Abstract A050: ARRY-380, an oral HER2 inhibitor: Final phase 1 results and conclusions
Authors: Borges Virginia F. , Chia Steven K.L , D'Aloisio Susan , Fernetich Gina , Sajan Bessie , McSpadden Tessa , Chavira Renae , Barrett Emma , Guthrie Kari , Garrus Jennifer , Baetz Tara , Moulder Stacy 
Published: May 2015

Abstract
Background: Overexpression of HER2 occurs in ~25% of breast cancers. Despite the treatment successes achieved to date, improved clinical outcomes remain needed, including prevention and treatment of CNS metastases. Small-molecule HER2 inhibitors may have the advantage of being able to treat CNS and systemic disease simultaneously, particularly if used in combination with antibody-based therapy. However, currently available small molecules also target EGFR, with associated use limiting toxicities. Therefore, a specific small-molecule inhibitor of HER2 is needed. ARRY-380 is an oral, potent, reversible, ATP competitive, small molecule inhibitor of HER2. In cell-based assays, ARRY-380 was ~500-fold selective for HER2 versus EGFR. In multiple preclinical models, ARRY-380 demonstrated significant single agent and combination activity. In models of CNS disease, ARRY-380 was highly active as a single agent and demonstrated superior activity compared to lapatinib or neratinib. Thus, ARRY-380 was evaluated in a first in human clinical study.
Methods: A Phase 1 clinical study of ARRY-380 was conducted in patients with advanced solid tumors that are believed to express HER2, with both dose-escalation (25 to 800 mg BID) and MTD expansion components. ARRY-380 was administered BID in 28 day cycles. Safety was assessed by AEs, clinical laboratory test results, physical examinations, vital signs and ECGs. Tumor response was assessed by RECIST every 2 cycles. Serial PK assessments were conducted in Cycle 1 on Days 1 and 3 and at steady state on Day 15.
Results: A total of 50 patients were enrolled (33 dose-escalation and 17 expansion). These results focus on the 31 patients treated at doses ≥ MTD: 27 at the MTD of 600/650 mg BID and 4 at 800 mg BID. All 31 patients had HER2+ metastatic breast cancer (MBC) that had progressed on a prior trastuzumab containing regimen and 94% had received prior lapatinib, many who progressed on treatment. Dose limiting toxicity consisting of reversible Grade (G) 3 AST (n=1) and AST/ALT elevations (n=1) occurred in 2 of 4 patients treated at 800 mg BID, with an onset that occurred within 1 week, resolved within 2 weeks, and patients resumed treatment at a lower dose.
Overall, ARRY-380 demonstrated an acceptable safety profile at the MTD. The most common treatment-related AEs were nausea, diarrhea, fatigue, vomiting, liver enzyme elevations and rash, and were primarily G1 with a low incidence of G2 (gastrointestinal events [n=2], fatigue [n=3], liver enzyme elevations [n=2]) or G3 (rash [n=1], liver enzyme elevations [n=1]) events. There were no treatment-related cardiac events, serious AEs or G4 AEs.
ARRY-380 Cmax and AUC increased with increasing dose, with a Tmax of 2 hours and a t1/2 of 5 hours. Twenty-two HER2+ MBC patients with measurable disease were treated with ARRY-380 at doses ≥ 600 mg BID. In this heavily pretreated population, there was a clinical benefit rate (PR [n=3] plus SD for at least 6 months [n=3]) of 27%. Notably, 2 patients with PRs on ARRY-380 had confirmed progressions while on prior lapatinib- and trastuzumab-containing regimens.
Conclusions: ARRY-380 has demonstrated an acceptable safety and PK profile at the MTD. As predicted for a HER2-selective agent that does not inhibit EGFR, there was a very low incidence of Grade 2/3 rash and diarrhea. ARRY-380 has shown promising signs of antitumor activity in a heavily pretreated HER2+ MBC population. These safety and preliminary efficacy data support the continued clinical development of ARRY-380 at the recommended dose of 600 mg BID.
Citation Format: Virginia F. Borges, Steven K.L Chia, Susan D'Aloisio, Gina Fernetich, Bessie Sajan, Tessa McSpadden, Renae Chavira, Emma Barrett, Kari Guthrie, Jennifer Garrus, Tara Baetz, Stacy Moulder. ARRY-380, an oral HER2 inhibitor: Final phase 1 results and conclusions. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A050.