CARE Gastrointestinal Cancer Faculty Canadian Perspectives from ASCO 2013

Abstract LBA3506: Randomized Comparison of FOLFIRI Plus Cetuximab Versus FOLFIRI Plus Bevacizumab As First-Line Treatment of KRAS Wild-Type Metastatic Colorectal Cancer: German AIO Study KRK-0306 (FIRE-3). Volker Heinemann et al.

Background: In patients (pts) with KRAS, wild-type metastatic colorectal cancer (mCRC) a head to head comparison of anti-EGFR- and anti-VEGF-directed first-line therapy has not been reported with regard to the FOLFIRI backbone. The AIO KRK-0306 study was therefore designed as a randomized multicenter trial to compare the efficacy of FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab in mCRC pts not pretreated for metastatic disease. 

Methods: Pts were randomized to FOLFIRI (Tournigand regimen) every two wks plus cetuximab (400 mg/m² day 1, followed by 250 mg/m² wkly = arm A) or bevacizumab (5 mg/kg every two wks = arm B). The intent-to-treat (ITT) population comprised all pts who had at least completed one application of therapy. While recruitment initially was independent of KRAS status, an amendment confined inclusion to KRAS wildtype (WT) tumors. Recruitment was completed in October 2012. The primary study endpoint was objective response rate (ORR, investigators read).

Results: Among 735 pts of the ITT-population, KRAS-WT was identified in 592. Of these, 297 pts were randomized to arm A and 295 to arm B. Median age was 64 years, 66% of pts were male, and ECOG PS 0-1 was observed in 98% of pts. Median duration of treatment was 4.7 mo vs 5.3 mo, respectively. While in the ITT analysis, ORR was comparable in arms A vs B (62% vs 57%, odds ratio 1.249), a significant superiority was found for assessable pts in arm A. Median PFS of the ITT population was nearly identical (10.3 vs 10.4 mo, HR 1.04, p = 0.69), however, overall survival (OS) showed a significantly better outcome in arm A vs arm B (28.8 vs 25.0 mo, HR 0.77, p = 0.0164, 95% CI: 0.620–0.953). Sixty-day mortality was low in both arms (1.01% vs 2.71%).

The findings from FIRE-3 were met with great interest as this study represents the first randomized clinical trial of FOLFIRI + bevacizumab vs. FOLFIRI + cetuximab in metastatic colorectal cancer where objective response rate (ORR) was selected as the primary endpoint. Despite comparable progression free survival (PFS) in both study arms, there was close to a 4 month difference in overall survival (OS) favoring the cetuximab group. The lack of PFS benefit makes the OS benefit difficult to explain and underscores the need to further explore the subsequent lines of therapies used among the participants. This is particularly relevant considering that the Kaplan-Meier curves appear to diverge at the time of progression and receipt of second line treatment. The chemotherapy backbones used in the subsequent treatments were not described, but study investigators indicate that additional details will be presented at the upcoming World Congress on GI Cancers in Barcelona that takes place in early July. We look forward to receiving more insights into whether these study findings will impact our current practice. Until more data become available, this study is unlikely to alter the present day management of metastatic colorectal cancer in Canada since most Canadian centers continue to reserve the use of anti-epidermal growth factor receptor antagonists to the third line treatment setting.
— CARE Gastrointestinal Cancer Faculty