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Poster display session

3385 - Predictive Assay for anti-angiogenic agents (AADx) identifies molecular subgroups of RASwt mCRC with differential efficacy of FOLFIRI plus bevacizumab in the FIRE-3 (AIO KRK-0306) trial


11 Sep 2017


Poster display session


Sebastian Stintzing


Annals of Oncology (2017) 28 (suppl_5): v22-v42. 10.1093/annonc/mdx363


S. Stintzing1, B. Price2, L. Knight2, A. McCavigan2, S. Walker2, P. Harkin2, R. Kennedy2, D. Neureiter3, S. Held4, A. Jung5, T. Kirchner6, V. Heinemann1

Author affiliations

  • 1 Medical Dept. Iii, Ludwig Maximilians University - Grosshadern, 81377 - Munich/DE
  • 2 Global & Eu Headquarters, Almac Diagnostics, BT63 5QD - Craigavon/GB
  • 3 Universitätsinstitut Für Pathologie Der Paracelsus Medical University, Salzburger Landeskrankenhaus, 5020 - Salzburg/AT
  • 4 Clinassess Gmbh, ClinAssess GmbH, Leverkusen/DE
  • 5 Pathologisches Institut-lmu München, Ludwig-Maximillians-Universität, 80337 - München/DE
  • 6 Institute Of Pathology, University of Munich (LMU), 80337 - München/DE


Abstract 3385


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-typeAADx scoreORRp ORPFS monthsp HROS monthsp HR
FOLFIRI + CetuximabANGIO ON65.2%0.69 0.8710.60.72 1.0729.80.88 1.04
ANGIO OFF68.3%10.630.6
FOLFIRI + BevacizumabANGIO ON46.3%0.0038 0.399.10.0002 0.5221.20.0062 0.59
ANGIO OFF69.1%13.129.1
RAS MutantAADx scoreORRp ORPFS monthsp HROS monthsp HR
FOLFIRI + CetuximabANGIO ON38.6%0.93 0.948.20.49 1.2323.00.81 0.92
ANGIO OFF40.0%7.719.2
FOLFIRI + BevacizumabANGIO ON58.8%0.13 1.3023.10.02 2.00
ANGIO OFF40.0%10.218.5


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.

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