Cixutumumab imc a12 ottobre 2010


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Cixutumumab imc a12 ottobre 2010

  1. 1. Cixutumumab (IMC-A12), a fully human IgG1 monoclonal antibody to the insulin-like growth factor I receptor (IGF-IR) <ul><li>In preclinical studies: </li></ul><ul><li>High affinity binding to human IGF-IR </li></ul><ul><ul><li>K d = 0.04 nM </li></ul></ul><ul><li>No binding to the human Insulin Receptor, but can bind IGF-IR - IR heterodimers </li></ul><ul><li>Mechanism of Action: </li></ul><ul><ul><li>Inhibits IGF-I and IGF-II binding to IGF-IR, IGF-IR phosphorylation and downstream signaling </li></ul></ul><ul><ul><li>Promotes IGF-IR internalization and degradation </li></ul></ul><ul><ul><li>Potential indirect effects (e.g., ADCC) </li></ul></ul>Rowinsky EK, Youssoufian H, Tonra JR, Solomon P, Burtrum D, Ludwig DL. IMC-A12, a human IgG1 monoclonal antibody to the insulin-like growth factor I receptor. Clin Cancer Res. 2007 Sep 15;13(18 Pt 2):5549s-5555s. IgG1 IGF-1 IGF-2 Antiproliferative Proapoptotic Necrosis Cell Death PI3K Akt mTOR BAD PDK1 IRS-1 IRS-1 Ras SOS Grb2 Raf MEK ERK 1 2 3 IMC-A12 Macrophage
  2. 2. IGF-1R pathway in lung cancer <ul><li>The IGF-1R pathway appears to play important roles in tumorigenesis, metastasis, and resistance to existing forms of anticancer therapy </li></ul><ul><li>In lung cancer, elevated plasma levels of IGF-1 have been associated with an increased risk of the disease, while high plasma levels of IGFBP3 have been associated with reduced risk. </li></ul><ul><li>High IGF-1R expression is associated with poor survival in surgically treated NSCLC patients. </li></ul><ul><li>IGF-1R gene copy number is associated with survival in operable NSCLC </li></ul>Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008 Dec;8(12):915-28. Yu H, Spitz MR, Mistry J, Gu J, Hong WK, Wu X. Plasma levels of insulin-like growth factor-I and lung cancer risk: a case-control analysis. J Natl Cancer Inst. 1999 Jan 20;91(2):151-6. London SJ, Yuan JM, Travlos GS, Gao YT, Wilson RE, Ross RK, Yu MC. Insulin-like growth factor I, IGF-binding protein 3, and lung cancer risk in a prospective study of men in China. J Natl Cancer Inst. 2002 May 15;94(10):749-54. D. T. Merrick, R. Dziadziuszko, B. Szostakiewicz, A. Szymanowska, W. Rzyman, E. Jassem, J. Jassem, W. A. Franklin, P. A. Bunn, Jr. and F. R. Hirsch. High insulin-like growth factor 1 receptor (IGF1R) expression is associated with poor survival in surgically treated non-small cell lung cancer (NSCLC) patients (pts). Abstract Journal of Clinical Oncology , 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 25, No 18S (June 20 Supplement), 2007: 7550 Rafal Dziadziuszko, Daniel T. Merrick, Samir E. Witta, Adelita D. Mendoza, Barbara Szostakiewicz, Amelia Szymanowska, Witold Rzyman, Katarzyna Dziadziuszko, Jacek Jassem, Paul A. Bunn Jr, Marileila Varella-Garcia and Fred R. Hirsch. Insulin-like Growth Factor Receptor 1 (IGF1R) Gene Copy Number Is Associated With Survival in Operable Non–Small-Cell Lung Cancer: A Comparison Between IGF1R Fluorescent In Situ Hybridization, Protein Expression, and mRNA Expression . J Clin Oncol. 2010 May 1;28(13):2174-80.
  3. 3. Cixutumumab (IMC-A12): ongoing phase II s tudies in lung cancer <ul><li>NCT00870870 </li></ul><ul><li>NSCLC </li></ul><ul><li>1 st line </li></ul>Gemcitabine / Carboplatin/ Cetuximab + IMC-A12 Gemcitabine / Carboplatin/ Cetuximab Cetuximab + IMC-A12 Cetuximab ORR N=90 <ul><li>NCT00955305 </li></ul><ul><li>Bev- eligible </li></ul><ul><li>NSCLC Non-squ </li></ul><ul><li>1 st line </li></ul>Carboplatin / Paclitaxel / Bevacizumab + IMC-A12 Carboplatin / Paclitaxel / Bevacizumab Bev + IMC-A12 Bev PFS N=180 1 2 1 1 <ul><li>NCT00986674 </li></ul><ul><li>All histology </li></ul><ul><li>NSCLC </li></ul><ul><li>1 st line </li></ul>Carboplatin / Paclitaxel / Cetuximab Cetux PFS N=200 Carboplatin / Paclitaxel / IMC-A12 Carboplatin / Paclitaxel / Cetuximab / IMC-A12 1 1 1 IMC-A12 Cetux / IMC-A12 <ul><li>NCT00778167 </li></ul><ul><li>NSCLC </li></ul><ul><li>≥ 2 nd line </li></ul>Erlotinib + IMC-A12 Erlotinib (optional crossover at PD) Erlotinib + IMC-A12 PFS N=120 1 1 Safety Lead-in <ul><li>NCT00887159 </li></ul><ul><li>SCLC </li></ul><ul><li>1 st line </li></ul>Cisplatin / Etoposide PFS N=170 Cisplatin / Etoposide + IMC-A12 Cisplatin / Etoposide + GDC-0449 1 1 1 IMC-A12 GDC-0449 ; accessed on August 27 th , 2010