Post-Hoc Analysis of the FIRE-3 Trial: Second-Line Treatment Choices Are Based on Induction Therapy
Although cetuximab and bevacizumab have each independently demonstrated improvement in clinical outcomes in patients with metastatic colorectal cancer (mCRC) when added to first-line chemotherapy regimens, their comparative efficacies in combination with the FOLFIRI (fluorouracil, folinic acid, and irinotecan) regimen is unknown. Modest and colleagues presented the primary results of the FIRE-3 study, an open-label, randomized, phase 3 clinical trial (Modest et al. ESMO 2014: Abstract 508PD).
The FIRE-3 trial compared the use of first-line therapy with bevacizumab plus FOLFIRI versus cetuximab plus FOLFIRI in 592 patients with KRAS wild-type mCRC. The results showed no difference in overall response rate or in progression-free survival (PFS); however, median overall survival (OS) was significantly prolonged for patients receiving cetuximab plus FOLFIRI compared with bevacizumab plus FOLFIRI (28.7 vs 25.0 months; hazard ratio [HR], 0.77; P = .017).
This post-hoc analysis of the FIRE-3 trial sought to investigate the choice and duration of second-line therapies according to first-line efficacy and OS, based on the type of second-line therapy received. The study protocol recommendations for the second-line therapy were (1) FOLFOX plus bevacizumab for patients who received first-line therapy with cetuximab plus FOLFIRI, and (2) irinotecan plus cetuximab for patients who received first-line therapy with bevacizumab plus FOLFIRI, based on which second-line therapy was administered to 78.5% of 260 patients and 76.4% of 250 patients, respectively.
Second-line PFS (6.5 vs 4.7 months; HR, 0.68; P = .0006) and OS (16.3 vs 13.2 months; HR, 0.70; P = .0021) were longer in patients who received first-line cetuximab compared with those who received first-line bevacizumab therapy. Duration of treatment with second-line therapy was longer for patients who received first-line cetuximab therapy compared with patients who received bevacizumab first-line therapy (4.6 vs 3.2 months; P = .007).
These findings suggest that the choice of first-line therapy influences the treatment outcome compared with the choice of second (or later) lines of therapy. Modest and colleagues recommended the first-line use of cetuximab followed by bevacizumab in the second-line rather than the reverse sequence for better overall outcomes.