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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 insulin-like growth factor (IGF) ligands IGF-1 and IGF-2, which are implicated in tumour proliferation, migration and invasion.1–3
Several clinical trials are underway to evaluate xentuzumab in the treatment of solid tumours.4–6
The role of IGF signalling
The IGF-1 and IGF-2 ligands bind to and activate insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor A (IR-A), respectively.1 These IGF receptors (IGFRs) activate pathways, including the RAS kinase and the phosphinositide-3 kinase (PI-3K) pathways, which are involved in cell proliferation, growth and survival.2,3 Increased expression of IGF-1 and IGF-2 is implicated in tumour proliferation, migration and invasion; high IGFR expression has been observed in solid tumours.1,7,8
In addition, dysregulation of IGF signalling has been shown to be associated with acquired resistance to hormone therapy in breast cancer,9–12 acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC)12 and progression to androgen-independent growth in prostate cancer.12
Xentuzumab's mechanism of action
Xentuzumab binds to IGF-1 and IGF-2 with high affinity, preventing the activation of the receptors IGF-1R and IR-A, respectively.1 This inhibits downstream signalling that would otherwise result in cell growth, proliferation and survival. 2,3,7 Xentuzumab has shown potent anti-proliferative effects (at low nmol/L effective concentration [EC50]) against a range of cancer cell lines, including NSCLC, squamous cell lung carcinoma (SCLC) and multiple myeloma.1
Xentuzumab’s mechanism of action
Advantage over other IGF pathway inhibitors
Xentuzumab’s inhibition of IGF-1 and -2 offers advantages over other therapies targeting IGF pathway inhibition. Small-molecule TKIs, for example, offer non-selective inhibition of all receptors in the IGF axis, while IGF-1R mAbs do not inhibit the IR-A-mediated signalling pathway.13 In contrast, xentuzumab inhibits both IGF-1R- and IR-A-mediated pathways, but spares insulin receptor B (IR-B),3 which regulates glucose metabolism and whose inhibition can cause metabolic toxicity.
TKI inhibition of IGF-1R and IR-A-mediated pathways
Watch xentuzumab’s mechanism of action
Watch xentuzumab’s mechanism of action
Preliminary antitumour activity of xentuzumab has been reported in solid tumours.14 Phase I dose-escalation studies in Asian and European patients have established a recommended Phase II dose of 1,000 mg/week (intravenous administration).15,16 Ongoing clinical trials are evaluating xentuzumab for the treatment of patients with breast cancer (HER2-, ER+ or PgR+) and NSCLC.4–6
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.
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 was associated with antitumour activity and a manageable safety profile in combination with exemestane and everolimus in initial results from a Phase Ib part of a trial in breast cancer (NCT02123823).5,11 However, the Phase II part of this trial was stopped early due to lack of efficacy in a planned interim analysis.17 In the primary analysis the trial did not meet its primary endpoint: median progression-free survival (PFS) was not significantly different in the xentuzumab arm compared with the control arm in the overall patient population (7.3 months [95% confidence interval (CI): 3.3‒not calculable; n=70] vs 5.6 months [95% CI: 3.7‒9.1; n=70]; hazard ratio [HR]=0.97 [95% CI: 0.57‒1.65]; p=0.906).17 Interestingly, a pre-specified subgroup found PFS was significantly longer in the xentuzumab arm (n=17) compared with the control arm (n=16) among patients with non-visceral metastases: HR=0.21 (95% CI: 0.05‒0.98; p=0.029).17
A separate, ongoing Phase II study (NCT03659136)6 is investigating the efficacy and safety of xentuzumub combined with exemestane and everolimus in postmenopausal women with hormone receptor-positive, HER2-, locally advanced/metastatic breast cancer with non-visceral disease.
Friedbichler K, et al. Mol Cancer Ther 2014;13(2):399–409.
ClinicalTrials.gov. NCT03099174. https://clinicaltrials.gov/ct2/show/study/NCT03099174 (Accessed: January 2019).
ClinicalTrials.gov. NCT02123823. https://clinicaltrials.gov/ct2/show/study/NCT02123823 (Accessed: January 2019).
ClinicalTrials.gov. NCT03659136. https://clinicaltrials.gov/ct2/show/study/NCT03659136 (Accessed: January 2019).
ClinicalTrials.gov. NCT02204072. https://clinicaltrials.gov/ct2/show/study/NCT02204072 (Accessed: January 2019).
Sachdev D, Yee D. Mol Cancer Ther 2007;6(1):1–12.
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.
Crown J, et al. Poster presented at the San Antonio Breast Cancer Symposium 2018 (Poster P6-21-01).
*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.
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Page last updated: May 2019
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