Novel anti-angiogenic therapeutic strategies in colorectal cancer

References

• Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.
   PubMed Web of Science ®Google Scholar
• Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–1186.
   PubMed Web of Science ®Google Scholar
• Hurwitz H, Saini S. Bevacizumab in the treatment of metastatic colorectal cancer: safety profile and management of adverse events. Semin Oncol. 2006;33(5 Suppl 10):S26–34.
   PubMed Web of Science ®Google Scholar
• Dougher-Vermazen M, Hulmes JD, Böhlen P, et al. Biological activity and phosphorylation sites of the bacterially expressed cytosolic domain of the KDR VEGF-receptor. Biochem Biophys Res Commun. 1994;205(1):728–738.
   PubMed Web of Science ®Google Scholar
• Martinelli E, Troiani T, Morgillo F, et al. Emerging VEGF-receptor inhibitors for colorectal cancer. Expert Opin Emerg Drugs. 2013 Mar;18(1):25–37.
   PubMed Web of Science ®Google Scholar
• Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer. 2008;8(8):579–591.
   PubMed Web of Science ®Google Scholar
• Fan F, Wey JS, McCarty MF, et al. Expression and function of vascular endothelial growth factor receptor-1 on human colon rectal cancer cells. Oncogene. 2005;24:2647–2653.
   PubMed Web of Science ®Google Scholar
• Mésange P, Poindessous V, Sabbah M, et al. Intrinsic bevacizumab resistance is associated with prolonged activation of autocrine VEGF signaling and hypoxia tolerance in colorectal cancer cells and can be overcome by nintedanib, a small molecule angiokinase inhibitor. Oncotarget. 2014;5(13):4709–4721.
   PubMed Web of Science ®Google Scholar
• Ellis LM, Hicklin DJ. Pathways mediating resistance to vascular endothelial growth factor-targeted therapy. Clin Cancer Res. 2008;14(20):6371–6375.
   PubMed Web of Science ®Google Scholar
• Custodio A, Barriuso J, de Castro J, et al. Molecular markers to predict outcome to antiangiogenic therapies in colorectal cancer: current evidence and future perspectives. Cancer Treat Rev. 2013;39(8):908–924.
   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):453–459.
   PubMed Web of Science ®Google Scholar
• Lieu CH, Tran H, Jiang ZQ, et al. The association of alternate VEGF ligands with resistance to anti-VEGF therapy in metastatic colorectal cancer. PLoS One. 2013;8(10):e77117.
   PubMed Web of Science ®Google Scholar
• Loupakis F, Cremolini C, Fioravanti A, et al. Pharmacodynamic and pharmacogenetic angiogenesis-related markers of first-line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer. Br J Cancer. 2011 Apr;104(8):1262–1269.
   PubMed Web of Science ®Google Scholar
• Scartozzi M, Galizia E, Chiorrini S, et al. Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab. Ann Oncol. 2009;20(2):227–230.
   PubMed Web of Science ®Google Scholar
• De Stefano A, Carlomagno C, Pepe S, et al. Bevacizumab related arterial hypertension as a predictive marker in metastatic colorectal cancer patients. Cancer Chemother Pharmacol. 2011;68(5):1207–1213.
   PubMed Web of Science ®Google Scholar
• Osterlund P, Soveri LM, Isoniemi H, et al. Hypertension and overall survival in metastatic colorectal cancer patients treated with bevacizumab-containing chemotherapy. Br J Cancer. 2011;104(4):599–604.
   PubMed Web of Science ®Google Scholar
• Khoja L, Kumaran G, Zee YK, et al. Evaluation of hypertension and proteinuria as markers of efficacy in antiangiogenic therapy for metastatic colorectal cancer. J Clin Gastroenterol. 2014;48(5):430–434.
   PubMed Web of Science ®Google Scholar
• Dewdney A, Cunningham D, Barbachano Y, et al. Correlation of bevacizumab-induced hypertension and outcome in the BOXER study, a phase II study of capecitabine, oxaliplatin (CAPOX) plus bevacizumab as peri-operative treatment in 45 patients with poor-risk colorectal liver-only metastases unsuitable for upfront resection. Br J Cancer. 2012;106(11):1718–1721.
