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The role of vascular endothelial growth factor inhibitors in the treatment of epithelial ovarian cancer

Abstract

Advanced epithelial ovarian, fallopian tube and primary peritoneal cancers (EOC) are a leading cause of gynaecological cancer-associated mortality and angiogenesis plays a key role in their growth. Vascular endothelial growth factor inhibitors (VEGFi) disrupt angiogenesis and improve the response rate, progression-free survival and in some cases, overall survival, when administered with and following cytotoxic chemotherapy, irrespective of the platinum sensitivity of EOC. Recent data have identified new indications for VEGFi in EOC: repeated exposure to VEGFi in the first- and then second-line treatment has sustained clinical efficacy; combinations of VEGFi with poly (ADP-ribose) polymerase inhibitors (PARPi) have proven effective as first-line or second-line maintenance regimens. However, recent trial data have not shown improved outcomes with combinations of VEGFi and immune checkpoint inhibitors. There remains a critical need to optimise patient selection for these effective yet somewhat toxic and expensive treatments. The search continues for validated biomarkers to optimise the use of VEGFi, of which the most promising at present is plasma Tie2. Based upon these studies, we propose a model of care incorporating VEGFi into the treatment of EOC, highlighting the need to change from the prescription of single courses of VEGFi, to allow use and re-use as clinically indicated.

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Fig. 1: Optimal first-line systemic treatment of advanced epithelial ovarian cancer.
Fig. 2: Optimal systemic treatment of progressive or recurrent epithelial ovarian cancer.

Data availability

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References

  1. 1.

    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Google Scholar 

  2. 2.

    Jayson GC, Kohn EC, Kitchener HC, Ledermann JA. Ovarian cancer. Lancet. 2014;384:1376–88.

    Article  Google Scholar 

  3. 3.

    Jayson GC, Kerbel R, Ellis LM, Harris AL. Antiangiogenic therapy in oncology: current status and future directions. Lancet. 2016;388:518–29.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  4. 4.

    Baeriswyl V, Christofori G. The angiogenic switch in carcinogenesis. Semin Cancer Biol. 2009;19:329–37.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  5. 5.

    Burger RA. Overview of anti-angiogenic agents in development for ovarian cancer. Gynecol Oncol. 2011;121:230–8.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  6. 6.

    Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473:298–307.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  7. 7.

    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  Google Scholar 

  8. 8.

    Chen H, Ye D, Xie X, Chen B, Lu W. VEGF, VEGFRs expressions and activated STATs in ovarian epithelial carcinoma. Gynecol Oncol. 2004;94:630–5.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  9. 9.

    Jain RK. Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science. 2005;307:58–62.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  10. 10.

    Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004;10:145–7.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. 11.

    Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018;15:325–40.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. 12.

    Higa GM, Abraham J. Biological mechanisms of bevacizumab-associated adverse events. Expert Rev Anticancer Ther. 2009;9:999–1007.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  13. 13.

    Cannistra SA, Matulonis UA, Penson RT, Hambleton J, Dupont J, Mackey H, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 2007;25:5180–6.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  14. 14.

    Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al. A phase 3 trial of bevacizumab in ovarian cancer. N. Engl J Med. 2011;365:2484–96.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  15. 15.

    Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N. Engl J Med. 2011;365:2473–83.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  16. 16.

    Oza AM, Cook AD, Pfisterer J, Embleton A, Ledermann JA, Pujade-Lauraine E, et al. 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;16:928–36.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. 17.

    Ozols RF. Treatment goals in ovarian cancer. Int J Gynecol Cancer. 2005;15:3–11.

    PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Karam A, Ledermann JA, Kim JW, Sehouli J, Lu K, Gourley C, et al. Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: first-line interventions. Ann Oncol. 2017;28:711–7.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  19. 19.

    Oza AM, Selle F, Davidenko I, Korach J, Mendiola C, Pautier P, et al. Efficacy and safety of bevacizumab-containing therapy in newly diagnosed ovarian cancer: ROSiA Single-Arm Phase 3B Study. Int J Gynecol Cancer. 2017;27:50–8.

    PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Pfisterer J, Joly F, Kristensen G, Rau J, Mahner S, Pautier P, et al. Optimal treatment duration of bevacizumab (BEV) combined with carboplatin and paclitaxel in patients (pts) with primary epithelial ovarian (EOC), fallopian tube (FTC) or peritoneal cancer (PPC): a multicenter open-label randomized 2-arm phase 3 ENGOT/GCIG. J Clin Oncol. 2021;39:5501–5501.

    Article  Google Scholar 

  21. 21.

    du Bois A, Floquet A, Kim JW, Rau J, Del Campo JM, Friedlander M, et al. Incorporation of pazopanib in maintenance therapy of ovarian cancer. J Clin Oncol. 2014;32:3374–81.

    PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    du Bois A, Kristensen G, Ray-Coquard I, Reuss A, Pignata S, Colombo N, et al. 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.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  23. 23.

    Ray-Coquard I, Cibula D, Mirza MR, Reuss A, Ricci C, Colombo N, et al. Final results from GCIG/ENGOT/AGO-OVAR 12, a randomised placebo-controlled phase III trial of nintedanib combined with chemotherapy for newly diagnosed advanced ovarian cancer. Int J Cancer. 2020;146:439–48.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  24. 24.

    Vergote I, du Bois A, Floquet A, Rau J, Kim J-W, del Campo JM, et al. Overall survival results of AGO-OVAR16: a phase 3 study of maintenance pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced ovarian cancer. Gynecol Oncol. 2019;155:186–91.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  25. 25.

    Ferron G, De Rauglaudre G, Chevalier A, Combe P, Joly F, Lortholary A, et al. Impact of adding nintedanib to neoadjuvant chemotherapy (NACT) for advanced epithelial ovarian cancer (EOC) patients: The CHIVA double-blind randomized phase II GINECO study. J Clin Oncol. 2019;37:5512.

    Article  Google Scholar 

  26. 26.

    Pölcher M, Eckhardt M, Coch C, Wolfgarten M, Kübler K, Hartmann G, et al. Sorafenib in combination with carboplatin and paclitaxel as neoadjuvant chemotherapy in patients with advanced ovarian cancer. Cancer Chemother Pharm. 2010;66:203–7.

    Article  CAS  Google Scholar 

  27. 27.

    Liu J, Nicum S, Reichardt P, Croitoru K, Illek B, Schmidinger M, et al. Assessment and management of diarrhea following VEGF receptor TKI treatment in patients with ovarian cancer. Gynecol Oncol. 2018;150:173–9.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  28. 28.

    Moore K, Colombo N, Scambia G, Kim B-G, Oaknin A, Friedlander M, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N. Engl J Med. 2018;379:2495–505.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  29. 29.

    Coleman RL, Fleming GF, Brady MF, Swisher EM, Steffensen KD, Friedlander M, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N. Engl J Med. 2019;381:2403–15.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. 30.

    González-Martín A, Pothuri B, Vergote I, DePont Christensen R, Graybill W, Mirza MR, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N. Engl J Med. 2019;381:2391–402.

    PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Ribatti D, Annese T, Ruggieri S, Tamma R, Crivellato E. Limitations of anti-angiogenic treatment of tumors. Transl Oncol. 2019;12:981–6.

    PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Rouzier R, Gouy S, Selle F, Lambaudie E, Floquet A, Fourchotte V, et al. Efficacy and safety of bevacizumab-containing neoadjuvant therapy followed by interval debulking surgery in advanced ovarian cancer: results from the ANTHALYA trial. Eur J Cancer. 2017;70:133–42.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  33. 33.

    Ray-Coquard I, Pautier P, Pignata S, Pérol D, González-Martín A, Berger R, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N. Engl J Med. 2019;381:2416–28.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  34. 34.

    Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30:2039–45.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35.

    Coleman RL, Brady MF, Herzog TJ, Sabbatini P, Armstrong DK, Walker JL, et al. Bevacizumab and paclitaxel–carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group Study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18:779–91.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  36. 36.

    Pfisterer J, Plante M, Vergote I, Du Bois A, Hirte H, Lacave AJ, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol. 2006;24:4699–707.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  37. 37.

    Parmar MKB, Ledermann JA, Colombo N, Du Bois A, Delaloye JF, Kirstensen GB, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet. 2003;361:2099–106.

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Matulonis UA, Oza AM, Ho TW, Ledermann JA. Intermediate clinical endpoints: a bridge between progression-free survival and overall survival in ovarian cancer trials. Cancer. 2015;121:1737–46.

    PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    Aghajanian C, Goff B, Nycum LR, Wang YV, Husain A, Blank SV. Final overall survival and safety analysis of OCEANS, a phase 3 trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent ovarian cancer. Gynecol Oncol. 2015;139:10–6.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  40. 40.

    Du Bois A, Vergote I, Ferron G, Reuss A, Meier W, Greggi S, et al. Randomized controlled phase III study evaluating the impact of secondary cytoreductive surgery in recurrent ovarian cancer: AGO DESKTOP III/ENGOT ov20. J Clin Oncol. 2017;35:5501–5501.

    Article  Google Scholar 

  41. 41.

    Du Bois A, Sehouli J, Vergote I, Ferron G, Reuss A, Meier W, et al. Randomized phase III study to evaluate the impact of secondary cytoreductive surgery in recurrent ovarian cancer: final analysis of AGO DESKTOP III/ENGOT-ov20. J Clin Oncol. 2020;38:6000–6000.

    Article  Google Scholar 

  42. 42.

    Lecuru F, du Bois A, Sehouli J, Vergote IB, Ferron G, Reuss A, et al. 816MO AGO DESKTOP III/ENGOT OV20: impact of surgical characteristics and time to first subsequent therapy (TFST). Ann Oncol. 2020;31:S617.

    Article  Google Scholar 

  43. 43.

    Coleman RL, Spirtos NM, Enserro D, Herzog TJ, Sabbatini P, Armstrong DK, et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N. Engl J Med. 2019;381:1929–39.

    PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Pfisterer J, Shannon CM, Baumann K, Rau J, Harter P, Joly F, et al. Bevacizumab and platinum-based combinations for recurrent ovarian cancer: a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;21:699–709.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  45. 45.

    Pignata S, Lorusso D, Joly F, Gallo C, Colombo N, Sessa C, et al. Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial. Lancet Oncol. 2021;22:267–76.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  46. 46.

    Ledermann JA, Embleton AC, Raja F, Perren TJ, Jayson GC, Rustin GJS, et al. Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;387:1066–74.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  47. 47.

    Ledermann JA, Embleton AC, Perren T, Jayson GC, Rustin GJS, Kaye SB, et al. Overall survival results of ICON6: a trial of chemotherapy and cediranib in relapsed ovarian cancer. J Clin Oncol. 2017;35:5506.

    Article  Google Scholar 

  48. 48.

    Rosenberg P, Andersson H, Boman K, Ridderheim M, Sorbe B, Puistola U, et al. Randomized trial of single agent paclitaxel given weekly versus every three weeks and with peroral versus intravenous steroid premedication to patients with ovarian cancer previously treated with platinum. Acta Oncol. 2002;41:418–24.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  49. 49.

    Markman M, Blessing J, Rubin SC, Connor J, Hanjani P, Waggoner S. Phase II trial of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: A Gynecologic Oncology Group Study. Gynecol Oncol. 2006;101:436–40.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  50. 50.

    Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol. 2001;19:3312–22.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  51. 51.

    Gordon AN, Tonda M, Sun S, Rackoff W. Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer. Gynecol Oncol. 2004;95:1–8.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  52. 52.

    Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: A Gynecologic Oncology Group Study. J Clin Oncol. 2007;25:5165–71.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  53. 53.

    Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA Open-Label Randomized Phase III Trial. J Clin Oncol. 2014;32:1302–8.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  54. 54.

    Bamias A, Gibbs E, Khoon Lee C, Davies L, Dimopoulos M, Zagouri F, et al. Bevacizumab with or after chemotherapy for platinum-resistant recurrent ovarian cancer: exploratory analyses of the AURELIA trial. Ann Oncol. 2017;28:1842–8.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  55. 55.

    Poveda AM, Selle F, Hilpert F, Reuss A, Savarese A, Vergote I, et al. Bevacizumab combined with weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan in platinum-resistant recurrent ovarian cancer: analysis by chemotherapy cohort of the randomized phase III AURELIA trial. J Clin Oncol. 2015;33:3836–8.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  56. 56.

    Shoji Eto, Sato Soma, Fukagawa Tomabechi, et al. A new therapeutic strategy for recurrent ovarian cancer―bevacizumab beyond progressive disease. Healthcare. 2019;7:109.

