Pilot study of dovitinib in patients with von Hippel-Lindau disease

Abstract

Von Hippel-Lindau (VHL) disease is an autosomal dominant disease occurring in 1 in 35,000 births and leads to an increased risk of a phenotypically diverse array of tumor types including, but not limited to, clear cell renal cell carcinoma (ccRCC) and hemangioblastomas (HBs). Previous studies of patients with VHL disease treated with the tyrosine kinase inhibitor (TKI) sunitinib did not show clinical response in HBs. Interestingly, VHL-related HBs displayed increased fibroblast growth factor receptor 3 (FGFR3) protein expression when compared to VHL-related ccRCCs. Therefore, in this pilot study, we assessed the safety and efficacy profile of TKI 258 (dovitinib), a multi-tyrosine kinase inhibitor of VEGF receptor and fibroblast growth factor (FGF), in patients with VHL disease who had measureable HBs. The trial was stopped after six patients enrolled after the toxicity stopping rule was triggered. With regards to safety, 6/6 subjects had at least one adverse event (AE). Best response in 6/6 subjects was stable disease (SD) in HBs. While the negative safety and efficacy results of this pilot study do not favor the use of dovitinib for the treatment of asymptomatic HBs in VHL disease patients, further investigation into alternative scheduling and other FGFR inhibitors for the treatment of HBs in VHL disease patients is warranted given the promising pre-clinical and molecular data.

<p>Von Hippel-Lindau Disease: Current Challenges and Future Prospects</p>

“…The best response was a stable disease of central nervous system hemangioblastomas. 186 Sorafenib is a multiple tyrosine kinase inhibitor of VEGFR2/3 and PDGFR β, among other receptors. In 2017, Choi et al report partial response to sorafenib of multiple small renal cell carcinomas and pancreatic cysts in 2 VHL patients.…”

Current Systemic Treatments for the Hereditary Cancer Syndromes: Drug Development in Light of Genomic Defects

“…The best response was stable disease. 101 In a phase II study of pazopanib, 31 patients with VHL were treated and had 52% ORR in renal cell carcinoma, 4% ORR in hemangioblastoma, and 53% ORR in pancreatic neuroendocrine tumor lesions. 102 In all these studies, diarrhea, fatigue, hypertension, and nausea were the most common tyrosine kinase inhibitor-related side effects.…”

Systemic Therapy Development in Von Hippel–Lindau Disease: An Outsized Contribution from an Orphan Disease

“…Notably, while RCC tissues demonstrated higher levels of phosphorylated VEGFR-2 when compared to hemangioblastomas, the protein levels of fibroblast growth factor receptor 3 (FGFR3) and FGFR ligand (FGFR substrate 2) were higher in hemangioblastomas relative to RCC [ 33 ]. This intriguing finding provided a mechanistic rationale for the clinical testing of dovitinib, a multi-kinase inhibitor targeting FGFR, VEGFR, and PDGFR, in patients with genetically-confirmed VHL and at least one measurable hemangioblastoma [ 35 ]. Unfortunately, the study was terminated following the treatment of only six patients due to intolerable toxicity.…”

“…Three of six patients (50%) discontinued therapy due to adverse effects including maculopapular rash, vomiting, and dyspnea, despite dose reduction and supportive measures. The best response observed was SD in hemangioblastomas, which occurred in five out of six patients [ 35 ].…”