A 56 year old woman was enrolled on a phase II trial to evaluate the efficacy of AZD6094 (HMPL-504) in patients with papillary renal cell carcinoma (PRCC) (NCT02127710) in September 2014. A diagnostic sample was collected from the patient in December 2012 during resections of several metastatic lesions to the abdominal lymph nodes. This archival tumor sample was analyzed by central pathology demonstrating high grade, poorly differentiated PRCC Type 2. The patient started savolitinib on 9/2/14. Prior systemic therapies included suntinib and cytokines with best response being progressive disease (PD) for both prior lines of therapies.
Next Generation Seqeuncing (NGS) of the diagnostic tumor sample (Foundation Medicine Inc, Cambridge, MA, USA) with a median exon coverage of 500x demonstrated the existence of a MET mutation MET_c.3583C > T with an allele fraction of 24%.
The amino acid substitution of L1195F is located in exon 18 within the kinase domain of the MET receptor tyrosine kinase and has been previously reported in papillary renal carcinoma patients (Schmidt et al Nature Genetics 1997, Albiges et al CCR 2014). We demonstrate for the first time that this MET L1195F mutant is actionable. MET L1195F is predicted as an activating mutation (PolyPhen and SIFT) and is phosphorylated in vitro when overexpressed demonstrating the activation of MET. The MET L1195F mutant is demonstrated to be sensitive to savolitinib, a selective and potent MET inhibitor.
Athough MET L1195F confers tumor control and benefit from savolitinb, after 36 weeks of treatment and 29.7% best tumor shrinkage from the baseline tumor measurement, the patient in which we found this mutation unfortunately relapsed and died shortly after. Plasma samples were collected from this subject prior to treatment, during the course of savolitinib treatment and upon relapse. NGS analysis of circulating tumor DNA (ctDNA) isolated from plasma can be used to monitor for emerging mechanisms of resistance to treatment. Characterization of the mechanisms of resistance to savolitinib will provide rationale for the management of such patients going forward.
Clinical trial identification
Legal entity responsible for the study
M.M. Frigault, D. Stetson, E. Maloney, E. Barry, B. Dougherty, J.C. Barrett, C. D'Cruz: Employed by AstraZeneca. All other authors have declared no conflicts of interest.