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Frontline cetuximab plus FOLFIRI chemotherapy improved overall survival by 3.7 months versus bevacizumab plus FOLFIRI in patients with KRAS wild-type metastatic colorectal cancer.
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 wild-type mCRC.
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 = .547).
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 = .017).
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.”
Regarding the contribution of future lines of treatment to the OS improvement, Heinemann said, “Approximately 60% of patients received second and further line treatments, 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.”
With side effects in FIRE-3, Heinemann said, “Toxicity profiles were as expected and manageable for both combinations.”
Regarding the next step for his research, Heinemann said, “We probably need to go one step further to define those patients who would specifically benefit from anti-EGFR as compared to an antiangeogenic treatment.” In this regard, Heinemann and his colleagues are conducting an analysis to identify biomarkers to predict response to cetuximab or bevacizumab.
Of note, Goldberg said that “In the United States it is more common to see FOLFOX in the first line [in mCRC], but there are [physicians in] both camps—some that preferentially start with FOLFOX and some that preferentially start with FOLFIRI.” He added that there is an ongoing study comparing cetuxmab/FOLFOX with bevacizumab/FOLFOX.
Cetuximab is marketed by Bristol-Myers Squibb and Eli Lilly and Company in North America, and by Merck KGaA in the rest of the world. Bevacizumab is marketed by Roche. The FIRE-3 research was supported by Merck KGaA.
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. 2013;(suppl; abstr LBA3506).