Comment
Steve Gschmeissner/Science Photo Library
Cetuximab or bevacizumab in metastatic colorectal cancer?
Published Online August 1, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70360-2 See Articles page 1065
1040
In The Lancet Oncology, Volker Heinemann and colleagues report the results of FIRE-3,1 a randomised phase 3 trial comparing cetuximab with bevacizumab, in combination with fluorouracil, folinic acid, and irinotecan (FOLFIRI), for the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer. The primary endpoint—the proportion of patients with an objective response—and the secondary endpoint of progression-free survival did not significantly differ between treatment groups. Despite these results, a statistically significant overall survival advantage was reported in favour of cetuximab (median duration 28·7 months [95% CI 24·0–36·6] vs 25·0 months [22·7–27·6]; HR 0·77 [95% CI 0·62–0·96]; p=0·017) and this was further increased in the subgroup of patients with tumours that were wild-type at all RAS loci (exon 2–4 KRAS and NRAS; 33·1 months vs 25·6 months; HR 0·70 [95% CI 0·53–0·92]; p=0·011). Cetuximab and bevacizumab are two monoclonal antibodies that target EGFR and VEGF, respectively.2 Although they have different mechanisms of action, both drugs are routinely used in combination with firstline chemotherapy in patients with metastatic colorectal cancer with KRAS wild-type tumours or tumours that are wild-type at all RAS loci.3,4 Some clinical equipoise exists when choosing between these two antibodies, and decisions are affected by the differences in the sideeffect profile—eg, the acneiform rash associated with cetuximab, which might affect patient compliance, and the increased risk of intestinal perforation and thrombosis associated with bevacizumab. Thus physician and patient preference rather than compelling outcome data can lead to the selection of one agent over the other. So, are the results of FIRE-3 sufficiently robust to change this paradigm and shift the balance in favour of cetuximab? As mentioned, the trial did not meet the primary endpoint of a difference in objective response; overall survival—although significantly longer with cetuximab—was a secondary endpoint, and in the absence of a difference in any of the other key outcome measures, the overall survival benefit with cetuximab is surprising. Also, the late divergence of the survival curves suggests an effect of post-progression treatments. In this respect, the proportion of all patients
assigned to bevacizumab who subsequently received an anti-EGFR agent at the time of analysis was relatively low (141 [48%] of 295 patients, of whom 79 [27%] received them as second-line treatment and 62 [21%] as third-line treatment) considering that study patients were selected on the basis of having KRAS exon 2 wildtype tumours. Furthermore, we are unaware of any a-priori evidence for a sustained effect of cetuximab beyond treatment cessation. The view that cetuximab and bevacizumab are interchangeable agents in the first-line setting of metastatic colorectal cancer is supported by the results of the CALGB/SWOG 80405 trial.5 The trial recruited 1137 patients, and similar survival outcomes were reported for patients with KRAS exon 2 wild-type tumours assigned to either cetuximab or bevacizumab in combination with oxaliplatin-containing or irinotecan-containing chemotherapy. Of note, on the basis of preliminary analyses of unaudited data, as many as 88% of patients are estimated to have received second-line treatment (Venook AP, University of California San Francisco, personal communication). Furthermore, the outcome of the cetuximab group did not seem to be negatively affected by the high number of patients (73%) who received an oxaliplatin chemotherapy backbone. Using tumour molecular characteristics to guide treatment decisions can help to refine the first-line treatment of patients with metastatic colorectal cancer and, clearly, only the 48–52% of patients with tumours that are wild-type at all RAS loci should receive cetuximab.3,6 Several mechanisms of resistance to cetuximab have now been identified, including the emergence of mutant RAS clones, mutations of EGFR, and amplification of MET, so continuous monitoring of patients through repeat biopsies or plasma DNA analysis could further enhance patient care.7,8 Unfortunately, a good biomarker for bevacizumab is not yet available, so all patients remain candidates for this drug.4 Another interesting biomarker is the BRAF mutation, which is present in about 8% of patients with metastatic disease and which confers a poor prognosis (median survival
Steve Gschmeissner/Science Photo Library
Cetuximab or bevacizumab in metastatic colorectal cancer?
