence-free interval; TC, docetaxel/cyclophosphamide; TaxAC, anthracycline/taxane-based chemotherapy. Slide credit: clinicaloptions.com Blum JL, et al. ASCO 2016. Abstract 1000.

TC vs TaxAC in HER2- Breast Cancer: Pt Characteristics B-46I/07132 (N = 1051) B-49 (N = 1819) Total (N = 4156) Median follow-up, yrs 6.3 4.8 2.2 3.2 Age, % ≤ 49 yrs 50-59 yrs ≥ 60 yrs 37 26 38 35 27 31 34 36 29 White, % 88 83 84 85 Positive nodes, % 1-3 4-9 10+ 51 11 3 43 14 5 46 40 4 41 44 ER+ or PgR+, % 71 67 68 69 ER, estrogen receptor; PgR, progesterone receptor; TC, docetaxel/cyclophosphamide; TaxAC, anthracycline/taxane-based chemotherapy. Slide credit: clinicaloptions.com Blum JL, et al. ASCO 2016. Abstract 1000.

TC vs TaxAC in HER2- Breast Cancer: Interim Analysis Data cutoff for interim analysis: October 31, 2015 399 of 668 iDFS events (59.7%) for definitive analysis reported Interim analysis performed on initial 334 events reported Observed HR for iDFS for TC vs TaxAC: 1.202, exceeding prespecified threshold for futility (> 1.18) DMC recommended early reporting in accordance with statistical plan All subsequent data reported based on 399 events reported by data cutoff DMC, Data Monitoring Committee; HR, hazard ratio; iDFS, invasive disease-free survival; TC, docetaxel/cyclophosphamide; TaxAC, anthracycline/taxane-based chemotherapy. Slide credit: clinicaloptions.com Blum JL, et al. ASCO 2016. Abstract 1000.

TC vs TaxAC in HER2- Breast Cancer: Invasive DFS 4-yr iDFS: 88.2% for TC vs 90.7% for TaxAC iDFS HR for TC vs TaxAC (95% CI) P Value Overall 1.23 (1.01-1.50) .04 Parent trial USOR06-090 B-46I/07132 B-49 1.31 (0.97-1.78) 1.34 (0.94-1.91) 1.00 (0.68-1.48) .57 Hormone status Negative Positive 1.42 (1.04-1.94) 1.12 (0.86-1.45) .28 Number of nodes 1-3 4-9 10+ 1.03 (0.74-1.44) 1.27 (0.92-1.76) 1.38 (0.85-2.22) 1.69 (0.89-3.19) .15 iDFS, invasive disease-free survival; TC, docetaxel/cyclophosphamide; TaxAC, anthracycline/taxane-based chemotherapy. Slide credit: clinicaloptions.com Blum JL, et al. ASCO 2016. Abstract 1000.

TC vs TaxAC in HER2- Breast Cancer: iDFS Exploratory Analysis 4-Yr iDFS, % 4-Yr iDFS Delta, % TaxAC AC HR for TC vs TaxAC (95% CI) P Value Overall 90.7 88.2 2.5 1.23 (1.01-1.50) .04 Positive nodes and ER/PgR negative 1-3 4+ 89.5 85.5 71.8 87.0 74.6 60.8 10.9 11.0 1.31 (0.86-1.99) 1.58 (0.90-2.79) 1.34 (0.62-2.91) .71 Positive nodes and ER or PgR positive 91.5 94.3 87.2 94.2 92.3 81.4 -2.7 2.0 5.8 0.69 (0.39-1.19) 1.14 (0.77-1.69) 1.46 (0.95-2.26) .026 ER, estrogen receptor; PgR, progesterone receptor; iDFS, invasive disease-free survival; TC, docetaxel/cyclophosphamide; TaxAC, anthracycline/taxane-based chemotherapy Slide credit: clinicaloptions.com Blum JL, et al. ASCO 2016. Abstract 1000.

TC vs TaxAC in HER2- Breast Cancer: First iDFS Events Type of Event TC (n = 2094) TaxAC (n = 2062) Total (N = 4156) Locoregional 46 34 80 Distant 110 75 185 Recurrence site unknown 19 12 31 CBC 3 6 Leukemia 5 Other 2nd primary 20 22 42 Death 28 50 CBC, contralateral breast cancer; iDFS, invasive disease-free survival; TC, docetaxel/cyclophosphamide; TaxAC, anthracycline/taxane-based chemotherapy 4-yr OS for TC vs TaxAC: 94.7% vs 95.0% HR: 1.08 (95% CI: 0.82-1.41; P = .60) Slide credit: clinicaloptions.com Blum JL, et al. ASCO 2016. Abstract 1000.

TC vs TaxAC in HER2- Breast Cancer: Conclusions Treatment with TaxAC results in superior iDFS vs TC iDFS HR for TC vs TaxAC: 1.202 Prespecified noninferiority boundary of 1.18 crossed, prompting early data reporting for futility 4-yr OS similar between groups (~ 95%) Exploratory subgroup analyses suggest TaxAC provides: Minimal or no benefit in ER+/node-negative pts Small benefit in ER+/1-3 node-positive and ER-/node-negative pts Large benefit in ER /≥ 4 node-positive and ER-/node-positive pts Additional analysis needed to identify biomarkers associated with anthracycline benefit across this heterogeneous pt population ER, estrogen receptor; iDFS, invasive disease-free survival; OS, overall survival; PgR, progesterone receptor; TC, docetaxel/cyclophosphamide; TaxAC, anthracycline/taxane-based chemotherapy Slide credit: clinicaloptions.com Blum JL, et al. ASCO 2016. Abstract 1000.

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