Nintedanib: examining the development and mechanism of action of a novel triple angiokinase inhibitor

References

• Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285(21):1182-6
   PubMed Web of Science ®Google Scholar
• Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407(6801):249-57
   PubMed Web of Science ®Google Scholar
• Loges S, Schmidt T, Carmeliet P. Mechanisms of resistance to anti-angiogenic therapy and development of third-generation anti-angiogenic drug candidates. Genes Cancer 2010;1(1):12-25
   PubMedGoogle Scholar
• Wang TF, Lockhart AC. Aflibercept in the treatment of metastatic colorectal cancer. Clin Med Insights Oncol 2012;6:19-30
   PubMedGoogle Scholar
• Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005;23(5):1011-27
   PubMed Web of Science ®Google Scholar
• Imai K, Takaoka A. Comparing antibody and small-molecule therapies for cancer. Nat Rev Cancer 2006;6(9):714-27
   PubMed Web of Science ®Google Scholar
• Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 2009;27(8):1227-34
   PubMed Web of Science ®Google Scholar
• Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355(24):2542-50
   PubMed Web of Science ®Google Scholar
• Soria JC, Mauguen A, Reck M, et al. Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 2013;24(1):20-30
   PubMed Web of Science ®Google Scholar
• Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350(23):2335-42
   PubMed Web of Science ®Google Scholar
• Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008;26(12):2013-19
   PubMed Web of Science ®Google Scholar
• National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Colon Cancer, Version 3 (2014). Available from: www.nccn.org/ [Last accessed 18 March 2014]
   Google Scholar
• Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007;25(12):1539-44
   PubMed Web of Science ®Google Scholar
• Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011;365(26):2473-83
   PubMed Web of Science ®Google Scholar
• Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359(4):378-90
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356(2):115-24
   PubMed Web of Science ®Google Scholar
• Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011;365(26):2484-96
   PubMed Web of Science ®Google Scholar
• Ortega J, Vigil CE, Chodkiewicz C. Current progress in targeted therapy for colorectal cancer. Cancer Control 2010;17(1):7-15
   PubMedGoogle Scholar
• Ballas MS, Chachoua A. Rationale for targeting VEGF, FGF, and PDGF for the treatment of NSCLC. Onco Targets Ther 2011;4:43-58
   PubMed Web of Science ®Google Scholar
• Paez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009;15(3):220-31
   PubMed Web of Science ®Google Scholar
• Shojaei F. Anti-angiogenesis therapy in cancer: current challenges and future perspectives. Cancer Lett 2012;320(2):130-7
   PubMed Web of Science ®Google Scholar
• Ebos JM, Lee CR, Cruz-Munoz W, et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 2009;15(3):232-9
   PubMed Web of Science ®Google Scholar
• Mancuso MR, Davis R, Norberg SM, et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 2006;116(10):2610-21
   PubMed Web of Science ®Google Scholar
• Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet 2004;20(11):563-9
   PubMed Web of Science ®Google Scholar
• Presta M, Dell’Era P, Mitola S, et al. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 2005;16(2):159-78
   PubMed Web of Science ®Google Scholar
• Rusnati M, Presta M. Fibroblast growth factors/fibroblast growth factor receptors as targets for the development of anti-angiogenesis strategies. Curr Pharm Des 2007;13(20):2025-44
   PubMedGoogle Scholar
• Levitzki A. PDGF receptor kinase inhibitors for the treatment of PDGF driven diseases. Cytokine Growth Factor Rev 2004;15(4):229-35
   PubMed Web of Science ®Google Scholar
• Beitz JG, Kim IS, Calabresi P, Frackelton ARJr. Human microvascular endothelial cells express receptors for platelet-derived growth factor. Proc Natl Acad Sci USA 1991;88(5):2021-5
   PubMed Web of Science ®Google Scholar
• Wu E, Palmer N, Tian Z, et al. Comprehensive dissection of PDGF-PDGFR signaling pathways in PDGFR genetically defined cells. PLoS One 2008;3(11):e3794
