The FIRE-3 trial compared 1st-line therapy of FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wildtype (wt) mCRC patients. The subgroup of extended RAS wt patients consisted of 400 patients. The AADx molecular assay has previously been shown to identify a poor prognosis angiogeneic subgroup across multiple cancer types including colorectal cancer. Both bevacizumab (through inhibition of VEGFR-activation) and cetuximab (through inhibition of EGFR-signaling) would be expected to have anti-angiogenic effects in colorectal cancer. The predictive role of AADx in FOLFIRI plus bevacizumab or cetuximab treated in colorectal cancer patients remains unclear.
Transcriptional profiling of 501 formalin fixed paraffin embedded pre-treatment samples from the ITT population was performed using the Almac Diagnostics XcelTM array. Patients were classified by the AADx assay as ANGIO ON or OFF based on a predefined score. ORRs were compared using Fischeŕs exact test. Progression free survival (PFS) and Overall survival (OS) times were compared using Kaplan-Meier estimation and log-rank tests. Hazard ratios (HR) were estimated according to the Cox proportional hazard method.
The AADX assay was successfully applied to 438 out of 501 specimens available from the study population (n = 752). Of those, 315 had a RAS wt tumor and 123 a RAS mutant. The correlation between RAS status and AADx score with respect to ORR; PFS, and OS were complex (Table). The addition of cetuximab to FOLFIRI was significantly superior to the addition bevacizumab in “ANGIO ON” tumors most likely reflecting the strong link between EGFR-signaling and angiogenesis in colorectal cancer.Table:
|RAS wild-type||AADx score||ORR||p OR||PFS months||p HR||OS months||p HR|
|FOLFIRI + Cetuximab||ANGIO ON||65.2%||0.69 0.87||10.6||0.72 1.07||29.8||0.88 1.04|
|FOLFIRI + Bevacizumab||ANGIO ON||46.3%||0.0038 0.39||9.1||0.0002 0.52||21.2||0.0062 0.59|
|RAS Mutant||AADx score||ORR||p OR||PFS months||p HR||OS months||p HR|
|FOLFIRI + Cetuximab||ANGIO ON||38.6%||0.93 0.94||8.2||0.49 1.23||23.0||0.81 0.92|
|FOLFIRI + Bevacizumab||ANGIO ON||58.8%||0.13 2.1||11.2||0.35 1.30||23.1||0.02 2.00|
Here, we present data demonstrating that it possible to define subgroups in the group of wt mCRC patients within the FIRE-3 trial that responded differently to the addition of cetuximab or bevacizumab.
Clinical trial identification
Legal entity responsible for the study
Klinikum der Universität München
S. Stintzing: Honoraria for talks and advisory board from: Amgen, Bayer, Lilly, Merck, Sanofi, Roche. B. Price, A. McCavigan, S. Walker, P. Harkin, R. Kennedy, L. Knight: ALMAC Diagnostics. V. Heinemann: Honoraria for talks and advisory boards by: Amgen, Servier, Sirtex, Merck, Roche, Bayer, Lilly, Sanofi. All other authors have declared no conflicts of interest.