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Journal of Thoracic Oncology:
doi: 10.1097/01.JTO.0000361751.79294.9f
Santa Monica Supplement

Insulin Growth Factor Pathway

Lilenbaum, Rogerio MD

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Mount Sinai Cancer Center, Miami Beach, Florida.

Disclosure: The author declares no conflict of interest.

Address for correspondence: Rogerio Lilenbaum, MD, Mount Sinai Cancer Center, 4306 Alton Rd, Miami Beach, FL 33140. E-mail:

The insulin growth factor pathway (IGF), a complex one with multiple receptors and ligands, is involved in essential steps of cancer development such as survival, proliferation, and metastases.1 Although expression of IGF signaling seems to have prognostic significance, predictive factors for benefit have not yet been identified. Cross talk between the IGF and other pathways, particularly EFGR, may be important for understanding and mitigating resistance. Several compounds, including monoclonal antibodies and tyrosine kinase inhibitors, are currently under clinical investigation for inhibition of the IGF pathway.

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Monoclonal Antibodies Against IGF1R

Dr. Ross Camidge presented data on IMC-A12, a monoclonal antibody with high affinity to IGF1R. Early trials revealed prolonged tumor stabilization in a variety of tumors, with an acceptable toxicity profile, primarily hyperglycemia and fatigue,2 which are in fact common to all monoclonal antibodies that target IGF1R. A phase II randomized trial of erlotinib with or without A12 in previously treated patients with NSCLC is ongoing, along with a more recently activated first-line trial of carboplatin, gemcitabine, and cetuximab, with or without A12.

Dr. Karen Kelly showed data on another anti-IGF1R monoclonal antibody, MK-0646. After a phase I trial defined the optimal dose and schedule and demonstrated favorable toxicity,3 a randomized phase II trial of cisplatin and pemetrexed with or without MK-0646 has been launched (“IMPACT”), along with a trial of erlotinib with or without MK-0646 in recurrent disease. Dr. Jeremy Barton presented information on BIIB022, also an anti-IGF1R antibody, which demonstrated antitumor activity in multiple xenograft models, and is currently undergoing phase I testing, with plans to initiate phase II studies in NSCLC in the near future.

Dr. Daniel Karp presented the figitumumab (CP-751, 871) data, the only anti-IGF1R monoclonal antibody that has reached phase III testing. A multicenter phase II randomized trial compared carboplatin-paclitaxel alone with the same chemotherapy plus two doses of fugitumumab as first-line therapy in advanced NSCLC.4 The study showed higher response rates with the antibody in both arms but more evident at a dose of 20 mg/kg. More importantly, patients with squamous cell histology had a very high-response rate of 78%, confirmed in a dedicated cohort. Median PFS was also improved with the addition of fugitumumab. Based on these promising data, there is an ongoing phase III trial in patients with first-line squamous cell cancer.

Dr. Jeffrey Crawford showed data on AMG 479, an anti-IGF1R monoclonal antibody that yielded promising results as a single agent and in combination with gemcitabine or panitunumab.5 These trials established the optimal dose of AMG for studies in ovarian, pancreatic, colorectal, and non-small cell lung cancer, among others, but none have been completed yet. Dr. Geoge Blumenschein showed preliminary data on AVE 1642 as a single agent and in combination with docetaxel. Ongoing trials with this compound include hormone-dependent breast cancer and hepatocarcinoma.

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IGF Receptor Tyrosine Kinase Inhibitors

Inhibition of the IGF pathway can also be accomplished by tyrosine kinase inhibitors, such as BMS-536924, presented by Dr. Haluska, which is currently limited to preclinical data, with plans for further testing in NSCLC in the near future.

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Inhibition of IGF pathway seems to be a promising area of research in lung cancer. The early-phase II results of figitumumab are quite promising. Ongoing phase III studies will define the role of this class of agents in the treatment of patients with NSCLC in the very near future.

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1. Yee D. Targeting insulin-like growth factor pathways. Br J Cancer 2006;94:465–468.

2. Higano CS, Yu EY, Whiting SH, et al. A phase I, first in man study of weekly IMC-A12, a fully human insulin like growth factor-I receptor IgG1 monoclonal antibody, in patients with advanced solid tumors. J Clin Oncol 2007;25:3505

3. Atzori F, Tabernero J, Cervantes A, et al. A phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of weekly (qW) MK-0646, an insulin-like growth factor-1 receptor (IGF1R) monoclonal antibody (MAb) in patients (pts) with advanced solid tumors. J Clin Oncol 2008;26:3519.

4. Karp DD, Paz-Ares LG, Novello S, et al. High activity of the anti-IGF-1R antibody CP-751,871 in combination with paclitaxel and carboplatin in squamous NSCLC. J Clin Oncol 2008;26:3583.

5. Sarantopoulos J, Mita AC, Mulay M, et al. A phase IB study of AMG 479, a type 1 insulin-like growth factor receptor (IGF1R) antibody, in combination with panitumumab (P) or gemcitabline (G). J Clin Oncol 2008;26:3583.

© 2009International Association for the Study of Lung Cancer


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