   PubMed Web of Science ®Google Scholar
• Cartwright TH. Adverse events associated with antiangiogenic agents in combination with cytotoxic chemotherapy in metastatic colorectal cancer and their management. Clinical Colorectal Cancer. 2013;12(2):86–89.
   PubMed Web of Science ®Google Scholar
• Hubbard JM, Grothey A. Colorectal cancer in 2014: progress in defining first-line and maintenance therapies. Nat Rev Clin Oncol. 2015;12(2):73–74.
   PubMed Web of Science ®Google Scholar
• Tournigand C, Chibaudel B, Samson B, et al. Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2015;16(15):1493–1505.
   PubMed Web of Science ®Google Scholar
• Macedo LT, da Costa Lima AB, Sasse AD. Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups. BMC Cancer. 2012;12:8937.
   Web of Science ®Google Scholar
• Chen YX, Yang Q, Kuang JJ, et al. Efficacy of adding bevacizumab in the first-line chemotherapy of metastatic colorectal cancer: evidence from seven randomized clinical trials. Gastroenterol Res Pract. 2014;2014:594930.
   PubMedGoogle Scholar
• Passardi A, Nanni O, Tassinari D, et al. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol. 2015;26(6):1201–1207.
   PubMed Web of Science ®Google Scholar
• de Gramont A, Van Cutsem E, Schmoll HJ, et al. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 2012;13(12):1225–1233.
   PubMed Web of Science ®Google Scholar
• Allegra CJ, Yothers G, O’Connell MJ, et al. Phase III trial assessing Bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 2010;29:11–16.
   PubMed 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):3499–3506.
   PubMed Web of Science ®Google Scholar
• Strumberg D, Scheulen ME, Schultheis B, et al. Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study. Br J Cancer. 2012;106(11):1722–1727.
   PubMed Web of Science ®Google Scholar
• Grothey A, Van Cutsem E, Sobrero A, et al. CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303–312.
   PubMed Web of Science ®Google Scholar
• McLellan B, Ciardiello F, Lacouture ME, et al. Regorafenib-associated hand-foot skin reaction: practical advice on diagnosis, prevention, and management. Ann Oncol. 2015;26(10):2017–2026.
   PubMed Web of Science ®Google Scholar
• Spratlin JL, Cohen RB, Eadens M, et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol. 2010;28(5):780–787.
   PubMed Web of Science ®Google Scholar
• Tabernero J, Yoshino T, Cohn AL, et al. RAISE study investigators. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16(5):499–508.
   PubMed Web of Science ®Google Scholar
• Diaz-Padilla I, Siu LL. Brivanib alaninate for cancer. Expert Opin Investig Drugs. 2011;20:577–586.
   PubMed Web of Science ®Google Scholar
• Huynh H, Ngo VC, Fargnoli J, et al. Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin Cancer Res. 2008;14(19):6146–6153.
   PubMed Web of Science ®Google Scholar
• Jonker DJ, Rosen LS, Sawyer M, et al. A phase I study of BMS-582664 (brivanib alaninate), an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in patients (pts) with advanced/metastatic solid tumors: safety, pharmacokinetic (PK), and pharmacodynamic (PD) findings. J Clin Oncol. 2007;25(Suppl):3559.f.
   Google Scholar
• Garrett CR, Siu LL, El-Khoueiry A, et al. Phase I dose-escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with full-dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy. Br J Cancer. 2011;105(1):44–52.
   PubMed Web of Science ®Google Scholar
• Siu LL, Shapiro JD, et al. Phase III randomized, placebo-controlled study of cetuximab plus brivanib alaninate versus cetuximab plus placebo in patients with metastatic, chemotherapy-refractory, wild-type K-Ras colorectal carcinoma: the NCIC clinical trials group and AGITG CO.20 trial. J Clin Oncol. 2013;31(19):2477–2484.
   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):4389–4400.
