Biomarker studies in a phase I trial of DKN-01 in advanced esophageal cancer.
Strickler, JH; Kagey, M; Sirard, CA; Duda, GD; Almenara, J; Powers, CN; Bendell, JC
Published in: Journal of Clinical Oncology
161 Background: DKK1 is a modulator of Wnt signaling that is frequently overexpressed in tumors and such expression has been associated with worse survival. Preclinical studies have shown that DKK1 can promote tumor growth by increasing angiogenesis and contributing to an immunosuppressive tumor microenvironment. DKN-01 is a humanized IgG4 monoclonal antibody against DKK1 that has shown encouraging efficacy signals in patients (pts) with advanced esophageal (EC) or esophagogastric junction (EGJ) cancer when administered in combination with paclitaxel. Correlative studies are evaluating DKK1 expression and genetics in archived tumor specimens and baseline and on-treatment plasma levels of angiogenesis and inflammation biomarkers as predictors of response. Methods: Formalin fixed paraffin embedded (FFPE) archived tumor tissue was evaluated for DKK1 expression by immunohistochemistry (IHC) and scored for fraction of positive cells, intensity, and localization of DKK1. Genetics were collected if known and/or performed using an Archer VariantPlex Solid Tumor Panel covering 67 genes. Plasma samples, pre- and on DKN-01 treatment were evaluated by multiplexed array for angiogenesis (bFGF, PIGF/PGF, sFLT1/sVEGFR1, sTIE-2/TEK, VEGF, VEGF-C, and VEGF-D) and inflammation (IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70 and IL-13) markers (Meso-Scale Discovery) and by ELISA for HGF and SDF-1α (R&D Systems). Results: ~90% of tissue samples showed DKK1+ expression in tumor cells (range 1 to 100%); intensity (weak 1+ to strong 3+); and localization (cytoplasmic and/or nuclear). Early data has not identified a correlation between DKK1 staining and response. One pt with an ongoing durable response had an activating mutation in β-catenin. Analysis of plasma biomarkers is ongoing. Conclusions: Analysis of DKK1 staining, tumor genetics, and prospective angiogenic/inflammatory biomarkers are ongoing to identify a predictive biomarker for DKN-01. The majority of EC/EGJ tumor biopsies were IHC DKK1+. Broader genomic screens are underway to further characterize DKN-01 sensitivity; mechanistically plausible activating mutations in β-catenin may be a biomarker for DKN-01. Clinical trial information: NCT02013154.
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