[en] INTRODUCTION: Trebananib, a peptide-Fc fusion protein, blocks angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. Trebananib plus trastuzumab and paclitaxel was evaluated in human epidermal growth factor receptor 2-positive breast cancer in an open-label phase 1b clinical study. PATIENTS AND METHODS: Women with human epidermal growth factor receptor 2-positive breast cancer received weekly paclitaxel (80 mg/m(2)), trastuzumab (8 mg/m(2) then 6 mg/kg every 3 weeks), and intravenous trebananib (10 mg/kg or 30 mg/kg weekly) beginning week 2. The primary end point was the incidence of dose-limiting toxicities. Secondary end points included incidence of adverse events (AEs), pharmacokinetics, and tumor response (objective response and duration of response). RESULTS: Forty women were enrolled; 2 experienced dose-limiting toxicities (grade 3 ocular transient ischemic attack [10 mg/kg cohort] and grade 3 elevation in gamma-glutamyl transferase [30 mg/kg cohort]). The most common treatment-emergent AEs were peripheral edema (n = 28), diarrhea (n = 27), alopecia (n = 26), fatigue (n = 24), and nausea (n = 24). Maximum observed concentration and area under the concentration-time curve increased proportionally with the trebananib dose. Objective response was confirmed in 31 patients. In the 10 mg/kg cohort, 16 patients (80%) experienced partial response, and none experienced complete response. In the 30 mg/kg cohort, 12 patients (71%) experienced partial response and 3 (18%) experienced complete response. Median (95% confidence interval) duration of response in the 10 and 30 mg/kg cohorts was 12.6 (4.3-20.2) and 16.6 (8.2-not estimable) months, respectively. CONCLUSION: This phase 1b study showed that trebananib was tolerated with manageable AEs at a dose up to 30 mg/kg weekly. Trebananib demonstrated anticancer activity, as indicated by objective response and duration of response.
Disciplines :
Oncology
Author, co-author :
Kaufman, Peter A.
Wildiers, Hans
Freyer, Gilles
Kemeny, Margaret
Goncalves, Anthony
JERUSALEM, Guy ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service d'oncologie médicale
Stopeck, Alison
Vrindavanam, Nandagopal
Dalenc, Florence
Nanayakkara, Nuwan
Wu, Benjamin
Pickett, Cheryl A.
Language :
English
Title :
Phase 1b Study of Trebananib Plus Paclitaxel and Trastuzumab in Patients With HER2-Positive Locally Recurrent or Metastatic Breast Cancer.
Banerjee, S., Dowsett, M., Ashworth, A., et al. Mechanisms of disease: angiogenesis and the management of breast cancer. Nat Clin Pract Oncol 4 (2007), 536–550.
Slamon, D.J., Clark, G.M., Wong, S.G., et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235 (1987), 177–182.
Arteaga, C.L., Engelman, J.A., ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25 (2014), 282–303.
Dokala, A., Thakur, S.S., Extracellular region of epidermal growth factor receptor: a potential target for anti-EGFR drug discovery. Oncogene 36 (2017), 2337–2344.
Kumar, R., Yarmand-Bagheri, R., The role of HER2 in angiogenesis. Semin Oncol 28:5 suppl 16 (2001), 27–32.
Wen, X.F., Yang, G., Mao, W., et al. HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy. Oncogene 25 (2006), 6986–6996.
Slamon, D.J., Godolphin, W., Jones, L.A., et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244 (1989), 707–712.
Slamon, D.J., Leyland-Jones, B., Shak, S., et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344 (2001), 783–792.
Baselga, J., Manikhas, A., Cortes, J., et al. Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer. Ann Oncol 25 (2014), 592–598.
Robert, N., Leyland-Jones, B., Asmar, L., et al. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 24 (2006), 2786–2792.
National Comprehensive Cancer Network, NCCN clinical practice guidelines in oncology: breast cancer, version 1.2018. Available at: https://www.nccn.org/professionals/physician_gls/default.aspx. (Accessed 16 October 2018)
Cardoso, F., Costa, A., Norton, L., et al. 1st International consensus guidelines for advanced breast cancer (ABC 1). Breast 21 (2012), 242–252.
Geyer, C.E., Forster, J., Lindquist, D., et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355 (2006), 2733–2743.
Baselga, J., Cortes, J., Kim, S.B., et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366 (2012), 109–119.
