Frontline cetuximab plus FOLFIRI improved overall survival by 3.7 months versus bevacizumab plus FOLFIRI in patients with KRAS wildtype metastatic colorectal cancer.
Volker Heinemann, MD, PhD
Frontline cetuximab plus FOLFIRI (folinic acid, fluorouracil, and irinotecan) improved overall survival (OS) by 3.7 months versus bevacizumab plus FOLFIRI in patients withKRASwildtype metastatic colorectal cancer (mCRC), according to results from the German phase III FIRE-3 study. However, the trial, presented at ASCO 2013, found no advantage for the primary endpoint of objective response rate (ORR) and a secondary endpoint of progression-free survival (PFS).
“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 colorectal cancer expert, as well as physician-in-chief at The Ohio State University Comprehensive Cancer CenterArthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus.
KRASwild-type tumors 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 advancedKRASwild-type colorectal cancer. FIRE-3 was the first head-to-head comparison of first-line cetuximab/FOLFIRI versus bevacizumab/FOLFIRI inKRASwild-type mCRC.
FIRE-3 initially enrolled patients with mCRC regardless ofKRASmutational status; however, becauseKRASmutations can negate the effect of EGFR agents such as cetuximab, the study was subsequently amended to include only patients withKRASwild-type tumors. Results were based on data from the 592 patients who wereKRASwild-type in the 735-patient intent-to-treat (ITT) population. The ITT population was defined as 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% 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 cetuximab and bevacizumab (62% vs 58%;P= .183). However, an analysis of patients considered “assessable for efficacy” (n = 526) found a significant difference in ORR. “If we look at the assessable patientsthat 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 and Comprehensive Cancer Center, Ludwig- Maximilian, in Germany.
There was no significant difference in PFS between cetuximab and bevacizumab: 10.0 versus 10.3 months, respectively (hazard ratio [HR] = 1.06;P= .547). 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= .017). Toxicity profiles were as expected and manageable for both combinations.
Approximately 60% of patients received second- and furtherline treatments, Heinemann noted. “We have an approximately 40% crossover between the two arms from either cetuximab to bevacizumab or bevacizumab to cetuximab, and we are presently exploring this question to see if further-line treatment has an impact on outcome.”
Given the inconsistent results, Goldberg believes additional investigation is necessary. “I would challenge the investigators to go back and study their data and study the second- and thirdand fourth-line treatments that their patients had and help to explain these findings, which do seem a bit anomalous.”
Heinemann V, von Weikersthal LF, Decker T, et al. Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS-wildtype metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3).J Clin Oncol