Abstract 866: ASP3026, a selective ALK inhibitor, induces tumor regression in a crizotinib-refractory model and prolongs survival in an intrapleurally xenograft model
Authors: Mori Masamichi , Kuromitsu Sadao , Ueno Yoko , Tanaka Ruriko , Shimada Itsuro , Kondoh Yutaka , Konagai Satoshi , Sakagami Hideki , Fushiki Hiroshi , Saito Rika , Sengoku Takanori 
Published: August 2012

Abstract
EML4-ALK translocation has been validated as a therapeutic target in a subset of non-small cell lung cancer (NSCLC) patients. In clinical settings, crizotinib has shown promising response rates in patients with EML4-ALK positive NSCLC, while disease relapse has been observed in several sites, including the lungs. Our previous studies found that ASP3026, a selective ALK inhibitor, had higher kinase selectivity than crizotinib and induced regression of tumors expressing EML4-ALK with a gate-keeper mutation that confers resistance to crizotinib. Here, we evaluated the antitumor activity of ASP3026 and crizotinib against orthotopic lung and intrapleural tumors in mice using luciferase-expressing NCI-H2228, a human NSCLC tumor cell line endogenously expressing EML4-ALK. In an orthotopic lung model, implanted cells were monitored using bioluminescent imaging (BLI) of the chest area. ASP3026 and crizotinib were administered orally at once daily doses ranging from 3 to 30 mg/kg (starting after confirmation of tumor growth). ASP3026 at 30 mg/kg induced tumor regression by 27 days after the start of administration; in contrast, crizotinib at 30 mg/kg induced regression during the first 7 days of administration, although tumors subsequently regrew despite continuous drug administration. After tumor regrowth had been established by the first cycle treatment of crizotinib, substantial regression was achieved by subsequent administration of ASP3026 at 30 mg/kg against the crizotinib-refractory tumors. In an intrapleural xenograft model, disease-related mortality was observed in tested animals, with a median survival time (MST) of 39 days in vehicle-treated control mice and 71 days in crizotinib-treated animals at 30 mg/kg. In contrast, no mice receiving ASP3026 treatment at 30 mg/kg died during the experimental period (90 days). These effects were accompanied by change in the bioluminescent emissions, with crizotinib-treated mice showing increased emissions following the initial reduction, while ASP3026-induced reduction continuing throughout the experimental period. The mean bioluminescent emission in the group treated with ASP3026 was significantly lower than in the crizotinib-treated group, indicating that ASP3026-treated animals exhibited lower tumor burden than crizotinib-treated ones.Taken together, these results suggest that ASP3026 is effective in producing shrinkage of tumors refractory to crizotinib and shows superior efficacy to crizotinib against intrapleural metastatic tumors with respect to prolonging survival.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 866. doi:1538-7445.AM2012-866