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The phase III CALGB/SWOG 80405 trial compared frontline therapy with bevacizumab or cetuximab combined with FOLFOX or FOLFIRI for patients with KRAS wild-type metastatic colorectal cancer (mCRC). The primary endpoint was overall survival (OS), with secondary endpoints focused on progression-free survival (PFS) and quality of life.
When the trial was initially designed, it had 3 arms and KRAS
mutations were not considered in the study inclusion. However, the trial was adjusted to look specifically at KRAS wild-type patients and to remove the third arm that was focused on the combination of bevacizumab and cetuximab. As a result of these changes, the study took approximately 10 years to complete, notes lead investigator Alan P. Venook, MD.
According to results presented at the 2014 ASCO Annual Meeting, the median OS was 29 months in the bevacizumab arm and 29.9 months in the cetuximab arm (HR = 0.925; P
= .34). The median PFS was 10.8 months with bevacizumab versus 10.4 months with cetuximab (HR = 1.04; P
= .55). In general, 10% of the patients enrolled in the trial went on to be treated with curative surgery and lived longer than 5 years, Venook notes.
A quality of life analysis was embedded in the trial, with over 90% compliance. In this assessment, bevacizumab performed numerically better than cetuximab; however, this advantage was not statistically significant (P
= .056), notes Venook. Skin rash was the leading complaint among patients in the cetuximab arm. These complaints peaked at 6 weeks and began to decline by week 9, notes Venook.
Overall, 73.4% of patients in the trial received FOLFOX as a chemotherapy backbone. When comparing the efficacy between the two chemotherapy groups, results were the same, suggesting the backbone did not impact overall results, Venook notes.
In the preceding phase III FIRE-3 trial presented in 2013, FOLFIRI plus cetuximab or bevacizumab was examined as a frontline treatment for patients with KRAS wild-type mCRC. Results from this analysis demonstrated equivalence for ORR and PFS; however, a 3.7-month OS advantage was seen with cetuximab versus bevacizumab. This advantage in OS was not seen until approximately 1 year after the completion of on-study therapy, notes Axel Grothey, MD.
As a consequence of these results, many practice patterns were changed to favor cetuximab, based on the secondary endpoint of OS, notes Grothey. This was further enhanced by an all-RAS
analysis that was presented at the 2013 European Cancer Congress that demonstrated a 7.5-month OS advantage with cetuximab versus bevacizumab.
Many looked to the 80405 trial to potentially confirm the FIRE-3 results, suggests Grothey. However, the findings of FIRE-3 were not upheld. More conversation on the optimal frontline therapy will likely take place, specifically as more data on each chemotherapy backbone and all-RAS
analyses are made available. At this point, both trials highlight the equivalent efficacy of two treatment options for patients with mCRC, Grothey states.