Cancer Therapy: Clinical Baseline Vascular Endothelial Growth Factor Concentration as a Potential Predictive Marker of Benefit from Vandetanib in Non–Small Cell Lung Cancer

Purpose: Vandetanib [vascular endothelial growth factor (VEGF) receptor/epidermal growth factor receptor/RET inhibitor] has shown improvements in progressionfree survival (PFS) in advanced non-small cell lung cancer in three randomized phase II studies: vandetanib versus gefitinib (study 3), docetaxel ± vandetanib (study 6), and carboplatin-paclitaxel and/or vandetanib (study 7). In study 7, vandetanib monotherapy was inferior to carboplatin-paclitaxel. We performed an exploratory retrospective analysis of the relationship between baseline circulating VEGF concentrations and PFS. Experimental Design: Mean baseline VEGF levels were determined by ELISA from two baseline samples of plasma (163 of 168 patients, study 3; 65 of 127, study 6) or serum (144 of 181, study 7). High baseline VEGF values were above the immunoassay reference range for healthy subjects; low baseline VEGF values were within the range. Results: Patients with low baseline VEGF had a lower risk of disease progression with vandetanib versus gefitinib [hazard ratio (HR), 0.55; 95% confidence interval (95% CI), 0.35-0.86; P = 0.01] or vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.25; 95% CI, 0.09-0.68; P = 0.01). High VEGF patients had a similar risk of disease progression with vandetanib monotherapy versus gefitinib (HR, 1.03; 95% CI, 0.60-1.75; P = 0.92) or vandetanib 100 mg/d + docetaxel versus docetaxel (HR, 0.95; 95% CI, 0.25-3.61; P = 0.94). In study 7, low VEGF patients had a similar risk of disease progression with vandetanib monotherapy 300 mg/d versus carboplatin-paclitaxel (HR, 0.80; 95% CI, 0.41-1.56; P = 0.51); high VEGF patients progressed more quickly (HR, 1.60; 95% CI, 0.81-3.15; P = 0.17). Conclusions: These analyses suggest that low baseline circulating VEGF may be predictive of PFS advantage in patients with advanced non-small cell lung cancer receiving vandetanib versus gefitinib or vandetanib + docetaxel versus docetaxel. Moreover, patients with low VEGF levels may have a similar outcome with either vandetanib monotherapy or carboplatin-paclitaxel. Angiogenesis is the process of new blood vessel formation from existing vessels. Generally, tumors cannot grow beyond 1 to 2mmwithout developing a vascular supply (1, 2). In normal physiologic processes, angiogenesis is closely controlled by the balance of proangiogenic and antiangiogenic factors, but this equilibrium is disrupted in the malignant state by the release of proangiogenic factors from the tumor and its stromal cells (3, 4). Vascular endothelial growth factor (VEGF), an up-regulated, critical proangiogenic factor in tumors, promotes endothelial cell growth, survival, and migration and mediates vessel permeability, thereby facilitating tumor progression and metastatic spread (5–7). Agents targeting the VEGF signaling pathway are Authors' Affiliations: The University of Texas M. D. Anderson Cancer Center, Houston, Texas; AstraZeneca, Macclesfield, United Kingdom; AstraZeneca, Wilmington, Delaware; Cedars-Sinai Cancer Center, Los Angeles, California; and Dana-Farber Cancer Institute, Boston, Massachusetts Received 10/4/08; revised 1/23/09; accepted 2/9/09; published online 5/15/09. Grant support: Damon Runyan Cancer Research Foundation grant CI 24-04 and American Society for Clinical Oncology Career Development Award (J.V. Heymach) and American Society for Clinical Oncology Young Investigator Award (E.O. Hanrahan). This study, including the editorial assistance provided by John Matthew (Mudskipper Bioscience), was supported financially by AstraZeneca. