Anti-VEGF/VEGFR2 Monoclonal Antibodies and their Combinations with PD-1/PD-L1 Inhibitors in Clinic

Feng       Gao; Chun       Yang
doi:10.2174/1568009619666191114110359
Abstract

The vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling pathway is one of the most important pathways responsible for tumor angiogenesis. Currently, two monoclonal antibodies, anti-VEGF-A antibody Bevacizumab and anti-VEGFR2 antibody Ramucizumab, have been approved for the treatment of solid tumors. At the same time, VEGF/VEGFR2 signaling is involved in the regulation of immune responses. It is reported that the inhibition of this pathway has the capability to promote vascular normalization, increase the intra-tumor infiltration of lymphocytes, and decrease the number and function of inhibitory immune cell phenotypes, including Myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and M2 macrophages. On this basis, a number of clinical studies have been performed to investigate the therapeutic potential of VEGF/VEGFR2-targeting antibodies plus programmed cell death protein 1 (PD-1)/ programmed cell death ligand 1 (PD-L1) inhibitors in various solid tumor types. In this context, VEGF/VEGFR2- targeting antibodies, Bevacizumab and Ramucizumab are briefly introduced, with a description of the differences between them, and the clinical studies involved in the combination of Bevacizumab/ Ramucizumab and PD-1/PD-L1 inhibitors are summarized. We hope this review article will provide some valuable clues for further clinical studies and usages.
Keywords: Cancer immunotherapy, immune checkpoint inhibitors, combination cancer therapy, PD-1/PD-L1 mechanism, tumor angiogenesis, VEGF/VEGFR2 signaling.
« Previous Next »
Graphical Abstract

[1] 
Groebe, K.; Vaupel, P. Evaluation of oxygen diffusion distances in human breast cancer xenografts using tumor-specific in vivo data: Role of various mechanisms in the development of tumor hypoxia. Int. J. Radiat. Oncol. Biol. Phys.,  1988, 15(3), 691-697.
[http://dx.doi.org/10.1016/0360-3016(88)90313-6] [PMID:  3417489] 
[2] 
Olive, P.L.; Vikse, C.; Trotter, M.J. Measurement of oxygen diffusion distance in tumor cubes using a fluorescent hypoxia probe. Int. J. Radiat. Oncol. Biol. Phys.,  1992, 22(3), 397-402.
[http://dx.doi.org/10.1016/0360-3016(92)90840-E] [PMID:  1735668] 
[3] 
Nakazawa, M.S.; Keith, B.; Simon, M.C. Oxygen availability and metabolic adaptations. Nat. Rev. Cancer,  2016, 16(10), 663-673.
[http://dx.doi.org/10.1038/nrc.2016.84] [PMID:  27658636] 
[4] 
Gao, F.; Liang, B.; Reddy, S.T.; Farias-Eisner, R.; Su, X. Role of inflammation-associated microenvironment in tumorigenesis and metastasis. Curr. Cancer Drug Targets,  2014, 14(1), 30-45.
[http://dx.doi.org/10.2174/15680096113136660107] [PMID:  24200082] 
[5] 
De Palma, M.; Biziato, D.; Petrova, T.V. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer,  2017, 17(8), 457-474.
[http://dx.doi.org/10.1038/nrc.2017.51] [PMID:  28706266] 
[6] 
Saharinen, P.; Eklund, L.; Pulkki, K.; Bono, P.; Alitalo, K. VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol. Med.,  2011, 17(7), 347-362.
[http://dx.doi.org/10.1016/j.molmed.2011.01.015] [PMID:  21481637] 
[7] 
Raica, M.; Cimpean, A.M. Platelet-Derived Growth Factor (PDGF)/PDGF Receptors (PDGFR) Axis as Target for Antitumor and Antiangiogenic Therapy. Pharmaceuticals (Basel),  2010, 3(3), 572-599.
[http://dx.doi.org/10.3390/ph3030572] [PMID:  27713269] 
[8] 
Kofler, N.M.; Shawber, C.J.; Kangsamaksin, T.; Reed, H.O.; Galatioto, J.; Kitajewski, J. Notch signaling in developmental and tumor angiogenesis. Genes Cancer,  2011, 2(12), 1106-1116.
[http://dx.doi.org/10.1177/1947601911423030] [PMID:  22866202] 
[9] 
Shibuya, M. Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies. Genes Cancer,  2011, 2(12), 1097-1105.
[http://dx.doi.org/10.1177/1947601911423031] [PMID:  22866201] 
[10] 
Sawano, A.; Iwai, S.; Sakurai, Y.; Ito, M.; Shitara, K.; Nakahata, T.; Shibuya, M. Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood,  2001, 97(3), 785-791.
[http://dx.doi.org/10.1182/blood.V97.3.785] [PMID:  11157498] 
[11] 
Gerber, H.P.; Malik, A.K.; Solar, G.P.; Sherman, D.; Liang, X.H.; Meng, G.; Hong, K.; Marsters, J.C.; Ferrara, N. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature,  2002, 417(6892), 954-958.
[http://dx.doi.org/10.1038/nature00821] [PMID:  12087404] 
[12] 
Gabrilovich, D.I.; Chen, H.L.; Girgis, K.R.; Cunningham, H.T.; Meny, G.M.; Nadaf, S.; Kavanaugh, D.; Carbone, D.P. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat. Med.,  1996, 2(10), 1096-1103.
[http://dx.doi.org/10.1038/nm1096-1096] [PMID:  8837607] 
[13] 
McMahon, G. VEGF receptor signaling in tumor angiogenesis. Oncologist,  2000, 5(Suppl. 1), 3-10.
[http://dx.doi.org/10.1634/theoncologist.5-suppl_1-3] [PMID:  10804084] 
[14] 
Hoeben, A.; Landuyt, B.; Highley, M.S.; Wildiers, H.; Van Oosterom, A.T.; De Bruijn, E.A. Vascular endothelial growth factor and angiogenesis. Pharmacol. Rev.,  2004, 56(4), 549-580.
[http://dx.doi.org/10.1124/pr.56.4.3] [PMID:  15602010] 
[15] 
Li, Y.L.; Zhao, H.; Ren, X.B. Relationship of VEGF/VEGFR with immune and cancer cells: staggering or forward? Cancer Biol. Med.,  2016, 13(2), 206-214.
[http://dx.doi.org/10.20892/j.issn.2095-3941.2015.0070] [PMID:  27458528] 
[16] 
Stacker, S.A.; Achen, M.G.; Jussila, L.; Baldwin, M.E.; Alitalo, K. Lymphangiogenesis and cancer metastasis. Nat. Rev. Cancer,  2002, 2(8), 573-583.
