Phase 1b trial of nintedanib in combination with bevacizumab in patients with advanced solid tumors
Vascular 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.
Patients were treated with escalating doses of nintedanib (150 mg or 200 mg oral twice daily) and bevacizumab (15 mg/kg once intravenously every 3 weeks) until disease progression or unacceptable toxicity using standard 3 + 3 phase 1 design. Plasma levels of angiogenic biomarkers were correlated with clinical outcomes.
Eighteen 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 200 mg 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-1α.
Nintedanib was well-tolerated with bevacizumab with no DLT. Significant clinical activity was observed, including in bevacizumab-pretreated patients, suggesting nintedanib can overcome bevacizumab resistance.
KeywordsNintedanib Bevacizumab Metastasis Solid tumors Vascular endothelial growth factors
The authors thank the patients and their caregivers, in addition to the research nurses, study coordinators, and operations staff who contributed to this study.
Conception, design and methodology: FR, AM, BJ, RP. Acquisition of data: MJ, JK, DM, RP. Writing, review, and/or revision of the manuscript: RP, FR, MS. Study enrollment and supervision: FR, RP. Analysis and interpretation of data: PL, RP.
The study was supported by Cancer Center core grant (CA 13148) and partially by Boehringer Ingelheim. This study was registered at ClinicalTrials.gov (NCT02835833).The funding sources provided financial resources only with no involvement in the study design, data collection, analysis and interpretation of data, and in the decision to submit the article for publication.
Compliance with ethical standards
Conflict of interest
Dr. Francisco Robert: He is a member of speaker bureau for Boehringer Ingelheim. He is not involved with any of the drugs in this clinical study. No affiliations with or involvement in any organization or entity with any financial interest. All the authors declare that they have no potential conflicts of interest.
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