PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Authors: Nasser H Hanna; Rolf Kaiser; Richard N Sullivan; Osvaldo Rudy Aren; Myung-Ju Ahn; Beatrice Tiangco; Isabelle Voccia; Joachim von Pawel; Vladimir Kovcin; Jason Agulnik; Birgit Gaschler-Markefski; José Barrueco; Patricia Sikken; Charles Schloss; Joo-Hang Kim Journal: Lung Cancer Date: 2016-10-27 Impact factor: 5.705
Authors: Benjamin S Jones; Mary S Jerome; Deborah Miley; Bradford E Jackson; Mollie R DeShazo; Vishnu V B Reddy; Karan P Singh; Olivia C Brown; Francisco Robert Journal: Lung Cancer Date: 2017-02-09 Impact factor: 5.705
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Authors: Hai T Tran; Yuan Liu; Amado J Zurita; Ying Lin; Katherine L Baker-Neblett; Anne-Marie Martin; Robert A Figlin; Thomas E Hutson; Cora N Sternberg; Rafael G Amado; Lini N Pandite; John V Heymach Journal: Lancet Oncol Date: 2012-07-02 Impact factor: 41.316
Authors: Bruce J Giantonio; Paul J Catalano; Neal J Meropol; Peter J O'Dwyer; Edith P Mitchell; Steven R Alberts; Michael A Schwartz; Al B Benson Journal: J Clin Oncol Date: 2007-04-20 Impact factor: 44.544
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