    PubMed Central  Article  Google Scholar 

  57. 57.

    Garcia AA, Hirte H, Fleming G, Yang D, Tsao-Wei DD, Roman L, et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: A trial of the California, Chicago, and Princess Margaret Hospital Phase II Consortia. J Clin Oncol. 2008;26:76–82.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  58. 58.

    Monk BJ, Sill MW, Walker JL, Darus CJ, Sutton G, Tewari KS, et al. Randomized phase II evaluation of bevacizumab versus bevacizumab plus fosbretabulin in recurrent ovarian, tubal, or peritoneal carcinoma: An NRG Oncology/Gynecologic Oncology Group Study. J Clin Oncol. 2016;34:2279–86.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  59. 59.

    Tew WP, Sill MW, Walker JL, Secord AA, Bonebrake AJ, Schilder JM, et al. Randomized phase II trial of bevacizumab plus everolimus versus bevacizumab alone for recurrent or persistent ovarian, fallopian tube or peritoneal carcinoma: An NRG Oncology/Gynecologic Oncology Group Study. Gynecol Oncol. 2018;151:257–63.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  60. 60.

    Nimeiri HS, Oza AM, Morgan RJ, Friberg G, Kasza K, Faoro L, et al. Efficacy and safety of bevacizumab plus erlotinib for patients with recurrent ovarian, primary peritoneal, and fallopian tube cancer: A trial of the Chicago, PMH, and California Phase II Consortia. Gynecol Oncol. 2008;110:49–55.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  61. 61.

    Pignata S, Lorusso D, Scambia G, Sambataro D, Tamberi S, Cinieri S, et al. Pazopanib plus weekly paclitaxel versus weekly paclitaxel alone for platinum-resistant or platinum-refractory advanced ovarian cancer (MITO 11): A Randomised, Open-label, Phase 2 Trial. Lancet Oncol. 2015;16:561–8.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  62. 62.

    Richardson DL, Sill MW, Coleman RL, Sood AK, Pearl ML, Kehoe SM, et al. Paclitaxel with and without pazopanib for persistent or recurrent ovarian cancer: a randomized clinical trial. JAMA Oncol. 2018;4:196–202.

    PubMed  Article  PubMed Central  Google Scholar 

  63. 63.

    Chekerov R, Hilpert F, Mahner S, El-Balat A, Harter P, De Gregorio N, et al. Sorafenib plus topotecan versus placebo plus topotecan for platinum-resistant ovarian cancer (TRIAS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2018;19:1247–58.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  64. 64.

    Lee JM, Annunziata CM, Hays JL, Cao L, Choyke P, Yu M, et al. Phase II trial of bevacizumab and sorafenib in recurrent ovarian cancer patients with or without prior-bevacizumab treatment. Gynecol Oncol. 2020;159:88–94.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  65. 65.

    Lan C-Y, Wang Y, Xiong Y, Li J-D, Shen J-X, Li Y-F, et al. Apatinib combined with oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer (AEROC): a phase 2, single-arm, prospective study. Lancet Oncol. 2018;19:1239–46.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  66. 66.

    Hall MR, Dehbi H-M, Banerjee S, Lord R, Clamp A, Ledermann JA, et al. A phase II randomised, placebo-controlled trial of low dose (metronomic) cyclophosphamide and nintedanib (BIBF1120) in advanced ovarian, fallopian tube or primary peritoneal cancer. Gynecol Oncol. 2020;159:692–8.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  67. 67.

    Matulonis UA, Berlin S, Ivy P, Tyburski K, Krasner C, Zarwan C, et al. Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol. 2009;27:5601–6.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  68. 68.

    Hirte H, Lheureux S, Fleming GF, Sugimoto A, Morgan R, Biagi J, et al. A phase 2 study of cediranib in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: a trial of the Princess Margaret, Chicago and California Phase II Consortia. Gynecol Oncol. 2015;138:55–61.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  69. 69.

    Baumann KH, du Bois A, Meier W, Rau J, Wimberger P, Sehouli J, et al. A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monother. Ann Oncol. 2012;23:2265–71.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  70. 70.

    Miao M, Deng G, Luo S, Zhou J, Chen L, Yang J, et al. A phase II study of apatinib in patients with recurrent epithelial ovarian cancer. Gynecol Oncol. 2018;148:286–90.

