Evaluation of efficacy and safety markers in a phase II study of metastatic colorectal cancer treated with aflibercept in the first-line setting.

Autor: Lambrechts D; Vesalius Research Center, VIB, Leuven, Belgium.; Department of Oncology, Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium., Thienpont B; Vesalius Research Center, VIB, Leuven, Belgium.; Department of Oncology, Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium., Thuillier V; Department of Biostatistics, Sanofi, Chilly-Mazarin, France., Sagaert X; Department of Pathology, KU Leuven, Leuven, Belgium., Moisse M; Vesalius Research Center, VIB, Leuven, Belgium.; Department of Oncology, Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium., Peuteman G; Vesalius Research Center, VIB, Leuven, Belgium.; Department of Oncology, Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium., Pericay C; Hospital de Sabadell, Corporació Sanitaria Parc, Taulí-Institut Universitari, Sabadell, Barcelona, Spain., Folprecht G; Universitätsklinikum Carl Gustav Carus, Dresden, Germany., Zalcberg J; School of Public Health and Preventive Medicine, Monash University, Melbourne, USA., Zilocchi C; Sanofi, Milan, Italy., Margherini E; Sanofi, Oncology Division, Vitry-sur-Seine, France., Chiron M; Translational and Experimental Medicine, Oncology, Sanofi, Vitry-sur-Seine, France., Van Cutsem E; Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2015 Sep 29; Vol. 113 (7), pp. 1027-34. Date of Electronic Publication: 2015 Sep 10.
DOI: 10.1038/bjc.2015.329
Abstrakt: 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.
Databáze: MEDLINE
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