cMet: Results in papillary renal cell carcinoma of a phase I study of AZD6094/volitinib leading to a phase 2 clinical trial with AZD6094/volitinib in patients with advanced papillary renal cell cancer (PRCC).

487 Background: Met is a receptor tyrosine kinase that is deregulated across multiple cancer types, leading to uncontrolled tumor cell growth, invasion and survival. MET is frequently dysregulated in PRCC. Activating Met mutations are present in hereditary and a subset of sporadic PRCC cases (up to 21% of type I PRCC, Albiges et al, 2014). Trisomy of chromosome 7 (containing both MET and HGF genes) has been reported in 45-75% of sporadic PRCC cases; 81% of type I and 46% of type II PRCC have copy number alterations of MET (Albiges et al, 2014). Methods: AZD6094 (HMPL-504/volitinib) is a potent, selective Met inhibitor. Preclinically, AZD6094 inhibits in vitro growth of MET-amplified gastric and lung cell lines. In vivo AZD6094 induces regressions in PRCC explant models. Results: In phase I, AZD6094 was well tolerated, with good exposure and low accumulation (Gan et al, 2014). Two PRCC pts in the 600 mg QD cohort (one with ongoing treatment at 19 months) and 1 PRCC in the 1,000 mg QD cohort (ongoing treatment at 13 months) achieved PR. A fourth patient, on 300 mg BD, showed a best tumor response of 25% decrease from baseline. Analysis of tumor samples showed that all the responders had MET copy number increase. Conclusions: These encouraging findings have triggered a phase II trial. This is an open label non-randomised multi-centre study to assess the efficacy of AZD6094 monotherapy in treatment naive and previously treated PRCC patients. Eligibility includes PRCC histopathology, ECOG status 0 or 1, ability to comply with the collection of tumor samples, adequate haematological, liver, and kidney function, and measurable disease (RECIST 1.1). The study is ongoing in collaboration with Sarah Cannon Research Institute in the United States, Canadian, EU centres. This study is sponsored by AstraZeneca, clinical trial information: NCT02127710. Clinical trial information: NCT01773018.