Multicenter, Phase II Study of Axitinib, a Selective Second-Generation Inhibitor of Vascular Endothelial Growth Factor Receptors 1, 2, and 3, in Patients with Metastatic Melanoma

Abstract

Purpose: This multicenter, open-label, phase II study evaluated the safety and clinical activity of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, 2, and 3, in patients with metastatic melanoma.Experimental Design: Thirty-two patients with a maximum of one prior systemic therapy received axitinib at a starting dose of 5 mg twice daily. The primary endpoint was objective response rate.Results: Objective response rate was 18.8% [95% confidence interval (CI), 7.2-36.4], comprising one complete and five partial responses with a median response duration of 5.9 months (95% CI, 5.0-17.0). Stable disease at 16 weeks was noted in six patients (18.8%), with an overall clinical benefit rate of 37.5%. Six-month progression-free survival rate was 33.9%, 1-year overall survival rate was 28.1%, and median overall survival was 6.6 months (95% CI, 5.2-9.0). The most frequently (>15%) reported nonhematologic, treatment-related adverse events were fatigue, hypertension, hoarseness, and diarrhea. Treatment-related fatal bowel perforation, a known class effect, occurred in one patient. Axitinib selectively decreased plasma concentrations of soluble VEGFR (sVEGFR)-2 and sVEGFR-3 compared with soluble stem cell factor receptor (sKIT). No significant association was noted between plasma levels of axitinib and response. However, post hoc analyses indicated potential relationships between efficacy endpoints and diastolic blood pressure of 90 mm Hg or higher as well as baseline serum lactate dehydrogenase levels.Conclusions: Axitinib was well tolerated, showed a selective VEGFR-inhibitory profile, and showed single-agent activity in metastatic melanoma. Further evaluations of axitinib, alone and combined with chemotherapy, are ongoing. Clin Cancer Res; 17(23); 7462-9. Ó2011 AACR.

Axitinib increases the infiltration of immune cells and reduces the suppressive capacity of monocytic MDSCs in an intracranial mouse melanoma model

“…22 It was approved by the FDA for the treatment of renal cell carcinoma and in a phase II clinical trial in melanoma patients an objective response rate of 18.8% was observed. 23 Taken together, these results justify the use of axitinib in the treatment of melanoma. In the current report, we describe the effects of axitinib on different immune cell populations in syngeneic subcutaneous and intracranial mouse melanoma models.…”

Antiangiogenic Therapy Inhibits Venous Thrombus Resolution

“…[7][8][9][10] There are a growing number of antiangiogenic agents under investigation for the prevention of tumor growth. 11 Vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) signaling through cognate VEGF receptors (VEGFR) 1, 2, and 3 has been a major target, resulting in the development of axitinib that is a potent and selective small-molecule pan-VEGFR inhibitor 12 now in phase I to III trials for multiple tumor types [13][14][15][16] and approved for treatment of metastatic renal cell carcinoma. 17 Axitinib inhibits angiogenesis by blocking ligand-induced VEGFR phosphorylation and affects downstream VEGF-mediated processes, including vascular permeability, endothelial cell survival, and tubule formation.…”

Meta-analysis of contribution of genetic polymorphisms in drug-metabolizing enzymes or transporters to axitinib pharmacokinetics

“…Statistical significance in each case was absent after adjustment for multiple testing CI, Confidence interval a For contrast "2/2-1/1" (or "fully expressed-not expressed" or "7/7-6/6" or "UM-PM"), a positive value suggests that genotype 2/2 (or fully expressed or 7/7 or UM) is associated with a higher AUC than 1/1 (or not expressed or 6/6 or PM), and a negative value suggests that 2/2 is associated with a lower AUC. This is also the case for the contrast "1/2-1/1" (or "intermediately expressed-not expressed" or "expressed-not expressed" or "6/7-6/6" or "EM-PM") b UGT1A1*6 results not reliable since n=1 for genotype 2/2 c UGT1A1*6 includes only Asian healthy volunteers d TA 6 and TA 7 are indicated as 6 and 7, respectively e CYP3A4*1B analysis includes Blacks and Other healthy volunteers on genotype-phenotype relationships for CYP3A4. Although in vitro data indicate that axitinib is metabolized primarily by CYP3A4/5, the influence of polymorphisms in the CYP3A4 gene on the pharmacokinetics of CYP3A4 substrates has previously been found to be generally weak and, consequently, CYP3A4 polymorphisms are not considered to play a major role in explaining the pharmacokinetic variability of CYP3A4 substrates.…”

“…Blockade of the VEGF/VEGFR pathway by axitinib inhibits the growth and survival of endothelial cells, thus reducing tumour vascularization and inducing cell death [1,2]. Axitinib has shown clinical efficacy in patients with advanced renal cell carcinoma (RCC), including those refractory to treatment with cytokines or sorafenib [3,4], as well as in patients with other types of solid tumours, such as non-small-cell lung cancer [5], melanoma [6], metastatic breast cancer [7] and thyroid cancer [8]. Axitinib is currently in phase III development in patients with advanced RCC; this trial met its primary endpoint with superior progressionfree survival for patients treated with axitinib versus sorafenib [9].…”