   PubMed Web of Science ®Google Scholar
• Yamamoto N, Tamura T, Yamamoto N, et al. Phase I, dose escalation and pharmacokinetic study of cediranib (RECENTIN), a highly potent and selective VEGFR signalling inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2009;64(6):1165–1172.
   PubMed Web of Science ®Google Scholar
• Satoh T, Yamaguchi K, Boku N, et al. Phase I results from a two-part phase I/II study of cediranib in combination with mFOLFOX6 in Japanese patients with metastatic colorectal cancer. Invest New Drugs. 2012;30(4):1511–1518.
   PubMed Web of Science ®Google Scholar
• Cunningham D, Wong RP, D’Haens G, et al. HORIZON I study group. Cediranib with mFOLFOX6 vs bevacizumab with mFOLFOX6 in previously treated metastatic colorectal cancer. Br J Cancer. 2013;108(3):493–502.
   PubMed Web of Science ®Google Scholar
• Hoff PM, Hochhaus A, Pestalozzi BC, et al. cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol. 2012;30:3596–3603.
   PubMed Web of Science ®Google Scholar
• Schmoll HJ, Cunningham D, Sobrero A, et al. cediranib with mfolfox6 versus bevacizumab with MFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a double-blind, randomized phase III study (HORIZON III). J Clin Oncol. 2012;30:3588–3595.
   PubMed Web of Science ®Google Scholar
• Matsui J, Yamamoto Y, Funahashi Y, et al. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer. 2008;122(3):664–671.
   PubMed Web of Science ®Google Scholar
• Yamada K, Yamamoto N, Yamada Y, et al. Phase I dose-escalation study and biomarker analysis of E7080 in patients with advanced solid tumor. Clin Cancer Res. 2011;17(8):2528–2537.
   PubMed Web of Science ®Google Scholar
• Wiegering A, Korb D, Thalheimer A, et al. E7080 (Lenvatinib) a multi targeted tyrosine kinase inhibitor, demonstrates antitumor activities against colorectal cancer xenografts. Neoplasia. 2014;16(11):972–981.
   PubMed Web of Science ®Google Scholar
• Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine refractory thyroid cancer. N Engl J Med. 2015;372(7):621–630.
   PubMed Web of Science ®Google Scholar
• Albert DH, Tapang P, Magoc TJ, et al. Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2006;5(4):995–1006.
   PubMed Web of Science ®Google Scholar
• Wong CI, Koh TS, Soo R, et al. Phase I and biomarker study of ABT-869, a multiple receptor tyrosine kinase inhibitor, in patient with refractory solid malignancies. J Clin Oncol. 2009;27(28):4718–4726.
   PubMed Web of Science ®Google Scholar
• Ramalingam SS, Shtivelband M, Soo RA, et al. Randomized phase II study of carboplatin and paclitaxel with either linifanib or placebo for advanced non squamous non–Small-Cell lung cancer. J Clin Oncol. 2015;33(5):433–441.
   PubMed Web of Science ®Google Scholar
• O’Neil BH, Cainap C, Van Cutsem E, et al. Randomized phase II open label study of mFOLFOX6 in combination with linifanib or bevacizumab for metastatic colorectal cancer. Clinical Colorectal Cancer. 2014;13(3):156–163.
   PubMed Web of Science ®Google Scholar
• Polverino A, Coxon A, Starnes C, et al. AMG 706, an oral, multikinase inhibitor that selective targets vascular endothelial growth factor, platelet derived growth factor, and Kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res. 2006;66(17):8715–8721.
   PubMed Web of Science ®Google Scholar
• Rosen LS, Kurzrock R, Mulay M, et al. Safety, pharmacokinetics, and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2007;25(17):2369–2376.
   PubMed Web of Science ®Google Scholar
• Schlumberger MJ, Elisei R, Bastholt L, et al. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol. 2009;27(23):3794–3801.
   PubMed Web of Science ®Google Scholar
• Benjamin RS, Schöffski P, Hartmann JT, et al. Efficacy and safety of motesanib, an oral inhibitor if VEGF, ODGF and Kit receptors, in patients with imatinib-resistant gastrointestinal stromal tumors. Cancer Chemother Pharmacol. 2011;68(1):69–77.
