Abstract
Fibroblast growth factor (FGF) signaling regulates tumor growth and vascularization and partly mediates antiangiogenic escape from VEGF receptor (VEGFR) inhibitors. Dovitinib (TKI258) is a tyrosine kinase inhibitor (TKI) that inhibits FGF receptor (FGFR), VEGFR, and platelet-derived growth factor receptor, which are known drivers of antiangiogenic escape, angiogenesis, and tumor growth in renal cell carcinoma (RCC). Patients with advanced or metastatic RCC were treated with oral dovitinib 500 mg/day (5-days-on/2-days-off schedule). The study population was enriched for patients previously treated with a VEGFR TKI and an mTOR inhibitor. Of 67 patients enrolled, 55 patients (82.1%) were previously treated with ≥1 VEGFR TKI and ≥1 mTOR inhibitor (per-protocol efficacy set). The 8-week overall response rate and disease control rate in this population were 1.8% and 52.7%, respectively. Disease control rate during the entire study period was 56.4% (50.9% ≥4 months). Median progression-free survival and overall survival in the entire population were 3.7 and 11.8 months, respectively. Pharmacodynamic analyses demonstrated dovitinib-induced inhibition of VEGFR (as determined by increased levels of placental growth factor and decreased levels of soluble VEGFR2) and FGFR (as determined by increased FGF23 serum measures). The most frequently reported treatment-related adverse events of all grades included nausea (65.7%), diarrhea (62.7%), vomiting (61.2%), decreased appetite (47.8%), and fatigue (32.8%). Dovitinib was shown to be an effective and tolerable therapy for patients with metastatic RCC who had progressed following treatment with VEGFR TKIs and mTOR inhibitors. Clin Cancer Res; 20(11); 3012-22. ©2014 AACR.
Highlights
Clear-cell renal cell carcinoma (RCC) is commonly associated with mutations, deletions, and modifications of the von Hippel–Lindau (VHL) gene that result in nonfunctional or reduced levels of VHL [1, 2]
Dovitinib (TKI258) is a tyrosine kinase inhibitors (TKI) that goes beyond VEGF receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) blockade by targeting fibroblast growth factor receptor, a pathway critical for antiangiogenic escape
Antitumor activity of dovitinib in patients with advanced or metastatic RCC previously treated with a VEGFR TKI and an mTOR inhibitor was observed in a phase I/II study, with disease control achieved in the majority of patients
Summary
Clear-cell renal cell carcinoma (RCC) is commonly associated with mutations, deletions, and modifications of the von Hippel–Lindau (VHL) gene that result in nonfunctional or reduced levels of VHL [1, 2]. VHL is involved in degrading hypoxia-inducible factor-a (HIF-a), a transcrip-. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Loss of VHL leads to increased levels of HIF-a, and a subsequent increase in proangiogenic factor levels. This knowledge has led to development of tyrosine kinase inhibitors (TKI) that target the VEGF pathway and mTOR inhibitors, which target pathways involved in HIF-a expression. Despite the multiple VEGF pathway [VEGF receptor (VEGFR) TKIs and antiVEGF antibodies] and mTOR inhibitors already approved, these treatments rarely induce complete responses in advanced RCC, and most patients will eventually progress [1]
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