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Xentuzumab: A humanised monoclonal antibody targeting IGF-1 and IGF-2
Xentuzumab* (BI 836845) is a humanised immunoglobulin G (IgG) 1 monoclonal antibody (mAb) that targets both insulin-like growth factor (IGF) ligands, IGF-1 and IGF-2, thereby inhibiting downstream signalling.1 Clinical trials to evaluate xentuzumab in the treatment of various solid tumours are being conducted.2‒5
The role of IGF signalling
IGF-1 and IGF-2 are ligands that bind to and activate their receptors, insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor A (IR-A), respectively.1 These insulin growth factor receptors activate pathways including the RAS kinase and the phosphinositide-3 kinase (PI-3K) pathways, which are involved in cell proliferation, growth and survival.6,7 Increased expression of IGF-1 and IGF-2 is implicated in tumour proliferation, migration and invasion, and high IGF and insulin growth factor receptor (IGFR) expression has been observed in solid tumours.1,8,9 In addition, dysregulation of IGF signalling is associated with acquired resistance to hormone therapy in breast cancer,10,11,12 progression to androgen-independent growth in prostate cancer,13 and acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)s in non-small cell lung cancer (NSCLC).13
Xentuzumab's mechanism of action
Xentuzumab binds to IGF-1 and IGF-2 with high affinity, preventing the activation of IGF-1R and IR-A, respectively.1 This inhibits downstream signalling that otherwise would result in cell growth, proliferation and survival.2,8,9
Xentuzumab’s mechanism of action offers an advantage over other therapies targeting this pathway: for example, IGF-1R mAbs do not inhibit the IR-A-mediated signalling pathway.14 Similarly, small-molecule TKIs inhibit all receptors in the IGF axis non-selectively, including insulin receptor B (IR-B),7 which xentuzumab spares. IR-B regulates glucose metabolism and its inhibition can therefore cause metabolic toxicity.
Xentuzumab has shown potent anti-proliferative effects in various cancer cell lines.1
Watch xentuzumab’s mechanism of action
Watch xentuzumab’s mechanism of action
Preliminary antitumour activity of xentuzumab has been reported in solid tumours.15,16 Phase I dose -escalation studies in Asian and European patients have established a recommended Phase II dose of 1,000 mg/week (intravenous administration).15‒17 Ongoing clinical trials are evaluating xentuzumab for the treatment of patients with breast cancer, prostate cancer and NSCLC.2‒5
Solid tumours, including breast cancer and NSCLC
CR, complete response; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; OR, objective response; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease.
Xentuzumab has shown encouraging antitumour activity and a manageable safety profile in combination with exemestane and everolimus in initial results from a Phase Ib/II trial in breast cancer.12
CR, complete response; DCR, disease control rate; DLT, dose-limiting toxicity; DoR, duration of response; MTD, maximum tolerated dose; OR, objective response; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease; TTP, time to progression.
Xentuzumab is being investigated in a Phase Ib/II trial in combination with enzalutamide in prostate cancer.5
CTC, circulating tumour cell; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen.
Friedbichler K, et al. Mol Cancer Ther 2014;13(2):399–409.
ClinicalTrials.gov. NCT03099174. https://clinicaltrials.gov/ct2/show/study/NCT03099174 (Accessed: September 2018).
ClinicalTrials.gov. NCT02123823. https://clinicaltrials.gov/ct2/show/study/NCT02123823 (Accessed: September 2018).
ClinicalTrials.gov. NCT03659136. https://clinicaltrials.gov/ct2/show/study/NCT03659136 (Accessed: September 2018).
ClinicalTrials.gov. NCT02204072. https://clinicaltrials.gov/ct2/show/study/NCT02204072 (Accessed: September 2018).
Sachdev D, Yee D. Mol Cancer Ther 2007;6(1):1–12.
Gao J, et al. Cancer Res 2012;72(1):3–12.
Schillaci R, et al. Br J Haematol 2005;130(1):58–66.
LeRoith D, Roberts CT Jr. Cancer Lett 2003;195(2):127–37.
Yaktapour N, et al. Blood 2013;122(9):1621–33.
Gallagher EJ, LeRoith D. Trends Endocrinol Metab 2010;21(10):610–8.
Cortés J, et al. J Clin Oncol 2016;34(Suppl):530.
Denduluri SK, et al. Genes Dis 2015;2(1):13–25.
Weroha SJ, Haluska P. J Mammary Gland Biol Neoplasia 2008;13(4):471–83.
Lin C-C, et al. J Clin Oncol 2014;32(Suppl. 15):2617.
Doi T, et al. Ann Oncol 2016;27(Suppl. 6):374P.
Rihawi K, et al. J Clin Oncol 2014;32(Suppl. 15):2622.
*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.
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Last updated: October 2018
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