Published Online August 1, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70360-2 See Articles page 1065
1040
In The Lancet Oncology, Volker Heinemann and colleagues report the results of FIRE-3,1 a randomised phase 3 trial comparing cetuximab with bevacizumab, in combination with fluorouracil, folinic acid, and irinotecan (FOLFIRI), for the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer. The primary endpoint—the proportion of patients with an objective response—and the secondary endpoint of progression-free survival did not significantly differ between treatment groups. Despite these results, a statistically significant overall survival advantage was reported in favour of cetuximab (median duration 28·7 months [95% CI 24·0–36·6] vs 25·0 months [22·7–27·6]; HR 0·77 [95% CI 0·62–0·96]; p=0·017) and this was further increased in the subgroup of patients with tumours that were wild-type at all RAS loci (exon 2–4 KRAS and NRAS; 33·1 months vs 25·6 months; HR 0·70 [95% CI 0·53–0·92]; p=0·011). Cetuximab and bevacizumab are two monoclonal antibodies that target EGFR and VEGF, respectively.2 Although they have different mechanisms of action, both drugs are routinely used in combination with firstline chemotherapy in patients with metastatic colorectal cancer with KRAS wild-type tumours or tumours that are wild-type at all RAS loci.3,4 Some clinical equipoise exists when choosing between these two antibodies, and decisions are affected by the differences in the sideeffect profile—eg, the acneiform rash associated with cetuximab, which might affect patient compliance, and the increased risk of intestinal perforation and thrombosis associated with bevacizumab. Thus physician and patient preference rather than compelling outcome data can lead to the selection of one agent over the other. So, are the results of FIRE-3 sufficiently robust to change this paradigm and shift the balance in favour of cetuximab? As mentioned, the trial did not meet the primary endpoint of a difference in objective response; overall survival—although significantly longer with cetuximab—was a secondary endpoint, and in the absence of a difference in any of the other key outcome measures, the overall survival benefit with cetuximab is surprising. Also, the late divergence of the survival curves suggests an effect of post-progression treatments. In this respect, the proportion of all patients
assigned to bevacizumab who subsequently received an anti-EGFR agent at the time of analysis was relatively low (141 [48%] of 295 patients, of whom 79 [27%] received them as second-line treatment and 62 [21%] as third-line treatment) considering that study patients were selected on the basis of having KRAS exon 2 wildtype tumours. Furthermore, we are unaware of any a-priori evidence for a sustained effect of cetuximab beyond treatment cessation. The view that cetuximab and bevacizumab are interchangeable agents in the first-line setting of metastatic colorectal cancer is supported by the results of the CALGB/SWOG 80405 trial.5 The trial recruited 1137 patients, and similar survival outcomes were reported for patients with KRAS exon 2 wild-type tumours assigned to either cetuximab or bevacizumab in combination with oxaliplatin-containing or irinotecan-containing chemotherapy. Of note, on the basis of preliminary analyses of unaudited data, as many as 88% of patients are estimated to have received second-line treatment (Venook AP, University of California San Francisco, personal communication). Furthermore, the outcome of the cetuximab group did not seem to be negatively affected by the high number of patients (73%) who received an oxaliplatin chemotherapy backbone. Using tumour molecular characteristics to guide treatment decisions can help to refine the first-line treatment of patients with metastatic colorectal cancer and, clearly, only the 48–52% of patients with tumours that are wild-type at all RAS loci should receive cetuximab.3,6 Several mechanisms of resistance to cetuximab have now been identified, including the emergence of mutant RAS clones, mutations of EGFR, and amplification of MET, so continuous monitoring of patients through repeat biopsies or plasma DNA analysis could further enhance patient care.7,8 Unfortunately, a good biomarker for bevacizumab is not yet available, so all patients remain candidates for this drug.4 Another interesting biomarker is the BRAF mutation, which is present in about 8% of patients with metastatic disease and which confers a poor prognosis (median survival
