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Cixutumumab (IMC-A12), a fully human IgG1 monoclonal antibody to the insulin-like growth factor I receptor (IGF-IR)

In preclinical studies:

High affinity binding to human IGF-IR– Kd = 0.04 nM

No binding to the human Insulin Receptor, but can bind IGF-IR - IR heterodimers

Mechanism of Action:1.Inhibits IGF-I and IGF-II binding to

IGF-IR, IGF-IR phosphorylation and downstream signaling

2.Promotes IGF-IR internalization and degradation

3.Potential indirect effects (e.g., ADCC)

IgG1

IGF-1 IGF-2

Antiproliferative

Proapoptotic

NecrosisCell Death

PI3K

Akt

mTORBAD

PDK1

IRS-1 IRS-1

RasSOS

Grb2Raf

MEK

ERK

1

2

3 IMC-A12

Macrophage

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.

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IGF-1R pathway in lung cancer

The IGF-1R pathway appears to play important roles in tumorigenesis, metastasis, and resistance to existing forms of anticancer therapyIn 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.High IGF-1R expression is associated with poor survival in surgically treated NSCLC patients.IGF-1R gene copy number is associated with survival in operable NSCLC

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: 7550Rafal 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.

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Cixutumumab (IMC-A12): ongoing phase II studies in lung cancer

NCT00870870• NSCLC• 1st line

Gemcitabine / Carboplatin/ Cetuximab+

IMC-A12

Gemcitabine / Carboplatin/ Cetuximab

Cetuximab+

IMC-A12

Cetuximab

ORRN=90

NCT00955305

Bev- eligible• NSCLC Non-squ• 1st line

Carboplatin / Paclitaxel / Bevacizumab+

IMC-A12

Carboplatin / Paclitaxel / Bevacizumab

Bev+

IMC-A12

Bev

PFSN=180

1

2

1

1

NCT00986674

All histology• NSCLC • 1st line

Carboplatin / Paclitaxel / Cetuximab Cetux

PFSN=200

Carboplatin / Paclitaxel / IMC-A12

Carboplatin / Paclitaxel / Cetuximab / IMC-A12

1

1

1

IMC-A12

Cetux / IMC-A12

NCT00778167• NSCLC• ≥ 2nd line

Erlotinib+

IMC-A12

Erlotinib (optional crossover at PD)Erlotinib

+IMC-A12

PFSN=120

1

1

SafetyLead-in

NCT00887159• SCLC • 1st line

Cisplatin / Etoposide

PFSN=170

Cisplatin / Etoposide + IMC-A12

Cisplatin / Etoposide + GDC-0449

1

1

1

IMC-A12

GDC-0449

www.clinicaltrials.gov ; accessed on August 27th, 2010

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