Final analysis of modified (m)-FOLFOXIRI plus cetuximab versus bevacizumab for
RAS
wild-type and left-sided metastatic colorectal cancer: The DEEPER trial (JACCRO CC-13).
Authors: Tsuji Akihito , Sunakawa Yu , Shiozawa Manabu , Kawai Takashi , Ota Hirofumi , Yasui Hisateru , Yabuno Taichi , Tei Mitsuyoshi , Kochi Mitsugu , Manaka Dai , Ohori Hisatsugu , Yamaguchi Tatsuro , Matsuura Masato , Katsuya Hiroo , Makiyama Akitaka , Ikenaga Masakazu , Takeuchi Masahiro , Ichikawa Wataru , Fujii Masashi 
Published: January 2025

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Background:
The DEEPER trial (NCT02515734), 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 therapy in terms of depth of response (DpR) as the primary endpoint in
RAS
wild-type metastatic colorectal cancer (mCRC), has demonstrated a significantly better DpR in the cet arm (ASCO 2021). Moreover, favorable progression-free survival (PFS) was reported in the cet arm for patients (pts) with
RAS
/
BRAF
wild-type and left-sided tumors (ESMO 2023). Due to the small number of overall survival (OS) events, it was decided to extend the observation period, and the final survival analysis was performed at the cutoff date of August 2024.
Methods:
Survival analysis was pre-planned in the per-protocol set (PPS), which consisted of pts evaluable for the DpR by an external review board. The clinical outcomes were evaluated according to clinical factors including primary tumor sidedness, liver metastasis status, and
BRAF
status using a log-rank test. All statistical tests were two-sided, and
P
values ≤ 0.05 were considered significant.
Results:
321 of 359 enrolled pts were defined as PPS (median age 65 years, 64% male, performance status [PS] 0/1: 91%/9%, left/right primary: 84%/16%). In
RAS
wild-type and left-sided tumors, median PFS and OS were 13.9 months vs. 12.1 months (HR 0.81, 95% CI 0.63-1.05) and 45.3 months vs. 41.9 months (HR 0.85, 95% CI 0.64-1.12) in the cet vs. bev arm, respectively.
BRAF
status was available in 234 (73%) of the 321 pts in the PPS. An exploratory analysis showed that PFS was significantly better in the cet arm compared to the bev arm (median 14.8 months vs. 11.9 months, HR 0.71, 95% CI 0.52-0.97) in 178 pts with
RAS
/
BRAF
wild-type and left-sided tumors. Additionally, OS was 50.2 months vs. 40.2 months (HR 0.74, 95% CI 0.53-1.05). Moreover, according to liver disease status, m-FOLFOXIRI plus cet was associated with longer PFS and OS in pts with
RAS
/
BRAF
wild-type and left-sided mCRC with extra-hepatic metastases (median 15.1 months vs. 11.4 months, HR 0.66, 95% CI 0.46-0.95 and 50.2 months vs. 38.6 months, HR 0.60, 95% CI 0.40-0.90), but not liver-limited disease (median 14.5 months vs. 15.5 months, HR 0.79, 95% CI 0.44-1.42 and 52.2 months vs. 49.9 months, HR 1.17, 95% CI 0.61-2.24).
Conclusions:
The final survival analysis of the DEEPER trial demonstrated favorable PFS and OS with m-FOLFOXIRI plus cet in pts with
RAS
/
BRAF
wild-type and left-sided mCRC. The m-FOLFOXIRI plus cet regimen may be a good option for initial therapy, offering longer survival times in pts with extra-hepatic metastases.
Clinical trial information: jRCTs061180022
.