Final Analysis of the DEEPER Study (JACCRO CC-13): m-FOLFOXIRI + Cetuximab Versus Bevacizumab in Left-sided RAS wild-type Metastatic Colorectal Cancer

Metastatic colorectal cancer (mCRC) presents several therapeutic options, but uncertainties remain regarding the clinical benefit of different therapeutic regimens in the era of triple therapies, especially for left-sided wild-type (WT) RAS tumors. These tumors have been shown to be more responsive to EGFR inhibitors due to specific molecular characteristics, such as gene expression, mutation profile, and chromosomal instability.

At the ASCO® Gastrointestinal (GI) Cancers Symposium 2025, the final results of the DEEPER study were presented, which evaluated the efficacy of m-FOLFOXIRI combined with cetuximab (cet) as initial therapy for these patients, comparing it with the use of bevacizumab (bev).

The DEEPER (NCT02515734) study was designed to evaluate depth of response (DpR) as the primary endpoint in patients with wild-type RAS mCRC treated with m-FOLFOXIRI combined with cet or bev. The final analysis included 321 of the 359 enrolled patients, who were defined as the per protocol set (PPS). Depth of response was assessed by an external review, while clinical outcomes such as progression-free survival (PFS) and overall survival (OS) were analysed by clinical factors including laterality of the primary tumour, liver metastasis status, and BRAF status. The statistical tests were applied in a two-tailed manner, and values of P ≤ 0.05 were considered significant.

The final analysis revealed significant differences in clinical outcomes for patients with wild-type and left-sided RAS/BRAF tumors . The median PFS was 14.8 months for the cetuximab group versus 11.9 months for the bevacizumab group (HR 0.71; 95% CI 0.52-0.97). OS showed a trend of benefit at 50.2 months in the cet group versus 40.2 months in the bev group (HR 0.74; 95% CI 0.53-1.05). When patients with extrahepatic metastases were analyzed, the cetuximab-treated group had significantly higher PFS (15.1 months versus 11.4 months; HR 0.66; 95% CI 0.46-0.95) and higher OS (50.2 months versus 38.6 months; HR 0.60; 95% CI 0.40-0.90). However, this benefit was not observed in patients with metastases limited to the liver.

Data from the DEEPER study reinforce that the m-FOLFOXIRI regimen combined with cetuximab offers an effective therapeutic option for patients with wild-type mCRC RAS/BRAF and left-sided tumors, especially in the presence of extrahepatic metastases. The combination was associated with a greater depth of response and longer survival, standing out as a promising alternative for the initial treatment of these patients.

Thus, the results emphasize the importance of personalized therapy selection based on molecular and clinical characteristics, contributing to significant advances in the management of metastatic colorectal cancer.