Reference Detail

Ref Type

PMID

Authors

D.G. Duda, C. Sirard

Title

Potential biomarkers of response to DKK1 blockade with DKN-01 in combination with paclitaxel in advanced esophagogastric cancer (EGC) patients (pts)

Journal	Vol	Issue	Date	Pages	Journal Short Title
Ann Oncol

URL

https://www.annalsofoncology.org/article/S0923-7534(20)37585-2/fulltext

Abstract Text

Background: Overexpression of DKK1, a modulator of canonical WNT signaling, is frequently seen in malignant tumors and is often associated with worse survival. Preclinical studies have shown that DKK1 can augment tumorigenesis by promoting angiogenesis as well as enhancing tumor-associated immunosuppression. In this Phase I trial, DKN-01 (a humanized IgG4 monoclonal antibody against DKK1) showed encouraging early efficacy signals when combined with paclitaxel (DP) in EGC pts (Strickler et al., GI ASCO 2017). We performed correlative studies of plasma biomarkers of angiogenesis and inflammation in these pts. Methods: Blood samples were collected from 34 patients treated with DP at baseline, and then weekly for 4 weeks (w). Plasma biomarkers were measured by multiplexed array for angiogenesis (bFGF, PIGF/PGF, sVEGFR1, sTIE-2, VEGF, VEGF-C, and VEGF-D) and inflammation (IFN-g, TNF-a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70 and IL-13) (Meso-Scale Discovery) and by ELISA for HGF and SDF-1a (R&D Systems). Biomarker changes were evaluated by Wilcoxon Sign-Rank test, and correlations with response using Kendall’s test values and with survival using two-sided Wald test in the Cox regression. Results: Six of 34 EGC pts in this subset analysis (18%) had a PR and 11/34 (32%) showed SD with preliminary median PFS and OS of 13.7w and 28.4w, respectively. DP treatment induced significant and sustained increases in plasma IFN-g, IL-8, VEGF-D and decreases in IL-10 (all p < 0.05). Transient increases in bFGF and PlGF and decreases in sTie2 were also observed. IFN-γ, IL-10, and VEGF-D correlated with overall response and change in target lesion size. Finally, OS was poor in pts with high IL-6, IL-8 and TNF-a (HR > 1 all time-points) and prolonged in pts with greater increases in IL-2 and VEGF-D after treatment. Conclusions: Prospective plasma biomarker analyses showed that DP treatment changed biomarkers of systemic immunity and angiogenesis in EGC pts, and indicated potential associations between inflammation biomarkers and outcomes. These hypothesis-generating results will inform future prospective investigation of these plasma biomarkers as well as paired evaluation of tumor biopsies for this combination regimen. Clinical trial identification: Clinical trial information: NCT02013154

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References