[http://dx.doi.org/10.1038/nrc863] [PMID:  12154350] 
[17] 
Hsu, M.C.; Pan, M.R.; Hung, W.C. Two Birds, One Stone: Double Hits on Tumor Growth and Lymphangiogenesis by Targeting Vascular Endothelial Growth Factor Receptor 3. Cells,  2019, 8(3), 8.
[http://dx.doi.org/10.3390/cells8030270] [PMID:  30901976] 
[18] 
Hurwitz, H.; Fehrenbacher, L.; Novotny, W.; Cartwright, T.; Hainsworth, J.; Heim, W.; Berlin, J.; Baron, A.; Griffing, S.; Holmgren, E.; Ferrara, N.; Fyfe, G.; Rogers, B.; Ross, R.; Kabbinavar, F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med.,  2004, 350(23), 2335-2342.
[http://dx.doi.org/10.1056/NEJMoa032691] [PMID:  15175435] 
[19] 
Giantonio, B.J.; Catalano, P.J.; Meropol, N.J.; O’Dwyer, P.J.; Mitchell, E.P.; Alberts, S.R.; Schwartz, M.A.; Benson, A.B. III Eastern Cooperative Oncology Group Study E3200. 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), 1539-1544.
[http://dx.doi.org/10.1200/JCO.2006.09.6305] [PMID:  17442997] 
[20] 
Sandler, A.; Gray, R.; Perry, M.C.; Brahmer, J.; Schiller, J.H.; Dowlati, A.; Lilenbaum, R.; Johnson, D.H. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med.,  2006, 355(24), 2542-2550.
[http://dx.doi.org/10.1056/NEJMoa061884] [PMID:  17167137] 
[21] 
Vredenburgh, J.J.; Desjardins, A.; Herndon, J.E., II; Marcello, J.; Reardon, D.A.; Quinn, J.A.; Rich, J.N.; Sathornsumetee, S.; Gururangan, S.; Sampson, J.; Wagner, M.; Bailey, L.; Bigner, D.D.; Friedman, A.H.; Friedman, H.S. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J. Clin. Oncol.,  2007, 25(30), 4722-4729.
[http://dx.doi.org/10.1200/JCO.2007.12.2440] [PMID:  17947719] 
[22] 
Escudier, B.; Pluzanska, A.; Koralewski, P.; Ravaud, A.; Bracarda, S.; Szczylik, C.; Chevreau, C.; Filipek, M.; Melichar, B.; Bajetta, E.; Gorbunova, V.; Bay, J.O.; Bodrogi, I.; Jagiello-Gruszfeld, A.; Moore, N. AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet,  2007, 370(9605), 2103-2111.
[http://dx.doi.org/10.1016/S0140-6736(07)61904-7] [PMID:  18156031] 
[23] 
Tewari, K.S.; Sill, M.W.; Long, H.J., III; Penson, R.T.; Huang, H.; Ramondetta, L.M.; Landrum, L.M.; Oaknin, A.; Reid, T.J.; Leitao, M.M.; Michael, H.E.; Monk, B.J. Improved survival with bevacizumab in advanced cervical cancer. N. Engl. J. Med.,  2014, 370(8), 734-743.
[http://dx.doi.org/10.1056/NEJMoa1309748] [PMID:  24552320] 
[24] 
Penson, R.T.; Huang, H.Q.; Wenzel, L.B.; Monk, B.J.; Stockman, S.; Long, H.J., III; Ramondetta, L.M.; Landrum, L.M.; Oaknin, A.; Reid, T.J.; Leitao, M.M.; Method, M.; Michael, H.; Tewari, K.S. Bevacizumab for advanced cervical cancer: patient-reported outcomes of a randomised, phase 3 trial (NRG Oncology-Gynecologic Oncology Group protocol 240). Lancet Oncol.,  2015, 16(3), 301-311.
[http://dx.doi.org/10.1016/S1470-2045(15)70004-5] [PMID:  25638326] 
[25] 
Tewari, K.S.; Sill, M.W.; Penson, R.T.; Huang, H.; Ramondetta, L.M.; Landrum, L.M.; Oaknin, A.; Reid, T.J.; Leitao, M.M.; Michael, H.E.; DiSaia, P.J.; Copeland, L.J.; Creasman, W.T.; Stehman, F.B.; Brady, M.F.; Burger, R.A.; Thigpen, J.T.; Birrer, M.J.; Waggoner, S.E.; Moore, D.H.; Look, K.Y.; Koh, W.J.; Monk, B.J. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet,  2017, 390(10103), 1654-1663.
[http://dx.doi.org/10.1016/S0140-6736(17)31607-0] [PMID:  28756902] 
[26] 
Burger, R.A.; Brady, M.F.; Bookman, M.A.; Fleming, G.F.; Monk, B.J.; Huang, H.; Mannel, R.S.; Homesley, H.D.; Fowler, J.; Greer, B.E.; Boente, M.; Birrer, M.J.; Liang, S.X. Gynecologic Oncology Group. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N. Engl. J. Med.,  2011, 365(26), 2473-2483.
[http://dx.doi.org/10.1056/NEJMoa1104390] [PMID:  22204724] 
[27] 
Perren, T.J.; Swart, A.M.; Pfisterer, J.; Ledermann, J.A.; Pujade-Lauraine, E.; Kristensen, G.; Carey, M.S.; Beale, P.; Cervantes, A.; Kurzeder, C.; du Bois, A.; Sehouli, J.; Kimmig, R.; Stähle, A.; Collinson, F.; Essapen, S.; Gourley, C.; Lortholary, A.; Selle, F.; Mirza, M.R.; Leminen, A.; Plante, M.; Stark, D.; Qian, W.; Parmar, M.K.; Oza, A.M. ICON7 Investigators. A phase 3 trial of bevacizumab in ovarian cancer. N. Engl. J. Med.,  2011, 365(26), 2484-2496.
[http://dx.doi.org/10.1056/NEJMoa1103799] [PMID:  22204725] 
[28] 
Burger, R.A.; Brady, M.F.; Rhee, J.; Sovak, M.A.; Kong, G.; Nguyen, H.P.; Bookman, M.A. Independent radiologic review of the Gynecologic Oncology Group Study 0218, a phase III trial of bevacizumab in the primary treatment of advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. Gynecol. Oncol.,  2013, 131(1), 21-26.
