Necitumumab imc 11 f8 ottobre 2010


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  • Karen: Do we have a more appropriate published reference?
  • Necitumumab imc 11 f8 ottobre 2010

    1. 1. <ul><li>In preclinical studies: </li></ul><ul><li>Binds EGFR, competitively inhibiting ligand binding </li></ul><ul><ul><li>Blocks receptor dimerization, tyrosine kinase phosphorylation, and signal transduction that lead to enhanced proliferation and survival, angiogenesis, and metastasis </li></ul></ul><ul><li>Blocks EGFR-mediated activation of DNA repair </li></ul><ul><ul><li>Enhances/restores sensitivity to chemotherapy and radiation </li></ul></ul><ul><li>IgG1-induced Antibody-Dependent Cell Cytotoxicity (ADCC) </li></ul><ul><ul><li>Tumor-directed host immune response </li></ul></ul>Necitumumab IgG1 MAb ADCC 1 3 PTEN AKT STAT PI3-K pY pY pY GRB2 SOS RAS RAF MEK MAPK Gene activation Cell-cycle progression Survival (↓ apoptosis) Angiogenesis Proliferation Metastasis Chemo- therapy Radiation EGFR pool ↑ DNA repair activity 2 Necitumumab (IMC-11F8), a fully human IgG1 monoclonal antibody, targets the Epidermal Growth Factor Receptor (EGFR) Kuenen B, Witteveen PO, Ruijter R, Giaccone G, Dontabhaktuni A, Fox F, Katz T, Youssoufian H, Zhu J, Rowinsky EK, Voest EE. A phase I pharmacologic study of necitumumab (IMC-11F8), a fully human IgG1 monoclonal antibody directed against EGFR in patients with advanced solid malignancies. Clin Cancer Res. 2010 Mar 15;16(6):1915-23. Epub 2010 Mar 2.
    2. 2. <ul><ul><li>Results to date suggest a role of epidermal growth factor receptor inhibition in NSCLC </li></ul></ul><ul><ul><li>Necitumumab increases antitumor activity when combined with either gemcitabine-cisplatin or pemetrexed-cisplatin in NSCLC xenograft models </li></ul></ul>Rationale for necitumumab ( IMC-11F8 ) in NSCLC <ul><ul><li>Cetuximab (a chimeric EGFR-antibody targeting similar epitope like necitumumab) plus cisplatin-vinorelbine showed statistically significant advantages over the same chemotherapy alone in terms of overall survival and response rate in the first line treatment of patients with advanced NSCLC </li></ul></ul>Marie Prewett, Rajiv Bassi, Hagop Youssoufian, Eric K. Rowinsky, James R. Tonra. The fully human EGFR antibody IMC-11F8 significantly increases the antitumor effects of cisplatin+gemcitabine in human non-small cell lung cancer models. AACR 2009, Abstract #2774 Imclone Systems, Data on File Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O'Byrne K, de Marinis F, Eberhardt W, Goddemeier T, Emig M, Gatzemeier U; FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009 May 2;373(9674):1525-31.
    3. 3. Studies of necitumumab (IMC-11F8) in NSCLC Ongoing trials ; accessed on August 28th, 2010 Study ID Ph Eligibility/Line Arm(s) N (projected) NCT00982111 (INSPIRE) III Stage IV, non-squamous, first line <ul><li>Necitumumab+cisplatin+pemetrexed </li></ul><ul><li>Cisplatin+pemetrexed </li></ul>947 NCT00981058 (SQUIRE) III Stage IV, squamous , first line <ul><li>Necitumumab+cisplatin+gemcitabine </li></ul><ul><li>Cisplatin+gemcitabine </li></ul>947
    4. 4. INSPIRE: phase III, 1st-line NSCLC, non-squamous ; NCT00982111; accessed on August 28 th , 2010 Primary endpoint: Overall Survival
    5. 5. SQUIRE: phase III, 1st-line NSCLC , squamous ; NCT00981058; accessed on August 28 th , 2010 Primary endpoint: Overall Survival