   Google Scholar
• Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 2005;8(4):299-309
   PubMed Web of Science ®Google Scholar
• Erber R, Thurnher A, Katsen AD, et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 2004;18(2):338-40
   PubMed Web of Science ®Google Scholar
• Bergers G, Song S, Meyer-Morse N, et al. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003;111(9):1287-95
   PubMed Web of Science ®Google Scholar
• Kopetz S, Hoff PM, Morris JS, et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 2010;28(3):453-9
   PubMed Web of Science ®Google Scholar
• Roth GJ, Heckel A, Colbatzky F, et al. Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120). J Med Chem 2009;52(14):4466-80
   PubMed Web of Science ®Google Scholar
• Hilberg F, Brandstetter I, Roth G. In vitro and in vivo efficacy of BIBF 1120, a small molecule triple angiokinase inhibitor, in combination with taxanes. Int Conf Mol Targets Cancer Ther 2005;59:A19
   Google Scholar
• Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 2008;68(12):4774-82
   PubMed Web of Science ®Google Scholar
• Hilberg F, Brandstetter I. Efficacy of BIBF 1120, a potent triple angiokinase inhibitor, in models of human non-small cell lung cancer is augmented by chemotherapy. Eur J Cancer 2007;2:S380
   Google Scholar
• Xiang QF, Wang F, Su XD, et al. Effect of BIBF 1120 on reversal of ABCB1-mediated multidrug resistance. Cell Oncol (Dordr) 2011;34(1):33-44
   PubMed Web of Science ®Google Scholar
• Stopfer P, Rathgen K, Bischoff D, et al. Pharmacokinetics and metabolism of BIBF 1120 after oral dosing to healthy male volunteers. Xenobiotica 2011;41(4):297-311
   PubMed Web of Science ®Google Scholar
• Gori B, Ricciardi S, Fulvi A, et al. New antiangiogenics in non-small cell lung cancer treatment: Vargatef (BIBF 1120) and beyond. Ther Clin Risk Manag 2011;7:429-40
   PubMed Web of Science ®Google Scholar
• Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004;64(19):7099-109
   PubMed Web of Science ®Google Scholar
• Wedge SR, Kendrew J, Hennequin LF, et al. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 2005;65(10):4389-400
   PubMed Web of Science ®Google Scholar
• Wood JM, Bold G, Buchdunger E, et al. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res 2000;60(8):2178-89
   PubMed Web of Science ®Google Scholar
• Bousquet G, Alexandre J, Le Tourneau C, et al. Phase I study of BIBF 1120 with docetaxel and prednisone in metastatic chemo-naive hormone-refractory prostate cancer patients. Br J Cancer 2011;105(11):1640-5
   PubMed Web of Science ®Google Scholar
• Doebele RC, Conkling P, Traynor AM, et al. A phase I, open-label dose-escalation study of continuous treatment with BIBF 1120 in combination with paclitaxel and carboplatin as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 2012;23(8):2094-102
   PubMed Web of Science ®Google Scholar
• du Bois A, Huober J, Stopfer P, et al. A phase I open-label dose-escalation study of oral BIBF 1120 combined with standard paclitaxel and carboplatin in patients with advanced gynecological malignancies. Ann Oncol 2010;21(2):370-5
   PubMed Web of Science ®Google Scholar
• Ellis PM, Kaiser R, Zhao Y, et al. Phase I open-label study of continuous treatment with BIBF 1120, a triple angiokinase inhibitor, and pemetrexed in pretreated non-small cell lung cancer patients. Clin Cancer Res 2010;16(10):2881-9
   PubMed Web of Science ®Google Scholar
• Kropff M, Kienast J, Bisping G, et al. An open-label dose-escalation study of BIBF 1120 in patients with relapsed or refractory multiple myeloma. Anticancer Res 2009;29(10):4233-8
   PubMed Web of Science ®Google Scholar
• Mross K, Stefanic M, Gmehling D, et al. Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors. Clin Cancer Res 2010;16(1):311-19
   PubMed Web of Science ®Google Scholar
• Okamoto I, Kaneda H, Satoh T, et al. Phase I safety, pharmacokinetic, and biomarker study of BIBF 1120, an oral triple tyrosine kinase inhibitor in patients with advanced solid tumors. Mol Cancer Ther 2010;9(10):2825-33
   PubMed Web of Science ®Google Scholar
