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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

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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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