Abstract S1-07: 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)
Authors: M Toi, S-J Lee, ES Lee, S Ohtani, Y-H Im, S-A Im, B-W Park, S-B Kim, Y Yanagita, S Takao, S Ohno, K Aogi, H Iwata, A Kim, H Sasano, I Yokota, Y Ohashi, N Masuda
Journal: Cancer Research (2016)

Abstract Background Patients (pts) with pathologic residual invasive disease after neoadjuvant chemotherapy (NAC) have an intermediate or high-risk for relapse. It is not clear whether further systemic chemotherapy is beneficial for these pts. CREATE-X is a multicenter open-label randomized phase III trial evaluating this major clinical issue using capecitabine (X) in pts without pCR after NAC (UMIN000000843). We have shown previously that the addition of 8 cycles of X to standard adjuvant therapy is feasible and well tolerated (Ohtani S, et al. SABCS2013#P3-12-03). We report the first efficacy results from a pre-planned interim analysis after 2-year follow-up. Methods Pts with HER2-negative residual invasive cancer after anthracycline- and/or taxane-containing NAC were randomized to standard treatment (RT, hormone therapy (HT) as appropriate) with or without 8 cycles of X (1250 mg/m2 bid, days1–14,q3w). Pts with hormone receptor (HR)-positive disease received HT either with or after X, according to each center's prespecified standard practice. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS), safety, and cost-effectiveness. It was originally planned to enroll 450 pts in each arm in order to detect a HR 0.74 improvement in the X arm with 80% power and a two-sided 5% significance level. We planned one interim analysis of DFS at 2-years after all pts enrolled using Lan-DeMets alpha spending function method (O'Brein-Fleming type). Results 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=0.001). 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: The clinical utility of X in the adjuvant setting for breast cancer pts has been proven to improve the prognosis based on the pathological response-guided strategy. Tolerability was consistent with the established safety profile of X in mBC. The benefit to risk balance of the addition of 8 cycles of X to standard adjuvant therapy seems to be satisfied. This evidence might allow the development of personalized individualized treatment based on the response to primary systemic therapy. Citation Format: Toi M, Lee S-J, Lee ES, Ohtani S, Im Y-H, Im S-A, Park B-W, Kim S-B, Yanagita Y, Takao S, Ohno S, Aogi K, Iwata H, Kim A, Sasano H, Yokota I, Ohashi Y, Masuda N. 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). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S1-07.