    PubMed  Article  CAS  Google Scholar 

  71. 71.

    Penson RT, Moore KM, Fleming GF, Braly P, Schimp V, Nguyen H, et al. A phase II study of ramucirumab (IMC-1121B) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma. Gynecol Oncol. 2014;134:478–85.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. 72.

    Tew WP, Colombo N, Ray-Coquard I, Del Campo JM, Oza A, Pereira D, et al. Intravenous aflibercept in patients with platinum-resistant, advanced ovarian cancer: results of a randomized, double-blind, phase 2, parallel-arm study. Cancer. 2014;120:335–43.

    PubMed  Article  CAS  Google Scholar 

  73. 73.

    Stockler MR, Hilpert F, Friedlander M, King MT, Wenzel L, Lee CK, et al. Patient-reported outcome results from the open-label phase III AURELIA trial evaluating bevacizumab-containing therapy for platinum-resistant ovarian cancer. J Clin Oncol. 2014;32:1309–16.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. 74.

    Sjoquist KM, Mileshkin LR, Ananda S, Shannon CM, Bowtell D, Yip S, et al. REZOLVE (ANZGOG-1101): A phase 2 trial of intraperitoneal (IP) bevacizumab (bev) for recurrent ascites in advanced, chemotherapy-resistant, epithelial ovarian cancer (CR-EOC). J Clin Oncol. 2018;36:10097.

    Article  Google Scholar 

  75. 75.

    Colombo N, Mangili G, Mammoliti S, Kalling M, Tholander B, Sternas L, et al. A phase II study of aflibercept in patients with advanced epithelial ovarian cancer and symptomatic malignant ascites. Gynecol Oncol. 2012;125:42–7.

    PubMed  Article  CAS  Google Scholar 

  76. 76.

    Welti J, Loges S, Dimmeler S, Carmeliet P. Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer. J Clin Invest. 2013;123:3190–200.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. 77.

    Giantonio BJ. Goldie–Coldman and bevacizumab beyond disease progression. Nat Rev Clin Oncol. 2009;6:311–2.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  78. 78.

    Loges S, Schmidt T, Carmeliet P. Mechanisms of resistance to anti-angiogenic therapy and development of third-generation anti-angiogenic drug candidates. Genes Cancer. 2010;1:12–25.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  79. 79.

    Mancuso MR, Davis R, Norberg SM, O’Brien S, Sennino B, Nakahara T, et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest. 2006;116:2610–21.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  80. 80.

    Grothey A, Sugrue MM, Purdie DM, Dong W, Sargent D, Hedrick E, et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol. 2008;26:5326–34.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  81. 81.

    Bennouna J, Sastre J, Arnold D, Österlund P, Greil R, Van Cutsem E, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14:29–37.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  82. 82.

    Essel KG, Behbakht K, Lai T, Hand L, Evans E, Dvorak J, et al. PARPi after PARPi in epithelial ovarian cancer. Gynecol Oncol Rep. 2021;35. https://doi.org/10.1016/j.gore.2021.100699.

  83. 83.

    Secord AA, McCollum M, Davidson BA, Broadwater G, Squatrito R, Havrilesky LJ, et al. Phase II trial of nintedanib in patients with bevacizumab-resistant recurrent epithelial ovarian, tubal, and peritoneal cancer. Gynecol Oncol. 2019;153:555–61.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  84. 84.

    Shoji T, Komiyama S, Kigawa J, Tanabe H, Kato K, Itamochi H, et al. An open-label, randomized, phase II trial evaluating the efficacy and safety of standard of care with or without bevacizumab in platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer patients previously treated with bevacizuma. BMC Cancer. 2018;18:1–8.

    Article  CAS  Google Scholar 

  85. 85.

    Chan N, Bristow RG. ‘Contextual’ synthetic lethality and/or loss of heterozygosity: Tumor hypoxia and modification of DNA repair. Clin Cancer Res. 2010;16:4553–60.

    PubMed  Article  PubMed Central  Google Scholar 

  86. 86.

    Kaplan AR, Gueble SE, Liu Y, Oeck S, Kim H, Yun Z, et al. Cediranib suppresses homology-directed DNA repair through down-regulation of BRCA1/2 and RAD51. Sci Transl Med. 2019;11. https://doi.org/10.1126/scitranslmed.aav4508.