   PubMed Web of Science ®Google Scholar
• Scagliotti GV, Vynnychenko I, Park K, et al. international, randomized, placebo-controlled, double-blind phase III study of Motesanib Plus Carboplatin/Paclitaxel in patients with advanced nonsquamous non–small-cell lung cancer: MONET1. J Clin Oncol. 2012;30(23):2829–2836.
   PubMed Web of Science ®Google Scholar
• Tebbutt N, Kotasek D, Burris HA, et al. Motesanib with or without panitumumab plus FOLFIRI or FOLFOX for the treatment of metastatic colorectal cancer. Cancer Chemoter Pharmacol. 2015;75(5):993–1004.
   PubMed Web of Science ®Google Scholar
• Mehta A, Sonpavde G, Escudier B. Tivozanib for the treatment of renal cell carcinoma: results and implications of the TIVO-1 trial. Future Oncol. 2014;10(11):1819–1826.
   PubMed Web of Science ®Google Scholar
• Hepgur M, Sadeghi S, Dorff TB, et al. Tivozanib in the treatment of renal cell carcinoma. Biologics. 2013;7:139–148.
   PubMedGoogle Scholar
• Motzer RJ, Nosov D, Eisen T, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013;31(30):3791–3799.
   PubMed Web of Science ®Google Scholar
• Oldenhuis CN, Loos WJ, Esteves B, et al. A phase Ib study of the VEGF receptor tyrosine kinase inhibitor tivozanib and modified FOLFOX-6 in patients with advanced gastrointestinal malignancies. Clin Colorectal Cancer. 2015;14(1):18–24.
   PubMed Web of Science ®Google Scholar
• Benson A, Bridgewater JA, Kiss I, et al. BATON-CRC: a phase 2 randomized trial comparing tivozanib (TIVO)+mFOLFOX6 with bevacizumab (BEV)+mFOLFOX6 in stage IV metastatic colorectal cancer (mCRC). Ann Oncol. 2014;25(Supplement 4):iv182. Abstr 533P
   Google Scholar
• Benson A, Krivoshik AK, Van Sant C, et al. Neuropilin-1 as a potential biomarker of progression-free survival benefit for tivozanib plus mFOLFOX6 versus bevacizumab plus mFOLFOX6 in metastatic colorectal cancer: post-hoc biomarker analysis of BATON-CRC phase II trial, Poster presented at the AACR Angiogeneis Meeting; 2015; Orlando, FL. Abstract 24.
   Google Scholar
• Wolpin BM, Ng K, Zhu AX, et al. Multicenter phase II study of Tivozanib (AV-951) and Everolimus (RAD001) for patients with refractory, metastatic colorectal cancer. TheOncologist. 2013;18(4):377–378.
   PubMed Web of Science ®Google Scholar
• Oliner J, Min H, Leal J, et al. Suppression of angiogenesis and tumour growth by selective inhibition of angiopoietin-2. Cancer Cell. 2004;6(5):507–516.
   PubMed Web of Science ®Google Scholar
• Fagiani E, Christofori G. Angiopoietins in angiogenesis. Cancer Lett. 2013;328:18–26.
   PubMed Web of Science ®Google Scholar
• Coxon A, Bready J, Min H, et al. Context-dependent role of angiopoietin-1 inhibition in the suppression of angiogenesis and tumour growth: implications for AMG 386, an angiopoietin-1/2-neutralizing peptibody. Mol Cancer Ther. 2010;9(10):2641–2651.
   PubMed Web of Science ®Google Scholar
• Herbst RS, Hong D, Chap L, et al. Safety, pharmacokinetics, and antitumor activity of AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumours. J Clin Oncol. 2009;27(21):3557–3565.
   PubMed Web of Science ®Google Scholar
• Peeters M, Strickland AH, Lichinitser M, et al. A randomised, double blind, placebo controlled phase 2 study of trebananib (AMG 386) in combination with FOLFIRI in patients with previously treated metastatic colorectal carcinoma. British J of Cancer. 2013;108(3):503–511.