[http://dx.doi.org/10.1016/j.ygyno.2013.07.100] [PMID:  23906656] 
[29] 
Miller, K.; Wang, M.; Gralow, J.; Dickler, M.; Cobleigh, M.; Perez, E.A.; Shenkier, T.; Cella, D.; Davidson, N.E. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N. Engl. J. Med.,  2007, 357(26), 2666-2676.
[http://dx.doi.org/10.1056/NEJMoa072113] [PMID:  18160686] 
[30] 
Robert, N.J.; Diéras, V.; Glaspy, J.; Brufsky, A.M.; Bondarenko, I.; Lipatov, O.N.; Perez, E.A.; Yardley, D.A.; Chan, S.Y.; Zhou, X.; Phan, S.C.; O’Shaughnessy, J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J. Clin. Oncol.,  2011, 29(10), 1252-1260.
[http://dx.doi.org/10.1200/JCO.2010.28.0982] [PMID:  21383283] 
[31] 
Brufsky, A.M.; Hurvitz, S.; Perez, E.; Swamy, R.; Valero, V.; O’Neill, V.; Rugo, H.S. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J. Clin. Oncol.,  2011, 29(32), 4286-4293.
[http://dx.doi.org/10.1200/JCO.2010.34.1255] [PMID:  21990397] 
[32] 
Zielinski, C.; Láng, I.; Inbar, M.; Kahán, Z.; Greil, R.; Beslija, S.; Stemmer, S.M.; Zvirbule, Z.; Steger, G.G.; Melichar, B.; Pienkowski, T.; Sirbu, D.; Petruzelka, L.; Eniu, A.; Nisenbaum, B.; Dank, M.; Anghel, R.; Messinger, D.; Brodowicz, T. TURANDOT investigators. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial. Lancet Oncol.,  2016, 17(9), 1230-1239.
[http://dx.doi.org/10.1016/S1470-2045(16)30154-1] [PMID:  27501767] 
[33] 
Fuchs, C.S.; Tomasek, J.; Yong, C.J.; Dumitru, F.; Passalacqua, R.; Goswami, C.; Safran, H.; Dos Santos, L.V.; Aprile, G.; Ferry, D.R.; Melichar, B.; Tehfe, M.; Topuzov, E.; Zalcberg, J.R.; Chau, I.; Campbell, W.; Sivanandan, C.; Pikiel, J.; Koshiji, M.; Hsu, Y.; Liepa, A.M.; Gao, L.; Schwartz, J.D.; Tabernero, J. REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet,  2014, 383(9911), 31-39.
[http://dx.doi.org/10.1016/S0140-6736(13)61719-5] [PMID:  24094768] 
[34] 
Wilke, H.; Muro, K.; Van Cutsem, E.; Oh, S.C.; Bodoky, G.; Shimada, Y.; Hironaka, S.; Sugimoto, N.; Lipatov, O.; Kim, T.Y.; Cunningham, D.; Rougier, P.; Komatsu, Y.; Ajani, J.; Emig, M.; Carlesi, R.; Ferry, D.; Chandrawansa, K.; Schwartz, J.D.; Ohtsu, A. RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol.,  2014, 15(11), 1224-1235.
[http://dx.doi.org/10.1016/S1470-2045(14)70420-6] [PMID:  25240821] 
[35] 
Al-Batran, S.E.; Van Cutsem, E.; Oh, S.C.; Bodoky, G.; Shimada, Y.; Hironaka, S.; Sugimoto, N.; Lipatov, O.N.; Kim, T.Y.; Cunningham, D.; Rougier, P.; Muro, K.; Liepa, A.M.; Chandrawansa, K.; Emig, M.; Ohtsu, A.; Wilke, H. Quality-of-life and performance status results from the phase III RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or gastroesophageal junction adenocarcinoma. Ann. Oncol.,  2016, 27(4), 673-679.
[http://dx.doi.org/10.1093/annonc/mdv625] [PMID:  26747859] 
[36] 
Garon, E.B.; Ciuleanu, T.E.; Arrieta, O.; Prabhash, K.; Syrigos, K.N.; Goksel, T.; Park, K.; Gorbunova, V.; Kowalyszyn, R.D.; Pikiel, J.; Czyzewicz, G.; Orlov, S.V.; Lewanski, C.R.; Thomas, M.; Bidoli, P.; Dakhil, S.; Gans, S.; Kim, J.H.; Grigorescu, A.; Karaseva, N.; Reck, M.; Cappuzzo, F.; Alexandris, E.; Sashegyi, A.; Yurasov, S.; Pérol, M. 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), 665-673.
[http://dx.doi.org/10.1016/S0140-6736(14)60845-X] [PMID:  24933332] 
[37] 
Reck, M.; Paz-Ares, L.; Bidoli, P.; Cappuzzo, F.; Dakhil, S.; Moro-Sibilot, D.; Borghaei, H.; Johnson, M.; Jotte, R.; Pennell, N.A.; Shepherd, F.A.; Tsao, A.; Thomas, M.; Carter, G.C.; Chan-Diehl, F.; Alexandris, E.; Lee, P.; Zimmermann, A.; Sashegyi, A.; Pérol, M. Outcomes in patients with aggressive or refractory disease from REVEL: A randomized phase III study of docetaxel with ramucirumab or placebo for second-line treatment of stage IV non-small-cell lung cancer. Lung Cancer,  2017, 112, 181-187.
[http://dx.doi.org/10.1016/j.lungcan.2017.07.038] [PMID:  29191593] 
[38] 
Tabernero, J.; Yoshino, T.; Cohn, A.L.; Obermannova, R.; Bodoky, G.; Garcia-Carbonero, R.; Ciuleanu, T.E.; Portnoy, D.C.; Van Cutsem, E.; Grothey, A.; Prausová, J.; Garcia-Alfonso, P.; Yamazaki, K.; Clingan, P.R.; Lonardi, S.; Kim, T.W.; Simms, L.; Chang, S.C.; Nasroulah, F. 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.
[http://dx.doi.org/10.1016/S1470-2045(15)70127-0] [PMID:  25877855] 
[39] 
Obermannová, R.; Van Cutsem, E.; Yoshino, T.; Bodoky, G.; Prausová, J.; Garcia-Carbonero, R.; Ciuleanu, T.; Garcia Alfonso, P.; Portnoy, D.; Cohn, A.; Yamazaki, K.; Clingan, P.; Lonardi, S.; Kim, T.W.; Yang, L.; Nasroulah, F.; Tabernero, J. Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression. Ann. Oncol.,  2016, 27(11), 2082-2090.
