197
Views
8
CrossRef citations to date
0
Altmetric
Review

Vascular endothelial growth factor receptor tyrosine kinase inhibitors for the treatment of advanced non-small cell lung cancer

, , &
Pages 491-506 | Received 07 Aug 2019, Accepted 06 Jan 2020, Published online: 20 Jan 2020

References

  • Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674.
  • Gasti G, Hermann T, Steurer M, et al. Angiogenesis as a target for tumor treatment. Oncology. 1997;54(3):177–184.
  • Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23(5):1011–1027.
  • Betsholtz C, Karlsson L, Lindahl P. Developmental roles of platelet-derived growth factors. Bioessays. 2001;23(6):494–507.
  • Dong J, Grunstein J, Tejada M, et al. VEGF-null cells require PDGFR alpha signalling mediated stromal fibroblast recruitment for tumorigenesis. Embo J. 2004;23(14):2800–2810.
  • Ahmad I, Iwata T, Leung HY. Mechanisms of FGFR-mediated carcinogenesis. Biochim Biophys Acta. 2012;1823(4):850–860.
  • Gaur P, Bose D, Samuel S, et al. Targeting tumor angiogenesis. Semin Oncol. 2009;36(Suppl 1):S12–S19.
  • Rajabi M, Mousa SA. The role of angiogenesis in cancer treatment. Biomedicines. 2017;5(2):34.
  • Ribatti D, Nico B, Crivellato E, et al. The history of the angiogenic switch concept. Leukemia. 2007;21:44–52.
  • Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–676.
  • Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in psychology and medicine. Genes Dev. 2008;22(10):1276–1312.
  • Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298–307.
  • O’Byrne KJ, Koukourakis MI, Giatromanolaki A, et al. Vascular endothelial growth factor, platelet-derived endothelial cell growth factor and angiogenesis in non-small cell lung cancer. Br J Cancer. 2000;82(8):1427–1432.
  • Gotink KJ, Verheul HM. Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis. 2010;13:1–14.
  • Liu Q, Yu S, Zhao W, et al. EGFR-TKIs resistance via EGFR independent signaling pathways. Mol Cancer. 2018;17:53.
  • Cowan-Jacob SW. Structural biology of protein tyrosine kinases. Cell Mol Life Sci. 2006;63:2608–2625.
  • Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2000;103:211–225.
  • Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011–1027.
  • Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov. 2009;8:235–253.
  • Regad T. Targeting RTK Signaling pathways in cancer. Cancers (Basel). 2015;7(3):1758–1784.
  • Ferguson FM, Gray NS. Kinase inhibitors: the road ahead. Nat Rev Drug Discov. 2018;17:353–377.
  • Niland S, Eble JA. Neuropilins in the context of tumor vasculature. Int J Mol Sci. 2019;20(3):E639.
  • Koch S, Tugues S, Li X, et al. Signal transduction by vascular endothelial growth factor receptors. Biochem J. 2011;437(2):169–183.
  • Wang J, Huang Y, Zhang J, et al. NRP-2 in tumor lymphangiogenesis and lymphatic metastasis. Cancer Lett. 2018;418:176–184.
  • Gemmill RM, Nasarre P, Nair-Menon J, et al. The neuropilin 2 isoform NRP2b uniquely supports TGFβ-mediated progression in lung cancer. Sci Signal. 2017;10(462):eaag0528.
  • Lambrechts D, Lenz HJ, de Haas S, et al. Markers of response for the antiangiogenic agent bevacizumab. J Clin Oncol. 2013;31(9):1219–1230.
  • Baumgarten P, Blank AE, Franz K, et al. Differential expression of vascular endothelial growth factor A, its receptors VEGFR-1, −2, and −3 and co-receptors neuropilin-1 and −2 does not predict bevacizumab response in human astrocytomas. Neuro Oncol. 2016;18(2):173–183.
  • Bais C, Mueller B, Brady MF, et al. Tumor microvessel density as a potential predictive marker for bevacizumab benefit: GOG-0218 biomarker analyses. J Natl Cancer Inst. 2017;109:11.
