Abstract C173: Anti‐tumor activity of SCH 900105 (AV299), an anti‐HGF antibody, in non‐small cell lung cancer models

Hepatocyte growth factor (HGF) is the soluble ligand for the c‐Met receptor tyrosine kinase. Signaling through the HGF/c‐Met pathway mediates a plethora of cellular activities that are involved in cancer cell dysregulation, tumorigenesis, and metastasis including cell proliferation and survival, angiogenesis, migration, invasion and drug resistance. HGF/c‐Met autocrine and paracrine regulatory loops have been reported in a number of non‐small cell lung cancer studies. Furthermore, studies have shown that HGF/c‐Met pathway upregulation via either c‐Met amplification or HGF secretion can result in intrinsic or acquired resistance to EGFR TKIs in lung adenocarcinoma. SCH 900105, formerly known as AV‐299, is a humanized IgG1 antibody with high affinity to HGF that neutralizes all its biological functions tested with sub‐nM potency. It is currently in phase 1 clinical trials that demonstrated good safety and tolerability. Anti‐tumor activity of SCH 900105 was observed in HGF autocrine and paracrine in vivo tumor models, such as GMB, pancreatic cancer and multiple myeloma. Anti‐tumor efficacy of SCH 900105 was evaluated in paracrine models of the HGF‐dependent NCI‐H596 NSCLC cell line xenografted in SCID mice engineered to produce human HGF. In these models, SCH 900105 treatment resulted in dose‐dependent decrease in tumor growth with concurrent increases in serum and tumor concentration of SCH900105 and increases in serum SCH 900105/HGF complex. Treatment also led to significant reduction in phospho‐c‐Met and phospho‐Akt levels in tumor lysates. Concurrently, increases in cleaved caspase‐3 and decreases in Ki67 and CD31 staining were also observed. Anti‐tumor activity of SCH 900105 was also explored in combination with EGFR inhibitors, erlotinib and Cetuximab that resulted in increased efficacy. SCH900105 treatment resulted in decreased phospho‐c‐Met levels with concurrent increases in phospho‐EGFR levels. Conversely, erlotinib treatment decreased phospho‐EGFR with concurrent increases in phospho‐Met levels. The combination of SCH900105 with Cetuximab resulted in complete response in all animals treated without tumor re‐growth 50 days after treatment withdrawal. Potent anti‐tumor activity of SCH 900105 in combination with EGFR inhibitors observed in these preclinical models suggests testing the combination in NSCLC is warranted in the clinic. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C173.