[http://dx.doi.org/10.1093/annonc/mdw402] [PMID:  27573561] 
[40] 
Chau, I.; Park, J.O.; Ryoo, B.Y.; Yen, C.J.; Poon, R.; Pastorelli, D.; Blanc, J.F.; Kudo, M.; Pfiffer, T.; Hatano, E.; Chung, H.C.; Kopeckova, K.; Phelip, J.M.; Brandi, G.; Ohkawa, S.; Li, C.P.; Okusaka, T.; Hsu, Y.; Abada, P.B.; Zhu, A.X. Alpha-fetoprotein kinetics in patients with hepatocellular carcinoma receiving ramucirumab or placebo: an analysis of the phase 3 REACH study. Br. J. Cancer,  2018, 119(1), 19-26.
[http://dx.doi.org/10.1038/s41416-018-0103-0] [PMID:  29808014] 
[41] 
Zhu, A.X.; Kang, Y.K.; Yen, C.J.; Finn, R.S.; Galle, P.R.; Llovet, J.M.; Assenat, E.; Brandi, G.; Pracht, M.; Lim, H.Y.; Rau, K.M.; Motomura, K.; Ohno, I.; Merle, P.; Daniele, B.; Shin, D.B.; Gerken, G.; Borg, C.; Hiriart, J.B.; Okusaka, T.; Morimoto, M.; Hsu, Y.; Abada, P.B.; Kudo, M. REACH-2 study investigators. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol.,  2019, 20(2), 282-296.
[http://dx.doi.org/10.1016/S1470-2045(18)30937-9] [PMID:  30665869] 
[42] 
Papadopoulos, N.; Martin, J.; Ruan, Q.; Rafique, A.; Rosconi, M.P.; Shi, E.; Pyles, E.A.; Yancopoulos, G.D.; Stahl, N.; Wiegand, S.J. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis,  2012, 15(2), 171-185.
[http://dx.doi.org/10.1007/s10456-011-9249-6] [PMID:  22302382] 
[43] 
Walker, A.; Chung, C.W.; Neu, M.; Burman, M.; Batuwangala, T.; Jones, G.; Tang, C.M.; Steward, M.; Mullin, M.; Tournier, N.; Lewis, A.; Korczynska, J.; Chung, V.; Catchpole, I. Novel Interaction Mechanism of a Domain Antibody-based Inhibitor of Human Vascular Endothelial Growth Factor with Greater Potency than Ranibizumab and Bevacizumab and Improved Capacity over Aflibercept. J. Biol. Chem.,  2016, 291(11), 5500-5511.
[http://dx.doi.org/10.1074/jbc.M115.691162] [PMID:  26728464] 
[44] 
Ferrara, N.; Hillan, K.J.; Gerber, H.P.; Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat. Rev. Drug Discov.,  2004, 3(5), 391-400.
[http://dx.doi.org/10.1038/nrd1381] [PMID:  15136787] 
[45] 
Michaelsen, S.R.; Staberg, M.; Pedersen, H.; Jensen, K.E.; Majewski, W.; Broholm, H.; Nedergaard, M.K.; Meulengracht, C.; Urup, T.; Villingshøj, M.; Lukacova, S.; Skjøth-Rasmussen, J.; Brennum, J.; Kjær, A.; Lassen, U.; Stockhausen, M.T.; Poulsen, H.S.; Hamerlik, P. VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance. Neuro-oncol.,  2018, 20(11), 1462-1474.
[http://dx.doi.org/10.1093/neuonc/noy103] [PMID:  29939339] 
[46] 
Lu, D.; Shen, J.; Vil, M.D.; Zhang, H.; Jimenez, X.; Bohlen, P.; Witte, L.; Zhu, Z. Tailoring in vitro selection for a picomolar affinity human antibody directed against vascular endothelial growth factor receptor 2 for enhanced neutralizing activity. J. Biol. Chem.,  2003, 278(44), 43496-43507.
[http://dx.doi.org/10.1074/jbc.M307742200] [PMID:  12917408] 
[47] 
Spratlin, J. Ramucirumab (IMC-1121B): Monoclonal antibody inhibition of vascular endothelial growth factor receptor-2. Curr. Oncol. Rep.,  2011, 13(2), 97-102.
[http://dx.doi.org/10.1007/s11912-010-0149-5] [PMID:  21222245] 
[48] 
Zhu, Z.; Hattori, K.; Zhang, H.; Jimenez, X.; Ludwig, D.L.; Dias, S.; Kussie, P.; Koo, H.; Kim, H.J.; Lu, D.; Liu, M.; Tejada, R.; Friedrich, M.; Bohlen, P.; Witte, L.; Rafii, S. Inhibition of human leukemia in an animal model with human antibodies directed against vascular endothelial growth factor receptor 2. Correlation between antibody affinity and biological activity. Leukemia,  2003, 17(3), 604-611.
[http://dx.doi.org/10.1038/sj.leu.2402831] [PMID:  12646950] 
[49] 
Lambrechts, D.; Lenz, H.J.; de Haas, S.; Carmeliet, P.; Scherer, S.J. Markers of response for the antiangiogenic agent bevacizumab. J. Clin. Oncol.,  2013, 31(9), 1219-1230.
[http://dx.doi.org/10.1200/JCO.2012.46.2762] [PMID:  23401453] 
[50] 
Clarke, J.M.; Hurwitz, H.I. Targeted inhibition of VEGF receptor 2: an update on ramucirumab. Expert Opin. Biol. Ther.,  2013, 13(8), 1187-1196.
[http://dx.doi.org/10.1517/14712598.2013.810717] [PMID:  23803182] 
[51] 
Hong, S.; Tan, M.; Wang, S.; Luo, S.; Chen, Y.; Zhang, L. Efficacy and safety of angiogenesis inhibitors in advanced non-small cell lung cancer: a systematic review and meta-analysis. J. Cancer Res. Clin. Oncol.,  2015, 141(5), 909-921.
[http://dx.doi.org/10.1007/s00432-014-1862-5] [PMID:  25373315] 
[52] 
Xiao, B.; Wang, W.; Zhang, D. Risk of bleeding associated with antiangiogenic monoclonal antibodies bevacizumab and ramucirumab: a meta-analysis of 85 randomized controlled trials. OncoTargets Ther.,  2018, 11, 5059-5074.
[http://dx.doi.org/10.2147/OTT.S166151] [PMID:  30174444] 
[53] 
Herbst, R.S.; O’Neill, V.J.; Fehrenbacher, L.; Belani, C.P.; Bonomi, P.D.; Hart, L.; Melnyk, O.; Ramies, D.; Lin, M.; Sandler, A. Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non small-cell lung cancer. J. Clin. Oncol.,  2007, 25(30), 4743-4750.