  • Weekes CD, Beeram M, Tolcher AW, et al. A phase I study of the human monoclonal anti-NRP1 antibody MNRP1685A in patients with advanced solid tumors. Invest New Drugs. 2014;32(4):653–660.
  • Patnaik A, LoRusso PM, Messersmith WA, et al. A phase Ib study evaluating MNRP1685A, a fully human anti-NRP1 monoclonal antibody, in combination with bevacizumab and paclitaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2014;73(5):951–960.
  • Jarvis A, Allerston CK, Jia H, et al. Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) interaction. J Med Chem. 2010;53(5):2215–2226.
  • Binétruy-Tournaire R, Demangel C, Malavaud B, et al. Identification of a peptide blocking vascular endothelial growth factor (VEGF)-mediated angiogenesis. Embo J. 2000;19(7):1525–1533.
  • Barr MP, Byrne AM, Duffy AM, et al. A peptide corresponding to the neuropilin-1-binding site on VEGF(165) induces apoptosis of neuropilin-1-expressing breast tumour cells. Br J Cancer. 2005;92(2):328–333.
  • Sidman RL, Li J, Lawrence M, et al. The peptidomimetic Vasotide targets two retinal VEGF receptors and reduces pathological angiogenesis in murine and nonhuman primate models of retinal disease. Sci Transl Med. 2015;7(309):309ra165.
  • Hong TM, Chen YL, Wu YY, et al. Targeting neuropilin 1 as an antitumor strategy in lung cancer. Clin Cancer Res. 2007;13(16):4759–4768.
  • Jia H, Aqil R, Cheng L, et al. N-terminal modification of VEGF-A C terminus-derived peptides delineates structural features involved in neuropilin-1 binding and functional activity. Chembiochem. 2014;15(8):1161–1170.
  • Powell J, Mota F, Steadman D, et al. Small molecule neuropilin-1 antagonists combine antiangiogenic and antitumor activity with immune modulation through reduction of transforming growth factor beta (TGFβ) production in regulatory T-cells. J Med Chem. 2018;61(9):4135–4154.
  • Zhang L, Parry GC, Levin EG. Inhibition of tumor cell migration by LD22-4, an N-terminal fragment of 24-kDa FGF2, is mediated by Neuropilin 1. Cancer Res. 2013;73(11):3316–3325.
  • Kim YJ, Bae J, Shin TH, et al. Immunoglobulin Fc-fused, neuropilin-1-specific peptide shows efficient tumor tissue penetration and inhibits tumor growth via anti-angiogenesis. J Control Release. 2015;216:56–68.
  • 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.
  • 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):143–155.
  • Novello S, Kaiser R, Mellemgaard A, et al. Analysis of patient-reported outcomes from the LUME-Lung 1 trial: a randomised, double-blind, placebo-controlled, Phase III study of second-line nintedanib in patients with advanced non-small cell lung cancer. Eur J Cancer. 2015;51(3):317–326.
  • Hanna NH, Kaiser R, Sullivan RN, et al. Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): a randomized, double-blind, phase III trial. Lung Cancer. 2016;102:65–73.
  • Xie C, Wan X, Quan H, et al. Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor-2 inhibitor. Cancer Sci. 2018;109:1207–1219.
  • Taurin S, Yang CH, Reyes M, et al. Treatment of endometrial cancer cells with a new small tyrosine kinase inhibitor targeting mutated fibroblast growth factor receptor-2. Cancer Res. 2017;77(Suppl 13):3244.
  • Lin B, Song X, Yang D, et al. Anlotinib inhibits angiogenesis via suppressing the activation of VEGFR2, PDGFRβ and FGFR1. Gene. 2018;654:77–86.
  • Chia Tai Tianqing Pharmaceutical. Anlotinib hydrochloride capsules. 2018. cited 2019 Jul 29]. Available from: https://www.cttq.com.
  • Taurin S, Yang CH, Reyes M, et al. Endometrial cancers harboring mutated fibroblast growth factor receptor 2 protein are successfully treated with a new small tyrosine kinase inhibitor in an orthotopic mouse model. Int J Gynecol Cancer. 2018;28(1):152–160.
  • Sun Y, Niu W, Du F, et al. Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors. J Hematol Oncol. 2016;9(1):105.
