Abstract 528: Evaluation of single agent merestinib (LY2801653) or emibetuzumab (LY2875358) and the combination in a xenograft tumor model bearing MET exon 14 skipping
Authors: Yan Sau-Chi Betty , Um Suzane L. , Peek Victoria L. , Stephens Jennifer R. , Zeng Wei , Konicek Bruce W. , Liu Ling , Wacheck Volker , Walgren Richard A. 
Published: July 2017

Background: MET ex14 skipping, present in ~3% of lung cancer, is a strong oncogenic driver which is further evidenced by case reports of patients response to MET TKI treatment. ~15% of tumors in patients that harbor MET ex14 skipping also have MET amplification (amp). Merestinib is a type II MET kinase inhibitor1. Emibetuzumab, a bivalent MET Ab, internalizes MET receptor. Each single agent and the combination were evaluated in the Hs746t gastric cancer line bearing MET ex14 skipping and MET amp. Methods: Each agent was evaluated in vitro for inhibition of Hs746t cell proliferation and pMET levels. In vivo study in Hs746t-derived xenograft mouse model (n=7 mice/ arm, 28 day dosing) initiated when tumors were 150-350mm3: merestinib at 6 mg/kg (suboptimal dose - insufficient target coverage for 24 hrs) or 12 mg/kg (optimal dose) qd orally, emibetuzumab at 10 mg/kg qw by IP. Results: Merestinib inhibited Hs746t cell proliferation with IC50=34 nM and totally eliminated pMET at 65-100 nM. Emibetuzumab slightly inhibited Hs746t cell proliferation (IC50&gt;100 nM), reduced 10-20% cell surface MET, and no effect on pMET expression (at 130-650 nM). In the Hs746t xenograft model, merestinib (12 mg/kg) treatment resulted in 91.8% tumor regression after 21 day dosing, while 6 mg/kg merestinib provided transient tumor regression followed by re-growth while on treatment with T/C=18.3% after 21 day dosing. No tumor re-growth was observed in 6/7 mice in the 12 mg/kg merestinib cohort during the 5 weeks post-treatment. Emibetuzumab treatment provided transient tumor regression (37.7%) after 3 doses, but tumors re-grew while on treatment. Combination of 6 mg/kg merestinib and 10 mg/kg emibetuzumab resulted in 85% tumor regression for the duration of the 28 day dosing period and the treatment was well tolerated. Tumors in animals re-grew upon termination of this combination treatment. Conclusion: Merestinib (12 mg/kg) treatment resulted in durable and complete response in 6/7 mice bearing Hs746t tumors with MET ex14 skipping and MET amp. When used singly, merestinib (6 mg/kg) or emibetuzumab (10 mg/kg) resulted in only transient tumor regression in this model, while the combination resulted in substantial tumor regression while on treatment. This combination treatment was however, not as durable as was observed with single agent 12 mg/kg merestinib. Single agents and the combinations were well tolerated. As a type II MET inhibitor, merestinib may provide a therapeutic option to treatment naïve patients or those who have progressed on type I MET inhibitor treatment, whose tumors have MET exon 14 skipping and/or MET amplification 2,3. Data in this study support a clinical evaluation of merestinib in patients with MET exon 14 skipping (NCT02920996). 1 - Yan et al. Invest New Drugs 2013;31:833-844 2 - Ou et al. J Thorac Oncol. 2016; PMID:27666659 3 - Heist et al. J Thorac Oncol. 2016;11:1242-1245

Citation Format: Sau-Chi Betty Yan, Suzane L. Um, Victoria L. Peek, Jennifer R. Stephens, Wei Zeng, Bruce W. Konicek, Ling Liu, Volker Wacheck, Richard A. Walgren. Evaluation of single agent merestinib (LY2801653) or emibetuzumab (LY2875358) and the combination in a xenograft tumor model bearing MET exon 14 skipping [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 528. doi:10.1158/1538-7445.AM2017-528