Volker Heinemann, MD, PhD
Frontline cetuximab (Erbitux) plus FOLFIRI chemotherapy (folinic acid, fluorouracil, and irinotecan) improved overall survival (OS) by 3.7 months versus bevacizumab (Avastin) plus FOLFIRI in patients with KRAS
wild-type metastatic colorectal cancer (mCRC), according to results from the German phase III FIRE-3 study. However, no advantage was observed with either the primary endpoint of objective response rate (ORR) or the secondary endpoint of progression-free survival (PFS), and the drugs remain equally valid options in the first-line setting. The results were presented at a press conference at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO).
“There is no clear winner in my perspective from this [trial] and either [regimen] would be reasonable to consider for patients [with mCRC],” said Richard M. Goldberg, MD, ASCO spokesperson and gynecologic cancers expert, as well as physician-in-chief at The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Institute.
Patients with KRAS
wild-type tumors (ie, those without KRAS
mutations) comprise roughly 60% of all colorectal cancer cases. Both the EGFR-inhibitor cetuximab and the VEGF-inhibitor bevacizumab are FDA-approved in combination with chemotherapy for the first-line treatment of patients with advanced KRAS
wild-type colorectal cancer. FIRE-3 was the first head-to-head comparison of first-line cetuximab/FOLFIRI versus bevacizumab/FOLFIRI in KRAS
FIRE-3 initially enrolled patients with mCRC regardless of their KRAS
mutational status; however, because KRAS
mutations can negate the effect of EGFR agents like cetuximab, the study was subsequently amended to include only patients with KRAS
wild-type tumors. The results presented at ASCO were based on data from the 592 patients who were KRAS
wild-type in the 735-patient intent-to-treat (ITT) population. The ITT group comprised patients who completed a minimum of one application of therapy.
Patients were randomized to first-line therapy with FOLFIRI every 2 weeks plus cetuximab (400 mg/m² day 1, followed by 250 mg/m² weekly; n = 297) or bevacizumab (5 mg/kg every 2 weeks; n = 295). The median patient age was 64 years, 98% of patients had an ECOG performance status of 0-1, and 66% of the patients were male. Patients who received adjuvant chemotherapy were still eligible for the study if the treatment ended more than 6 months before enrollment.
There was no significant difference in the ORR primary endpoint between the cetuximab and bevacizumab arms (62% vs 58%; P =
.183). However, there was a significant ORR difference among patients considered “assessable for efficacy” (n = 526). “If we look at the assessable patients—that is, patients who received at least three cycles of treatment and had at least one imaging procedure after baseline—we find a [statistically significant] ORR difference in favor of the cetuximab arm [72.2% vs 63.1%; P
= .017],” said lead author Volker Heinemann, MD, PhD, professor of Medical Oncology at the University of Munich in Germany.
There was no significant difference in PFS between the cetuximab and bevacizumab arms: 10.0 versus 10.3 months, respectively (hazard ratio [HR] = 1.06; P
Despite the comparable ORR and PFS data, a significant improvement in OS was observed with the cetuximab group (28.7 vs 25.0 months; HR = 0.77; 95% CI, 0.62-0.96; P
Given the inconsistent results, Goldberg believes additional investigation is necessary to determine the extent to which each post–first-line treatment factored into the OS benefit. “I would challenge the investigators…to go back and study their data and study the second and third and fourth line treatments that their patients had and help to explain these findings, which do seem a bit anomalous.”