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Cediranib in combination with fulvestrant in hormone-sensitive metastatic breast cancer: a randomized Phase II study

  • PHASE II STUDIES
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Summary

Hormone receptor-positive breast cancer is treated with estrogen inhibitors. Fulvestrant (FASLODEX™), an estrogen receptor (ER) antagonist with no known agonist effects, competitively binds, blocks and degrades the ER. Vascular endothelial growth factor (VEGF) may mediate resistance to ER antagonists. Cediranib is a highly potent VEGF signaling inhibitor with activity against all three VEGF receptors. This randomized Phase II study evaluated cediranib plus fulvestrant. Postmenopausal women with hormone-sensitive metastatic breast cancer were eligible. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), duration of response, clinical benefit rate (CBR), safety/tolerability and pharmacokinetics (PK). Patients received cediranib 45 mg/day (n = 31) or placebo (n = 31) both plus fulvestrant. Demographic/baseline characteristics were well balanced. Patients treated with cediranib had a numerical advantage in PFS (hazard ratio = 0.867, P = 0.669; median 223 vs. 112 days, respectively) and ORR (22 vs. 8 %, respectively) vs. placebo, although not statistically significant. CBR was 42 % in both arms. The most common adverse events (AEs) in the cediranib arm were diarrhea (68 %), fatigue (61 %) and hypertension (55 %). The incidence of grade ≥3 AEs (68 % vs. 32 %), serious AEs (48 % vs. 13 %), discontinuation AEs (39 % vs. 10 %), and cediranib dose reductions/interruptions (74 % vs. 32 %) were higher in the cediranib arm. There was no evidence of a clinically relevant effect of cediranib on fulvestrant PK. Cediranib plus fulvestrant may demonstrate clinical activity in this population, but cediranib 45 mg was not sufficiently well tolerated. Investigation of lower doses of cediranib plus hormonal/chemotherapy could be considered.

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References

  1. GLOBOCAN statistics. 2008. Available at: https://doi.org/globocan.iarc.fr/.

  2. Gennari A, Conte P, Rosso R, Orlandini C, Bruzzi P (2005) Survival of metastatic breast carcinoma patients over a 20-year period: a retrospective analysis based on individual patient data from six consecutive studies. Cancer 104:1742–1750

    Article  Google Scholar 

  3. Wilcken N, Dear R (2008) Chemotherapy in metastatic breast cancer: A summary of all randomised trials reported 2000–2007. Eur J Cancer 44:2118–2225

    Article  Google Scholar 

  4. Cleator SJ, Ahamed E, Coombes RC, Palmieri C (2009) A 2009 update on the treatment of patients with hormone receptor-positive breast cancer. Clin Breast Cancer Suppl 1:S6–S17

    Article  Google Scholar 

  5. Addo S, Yates RA, Laight A (2002) A phase I trial to assess the pharmacology of the new oestrogen receptor antagonist fulvestrant on the endometrium in healthy postmenopausal volunteers. Br J Cancer 87:1354–1359

    Article  CAS  Google Scholar 

  6. Morris C, Wakeling A (2002) Fulvestrant (‘Faslodex’)–a new treatment option for patients progressing on prior endocrine therapy. Endocr Relat Cancer 9:267–276

    Article  CAS  Google Scholar 

  7. Robertson JF, Osborne CK, Howell A, Jones SE, Mauriac L, Ellis M, Kleeberg UR, Come SE, Vergote I, Gertler S, Buzdar A, Webster A, Morris C (2003) Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: a prospective combined analysis of two multicenter trials. Cancer 98:229–238

    Article  CAS  Google Scholar 

  8. Howell A, Pippen J, Elledge RM, Mauriac L, Vergote I, Jones SE, Come SE, Osborne CK, Robertson JF (2005) Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: A prospectively planned combined survival analysis of two multicenter trials. Cancer 104:236–239

    Article  CAS  Google Scholar 

  9. Massarweh S, Schiff R (2007) Unraveling the mechanisms of endocrine resistance in breast cancer: New therapeutic opportunities. Clin Cancer Res 13:1950–1954

    Article  CAS  Google Scholar 

  10. Linderholm B, Grankvist K, Wilking N, Johansson M, Tavelin B, Henriksson R (2000) Correlation of vascular endothelial growth factor content with recurrences, survival, and first relapse site in primary node-positive breast carcinoma after adjuvant treatment. J Clin Oncol 18:1423–1431

    Article  CAS  Google Scholar 

  11. Foekens JA, Peters HA, Grebenchtchikov N, Look MP, Meijer-Van Gelder ME, Geurts-Moespot A, van der Kwast TH, Sweep CG, Klijn JG (2001) High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer. Cancer Res 61:5407–5414

