In vivo activity of ARRY-543, a potent, small molecule inhibitor of EGFR/ErbB-2 in combination with trastuzumab or docetaxel.
Authors: Lee PA , Anderson D , Avrutskaya A , White A , Pheneger T , Winkler JD 
Published: December 2010

Abstract
Abstract #2150
ARRY-543 is an orally active, potent small molecule tyrosine kinase inhibitor targeting both EGFR and ErbB2. The compound is a reversible, ATP-competitive inhibitor with nanomolar potency in both in vitro and in cell-based assays showing strong activity against EGFR, HER-2 and ErbB-4. This compound has very good in vivo and in vitro PK/ADME properties and has shown excellent activity in numerous mouse tumor models including epidermoid (A431), breast (BT-474, MDA-MB-453), non-small cell lung (H1650, A549, 292), colorectal (Lovo, HT-29) and gastric (N87) carcinoma models. Here we demonstrate excellent single agent activity and combinability with trastuzumab or docetaxel in breast, gastric and ovarian carcinoma models. For the BT-474 studies, female SCID beige mice were implanted with tumor fragments. For the SKOV-3 and N87 tumor studies, female nude mice were inoculated with cells subcutaneously in the flank. Animals received: doses of ARRY-334543 ranging up to 200 mg/kg/d, PO; and/or trastuzumab at 20 mg/kg, IP, Q3D or QW; and/or docetaxel at 10 mg/kg, IV, Q3D. Tumor size was measured at regular intervals for up to 21 days. In the BT-474 model, ARRY-334543 demonstrated significant dose-related tumor growth inhibition (69% at 100 mg/kg/d and 98% at 200 mg/kg/d with significant regressions (&gt;50% reduction from baseline size) at both dose levels (3/12 in the 100 mg/kg/d group and 10/10 in the 200 mg/kg/day group). Trastuzumab alone provided a 53% TGI with a regression (1/12 animals). ARRY-543 (100 mg/kg/d) in combination with trastuzumab showed a 99% TGI with significant, regressions in 11/11 animals with 8CRs. Docetaxel as a single agent produced a 67% TGI with no regressions. In combination with ARRY-543 (100 mg/kg/d) there was an 88% TGI and significant regressions in 8/12 animals. In the SKOV-3 carcinoma tumor line (high ErbB2/medium EGFR expression), ARRY-334543 demonstrated significant dose related tumor growth inhibition (up to 90%) producing significant regressions in 6/8 animals. Trastuzumab alone produced a 71% TGI with significant regressions in 2/9 animals. ARRY-543 (100 mg/kg/d) in combination with trastuzumab yielded a 89% TGI with significant regressions in 8/9 animals. In the ErbB2-over-expressing gastric carcinoma tumor line N87, ARRY-334543 (100 mg/kg/d) demonstrated significant dose-related tumor growth inhibition (up to 74%) with 7/8 significant regressions. Trastuzumab alone provided a 52% TGI with no regressions. ARRY-543 (100 mg/kg/d) in combination with trastuzumab showed a 91% TGI with significant regressions in 7/8 animals. We have demonstrated excellent single agent activity for ARRY-543 in the SKOV-3 ovarian carcinoma xenograft model as well as additive activity to trastuzumab in SKOV-3, BT-474 and N87 models. In the BT-474 model, ARRY-543 showed excellent additive activity to, and tolerability with, docetaxel. ARRY-543 is in several Phase II clinical trials in patients with advanced cancers.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2150.