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COOL - Community in Oncology On Lung Cancerwww.esanum.it/cool
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In preclinical studies:
1. Binds EGFR, competitively inhibiting ligand binding– Blocks receptor dimerization,
tyrosine kinase phosphorylation, and signal transduction that lead to enhanced proliferation and survival, angiogenesis, and metastasis
2. Blocks EGFR-mediated activation of DNA repair– Enhances/restores sensitivity to
chemotherapy and radiation
3. IgG1-induced Antibody-Dependent Cell Cytotoxicity (ADCC)– Tumor-directed host immune
response
Necitumumab
IgG1 MAb ADCC
1
3
PTEN AKTSTAT
PI3-K pYpY
pY
GRB2
SOS
RAS
RAF
MEK
MAPK
Gene activationCell-cycle progression
Survival (↓ apoptosis) Angiogenesis
ProliferationMetastasis
Chemo-therapy
Radiation
EGFR pool ↑ DNA repair
activity2
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.
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Results to date suggest a role of epidermal growth factor receptor inhibition in NSCLC
Necitumumab increases antitumor activity when combined with either gemcitabine-cisplatin or pemetrexed-cisplatin in NSCLC xenograft models
Rationale for necitumumab (IMC-11F8) in NSCLC
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
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.
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Studies of necitumumab (IMC-11F8) in NSCLC
Ongoing trials
Study ID Ph Eligibility/Line Arm(s) N (projected)
NCT00982111(INSPIRE)
III Stage IV, non-squamous, first line
Necitumumab+cisplatin+pemetrexed
Cisplatin+pemetrexed947
NCT00981058(SQUIRE)
III Stage IV, squamous , first line
Necitumumab+cisplatin+gemcitabine
Cisplatin+gemcitabine947
www.clinicaltrials.gov; accessed on August 28th, 2010
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INSPIRE: phase III, 1st-line NSCLC, non-squamous
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www.clinicaltrials.gov; NCT00982111; accessed on August 28th, 2010
Primary endpoint: Overall Survival
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SQUIRE: phase III, 1st-line NSCLC , squamous
www.clinicaltrials.gov; NCT00981058; accessed on August 28th, 2010
Primary endpoint: Overall Survival
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