Vandetanib, designed to inhibit VEGFR2 and EGFR signaling, had no clinical activity as monotherapy for recurrent ovarian cancer and no detectable modulation of VEGFR2

Abstract

Purpose: To evaluate clinical activity and target modulation of vandetanib in women with recurrent ovarian cancer.

Experimental design: A phase II trial of orally administered vandetanib 300 mg daily was designed to include analyses of target inhibition through paired biopsies and dynamic imaging. Core 18-gauge needle biopsies and dynamic contrast-enhanced magnetic resonance imaging were obtained before initiation of therapy and 6 weeks into therapy. Biopsy samples were subjected to reverse-phase protein lysate array endpoint analysis. Cytokine concentrations were measured by enzyme-linked immunosorbent assay in serially collected plasma samples.

Results: Twelve patients entered the study, and accrual was terminated in the first stage because of lack of response or disease stabilization beyond 6 months. Adverse events included rash, diarrhea, and prolonged QT interval corrected for heart rate, but not hypertension. Exploratory analyses showed that epidermal growth factor receptor (EGFR) phosphorylation was reduced in the eight paired biopsy sets obtained; vascular endothelial growth factor (VEGF) receptor-2 phosphorylation was not consistently affected nor were dynamic contrast-enhanced MRI permeability and flow parameters. Serial plasma VEGF concentrations were variable and did not significantly change in the 11 patients assessed.

Conclusions: Vandetanib 300 mg daily monotherapy had no significant clinical benefit in this disease setting. Proteomic analysis of paired biopsies detected both phosphorylated-EGFR and phosphorylated-VEGF receptor-2 in ovarian tumor tissue, but only phosphorylated-EGFR was measurably inhibited by vandetanib.

Figure 1. Changes in paired tumor tissue proteins with vandetanib administration

(A) The relative level of phosphorylated EGFR decreased after 6 weeks of vandetanib administration in paired tumor biopsies from 8 patients. Total EGFR and phosphorylated EGFR were measured on reverse-phase tissue lysate array (RPTA), and normalized to total protein level. The relative level of EGFR phosphorylation was estimated by calculating the ratio between the two normalized values for each sample. Mean value and range of expression for the group is plotted for each of the indicated timepoints. (B) The relative level of phosphorylated AKT similarly decreased in the same patients. AKT phosphorylation was calculated as EGFR in (A). (C) Cleaved PARP was significantly increased in tumor tissue following vandetanib administration, as measured by RPTA. (D) The relative level of phosphorylated VEGFR2, the other main target of vandetanib, was not significantly changed in paired tumor samples with vandetanib administration.

Figure 2. Levels of circulating cytokines and tumor marker CA125

(A) Plasma VEGF was not significantly changed in 11 patients on study for 4 weeks or 8 patients who remained on study 8 weeks or longer. Median fold change from baseline was 1.45 at 4 weeks and 0.97 at 8 weeks (p=NS). (B) Plasma IL-8 level was higher at baseline in patients who went on to disease progression before 4 months of vandetanib administration. (C) Plasma levels of VEGF at 8 weeks on study were higher in patients whose disease progressed before 4 months of vandetanib administration. (D) The CA125 measurements were variable, and tended rise faster in patients with progressive disease in the first cycle.

Figure 3. Quality of life assessment

Quality of life was estimated by administering the FACT-O questionnaire to patients before starting study treatment and after 4, 8 and 16 weeks of vandetanib administration. No significant changes were noted except for an increase in the physical well being subscale score at 8 weeks compared to baseline.