Combination therapy with oral fluoropyrimidine and irinotecan (CPT-11) has not yet been established as first-line treatment for metastatic colorectal cancer (mCRC). However, several studies of S-1 and CPT-11 plus bevacizumab (Bmab) combination therapy have shown promising efficacy in mCRC, suggesting the potential to replace mFOLFOX6 or CapeOX plus Bmab. We performed a randomized phase 3 trial to determine whether S-1 and CPT-11 plus Bmab is non-inferior or superior to mFOLFOX6 or CapeOX plus Bmab in terms of progression-free survival (PFS).
The TRICOLORE trial was a randomized, open-label, phase 3 trial. Chemotherapy-naïve patients with mCRC were randomized to receive either mFOLFOX6 or CapeOX plus Bmab (group A) or S-1 and CPT-11 plus Bmab (group B; 3-week regimen: 7.5 mg/kg Bmab, 150 mg/m2 CPT-11 on day 1, and 40 − 60 mg S-1 twice daily for 2 weeks, followed by a 1-week rest; or 4-week regimen: 5 mg/kg Bmab, 100 mg/m2 CPT-11 on days 1 and 15, and 40 − 60 mg S-1 twice daily for 2 weeks, followed by a 2-week rest). The primary endpoint was PFS. The non-inferiority margin was a hazard ratio (HR) of 1.25 based on the assumption of a median PFS of 11/12 months in group A/group B (power 0.85, 1-sided alpha 0.025). The primary tumor RAS status of patients consented to submit tissue sample were centrally analyzed.
A total of 487 patients were enrolled from June 2012 to September 2014. Data were analyzed after confirming >374 events as planned. All demographic factors were well balanced. Median PFS was 10.8 months in group A and 14.0 months in group B (HR 0.85, 95% CI: 0.70–1.03, p
S-1 and CPT-11 plus Bmab was non-inferior to mFOLFOX6 or CapeOX plus Bmab with respect to PFS and has now become a recommended 1st-line treatment for mCRC irrespective of RAS status.
Clinical trial identification
Legal entity responsible for the study
The Tokyo Cooprative Oncology Group
The Tokyo Cooprative Oncology Group (with funding from Taiho)
Y. Komatsu: Other substantive relationships: Taiho Pharmaceutical, Lilly, MSD, Ono Pharmaceutical, Novartis, Chugai Pharma, Yakult, Merck Serono, Pfizer, Bayer. A. Takashima: Corporate-sponsored research: Taiho Pharmaceutical, Gilead Sciences, Merck Serono. M. Gamoh: Corporate-sponsored research: Taiho Pharmaceutical, Gilead Sciences, Merck Serono. H. Shimodaira: Corporate-sponsored research: Taiho, Eisai, Bayer. H. Baba: Advisory board or Board of directors: Taiho Pharmaceutical Co., Ltd.; corporate-sponsored research: Taiho Pharmaceutical Co., Ltd. C. Ishioka: Mochida, Kyowa-K, Eisai, Chugai, Tsumura, Novartis, Merck Serono, Daiichi Sankyo, Takeda, Nihon-Kayaku, Yakult, Taiho, Ono, Astellas, Asahi Kasei, Kissei, Bristol-Myers Squibb, Mochida, Chugai, Novartis, Lilly, Bayer. A. Sato: Advisory board or Board of directors: Taiho Pharmaceutical Co., Ltd. Chugai Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.; corporate-sponsored research: Taiho Pharmaceutical Co., Ltd.Chugai Pharma Co., Ltd. S. Yuki: Speakers’ bureau: Chugai Pharmaceutical, Eli Lilly Japan, Bayer Yakuhin, Takeda Pharmaceutical, Taiho Pharmaceutical, Merck Serono. S. Morita: Corporate-sponsored research: Taiho; honorarium: Taiho. All other authors have declared no conflicts of interest.