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). J.V. Heymach is a Damon Runyan-Lilly Clinical Investigator. Trademark statement: ZACTIMA and IRESSA are trademarks of the AstraZeneca group of companies. Requests for reprints: John V. Heymach, Department of Thoracic/Head and NeckMedical Oncology and Cancer Biology, University of Texas M. D. Anderson Cancer Center, Unit 432, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-6363; Fax: 713-792-1220; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-08-2568 3600 Clin Cancer Res 2009;15(10) May 15, 2009 www.aacrjournals.org Research. on April 13, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from now in clinical use for a variety of advanced solid tumors. These include bevacizumab, an anti-VEGF monoclonal antibody, for non-small cell lung cancer (NSCLC), colorectal and breast cancers, and sunitinib and sorafenib, multitargeted receptor tyrosine kinase inhibitors (TKI) with activity against VEGF receptors (VEGFR), for the treatment of renal cell carcinoma (8–13). Many other VEGFR TKIs are currently in clinical development (14). Vandetanib (ZACTIMA) is a once-daily oral receptor TKI with activity against VEGFR-2, epidermal growth factor receptor (EGFR), and RET. It has shown improvements in progressionfree survival (PFS) in advanced NSCLC in three randomized phase II trials (Table 1), 6474IL/0003, 0006, and 0007 (hereafter called studies 3, 6, and 7, respectively), and is now being further evaluated in the phase III setting. In study 3, there was an improvement in PFS with vandetanib 300 mg/d compared with gefitinib (IRESSA) 250 mg/d (15). Study 6 compared docetaxel alone or in combination with vandetanib at either 100 or 300 mg/d (16). PFS was superior with docetaxel + vandetanib 100 mg/d versus docetaxel alone. In study 7, combining vandetanib 300 mg/d with carboplatin-paclitaxel produced a greater PFS benefit than carboplatin-paclitaxel alone (17). In this study, the vandetanib 300 mg/d monotherapy arm was inferior to carboplatin-paclitaxel alone. Nevertheless, the disease control rate with vandetanib monotherapy was 26% (partial response or stable disease for at least 12 weeks), and a subset of patients (11%) remained on single-agent vandetanib for at least 6 months. Whereas these phase II results show the potential of vandetanib therapy in NSCLC, the identification of pretreatment biomarkers that may predict which patients are most likely to derive the greatest benefit from vandetanib or other inhibitors of VEGF signaling is of considerable interest. Circulating VEGF levels have been shown previously to be both a prognostic marker in cancer(18) and a pharmacodynamic marker of VEGFR-2 inhibition (11, 19–21).We hypothesized that circulating VEGF levels have the potential to be a predictive marker of clinical benefit in patients with advanced NSCLC treated with vandetanib. We therefore performed exploratory analyses of pretreatment blood samples from patients enrolled in studies 3, 6, and 7 to determine if VEGF concentrations might be predictive of benefit from vandetanib monotherapy or vandetanib in combination with docetaxel or carboplatin-paclitaxel chemotherapy. Materials and Methods Data from three separate randomized phase II trials of vandetanib in advanced NSCLC are included in this analysis: studies 3, 6, and 7. The design and results of these trials are described in detail elsewhere and are briefly outlined here and summarized in Table 1 (15–17). Study designs and treatments administered. In study 3, 168 patients with advanced NSCLC who had progressed despite firstor second-line platinum-based therapy were randomized 1:1 to receive continuous oral dosing with vandetanib 300 mg/d or gefitinib 250 mg/d (Table 1). The primary objective was to determine if vandetanib prolonged PFS relative to gefitinib. On disease progression, eligible patients had the option of switching to the alternative therapy. In study 6, 127 patients with locally advanced or metastatic NSCLC who had progressed following first-line platinum-based chemotherapy were randomized 1:1:1 to one of three treatment arms: docetaxel (75 mg/m intravenously every 21 days) + placebo, docetaxel + vandetanib 100 mg/d, or docetaxel + vandetanib 300 mg/d. The primary objective was to determine whether vandetanib (100 or 300 mg) + docetaxel prolonged PFS compared with placebo + docetaxel. In study 7, 181 patients with previously untreated, locally advanced, metastatic, or recurrent NSCLC were randomized 2:1:1 to one of three treatment arms: vandetanib 300 mg/d, carboplatin-paclitaxel (carboplatin, AUC 6 mg/mL min; paclitaxel, 200 mg/m; intravenously every 21 days) + placebo, or carboplatin-paclitaxel + vandetanib 300 mg/d. The primary objective was to determine whether vandetanib ± carboplatin-paclitaxel prolonged PFS compared with carboplatin-paclitaxel