Abstract #3603: ARRY-334543 in ErbB2 positive metastatic breast cancer and other ErbB expressing-cancers: experience from expansion cohorts on a phase I study
Authors: Susan Ellard, Mace Rothenberg, Roger Cohen, Marianne Taylor, Nancy Hartt, Jordan Berlin, Patricia Murphy, Christian Kollmannsberger, Lara Maloney, Mieke Ptaszynski, Karen Gelmon
Journal: Cancer Research (2009)

ARRY-334543 is an oral, potent, ATP-competitive, selective, reversible inhibitor of ErbB1 (EGFR), ErbB2 (HER2), and ErbB4 (HER4) with activity in a wide range of human tumor cell lines and xenografts dependent on ErbB signaling. Part A of a two-part clinical trial determined that 400 mg twice daily was the recommended dose of ARRY-334543.1 This is a presentation of the interim results from Part B of the study, an expansion phase at the recommended phase II dose to confirm the safety profile of ARRY-334543 and to obtain preliminary efficacy data in two patient cohorts (n=20). Cohort 1 includes patients with ErbB2 positive metastatic breast cancer (MBC) previously treated with trastuzumab. Cohort 2 includes patients with other cancers historically shown to express ErbB-family members. All patients were required to have measurable disease and to provide archival tumor tissue to assess ErbB receptor status by immunohistochemistry (IHC) and gene amplification by fluorescence in situ hybridization (FISH). As of November 2008, 36 patients were enrolled in the Part B expansion (15 patients in Cohort 1 and 21 patients in Cohort 2). As of the data cut-off date, the most commonly reported treatment-related adverse events (AEs) were: fatigue, nausea, anorexia, rash, vomiting, and diarrhea. The 400 mg oral BID dose was generally well-tolerated with mild-moderate, reversible AEs that were consistent with the mechanism-based AEs reported with other ErbB tyrosine kinase inhibitors. Evidence of clinical benefit was observed in both cohorts. In Cohort 1, one partial response was observed in a MBC patient who had previously progressed while receiving paclitaxel and trastuzumab in the adjuvant setting. In addition, 5/14 (36%) of the ErbB2 positive MBC patients evaluable for response had stable disease (SD) \#8805; 16 weeks. Archival biopsies of primary tumor from 12 patients in Cohort 1 were assessed for ErbB2 status in a central laboratory; 8 (66%) biopsies were confirmed to be ErbB2 positive by IHC and/or FISH and 4 (33%) were determined to be ErbB2 negative. Of note, all patients in Cohort 1 who showed clinical benefit were confirmed ErbB2 positive by IHC and/or FISH via independent testing. In Cohort 2, the best response observed was SD \#8805; 16 weeks in 3 patients (ovarian, cervical, cholangiocarcinoma). The patient with cholangiocarcinoma had a minor regression of tumor (25%) and 80% reduction in CA19-9 after six cycles on ARRY-334543. The tumor was ErbB1 positive but ErbB2 negative. In summary, the novel ErbB family inhibitor ARRY-334543 is well-tolerated and has shown evidence of clinical benefit (tumor regression and prolonged SD) in ErbB1 positive, ErbB2 positive, and dual-receptor-expressing cancers. Enrollment of the ErbB2 positive MBC cohort is ongoing and updated results will be discussed. 1 Gelmon, K et al. Breast Cancer Res Tr. 2007;106 Suppl 1: S271.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3603.