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

17 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 .