Vascular effects, efficacy and safety of nintedanib in patients with advanced, refractory colorectal cancer: a prospective phase I subanalysis

Abstract

BackgroundNintedanib is a potent, oral angiokinase inhibitor that targets VEGF, PDGF and FGF signalling, as well as RET and Flt3. The maximum tolerated dose of nintedanib was evaluated in a phase I study of treatment-refractory patients with advanced solid tumours. In this preplanned subanalysis, the effect of nintedanib on the tumour vasculature, along with efficacy and safety, was assessed in 30 patients with colorectal cancer (CRC).MethodsPatients with advanced CRC who had failed conventional treatment, or for whom no therapy of proven efficacy existed, were treated with nintedanib ranging from 50–450 mg once-daily (n = 14) or 150–250 mg twice-daily (n = 16) for 28 days. After a 1-week rest, further courses were permitted in the absence of progression or undue toxicity. The primary objective was the effect on the tumour vasculature using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and expressed as the initial area under the DCE-MRI contrast agent concentration–time curve after 60 seconds (iAUC60) or the volume transfer constant between blood plasma and extravascular extracellular space (Ktrans).ResultsPatients received a median of 4.0 courses (range: 1–13). Among 21 evaluable patients, 14 (67%) had a ≥40% reduction from baseline in Ktrans and 13 (62%) had a ≥40% decrease from baseline in iAUC60, representing clinically relevant effects on tumour blood flow and permeability, respectively. A ≥40% reduction from baseline in Ktrans was positively associated with non-progressive tumour status (Fisher’s exact: p = 0.0032). One patient achieved a partial response at 250 mg twice-daily and 24 (80%) achieved stable disease lasting ≥8 weeks. Time to tumour progression (TTP) at 4 months was 26% and median TTP was 72.5 days (95% confidence interval: 65–114). Common drug-related adverse events (AEs) included nausea (67%), vomiting (53%) and diarrhoea (40%); three patients experienced drug-related AEs ≥ grade 3. Four patients treated with nintedanib once-daily had an alanine aminotransferase and/or aspartate aminotransferase increase ≥ grade 3. No increases > grade 2 were seen in the twice-daily group.ConclusionsNintedanib modulates tumour blood flow and permeability in patients with advanced, refractory CRC, while achieving antitumour activity and maintaining an acceptable safety profile.

An Optimized 3D Coculture Assay for Preclinical Testing of Pro- and Antiangiogenic Drugs

“…These FDA-approved drugs were chosen because they proved to work in man. 27,28 The complete inhibition of angiogenesis by nintedanib might be due to the simultaneous action of the inhibitor on ECs and fibroblasts. 29,30 It is tempting to speculate that despite there being no obvious phenotypical change detectable, nintedanib might cause a change of the fibroblast secretome and ECM production, leading to the effective block of vessel formation.…”

Protracted inhibition of vascular endothelial growth factor signaling improves survival in metastatic colorectal cancer: A systematic review

“…[19] Preliminary results showed clinical activity also in colorectal cancer and results of ongoing trials are awaited in the coming years (NCT02149108, NCT02393755, NCT00904839). [20] INTRODUCTION Rationale 3. Describe the rationale for the review in the context of what is already known.…”

Update on Anti-angiogenesis Therapy in Colorectal Cancer

“…Interestingly, clinically relevant effects of nintedanib on tumor blood flow and permeability in colorectal cancer patients evaluable for DCE-MRI analysis were seen. (38) Further studies of nintedanib with chemotherapy or versus placebo for refractory CRC are ongoing. Clinical data on other anti-angiogenic agents in development for the treatment of mCRC are awaited.…”