Xentuzumab (BI 836845)

Insulin-like growth factor-1 (IGF-1) and -2 (IGF-2) are predominantly made and secreted by the liver, which bind to and activate insulin-like growth factor receptors, IGF-1R, IGF-2R and the insulin receptor (IR).1 Signal transduction via the IGFRs activates pathways including the RAS kinase and phosphinositide-3 kinase (PI3K) 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, and high IGF and IGFR expression is observed in both solid tumour cancers and haematological malignancies.1,4,5

Boehringer Ingelheim is currently investigating xentuzumab, a humanised immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to and neutralises the function of human insulin-like growth factor-1 and 2 (IGF-1, IGF-2). This results in effective inhibition of IGF-induced activation of both IGF-IR and IR-A (the ‘A’ isoform of the IR).6 This IGF ligand inhibitor has shown potent anti-proliferative effects against a range of cancer cell lines.6 Treatment of human serum with xentuzumab resulted in complete inhibition of IGF-1R phosphorylation.6

Clinical trials to evaluate xentuzumab as a treatment for patients with solid tumours7-9 including non-small cell lung cancer (NSCLC),10 breast cancer11 and prostate cancer12 are being conducted. Preliminary antitumour activity against solid tumours, including primitive neuroectodermal tumour,13 nasopharyngeal cancer13 and desmoid tumour,14 has been observed in Phase I trials in Asian13,14 and European patients.15 The combination of xentuzumab and afatinib has also shown preliminary antitumour activity in Phase I trials involving patients with NSCLC.16

  1. LeRoith D, Roberts CT, Jr. The insulin-like growth factor system and cancer. Cancer Lett 2003;195(2):127-137.
  2. Yaktapour N, Ubelhart R, Schuler J, et al. Insulin-like growth factor-1 receptor (IGF1R) as a novel target in chronic lymphocytic leukemia. Blood 2013;122(9):1621-1633.
  3. Gallagher EJ, LeRoith D. The proliferating role of insulin and insulin-like growth factors in cancer. Trends Endocrinol Metab 2010;21(10):610-618.
  4. Schillaci R, Galeano A, Becu-Villalobos D, et al. Autocrine/paracrine involvement of insulin-like growth factor-I and its receptor in chronic lymphocytic leukaemia. Br J Haematol 2005;130(1):58-66.
  5. Sachdev D, Yee D. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther 2007;6(1):1-12.
  6. Friedbichler K, Hofmann MH, Kroez M, et al. Pharmacodynamic and antineoplastic activity of BI 836845, a fully human IGF ligand-neutralizing antibody, and mechanistic rationale for combination with rapamycin. Mol Cancer Ther 2014;13(2):399-409.
  7. ClinicalTrials.gov. NCT01403974. https://clinicaltrials.gov/ct2/show/study/NCT01403974 (Accessed: November 2016).
  8. ClinicalTrials.gov. NCT01317420. https://clinicaltrials.gov/ct2/show/study/NCT01317420 (Accessed: November 2016).
  9. ClinicalTrials.gov. NCT02145741. https://clinicaltrials.gov/ct2/show/study/NCT02145741 (Accessed: November 2016).
  10. ClinicalTrials.gov. NCT02191891. https://clinicaltrials.gov/ct2/show/study/NCT02191891 (Accessed: November 2016).
  11. ClinicalTrials.gov. NCT02123823. https://clinicaltrials.gov/ct2/show/study/NCT02123823 (Accessed: November 2016).
  12. ClinicalTrials.gov. NCT02204072. https://clinicaltrials.gov/ct2/show/study/NCT02204072 (Accessed: November 2016).
  13. Lin CC, Chang KY, Huang DC, et al. A phase I dose escalation study of weekly BI 836845, a fully human, affinity-optimized, insulin-like growth factor (IGF) ligand neutralizing antibody, in patients with advanced solid cancers. J Clin Oncol 2014;32:5s, (Suppl; Abstract 2617).
  14. Doi T, Shitara K, Naito Y, et al. Phase I dose escalation (esc) trial of weekly intravenous (i.v.) BI 836845 in Japanese patients (pts) with advanced solid tumors. Ann Oncol 2016; 27(Suppl. 6):374P.
  15. Rihawi K, Ong M, Michalarea V, et al. Phase I dose escalation study of 3-weekly BI 836845, a fully human, affinity-optimized, insulin-like growth factor (IGF) ligand neutralizing antibody, in patients with advanced solid tumors. J Clin Oncol 2014;32:5s, (Suppl; Abstract 2622).
  16. Park K, Cho BC, Lee KH, et al. Phase Ib trial of afatinib and BI 836845 in advanced NSCLC: dose escalation and safety results. J Thorac Oncol 2017;12(Suppl.):S1187–S1188 (Abstract P3.02b-005).