Abstract 1477: Pharmacodynamic response and anti-tumor activity of the MET inhibitor AZD6094 in papillary renal cell carcinoma patient derived xenograft models
Authors: Schuller Alwin , Barry Evan , Jones Rhys , Frigault Melanie , Beran Garry , Henry Ryan , Linsenmayer David , Hattersley Maureen , Smith Aaron , Wilson Joanne , Adam Ammar , Zinda Michael , Reimer Corinne , Fawell Stephen , Clark Edwin , D'Cruz Celina 
Published: August 2015

Abstract
Papillary renal cell carcinoma (PRCC) is the second most common cancer of the kidney and carries a poor prognosis for patients with non-localized disease. The central role of the hepatocyte growth factor (HGF) receptor MET in PRCC has been explored, demonstrating that MET aberrations, either through mutation, copy number gain, or trisomy of chromosome 7 (the location of MET and HGF) occur in the majority of PRCC cases. We sought to evaluate AZD6094 (HMPL-504), a potent and selective small molecule MET kinase inhibitor, in this disease setting. However, the development of effective therapies targeting MET and other targets in PRCC has been hampered in part by a lack of available preclinical models to test novel targeted therapies. Here we describe for the first time the pharmacodynamic (PD) response and anti-tumor activity of the selective MET inhibitor AZD6094 in two preclinical patient derived xenograft (PDX) models of PRCC (RCC-43b and RCC-47). Both PDX models have increased MET copy number of 8 and 9 copies by FISH in RCC-43b, and RCC-47 respectively, and robust MET protein staining by IHC. AZD6094 treatment resulted in dose dependent anti-tumor responses reaching ∼85% tumor growth inhibition (TGI) when dosed at 2.5 mg/kg daily (qd), stasis when dosed 10 mg/kg qd, and ∼20% regression when dosed at 25 mg/kg qd in the RCC-43b model and ∼63% TGI, ∼89% TGI, ∼64% regression, and ∼96% regression in the RCC-47 model when dosed 0.5, 2.5, 10, and 25 mg/kg qd respectively. The standard of care for RCC, sunitinib, showed no activity in RCC-43b when dosed at 10 mg/kg qd (∼10% TGI, p&gt;0.05 vs vehicle) and ∼60% TGI when dosed at 80 mg/kg qd. Pharmacodynamic analysis of RCC-47 tumors revealed that two hours after an acute dose of AZD6094 pMET levels were reduced &gt;95% at all dose levels tested (0.5 - 25 mg/kg). Eight hours after dosing, pMET levels returned to ∼50% in the 0.5 and 2.5 mg/kg dose groups whereas pMET was still inhibited &gt;90% in the 10 and 25 mg/kg dose groups indicating that the duration of target inhibition was dose related. AZD6094 inhibited multiple signaling nodes including MAPK, PI3K, and EGFR. Finally, at doses that induced tumor regression, AZD6094 resulted in a dose and time dependent induction of cleaved PARP, a marker of cell death. The finding that lower, sub-optimal doses of AZD6094 showed return of pMET 8 hours after a single administration, raised the question whether splitting the dose over a longer duration would increase anti-tumor activity. Indeed, twice a day dosing (bid, 8;16 hours) of AZD6094 at 1.25 mg/kg was more efficacious than daily administration of 2.5 mg/kg resulting in 8% regression compared to 89% TGI (p&lt;0.05). Taken together, these data provide the first report testing therapeutics in preclinical in vivo models of PRCC and support the clinical development of AZD6094 in this indication.
Citation Format: Alwin Schuller, Evan Barry, Rhys Jones, Melanie Frigault, Garry Beran, Ryan Henry, David Linsenmayer, Maureen Hattersley, Aaron Smith, Joanne Wilson, Ammar Adam, Michael Zinda, Corinne Reimer, Stephen Fawell, Edwin Clark, Celina D'Cruz. Pharmacodynamic response and anti-tumor activity of the MET inhibitor AZD6094 in papillary renal cell carcinoma patient derived xenograft models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1477. doi:10.1158/1538-7445.AM2015-1477