   PubMed Web of Science ®Google Scholar
• Monk BJ, Poveda A, Vergote I, et al. Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014;15(8):799–808.
   PubMed Web of Science ®Google Scholar
• Atkins MB, Gravis G, Drosik K, et al. Trebananib (AMG 386) in combination with sunitinib in patients with metastatic renal cell cancer: an open label, multicentre, phase II study. J Clin Oncol. 2015;33(30):3431–3438.
   Web of Science ®Google Scholar
• Carlomagno F, Vitagliano D, Guida T, et al. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res. 2002;62(24):7284–7290.
   PubMed Web of Science ®Google Scholar
• Wedge SR, Ogilvie DJ, Dukes M, et al. ZD6474 inhibits vascular endothelial growth factor signalling, angiogenesis, and tumour growth following oral administration. Cancer Res. 2002;62(16):4645–4655.
   PubMed Web of Science ®Google Scholar
• Holden SN, Eckhardt SG, Basser R, et al. Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signalling, in patients with solid, malignant tumours. Ann Oncol. 2005;16(8):1391–1397.
   PubMed Web of Science ®Google Scholar
• Saunders MP, Wilson R, Peeters M, et al. Vandetanib with FOLFIRI in patients with advanced colorectal adenocarcinoma: results from an open label, multicentre Phase I study. Cancer Chemother Pharmacol. 2009;64(9):665–672.
   PubMed Web of Science ®Google Scholar
• Michael M, Gibbs P, Smith R, et al. Open-label phase I trial of vandetanib in combination with mFOLFOX6 in patients with advanced colorectal cancer. Invest New Drugs. 2009;27(3):253–261.
   PubMed Web of Science ®Google Scholar
• Meyerhardt JA, Ancukiewicz M, Abrams TA, et al. Phase I study of cetuximab, irinotecan, and vandetanib (ZD6474) as therapy for patients with previously treated metastatic colorectal cancer. Plos One. 2012;7(6):e38231.
   PubMed Web of Science ®Google Scholar
• Cabebe EC, Fisher GA, Sikic BI. A phase I trial of vandetanib with capecitabine, oxaliplatin and bevacizumab for the first line treatment of metastatic colorectal cancer. Invest New Drugs. 2012;30(3):1082–1087.
   PubMed Web of Science ®Google Scholar
• Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III Trial. J Clin Oncol. 2011;30(2):134–141.
   PubMed Web of Science ®Google Scholar
• Lee JS, Hirsh V, Park K, et al. Vandetanib versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor: a randomized, double-blind phase III trial (ZEPHYR). J Clin Oncol. 2012;30(10):1114–1121.
   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 factors induced responses and tumor growth after oral administration. Cancer Res. 2000;60(8):2178–2189.
   PubMed Web of Science ®Google Scholar
• Drevs J, Hofmann I, Hugenschmidt H, et al. Effects of PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessels density, and blood flow in a murine renal cell carcinoma model. Cancer Res. 2000;60(17):4819–4824.
   PubMed Web of Science ®Google Scholar
• Thomas AL, Trarbach T, Bartel C, et al. A phase Ib, open label dose escalating study of the oral angiogenesis inhibitor PTK787/ZK 222584 in combination with FOLFOX4 chemotherapy in patients with advanced colorectal cancer. Ann Oncol. 2007;18(4):782–788.
   PubMed Web of Science ®Google Scholar
• Hecht JR, Trarbach T, Hainsworth JD, et al. Randomized, placebo controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol. 2011;29(15):1997–2003.
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, Bajetta E, Valle J, et al. Randomized, placebo-controlled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK 222584 in patients with previously treated metastatic colorectal adenocarcinoma. J Clin Oncol. 2011;29(15):2004–2010.
   PubMed Web of Science ®Google Scholar
• Sobrero AF, Bruzzi P. Vatalanib in advanced colorectal cancer: two studies with identical results. J Clin Oncol. 2011;29(15):1938–1940.