Tiwari, S.R., Mishra, P., Abraham, J., Neratinib, a novel HER2-targeted tyrosine kinase inhibitor. Clin Breast Cancer 16 (2016), 344–348.
Swain, S.M., Baselga, J., Kim, S.B., et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372 (2015), 724–734.
Toi, M., Kashitani, J., Tominaga, T., Tumor angiogenesis is an independent prognostic indicator in primary breast carcinoma. Int J Cancer 55 (1993), 371–374.
Weidner, N., Semple, J.P., Welch, W.R., et al. Tumor angiogenesis and metastasis–correlation in invasive breast carcinoma. N Engl J Med 324 (1991), 1–8.
Augustin, H.G., Koh, G.Y., Thurston, G., et al. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol 10 (2009), 165–177.
Folkman, J., Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29:6 suppl 16 (2002), 15–18.
Imanishi, Y., Hu, B., Jarzynka, M.J., et al. Angiopoietin-2 stimulates breast cancer metastasis through the alpha(5)beta(1) integrin-mediated pathway. Cancer Res 67 (2007), 4254–4263.
Li, P., He, Q., Luo, C., et al. Diagnostic and prognostic potential of serum angiopoietin-2 expression in human breast cancer. Int J Clin Exp Pathol 8 (2015), 660–664.
Sfiligoi, C., de Luca, A., Cascone, I., et al. Angiopoietin-2 expression in breast cancer correlates with lymph node invasion and short survival. Int J Cancer 103 (2003), 466–474.
Martin, M., Makhson, A., Gligorov, J., et al. Phase II study of bevacizumab in combination with trastuzumab and capecitabine as first-line treatment for HER-2–positive locally recurrent or metastatic breast cancer. Oncologist 17 (2012), 469–475.
Gianni, L., Romieu, G.H., Lichinitser, M., et al. AVEREL: a randomized phase III trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol 31 (2013), 1719–1725.
Carter, W.B., Ward, M.D., HER2 regulatory control of angiopoietin-2 in breast cancer. Surgery 128 (2000), 153–158.
Niu, G., Carter, W.B., Human epidermal growth factor receptor 2 regulates angiopoietin-2 expression in breast cancer via AKT and mitogen-activated protein kinase pathways. Cancer Res 67 (2007), 1487–1493.
Coxon, A., Bready, J., Min, H., et al. Context-dependent role of angiopoietin-1 inhibition in the suppression of angiogenesis and tumor growth: implications for AMG 386, an angiopoietin-1/2–neutralizing peptibody. Mol Cancer Ther 9 (2010), 2641–2651.
Oliner, J., Min, H., Leal, J., et al. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 6 (2004), 507–516.
Herbst, R.S., Hong, D., Chap, L., et al. Safety, pharmacokinetics, and antitumor activity of AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors. J Clin Oncol 27 (2009), 3557–3565.
Hong, D.S., Gordon, M.S., Samlowski, W.E., et al. A phase I, open-label study of trebananib combined with sorafenib or sunitinib in patients with advanced renal cell carcinoma. Clin Genitourin Cancer 12 (2014), 167–177.e162.
Hong, D.S., Kurzrock, R., Mulay, M., et al. A phase 1b, open-label study of trebananib plus bevacizumab or motesanib in patients with solid tumours. Oncotarget 5 (2014), 11154–11167.
Rini, B., Szczylik, C., Tannir, N.M., et al. AMG 386 in combination with sorafenib in patients with metastatic clear cell carcinoma of the kidney: a randomized, double-blind, placebo-controlled, phase 2 study. Cancer 118 (2012), 6152–6161.
Atkins, M.B., Gravis, G., Drosik, K., et al. Trebananib (AMG 386) in combination with sunitinib in patients with metastatic renal cell cancer: an open-label, multicenter, phase II study. J Clin Oncol 33 (2015), 3431–3438.
Mita, A.C., Takimoto, C.H., Mita, M., et al. Phase 1 study of AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, in combination with chemotherapy in adults with advanced solid tumors. Clin Cancer Res 16 (2010), 3044–3056.
Peeters, M., Strickland, A.H., Lichinitser, M., et al. A randomised, double-blind, placebo-controlled phase 2 study of trebananib (AMG 386) in combination with FOLFIRI in patients with previously treated metastatic colorectal carcinoma. Br J Cancer 108 (2013), 503–511.
Karlan, B.Y., Oza, A.M., Richardson, G.E., et al. Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer. J Clin Oncol 30 (2012), 362–371.
