Phase 1b trial of nintedanib in combination with bevacizumab in patients with advanced solid tumors

PurposeVascular endothelial growth factor (VEGF) inhibitors have produced demonstrable but limited benefit for various cancers. One mechanism of resistance includes revascularization, secondary to upregulation of alternative pro-angiogenic platelet-derived growth factor receptor and fibroblast growth factor receptor pathways. Nintedanib is an oral, triple kinase inhibitor that blocks these pathways and may improve anti-tumor activity by overcoming resistance to anti-VEGF therapies. The primary objective of this first in-human study was to evaluate the safety and tolerability of nintedanib in combination with bevacizumab.MethodsPatients were treated with escalating doses of nintedanib (150mg or 200mg oral twice daily) and bevacizumab (15mg/kg once intravenously every 3weeks) until disease progression or unacceptable toxicity using standard 3+3 phase 1 design. Plasma levels of angiogenic biomarkers were correlated with clinical outcomes.ResultsEighteen patients with advanced tumors [lung (n=9), colon (n=8), and cervical (n=1)] previously treated with at least two lines of chemotherapy including bevacizumab (n=9, 50%) were enrolled. The highest dose of nintedanib was 200mg twice a day with no observed dose-limiting toxicities (DLT). Common adverse events (AE) were fatigue (grade 1-3) and diarrhea (grade 1-2). Durable clinical response was observed in 55% patients pretreated with bevacizumab (1 complete and 4 stable response). Better disease control was correlated with higher than median baseline values for VEFGR2 and E-selectin, and lower levels for SDF-1.ConclusionNintedanib was well-tolerated with bevacizumab with no DLT. Significant clinical activity was observed, including in bevacizumab-pretreated patients, suggesting nintedanib can overcome bevacizumab resistance.