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First-line cetuximab, bevacizumab show similar outcomes in colorectal cancer
The addition of cetuximab or bevacizumab to a first-line chemotherapy regimen demonstrated similar OS, PFS and response rates in patients with KRAS wild-type untreated advanced or metastatic colorectal cancer, according to results of a phase 3 clinical trial.
Standard chemotherapy regimens for KRAS wild-type metastatic colorectal cancer include leucovorin and fluorouracil with oxaliplatin (mFOLFOX6) or irinotecan (FOLFIRI). Data have suggested that the addition of cetuximab (Erbitux, Eli Lilly), an EGFR inhibitor, or bevacizumab (Avastin, Genentech), a humanized murine antihuman VEGF monoclonal antibody, to either chemotherapy regimen may enhance activity.
“This is technically a negative study, but the information we gain is from analysis of the biology of cancer,” Alan P. Venook, MD, Shorenstein associate director for program development at Helen Diller Family Comprehensive Cancer Center at University of California, San Francisco, told HemOnc Today. “The fundamental question we wanted to address was which of these therapies is better and our data suggested, over the whole population, that there is no difference.”
Treatment decision-making will be based on costs and toxicities between the two drugs because efficacy was similar between the agents, Venook added.
The analysis included 1,137 patients (median age, 59.1 years; range, 20.8-89.5) from centers in the United States and Canada with previously untreated KRAS wild-type metastatic colorectal cancer. Researchers randomly assigned patients to receive cetuximab (n = 578) or bevacizumab (n = 559) along with the chemotherapy regimen chosen by the patient and the doctors prior to study enrollment.
Prior to cytotoxic chemotherapy, patients received 400 mg/m2 IV cetuximab on day 1 followed by then 250 mg/m2 every week, or 5 mg/m2 bevacizumab in week 1. Subsequent infusions occurred biweekly, assuming no adverse events occurred.
OS served as the primary endpoint. Response rate and PFS until progression or death served as secondary endpoints.
Over follow-up, 938 patients (82%) experienced disease progression and 874 patients (76.9%) died. The median follow-up for survivors (n = 263) was 47.4 months (range, 0-110.7).
Researchers observed no differences between OS and PFS in the primary analysis cohort.
The median OS was 30 months for patients in the cetuximab–chemotherapy group and 29 months among patients in the bevacizumab-chemotherapy group (stratified HR = 0.88; 95% CI, 0.77-1.01).
Researchers reported median PFS of 10.5 months in the cetuximab group and 10.6 months in the bevacizumab group (stratified HR = 0.95; 95% CI, 0.84-1.08).
A 4.4% difference in response rate occurred between patients treated with cetuximab and bevacizumab (59.6% vs. 55.2%; difference, 4.4; 95% CI, 1-9), but this was not statistically significant.
One-hundred four patients remained alive without disease after chemotherapy and surgery. For these patients, median OS was 62.2 months for bevacizumab-treated patients and 64.7 months for cetuximab-treated patients. On the last survey, 58 patients were alive and disease free.
Ninety-six percent of the entire cohort experienced at least one adverse event, of which 53% were grade 3 or higher and 14% were grade 4 or higher. Eight deaths in the bevacizumab group and seven in the cetuximab group may have been related to protocol treatment, the researchers noted.
Subgroup analyses conducted to evaluate RAS, sex, race and chemotherapy subsets indicated OS (HR = 0.88; 95% CI, 0.72-1.08) and PFS (HR = 1.03; 95% CI, 0.86-1.24) in the expanded RAS cohort appeared similar to results of the full cohort. In the RAS wild-type subgroup, researchers observed a trend toward a difference in OS with mFOLFOX6 in favor of cetuximab (HR = 0.83; 95% CI, 0.71-0.98), but not with FOLFIRI.
Venook said future subset analyses are pending.
“Now that we have established the main results, we will quickly follow with other analyses looking at molecular features,” he said. “The subset analyses will help us distinguish what patients need which treatment to give us some idea of how to individualize therapy rather than treating patients globally, which is what we have been doing. This goes well beyond RAS.”
Researchers lacked enough tissue on all patients for RAS analysis, Venook said, which may have created a bias interpretation of the subset analysis.
“Many didn’t have enough tissue to determine what their molecular features were. In fact, we were left with a potentially biased subset analysis,” Venook said. “Subset analyses are really valuable because they generate hypotheses, and this is something we will address in the future.”
The results reported by Venook and colleagues indicated either cetuximab or bevacizumab may be reasonable for the treatment of metastatic colorectal cancer. However, the effect of subsequent therapy or whether EGFR inhibitors can be used for RAS wild-type right-sided colorectal cancer as second-line treatment remains unanswered, Christopher H. Lieu, MD, and Wells A. Messersmith, MD, both from the University of Colorado, wrote in a related editorial.
“The initial OS results are indeed clinically important, although additional analyses such as right vs. left primary tumor location, consensus molecular subtypes and other factors likely will influence the treatment management for this patient population,” Lieu and Messersmith wrote. “Even though there were no significant differences in outcomes between the EGFR and VEGF inhibition groups in this initial report, it is clear that these therapies are not the same with regard to other clinical and biological variables among patients with advanced or metastatic colorectal cancer.” – by Melinda Stevens
For more information:
Alan Venook, MD, can be reached at University of California, San Francisco, 1450 Third St., HD 376, San Francisco, CA 94158; email: alan.venook@ucsf.edu.
Disclosure: Venook reports grants from Bristol-Myers Squibb, Genentech/Roche and University of California, San Francisco. Please see the full study for a list of all other researchers’ relevant financial disclosures. Lieu reports consultant roles with Merck and Merrimack Pharmaceuticals. Messersmith reports a co-chair position with the Southwest Oncology Group subcommittee on colorectal cancer and grant support from Genentech/Roche and Pfizer.