Table 1.

IGF1R TKIs and antibodies

    A-928605AbbottPreclinicalPyrazolopyrimidine TKI
    BMS-536924Bristol-Myers SquibbPreclinicalATP-competitive, equipotent inhibition of IGF1R and IR
    INSM-18 (NDGA)InsmedPhase I-IIDual inhibitor of the IGF-I and HER2 receptor kinases
Phase I data suggest modest PSA responses in patients with nonmetastatic prostate cancer
    PPPKarolinska Cancer Institute and BiovitrumPreclinicalInhibits phosphorylation of Y1136 in the kinase activation loop. Does not inhibit IR
Preferentially inhibits PI3K-Akt pathway, blocks growth of a range of tumors in vitro and in vivo
Induces IGF1R down-regulation via involvement of β-arrestin 1/MDM2
    NVP-ADW742Novartis PharmaPreclinicalATP-competitive inhibitor, shows ∼15-fold selectivity for IGF1R relative to IR in intact cells
In SCLC, inhibits PI3K-AKT and induces synergy in combination with chemotherapy
    NVP-AEW541Novartis PharmaPreclinicalATP-competitive inhibitor, shows ∼27-fold selectivity for IGF1R relative to IR within intact cells
Inhibits Akt/mTOR pathway, enhances growth inhibition of MM cells in combination with dexamethasone and bortezomib
    OSI-906OSI PharmaceuticalsPhase IShows ∼10-fold selectivity for IGF1R relative to IR. Synergistic antiproliferative effects in combination with erlotinib in CRC cell lines via blockade of AKT and ERK phosphorylation
    XL-228ExelixisPhase IInhibitor of IGF1R, BCR-ABL and Src
IGF1R antibodies
    AVE1642Sanofi-AventisPhase I-IIHumanized version of murine EM164 IgG1 antibody. Phase I single agent in MM, with docetaxel in solid tumors, well-tolerated, no DLT. Planned combination with bortezomib in MM
    SCH-717454 (19D12)Schering-PloughPhase I-IIFully human monoclonal antibody
Activity against IGF1R/IR hybrid receptors via interaction with the IGF1R component
    CP-751,871PfizerPhase I-IIIFully human IgG2. Phase I: mild hyperglycemia, no DLT, MTD not achieved. At 20 mg/kg, 10 of 15 patients had SD. Phase II in adrenocortical carcinoma, sarcoma: SD in 60% patients. Phase II in NSCLC: RR 51% to CP-751,871 with TC vs. 36% on TC alone. Objective responses to TC with antibody in 72% of squamous tumors, including “striking” responses in bulky disease, and some PR/SD on CP-751,871 afterPD on TC alone
    IMC-A12ImClone Systems, Inc.Phase I-IIRecombinant human monoclonal IgG1 antibody, binds IGF1R and IGF1R/IR hybrid receptors but not IR alone. Stable disease in 46% of patients with solid tumors in phase I
    BIIB022Biogen IdecPhase I-IIFully human nonglycosylated version of IgG4.P antibody lacking Fc-effector function
    MK-0646MerckPhase I-IIIHumanized monoclonal IgG1. Phase I toxicity hyperglycemia and thrombocytopenia. Current studies: phase II in neuroendocrine tumors and NSCLC; phase II/III in metastatic CRC with cetuximab and irinotecan
    R1507RochePhase I-IIHuman monoclonal IgG1 antibody. Phase I showed PR in four of eight patients with sarcoma
    AMG 479AmgenPhase I-IIFully human monoclonal IgG1 antibody. Phase I activity: CR in Ewing's, PR in neuroendocrine tumor. Phase IB with panitumumab or gemcitabine: one DLT (hyperglycemia)
  • NOTE: A summary of IGF1R small molecule inhibitors and antibodies currently in preclinical and early clinical development. Data from (refs. 27, 57, 58); A. Tolcher (personal communication), and the NIH's ( and ( web sites.

    Abbreviations: PSA, prostate-specific antigen; SCLC, small cell lung cancer; NSCLC, non–small cell lung cancer; CRC, colorectal cancer; MM, multiple myeloma; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; TC, taxol/carboplatin; RR, response rate; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.