Monk, B.J., Poveda, A., Vergote, I., et al. Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 15 (2014), 799–808.
Marth, C., Vergote, I., Scambia, G., et al. ENGOT-ov-6/TRINOVA-2: randomized, double-blind, phase 3 study of pegylated liposomal doxorubicin plus trebananib or placebo in women with recurrent partially platinum-sensitive or resistant ovarian cancer. Eur J Cancer 70 (2016), 111–121.
Vergote, I., Scambia, G., O'Malley, D.M., et al. Trinova-3/ENGOT-OV-2/GOG-3001: a randomized, double-blind phase 3 study of trebananib plus carboplatin/paclitaxel as first-line treatment in advanced ovarian cancer. Int J Gynecol Cancer 26:suppl 3 (2016), 13–14.
Dieras, V., Wildiers, H., Jassem, J., et al. Trebananib (AMG 386) plus weekly paclitaxel with or without bevacizumab as first-line therapy for HER2-negative locally recurrent or metastatic breast cancer: a phase 2 randomized study. Breast 24 (2015), 182–190.
Therasse, P., Arbuck, S.G., Eisenhauer, E.A., et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92 (2000), 205–216.
Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Available at: http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev3.pdf. (Accessed 30 January 2017)
Weeraratne, D.K., Lofgren, J., Dinnogen, S., et al. Development of a biosensor-based immunogenicity assay capable of blocking soluble drug target interference. J Immunol Methods 396 (2013), 44–55.
Monk, B.J., Minion, L., Lambrechts, S., et al. Incidence and management of edema associated with trebananib (AMG 386). Gynecol Oncol 130 (2013), 636–641.
Eatock, M., Tebbutt, N., Bampton, C.L., et al. Phase II randomized, double-blind, placebo-controlled study of AMG 386 (trebananib) in combination with cisplatin and capecitabine in patients with metastatic gastro-oesophageal cancer. Ann Oncol 24 (2013), 710–718.
Eskens, F.A., Verweij, J., The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. Eur J Cancer 42 (2006), 3127–3139.
Wu, B., Johnson, J., Soto, M., et al. Investigation of the mechanism of clearance of AMG 386, a selective angiopoietin-1/2 neutralizing peptibody, in splenectomized, nephrectomized, and FcRn knockout rodent models. Pharm Res 29 (2012), 1057–1065.
Suzuki, T., Ishii-Watabe, A., Tada, M., et al. Importance of neonatal FcR in regulating the serum half-life of therapeutic proteins containing the Fc domain of human IgG1: a comparative study of the affinity of monoclonal antibodies and Fc-fusion proteins to human neonatal FcR. J Immunol 184 (2010), 1968–1976.
Perjeta (pertuzumab). Full prescribing information, 2017, Genentech, South San Francisco, CA.
Perjeta (pertuzumab). Summary of product characteristics. Full prescribing information, 2017, CAL Genentech, South San Francisco.
Slamon, D.J., Swain, S.M., Buyse, M., et al. Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive or high risk node-negative breast cancer. Cancer Res, 73(24 suppl), 2013 S1-03.
Pierga, J.Y., Petit, T., Delozier, T., et al. Neoadjuvant bevacizumab, trastuzumab, and chemotherapy for primary inflammatory HER2-positive breast cancer (BEVERLY-2): an open-label, single-arm phase 2 study. Lancet Oncol 13 (2012), 375–384.
Yardley, D.A., Raefsky, E., Castillo, R., et al. Phase II study of neoadjuvant weekly nab-paclitaxel and carboplatin, with bevacizumab and trastuzumab, as treatment for women with locally advanced HER2 + breast cancer. Clin Breast Cancer 11 (2011), 297–305.
Rugo, H.S., Chien, A.J., Franco, S.X., et al. A phase II study of lapatinib and bevacizumab as treatment for HER2-overexpressing metastatic breast cancer. Breast Cancer Res Treat 134 (2012), 13–20.
Argiris, A., Kotsakis, A.P., Hoang, T., et al. Cetuximab and bevacizumab: preclinical data and phase II trial in recurrent or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 24 (2013), 220–225.
Tournigand, C., Chibaudel, B., Samson, B., et al. Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label, phase 3 trial. Lancet Oncol 16 (2015), 1493–1505.
Seto, T., Kato, T., Nishio, M., et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol 15 (2014), 1236–1244.