• Stopfer P, Roth W, Mross K, et al. Pharmacokinetic characterization of BIBF 1120, an orally active triple angiokinase inhibitor (VEGFR, PDGFR, FGFR) in advanced cancer patients. Eur J Cancer Suppl 2006;4(13):26 Abstract 73
   Google Scholar
• Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004;22(11):2184-91
   PubMed Web of Science ®Google Scholar
• Sculier JP, Moro-Sibilot D. First- and second-line therapy for advanced nonsmall cell lung cancer. Eur Respir J 2009;33(4):915-30
   PubMedGoogle Scholar
• Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22(9):1589-97
   PubMed Web of Science ®Google Scholar
• Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18(10):2095-103
   PubMed Web of Science ®Google Scholar
• Ciuleanu T, Stelmakh L, Cicenas S, et al. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol 2012;13(3):300-8
   PubMed Web of Science ®Google Scholar
• Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368(25):2385-94
   PubMed Web of Science ®Google Scholar
• Scagliotti GV, Krzakowski M, Szczesna A, et al. Sunitinib plus erlotinib versus placebo plus erlotinib in patients with previously treated advanced non-small-cell lung cancer: a phase III trial. J Clin Oncol 2012;30(17):2070-8
   PubMed Web of Science ®Google Scholar
• de Boer RH, Arrieta O, Yang CH, et al. Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial. J Clin Oncol 2011;29(8):1067-74
   PubMed Web of Science ®Google Scholar
• Herbst RS, Sun Y, Eberhardt WE, et al. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol 2010;11(7):619-26
   PubMed Web of Science ®Google Scholar
• Paz-Ares L, Hirsh V, Zhang L, et al. Monotherapy administration of sorafenib in patients with non-small cell lung cancer: phase III randomized, double-blind, placebo-controlled MISSION trial. Ann Oncol 2012;23(Suppl 9):Abstract LBA33_PR
   Google Scholar
• Zhang L, Shi M, Huang C, et al. A phase II multicenter, placebo controlled trial of apatinib in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after two previous treatment regimens. J Clin Oncol 2012;30(Suppl 1):Abstract 7458
   Google Scholar
• Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014;384(9944):665-73
   PubMed Web of Science ®Google Scholar
• Reck M, Kaiser R, Eschbach C, et al. A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung cancer. Ann Oncol 2011;22(6):1374-81
   PubMed Web of Science ®Google Scholar
• LUME-Lung 1: BIBF 1120 plus docetaxel as compared to placebo plus docetaxel in 2nd line non small cell lung cancer. Available from: https://clinicaltrials.gov/ct2/show/NCT00805194 [Last accessed March 2015]
   Google Scholar
• Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol 2014;15(2):143-55
   PubMed Web of Science ®Google Scholar
• Mountzios G, Dimopoulos MA, Soria JC, et al. Histopathologic and genetic alterations as predictors of response to treatment and survival in lung cancer: a review of published data. Crit Rev Oncol Hematol 2010;75(2):94-109
   PubMedGoogle Scholar
• Larrayoz M, Pio R, Pajares MJ, et al. Contrasting responses of non-small cell lung cancer to antiangiogenic therapies depend on histological subtype. EMBO Mol Med 2014;6(4):539-50
   PubMedGoogle Scholar
• Morishita C, Jin E, Kikuchi M, et al. Angiogenic switching in the alveolar capillaries in primary lung adenocarcinoma and squamous cell carcinoma. J Nippon Med Sch 2007;74(5):344-54
   PubMedGoogle Scholar
• Li B, Hasovits C, Lee A, et al. The addition of anti-angiogenic tyrosine kinase inhibitors to chemotherapy for advanced non-small cell lung cancer: systematic review and meta-analysis of randomised controlled trials. J Thorac Oncol 2013;8(Suppl 2):S1210
   Google Scholar
• Reck M, Novello S, Mellemgaard A, et al. Impact of tumor burden on the overall survival analysis of the LUME-Lung 1 study: A randomized, double-blind phase 3 trial of nintedanib (BIBF 1120) + docetaxel in NSCLC patients progressing after first-line chemotherapy. J Thorac Oncol 2013;8(Suppl 2):Abstract S196
   Google Scholar