  • Han B, Li K, Zhao Y, et al. Anlotinib as a third-line therapy in patients with refractory advanced non-small cell lung cancer: a multicentre, randomised phase II trial (ALTER0302). Br J Cancer. 2018;118:654–661.
  • Han B, Li K, Wang Q, et al. Third-line treatment: a randomized, double-blind, placebo-controlled phase III ALTER-0303 study – efficacy and safety of anlotinib treatment in patients with refractory advanced NSCLC. J Clin Oncol. 2017;35(Suppl 15):9053.
  • Li K, Han B, Wang Q, et al. OS outcomes to anlotinib in patients (pts) with refractory NSCLC of both wild-type (WT) and mutant EGFR. J Clin Oncol. 2018;36(Suppl 15):e21013.
  • Shi J, Han B, Li K, et al. Subgroup analysis of elderly patients (pts) in ALTER0303: anlotinib hydrochloride as 3rd-line and further line treatment in refractory advanced NSCLC pts from a randomized, double-blind, placebo-controlled phase III ALTER0303 trial. J Clin Oncol. 2018;36(Suppl 15):e21181.
  • Cheng Y, Han B, Li K, et al. Subgroup analysis of histology in ALTER0303: anlotinib hydrochloride as 3rd line and further line treatment in refractory advanced NSCLC patients (pts). J Clin Oncol. 2018;36(Suppl 15):9080.
  • Han B, Li K, Wang Q, et al. Efficacy and safety of third-line treatment with anlotinib in patients with refractory advanced non-small cell lung cancer (ALTER-0303): a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2017;18(Suppl 1):S3.
  • Liu Z, Wang J, Meng Z, et al. Analysis on ALTER0303 trial: aCECs level may correlate with metastases burden and predict PFS of anlotinib in advanced NSCLC. J Thorac Oncol. 2017;12:S2234–5.
  • Han B, Zhao Y, Li K, et al. P3. Blood samples NGS for baseline molecular signature of anlotinib treated advanced NSCLC patients in ALTER0303 trial. J Thorac Oncol. 2017;12:S2279.
  • Wakelee HA, Lee JW, Hanna NH, et al. A double-blind randomized discontinuation phase II study of sorafenib (BAY 43-9006) in previously treated non-small cell lung cancer patients: eastern cooperative oncology group study E2501. J Thorac Oncol. 2012;7:1574–1582.
  • Spigel DR, Burris HA 3rd, Greco FA, et al. Randomized, double-blind, placebo-controlled, phase II trial of sorafenib and erlotinib or erlotinib alone in previously treated advanced non-small cell lung cancer. J Clin Oncol. 2011;29:2582–2589.
  • Molina JR, Dy GK, Foster NR, et al. A randomized phase II study of pemetrexed (PEM) with or without sorafenib (S) as second-line therapy in advanced non-small cell lung cancer (NSCLC) of nonsquamous histology: NCCTG N0626 study. J Clin Oncol. 2011;29(Suppl 15):7513.
  • Paz-Ares L, Hirsh V, Zhang L, et al. Monotherapy administration of sorafenib in patients with non-small cell lung cancer (MISSION) trial. J Thorac Oncol. 2015;10:1745–1753.
  • Paz-Ares LG, Biesma B, Heigener D, et al. Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small cell lung cancer. J Clin Oncol. 2012;30:3084–3092.
  • Scagliotti G, Novello S, von Pawel J, et al. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small cell lung cancer. J Clin Oncol. 2010;28:1835–1842.
  • Nassif E, Thibault C, Vano Y, et al. Sunitinib in kidney cancer: 10 years of experience and development. Expert Rev Anticancer Ther. 2017;17(2):129–142.
  • Heist RS, Wang X, Hodgson L, et al. A randomized phase II study to assess the efficacy of pemetrexed or sunitinib or pemetrexed plus sunitinib in the second-line treatment of advanced non-small-cell lung cancer. J Thorac Oncol. 2014;9:214–221.
  • Baggstrom MQ, Socinski MA, Wang XF, et al. Maintenance sunitinib following initial platinum-based combination chemotherapy in advanced-stage IIIB/IV non-small cell lung cancer: a randomized, double-blind, placebo-controlled phase III study-CALGB 30607. J Thorac Oncol. 2017;12(5):843–849.