    CAS  PubMed  Google Scholar 

  12. Rydén L, Linderbolm B, Nielsen NH, Emdin S, Jönsson PE, Landberg G (2003) Tumor specific VEGF-A and VEGFR2/KDR protein are co-expressed in breast cancer. Breast Cancer Res Treat 82:147–154

    Article  Google Scholar 

  13. Rydén L, Stendahl M, Jonsson H, Emdin S, Bengtsson NO, Landberg G (2005) Tumor-specific VEGF-A and VEGFR2 in postmenopausal breast cancer patients with long-term follow-up. Implication of a link between VEGF pathway and tamoxifen response. Breast Cancer Res Treat 89:135–143

    Article  Google Scholar 

  14. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676

    Article  CAS  Google Scholar 

  15. Wedge SR, Kendrew J, Hennequin LF, Valentine PJ, Barry ST, Brave SR, Smith NR, James NH, Dukes M, Curwen JO, Chester R, Jackson JA, Boffey SJ, Kilburn LL, Barnett S, Richmond GH, Wadsworth PF, Walker M, Bigley AL, Taylor ST, Cooper L, Beck S, Jürgensmeier JM, Ogilvie DJ (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65:4389–4400

    Article  CAS  Google Scholar 

  16. Drevs J, Siegert P, Medinger M, Mross K, Strecker R, Zirrgiebel U, Harder J, Blum H, Robertson J, Jürgensmeier JM, Puchalski TA, Young H, Saunders O, Unger C (2007) Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol 25:3045–3054

    Article  CAS  Google Scholar 

  17. Yamamoto N, Tamura T, Yamamoto N, Yamada K, Yamada Y, Nokihara H, Fujiwara Y, Takahashi T, Murakami H, Boku N, Yamazaki K, Puchalski TA, Shin E (2009) Phase I, dose escalation and pharmacokinetic study of cediranib (RECENTIN), a highly potent and selective VEGFR signaling inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 64:1165–1172

    Article  CAS  Google Scholar 

  18. Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95

    Article  CAS  Google Scholar 

  19. Matulonis UA, Berlin S, Ivy P, Tyburski K, Krasner C, Zarwan C, Berkenblit A, Campos S, Horowitz N, Cannistra SA, Lee H, Lee J, Roche M, Hill M, Whalen C, Sullivan L, Tran C, Humphreys BD, Penson RT (2009) 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 27:5601–5606

    Article  CAS  Google Scholar 

  20. Fiedler W, Mesters R, Heuser M, Ehninger G, Berdel WE, Zirrgiebel U, Robertson JD, Puchalski TA, Collins B, Jurgensmeier JM, Serve H (2010) An open-label, Phase I study of cediranib (RECENTIN) in patients with acute myeloid leukemia. Leuk Res 34:196–202

    Article  CAS  Google Scholar 

  21. Langenberg MH, van Herpen CM, de Bono J, Schellens JH, Unger C, Hoekman K, Blum HE, Fiedler W, Drevs J, Le Maulf F, Fielding A, Robertson J, Voest EE (2009) Effective strategies for management of hypertension after vascular endothelial growth factor signaling inhibition therapy: results from a phase II randomized, factorial, double-blind study of cediranib in patients with advanced solid tumors. J Clin Oncol 27:6152–6159

    Article  CAS  Google Scholar 

  22. Laurie SA, Gauthier I, Arnold A, Shepherd FA, Ellis PM, Chen E, Goss G, Powers J, Walsh W, Tu D, Robertson J, Puchalski TA, Seymour L (2008) Phase I and pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer: the National Cancer Institute of Canada clinical trials group. J Clin Oncol 26:1871–1878

    Article  CAS  Google Scholar 

  23. Chen E, Jonker D, Gauthier I, Maclean M, Wells J, Powers J, Seymour L (2009) Phase I study of cediranib in combination with oxaliplatin and infusional 5-fluorouracil in patients with advanced colorectal cancer. Clin Cancer Res 15:1481–1486

    Article  CAS  Google Scholar 

  24. Goss G, Shepherd FA, Laurie S, Gauthier I, Leighl N, Chen E, Feld R, Powers J, Seymour L (2009) A phase I and pharmacokinetic study of daily oral cediranib, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with cisplatin and gemcitabine in patients with advanced non-small cell lung cancer: A study of the National Cancer Institute of Canada Clinical Trials Group. Eur J Cancer 45:782–788

    Article  CAS  Google Scholar 

  25. Goss GD, Arnold A, Shepherd FA, Dediu M, Ciuleanu TE, Fenton D, Zukin M, Walde D, Laberge F, Vincent MD, Ellis PM, Laurie SA, Ding K, Frymire E, Gauthier I, Leighl NB, Ho C, Noble J, Lee CW, Seymour L (2010) Randomized, double-blind trial of carboplatin and paclitaxel with either daily oral cediranib or placebo in advanced non-small-cell lung cancer: NCIC clinical trials group BR24 study. J Clin Oncol 28:49–55

