Phase II Results of Dovitinib (TKI258) in Patients with Metastatic Renal Cell Cancer

Abstract

Purpose: 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).Experimental Design: 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.Results: 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%).Conclusion: 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.

A phase II evaluation of brivanib in the treatment of persistent or recurrent carcinoma of the cervix: An NRG Oncology/Gynecologic Oncology Group study

“…In advanced or recurrent cervical cancer, the European Network of Gynaecological Oncological Trial Groups and Belgium and Luxembourg Gynaecologic Oncology Group is currently comparing carboplatin plus paclitaxel with or without nintedanib. Another FGF inhibitor, dovitinib, was found to be active in progressive renal cell cancer following VEGFR tyrosine kinase inhibitors and mTOR inhibitors [41]. In addition to identifying more specific and effective FGF inhibitors in cervical cancer, novel biomarkers are needed to identify those patients who are more likely to respond to these agents.…”

Treatment options in advanced renal cell carcinoma after first-line treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors

“…Despite positive phase 2 data with this drug, 15 the GOLD study failed to show any improvement in outcomes with dovitinib. 16 Other data from phase 3 trials suggest the potential use of approved second-line agents in the third-line setting.…”

Nine-year change in statistical design, profile, and success rates of Phase II oncology trials

“…One trial (Baselga et al, 2010) used an extension of Simon’s design to ordinal outcomes (Lu et al, 2005), tumor response, and disease control. In another trial (Escudier et al, 2014) similar Simon’s-like two-stage design for ordinal outcomes (Dent et al, 2001) was used. Two trials published in 2010 used the design by Sargent et al (2001).…”