• LUME-Lung 2: nintedanib plus pemetrexed compared to placebo plus pemetrexed in 2nd line nonsquamous NSCLC. Available from: https://clinicaltrials.gov/ct2/show/NCT00806819 [Last accessed March 2015]
   Google Scholar
• Hanna NH, Kaiser R, Sullivan RN, et al. LUME-Lung 2: A multicenter, randomized, double-blind, phase III study of nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after failure of first-line chemotherapy. J Clin Oncol 2013;31(15 Suppl):Abstract 8034
   Google Scholar
• Roche Products Limited. Avastin (bevacizumab) Summary of Product Characteristics (2014). Available from: www.medicines.org.uk/emc/medicine/15748/SPC [Last accessed March 2014]
   Google Scholar
• Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2012;30(17):2039-45
   PubMed Web of Science ®Google Scholar
• Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol 2014;32(13):1302-8
   PubMed Web of Science ®Google Scholar
• Gotlieb WH, Amant F, Advani S, et al. Intravenous aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Oncol 2012;13(2):154-62
   PubMed Web of Science ®Google Scholar
• Penson RT, Moore KM, Fleming GF, et al. A phase II study of ramucirumab (IMC-1121B) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma. Gynecol Oncol 2014;134(3):478-85
   PubMed Web of Science ®Google Scholar
• Coleman RL, Moon J, Sood AK, et al. Randomised phase II study of docetaxel plus vandetanib versus docetaxel followed by vandetanib in patients with persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma: SWOG S0904. Eur J Cancer 2014;50(9):1638-48
   PubMed Web of Science ®Google Scholar
• Oaknin A, Gonzalez-Martin A, Garcia Y, et al. A phase II study of pazopanib in recurrent or persistent ovarian (EOC), peritoneal (PPC), or Fallopian tube cancer (FTC): A Spanish Ovarian Cancer Group (GEICO) study. J Clin Oncol 2012;30(Suppl):Abstract 5068
   Google Scholar
• Matulonis UA, Berlin S, Ivy P, et al. Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol 2009;27(33):5601-6
   PubMed Web of Science ®Google Scholar
• Matei D, Sill MW, Lankes HA, et al. Activity of sorafenib in recurrent ovarian cancer and primary peritoneal carcinomatosis: a gynecologic oncology group trial. J Clin Oncol 2011;29(1):69-75
   PubMed Web of Science ®Google Scholar
• Baumann KH, du Bois A, Meier W, et al. A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy. Ann Oncol 2012;23(9):2265-71
   PubMed Web of Science ®Google Scholar
• Biagi JJ, Oza AM, Chalchal HI, et al. A phase II study of sunitinib in patients with recurrent epithelial ovarian and primary peritoneal carcinoma: an NCIC Clinical Trials Group Study. Ann Oncol 2011;22(2):335-40
   PubMed Web of Science ®Google Scholar
• Ledermann JA, Hackshaw A, Kaye S, et al. Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. J Clin Oncol 2011;29(28):3798-804
   PubMed Web of Science ®Google Scholar
• LUME-Ovar 1: nintedanib (BIBF 1120) or placebo in combination with paclitaxel and carboplatin in first line treatment of ovarian cancer. Available from: https://clinicaltrials.gov/ct2/show/NCT01015118 [Last accessed March 2015]
   Google Scholar
• du Bois A, Kristensen G, Ray-Coquard I, et al. AGO-Ovar 12: a randomized placebo-controlled GCIG/ENGOT-intergroup phase III trial of standard frontline chemotherapy +/- nintedanib for advanced ovarian cancer. Int J Gynecol Cancer 2013;23(8 Suppl 1):7-8
   Web of Science ®Google Scholar
• Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012;30(28):3499-506
   PubMed Web of Science ®Google Scholar
• Wilhelm SM, Dumas J, Adnane L, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer 2011;129(1):245-55
   PubMed Web of Science ®Google Scholar
• Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381(9863):303-12
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, Prenen H, Guillen-Ponce C, et al. A phase I/II, open-label, randomised study of BIBF 1120 plus mFOLFOX6 compared to bevacizumab plus mFOLFOX6 in patients with metastatic colorectal cancer. Eur J Cancer 2011;47(Suppl 2):8-9
   PubMedGoogle Scholar
• Nintedanib (BIBF 1120) vs placebo in refractory colorectal cancer. Available from: https://clinicaltrials.gov/ct2/show/NCT02149108 [Last accessed March 2015]
   Google Scholar
