Background/Aims: Epithelial ovarian cancer (EOC) is the sixth most commonly diagnosed cancer among women. Results with available therapies are far from being satisfactory and, therefore, current research is focusing on new anticancer drugs to improve the clinical response of these patients. Nintedanib is an oral multiple tyrosine kinases inhibitor, which targets angiogenesis. Considering the current scenario, the aim of this systematic review is to highlight the prevailing knowledge about pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of Nintedanib for the treatment of advanced EOC. Methods: We performed a systematic review of the literature, screening all available articles about the treatment of advanced EOC with Nintedanib, including phase I, II, and III trials. Results: Although in early phase clinical trials, Nintedanib has demonstrated anticancer activity and tolerability as monotherapy or in combination with carboplatin and paclitaxel. In the phase III trial AGO-OVAR 12, it obtained a modest improvement in progression-free survival (PFS) as first-line combination therapy for patients with advanced EOC. Interestingly, a PFS increase was observed in patients with non-high progression risk or low tumor burden. Conclusion: Despite the promising results, further studies are needed to evaluate Nintedanib efficacy in women affected by EOC.

Journal Section:
Editor's choice
Keywords:
Nintedanib, Epithelial ovarian cancer, BIBF 1120, Antiangiogenic drugs, Multi tyrosine kinase inhibitors, Angiogenesis
1.
IARC Publications Website – GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012 v1.0, 2016.
2.
Cannistra SA: Cancer of the ovary. N Engl J Med 1993; 329: 1550–1559.
3.
Colombo N, Peiretti M, Parma G, Lapresa M, Mancari R, Carinelli S, Sessa C, Castiglione M; ESMO Guidelines Working Group: Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21(suppl 5): v23–v30.
4.
National Comprehensive Cancer N: NCCN Clinical Practice Guidelines in OncologyTM. Ovarian Cancer. Version 1.2016.
5.
Kim SJ, Rosen B, Fan I, Ivanova A, McLaughlin JR, Risch H, Narod SA, Kotsopoulos J: Epidemiologic factors that predict long-term survival following a diagnosis of epithelial ovarian cancer. Br J Cancer 2017; 116: 964–971.
6.
Morotti M, Becker CM, Menada MV, Ferrero S: Targeting tyrosine-kinases in ovarian cancer. Expert Opin Investig Drugs 2013; 22: 1265–1279.
7.
Tangjitgamol S, Manusirivithaya S, Laopaiboon M, Lumbiganon P: Interval debulking surgery for advanced epithelial ovarian cancer: a Cochrane systematic review. Gynecol Oncol 2009; 112: 257–264.
8.
Colombo N, Peiretti M, Castiglione M; ESMO Guidelines Working Group: Non-epithelial ovarian cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009; 20(suppl 4): 24–26.
9.
Oberaigner W, Minicozzi P, Bielska-Lasota M, Allemani C, de Angelis R, Mangone L, Sant M; Eurocare Working Group: Survival for ovarian cancer in Europe: the across-country variation did not shrink in the past decade. Acta Oncol 2012; 51: 441–453.
10.
Bogliolo S, Cassani C, Dominoni M, Musacchi V, Venturini PL, Spinillo A, Ferrero S, Gardella B: Veliparib for the treatment of ovarian cancer. Expert Opin Investig Drugs 2016; 25: 367–374.
11.
Bergamini A, Ferrero S, Leone Roberti Maggiore U, Scala C, Pella F, Vellone VG, Petrone M, Rabaiotti E, Cioffi R, Candiani M, Mangili G: Folate receptor alpha antagonists in preclinical and early stage clinical development for the treatment of epithelial ovarian cancer. Expert Opin Investig Drugs 2016; 25: 1405–1412.
12.
Leone Roberti Maggiore U, Valenzano Menada M, Venturini PL, Ferrero S: The potential of sunitinib as a therapy in ovarian cancer. Expert Opin Investig Drugs 2013; 22: 1671–1686.
13.
Leone Roberti Maggiore U, Valenzano Menada M, Venturini PL, Ferrero S: Sorafenib for ovarian cancer. Expert Opin Investig Drugs 2013; 22: 1049–1062.
14.
Gavalas NG, Liontos M, Trachana SP, Bagratuni T, Arapinis C, Liacos C, Dimopoulos MA, Bamias A: Angiogenesis-related pathways in the pathogenesis of ovarian cancer. Int J Mol Sci 2013; 14: 15885–15909.
15.
