The use of bevacizumab or cetuximab, in combination with either the FOLFOX (leucovorin/5-fluorouracil/ oxaliplatin) or FOLFIRI (leucovorin/5-fluoruracil/irinotecan) chemotherapy regimen, achieved similarly effective overall survival (OS) outcomes in a large-scale phase III, randomized, controlled clinical trial conducted among patients with metastatic colorectal cancer (CRC) and no KRAS mutations. Findings were reported last month by Alan P. Venook, MD, of the University of California, San Francisco, at the annual meeting of the American Society of Clinical Oncology (Abstract LBA3).
OS in the bevacizumab and chemotherapy group was 29.0 months, compared with 29.9 months in the cetuximab and chemotherapy group. This is “substantially longer” than the prevailing OS when the trial began in 2004. (Median OS at that time was around 21 months.) Progression-free survival (PFS) rates were also similar: 10.8 months for bevacizumab and 10.4 months for cetuximab.
In its original design, the study (CALGB/SWOG 80405) included 1,137 patients who were previously untreated. Patients were unselected for KRAS status, and a combination bevacizumab/cetuximab arm was included. The design was later amended to focus on patients without KRAS mutations, and only patients originally enrolled who were KRAS wild-type (codons 12 and 13) were included (n = 333), along with the post-amendment accrual (804 patients). The combination arm was discontinued.
All 1,137 patients were stratified to either FOLFOX or FOLFIRI based on physician preference; 73% of patients received FOLFOX and 27% received FOLFIRI. Patients were then randomly assigned to receive either bevacizumab (n = 559) or cetuximab (n = 578). Venook noted that 124 patients (10.9%) were rendered disease-free by surgery and the study treatment. Median OS in that group exceeded 5.5 years. “There is a subset of patients with metastatic CRC who will do exceedingly well and we need to take that message home with us,” he said.
A substantial amount of data from the trial is still pending. Venook said forthcoming analyses will include response rate, duration of therapy, specific surgery undergone by some patients, and details pertaining to therapies received after progression on the study regimens. One already-completed analysis found no major differences in quality of life. The skin rash commonly associated with cetuximab did not lead to a significant difference on the European Organisation for Research and Treatment of Cancer Global Quality of Life Measure.
Commenting on the findings, Josep Tabernero, MD, PhD, of Vall d’Hebron University Hospital and Institute of Oncology, Spain, said the forthcoming analyses should help identify those patients who might benefit most from these therapies. He noted that codons 12 and 13 account for approximately 40% of patients with metastatic CRC, but adding in various other genetic markers, as has been recently suggested, would be more exclusive and bring the population for a trial such as the present study down to approximately 45% of patients. With expanded RAS definitions, he suggested, the 1,137 patients in this trial would likely drop to approximately 950 patients, and differences between the groups could emerge.
Tabernero also noted that conflicting data in the past has led the National Comprehensive Cancer Network (NCCN) and others to question the use of cetuximab with chemotherapy; however “the data presented with FOLFOX/cetuximab may make the NCCN reconsider its position in the metastatic CRC guidelines.” He said the median survival of patients with metastatic CRC achieved in the study has set “a new benchmark of around 30 months.”
“There may be some temptation to top-line this as a negative trial because the two arms are the same,” commented ASCO President Clifford A. Hudis, MD, of Memorial Sloan Kettering Cancer Center, New York. “But the really important thing is that this sets an entirely new high standard and a new high bar for clinical trials in advanced CRC.”