  87. 87.

    Tewari KS, Burger RA, Enserro D, Norquist BM, Swisher EM, Brady MF, et al. Final overall survival of a randomized trial of bevacizumab for primary treatment of ovarian cancer. J Clin Oncol. 2019;37:2317–28.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  88. 88.

    Banerjee S, Moore KN, Colombo N, Scambia G, Kim B-G, Oaknin A, et al. 811MO Maintenance olaparib for patients (pts) with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): 5-year (y) follow-up (f/u) from SOLO1. Ann Oncol. 2020;31:S613.

    Article  Google Scholar 

  89. 89.

    Mirza MR, Åvall Lundqvist E, Birrer MJ, dePont Christensen R, Nyvang G-B, Malander S, et al. Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial. Lancet Oncol. 2019;20:1409–19.

  90. 90.

    Penson RT, Valencia RV, Cibula D, Colombo N, Leath CA, Bidzinski M, et al. Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): a randomized phase III trial. J Clin Oncol. 2020;38:1164–74.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  91. 91.

    Moore KN, Secord AA, Geller MA, Miller DS, Cloven N, Fleming GF, et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019;20:636–48.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  92. 92.

    Oza AM, Tinker AV, Oaknin A, Shapira-Frommer R, McNeish IA, Swisher EM, et al. Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: integrated analysis of data from Study 10 and ARIEL2. Gynecol Oncol. 2017;147:267–75.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  93. 93.

    Liu JF, Barry WT, Birrer M, Lee JM, Buckanovich RJ, Fleming GF, et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol. 2014;15:1207–14.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  94. 94.

    Liu JF, Barry WT, Birrer M, Lee JM, Buckanovich RJ, Fleming GF, et al. Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer. Ann Oncol. 2019;30:551–7.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  95. 95.

    Liu JF, Brady MF, Matulonis UA, Miller A, Kohn EC, Swisher EM, et al. A phase III study comparing single-agent olaparib or the combination of cediranib and olaparib to standard platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer. J Clin Oncol. 2020;38:6003–6003.

    Article  Google Scholar 

  96. 96.

    Lee J, Moore RG, Ghamande SA, Park MS, Diaz JP, Chapman JA, et al. Cediranib in combination with olaparib in patients without a germline BRCA1/2 mutation with recurrent platinum-resistant ovarian cancer: Phase IIb CONCERTO Trial. J Clin Oncol. 2020;38:6056–6056.

    Article  Google Scholar 

  97. 97.

    Colombo N, Nicoletto MO, Benedetti Panici P, Tognon G, Bologna A, Lissoni AA, et al. BAROCCO: a randomized phase II study of weekly paclitaxel vs cediranib-olaparib combination given with continuous or intermittent schedule in patients with recurrent platinum resistant ovarian cancer (PROC). Ann Oncol. 2019;30:v896.

    Article  Google Scholar 

  98. 98.

    Lheureux S, Oaknin A, Garg S, Bruce JP, Madariaga A, Dhani NC, et al. EVOLVE: a multicenter open-label single-arm clinical and translational phase II trial of cediranib plus olaparib for ovarian cancer after PARP inhibition progression. Clin Cancer Res. 2020;26:4206–15.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  99. 99.

    Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl J Med. 2003;348:203–13.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  100. 100.

    Hwang WT, Adams SF, Tahirovic E, Hagemann IS, Coukos G. Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecol Oncol. 2012;124:192–8.

    PubMed  Article  PubMed Central  Google Scholar 

  101. 101.

    Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA. 2007;104:3360–5.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  102. 102.

    Abiko K, Mandai M, Hamanishi J, Yoshioka Y, Matsumura N, Baba T, et al. PD-L1 on tumor cells is induced in ascites and promotes peritoneal dissemination of ovarian cancer through CTL dysfunction. Clin Cancer Res. 2013;19:1363–74.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  103. 103.

    Disis ML, Taylor MH, Kelly K, Beck JT, Gordon M, Moore KM, et al. Efficacy and safety of avelumab for patients with recurrent or refractory ovarian cancer: phase 1b results from the JAVELIN Solid Tumor Trial. JAMA Oncol. 2019;5:393–401.

    PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Hamanishi J, Mandai M, Ikeda T, Minami M, Kawaguchi A, Murayama T, et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2015;33:4015–22.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  105. 105.

    Liu JF, Gordon M, Veneris J, Braiteh F, Balmanoukian A, Eder JP, et al. Safety, clinical activity and biomarker assessments of atezolizumab from a phase I study in advanced/recurrent ovarian and uterine cancers. Gynecol Oncol. 2019;154:314–22.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  106. 106.

    Zamarin D, Burger RA, Sill MW, Powell DJ, Lankes HA, Feldman MD, et al. Randomized phase II trial of nivolumab versus nivolumab and ipilimumab for recurrent or persistent ovarian cancer: An NRG Oncology Study. J Clin Oncol. 2020;38:1814–23.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  107. 107.

    Ghosh M, Saha S, Bettke J, Nagar R, Parrales A, Iwakuma T, et al. Mutant p53 suppresses innate immune signaling to promote tumorigenesis. Cancer Cell. 2021;39:494–508.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  108. 108.

    Wu JN, Roberts CWM. ARID1A mutations in cancer: another epigenetic tumor suppressor. Cancer Disco. 2013;3:35–43.

    Article  CAS  Google Scholar 

  109. 109.

    Matulonis UA, Shapira-Frommer R, Santin AD, Lisyanskaya AS, Pignata S, Vergote I, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann Oncol. 2019;30:1080–7.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  110. 110.

    Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim T-Y, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl J Med. 2020;382:1894–905.

    PubMed  Article  CAS  Google Scholar 

  111. 111.

    Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl J Med. 2019;380:1116–27.

    PubMed  Article  CAS  Google Scholar 

  112. 112.

    Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): A Multicentre, Open-label, Phase 3, Randomised Controlled Trial. Lancet. 2019;393:2404–15.

    PubMed  Article  Google Scholar 

  113. 113.

    Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl J Med. 2018;378:2288–301.

    Article  CAS  Google Scholar 

  114. 114.

    Makker V, Taylor MH, Aghajanian C, Oaknin A, Mier J, Cohn AL, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol. 2020;38:2981–92.

    PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Liu JF, Herold C, Gray KP, Penson RT, Horowitz N, Konstantinopoulos PA, et al. Assessment of combined nivolumab and bevacizumab in relapsed ovarian cancer: A Phase 2 Clinical Trial. JAMA Oncol. 2019;5:1731–8.

    PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Moroney JW, Powderly J, Lieu CH, Bendell JC, Eckhardt SG, Chang C-W, et al. Safety and clinical activity of atezolizumab plus bevacizumab in patients with ovarian cancer: A Phase Ib Study. Clin Cancer Res. 2020;26:5631–7.

    PubMed  Article  CAS  Google Scholar 

  117. 117.

    Moore KN, Bookman M, Sehouli J, Miller A, Anderson C, Scambia G, et al. Atezolizumab, bevacizumab, and chemotherapy for newly diagnosed stage III or IV ovarian cancer: Placebo-Controlled Randomized Phase III Trial (IMagyn050/GOG 3015/ENGOT-OV39). J Clin Oncol. 2021. https://doi.org/10.1200/JCO.21.00306.

  118. 118.

    Konstantinopoulos PA, Cannistra SA. Immune checkpoint inhibitors in ovarian cancer: can we bridge the gap between imagynation and reality? J Clin Oncol. 2021. https://doi.org/10.1200/JCO.21.00571.

  119. 119.

    Harter P, Pautier P, Van Nieuwenhuysen E, Reuss A, Redondo A, Lindemann K, et al. Atezolizumab in combination with bevacizumab and chemotherapy versus bevacizumab and chemotherapy in recurrent ovarian cancer – a randomized phase III trial (AGO-OVAR 2.29/ENGOT-ov34). Int J Gynecol Cancer. 2020;30:1997–2001.

    PubMed  Article  PubMed Central  Google Scholar 

  120. 120.

    Zimmer AS, Nichols E, Cimino-Mathews A, Peer C, Cao L, Lee M-J, et al. A phase I study of the PD-L1 inhibitor, durvalumab, in combination with a PARP inhibitor, olaparib, and a VEGFR1–3 inhibitor, cediranib, in recurrent women’s cancers with biomarker analyses. J Immunother Cancer. 2019;7:197.

    PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Hodgson DR, Dougherty BA, Lai Z, Fielding A, Grinsted L, Spencer S, et al. Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. Br J Cancer. 2018;119:1401–9.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  122. 122.

    Hegde PS, Wallin JJ, Mancao C. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin Cancer Biol. 2018;52:117–24.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  123. 123.

    Hegde PS, Jubb AM, Chen D, Li NF, Meng YG, Bernaards C, et al. Predictive impact of circulating vascular endothelial growth factor in four phase III trials evaluating bevacizumab. Clin Cancer Res. 2013;19:929–37.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  124. 124.

    Miles D, Cameron D, Bondarenko I, Manzyuk L, Alcedo JC, Lopez RI, et al. Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): a double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation. Eur J Cancer. 2017;70:146–55.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  125. 125.

    Birrer MJ, Lankes H, Burger RA, Mannel R, Homesley H, Henschel V, et al. Biomarker (BM) results from GOG-0218, a phase 3 trial of front-line bevacizumab (BV) + chemotherapy (CT) for ovarian cancer (OC). Ann Oncol. 2012;23:ix81–2.

    Article  Google Scholar 

  126. 126.

    Bais C, Mueller B, Brady MF, Mannel RS, Burger RA, Wei W, et al. Tumor microvessel density as a potential predictive marker for bevacizumab benefit: GOG-0218 biomarker analyses. J Natl Cancer Inst. 2017;109:1–10.

    Article  CAS  Google Scholar 

  127. 127.

    Jayson GC, Zhou C, Backen A, Horsley L, Marti-Marti K, Shaw D, et al. Plasma Tie2 is a tumor vascular response biomarker for VEGF inhibitors in metastatic colorectal cancer. Nat Commun. 2018;9. https://doi.org/10.1038/s41467-018-07174-1.

  128. 128.

    Backen A, Renehan AG, Clamp AR, Berzuini C, Zhou C, Oza A, et al. The combination of circulating Ang1 and Tie2 levels predicts progression-free survival advantage in bevacizumab-treated patients with ovarian cancer. Clin Cancer Res. 2014;20:4549–58.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  129. 129.

    Zhou C, Clamp A, Backen A, Berzuini C, Renehan A, Banks RE, et al. Systematic analysis of circulating soluble angiogenesis-associated proteins in ICON7 identifies Tie2 as a biomarker of vascular progression on bevacizumab. Br J Cancer. 2016;115:228–35.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  130. 130.

    Cancer Research UK. A study of the new Tie2 blood test in women having bevacizumab for ovarian cancer (VALTIVE1). 2021. https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-of-the-new-tie2-blood-test-in-women-having-bevacizumab-for-ovarian-cancer-valtive1. Accessed 5 May 2021.

  131. 131.

    Ferriss JS, Java JJ, Bookman MA, Fleming GF, Monk BJ, Walker JL, et al. Ascites predicts treatment benefit of bevacizumab in front-line therapy of advanced epithelial ovarian, fallopian tube and peritoneal cancers: An NRG Oncology/GOG Study. Gynecol Oncol. 2015;139:17–22.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  132. 132.

    Friedlander M, Hancock KC, Rischin D, Messing MJ, Stringer CA, Matthys GM, et al. A phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer. Gynecol Oncol. 2010;119:32–7.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  133. 133.

    Matei D, Sill MW, Lankes HA, DeGeest K, Bristow RE, Mutch D, et al. Activity of sorafenib in recurrent ovarian cancer and primary peritoneal carcinomatosis: A Gynecologic Oncology Group Trial. J Clin Oncol. 2011;29:69–75.

    PubMed  Article  PubMed Central  Google Scholar 

  134. 134.

    Biagi JJ, Oza AM, ChalChal HI, Grimshaw R, Ellard SL, Lee U, et al. A phase II study of sunitinib in patients with recurrent epithelial ovarian and primary peritoneal carcinoma: An NCIC Clinical Trials Group Study. Ann Oncol. 2011;22:335–40.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

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Murphy, A.D., Morgan, R.D., Clamp, A.R. et al. The role of vascular endothelial growth factor inhibitors in the treatment of epithelial ovarian cancer. Br J Cancer (2021). https://doi.org/10.1038/s41416-021-01605-5

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