[http://dx.doi.org/10.1200/JCO.2007.12.3026] [PMID:  17909199] 
[54] 
Moore, M.; Gill, S.; Asmis, T.; Berry, S.; Burkes, R.; Zbuk, K.; Alcindor, T.; Jeyakumar, A.; Chan, T.; Rao, S.; Spratlin, J.; Tang, P.A.; Rothenstein, J.; Chan, E.; Bendell, J.; Kudrik, F.; Kauh, J.; Tang, S.; Gao, L.; Kambhampati, S.R.; Nasroulah, F.; Yang, L.; Ramdas, N.; Binder, P.; Strevel, E. Randomized phase II study of modified FOLFOX-6 in combination with ramucirumab or icrucumab as second-line therapy in patients with metastatic colorectal cancer after disease progression on first-line irinotecan-based therapy. Ann. Oncol.,  2016, 27(12), 2216-2224.
[http://dx.doi.org/10.1093/annonc/mdw412] [PMID:  27733377] 
[55] 
Berger, M.D.; Lenz, H.J. The safety of monoclonal antibodies for treatment of colorectal cancer. Expert Opin. Drug Saf.,  2016, 15(6), 799-808.
[http://dx.doi.org/10.1517/14740338.2016.1167186] [PMID:  26982510] 
[56] 
Bai, Z.G.; Zhang, Z.T. A systematic review and meta-analysis on the effect of angiogenesis blockade for the treatment of gastric cancer. OncoTargets Ther.,  2018, 11, 7077-7087.
[http://dx.doi.org/10.2147/OTT.S169484] [PMID:  30410364] 
[57] 
Zhao, TT; Xu, H; Xu, HM; Wang, ZN; Xu, YY; Song, YX The efficacy and safety of targeted therapy with or without chemotherapy in advanced gastric cancer treatment: a network meta-analysis of well-designed randomized controlled trials. Gastric cancer: Official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association,  2018, 21, 361-71.
[http://dx.doi.org/10.1007/s10120-018-0813-2] 
[58] 
Arnold, D.; Fuchs, C.S.; Tabernero, J.; Ohtsu, A.; Zhu, A.X.; Garon, E.B.; Mackey, J.R.; Paz-Ares, L.; Baron, A.D.; Okusaka, T.; Yoshino, T.; Yoon, H.H.; Das, M.; Ferry, D.; Zhang, Y.; Lin, Y.; Binder, P.; Sashegyi, A.; Chau, I. Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab. Ann. Oncol.,  2017, 28(12), 2932-2942.
[http://dx.doi.org/10.1093/annonc/mdx514] [PMID:  28950290] 
[59] 
Spratlin, J.L.; Cohen, R.B.; Eadens, M.; Gore, L.; Camidge, D.R.; Diab, S.; Leong, S.; O’Bryant, C.; Chow, L.Q.; Serkova, N.J.; Meropol, N.J.; Lewis, N.L.; Chiorean, E.G.; Fox, F.; Youssoufian, H.; Rowinsky, E.K.; Eckhardt, S.G. 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.
[http://dx.doi.org/10.1200/JCO.2009.23.7537] [PMID:  20048182] 
[60] 
Kosumi, H.; Nishie, W.; Sugai, T.; Toyonaga, E.; Yoshimoto, N.; Nakamura, H.; Horibe, R.; Kitamura, Y.; Nakatsumi, H.; Shimizu, H. Ramucirumab-induced Multiple Haemangiomas of the Skin: Two Case Reports. Acta Derm. Venereol.,  2018, 98(4), 454-455.
[http://dx.doi.org/10.2340/00015555-2869] [PMID:  29327066] 
[61] 
Lee, S.J.; Lee, S.Y.; Lee, W.S.; Yoo, J.S.; Sun, J.M.; Lee, J.; Park, S.H.; Park, J.O.; Ahn, M.J.; Lim, H.Y.; Kang, W.K.; Park, Y.S. Phase I trial and pharmacokinetic study of tanibirumab, a fully human monoclonal antibody to vascular endothelial growth factor receptor 2, in patients with refractory solid tumors. Invest. New Drugs,  2017, 35(6), 782-790.
[http://dx.doi.org/10.1007/s10637-017-0463-y] [PMID:  28391576] 
[62] 
Ton, NC; Parker, GJ; Jackson, A; Mullamitha, S; Buonaccorsi, GA; Roberts, C Phase I evaluation of CDP791, a PEGylated di-Fab' conjugate that binds vascular endothelial growth factor receptor 2.  Clinical cancer research: An official journal of the American Association for Cancer Research.,  2007, 13, 7113-8.
[63] 
Lim, Y.H.; Odell, I.D.; Ko, C.J.; Choate, K.A. Somatic p.T771R KDR (VEGFR2) Mutation Arising in a Sporadic Angioma During Ramucirumab Therapy. JAMA Dermatol.,  2015, 151(11), 1240-1243.
[http://dx.doi.org/10.1001/jamadermatol.2015.1925] [PMID:  26422291] 
[64] 
Mackey, J.R.; Ramos-Vazquez, M.; Lipatov, O.; McCarthy, N.; Krasnozhon, D.; Semiglazov, V.; Manikhas, A.; Gelmon, K.A.; Konecny, G.E.; Webster, M.; Hegg, R.; Verma, S.; Gorbunova, V.; Abi Gerges, D.; Thireau, F.; Fung, H.; Simms, L.; Buyse, M.; Ibrahim, A.; Martin, M. Primary results of ROSE/TRIO-12, a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer. J. Clin. Oncol.,  2015, 33(2), 141-148.
[http://dx.doi.org/10.1200/JCO.2014.57.1513] [PMID:  25185099] 
[65] 
Wang, X.; Teng, F.; Kong, L.; Yu, J. PD-L1 expression in human cancers and its association with clinical outcomes. OncoTargets Ther.,  2016, 9, 5023-5039.
[http://dx.doi.org/10.2147/OTT.S105862] [PMID:  27574444] 
[66] 
Zou, W.; Wolchok, J.D.; Chen, L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci. Transl. Med.,  2016, 8(328)328rv4
[http://dx.doi.org/10.1126/scitranslmed.aad7118] [PMID:  26936508] 
[67] 
Gong, J.; Chehrazi-Raffle, A.; Reddi, S.; Salgia, R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J. Immunother. Cancer,  2018, 6(1), 8.
