A multicenter, randomized phase 2 trial, DEEPER, has revealed that the combination of modified FOLFOXIRI (m-FOLFOXIRI) plus cetuximab demonstrates a superior depth of response (DpR) compared to m-FOLFOXIRI plus bevacizumab as a first-line treatment for patients with unresectable RAS wild-type metastatic colorectal cancer (mCRC). The study, published in Nature Communications, highlights the potential of cetuximab-based regimens in achieving greater tumor shrinkage in this patient population.
The DEEPER trial enrolled patients with histologically confirmed RAS wild-type mCRC and randomly assigned them to receive either m-FOLFOXIRI plus cetuximab or m-FOLFOXIRI plus bevacizumab. The primary endpoint, DpR, was defined as the percentage reduction in the sum of the longest diameters of target lesions from baseline to nadir. Secondary endpoints included overall response rate (ORR), early tumor shrinkage (ETS), progression-free survival (PFS), and overall survival (OS).
The results indicated a statistically significant difference in DpR between the two arms, favoring the cetuximab combination. Further post-hoc analysis revealed that in patients with both RAS and BRAF wild-type tumors and left-sided primary tumors, the cetuximab arm showed improved DpR, PFS, and OS compared to the bevacizumab arm. These findings suggest a potential benefit of cetuximab in a specific subgroup of mCRC patients.
The study involved a 2-week course of treatment, up to 12 cycles, with cetuximab administered weekly (initial dose 400 mg/m², subsequent doses 250 mg/m²), irinotecan (150 mg/m²), oxaliplatin (85 mg/m²), levofolinate (200 mg/m²), and 5-FU (2400 mg/m²). The bevacizumab arm received a similar regimen with bevacizumab (5 mg/kg) replacing cetuximab. The primary endpoint was assessed using a t-test with Welch’s adjusted degree of freedom.
Implications for Clinical Practice
The DEEPER trial's findings offer valuable insights into optimizing first-line treatment strategies for mCRC. The improved DpR with m-FOLFOXIRI plus cetuximab, particularly in patients with RAS/BRAF wild-type tumors and left-sided primary tumors, suggests that this combination may be a more effective option for achieving significant tumor regression. These results could influence treatment decisions and patient stratification in clinical practice, potentially leading to improved outcomes for select mCRC patients.
Study Limitations
It is important to note that the DEEPER trial was a phase 2 study with an open-label design, which may introduce bias. Additionally, the post-hoc subgroup analysis, while informative, requires validation in larger, prospective studies. The study also allowed for irinotecan dose reduction based on UGT1A1 genotype, which could have influenced the results.
