474O - Treatment outcome according to tumor RAS mutation status in TRICOLORE trial: A randomized phase 3 trial of S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment for metastatic colorectal cancer

Abstract

Background: 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). Methods: 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. Results: 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 < 0.001 for non-inferiority, p = 0.087 for superiority). The RAS mutation status was evaluable in 67.6%. In the RAS wild-type subgroup, median PFS was 11.6 months in group A and 15.9 months in group B. In the RAS mutant-type subgroup, median PFS was 9.3 months in group A and 11.3 months in group B. Conclusions: 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: UMIN000007834 2012/05/11 Legal entity responsible for the study: The Tokyo Cooprative Oncology Group Funding: The Tokyo Cooprative Oncology Group (with funding from Taiho) Disclosure: 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.