Abstract #1757: In vivo activity of ARRY-334543, a potent, small molecule inhibitor of EGFR/ErbB2 in combination with trastuzumab or docetaxel
Authors: Deborah Anderson, Cheryl Napier, Anna Avrustkaya, Angela White, Tracy Pheneger, Jim Winkler, Patrice Lee
Journal: Cancer Research (2009)

ARRY-334543 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, ErbB2 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 (NCI-N87) carcinoma. Here we demonstrate single agent activity and combinability with trastuzumab, capecitabine or docetaxel in breast, gastric and ovarian carcinoma models. 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 capecitabine (200 mg/kg, PO, BID) and/or docetaxel at 10 mg/kg, IV, Q3D. Tumor size was measured up to 21 days. In the BT-474 model, ARRY-334543 demonstrated significant dose-related tumor growth inhibition (TGI; 69% at 100 mg/kg/d and 98% at 200 mg/kg/d with significant regressions (>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-334543 (100 mg/kg/d) in combination with trastuzumab showed a 99% TGI with regressions in 11/11 animals with 8CRs. Docetaxel as a single agent produced a 67% TGI with no regressions. In combination with ARRY-334543, there was an 88% TGI and regressions in 8/12 animals. In the SK-OV-3 carcinoma tumor line (high ErbB2/medium EGFR expression), ARRY-334543 demonstrated dose related tumor growth inhibition (up to 90%) producing regressions in 6/8 animals. Trastuzumab alone produced a 71% TGI with regressions in 2/9 animals. ARRY-334543 (100 mg/kg/d) in combination with trastuzumab yielded an 89% TGI with regressions in 8/9 animals. In the ErbB2-over-expressing gastric carcinoma tumor line NCI-N87, ARRY-334543 (100 mg/kg/d) demonstrated significant dose-related tumor growth inhibition (up to 74%) with 7/8 regressions. Trastuzumab or capecitabine alone provided a 52% and 36% TGI, respectively with no regressions in either treatment group. ARRY-334543 in combination with trastuzumab showed a 91% TGI with regressions in 7/8 animals. In combination with capecitabine, ARRY-334543 showed an 82% TGI with marked regressions in 6/8 animals. We have demonstrated excellent single agent activity for ARRY-334543 in SK-OV-3, BT-474 and NCI-N87 xenograft models as well as additive activity to trastuzumab in these models. In the BT-474 and the N87 models, ARRY-334543 showed additive activity to, and tolerability with, docetaxel and capecitabine, respectively. ARRY-334543 is entering several Phase II clinical trials in patients with advanced cancers.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1757.