  • Groen HJ, Socinski MA, Grossi F, et al. A randomized, double-blind, phase II study of erlotinib with or without sunitinib for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC). Ann Oncol. 2013;24:2382–2389.
  • 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;30:2070–2078.
  • 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;11:619–626.
  • 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;29:1067–1074.
  • Natale RB, Thongprasert S, Greco FA, et al. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small cell lung cancer. J Clin Oncol. 2011;29:1059–1066.
  • 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;30:1114–1121.
  • Gainor JF, Shaw AT. Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist. 2013;18(7):865–875.
  • Yoh K, Seto T, Satouchi M, et al. Vandetanib in patients with previously treated RET-rearranged advanced non-small cell lung cancer (LURET): an open-label, multicentre phase 2 trial. Lancet Respir Med. 2017;5(1):42–50.
  • Lee SH, Lee JK, Ahn MJ, et al. Vandetanib in pretreated patients with advanced non-small cell lung cancer-harboring RET rearrangement: a phase II clinical trial. Ann Oncol. 2017;28(2):292–297.
  • Heymach J, Paz-Ares L, De Braud F, et al. Randomized phase II study of vandetanib alone or with paclitaxel and carboplatin as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol. 2008;26:5407–5415.
  • Gridelli C, Novello S, Zilembo N, et al. Phase II randomized study of vandetanib plus gemcitabine or gemcitabine plus placebo as first-line treatment of advanced non-small cell lung cancer in elderly patients. J Thorac Oncol. 2014;9(5):733–737.
  • 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;102:1374–1380.
  • Ding J, Chen X, Gao Z, et al. Metabolism and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor apatinib in humans. Drug Metab Dispos. 2013;41:1195–1210.
  • Mi YJ, Liang YJ, Huang HB, et al. Apatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters. Cancer Res. 2010;70:7981–7991.
  • Zhang L, Shi MQ, 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 15):7548.
  • Song Z, Yu X, Lou G, et al. Salvage treatment with apatinib for advanced non-small cell lung cancer. Onco Targets Ther. 2017;10:1821–1825.
  • Liu Z, Ou W, Li N, et al. Apatinib monotherapy for advanced non-small cell lung cancer after the failure of chemotherapy or other targeted therapy. Thorac Cancer. 2018;9(10):1285–1290.
  • Wu D, Liang L, Nie L, et al. Efficacy, safety and predictive indicators of apatinib after multilines treatment in advanced nonsquamous nonsmall cell lung cancer: apatinib treatment in nonsquamous NSCLC. Asia Pac J Clin Oncol. 2018;14(6):446–452.
  • Hellerstedt BA, Edelman G, Vogelzang NJ, et al. Activity of cabozantinib (XL184) in metastatic NSCLC: results from a phase II randomized discontinuation trial (RDT). J Clin Oncol. 2012;30(Suppl 15):7514.
  • Neal JW, Dahlberg SE, Wakelee HA, et al. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol. 2016;17:1661–1671.
  • Belani CP, Yamamoto N, Bondarenko IM, et al. Randomized phase II study of pemetrexed/cisplatin with or without axitinib for non-squamous non-small cell lung cancer. BMC Cancer. 2014;14:290.
  • Twelves C, Chmielowska E, Havel L, et al. Randomised phase II study of axitinib or bevacizumab combined with paclitaxel/carboplatin as first-line therapy for patients with advanced non-small cell lung cancer. Ann Oncol. 2014;25:132–138.
  • Bondarenko IM, Ingrosso A, Bycott P, et al. Phase II study of axitinib with doublet chemotherapy in patients with advanced squamous non-small cell lung cancer. BMC Cancer. 2015;15:339.
  • Goss GD, Arnold A, Shepherd FA, et al. Randomized, double-blind trial of carboplatin and paclitaxel with either daily oral cediranib or placebo in advanced non-small cell lung cancer: NCIC Clinical Trials Group BR24 study. J Clin Oncol. 2010;28:49–55.
