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Poster Display session 2

3888 - 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


29 Sep 2019


Poster Display session 2


Tumour Site

Colon and Rectal Cancer


Takeshi Nagasaka


Annals of Oncology (2019) 30 (suppl_5): v198-v252. 10.1093/annonc/mdz246


T. Nagasaka1, R. Inada2, H. Ojima3, S. Noura4, H. Tanioka1, Y. Munemoto5, Y. Shimada6, K. Ishibashi7, Y. Shindo8, Y. Kagawa9, A. Tomibayashi10, K. Okamoto11, A. Tsuji12, Y. Tsuji13, S. Yamaguchi14, A. SAWAKI15, H. Mishima16, M. Shimokawa17, M. Okajima18, Y. Yamaguchi1

Author affiliations

  • 1 Clinical Oncology, Kawasaki Medical School Hospital, 701-0192 - Kurashiki/JP
  • 2 Gastroenterological Surgery, Kochi Health Sciences Center, 781-8555 - Kochi/JP
  • 3 Gastroenterological Surgery, Gunma Prefectural Cancer Center, 373-0828 - Ota/JP
  • 4 Surgery, Osaka Rosai Hospital, 591-8025 - Sakai/JP
  • 5 Surgery, Fukui-ken Saiseikai Hospital, 918-8503 - Fukui/JP
  • 6 Clinical Oncology, Kochi Health Sciences Center, 781-8555 - Kochi/JP
  • 7 Department Of Digestive Tract And General Surgery, Saitama Medical University, Saitama/JP
  • 8 Gastroenterological Surgery, Nakadori General Hospital, 010-8577 - Akita/JP
  • 9 Surgery, Kansai Rosai Hospital, 6600064 - Amagasaki/JP
  • 10 Surgery, Tokushima Red Cross Hospital, 773-8502 - Tokushima/JP
  • 11 Cancer Treatment Center, Kochi Medical School Hospital, 783-8505 - Nangoku/JP
  • 12 Clinical Oncology, Kagawa University Faculty of Medicine/Graduate School of Medicine, 761-0793 - Miki-cho, Kita-gun/JP
  • 13 Medical Oncology, KKR Tonan Hospital, 060-0001 - Sapporo/JP
  • 14 Gastroenterological Surgery, Saitama Medical University International Medical Center, 350-1298 - Hidaka/JP
  • 15 Medical Oncology, Fujita Health University, 470-1192 - Toyoake/JP
  • 16 Cancer Center, Aichi Medical University, 480-1195 - Nagakute/JP
  • 17 Biostatistics, Yamaguchi University Graduate School of Medicine, 8755-8505 - Ube/JP
  • 18 Department Of Surgery, Hiroshima City Hiroshima Citizens Hospital, 30-8518 - Hiroshima/JP


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Abstract 3888


The 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.


The 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.


Between 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.Table:


TableEndpointArm 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)<.0001
OS (FAS)27.5 (24.4 – 32.7)29.4 (24.1 – 36.0)0.6692
FactorRAS 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)0.3126
Arm B7.8 (7.0 – 10.5)7.4 (5.2 – 9.6)0.1615
OSArm A27.5 (22.6 – NC)28.0 (23.4 – 32.7)0.3143
Arm B34.7 (24.5 – NC)24.3 (19.1 – 32.8)0.0265


The 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 identification


Editorial acknowledgement

Legal entity responsible for the study

Japan South West Oncology Group (JSWOG).


Chugai Pharmaceutical Co., Ltd.


T. 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.

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