Abstract A158: Characterization of antitumor activity of TAS6417, a novel EGFR-TKI targeting exon 20 insertions
Authors: Hasako Shinichi , Terasaka Miki , Fujita Ryoto , Abe Naomi , Hashimoto Akihiro , Matsuo Kenichi , Utsugi Teruhiro , Iwasawa Yoshikazau 
Published: August 2018

Abstract
Background: Activating mutations in the EGFR gene are important targets in cancer therapy because they are key drivers of NSCLC. EGFR-TKIs (gefitinib, erlotinib and afatinib) are eligible for first-line therapy in NSCLC patients with EGFR activating mutations such as exon 19 deletions and L858R. However, NSCLC driven by EGFR exon 20 insertions, the third most common mutation in the EGFR gene, are associated with poor clinical response to the existing EGFR-TKI therapies, suggesting an unmet medical need for these patients. TAS6417 (previously termed TPC-064) is a novel EGFR inhibitor that has a potent inhibitory activity against exon 20 insertions while sparing wild-type (WT) EGFR, and could be an efficacious treatment option for these patients without the risk of severe diarrhea associated with inhibition of WT EGFR. Materials and Methods: Tumor growth analysis was conducted in athymic nude mice or nude rats bearing a patient-derived xenograft (PDX) (LXF2478, an NSCLC harboring EGFR V769_D770insASV mutation), or genetically engineered cells expressing EGFR exon 20 insertions (NCI-H1975 EGFR D770_N771insSVD and NIH-3T3 EGFR H773_V774insNPH). The protein and phosphoprotein expression level in tumors were determined by Western blot analysis. Results: TAS6417 was discovered as a more potent and selective inhibitory activity on the EGFR harboring exon 20 insertions compared to WT. The effect of TAS6417 on antitumor activity was evaluated in subcutaneously implantation model in nude mice and nude rats, and also in orthotopic lung implantation in nude mice. In sc mouse models, once-daily dosing of TAS6417 at 50 mg/kg or more inhibited tumor growth of genetically engineered cell lines, NCI-H1975 EGFR D770_N771insSVD (expressing exon 20 insertion mutation instead of endogenous L858R/T790M mutations) and NIH-3T3 EGFR N773_V774insNPH. Furthermore, a PDX harboring EGFR V769_D770insASV showed a striking response to TAS6417, resulting in tumor regression at 100 mg/kg. In nude rats bearing NCI-H1975 EGFR D770_N771insSVD xenografts, TAS6417 inhibited tumor growth at 10 mg/kg or more, and tumor shrinkage was observed at 40 mg/kg without any effect on body weight gain. Furthermore, TAS6417 provided a survival benefit with good tolerability in lung orthotopic implantation mouse model. Pharmacodynamics marker analysis revealed that TAS6417 inhibited EGFR signaling including both AKT and ERK pathways in tumors, leading to caspase activation with an increase in Bim protein expression. Conclusions: These findings demonstrated that TAS6417 had potent antitumor activity with good tolerability in not only genetically engineered xenografts but also in a PDX harboring EGFR exon 20 insertions, suggesting a promising therapeutic option for patients with NSCLC harboring EGFR exon 20 insertions.
Citation Format: Shinichi Hasako, Miki Terasaka, Ryoto Fujita, Naomi Abe, Akihiro Hashimoto, Kenichi Matsuo, Teruhiro Utsugi, Yoshikazau Iwasawa. Characterization of antitumor activity of TAS6417, a novel EGFR-TKI targeting exon 20 insertions [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A158.