   PubMed Web of Science ®Google Scholar
• Xu JM, Wang Y, Chen Y, et al. First-in-human (FIH) phase I study of a selective VEGFR/FGFR dual inhibitor sulfatinib with milled formulation in patients with advanced solid tumors. J Clin Oncol. 2014;32:5s (suppl; abstr 2615).
   PubMed Web of Science ®Google Scholar
• Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10(12):2298–2308.
   PubMed Web of Science ®Google Scholar
• Bardelli A, Corso S, Bertotti A, et al. Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov. 2013;3(6):658–673.
   PubMed Web of Science ®Google Scholar
• Hong SW, Jung KH, Park BH, et al. A novel c-Met inhibitor, suppresses cell proliferation and angiogenesis of gastric cancer. Cancer Lett. 2013;332(1):74–82.
   PubMed Web of Science ®Google Scholar
• Elisei R, Schlumberger MJ, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31(29):3639–3646.
   PubMed Web of Science ®Google Scholar
• Sun Y, Sun L, An Y, et al. Cabozantinib a novel c-Met inhibitor inhibits colorectal cancer development in a xenografts model. Med Sci Monit. 2015;21:2316–2321.
   PubMed Web of Science ®Google Scholar
• Song EK, Tai WM, Messersmith WA, et al. Potent antitumor activity of cabozantinib, a c-MET and VEGFR2 inhibitor, in a colorectal cancer patient-derived tumor explant model. Int J Cancer. 2015;136(8):1967–1975.
   PubMed Web of Science ®Google Scholar
• Lee SH. Tanibirumab (TTAC-0001): a fully human monoclonal antibody targets vascular endothelial growth factor receptor 2 (VEGFR). Arch Pharm Res. 2011;34(8):1223–1226.
   PubMed Web of Science ®Google Scholar
• Lee SJ, Ham JS, Kim HK, et al. Phase I trial and pharmacokinetic study of Tanibirumab, a fully human monoclonal antibody to the vascular endothelial growth factor receptor 2 in patients with refractory solid tumors. J Clin Oncol. 2015;33(15):2522.
   Web of Science ®Google Scholar
• Baldwin ME, Tester A, Phelan D, et al. The novel therapeutic monoclonal antibody VGX-100 neutralizes VEGF-C and inhibits tumor growth and metastasis in subcutaneous and orthotropic models of human cancer. Cancer Res. 2011;71(8 Suppl.):LB-24.
   PubMed Web of Science ®Google Scholar
• Falchook GS, Goldman JW, Desai J, et al. A first-in-human phase I study of VGX-100, a selective anti-VEGF-C antibody, alone and in combination with bevacizumab in patients with advanced solid tumors. J Clin Oncol. 2014;32:5s (suppl; abstr 2524).
   PubMed Web of Science ®Google Scholar
• Tian S, Quan H, Xie C, et al. YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci. 2011;102(7):1374–1380.
   PubMed Web of Science ®Google Scholar
• Li J, Zhao X, Chen L, et al. Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies. BMC Cancer. 2010;10:529.
   PubMed Web of Science ®Google Scholar
• Li J, Qin S, Xu J, et al. Apatinib for chemotherapy refractory advanced metastatic gastric cancer: results from a randomized, placebo controlled, parallel arm, phase II trial. J Clin Oncol. 2013;31(26):3219–3225.
   PubMed Web of Science ®Google Scholar
• Qin S, Phase III study of apatinib in advanced gastric cancer: A randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2014;32:5s (suppl; abstr 4003).
   PubMed Web of Science ®Google Scholar
• Kienast Y, Klein C, Scheuer W, et al. Ang-2-VEGF-A CrossMab, a novel bispecific human IgG1 antibody blocking VEGF-A and Ang-2 functions simultaneously, mediates potent antitumor, antiangiogenic, and antimetastatic efficacy. Clin Cancer Res. 2013;19(24):6730–6740.
