BY PETER GOODWIN
CHICAGO -- Patients with metastatic KRAS wild-type colorectal cancer lived longer if cetuximab was added to their chemotherapy rather than bevacizumab, according to the results of a Phase III study from Germany reported here at the American Society of Clinical Oncology Annual Meeting (Abstract LBA3506).
Volker Heinemann, MD, Professor of Medical Oncology and Director of the Comprehensive Cancer Center at Klinikum der Universität in Munich, presented the data from the study, KRK-0306 (FIRE-3), showing that patients receiving cetuximab lived 3.7 months longer.
He emphasized that recruitment was restricted to patients with the non-mutated form of the KRAS gene (60 percent of all colorectal cancer cases), based on the discovery in 2008 that mutant KRAS disables cetuximab in colorectal cancer. Bevacizumab, on the other hand, is unaffected by KRAS status and is an effective and licensed treatment for all patients.
“It became clear that cetuximab -- as an anti-EGFR [epidermal growth factor receptor] agent -- is active only in patients with KRAS wild-type tumors. For this reason we could include only such patients in the trial, he said in an interview. “Cetuximab targets the EGF receptor, which is involved in cell growth, while bevacizumab targets vascular endothelial growth factor – i.e., it targets blood supply to the tumor.”
The FIRE-3 study investigated whether cetuximab could be superior to its sister targeted agent in the subgroup of patients who are sensitive to it; the updated results from FIRE-3 provide the first Phase III evidence that it is.
A total of 592 patients with KRAS wild-type metastatic colorectal cancer (median age of 64) were randomized to receive either cetuximab or bevacizumab to supplement their first-line FOLFIRI chemotherapy (leucovorin, fluorouracil, and irinotecan). Median overall survival times were 25 months in patients receiving FOLFIRI plus bevacizumab vs. 28.7 months in patients receiving FOLFIRI plus cetuximab, with a hazard ratio of 0.77, which is equivalent to a 23 percent reduction in the risk of death and 3.7 months extension of life.
In the intention-to-treat (ITT) analysis, progression-free survival was similar between the two arms: 10.3 months with bevacizumab versus 10.0 months among patients receiving cetuximab. Objective response rates and complete remission rates were also similar: 62 and 4.4 percent, respectively, with cetuximab vs. 58 and 1.4 percent with bevacizumab.
But when patients who did not actually receive their allocated treatment were excluded, a statistically significant superiority in response rate emerged in favor of cetuximab: 72.2 vs. 63.1 per cent, p = 0.17, which Heinemann said could be driving the observed extension of overall survival in patients on cetuximab in the ITT analysis: “The finding was that with regard to the primary endpoint of the objective response rate, there was no difference in the ITT population, while in patients assessable for efficacy there was a significant difference between the cetuximab and bevacizumab arms.”
To qualify as “assessable,” patients needed to have received enough of the allocated treatment and have been assessed by computed tomography. “If you look at the efficacy of a treatment with regard to response rate you want to make sure that patients also actually received your agent and didn’t drop out before,” Heinemann explained. “For that reason we decided to look at patients who had received at least three cycles of treatment and also had one CT imaging, which could demonstrate for us the efficacy of that agent.”
Toxicities for either of the targeted agents was “as expected, and manageable,” he said, with both arms equivalent overall. The two agents gave different toxicities, but this was not considered to change the overall iatrogenic morbidity rates.
Heinemann noted that the FIRE-3 findings are consistent with earlier smaller Phase II studies such as the PEAK trial, which provided preliminary indications of a survival benefit among patients with KRAS wild-type cancers who had an anti-EGFR agent added to their regimen in comparison with those having bevacizumab added. “Now, with the data from a large randomized Phase III trial, this points to a clear way of clarifying your choice of targeted therapy,” he said.
No ‘Home Run’
Another expert in this area, Richard M. Goldberg, MD, Physician-in-Chief at Ohio State University Comprehensive Cancer Center, stressed in an interview that the results should not be viewed as a “home run” – “The huge progress in extending life recently for patients with metastatic colorectal cancer has been achieved by a number of different important developments in treatment, not just one ‘inning.’”
He was also cautious because the primary goal of the FIRE-3 study (in the ITT analysis) -- objective response rate -- had not been met. “There also was no difference in progression-free survival between the two regimens.”
Nevertheless, Goldberg said he believed the data, and speculated about the extent that subsequent – i.e., second, third, and fourth -- lines of treatments after the initial five months of therapy with the target agents might have influenced the outcome: “Perhaps starting with FOLFIRI plus cetuximab allows a different sequencing later?,” he suggested.
He said that although he would not change his own standard practice on the basis of the FIRE-3 evidence alone, but the results are definitely something to pay attention to: “There’s something there about the 3.7 month advantage in median overall survival -- we need to understand why these patients lived longer.”
Key CALGB Trial Results Expected Soon
Goldberg also said that since US practice is to use FOLFOX rather than FOLFIRI as first-line chemotherapy rather than FOLFIRI, and that he considers the regimens to be generally equivalent in efficacy, it is worth waiting for more data comparing cetuximab with bevacizumab as an addition to chemotherapy in patients expressing wild-type KRAS. Results are soon to be released from the Cancer and Leukemia Group B 80405 study, he said, which, like FIRE 3, also puts cetuximab head to head with bevacizumab but with the option of using either FOLFOX or FOLFIRI chemotherapy.
“That study has completed accrual of over 1,700 patients: 70 percent of the patients were treated with FOLFOX, and 30 percent with FOLFIRI, and that will give us additional information about the cetuximab-versus- bevacizumab comparison.,” he said.
Heinemann agreed: “Our Phase III trial supports these data, and we are presently waiting for the larger CALGB trial to confirm these data: and then we’re going to make a final decision.” But he was adamant that these were important data advancing the state of knowledge significantly.