555MO - Modified (m)-FOLFOXIRI plus cetuximab treatment and predictive clinical factors for RAS/BRAF wild-type and left-sided metastatic colorectal cancer (mCRC): The DEEPER trial (JACCRO CC-13)

Background

The DEEPER trial, which evaluated m-FOLFOXIRI (irinotecan 150 mg/m², oxaliplatin 85 mg/m², 5-FU 2400 mg/m²) plus cetuximab (cet) vs. bevacizumab (bev) as initial treatment in terms of depth of response (DpR) as the primary endpoint in RAS wild-type mCRC, has demonstrated a significantly better DpR of the cet arm (Tsuji A, et al. ASCO 2021 ). Moreover, longer PFS and OS in the cet arm were observed in RAS/BRAF wild-type and left-sided tumors although BRAF status was available for only half of the patients (pts) ( JSMO 2023 ). An updated survival analysis was performed using BRAF status added by tumor tissue biomarker analysis.

Methods

The DpR and other clinical outcomes were evaluated in per protocol set (PPS) consisted of pts evaluable for the DpR at external review board. Survival analysis was performed according to clinical factors including primary tumor sidedness which was one of the stratification factors using a log-rank test. In 359 enrolled pts, BRAF status was available in 255 pts with biomarker analysis for 71 pts. All statistical tests were two-sided, and P values ≤ 0.05 were deemed significant.

Results

321 pts were defined as PPS (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 84%/16%). In 178 pts with RAS/BRAF wild-type and left-sided tumors, DpR and PFS both were significantly better in the cet compared to the bev arm (DpR, median 59.2% vs. 47.5%, P=0.0017; PFS, median 14.5 vs. 11.9 months, HR 0.71, P=0.032). A sub-group analysis by clinical factors showed that PFS was better in the cet arm among pts without surgical resection of R0/1 (HR 0.66, P=0.029), and it was significantly longer in pts with extra-hepatic metastases (HR 0.63, P=0.015) but not liver-limited disease. In addition, in the cet arm, male had a better PFS compared to female. Median PFS was longer in the cet compared to the bev arm among male (18.0 vs. 13.1 months, HR 0.72, P=0.096) but not female.

Conclusions

m-FOLFOXIRI plus cet regimen could be a good option for upfront chemotherapy with high DpR and longer PFS in mCRC pts with RAS/BRAF wild-type and left-sided tumors. The benefit may be relevant for pts with extra-hepatic metastases or male.

Clinical trial identification

NCT02515734.

Editorial acknowledgement

Legal entity responsible for the study

Japan Clinical Cancer Research Organization.

Funding

Merck Biopharma Co., Ltd.

Disclosure

Y. Sunakawa: Financial Interests, Personal, Invited Speaker: Eli Lilly Japan, Bristol Myers Squibb, Chugai Pharmaceutical, Takeda, Taiho Pharmaceutical, Merck Biopharma, Daiichi Sankyo, Ono Pharmaceutical; Financial Interests, Personal, Advisory Board: Merck Biopharma; Financial Interests, Personal and Institutional, Research Grant: Chugai Pharmaceutical, Taiho Pharmaceutical, Takeda, Otsuka Pharm, Parexel International Inc., IQVIA, Ono Pharmaceutical, CMIC Shift Zero K.K., PRA Health Sciences, Inc., Amgen; Non-Financial Interests, Project Lead: Japan Clinical Cancer Research Organization. M. Shiozawa: Financial Interests, Personal, Invited Speaker: Lilly Japan, Merck Serono, Taiho Pharmaceutical, Yakult Honsha, Takeda, Ono Pharmaceutical, Johnson & Johnson, Kaken. H. Yasui: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Chugai Pharma, Bristol Myers Squibb, Daiichi Sankyo, Terumo, Eli Lilly Japan, Merck Biopharma, Yakult Honsha, Bayer Yakuhin; Financial Interests, Institutional, Local PI: MSD, Daiichi Sankyo, Ono Pharmaceutical, Astellas Pharma, Amgen. H. Ohori: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Nippon Kayaku Co. Ltd., Chugai Pharmaceutical Co., Ltd., MSD K.K., Bristol Myers Squibb Company, Takeda Pharmaceutical Company Limited, Eli Lilly Japan K.K., Yakult Honsha Co. Ltd. W. Ichikawa: Financial Interests, Personal, Invited Speaker: Merck BioPharma, Bristol Myers Squibb, Chugai Pharmaceutical, Yakult Honsha, AstraZeneca, Daiichi Sankyo, Taiho Pharmaceutical; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, Taiho Pharmaceutical, Daiichi Sankyo, Shionogi, Takeda Pharmaceutical. A. Tsuji: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Eli Lilly Japan Co., Ltd., MSD Corporation, Daiichi Sankyo Co., Ltd., Bristol Myers Squibb Corporation, Merck Biopharma Co., Ltd; Financial Interests, Personal, Local PI: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical Co., Ltd. All other authors have declared no conflicts of interest.