Important ERBITUX(R) (cetuximab) clinical data were the focus of two back-to-back oral presentations leading off the "Breakthroughs in Clinical Research" Plenary Session on April 16, 2007, which highlights the most important clinical studies presented at this prestigious meeting. The remaining presentations showcased ImClone's extensive research and development program with results from studies involving both ERBITUX, an IgG1 monoclonal antibody that targets the epidermal growth factor receptor (EGFR), and multiple investigational monoclonal antibodies in the ImClone pipeline that target other critical cancer pathways.
Like ERBITUX, the monoclonal antibodies in the ImClone pipeline are all type 1 immunoglobulin G (IgG1) antibodies. In vitro, IgG1 antibodies elicit antibody-dependent cellular cytotoxicity (ADCC), which can kill cancer cells and may contribute to their overall therapeutic effects. These novel fully human antibodies, many of which are in early phase clinical testing, target cell surface receptors in various signaling pathways known or believed to play important roles in the growth and proliferation of tumors or tumor vasculature. Specific targets include insulin-like growth factor-1 receptor (IGF-1R), vascular endothelial growth factor receptor-1 (VEGFR-1), VEGFR-2, VEGFR-3, platelet-derived growth factor receptor alpha (PDGFR(alpha)), FMS-like tyrosine kinase 3 receptor (FLT3), fibroblast growth factor receptor 3 (FGFR3), among others.
"Our pipeline consists of a robust collection of IgG1 monoclonal antibodies targeted against cellular pathways that are emerging as cri tical drivers of cancer growth, proliferation, and survival," said Eric Rowinsky, M.D., Chief Medical Officer and Senior Vice President of ImClone Systems. "With ERBITUX as our cornerstone, we are uniquely positioned to drive the science that will lead to new therapies of major clinical impact as well as define new combinatorial biologic therapies that may improve patient care."
"We are extremely excited by the potential of ERBITUX and we are also increasingly enthusiastic about our pipeline of novel antibodies," said Alexander J. Denner, Ph.D., Chairman of ImClone System's Executive Committee.
Among others, ERBITUX findings presented at the meeting included
-- In a large randomized phase III trial ERBITUX added to irinotecan significantly improved the secondary end points of progression free survival and tumor response compared to irinotecan alone in patients with metastatic colorectal cancer (mCRC) after failure of first-line therapy. Overall survival, the trial's primary end point, was similar between the treatment groups, plausibly due to the survival benefit of extensive post-study treatment with ERBITUX in patients in the irinotecan-alone arm. (#LB-2 in the "Breakthroughs in Clinical Research" Plenary Session, Sobrero et al. Randomized Phase III trial of cetuximab plus irinotecan versus irinotecan alone for metastatic colorectal cancer in 1298 patients who have failed prior oxaliplatin-based therapy: The EPIC trial.)
-- ERBITUX administered in patients with mCRC as a 500 mg/m(2) dose administered every 2 weeks showed similar pharmacokinetics and efficacy, and no increased toxicity compared to the current standard weekly dosing regimen. (#LB-352, Cervantes et al: Optimal dose of cetuximab administered every 2 weeks (q2w): A phase I safety, pharmacokinetics (PK) and pharmacodynamics (PD) study of weekly (q1w) and q2w schedules in patients (pts) with metastatic colorectal cancer (mCRC).)
-- Different anti-EGFR agents, including other monoclonal antibodies, have different biological effects. (#336 Meira et al. Differences in activity between matuzumab and cetuximab in A431 cells may rely on MAPK cascade inhibition.)
-- Emerging biomarkers may serve as predictors of clinical response to ERBITUX. (#5670 Ford et al. Expression of epiregulin and amphiregulin and K-RAS mutation status may predict disease control in metastatic colorectal cancer patients treated with cetuximab (ERBITUX(R)); #5671 Lievre et al. K-RAS mutation in colorectal cancer is a predictive factor of response and progression free survival in patients treated with cetuximab.)
-- It is well established that the combination of ERBITUX and irinotecan can overcome irinotecan resistance in chemotherapy refractory patients with mCRC (Cunningham et al, N Engl J Med. 2004;351:337.) Results presented by Deevi et al. show that ERBITUX may also reverse oxaliplatin resistance. (#2329 Deevi et al. Mechanism for the benefits of cetuximab in combination with oxaliplatin, in oxaliplatin sensitive and resistant colon cancer cell lines.)
-- It is also well established that ERBITUX in combination with radiation therapy improves survival in patients with locally advanced head and neck cancer (Bonner et al, N Engl J Med. 2006;354:567.) In vitro studies presented show enhanced anticancer effects with ERBITUX in combination with radiation in non-small cell lung cancer cells and in combination with HDAC or Src inhibition in colon cancer cells. (#3111 Brooks et al. Targeting EGFR signaling to enhance response of non-small cell lung cancer cells to radiation; #683 LaBonte et al. The effects of histone deacetylase inhibitors on epidermal growth factor receptor expression in colon cancer cell lines: implications for combination therapy; #4079 Kopetz et al. Synergistic activity of Src and EGFR inhibitors in colon cancer.)
ImClone's broad portfolio of investigational fully human IgG1 monoclonal antibodies was featured in 14 AACR presentations. Much of the reported data provides scientific support for the continued evaluation of these antibodies in novel combinations of biologic therapies.
-- IMC-A12 (anti-IGF-1R MAb) (#425 Burtrum et al., Abrogation of PTEN does not confer resistance to anti IGF-1R targeted therapy in IGF responsive tumor cells ,#652 Prewett et al. IMC-A12 enhances the efficacy of cetuximab and gemcitabine therapy in human pancreatic carcinoma xenografts; #4396 Krystal et al. Selective inhibition of SCLC growth by the A12 anti-IGF-1R monoclonal antibody correlates with inhibition of Akt.)
-- IMC-18F1 (anti-VEGFR-1 MAb) (#4100 Wang et al. Expression of vascular endothelial growth factor receptor-1 in human tumor arrays.)
-- IMC-1121b (anti-VEGFR-2 MAb) (#4097 Corcoran et al. Comparison of combination anti-EGFR and anti-VEGFR2 therapy to MTD standard chemotherapeutic regimens.)
-- IMC-3G3 (anti-PDGFR(alpha) MAb) and IMC 1121b (anti-VEGFR-2 MAb) (#4790 Shen et al. An antibody directed against platelet-derived growth factor (beta) receptor suppresses growth of human tumor xenografts and enhances antitumor activity of an anti-VEGFR2 antibody.)
-- IMC-EB10, NC7, and D4-3 (Anti-FLT3 MAb) (#4110 Williams et al. Elucidation of the antagonistic mechanisms of various anti-FLT3 antibodies via binding epitope dissection.)
-- IMC-D11 (anti-FGFR3 MAb) (#2080 DiRenzo et al. Neutralizing antibody against FGFR3 shows anti-tumor effects in multiple tumor models in vivo.)
Additional details of the presentations can be found on the AACR website at http://www.aacr.org/.
About ImClone Systems Incorporated
ImClone Systems Incorporated is committed to advancing oncology care by developing and commercializing a portfolio of targeted biologic treatments designed to address the medical needs of patients with a variety of cancers. The Company's research and development programs include growth factor blockers and angiogenesis inhibitors. ImC lone Systems' strategy is to become a fully integrated biopharmaceutical company, taking its development programs from the research stage to the market. ImClone Systems' headquarters and research operations are located in New York City, with additional administration and manufacturing facilities in Branchburg, New Jersey.
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ImClone Systems Incorporated
Rebecca Gregory, 646-638-5058