San Antonio Breast Cancer Symposium, December 8-12, 2015 A phase III trial of adjuvant capecitabine in breast cancer patients with HER2-negative pathologic residual invasive disease after neoadjuvant chemotherapy (CREATE-X/JBCRG-04) Capecitabine for REsidual cancer as Adjuvant ThErapy Lee S-J1, Toi M2, Lee E-S3, Ohtani S4, Im Y-H5, Im S-A6, Park B-W7, Kim S-B8, Yanagita Y9, Takao S10, Ohno S11, Aogi K12, Iwata H13, Kim A14, Sasano H15, Yokota I16, Ohashi Y17 and Masuda N18 1Yeungnam University Hospital; 2Kyoto University Hospital; 3National Cancer Center; 4Hiroshima City Hospital; 5Samsung Medical Center; 6Seoul National University Hospital; 7Severance Hospital, Yonsei University College of Medicine; 8Asan Medical Center; 9Gunma Prefectural Cancer Center; 10Hyogo Cancer Center; 11National Kyusyu Cancer Center; 12NHO Shikoku Cancer Center; 13Aichi Cancer Center; 14Korea University Guro Hospital; 15Tohoku University; 16Kyoto Prefectural University of Medicine; 17Chuo University and 18NHO Osaka National Hospital This presentation is the intellectual property of the presenter. Contact to toi@kuhp.kyoto-u.ac.jp for permission to reprint and/or distribute.

Background Standard regimens of neoadjuvant chemotherapy (NAC) contain anthracycline and taxane. Patients (pts) with pathologic residual invasive disease after NAC have higher risk for relapse. It is unclear whether postoperative systemic chemotherapy following NAC is able to prolong survival. This trial was designed as a multicenter open-labeled randomized phase III trial evaluating the efficacy of adjuvant capecitabine (X) use for pts having residual invasive disease (non-pCR/ n+) after NAC.

CREATE-X: Trial Design HER2- Control: Standard therapy Pathology Non-pCR or node + NAC Surgery R Standard therapy + Capecitabine (n=900) Stratification factors: ER, Age, NAC, ypN, 5FU and institution Standard therapy: HR+: Hormone therapy HR-: No further systemic treatment * ER-positive: 10% and more by immunohistochemistry or positive in Allred score (including weak positive) ** Patients with axillary lymph node micrometastases, isolated tumor cells, pN0(i), and/or pN0(mol) are classed as n0. Classification of n0, n1-3, n>=4 based on sentinel lymph node (SLN) biopsy should comply with Appendix 7.

Capecitabine Therapy Capecitabine (X): 2,500 mg/m2/day, po, day 1-14 Repeat every 3 weeks for 8 cycles 1 2 3 4 5 6 7 8 3w 6w 12w 18w 24w According to the safety interim analysis of the first 50 pts treated with 6 cycles of X, the IDMC recommended extending X to 8 cycles.

Endpoints Primary endpoint: Disease free survival (DFS) Secondary endpoints: Overall survival (OS) Period from the first day of preoperative chemotherapy to recurrence or death Safety Cost-effectiveness

Consort Diagram and Trial Progress 2007/2 ~ 2012/7 304 Korean and 606 Japanese Randomized (N=910) Capecitabine (N=455) (N=440) Control (N=445) In 2013, the safety analysis indicated that the postoperative 8 cycles X treatment was feasible. (SABCS2013#P3-12-03, Ohtani S et al.) In 2015, the first pre-planned interim analysis was carried out at the point of two years follow-up from the last patient enrollment. The IDMC recommended that this study should be discontinued according to the protocol. Not meet inclusion criteria (n=10) Patients withdrawal (n=4) No follow-up data (n=1) Not meet inclusion criteria (n=5) Patients withdrawal (n=5) Full Analysis Set Data cut-off point: 30th Sep. 2015

Disease Free Survival 82.8% 74.1% Capecitabine 74.0% 67.7% Control 5yr DFS 74.1% Capecitabine 74.0% 67.7% Control HR (95%CI) 0.70 (0.53-0.93) One-sided p=0.00524 < 0.00671 Between Feb 2007 and Jul 2012, 910 pts were randomized, with 455 pts to receive X. The full analysis consisted of 902 pts who matched the inclusion criteria. Baseline characteristics were well balanced. The median age was 48 years in both arms; 63.5% were HR-positive. In the investigational arm, HT was given with X concurrently in 200 pts and after X in 24 pts. The relative dose intensity of X was 78.8%. At the time of the interim analysis, DFS events were confirmed in 81 (18.8%) in the investigational arm and 109 (24.7%) in the standard arm, and OS events were 28 (6.5%) and 41 (9.3%), respectively. On Kaplan-Meier analysis, 2-year DFS was 87.3% for the arm with X and 80.5% for no X (HR:0.688, 98.66%CI: 0.479-0.989, log-rank P=0.0010). The tendency for improvement of OS by adding X was also confirmed; 2-year OS was 96.2% and 93.9%, respectively (HR: 0.658, 95%CI: 0.407-1.065, log-rank P=0.086). In the experimental arm with X, grade 3/4 toxicities included HFS (11%), neutropenia (9%), diarrhea (3%), and fatigue (1%); all were controllable. No SAE was related to X administration. Because the study met the primary endpoint, an independent data monitoring committee recommended discontinuation of the study.

Conclusions After standard neoadjuvant chemotherapy containing A and/or T, postoperative adjuvant use of capecitabine improved DFS significantly in HER2-negative primary breast cancer patients with pathologically proven residual invasive disease. OS was significantly improved by capecitabine adjuvant therapy for non-pCR or node-positive patients after NAC. The balance of benefit and toxicity would favor the use of capecitabine in the post-NAC situation, but prediction for the therapeutic benefit needs to be investigated further. The cost-effectiveness analysis will be carried out.