[http://dx.doi.org/10.1186/s40425-018-0316-z] [PMID:  29357948] 
[68] 
Gettinger, S.; Horn, L.; Jackman, D.; Spigel, D.; Antonia, S.; Hellmann, M.; Powderly, J.; Heist, R.; Sequist, L.V.; Smith, D.C.; Leming, P.; Geese, W.J.; Yoon, D.; Li, A.; Brahmer, J. Five-year follow-up of nivolumab in previously treated advanced non-small-cell lung cancer: Results from the CA209-003 study. J. Clin. Oncol.,  2018, 36(17), 1675-1684.
[http://dx.doi.org/10.1200/JCO.2017.77.0412] [PMID:  29570421] 
[69] 
Havel, J.J.; Chowell, D.; Chan, T.A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat. Rev. Cancer,  2019, 19(3), 133-150.
[http://dx.doi.org/10.1038/s41568-019-0116-x] [PMID:  30755690] 
[70] 
Chalmers, Z.R.; Connelly, C.F.; Fabrizio, D.; Gay, L.; Ali, S.M.; Ennis, R.; Schrock, A.; Campbell, B.; Shlien, A.; Chmielecki, J.; Huang, F.; He, Y.; Sun, J.; Tabori, U.; Kennedy, M.; Lieber, D.S.; Roels, S.; White, J.; Otto, G.A.; Ross, J.S.; Garraway, L.; Miller, V.A.; Stephens, P.J.; Frampton, G.M. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med.,  2017, 9(1), 34.
[http://dx.doi.org/10.1186/s13073-017-0424-2] [PMID:  28420421] 
[71] 
Hirsch, FR; McElhinny, A; Stanforth, D; Ranger-Moore, J; Jansson, M; Kulangara, K PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2017, 12, 208-22.
[72] 
Hendry, S; Byrne, DJ; Wright, GM; Young, RJ; Sturrock, S  Cooper, WA Comparison of Four PD-L1 Immunohistochemical Assays in Lung Cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2018, 13, 367-76.
[73] 
Fujimoto, D; Sato, Y; Uehara, K; Ishida, K; Fukuoka, J Morimoto, T Predictive Performance of Four Programmed Cell Death Ligand 1 Assay Systems on Nivolumab Response in Previously Treated Patients with Non-Small Cell Lung Cancer Journal of thoracic oncology: Official publication of the International Association for the Study of Lung Cancer 2018, 13, 377-86.
[74] 
Weber, J.S.; D’Angelo, S.P.; Minor, D.; Hodi, F.S.; Gutzmer, R.; Neyns, B.; Hoeller, C.; Khushalani, N.I.; Miller, W.H., Jr; Lao, C.D.; Linette, G.P.; Thomas, L.; Lorigan, P.; Grossmann, K.F.; Hassel, J.C.; Maio, M.; Sznol, M.; Ascierto, P.A.; Mohr, P.; Chmielowski, B.; Bryce, A.; Svane, I.M.; Grob, J.J.; Krackhardt, A.M.; Horak, C.; Lambert, A.; Yang, A.S.; Larkin, J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol.,  2015, 16(4), 375-384.
[http://dx.doi.org/10.1016/S1470-2045(15)70076-8] [PMID:  25795410] 
[75] 
Hahn, N.M.; Powles, T.; Massard, C.; Arkenau, H-T.; Friedlander, T.W.; Hoimes, C.J. Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma (UC). J. Clin. Oncol.,  2017, 35, 4525.
[http://dx.doi.org/10.1200/JCO.2017.35.15_suppl.4525] 
[76] 
Sul, J.; Blumenthal, G.M.; Jiang, X.; He, K.; Keegan, P.; Pazdur, R. FDA approval summary: Pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1. Oncologist,  2016, 21(5), 643-650.
[http://dx.doi.org/10.1634/theoncologist.2015-0498] [PMID:  27026676] 
[77] 
Brahmer, J.; Reckamp, K.L.; Baas, P.; Crinò, L.; Eberhardt, W.E.; Poddubskaya, E.; Antonia, S.; Pluzanski, A.; Vokes, E.E.; Holgado, E.; Waterhouse, D.; Ready, N.; Gainor, J.; Arén Frontera, O.; Havel, L.; Steins, M.; Garassino, M.C.; Aerts, J.G.; Domine, M.; Paz-Ares, L.; Reck, M.; Baudelet, C.; Harbison, C.T.; Lestini, B.; Spigel, D.R. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N. Engl. J. Med.,  2015, 373(2), 123-135.
[http://dx.doi.org/10.1056/NEJMoa1504627] [PMID:  26028407] 
[78] 
Khalil, D.N.; Smith, E.L.; Brentjens, R.J.; Wolchok, J.D. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat. Rev. Clin. Oncol.,  2016, 13(6), 394.
[http://dx.doi.org/10.1038/nrclinonc.2016.65] [PMID:  27118494] 
[79] 
Galon, J.; Bruni, D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat. Rev. Drug Discov.,  2019, 18(3), 197-218.
[http://dx.doi.org/10.1038/s41573-018-0007-y] [PMID:  30610226] 
[80] 
Schmidt, C. The benefits of immunotherapy combinations. Nature,  2017, 552(7685), S67-S69.
[http://dx.doi.org/10.1038/d41586-017-08702-7] [PMID:  29293245] 
[81] 
Rini, B.I.; Plimack, E.R.; Stus, V.; Gafanov, R.; Hawkins, R.; Nosov, D.; Pouliot, F.; Alekseev, B.; Soulières, D.; Melichar, B.; Vynnychenko, I.; Kryzhanivska, A.; Bondarenko, I.; Azevedo, S.J.; Borchiellini, D.; Szczylik, C.; Markus, M.; McDermott, R.S.; Bedke, J.; Tartas, S.; Chang, Y.H.; Tamada, S.; Shou, Q.; Perini, R.F.; Chen, M.; Atkins, M.B.; Powles, T. KEYNOTE-426 Investigators. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N. Engl. J. Med.,  2019, 380(12), 1116-1127.
[http://dx.doi.org/10.1056/NEJMoa1816714] [PMID:  30779529] 
[82] 
Gandhi, L.; Rodríguez-Abreu, D.; Gadgeel, S.; Esteban, E.; Felip, E.; De Angelis, F.; Domine, M.; Clingan, P.; Hochmair, M.J.; Powell, S.F.; Cheng, S.Y.; Bischoff, H.G.; Peled, N.; Grossi, F.; Jennens, R.R.; Reck, M.; Hui, R.; Garon, E.B.; Boyer, M.; Rubio-Viqueira, B.; Novello, S.; Kurata, T.; Gray, J.E.; Vida, J.; Wei, Z.; Yang, J.; Raftopoulos, H.; Pietanza, M.C.; Garassino, M.C. KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N. Engl. J. Med.,  2018, 378(22), 2078-2092.