  • Laurie SA, Solomon BJ, Seymour L, et al. Randomized, double-blind trial of carboplatin and paclitaxel with daily cediranib or placebo in patients with advanced non-small cell lung cancer: NCIC Clinical Trials Group study BR29. Eur J Cancer. 2014;50:706–712.
  • Dy GK, Mandrekar SJ, Nelson GD, et al. A randomized phase II study of gemcitabine and carboplatin with or without cediranib as first-line therapy in advanced non-small cell lung cancer: North central cancer treatment group study N0528. J Thorac Oncol. 2013;8(1):79–88.
  • Gadgeel SM, Ruckdeschel JC, Wozniak AJ, et al. Cediranib, a VEGF receptor 1, 2, and 3 inhibitor, and pemetrexed in patients (pts) with recurrent non-small cell lung cancer (NSCLC). J Clin Oncol. 2011;29(Suppl 15):7564.
  • Polverino A, Coxon A, Starnes C, et al. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res. 2006;66:8715–8721.
  • 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;30:2829–2836.
  • Kubota K, Yoshioka H, Oshita F, et al. Phase III, randomized, placebo-controlled, double-blind trial of motesanib (AMG-706) in combination with paclitaxel and carboplatin in East Asian patients with advanced nonsquamous non-small cell lung cancer. J Clin Oncol. 2017;35(32):3662–3670.
  • Tan EH, Goss GD, Salgia R, et al. Phase 2 trial of linifanib (ABT-869) in patients with advanced non-small cell lung cancer. J Thorac Oncol. 2011;6(8):1418–1425.
  • Ramalingam SS, Shtivelband M, Soo RA, et al. Randomized phase II study of carboplatin and paclitaxel with either linifanib or placebo for advanced nonsquamous non-small cell lung cancer. J Clin Oncol. 2015;33(5):433–441.
  • Podar K, Tonon G, Sattler M, et al. The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma. Proc Natl Acad Sci U S A. 2006;103(51):19478–19483.
  • Spigel DR, Burris HA 3rd, Greco FA, et al. Erlotinib plus either pazopanib or placebo in patients with previously treated advanced non-small cell lung cancer: a randomized, placebo-controlled phase 2 trial with correlated serum proteomic signatures. Cancer. 2018;124(11):2355–2364.
  • Xu JM, Wang Y, Chen YL, et al. Sulfatinib, a novel kinase inhibitor, in patients with advanced solid tumors: results from a phase I study. Oncotarget. 2017;8:42076–42086.
  • Shirley M. Fruquintinib: first global approval. Drugs. 2018;78(16):1757–1761.
  • Westendorf A, Skibbe K, Adamczyk A, et al. Hypoxia enhances immunosuppression by inhibiting CD4+ effector T cell function and promoting Treg activity. Cell Physiol Biochem. 2017;41(4):1271–1284.
  • Gabrilovich D, Ishida T, Oyama T, et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood. 1998;92(11):4150–4166.
  • Dirkx AEM, Oude Egbrink MGA, Kuijpers MJE, et al. Tumor angiogenesis modulates leukocyte-vessel wall interactions by reducing endothelial adhesion molecule expression. Cancer Res. 2003;63(9):2322–2329.
  • Fukumura D, Kloepper J, Amoozgar Z, et al. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018;15:325.
  • De Bock K. Cauwenberghs S, Carmeliet P. Vessel abnormalization: another hallmark of cancer? Molecular mechanisms and therapeutic implications. Curr Opin Genet Dev. 2011;21(1):73–79.
  • Mauge L, Terme M, Tartour E, et al. Control of the adaptive immune response by tumor vasculature. Front Oncol. 2014;4:61.
  • Slaney CY, Kershaw MH, Darcy PK. Trafficking of T cells into tumors. Cancer Res. 2014;74(24):7168–7174.
  • Peske JD, Woods AB, Engelhard VH. Control of CD8 T-cell infiltration into tumors by vasculature and microenvironment. Adv Cancer Res. 2015;128:263–307.
  • Lanitis E, Irving M, Coukos G. Targeting the tumor vasculature to enhance T cell activity. Curr Opin Immunol. 2015;33:55–63.
