PMID- 26355232 OWN - NLM STAT- MEDLINE DCOM- 20160104 LR - 20220321 IS - 1532-1827 (Electronic) IS - 0007-0920 (Print) IS - 0007-0920 (Linking) VI - 113 IP - 7 DP - 2015 Sep 29 TI - Evaluation of efficacy and safety markers in a phase II study of metastatic colorectal cancer treated with aflibercept in the first-line setting. PG - 1027-34 LID - 10.1038/bjc.2015.329 [doi] AB - 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. FAU - Lambrechts, Diether AU - Lambrechts D AD - Vesalius Research Center, VIB, Leuven, Belgium. AD - Department of Oncology, Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium. FAU - Thienpont, Bernard AU - Thienpont B AD - Vesalius Research Center, VIB, Leuven, Belgium. AD - Department of Oncology, Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium. FAU - Thuillier, Vincent AU - Thuillier V AD - Department of Biostatistics, Sanofi, Chilly-Mazarin, France. FAU - Sagaert, Xavier AU - Sagaert X AD - Department of Pathology, KU Leuven, Leuven, Belgium. FAU - Moisse, Matthieu AU - Moisse M AD - Vesalius Research Center, VIB, Leuven, Belgium. AD - Department of Oncology, Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium. FAU - Peuteman, Gilian AU - Peuteman G AD - Vesalius Research Center, VIB, Leuven, Belgium. AD - Department of Oncology, Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium. FAU - Pericay, Carles AU - Pericay C AD - Hospital de Sabadell, Corporacio Sanitaria Parc, Tauli-Institut Universitari, Sabadell, Barcelona, Spain. FAU - Folprecht, Gunnar AU - Folprecht G AD - Universitatsklinikum Carl Gustav Carus, Dresden, Germany. FAU - Zalcberg, John AU - Zalcberg J AD - School of Public Health and Preventive Medicine, Monash University, Melbourne, USA. FAU - Zilocchi, Chiara AU - Zilocchi C AD - Sanofi, Milan, Italy. FAU - Margherini, Emmanuelle AU - Margherini E AD - Sanofi, Oncology Division, Vitry-sur-Seine, France. FAU - Chiron, Marielle AU - Chiron M AD - Translational and Experimental Medicine, Oncology, Sanofi, Vitry-sur-Seine, France. FAU - Van Cutsem, Eric AU - Van Cutsem E AD - Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium. LA - eng PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150910 PL - England TA - Br J Cancer JT - British journal of cancer JID - 0370635 RN - 0 (Angiogenesis Inhibitors) RN - 0 (Biomarkers, Tumor) RN - 0 (CXCL8 protein, human) RN - 0 (Interleukin-8) RN - 0 (Organoplatinum Compounds) RN - 0 (Recombinant Fusion Proteins) RN - 0 (VEGFB protein, human) RN - 0 (Vascular Endothelial Growth Factor B) RN - 15C2VL427D (aflibercept) RN - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor) RN - Q573I9DVLP (Leucovorin) RN - U3P01618RT (Fluorouracil) RN - Folfox protocol SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Angiogenesis Inhibitors/*administration & dosage/adverse effects MH - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse effects/therapeutic use MH - Biomarkers, Tumor/*blood/genetics MH - Colorectal Neoplasms/blood/*drug therapy/genetics MH - Female MH - Fluorouracil/administration & dosage/therapeutic use MH - Humans MH - Interleukin-8/*blood MH - Leucovorin/administration & dosage/therapeutic use MH - Male MH - Middle Aged MH - Mutation MH - Neoplasm Metastasis MH - Organoplatinum Compounds/administration & dosage/therapeutic use MH - Polymorphism, Single Nucleotide MH - Receptors, Vascular Endothelial Growth Factor/*administration & dosage/adverse effects MH - Recombinant Fusion Proteins/*administration & dosage/adverse effects MH - Survival Analysis MH - Treatment Outcome MH - Vascular Endothelial Growth Factor B/genetics PMC - PMC4651136 COIS- DL and EVC have served on advisory boards for Sanofi and received research funding from Sanofi to conduct this study. GF has received honoraria for participation in ad hoc advisory boards and for lectures from Sanofi. JZ has received travel and research support and honoraria for participation in advisory boards from Sanofi. VT, CZ, EM and MC are employees of Sanofi. BT, MM, XS, CP and GP declare no conflict of interest. The clinical trial, collection of tissue for biomarker evaluation and the evaluation of biomarkers were sponsored and funded by Sanofi-Aventis, Paris, France. BT holds a postdoctoral fellowship of the Fund for Scientific Research Flanders (FWO-F). EDAT- 2015/09/12 06:00 MHDA- 2016/01/05 06:00 PMCR- 2016/09/29 CRDT- 2015/09/11 06:00 PHST- 2014/03/21 00:00 [received] PHST- 2015/07/27 00:00 [revised] PHST- 2015/08/04 00:00 [accepted] PHST- 2015/09/11 06:00 [entrez] PHST- 2015/09/12 06:00 [pubmed] PHST- 2016/01/05 06:00 [medline] PHST- 2016/09/29 00:00 [pmc-release] AID - bjc2015329 [pii] AID - 10.1038/bjc.2015.329 [doi] PST - ppublish SO - Br J Cancer. 2015 Sep 29;113(7):1027-34. doi: 10.1038/bjc.2015.329. Epub 2015 Sep 10.