David H. Ilson, MD, PhD

Overall survival was superior with cetuximab versus bevacizumab in first-line chemotherapy, but survival curves diverged only after 24 months.

Overall survival (OS) has improved for patients with metastatic colorectal cancer (CRC) since the advent of more-effective systemic chemotherapy and agents targeting the vascular endothelial growth factor receptor (VEGFr) and epidermal growth factor receptor (EGFr) pathways. Although the EGFr agents cetuximab and panitumumab benefit only RAS wild-type tumors, similar benefits are seen for bevacizumab regardless of RAS status. However, the optimal sequencing of these agents in the treatment of RAS wild-type metastatic CRC has not been clearly established.

European investigators now report results of the phase III, randomized, open-label FIRE-3 trial, comparing first-line treatment of exon 2 KRAS wild-type CRC with FOLFIRI (irinotecan, leucovorin, and 5-fluorouacil) combined with either bevacizumab or cetuximab. Of 592 patients with metastatic disease, the majority had two or more metastatic sites (55%–58%) and had undergone prior surgery (84%–85%); a minority had received prior adjuvant chemotherapy (19%–22%).

Response rate (RR; the primary endpoint) was similar with bevacizumab or cetuximab (58% and 62%, respectively) as was progression-free survival (PFS; 10.3 and 10.0 months). OS favored cetuximab over bevacizumab (28.7 vs. 25.0 months; P=0.017), although survival curves diverged only after 24 months. When patients with any RAS mutation were excluded, between-group RR and PFS continued to be similar, but the late divergent OS improvement further favored cetuximab (33.1 vs. 25.6 months; P=0.011). No new safety signals were reported.

Citation(s):

Heinemann V et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): A randomised, open-label, phase 3 trial. Lancet Oncol 2014 Sep; 15:1065.