  • Motz GT, Santoro SP, Wang LP, et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med. 2014;20(6):607–615.
  • Meder L, Schuldt P, Thelen M, et al. Combined VEGF and PD-L1 blockade displays synergistic treatment effects in an autochthonous mouse model of small cell lung cancer. Cancer Res. 2018;78(15):4270–4281.
  • Yasuda S, Sho M, Yamato I, et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clin Exp Immunol. 2013;172(3):500–506.
  • Schmittnaegel M, Rigamonti N, Kadioglu E, et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci Transl Med. 2017;9(385):eaak9670.
  • Du Four S, Maenhout SK, Niclou SP, et al. Combined VEGFR and CTLA-4 blockade increases the antigen-presenting function of intratumoral DCs and reduces the suppressive capacity of intratumoral MDSCs. Am J Cancer Res. 2016;6(11):2514–2531.
  • Voron T, Colussi O, Marcheteau E, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med. 2015;212(2):139–148.
  • Ager A. High endothelial venules and other blood vessels: critical regulators of lymphoid organ development and function. Front Immunol. 2017;8:45.
  • Sautès-Fridman C, Lawand M, Giraldo NA, et al. Tertiary lymphoid structures in cancers: prognostic value, regulation, and manipulation for therapeutic intervention. Front Immunol. 2016;7:407.
  • Noman MZ, Desantis G, Janji B, et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211(5):781–790.
  • Allen E, Jabouille A, Rivera LB, et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med. 2017;12(385):9.
  • Varga A, Baldini C, Martin-Roman P, et al. Safety and efficacy results from a phase I dose-escalation trial of nintedanib in combination with pembrolizumab in patients with advanced solid tumors (PEMBIB trial). J Clin Oncol. 2018;36(Suppl 15):3080.
  • Conesa-Milián L, Falomir E, Murga J, et al. Novel multitarget inhibitors with antiangiogenic and immunomodulator properties. Eur J Med Chem. 2019;170:87–98.
  • De Luca A, Carotenuto A, Rachiglio A, et al. The role of the EGFR signaling in tumor microenvironment. J Cell Physiol. 2007;214(3):559–567.
  • Ciardiello F, Caputo R, Damiano V, et al. Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase. Clin Cancer Res. 2003;9(4):1546–1556.
  • Natale RB, Bodkin D, Govindan R, et al. Vandetanib versus gefitinib in patients with advanced non-small cell lung cancer: results from a two-part, double-blind, randomized phase II study. J Clin Oncol. 2009;27(15):2523–2529.
  • Herbst RS, Ansari R, Bustin F, et al. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet. 2011;377(9780):1846–1854.
  • Zhao Y, Wang H, Shi Y, et al. Comparative effectiveness of combined therapy inhibiting EGFR and VEGF pathways in patients with advanced non-small cell lung cancer: a meta-analysis of 16 phase II/III randomized trials. Oncotarget. 2017;8(4):7014–7024.
  • Hall RD, Le TM, Haggstrom DE, et al. Angiogenesis inhibition as a therapeutic strategy in non-small cell lung cancer (NSCLC). Transl Lung Cancer Res. 2015;4(5):515–523.
  • 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):1227–1234.
  • Zhou C, Wu YL, Chen G, et al. BEYOND: a randomized, double-blind, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small cell lung cancer. J Clin Oncol. 2015;33(19):2197–2204.
  • 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):2542–2550.
  • Garon EB, Ciuleanu T-E, 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, randomized phase 3 trial. Lancet. 2014;384(9944):665–673.
  • Zhao Y, Adjei AA. Targeting angiogenesis in cancer therapy: moving beyond vascular endothelial growth factor. Oncologist. 2015;20:660–673.
  • Soria J-C, Mauguen A, Reck M, et al. Systematic review and meta-analysis of randomized, 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.
  • Lima ABC, Macedo LT, Sasse AD. Addition of bevacizumab to chemotherapy in advanced non-small cell lung cancer: a systematic review and meta-analysis. PLoS One. 2011;6(8):e22681.
  • Raphael J, Chan K, Karim S, et al. Antiangiogenic therapy in advanced non-small cell lung cancer: a meta-analysis of phase III randomized trials. Clin Lung Cancer. 2017;18(4):345–353.
