ASCO 2013: Cetuximab Offers Survival Advantage over Bevacizumab When Combined with FOLFIRI for First-line Treatment of Advanced Colorectal Cancer
First-line cetuximab (Erbitux) plus FOLFIRI chemotherapy (leucovorin, fluorouracil [5-FU], irinotecan) offered a roughly 4-month survival advantage over bevacizumab (Avastin) plus FOLFIRI for patients with KRAS wild-type metastatic colorectal cancer in the German phase III clinical trial FIRE-3.
A key finding of the trial was that median survival was 3.7 months longer in the cetuximab arm than in the bevacizumab arm. “This was accompanied by a hazard ratio of 0.77, which means that patients in the cetuximab arm had about a 22% lower risk of death during the observation period,” the study’s lead author, Volker Heinemann, MD, PhD, Professor of Medical Oncology at the University of Munich in Munich, Germany, reported at the ASCO 2013 Annual Meeting (Abstract LBA3506).
“This degree of survival benefit was equivalent to the survival benefit seen in clinical trials that led to the approval of cetuximab and bevacizumab in this setting,” Dr. Heinemann said. “We suspected that cetuximab would produce a better response, but we didn’t know this would translate into better survival.” He noted that this is the “first head-to-head comparison” of cetuximab vs bevacizumab in KRAS wild-type metastatic colorectal cancer patients.
Confined to KRAS Wild-type Tumors
Patients in the study were randomly assigned to first-line therapy with FOLFIRI every 2 weeks plus cetuximab at 400 mg/m2 on day 1, followed by 250 mg/m2 weekly (arm A) or FOLFIR plus bevacizumab at 5 mg/kg every 2 weeks (arm B). Recruitment initially was independent of KRAS status, but the protocol was amended to confine inclusion to KRAS wild-type tumors.
Among 592 patients in the intent-to-treat population identified with KRAS wild-type tumors, 297 patients were randomly assigned to arm A and 295 to arm B. The median age of the patients was 64 to 65 years. Median duration of treatment was 4.7 months in arm A vs 5.3 months in arm B.
The objective response rate, the primary endpoint of the study, favored FOLFIRI plus cetuximab but reached the level of significance only in the 526 assessable patients (72.7% in arm A vs 63.1% in arm B). These patients were required to have at least one imaging procedure after baseline.
Longer Overall Survival
Median progression-free survival was nearly identical in the two arms (10.0 vs 10.3 months), but the overall survival was longer in the cetuximab arm (28.7 months) compared to the bevacizumab arm (25.0 months). “Toxicity profiles were as expected and manageable for both combinations,” Dr. Heinemann said.
“The study prescribed the initial chemotherapy, and in both groups tumors eventually grew at a similar pace,” commented Richard M. Goldberg, MD, Physician-in-Chief of Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus, Ohio. “More research is needed to explain the overall survival benefit observed in this study, given the lack of improvement in progression-free survival.”
Drugs and Regimens
Cetuximab and bevacizumab, both in combination with chemotherapy, are approved and commonly used as initial therapy for colorectal cancer. Cetuximab targets the epidermal growth factor receptor (EGFR) and is currently approved only for patients with no KRAS gene mutations (KRAS wild-type), which account for about 60% of all colorectal cancer cases. Prior studies have shown that mutations in KRAS undermine the activity of anti-EGFR treatments.
Bevacizumab targets vascular endothelial growth factor (VEGF), which is involved in angiogenesis. It appears that KRAS mutation status does not affect responsiveness to bevacizumab. Researchers are working on identifying molecular markers that predict response to bevacizumab vs cetuximab.
FOLFIRI is standard chemotherapy for patients with metastatic colorectal cancer in Germany, but patients in the United States more commonly receive FOLFOX (leucovorin, 5-FU, oxaliplatin). Both chemotherapy regimens have been found to be effective in combination with cetuximab and bevacizumab in prior studies. A head-to-head comparison study of bevacizumab plus FOLFOX vs cetuximab plus FOLFOX is ongoing.
This research was supported by Merck. Dr. Heinemann reported honoraria from Merck and Roche, research funding from Merck, and other remuneration from Merck and Roche.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
