CREATE-X: Adjuvant Capecitabine in HER2-Negative Breast Cancer CCO Independent Conference Coverage*: The 2015 Annual Meeting of the CTRC-AACR San Antonio Breast Cancer Symposium, December 8-12, 2015 San Antonio, Texas *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. This program is supported by educational grants from Genentech and Novartis.

CREATE-X: Background Pts with pathologic residual disease after standard anthracycline/taxane neoadjuvant chemotherapy have a high risk of relapse Adjuvant chemotherapy in pts who received neoadjuvant chemotherapy may not prolong survival The phase III CREATE-X trial evaluated efficacy of adjuvant capecitabine for HER2-negative breast cancer pts with residual invasive disease (non-pCR, node positive) following anthracycline/taxane neoadjuvant chemotherapy pCR, pathologic complete response. Slide credit: clinicaloptions.com Toi M, et al. SABCS 2015. Abstract S1-07.

CREATE-X: Study Design Preplanned interim analysis of a randomized, open-label phase III study[1] Stratified by ER status, age, neoadjuvant chemotherapy, use of 5-FU, institution, node status Wk 24 Capecitabine 2500 mg/m²/day PO Days 1-14 Q3W for 8 cycles‡ Hormonal therapy if ER/PgR+ (n = 455)† Pts 20-74 yrs of age with stage I-IIIB HER2- BC and residual disease (non-pCR, N+) after neoadjuvant chemotherapy* and surgery; ECOG PS 0 or 1; no previous oral fluoropyrimidines (N = 910)† Hormonal therapy if ER/PgR+ No further therapy if ER/PgR- (n = 455)† Primary endpoint: DFS Secondary endpoints: OS, time from first day of preoperative chemotherapy to recurrence or death, safety, cost-effectiveness 5-FU, 5-fluorouracil; BC, breast cancer; ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; IDMC, Independent Data Monitoring Committee; N+, positive lymph nodes; pCR, pathologic complete response; PgR, progesterone receptor; PS, performance status. *Anthracycline/taxane, anthracycline containing, or docetaxel/cyclophosphamide. †25 pts were removed from treatment (n = 10) and control (n = 15) arms due to failure to meet eligibility criteria. ‡IDMC recommended extension to 8 cycles following interim safety analysis of first 50 pts receiving 6 cycles.[2] 1. Toi M, et al. SABCS 2015. Abstract S1-07. 2. Ohtani S, et al. SABCS 2013. Abstract P3-12-03. Slide credit: clinicaloptions.com

CREATE-X: Baseline Characteristics Capecitabine (n = 440) No Capecitabine (n = 445) Age, median yrs (range) 48 (25-74) Menopausal status, % Pre Post 59.3 40.7 56.0 44.0 Stage, % I, IIA, IB IIIA, IIIB 58.9 40.5 62.0 37.5 Hormonal receptor status, % ER+ or PgR+ ER- and PgR- 63.9 33.4 62.9 33.5 Lymph nodes with metastatic disease, % 1-3 ≥ 4 39.3 22.7 38.7 39.1 22.2 Histologic effect grading by NAC, % 0, 1a, 1b 2, 3 56.4 41.6 52.6 45.4 ER, estrogen receptor; NAC, neoadjuvant chemotherapy; PgR, progesterone receptor. Slide credit: clinicaloptions.com Toi M, et al. SABCS 2015. Abstract S1-07.