  • Potente M, Carmeliet P. The link between angiogenesis and endothelial metabolism. Annu Rev Physiol. 2017;79:43–66.
  • Zecchin A, Kalucka J, Dubois C, et al. How endothelial cells adapt their metabolism to form vessels in tumors. Front Immunol. 2017;8:1750.
  • Manzo A, Montanino A, Carillio G, et al. Angiogenesis inhibitors in NSCLC. Int J Mol Sci. 2017;18(10):e2021.
  • Lung-MAP precision medicine trial expands to include more patients. Lung Cancer Master Protocol. Published January 29, 2019. [cited 2019 Jul 29]. Available from: https://bit.ly/2HD4GLf.
  • Duignan IJ, Corcoran E, Pennello A, et al. Pleiotropic stromal effects of vascular endothelial growth factor receptor 2 antibody therapy in renal cell carcinoma models. Neoplasia. 2011;13:49–59.
  • Espinosa Bosch M, Asensi Diez R, García Agudo S, et al. Nintedanib in combination with docetaxel for second-line treatment of advanced non-small cell lung cancer; GENESIS-SEFH drug evaluation report. Farm Hosp. 2016;40(4):316–327.
  • Hong SD, Fang WF, Liang WH, et al. Risk of treatment-related deaths with vascular endothelial growth factor receptor tyrosine kinase inhibitors: a meta-analysis of 41 randomized controlled trial. Onco Targets Ther. 2014;7:1851–1867.
  • Wang S, Yang Z, Wang Z. Are VEGFR-TKIs effective or safe for patients with advanced non-small cell lung cancer? Oncotarget. 2015;6:18206–18223.
  • Gu B, Gao WC, Chu HJ, et al. Adverse events risk associated with anti-VEGFR agents in the treatment of advanced non-small cell lung cancer: a meta-analysis. Medicine (Baltimore). 2016;95(48):e3752.
  • Li BT, Barnes TA, Chan DL, et al. The addition of anti-angiogenic tyrosine kinase inhibitors to chemotherapy for patients with advanced non-small cell lung cancers: a meta-analysis of randomized trials. Lung Cancer. 2016;102:21–27.
  • Lv WW, Zhang JJ, Zhou XL, et al. Safety of combining vascular endothelial growth factor receptor tyrosine-kinase inhibitors with chemotherapy in patients with advanced non-small cell lung cancer: A PRISMA-compliant meta-analysis. Medicine (Baltimore). 2019;98(23):e15806.
  • Liu L, Zhang Y, Wei J, et al. VEGFR-TKIs combined with chemotherapy for advanced non-small cell lung cancer: a systematic review. J Cancer. 2019;10(4):799–809.
  • Ma W, Xu M, Liu Y, et al. Safety profile of combined therapy inhibiting EFGR and VEGF pathways in patients with advanced non-small cell lung cancer: a meta-analysis of 15 phase II/III randomized trials. Int J Cancer. 2015;137(2):409–419.
  • Gottfried M, Bennouna J, Bondarenko I, et al. Efficacy and safety of nintedanib plus docetaxel in patients with advanced lung adenocarcinoma: complementary and exploratory analyses of the phase III LUME-Lung 1 study. Target Oncol. 2017;12(4):475–485.
  • Commmitee for Medicinal Products for Human Use (CHMP). European Medicines Agency Assessment report of Opdivo. EMA/246304/2016.
  • Corral J, Majem M, Rodríguez-Abreu D, et al. Efficacy of nintedanib and docetaxel in patients with advanced lung adenocarcinoma treated with first-line chemotherapy and second-line immunotherapy in the nintedanib NPU program. Clin Transl Oncol. 2019 Feb 15. DOI:10.1007/s12094-019-02053-7.
  • Grohé C, Blau W, Gleiber W, et al. Nintedanib plus docetaxel in lung adenocarcinoma patients (pts) following treatment with immune checkpoint inhibitors (ICIs): preliminary efficacy and safety results of the non-interventional study VARGADO. J Clin Oncol. 2019;37(Suppl 15):9074.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.