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Modified (m)-FOLFOXIRI plus cetuximab versus m-FOLFOXIRI plus bevacizumab as initial treatment for RAS and BRAF wild-type metastatic colorectal cancer: Updated survival analysis of the DEEPER trial by JACCRO
We conducted a randomized phase II trial, DEEPER trial (JACCRO CC-13)[NCT02515734], to evaluate modified (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 metastatic colorectal cancer (mCRC) patients (pts) with RAS wild-type tumors and have reported a significantly better depth of response (DpR) in m-FOLFOXIRI plus cet (Tsuji A, et al. ASCO 2021 abst3501). Pre-planned survival analysis was performed at the time of 3-year after last pts’ enrollment, including the exploratory analysis using BRAF status.
The primary endpoint was DpR in per protocol set (PPS) consisted of pts evaluable for the DpR, which was evaluated at external review board. Secondary endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), early tumor shrinkage rate, secondary resection rate, and toxicity. Pre-planned survival analysis was performed to compare the 2 treatment arms according to primary tumor sidedness which was included in the stratification factor using a log-rank test. Additionally, BRAF status data were collected for sub-group analysis in pts with RAS/BRAF wild-type tumors. All statistical tests are two-sided, and P values ≤ 0.05 are deemed significant.
In a total of 359 enrolled pts, 321 pts were defined as PPS. In the PPS population (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 84%/16%), dose intensity (DI) of cytotoxic agents was comparable in the 2 arms and DI of cet was 77% during 8 cycles. Median DpR, PFS, and OS were 57.3% vs. 46.0% (P=0.0029), 13.0m vs. 12.3m (HR 0.89, P=0.32), and 42.9m vs. 42.1m (HR 0.94, P=0.68), respectively, in the cet vs. bev arm. BRAF status information was available in 167 of 321 pts of PPS; 14 pts with BRAF V600E mutation. In 153 pts with RAS/BRAF wild-type tumors, median DpR, PFS, and OS were 60.4% vs. 47.9% (P=0.007), 13.8m vs. 12.3m (HR 0.80 [95%CI, 0.57-1.12]), and 53.4m vs. 42.1m (HR 0.67 [95%CI, 0.42-1.07]), respectively, in the cet vs. bev arm. In 131 pts with RAS/BRAF wild-type and left-sided tumors, median DpR and ORR were 63.6% vs. 47.8% (P=0.0003) and 83.6% vs. 72.9%. PFS and OS both were significantly better in the cet compared to the bev arm (median PFS, 15.3m vs. 11.7m, HR 0.68 [95%CI, 0.47-0.98]; median OS, 53.6m vs. 40.2m, HR 0.54 [95%CI, 0.32-0.91]). R0 resection rate was 32.8% vs. 20.0% (cet vs. bev). Pts with R0 resection had significantly longer OS in each arm; however, there was no difference in OS between the 2 arms in pts with RAS/BRAF wild-type and left-sided tumors who achieved R0 resection.
m-FOLFOXIRI plus cet regimen could be a good option for upfront chemotherapy in mCRC pts with RAS/BRAF wild-type and left-sided primary tumor. Further survival analysis will be performed by updated BRAF information from a biomarker study using tissue samples.
NCT02515734.
Japan Clinical Cancer Research Organization.
The authors.
Merck Biopharma Co., Ltd.
Y. Sunakawa: Honoraria (self): Bristol-Myers Squibb, Chugai Pharm, Eli Lilly Japan; Advisory / Consultancy: Daiichi-Sankyo, Merck Biopharm, Guardant Health; Research grant / Funding (self): Chugai Pharm, Takeda, Taiho Pharm; Research grant / Funding (institution): Ono Pharm, Parexel International, PRA health science. M. Shiozawa: Speaker Bureau / Expert testimony: Ono Pharmaceutial, Merck Serono. H. Yasui: Honoraria (self): Daiichi Sankyo, Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharma, Bristol-Myers Squibb Japan, TERUMO, Eli Lilly Japan, Merk Biopharma, Yakult Honsha, Bayer Yakuhin, Takeda Pharmaceutical; Research grant / Funding (self): MSD, Ono Pharmaceutical, Daiichi Sankyo, Astellas Pharma, Amgen. T. Masuishi: Honoraria (self): Ono, Merck Biopharma. M. Kotaka: Honoraria (self): Chugai pharmaceutical, Lilly. M. Nakamura: Honoraria (self): Bayer Yakuhin, Ltd., Bristol-Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan Co., Ltd., Merck Bio Pharma Co., Ltd., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd. W. Ichikawa: Honoraria (self): Chugai Pharma, Merck Biopharma, Bristol-Myers Squibb ; Research grant / Funding (institution): Taiho Pharma, Chugai Pharma, Daiichi Sankyo. A. Tsuji: Speaker Bureau / Expert testimony: Taiho Pharmaceutical Co., Ltd. , Chugai Pharmaceutical Co., Ltd. , Eli Lilly Japan Co., ; Research grant / Funding (institution): Taiho Pharmaceutical Co., Ltd. , Sanofi Corporation, Ono Pharmaceutical Co.,. All other authors have declared no conflicts of interest.
