Modest DP, et al. - In a 1:1 randomized, controlled phase 3 trial, researchers assessed the noninferiority of initial treatment with a fluoropyrimidine plus bevacizumab, then adding irinotecan at first progression (arm A) vs upfront use of fluoropyrimidine plus irinotecan plus bevacizumab (arm B). Findings revealed that noninferiority of sequential escalation therapy vs initial combination chemotherapy couldn't be shown for time to failure of the strategy (TFS). Patients treated with upfront combination therapy had clearly superior results in RAS/BRAF wild-type tumors, so RAS status might be crucial in guiding therapy. On the other hand, sequential escalation chemotherapy appears to deliver similar outcomes in patients with RAS mutant tumors.

Methods

• TFS was the primary efficacy end point.
• Given a 90% CI, a power of 70%, and a one-sided α of .05, the margin for noninferiority was set at 0.8.
• An analysis of symptomatic toxicities during TFS would characterize superior strategy in the case of exhibited noninferiority of TFS.
• The effect of molecular subgroups on efficacy parameters was the included secondary end point.

Results

• Four hundred twenty-one randomly assigned patients (arm A: n = 212; arm B: n = 209) formed the full analysis set.
• It was noted that median age was 71 and 69 years, respectively.
• Noninferiority of TFS was not seen (hazard ratio [HR], 0.86; 90% CI, 0.73 to 1.02) in this analysis.
• Patients with RAS/BRAF wild-type tumors benefitted from combination chemotherapy (HR, 0.61; 90% CI, 0.46 to 0.82; P=.005); patients with RAS mutant tumors (HR, 1.09; 90% CI, 0.81 to 1.46; P=.58) did not (Cox model for interaction of study arm and RAS status: P=.03).
• For overall survival, similar outcomes were obtained.