   PubMed Web of Science ®Google Scholar
• Hidalgo M, Le Tourneau C, Massard C, et al. Results from the fist in human (FIH) phase I study of RO5520985 (RG7221), a novel bispecific human anti ANG2/anti VEGF-A antibody, administered as an intravenous infusion to patients with advanced tumors. J Clin Oncol. 2014;32:5s (suppl; abstr 2525).
   PubMed Web of Science ®Google Scholar
• Oaknin A, Floquet A, Le Tourneau C, et al. Single agent vanucizumab (RO5520985) for platinum (Pt)-resistant recurrent ovarian cancer (OC): results from a single arm extension phase of the phase I FIH study. J Clin Oncol. 2015;33(15):5549.
   Web of Science ®Google Scholar
• Xie C, Zhou J, Guo Z, et al. Metabolism and bio activation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Br J Pharmacol. 2013;168(7):1687–1706.
   PubMed Web of Science ®Google Scholar
• Zhou A, Zhang W, Chang C, et al. Phase I study of the safety, pharmacokinetics and antitumor activity of famitinib. Cancer Chemother Pharmacol. 2013;72(5):1043–1053.
   PubMed Web of Science ®Google Scholar
• Zhang W, Zhou AP, Qin Q, et al. Famitinib in metastatic renal cell carcinoma: a single centre study. Chin Med J. 2013;126(22):4277–4281.
   PubMed Web of Science ®Google Scholar
• Cao J, Zhang J, Wang Z, et al. Hypothyroidism as a potential biomarker of efficacy of famitinib, a novel VEGFR-2 inhibitor in metastatic breast cancer. Cancer Chemother Pharmacol. 2014;74(2):389–398.
   PubMed Web of Science ®Google Scholar
• Xu R, Shen L, Wang K, et al. A randomized, double-blind, parallel-group, placebo-controlled, multicenter, phase II clinical study of famitinib in the treatment of advanced metastatic colorectal cancer. J Clin Oncol. 2015;33(15):513.
   Google Scholar
• Sun Q, Zhou J, Zhang Z, et al. Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR1,2,3 tyrosine kinases for cancer therapy. Cancer Biol Ther. 2014;15(12):1635–1645.
   PubMed Web of Science ®Google Scholar
• Jin L, Cao J, Xu R, et al. A phase Ib study of VEGFR inhibitor fruquintinib in patients with pre-treated advanced colorectal cancer. J Clin Oncol. 2014;32:5s (suppl; abstr 3548).
   PubMed Web of Science ®Google Scholar
• Li J, Xu R, Bai Y, et al. A randomized, double-blind, placebo-controlled multicentre phase II clinical trial of fruquintinib in patients with metastatic colorectal cancer (mCRC). ECCO. 2015. abs.2111
   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):4774–4782.
   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):311–319.
   PubMed Web of Science ®Google Scholar
• Bouche O, Maindrault-Goebel F, Ducreux M, et al. Phase II trial of weekly alternating sequential BIBF 1120 and Afatinib for advanced colorectal cancer. Anticancer Res. 2011;31(6):2271–2282.
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, Prenen H, D’Haens G, et al. A phase I/II, open label, randomised study of nintedanib plus mFOLFOX6 versus bevacizumab plus mFOLOFX6 in first line metastatic colorectal cancer patients. Ann Oncol. 2015;26(10):2085–2091.
   PubMed Web of Science ®Google Scholar
• Lenz HJ, Tabernero J, Yoshino T, et al. LUME-Colon 1: a double blind, randomized phase III study of nintedanib plus best supportive care (BSC) versus placebo plus BCS in patients with colorectal cancer refractory to standard therapies. J Clin Oncol. 2015;33(15):TPS794.
   Google Scholar
• Palmer DH, Ma YT, Peck-Radosavljevic M, et al. Randomized phase II trial comparing the efficacy and safety of nintedanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2015;33(15):238.
   Web of Science ®Google Scholar
• Ellis LM, Bernstein DS, Voest EE, et al. American Society of Clinical Oncology perspective: raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol. 2014;32(12):1277–1280.
   PubMed Web of Science ®Google Scholar