Abstract A143: ARRY-380, a selective HER2 inhibitor: From drug design to clinical evaluation.
Authors: Moulder Stacy L. , Baetz Tara , Borges Virginia , Chia Stephen K.L. , Barrett Emma , Garrus Jennifer , Guthrie Kari , Kass Carrie L. , Laird Ellen , Lyssikatos Joseph , Marmsater Fredrik , Wallace Eli 
Published: June 2012

Abstract
In recent years, there has been discussion on the relative benefits of drugs that are kinase selective and those targeting multiple kinases, both in terms of clinical activity and safety. While the value of selectivity may be target dependent, there is now evidence that HER2 can be effectively targeted with a selective small molecule. Designing a selective HER2 inhibitor is challenging, as the ATP-binding pockets of EGFR and HER2 differ by only 2 amino acids and only 1 of these is involved with inhibitor binding (Cys775 vs. Ser783). While obtaining this selectivity was difficult, the goal of developing a drug that would inhibit HER2 without EGFR-related side effects was deemed advantageous, especially since it appears that inhibition of EGFR does not improve the efficacy of HER2-targeted therapy in patients (pts) with HER2+ metastatic breast cancer (MBC) (Arteaga, et al. Clin Cancer Res. 2008; 14(19):6277–83).
ARRY-380 is an orally active, potent, small-molecule tyrosine kinase inhibitor of HER2. The compound is a reversible, ATP-competitive inhibitor with nanomolar potency in enzymatic and cellular assays. In cell-based assays, ARRY-380 is ∼500-fold selective for HER2 versus EGFR and is equipotent against truncated p95-HER2. ARRY-380 is currently undergoing evaluation in a first-inhuman Phase 1 dose-escalation and expansion study designed to identify the maximum tolerated dose (MTD) and to assess the safety, pharmacokinetics (PK) and preliminary efficacy in pts with advanced solid tumors that express the HER2 target.
In the dose-escalation phase, pts with HER2+ MBC or other documented HER2+ cancers were treated with ARRY-380 as a single oral dose on Cycle (C)1 Day (D)1 followed by twice daily (BID) dosing, beginning on C1 D3, in 28-day dosing cycles. Safety was assessed by adverse events (AEs), clinical laboratory test results, physical examinations, vital signs and ECGs. Tumor response was assessed every 2 cycles.
As of August 31, 2011, 50 pts (43 with MBC) have received ARRY-380. In the completed dose-escalation phase, 33 pts were enrolled and treated at doses ranging from 25 mg to 800 mg BID; of these, 26 had HER2+ MBC and all were previously treated with trastuzumab and 81% with lapatinib. The MTD was determined to be 600 mg BID. Of 19 evaluable pts with HER2+ MBC receiving doses ≥ 200 mg BID, 6 (32%) had a partial response (PR) or stable disease (SD) ≥ 6 months; 10 pts had regression of tumor lesions, of these, 1 pt (5%) had a PR and 9 pts (47%) had SD. Treatment-related AEs included Grade 2 events of increased ALT/AST (5), constipation (1), fatigue (3), hyperbilirubinemia (1) and nausea (1) and Grade 3 AEs of increased ALT/AST (3), night sweats (1) and rash (1). No Grade 4 treatment-related AEs have been reported, nor has any treatment-related AE led to study drug discontinuation. An expansion cohort to confirm safety and further examine activity of ARRY-380 at the MTD in pts with HER2+ MBC is ongoing; enrollment is complete (N = 17) and data analysis is continuing. In conclusion, in the small number of pts treated to date, ARRY-380 is associated with few EGFR-related side effects. In heavily pre-treated MBC pts, ARRY-380 is exhibiting preliminary signs of efficacy with an acceptable safety profile. Thus, continued clinical development of ARRY-380 is warranted to further evaluate if a selective, small-molecule HER2 inhibitor may be an alternative treatment option to a multi-kinase inhibitor in pts with HER2+ cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A143.