Updated Results of the FIRE-3 Trial in the Final RAS Status Evaluable Population
Although both cetuximab and bevacizumab have separately demonstrated improvements in clinical outcomes in patients with metastatic colorectal cancer (mCRC) when added to first-line chemotherapy regimens, their comparative efficacies in combination with fluorouracil, folinic acid, and irinotecan (FOLFIRI) are unknown. The open-label, randomized, phase 3 FIRE-3 (AIO KRK-0306) trial was initiated to compare first-line bevacizumab plus FOLFIRI with cetuximab plus FOLFIRI in 592 patients with wild-type KRAS exon 2 mCRC. Results from the primary analysis of the intent-to-treat (ITT) population showed that the median overall survival (OS) was significantly prolonged for patients who received cetuximab plus FOLFIRI compared with bevacizumab plus FOLFIRI (28.7 vs 25 months; hazard ratio [HR], 0.77; P = .017); however, the overall response rate (ORR) and progression-free survival (PFS) were similar (Stintzing S, et al. FIRE-3 [AIO KRK-0306]. ESMO 2014: Abstract LBA11).
An expanded analysis of RAS status was conducted in exons 2, 3, and 4 (codons 12, 13, 59, 61, 117, and 146) using a pyrosequencing technique (n = 475), and new RAS mutations were detected in 15.8% of patients. Consistent with the earlier analysis, the analysis of the final expanded population of patients with RAS mutations (n = 400) also showed similar ORR and PFS; however, the OS benefit with FOLFIRI plus cetuximab therapy was more pronounced (33.1 vs 25 months; HR, 0.697; P = .0059).
Based on an independent radiologic review and correlation with clinical outcomes, FOLFIRI plus cetuximab resulted in a significantly higher ORR in the ITT population (72% vs 63.1%; P = .017) and the final RAS wild-type population (72% vs 56.1%; P = .0005). The rate of early tumor shrinkage, which was defined as a reduction in tumor diameter of >20% at first tumor assessment after baseline, was significantly higher with cetuximab plus FOLFIRI (68.2% vs 49.1%; P = .0013) in the final RAS wild-type group and in the KRAS exon 2 group. This early tumor shrinkage population was also associated with significantly better survival in both of the study arms. The depth of response, which was defined as the maximal tumor shrinkage observed, was also significantly greater in the final RAS wild-type group for the cohort receiving FOLFIRI plus cetuximab (48.9% vs 32.3%; P <.0001), which correlated with postprogression survival (P <.0001).
Stintzing and colleagues concluded that the findings of the independent radiologic review demonstrated a significantly higher ORR, a greater rate of early tumor shrinkage, and an increased depth of response with FOLFIRI plus cetuximab compared with FOLFIRI plus bevacizumab, which they proposed might partly explain the observed OS advantage of this regimen.