The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces Regression in Papillary Renal Cell Carcinoma Patient–Derived Xenograft Models

Abstract

Purpose: Papillary renal cell carcinoma (PRCC) is the second most common cancer of the kidney and carries a poor prognosis for patients with nonlocalized disease. The HGF receptor MET plays a central role in PRCC and aberrations, either through mutation, copy number gain, or trisomy of chromosome 7 occurring in the majority of cases. The development of effective therapies in PRCC has been hampered in part by a lack of available preclinical models. We determined the pharmacodynamic and antitumor response of the selective MET inhibitor AZD6094 in two PRCC patient-derived xenograft (PDX) models.Experimental Design: Two PRCC PDX models were identified and MET mutation status and copy number determined. Pharmacodynamic and antitumor activity of AZD6094 was tested using a dose response up to 25 mg/kg daily, representing clinically achievable exposures, and compared with the activity of the RCC standard-of-care sunitinib (in RCC43b) or the multikinase inhibitor crizotinib (in RCC47).Results: AZD6094 treatment resulted in tumor regressions, whereas sunitinib or crizotinib resulted in unsustained growth inhibition. Pharmacodynamic analysis of tumors revealed that AZD6094 could robustly suppress pMET and 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 doseand time-dependent induction of cleaved PARP, a marker of cell death.Conclusions: Data presented provide the first report testing therapeutics in preclinical in vivo models of PRCC and support the clinical development of AZD6094 in this indication.

MET expression and copy number status in clear-cell renal cell carcinoma: prognostic value and potential predictive marker

“…Several compounds including small-molecule TKIs, monoclonal antibodies, and anti-HGF compounds are available for selective inhibition of MET signaling [48, 49] or inhibition of MET in combination with vascular endothelial growth factor receptor (VEGFR) [32, 50] and are already tested in preclinical and clinical trials [51], making anti-MET therapy a near-term feasible treatment option.…”

Acquired METD1228V Mutation and Resistance to MET Inhibition in Lung Cancer

“…Here, we describe a patient with metastatic NSCLC with MET-mediated resistance to EGFR TKI who responded to treatment with a type I MET inhibitor, savolitinib (11), given in combination with a third-generation EGFR inhibitor, osimertinib (2). The patient then developed acquired resistance mediated by a novel MET kinase domain mutation.…”

PD-L1 expression in papillary renal cell carcinoma

“…Although patients with sporadic RCC of any histological subtype usually show a good clinical outcome, patients with metastatic pRCC show a significantly worse clinical course than patients with ccRCC or chromophobe RCC [2–4]. Recent findings have indicated that MET gene　activation, which is known to promote proliferative activity and cell survival, is frequently observed in pRCC, and MET inhibitors have become a new type of therapeutic agent for patients with advanced pRCC [5, 6]. …”