[http://dx.doi.org/10.1056/NEJMoa1801005] [PMID:  29658856] 
[83] 
Paz-Ares, L.; Luft, A.; Vicente, D.; Tafreshi, A.; Gümüş, M.; Mazières, J.; Hermes, B.; Çay Şenler, F.; Csőszi, T.; Fülöp, A.; Rodríguez-Cid, J.; Wilson, J.; Sugawara, S.; Kato, T.; Lee, K.H.; Cheng, Y.; Novello, S.; Halmos, B.; Li, X.; Lubiniecki, G.M.; Piperdi, B.; Kowalski, D.M. KEYNOTE-407 investigators. pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N. Engl. J. Med.,  2018, 379(21), 2040-2051.
[http://dx.doi.org/10.1056/NEJMoa1810865] [PMID:  30280635] 
[84] 
Hodi, F.S.; Chesney, J.; Pavlick, A.C.; Robert, C.; Grossmann, K.F.; McDermott, D.F.; Linette, G.P.; Meyer, N.; Giguere, J.K.; Agarwala, S.S.; Shaheen, M.; Ernstoff, M.S.; Minor, D.R.; Salama, A.K.; Taylor, M.H.; Ott, P.A.; Horak, C.; Gagnier, P.; Jiang, J.; Wolchok, J.D.; Postow, M.A. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol.,  2016, 17(11), 1558-1568.
[http://dx.doi.org/10.1016/S1470-2045(16)30366-7] [PMID:  27622997] 
[85] 
Cella, D.; Grünwald, V.; Escudier, B.; Hammers, H.J.; George, S.; Nathan, P.; Grimm, M.O.; Rini, B.I.; Doan, J.; Ivanescu, C.; Paty, J.; Mekan, S.; Motzer, R.J. Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial. Lancet Oncol.,  2019, 20(2), 297-310.
[http://dx.doi.org/10.1016/S1470-2045(18)30778-2] [PMID:  30658932] 
[86] 
Tian, L.; Goldstein, A.; Wang, H.; Ching , Lo. H.; Sun Kim, I.; Welte, T.; Sheng, K.; Dobrolecki, L.E.; Zhang, X.; Putluri, N.; Phung, T.L.; Mani, S.A.; Stossi, F.; Sreekumar, A.; Mancini, M.A.; Decker, W.K.; Zong, C.; Lewis, M.T.; Zhang, X.H. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature,  2017, 544(7649), 250-254.
[http://dx.doi.org/10.1038/nature21724] [PMID:  28371798] 
[87] 
Goel, S.; Duda, D.G.; Xu, L.; Munn, L.L.; Boucher, Y.; Fukumura, D.; Jain, R.K. Normalization of the vasculature for treatment of cancer and other diseases. Physiol. Rev.,  2011, 91(3), 1071-1121.
[http://dx.doi.org/10.1152/physrev.00038.2010] [PMID:  21742796] 
[88] 
Wu, J.B.; Tang, Y.L.; Liang, X.H. Targeting VEGF pathway to normalize the vasculature: an emerging insight in cancer therapy. OncoTargets Ther.,  2018, 11, 6901-6909.
[http://dx.doi.org/10.2147/OTT.S172042] [PMID:  30410348] 
[89] 
Yasuda, S.; Sho, M.; Yamato, I.; Yoshiji, H.; Wakatsuki, K.; Nishiwada, S.; Yagita, H.; Nakajima, Y. 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.
[http://dx.doi.org/10.1111/cei.12069] [PMID:  23600839] 
[90] 
Allen, E.; Jabouille, A.; Rivera, L.B.; Lodewijckx, I.; Missiaen, R.; Steri, V.; Feyen, K.; Tawney, J.; Hanahan, D.; Michael, I.P.; Bergers, G. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci. Transl. Med.,  2017, 9(385), 9.
[http://dx.doi.org/10.1126/scitranslmed.aak9679] [PMID:  28404866] 
[91] 
Ramjiawan, R.R.; Griffioen, A.W.; Duda, D.G. Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy? Angiogenesis,  2017, 20(2), 185-204.
[http://dx.doi.org/10.1007/s10456-017-9552-y] [PMID:  28361267] 
[92] 
Wallin, J.J.; Bendell, J.C.; Funke, R.; Sznol, M.; Korski, K.; Jones, S.; Hernandez, G.; Mier, J.; He, X.; Hodi, F.S.; Denker, M.; Leveque, V.; Cañamero, M.; Babitski, G.; Koeppen, H.; Ziai, J.; Sharma, N.; Gaire, F.; Chen, D.S.; Waterkamp, D.; Hegde, P.S.; McDermott, D.F. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat. Commun.,  2016, 7, 12624.
[http://dx.doi.org/10.1038/ncomms12624] [PMID:  27571927] 
[93] 
Lai, Y.S.; Wahyuningtyas, R.; Aui, S.P.; Chang, K.T. Autocrine VEGF signalling on M2 macrophages regulates PD-L1 expression for immunomodulation of T cells. J. Cell. Mol. Med.,  2019, 23(2), 1257-1267.
[PMID:  30456891] 
[94] 
Terme, M.; Pernot, S.; Marcheteau, E.; Sandoval, F.; Benhamouda, N.; Colussi, O.; Dubreuil, O.; Carpentier, A.F.; Tartour, E.; Taieb, J. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res.,  2013, 73(2), 539-549.
[http://dx.doi.org/10.1158/0008-5472.CAN-12-2325] [PMID:  23108136] 
[95] 
Meder, L.; Schuldt, P.; Thelen, M.; Schmitt, A.; Dietlein, F.; Klein, S.; Borchmann, S.; Wennhold, K.; Vlasic, I.; Oberbeck, S.; Riedel, R.; Florin, A.; Golfmann, K.; Schlößer, H.A.; Odenthal, M.; Buettner, R.; Wolf, J.; Hallek, M.; Herling, M.; von Bergwelt-Baildon, M.; Reinhardt, H.C.; Ullrich, R.T. 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.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-2176] [PMID:  29776963] 
[96] 
Sakuishi, K.; Jayaraman, P.; Behar, S.M.; Anderson, A.C.; Kuchroo, V.K. Emerging Tim-3 functions in antimicrobial and tumor immunity. Trends Immunol.,  2011, 32(8), 345-349.
