Evaluation of efficacy and safety markers in a phase II study of metastatic colorectal cancer treated with aflibercept in the first-line setting.
BACKGROUND
Aflibercept (ziv-aflibercept) is an anti-angiogenic agent recently approved in combination with FOLFIRI for the treatment of metastatic colorectal cancer (mCRC) patients previously treated with oxaliplatin. Despite heterogeneity in response to aflibercept, no biomarkers for efficacy or adverse effects have been identified. Here we present biomarker data from the randomised phase II AFFIRM trial assessing aflibercept in combination with mFOLFOX6 first line in mCRC.


METHODS
Ninety-six somatic mutations in key oncogenic drivers of mCRC and 133 common single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) pathway genes were analysed, and 27 plasma markers measured at baseline, during and after treatment. We assessed correlations of these three classes of biomarkers with progression-free survival (PFS) and adverse events (AEs).


RESULTS
Somatic mutations identified in KRAS, BRAF, NRAS, PIK3CA and PIK3R1 did not significantly correlate with PFS (multiple testing-adjusted false discovery rate (FDR) or multiple testing-adjusted FDR>0.3). None of the individual SNPs correlated with PFS (multiple testing-adjusted FDR>0.22), but at the gene level variability in VEGFB significantly correlated with PFS (multiple testing-adjusted FDR=0.0423). Although none of the plasma markers measured at baseline significantly correlated with PFS, high levels of circulating IL8 at baseline together with increased levels of IL8 during treatment were significantly associated with reduced PFS (multiple testing-adjusted FDR=0.0478). No association was found between biomarkers and AEs.


CONCLUSIONS
This represents the first biomarker study in mCRC treated with aflibercept. High IL8 plasma levels at baseline and subsequent increases in IL8 were associated with worse PFS, suggesting that IL8 may act as a potentially predictive biomarker of aflibercept treatment outcome.
Vesalius Research Center, VIB, Leuven, Belgium.|Department of Oncology, Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium.
Diether
D
Lambrechts
Vesalius Research Center, VIB, Leuven, Belgium.|Department of Oncology, Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium.
Bernard
B
Thienpont
Department of Biostatistics, Sanofi, Chilly-Mazarin, France.
Vincent
V
Thuillier
Department of Pathology, KU Leuven, Leuven, Belgium.
Xavier
X
Sagaert
Vesalius Research Center, VIB, Leuven, Belgium.|Department of Oncology, Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium.
Matthieu
M
Moisse
Vesalius Research Center, VIB, Leuven, Belgium.|Department of Oncology, Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium.
Gilian
G
Peuteman
Hospital de Sabadell, Corporació Sanitaria Parc, Taulí-Institut Universitari, Sabadell, Barcelona, Spain.
Carles
C
Pericay
Universitätsklinikum Carl Gustav Carus, Dresden, Germany.
Gunnar
G
Folprecht
School of Public Health and Preventive Medicine, Monash University, Melbourne, USA.
John
J
Zalcberg
Sanofi, Milan, Italy.
Chiara
C
Zilocchi
Sanofi, Oncology Division, Vitry-sur-Seine, France.
Emmanuelle
E
Margherini
Translational and Experimental Medicine, Oncology, Sanofi, Vitry-sur-Seine, France.
Marielle
M
Chiron
Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium.
Eric
E
Van Cutsem
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D016209:Interleukin-8 / Q000097:blood*; D002955:Leucovorin / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D040262:Receptors, Vascular Endothelial Growth Factor / Q000008:administration & dosage* / Q000009:adverse effects; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects; D016019:Survival Analysis; D016896:Treatment Outcome; D042561:Vascular Endothelial Growth Factor B / Q000235:genetics
D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; C508606:CXCL8 protein, human; D016209:Interleukin-8; D009944:Organoplatinum Compounds; D011993:Recombinant Fusion Proteins; C467485:VEGFB protein, human; D042561:Vascular Endothelial Growth Factor B; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D002955:Leucovorin; D005472:Fluorouracil