Zebrowski BK, Liu W, Ramirez K, Akagi Y, Mills GB, Ellis LM: Markedly elevated levels of vascular endothelial growth factor in malignant ascites. Ann Surg Oncol 1999; 6: 373–378.
16.
Wimberger P, Chebouti I, Kasimir-Bauer S, Lachmann R, Kuhlisch E, Kimmig R, Suleyman E, Kuhlmann JD: Explorative investigation of vascular endothelial growth factor receptor expression in primary ovarian cancer and its clinical relevance. Gynecol Oncol 2014; 133: 467–472.
17.
Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, Carey MS, Beale P, Cervantes A, Kurzeder C, du Bois A, Sehouli J, Kimmig R, Stahle A, Collinson F, Essapen S, Gourley C, Lortholary A, Selle F, Mirza MR, Leminen A, Plante M, Stark D, Qian W, Parmar MK, Oza AM; ICON7 Investigators: A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011; 365: 2484–2496.
18.
Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, Mannel RS, Homesley HD, Fowler J, Greer BE, Boente M, Birrer MJ, Liang SX; Gynecologic Oncology Group: Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011; 365: 2473–2483.
19.
Leone Roberti Maggiore U, Bellati F, Ruscito I, Gasparri ML, Alessandri F, Venturini PL, Ferrero S: Monoclonal antibodies therapies for ovarian cancer. Expert Opin Biol Ther 2013; 13: 739–764.
20.
Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, Sovak MA, Yi J, Nycum LR: OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2012; 30: 2039–2045.
21.
Zhang J, Yang PL, Gray NS: Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 2009; 9: 28–39.
22.
Burger RA: Overview of anti-angiogenic agents in development for ovarian cancer. Gynecol Oncol 2011; 121: 230–238.
23.
Mross K, Stefanic M, Gmehling D, Frost A, Baas F, Unger C, Strecker R, Henning J, Gaschler-Markefski B, Stopfer P, de Rossi L, Kaiser R: Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors. Clin Cancer Res 2010; 16: 311–319.
24.
Okamoto I, Kaneda H, Satoh T, Okamoto W, Miyazaki M, Morinaga R, Ueda S, Terashima M, Tsuya A, Sarashina A, Konishi K, Arao T, Nishio K, Kaiser R, Nakagawa K: Phase I safety, pharmacokinetic, and biomarker study of BIBF 1120, an oral triple tyrosine kinase inhibitor in patients with advanced solid tumors. Mol Cancer Ther 2010; 9: 2825–2833.
25.
du Bois A, Huober J, Stopfer P, Pfisterer J, Wimberger P, Loibl S, Reichardt VL, Harter P: A phase I open-label dose-escalation study of oral BIBF 1120 combined with standard paclitaxel and carboplatin in patients with advanced gynecological malignancies. Ann Oncol 2010; 21: 370–375.
26.
Ledermann JA, Hackshaw A, Kaye S, Jayson G, Gabra H, McNeish I, Earl H, Perren T, Gore M, Persic M, Adams M, James L, Temple G, Merger M, Rustin G: Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. J Clin Oncol 2011; 29: 3798–3804.
27.
du Bois A, Kristensen G, Ray-Coquard I, Reuss A, Pignata S, Colombo N, Denison U, Vergote I, Del Campo JM, Ottevanger P, Heubner M, Minarik T, Sevin E, de Gregorio N, Bidzinski M, Pfisterer J, Malander S, Hilpert F, Mirza MR, Scambia G, Meier W, Nicoletto MO, Bjorge L, Lortholary A, Sailer MO, Merger M, Harter P; AGO Study Group led Gynecologic Cancer Intergroup/European Network of Gynaecologic Oncology Trials Groups Intergroup Consortium: Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 2016; 17: 78–89.
28.
Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ: BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 2008; 68: 4774–4782.
29.
Dallinger C, Trommeshauser D, Marzin K, Liesener A, Kaiser R, Stopfer P: Pharmacokinetic properties of nintedanib in healthy volunteers and patients with advanced cancer. J Clin Pharmacol 2016; 56: 1387–1394.
30.
Marzin K, Kretschmar G, Luedtke D, Kraemer S, Kuelzer R, Schlenker-Herceg R, Schmid U, Schnell D, Dallinger C: Pharmacokinetics of nintedanib in subjects with hepatic impairment. J Clin Pharmacol 2017, Epub ahead of print.
31.
Stopfer P, Rathgen K, Bischoff D, Ludtke S, Marzin K, Kaiser R, Wagner K, Ebner T: Pharmacokinetics and metabolism of BIBF 1120 after oral dosing to healthy male volunteers. Xenobiotica 2011; 41: 297–311.
