Oral VEGFR Inhibitor Research Articles

Vandetanib plus pemetrexed versus pemetrexed as second-line therapy in patients with advanced non-small cell lung cancer (NSCLC): A randomized, double-blind phase III trial (ZEAL)

8010 Background: Vandetanib is a once-daily oral inhibitor of VEGFR, EGFR and RET signaling. A phase I trial of vandetanib + pemetrexed (pem) supported further investigation of this combination (de Boer et al, Ann Oncol 2008). Methods: The primary objective was to determine whether vandetanib 100 mg/day + pem 500 mg/m2 every 21 days (max 6 cycles) prolonged progression-free survival (PFS) vs placebo + pem. Overall survival (OS), objective response rate (ORR), time to deterioration of symptoms (TDS, by Lung Cancer Symptom Scale) and safety were secondary endpoints. Efficacy and safety were assessed in females as a co-primary analysis population. Eligibility criteria included stage IIIB/IV NSCLC, PS 0–2, and previous 1st-line therapy. Results: Between Jan 07-Mar 08, 534 patients (mean age 59 yrs; 38% female; 21% squamous histology; 8% brain metastases; stage IV 84%; PS 0/1/2: 41%/53%/6%) were randomized 1:1 to receive vandetanib + pem (n=256) or placebo + pem (n=278). Baseline characteristics were similar in both arms. Median duration of follow-up was 9.0 months, with 83% patients progressed and 50% deceased. There were positive trends seen for vandetanib + pem for both PFS (hazard ratio [HR] 0.86, 97.58% CI 0.69–1.06; P=0.108) and OS (HR 0.86, 97.54% CI 0.65–1.13; P=0.219); similar advantages were observed for females. There were statistically significant advantages for ORR (19.1% vs 7.9%, P<0.001) and TDS (HR 0.61, P=0.004). The adverse event profile was consistent with previous studies of vandetanib: rash (38% vs 26%), diarrhea (26% vs 18%) and hypertension (12% vs 3%) being more frequent in the vandetanib arm. There was evidence of reduced pem toxicity with the addition of vandetanib: anemia 8% vs 22%, nausea 29% vs 37%, vomiting 15% vs 22%, fatigue 37% vs 45%, and asthenia 11% vs 17%. The incidence of protocol-defined QTc prolongation was <1%. There was no increase in bleeding or thrombotic events in the vandetanib arm. Conclusions: The combination of vandetanib + pem demonstrated evidence of clinical benefit in patients with pretreated advanced NSCLC, although the study did not meet the primary endpoint of statistically significant PFS prolongation vs pem alone. Vandetanib + pem was generally well tolerated. [Table: see text]

DCE-MRI assessment of the effect of vandetanib on tumor vasculature in patients with advanced colorectal cancer and liver metastases: a randomized phase I study.

BackgroundVandetanib is a once-daily oral inhibitor of VEGFR, EGFR and RET signaling pathways. In patients with advanced colorectal cancer and liver metastases, the effect of vandetanib on tumor vasculature was assessed using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).MethodsEligible patients received vandetanib 100 or 300 mg/day. DCE-MRI (iAUC60 and Ktrans) was used to quantify the primary endpoints of tumor perfusion and vascular permeability. An exploratory assessment of tumor oxygenation was performed using MRI/T2*. All MRI parameters were measured at baseline (twice) and on days 2, 8, 29 and 57.ResultsTwenty-two patients received vandetanib (n = 10, 100 mg; n = 12, 300 mg). Baseline measurements of iAUC60 and Ktrans were reproducible, with low intrapatient coefficients of variation (11% and 24%, respectively). Estimates of mean % changes from baseline were -3.4% (100 mg) and -4.6% (300 mg) for iAUC60, and -4.6% (100 mg) and -2.7% (300 mg) for Ktrans; these changes were not significantly different between doses. The exploratory T2* measurement showed a significant increase at 300 mg versus 100 mg (P = 0.006). Both doses of vandetanib were generally well tolerated; common toxicities were fatigue, rash and diarrhea (majority CTC grade 1 or 2). The pharmacokinetic profile of vandetanib was similar to that observed previously. There were no RECIST-defined objective responses; five patients experienced stable disease ≥8 weeks.ConclusionIn this study in patients with advanced colorectal cancer, vandetanib did not modulate gadolinium uptake in tumor vasculature and tissue measured by the DCE-MRI parameters iAUC60 and Ktrans.Trial registrationNCT00496509 (ClinicalTrials.gov); D4200C00050 (AstraZeneca)

Correlative analyses of plasma cytokine/angiogenic factor (C/AF) profile, gender and outcome in a randomized, three-arm, phase II trial of first-line vandetanib (VAN) and/or carboplatin plus paclitaxel (CP) for advanced non-small cell lung cancer (NSCLC)

7593 Background: VAN (ZD6474) is an oral inhibitor of VEGFR, EGFR and RET. In a phase II trial, 181 patients with advanced NSCLC were randomized to 1st-line treatment with VAN, CP or VAN + CP. Progression free survival (PFS) was prolonged for VAN + CP vs CP (Heymach et al, submitted for ASCO 2007). Exploratory subgroup analyses suggest gender differences in PFS benefit for VAN + CP vs CP (HR 0.47 in females vs 1.05 in males). We performed exploratory analyses of plasma levels of 35 C/AFs to investigate gender differences and potential prognostic or predictive markers. Methods: Plasma was collected at baseline (n = 123; VAN 55, CP 32, VAN + CP 36), day (D) 8 (n = 104), D22 (n = 95), and D43 (n = 83). We used multiplex bead assays to measure 33 plasma C/AFs, including VEGF, basic FGF, EGF, HGF, E-selectin, ICAM-1, MMP-9, multiple chemokines and interleukins (IL). Osteopontin and sVEGFR-2 were measured by ELISA. Cox models were applied on PFS to identify prognostic/predictive markers after rank transformation and adjusted for covariates. Results: Significant gender differences in baseline C/AF levels were seen for IL-15, IL-1RA, IL-2R, MIG, and MIP-1A (all higher in females, all p = 0.022). Controlling for gender and treatment, high baseline E-selectin (p = .01), IL-6 (p = 0.018), and IL-2R (p = 0.008) were adverse prognostic indicators for PFS. Controlling for gender, the tests for treatment by factor interactions (to assess whether treatment effect was different in patients with low and high C/AF levels) were significant for baseline HGF (p = 0.04) and IL-2R (p = 0.008). For both HGF and IL- 2R, low levels were associated with prolonged PFS in the VAN arm, but were not associated with differences in the CP or VAN + CP arms. Significant changes in VEGF (rise) and sVEGFR-2 (decrease) occurred with treatment in the VAN arm; IL12, IL-1RA, MMP-9 and MCP-1 changed in the CP and VAN + CP arms. Conclusions: There are gender differences in PFS benefit from VAN and in plasma C/AF profile. Several C/AFs were of prognostic value, whereas low HGF and IL-2R were predictive of benefit in the VAN but not CP and VAN + CP arms. These gender differences and markers warrant further investigation. [Table: see text]