Abstract C112: Characterization of TAS-121, a novel mutant-specific EGFR-TKI, on pharmacokinetics, pharmacodynamics, and antitumor activity.

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), Gefitinib and Erlotinib, show good responsiveness in non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. Notably, skin rash and diarrhea, the most common EGFR-TKIs-related adverse effects, are due to wild type EGFR inhibition in dermal and intestinal tissue, respectively. Acquired resistance to EGFR-TKIs, however, arises in most cases and is caused in about half the cases by a secondary gatekeeper T790M mutation of EGFR. Therefore, an EGFR-TKI that specifically inhibits EGFR harboring mutations including T790M without affecting wild-type EGFR represents an attractive therapeutic agent. Materials and Methods: Pharmacokinetics studies were performed in mice, rats, dogs and monkeys, and tumor growth and pharmacodynamics evaluation was analyzed in athymic nude mice bearing NSCLC cell lines, NCI-H1975 (harboring the EGFR T790M/L858R mutation) and HCC827 (harboring the EGFR exon 19 deletion). Results: TAS-121 is a newly synthesized compound which is a mutant selective EGFR inhibitor with improved oral bioavailability in various animal species and in vivo antitumor potency compared to the previously described prototype compound, TAS-2913. TAS-121 showed a higher plasma concentration than TAS-2913 following oral administration in mice. Once daily dosing of TAS-121 inhibited NCI-H1975 (EGFR T790M/L858R) tumor growth at a low dose, with an ED50 of less than 12.5 mg/kg/day. TAS-121 also showed tumor growth inhibition of HCC-827 cells, harboring an EGFR activating mutation. In an orthotopic lung xenograft model, TAS-121 significantly prolonged survival in mice compared to first- and second-generation EGFR-TKIs. Pharmacodynamics analysis revealed that TAS-121 dose-dependently inhibited phosphorylation of EGFR T790M/L858R in a xenografted tumor, whereas it did not inhibit that of wild-type EGFR in mouse skin. Conclusion: Our study demonstrates that TAS-121 is a highly potent and mutant-specific EGFR-TKI with a favorable oral bioavailability, and provides a promising therapeutic option for patients harboring T790M mutation after the failure of pre-existing EGFR-TKIs. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C112. Citation Format: Masanori Kato, Kazutaka Miyadera, Yoshihiro Shibata, Kimihiro Ito, Yoshimi Aoyagi, Masato Chiba, Kazuhiko Yonekura, Yoshikazu Iwasawa, Teruhiro Utsugi. Characterization of TAS-121, a novel mutant-specific EGFR-TKI, on pharmacokinetics, pharmacodynamics, and antitumor activity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C112.