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A humanised IGF-1 and IGF-2 co-neutralising mAb
Xentuzumab* is a humanised IgG1 monoclonal antibody (mAb) that targets both insulin-like growth factor (IGF) ligands, IGF-1 and IGF-2, thereby inhibiting downstream signalling.1,2 Clinical trials to evaluate xentuzumab as a treatment for patients with solid tumours3-8 including non-small cell lung cancer (NSCLC),9,10 breast cancer11,12 and prostate cancer13 are being conducted.
Mechanism of action
Xentuzumab binds to IGF-1 and IGF-2 with high affinity, preventing activation of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor A (IR-A), respectively.1,2 This inhibits downstream signalling which would result in cell growth, proliferation and survival.2,14,15
Xentuzumab’s mode of action offers an advantage over other therapies: for example, IGF-1R mAbs do not inhibit the IR-A-mediated signalling pathway.16,17 Similarly, small molecule tyrosine kinase inhibitors (TKIs) inhibit all receptors in the IGF axis non-selectively, including IR-B, which xentuzumab spares. IR-B regulates glucose metabolism and its inhibition could therefore cause metabolic toxicity.
Xentuzumab has shown potent anti-proliferative effects against a range of cancer cell lines, including NSCLC, small cell lung cancer (SCLC) and multiple myeloma.17
Watch xentuzumab’s mechanism of action
The role of IGF signalling
IGF-1 and IGF-2 are ligands that bind to and activate their receptors, IGF-1R and IR-A, respectively.18 These insulin growth factor receptors activate pathways including the RAS kinase and the phosphinositide-3 kinase pathways, which are involved in cell proliferation, growth and survival.19,20 Increased expression of IGF-1 and IGF-2 is implicated in tumour proliferation, migration and invasion, and high IGF and IGFR expression is observed in both solid tumours and haematological malignancies.14,15,18 In addition, dysregulation of IGF signalling is associated with acquired resistance to hormone therapy in breast cancer,21,22 progression to an androgen-independent state in prostate cancer11 and acquired resistance to third-generation EGFR TKIs in NSCLC.22
Preliminary anti-tumour activity of xentuzumab has been reported in solid tumours, including primitive neuroectodermal tumours,4 nasopharyngeal cancer4 and desmoid tumours.8 Phase I dose escalation studies in Asian and European patients have established a recommended Phase II dose of 1,000 mg/week (intravenous administration).4,6,8 Two clinical trials (1280.4 and 1280.16) have shown that xentuzumab can be combined with established agents at full dose with a manageable safety profile.10,12 Clinical trials to evaluate xentuzumab as a treatment for patients with solid tumours3-8 including NSCLC,9,10 breast cancer11,12 and prostate cancer13 are being conducted.
The combination of xentuzumab and afatinib** has also shown preliminary antitumour activity in Phase I trials; further studies are ongoing to investigate xentuzumab as a treatment for NSCLC.9,10,23
CR, complete response; DOR, duration of response; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer; 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.4,10
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 Tumours; SD, stable disease; TTP, time to progression.
Xentuzumab is being investigated in a Phase Ib/II trial in combination with enzalutamide in prostate cancer.11
CTC, circulating tumour cells; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; OS, overall survival; PFS, progression-free survival; PSA, prostate surface antigen.
Weroha SJ, Haluska P. J Mammary Gland Biol Neoplasia 2008;13(4):471-83.
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ClinicalTrials.gov. NCT01403974. https://clinicaltrials.gov/ct2/show/study/NCT01403974 (Accessed: July 2017).
Lin C-C, et al. J Clin Oncol 2014;32(5s):Abstract 2617.
ClinicalTrials.gov. NCT01317420. https://clinicaltrials.gov/ct2/show/study/NCT01317420 (Accessed: July 2017).
Rihawi K, et al. J Clin Oncol 2014;32(5s):Abstract 2622.
ClinicalTrials.gov. NCT02145741. https://clinicaltrials.gov/ct2/show/study/NCT02145741 (Accessed: July 2017).
Doi T, et al. Ann Oncol 2016;27(Suppl 6):374P.
ClinicalTrials.gov. NCT02191891. https://clinicaltrials.gov/ct2/show/study/NCT02191891 (Accessed: July 2017).
Park K, et al. J Thorac Oncol 2017;12(Suppl):S1187–S8(P3.02b-005).
ClinicalTrials.gov. NCT02123823. https://clinicaltrials.gov/ct2/show/study/NCT02123823 (Accessed: July 2017).
Cortés J, et al. J Clin Oncol 2016;34(Suppl):Abstract 530.
ClinicalTrials.gov. NCT02204072. https://clinicaltrials.gov/ct2/show/study/NCT02204072 (Accessed: July 2017).
Schillaci R, et al. Br J Haematol 2005;130(1):58–66.
Sachdev D, Yee D. Mol Cancer Ther 2007;6(1):1–12.
Gao J, et al. Cancer Res 2012;72(1):3-12.
Friedbichler K, et al. Mol Cancer Ther 2014;13(2):399–409.
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.
Zhao M, et al. World J Clin Oncol 2014;5(3):248-62.
Denduluri SK, et al. Genes Dis 2015;2(1):13-25.
Yee D, et al. Presented at WCLC 2017; Abstract 1280.18.
*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.
**Afatinib is approved in more than 70 markets including the EU, Japan, Taiwan, and Canada under the brand name GIOTRIF®, in the US under the brand name GILOTRIF® and in India under the brand name Xovoltib®; for the full list please see here. Registration conditions differ internationally; please refer to locally approved prescribing information.
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