Post-Hoc Analysis of the FIRE-3 Trial: Second-Line Treatment Choices Are Based on Induction Therapy

Conference Correspondent - ESMO 2014 - Gastrointestinal and Head & Neck Cancer


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.