    Article  CAS  Google Scholar 

  26. Liang Y, Brekken RA, Hyder SM (2006) Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the anti-proliferative activity of anti-hormones. Endocr Relat Cancer 13:905–919

    Article  CAS  Google Scholar 

  27. Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, Fein L, Romieu G, Buzdar A, Robertson JF, Brufsky A, Possinger K, Rennie P, Sapunar F, Lowe E, Piccart M (2008) Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol 26:1664–1670

    Article  CAS  Google Scholar 

  28. Osborne CK, Pippen J, Jones SE, Parker LM, Ellis M, Come S, Gertler SZ, May JT, Burton G, Dimery I, Webster A, Morris C, Elledge R, Buzdar A (2002) Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol 20:3386–3395

    Article  CAS  Google Scholar 

  29. Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko I, Khasanov R, Verhoeven D, Pedrini J, Lichinitser M, Pendergrass K, Garnett S, Lindemann J, Sapunar F, Martin M (2009) CONFIRM: Phase III, randomized, parallel-group trial comparing fulvestrant 250 mg vs fulvestrant 500 mg in postmenopausal women with oestrogen receptor-positive advanced breast cancer. Cancer Res 69(Suppl 3):25

    Article  Google Scholar 

  30. Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, Verhoeven D, Pedrini JL, Smirnova I, Lichinitser MR, Pendergrass K, Garnett S, Rukazenkov Y, Martin M (2012) Final analysis of overall survival for the Phase III CONFIRM trial: fulvestrant 500 mg versus 250 mg. Cancer Res 72(24):S1–4

    Google Scholar 

  31. van Cruijsen H, Voest EE, Punt CJ, Hoekman K, Witteveen PO, Meijerink MR, Puchalski TA, Robertson J, Saunders O, Jürgensmeier JM, van Herpen CM, Giaccone G (2010) Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours. Eur J Cancer 46:901–911

    Article  Google Scholar 

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Acknowledgments

Funding for this study was provided by AstraZeneca. We thank Dr Helen Jones, from Mudskipper Bioscience, who provided medical writing assistance funded by AstraZeneca.

Conflicts of interest

D.M.H. has received research funding from AstraZeneca, consulting income and honoraria from Genomic Health, research funding and honoraria from Centocor Ortho Biotec, and honoraria from Genentech. P.K. received remuneration for an advisory board for Genentech. J.V. was a member of an AstraZeneca advisory board. M.W.A. has received consultancy fees and research funding from AstraZeneca. J.L. received honoraria from AstraZeneca. B.M. was employed by AstraZeneca and owns stock in the company. J.X. and K.B. are employees of AstraZeneca and own stock in the company. All other authors declared no conflicts of interest.

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Author notes

  1. Bijoyesh Mookerjee

    Present address: Incyte, Wilmington, DE, USA

Authors and Affiliations

  1. Desert Regional Medical Center Comprehensive Cancer Center, Palm Springs, CA, USA

    David M. Hyams

  2. Mount Medical Centre, Perth, WA, Australia

    Arlene Chan

  3. Instituto Brasileiro de Controle do Câncer, São Paulo, Brazil

    Celia de Oliveira

  4. St Vincent’s Hospital, Fitzroy, VIC, Australia

    Raymond Snyder

  5. Clinionco-Unidade de Novos Tratamentos, Porto Alegre, Brazil

    Jeferson Vinholes

  6. Cedars-Sinai Outpatient Cancer Center, Los Angeles, CA, USA

    M. William Audeh

  7. Centro Regional Integrado de Oncologia, Fortaleza, Brazil

    Victor M. Alencar

  8. Newcastle Mater Misericordiae Hospital, Newcastle, NSW, Australia

    Janine Lombard

  9. AstraZeneca, Wilmington, DE, USA

    Bijoyesh Mookerjee & John Xu

  10. AstraZeneca, Macclesfield, UK

    Kathryn Brown

  11. Beth Israel Medical Center and Continuum Cancer Centers of New York, 325 West 15th Street, New York, NY, 10011, USA

    Paula Klein

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Hyams, D.M., Chan, A., de Oliveira, C. et al. Cediranib in combination with fulvestrant in hormone-sensitive metastatic breast cancer: a randomized Phase II study. Invest New Drugs 31, 1345–1354 (2013). https://doi.org/10.1007/s10637-013-9991-2

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  • DOI: https://doi.org/10.1007/s10637-013-9991-2

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