Modulation of pharmacodynamic (PD) biomarkers in dermal biopsies from patients treated on a phase I study of bevacizumab (Bev) in combination with everolimus (Ev) and erlotinib (Erl) for advanced solid tumors

Abstract

BACKGROUND: Tumor growth and angiogenesis are regulated by multiple cellular pathways, including the VEGF, mTOR, and EGFR pathways. We have previously reported our clinical experience combining Bev, Ev and Erl therapies. Taking advantage of the similarities between tumor growth and wound healing, we conducted a PD analysis of these agents using novel dermal wound angiogenesis assays. METHODS: Patients with advanced solid tumors received either 1) Bev-Ev doublet therapy; 2) Bev-Ev-Erl triplet therapy; 3) Ev monotherapy for 14 days followed by addition of Bev-Erl; 4) Erl monotherapy for 14 days followed by addition of Bev-Ev. Full-thickness dermal granulation biopsies were harvested; the phospho (p) and total (t) levels of VEGFR2, EGFR, and S6RP were measured at baseline, end of the monotherapy lead-in period (day 14), and 35 days post doublet or triplet therapy. A dermal wound angiogenesis assay, which quantifies peripheral wound vascularization was also incorporated in the study. RESULTS: 38 pts were evaluable for biomarker analysis. Wilcoxon signed rank tests indicated that both VEGFR2 and S6RP were significantly down-regulated after Bev-Ev-Erl triplet therapy: tVEGFR2 (q=5.1E-05), pVEGFR2 (q=0.01), tS6RP (q=0.007), pS6RP (q=9.7E-04). Levels of tVEGFR2 (q=5.5E-04) and pS6RP (q=6.9E-04) were also found to be significantly down-regulated after Bev-Ev doublet therapy. Ev monotherapy for 14 days led to significant tVEGFR2 down-regulation (q=0.035). No significant changes in EGFR levels were observed in any cohort. Additionally, Bev-Ev-Erl triplet therapy led to a slight decrease in dermal wound vascularization (p=0.098), which positively correlated with changes in tVEGFR2 levels (q=0.008). CONCLUSIONS: This is the first investigation evaluating the PD effects of VEGF, mTOR, and EGFR inhibition in a clinical wound-healing model. Our results indicate that targeting of all three pathways is associated with overall down-regulation of both VEGF and mTOR pathways. These data suggest that this dermal wound model can be used to quantify PD markers in evaluating multiple classes of targeted therapies.