CREATE-X: Pt Treatment Status and Disposition Characteristic Capecitabine (n = 440) No Capecitabine (n = 445) Neoadjuvant chemotherapy, % Anthracycline containing Sequential anthracycline/taxane Concurrent anthracycline/taxane Docetaxel + cyclophosphamide 5-FU containing 4.1 81.1 13.6 1.1 59.1 3.6 83.4 11.9 0.7 60.4 Adjuvant endocrine therapy, % Premenopausal Postmenopausal 42.5 24.5 40.0 28.5 Previous RT, % 72.3 73.5 Measure, % (n = 439*) 6-Cycle Regimen (n = 159) 8-Cycle Regimen (n = 280) Completed all cycles 58.0 37.9 Dose reduction 23.9 37.1 Discontinuation 18.2 25.0 Relative dose intensity, mean ( SD) 87.9 ( 21.6) 79.1 ( 29.0) 5-FU, 5-fluorouracil; RT, radiation therapy; SD, standard deviation. *Pts who received capecitabine; data for 1 pt not reported. Slide credit: clinicaloptions.com Toi M, et al. SABCS 2015. Abstract S1-07.

CREATE-X: 5-Yr Efficacy Capecitabine achieved significantly higher 5-yr DFS and OS in HER2- BC pts with residual disease Characteristic, % Capecitabine (n = 440) No Capecitabine (n = 445) HR (95% CI) P Value 5-yr DFS 74.1 67.7 0.70 (0.53-0.93) .00524 5-yr OS 89.2 83.9 0.60 (0.40-0.92) < .01 BC, breast cancer; DFS, disease-free survival; OS, overall survival. Slide credit: clinicaloptions.com Toi M, et al. SABCS 2015. Abstract S1-07.

CREATE-X: DFS by Subgroup HR (95% CI) Total (N = 885) 0.70 (0.53-0.93) Age < 50 yrs (n = 531) ≥ 50 yrs (n = 354) 0.72 (0.50-1.03) 0.68 (0.45-1.04) Hormone receptor status Positive (n = 561) Negative (n = 296) 0.84 (0.57-1.23) 0.58 (0.39-0.87) Node stage ypN0 (n = 345) ypN1 (n = 339) ypN2 or 3 (n = 199) 0.88 (0.48-1.62) 0.54 (0.36-0.83) 0.82 (0.52-1.29) Path grade by NAC 0-1b (n = 482) 2-3 (n = 385) 0.63 (0.45-0.88) 0.84 (0.52-1.34) Subgroup HR (95% CI) Total (N = 885) 0.70 (0.53-0.93) Taxane-containing NAC Yes (n = 849) No (n = 36) 0.87 (0.12-6.24) 5-FU–containing NAC Yes (n = 529) No (n = 356) 0.74 (0.52-1.04) 0.65 (0.42-1.02) Nationality Japanese (n = 599) Korean (n = 286) 0.74 (0.53-1.02) 0.63 (0.37-1.05) 5-FU, 5-fluorouracil; NAC, neoadjuvant chemotherapy; ypN, posttreatment pathologic node stage. Slide credit: clinicaloptions.com Toi M, et al. SABCS 2015. Abstract S1-07.

CREATE-X: Adverse Events AE, % Capecitabine (n = 440) No Capecitabine (n = 445) P Value Neutropenia, grade ≥ 3 6.6 1.6 < .001 Diarrhea, grade ≥ 3 3.0 0.4 .004 Capecitabine hand–foot syndrome, grade: 1 2 3 27.7 36.4 25.0 10.9 -- All grade AEs that are significantly higher in capecitabine arm include: Leukopenia, neutropenia, anemia, thrombocytopenia, elevated ALT/AST, total bilirubin, appetite loss, diarrhea, stomatitis, fatigue AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase. Slide credit: clinicaloptions.com Toi M, et al. SABCS 2015. Abstract S1-07.

CREATE-X: Conclusions Adjuvant capecitabine significantly improved DFS and OS in HER2- breast cancer pts with pathologic residual disease following standard anthracycline/ taxane neoadjuvant chemotherapy The authors concluded that the risk vs benefit of capecitabine therapy supports further investigation of its use as adjuvant therapy in this breast cancer population Cost–benefit analysis of adjuvant capecitabine in this population is planned DFS, disease-free survival; OS, overall survival. Toi M, et al. SABCS 2015. Abstract S1-07.

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