BIBF 1120: Triple Angiokinase Inhibitor with Sustained Receptor Blockade and Good Antitumor Efficacy

Abstract

Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a novel treatment modality in oncology. Preclinical findings suggest that long-term clinical outcomes may improve with blockade of additional proangiogenic receptor tyrosine kinases: platelet-derived growth factor receptors (PDGFR) and fibroblast growth factor receptors (FGFR). BIBF 1120 is an indolinone derivative potently blocking VEGF receptor (VEGFR), PDGFR and FGFR kinase activity in enzymatic assays (IC50, 20–100 nmol/L). BIBF 1120 inhibits mitogen-activated protein kinase and Akt signaling pathways in three cell types contributing to angiogenesis, endothelial cells, pericytes, and smooth muscle cells, resulting in inhibition of cell proliferation (EC50, 10–80 nmol/L) and apoptosis. In all tumor models tested thus far, including human tumor xenografts growing in nude mice and a syngeneic rat tumor model, BIBF 1120 is highly active at well-tolerated doses (25–100 mg/kg daily p.o.), as measured by magnetic resonance imaging of tumor perfusion after 3 days, reducing vessel density and vessel integrity after 5 days, and inducing profound growth inhibition. A distinct pharmacodynamic feature of BIBF 1120 in cell culture is sustained pathway inhibition (up to 32 hours after 1-hour treatment), suggesting slow receptor off-kinetics. Although BIBF 1120 is rapidly metabolized in vivo by methylester cleavage, resulting in a short mean residence time, once daily oral dosing is fully efficacious in xenograft models. These distinctive pharmacokinetic and pharmacodynamic properties may help explain clinical observations with BIBF 1120, currently entering phase III clinical development. [Cancer Res 2008;68(12):4774–82]

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

“…The highest activity is against VEGFR1, 2, and 3 and FGFR2. It also targets SRC, LYN, LCK, and FLT-3 ( 65 ). In a phase I dose-escalating study, 61 patients with advanced cancers were investigated after treatment with, fi rst, once-and, then, twice-daily dosing schedules of BIBF1120.…”

Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

“…For comparison, the in vitro kinase and cellular activities of 4 other multitargeted TKIs that have been reported to have anti-FGFR activity (and whose structures were published at the time of these studies), dovitinib, cediranib, BIBF 1120, and brivanib (29)(30)(31)(32)(33)(34)(35), were also examined. By both measures, ponatinib was found to be the most potent inhibitor of each of the 4 FGFRs ( Fig.…”

“…BIBF 1120 (intedanib) inhibits FGFR1-4 (29) and cediranib (AZD2171) has activity against FGFR1 and FGFR2 (30,31), which translated to antitumor effects in gastric cancer cells carrying activating FGFR2 amplifications (31). Brivanib (BMS-540215) targets FGFR1 (32) and selectively inhibits growth of breast cancer cell lines with FGFR1 gene amplification (33).…”

Novel anti-angiogenic therapeutic strategies in colorectal cancer

“…Inhibition of tumor growth was demonstrated in vivo in several xenograft models [113] and clinically in refractory tumors, demonstrating to be active in colorectal cancer, renal cancer and hepatocarcinoma [114]. Nintedanib in combination with docetaxel is indicated in locally advanced or metastatic lung adenocarcinoma patients who failed a first-line treatment.…”