The German phase III clinical trial FIRE-3 reports that first-line cetuximab plus FOLFIRI chemotherapy (folinic acid, fluorouracil, irinotecan) offers a roughly four-month survival advantage for patients with metastatic colorectal cancer, compared with bevacizumab plus FOLFIRI.
The targeted drugs cetuximab and bevacizumab, both in combination with chemotherapy, are approved and commonly used as initial therapy but, until this study, it has been unclear which approach is better for patients with non-mutated forms of the KRAS gene.
These findings suggest that first-line treatment with cetuximab in combination with FOLFIRI is superior, whereas bevacizumab could be reserved for second-line therapy.
“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,” said Volker Heinemann, MD, PhD, a professor of medical oncology at the University of Munich in Munich, Germany.
“We suspected that cetuximab would produce a better response, but we didn’t know this would translate into better survival.”
In the study, 592 patients with non-mutated (wild-type) KRAS metastatic colorectal cancer were randomly assigned to first-line therapy with FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab.
Overall response rate favored FOLFIRI plus cetuximab, but reached the level of significance only in assessable patients. These patients (n=526) were required to have at least one imaging procedure after baseline. The median time to disease progression (progression-free survival) was nearly identical in the two arms (10.0 vs. 10.3 months), but the overall survival was markedly longer in the cetuximab arm (28.7 months) compared to the bevacizumab arm (25.0 months).
While FOLFIRI is standard chemotherapy for patients with metastatic colorectal cancer in Germany, in the United States, patients more commonly receive FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin). Both chemotherapy regimens have been found to be very 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.
“Patients confronting advanced colorectal cancer and their doctors are striving to extend lives. In the FIRE-3 trial initial therapy with FOLFIRI and cetuximab helped achieve that goal,” said Richard M. Goldberg, MD, ASCO spokesperson and gastrointestinal cancers expert. “The study prescribed the initial chemotherapy and in both groups tumors eventually grew at a similar pace. More research is needed to explain the overall survival benefit observed in this study, given the lack of improvement in progression- free survival.”
Cetuximab targets the epidermal growth factor receptor (EGFR), blocking tumor growth. The agent is currently approved only for patients with no KRAS gene mutations in their tumours, which account for about 60 percent of all colorectal cancer cases. Prior studies have shown that mutations in KRAS undermine the activity of anti-EGFR treatments. Bevacizumab targets a protein called VEGF, which is involved in the growth of tumour blood vessels. It appears that KRAS mutation status does not affect responsiveness to bevacizumab. Researchers are also working on identifying molecular markers that predict response to bevacizumab vs. cetuximab.
This research was supported by Merck.
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