[http://dx.doi.org/10.1016/j.it.2011.05.003] [PMID:  21697013] 
[97] 
Anderson, A.C. Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol. Res.,  2014, 2(5), 393-398.
[http://dx.doi.org/10.1158/2326-6066.CIR-14-0039] [PMID:  24795351] 
[98] 
Herbst, R.S.; Martin-Liberal, J.; Calvo, E.; Isambert, N.; Bendell, J.; Cassier, P. 90PDPreviously treated advanced NSCLC cohort from a multi-disease phase 1 study of ramucirumab (R) plus pembrolizumab (P): Efficacy and safety data. Ann. Oncol.,  2017, 28.
[http://dx.doi.org/10.1093/annonc/mdx091.010] 
[99] 
Chau, I.; Bendell, J.C.; Calvo, E.; Santana-Davila, R.; Ahnert, J.R.; Penel, N. Interim safety and clinical activity in patients (pts) with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma from a multicohort phase 1 study of ramucirumab (R) plus pembrolizumab (P). J. Clin. Oncol.,  2017, 35, 102.
[http://dx.doi.org/10.1200/JCO.2017.35.4_suppl.102] 
[100] 
Chau, I.; Penel, N.; Arkenau, H-T.; Santana-Davila, R.; Calvo, E.; Soriano, A.O. Safety and antitumor activity of ramucirumab plus pembrolizumab in treatment naïve advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: Preliminary results from a multi-disease phase I study (JVDF). J. Clin. Oncol.,  2018, 36, 101.
[http://dx.doi.org/10.1200/JCO.2018.36.4_suppl.101] 
[101] 
Bang, Y-J.; Golan, T.; Lin, C-C.; Kang, Y-K.; Wainberg, Z.A.; Wasserstrom, H. Interim safety and clinical activity in patients (pts) with locally advanced and unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma from a multicohort phase I study of ramucirumab (R) plus durvalumab (D). J. Clin. Oncol.,  2018, 36, 92.
[http://dx.doi.org/10.1200/JCO.2018.36.4_suppl.92] 
[102] 
Hara, H.; Shoji, H.; Takahari, D.; Esaki, T.; Machida, N.; Nagashima, K. Phase I/II study of ramucirumab plus nivolumab in patients in second-line treatment for advanced gastric adenocarcinoma (NivoRam study). J. Clin. Oncol.,  2019, 37, 129.
[http://dx.doi.org/10.1200/JCO.2019.37.4_suppl.129] 
[103] 
Takahari, D.; Shoji, H.; Hara, H.; Esaki, T.; Machida, N.; Nagashima, K. Preliminary result of phase 1/2 study of ramucirumab plus nivolumab in patients with previously treated advanced gastric adenocarcinoma (NivoRam study). J. Clin. Oncol.,  2018, 36, 4047.
[http://dx.doi.org/10.1200/JCO.2018.36.15_suppl.4047] 
[104] 
Petrylak, D.P.; Arkenau, H-T.; Perez-Gracia, J.L.; Krebs, M.; Santana-Davila, R.; Yang, J. A multicohort phase I study of ramucirumab (R) plus pembrolizumab (P): Interim safety and clinical activity in patients with urothelial carcinoma. J. Clin. Oncol.,  2017, 35, 349.
[http://dx.doi.org/10.1200/JCO.2017.35.6_suppl.349] 
[105] 
Arkenau, H.T.; Martin-Liberal, J.; Calvo, E.; Penel, N.; Krebs, M.G.; Herbst, R.S.; Walgren, R.A.; Widau, R.C.; Mi, G.; Jin, J.; Ferry, D.; Chau, I. Ramucirumab plus pembrolizumab in patients with previously treated advanced or metastatic biliary tract cancer: Nonrandomized, open-label, phase I trial (JVDF). Oncologist,  2018, 23(12), 1407-e136.
[http://dx.doi.org/10.1634/theoncologist.2018-0044] [PMID:  29853658] 
[106] 
McDermott, D.F.; Atkins, M.B.; Motzer, R.J.; Rini, B.I.; Escudier, B.J.; Fong, L. A phase II study of atezolizumab (atezo) with or without bevacizumab (bev) versus sunitinib (sun) in untreated metastatic renal cell carcinoma (mRCC) patients (pts). J. Clin. Oncol.,  2017, 35, 431.
[http://dx.doi.org/10.1200/JCO.2017.35.6_suppl.431] 
[107] 
Motzer, R.J.; Powles, T.; Atkins, M.B.; Escudier, B.; McDermott, D.F.; Suarez, C. IMmotion151: A randomized phase III study of atezolizumab plus bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma (mRCC). J. Clin. Oncol.,  2018, 36, 578.
[http://dx.doi.org/10.1200/JCO.2018.36.6_suppl.578] 
[108] 
Stein, S.; Pishvaian, M.J.; Lee, M.S.; Lee, K-H.; Hernandez, S.; Kwan, A. Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase Ib study in hepatocellular carcinoma (HCC). J. Clin. Oncol.,  2018, 36, 4074.
[http://dx.doi.org/10.1200/JCO.2018.36.15_suppl.4074] 
[109] 
Reardon, D.A.; Groot, J.F.D.; Colman, H.; Jordan, J.T.; Daras, M.; Clarke, J.L. Safety of pembrolizumab in combination with bevacizumab in recurrent glioblastoma (rGBM). J. Clin. Oncol.,  2016, 34, 2010.
[http://dx.doi.org/10.1200/JCO.2016.34.15_suppl.2010] 
[110] 
Zhao, S.; Ren, S.; Jiang, T.; Zhu, B.; Li, X.; Zhao, C.; Jia, Y.; Shi, J.; Zhang, L.; Liu, X.; Qiao, M.; Chen, X.; Su, C.; Yu, H.; Zhou, C.; Zhang, J.; Camidge, D.R.; Hirsch, F.R. Low-dose apatinib optimizes tumor microenvironment and potentiates antitumor effect of PD-1/PD-L1 blockade in lung cancer. Cancer Immunol. Res.,  2019, 7(4), 630-643.
[http://dx.doi.org/10.1158/2326-6066.CIR-17-0640] [PMID:  30755403] 
Rights & Permissions Print Cite
Article Metrics
83
11
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1568009619666191114110359	Print ISSN 1568-0096
Publisher Name Bentham Science Publisher	Online ISSN 1873-5576
Current Cancer Drug Targets

Anti-VEGF/VEGFR2 Monoclonal Antibodies and their Combinations with PD-1/PD-L1 Inhibitors in Clinic

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Related Articles

Abstract