32.
Mross K, Maessen P, van der Vijgh WJ, Bogdanowicz JF, Kurth KH, Pinedo HM: Absorption of epi-doxorubicin after intravesical administration in patients with in situ transitional cell carcinoma of the bladder. Eur J Cancer Clin Oncol 1987; 23: 505–508.
33.
Kropff M, Kienast J, Bisping G, Berdel WE, Gaschler-Markefski B, Stopfer P, Stefanic M, Munzert G: An open-label dose-escalation study of BIBF 1120 in patients with relapsed or refractory multiple myeloma. Anticancer Res 2009; 29: 4233–4238.
34.
Tai WT, Shiau CW, Li YS, Chang CW, Huang JW, Hsueh TT, Yu HC, Chen KF: Nintedanib (BIBF-1120) inhibits hepatocellular carcinoma growth independent of angiokinase activity. J Hepatol 2014; 61: 89–97.
35.
Awasthi N, Hinz S, Brekken RA, Schwarz MA, Schwarz RE: Nintedanib, a triple angiokinase inhibitor, enhances cytotoxic therapy response in pancreatic cancer. Cancer Lett 2015; 358: 59–66.
36.
Awasthi N, Schwarz RE: Profile of nintedanib in the treatment of solid tumors: the evidence to date. OncoTargets Ther 2015; 8: 3691–3701.
37.
Kutluk Cenik B, Ostapoff KT, Gerber DE, Brekken RA: BIBF 1120 (nintedanib), a triple angiokinase inhibitor, induces hypoxia but not EMT and blocks progression of preclinical models of lung and pancreatic cancer. Mol Cancer Ther 2013; 12: 992–1001.
38.
Ge YZ, Wu R, Lu TZ, Xin H, Yu P, Zhao Y, Liu H, Xu Z, Xu LW, Shen JW, Xu X, Zhou LH, Li WC, Zhu JG, Jia RP: Circulating endothelial progenitor cell: a promising biomarker in clinical oncology. Medical Oncol 2015; 32: 332.
39.
du Bois A, Floquet A, Kim JW, Rau J, del Campo JM, Friedlander M, Pignata S, Fujiwara K, Vergote I, Colombo N, Mirza MR, Monk BJ, Kimmig R, Ray-Coquard I, Zang R, Diaz-Padilla I, Baumann KH, Mouret-Reynier MA, Kim JH, Kurzeder C, Lesoin A, Vasey P, Marth C, Canzler U, Scambia G, Shimada M, Calvert P, Pujade-Lauraine E, Kim BG, Herzog TJ, Mitrica I, Schade-Brittinger C, Wang Q, Crescenzo R, Harter P: Incorporation of pazopanib in maintenance therapy of ovarian cancer. J Clin Oncol 2014; 32: 3374–3382.
40.
Oza AM, Cook AD, Pfisterer J, Embleton A, Ledermann JA, Pujade-Lauraine E, Kristensen G, Carey MS, Beale P, Cervantes A, Park-Simon TW, Rustin G, Joly F, Mirza MR, Plante M, Quinn M, Poveda A, Jayson GC, Stark D, Swart AM, Farrelly L, Kaplan R, Parmar MK, Perren TJ, ICON7 trial investigators: Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol 2015; 16: 928–936.
41.
Griffiths CT, Parker LM, Fuller AF Jr: Role of cytoreductive surgical treatment in the management of advanced ovarian cancer. Cancer Treat Rep 1979; 63: 235–240.
42.
Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski MJ, Von Pawel J, Gottfried M, Bondarenko I, Liao M, Barrueco J, Gaschler-Markefski B, Novello S: Nintedanib (BIBF 1120) plus docetaxel in NSCLC patients progressing after first-line chemotherapy: LUME Lung 1, a randomized, double-blind phase III trial. J Clin Oncol 2013; 31:LBA8011.
43.
Laganà AS, Colonese F, Colonese E, Sofo V, Salmeri FM, Granese R, Chiofalo B, Ciancimino L, Triolo O: Cytogenetic analysis of epithelial ovarian cancer'’s stem cells: an overview on new diagnostic and therapeutic perspectives. Eur J Gynaecol Oncol 2015; 36: 495–505.
44.
Laganà AS, Sofo V, Vitale SG, Triolo O: Epithelial ovarian cancer inherent resistance: may the pleiotropic interaction between reduced immunosurveillance and drug-resistant cells play a key role? Gynecol Oncol Rep 2016; 18: 57–58.
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