• Palmer D, Loembé AB, Studeny M, et al. Phase I study of nintedanib (BIBF 1120) in European patients with advanced hepatocellular carcinoma. Ann Oncol 2012;23(Suppl 9):Abstract 740P
   Google Scholar
• Yen C, Shen YC, Shiah H. Early data from a phase I study of nintedanib (BIBF 1120) in Asian patients with advanced hepatocellular carcinoma. Ann Oncol 2012;23(Suppl 9):Abstract 744P
   Google Scholar
• Phase I/II comparison of efficacy and safety of BIBF 1120 and sorafenib in patients with advanced hepatocellular carcinoma. Available from: https://clinicaltrials.gov/ct2/show/NCT01004003 [Last accessed March 2015]
   Google Scholar
• A Phase I/ II trial of nintedanib in Asian hepatocellular carcinoma patients. Available from: https://clinicaltrials.gov/ct2/show/NCT00987935 [Last accessed March 2015]
   Google Scholar
• Eisen T, Shparyk Y, Jones R, et al. Phase II efficacy and safety study of nintedanib versus sunitinib in previously untreated renal cell carcinoma (RCC) patients. J Clin Oncol 2013;31(Suppl):Abstract 4506
   Google Scholar
• Eisen T, Shparyk Y, Macleod N, et al. Effect of small angiokinase inhibitor nintedanib (BIBF 1120) on QT interval in patients with previously untreated, advanced renal cell cancer in an open-label, phase II study. Invest New Drugs 2013;31(5):1283-93
   PubMed Web of Science ®Google Scholar
• Nintedanib (BIBF 1120) in mesothelioma. Available from: https://clinicaltrials.gov/ct2/show/NCT01907100 [Last accessed March 2015]
   Google Scholar
• Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014;370(22):2071-82
   PubMed Web of Science ®Google Scholar
• Boehringer Ingelheim. Ofev® (nintedanib) prescribing information (2014). Available from: www.accessdata.fda.gov/drugsatfda_docs/label/2014/205832s000lbl.pdf [Last accessed January 2015]
   Google Scholar
• George DJ, Halabi S, Shepard TF, et al. Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480. Clin Cancer Res 2001;7(7):1932-6
   PubMed Web of Science ®Google Scholar
• Nishimura R, Nagao K, Miyayama H, et al. Higher plasma vascular endothelial growth factor levels correlate with menopause, overexpression of p53, and recurrence of breast cancer. Breast Cancer 2003;10(2):120-8
   PubMedGoogle Scholar
• Werther K, Christensen IJ, Nielsen HJ, Danish RCCSG. Prognostic impact of matched preoperative plasma and serum VEGF in patients with primary colorectal carcinoma. Br J Cancer 2002;86(3):417-23
   PubMedGoogle Scholar
• Jubb AM, Hurwitz HI, Bai W, et al. Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol 2006;24(2):217-27
   PubMed Web of Science ®Google Scholar
• Poon RT, Fan ST, Wong J. Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 2001;19(4):1207-25
   PubMed Web of Science ®Google Scholar
• Kudo K, Arao T, Tanaka K, et al. Antitumor activity of BIBF 1120, a triple angiokinase inhibitor, and use of VEGFR2+pTyr+ peripheral blood leukocytes as a pharmacodynamic biomarker in vivo. Clin Cancer Res 2011;17(6):1373-81
   PubMedGoogle Scholar
• LUME-Columbus: Nintedanib plus docetaxel in advanced non-small cell lung cancer with translational research. Available from: https://clinicaltrials.gov/ct2/show/NCT02231164 [Last accessed March 2015]
   Google Scholar
• Nintedanib in molecularly selected patients with advanced non-small cell lung cancer. Available from: https://clinicaltrials.gov/ct2/show/NCT02299141 [Last accessed March 2015]
   Google Scholar
• Casanovas O. The adaptive stroma joining the antiangiogenic resistance front. J Clin Invest 2011;121(4):1244-7
   PubMedGoogle Scholar
• Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353(2):123-32
   PubMed Web of Science ®Google Scholar
• Boehringer Ingelheim. Vargatef® (nintedanib) summary of product characteristics (2014). Available from: www.ema.europa.eu [Last accessed January 2015]
   Google Scholar
• Molife R, De Bono JS, Bell S, et al. A phase II trial to compare BIBF 1120 or BIBW 2992 monotherapy versus a combination of sequential administration of both medications in patients with hormone refractory prostate cancer (HRPC). ASCO Genitourinary Cancers Symposium 2009. abstract 203
   Google Scholar