571P - Randomized phase III study of sequential treatment with capecitabine or 5-fluorouracil (FP) plus bevacizumab (BEV) followed by the addition with oxaliplatin (OX) versus initial combination with OX+FP+ BEV in the first-line chemotherapy for metastatic colorectal cancer: The C-cubed study

Abstract

BackgroundThe C-cubed study investigates the optimal treatment strategy in patients with untreated metastatic colorectal cancer (mCRC). We tested the superiority of a sequential treatment of FP+BEV followed by OX+FP+BEV (arm A: OX “wait & go”) at first progression to a combination treatment of OX+FP+BEV (arm B: OX “stop & go”), trial information: UMIN000015405. MethodsThe Primary endpoint was time-to-failure of strategy (TFS). A target sample size of 304 patients was considered sufficient to validate an expected Hazard Ratio (HR) for TFS of arm A compared with arm B with 80% power and 2-sided 5% α in case of a true HR value of<0.69. Secondary endpoints included overall response rate, overall survival (OS), progression-free survival, and safety. ResultsBetween Dec 2014 and Sep 2016, 311 patients were enrolled, and 302 patients were randomized either to receive the arm A (n=151) or B (n=151) as a full analysis set (FAS). Superiority of TFS in the arm A was established in this study (HR, 0.475; 95% CI, 0.362–0.623; p<0.0001). OSs in the arms A and B were not considered significantly different (HR, 0.930; 95% CI, 0.666–1.298). The patient population was predominantly positive for RAS mutant tumors (RAS MT) compared with that for RAS wild-type tumors (RAS WT), but this did not confer any clinical disadvantage in TFS to either arms (see table for details). We will present additional data associated with RAS status and differences between capecitabine and 5-fluorouracil at the meeting.Table571PTableTableEndpointArm A, “wait & go” (n=151) Months (95%CI)Arm B, “stop & go” (n=151) Months (95%CI)p-value (log rank)TFS (FAS)15.2 (12.5 – 17.2)7.6 (6.2 – 9.5)<.0001OS (FAS)27.5 (24.4 – 32.7)29.4 (24.1 – 36.0)0.6692FactorRAS WT (n=112) Months (95%CI)RAS MT (n=167) Months (95%CI)p-value (log rank)TFSArm A14.0 (11.2 – 19.0)15.3 (12.4 – 17.2)0.3126Arm B7.8 (7.0 – 10.5)7.4 (5.2 – 9.6)0.1615OSArm A27.5 (22.6 – NC)28.0 (23.4 – 32.7)0.3143Arm B34.7 (24.5 – NC)24.3 (19.1 – 32.8)0.0265 ConclusionsThe sequential “wait & go” strategy for OX was superior in TFS compared with the combinational “stop & go” accompanying with the equal survival benefit of nearly 30 months. Thus, the sequential approach with FP+BEV followed by OX is deemed an acceptable treatment strategy for patients with mCRC. Clinical trial identificationUMIN000015405. Legal entity responsible for the studyJapan South West Oncology Group (JSWOG). FundingChugai Pharmaceutical Co., Ltd. DisclosureT. Nagasaka: Speaker Bureau / Expert testimony: Eli Lilly Japan. Y. Shindo: Research grant / Funding (institution): Chugai; Research grant / Funding (institution): MSD; Research grant / Funding (self): Ono; Research grant / Funding (institution): Daiichi-Sankyo; Research grant / Funding (institution): Lilly. A. Tsuji: Honoraria (institution): Daiichi Sankyo; Honoraria (institution), Speaker Bureau / Expert testimony: Taiho Pharmaceutical; Honoraria (institution), Speaker Bureau / Expert testimony: Chugai Pharma; Honoraria (institution), Speaker Bureau / Expert testimony: Merck Serono; Honoraria (institution), Speaker Bureau / Expert testimony: Takeda Pharmaceutical; Honoraria (institution): Bristol-Myers Squibb Japan. Y. Tsuji: Honoraria (institution): Bayer Co. Ltd; Honoraria (institution): Merck Serono Co. Ltd; Honoraria (institution): Eli Lilly Japan; Honoraria (institution): Chugai Pharmaceutical Co. Ltd; Honoraria (institution): Taiho Pharmaceutical Co. Ltd; Honoraria (institution): Ono Pharmaceutical Co. Ltd; Honoraria (institution): Takeda Pharmaceutical Co. Ltd; Honoraria (institution): Medicon Co. Ltd. H. Mishima: Research grant / Funding (institution): Chugai Pharmaceutical Co. Ltd. All other authors have declared no conflicts of interest.