M. M. Frigault1, S. Signoretti2, A. Markovets3, D. Stetson3, W. Howat4, M. Roudier4, V. Haddad4, B. Dougherty3, T. K. Choueiri5, J. C. Barrett3;
1Acerta Pharma, Redwood City, MA, 2Brigham and Women’s Hosp., Boston, MA, 3AstraZeneca Pharmaceuticals LP, Waltham, MA, 4AstraZeneca Pharmaceuticals LP, Cambridge, United Kingdom, 5Dana-Farber Cancer Inst., Boston, MA
M.M. Frigault: ; AstraZeneca. S. Signoretti: None. A. Markovets: ; AstraZeneca. D. Stetson: ; AstraZeneca. W. Howat: ; AstraZeneca. M. Roudier: ; AstraZeneca. V. Haddad: ; AstraZeneca. B. Dougherty: ; AstraZeneca. ; AstraZeneca. T.K. Choueiri: ; Travel expenses (for Ad board); AstraZeneca. ; Travel expenses (for Ad board); Bayer. ; Travel expenses (for Ad board); BMS. ; Travel expenses (for Ad board); Cerulian. ; Travel expenses (for Ad board); Eisai. ; Exelixis. ; Travel expenses (for Ad board); Foundation Medicine Inc. ; Travel expenses (for Ad board); Genentech. ; Travel expenses (for Ad board); GSK. ; Travel expenses (for Ad board); Merck. J.C. Barrett: ; AstraZeneca. ; AstraZeneca.
There is no approved therapy specifically for the treatment of papillary renal cell carcinoma (PRCC). Advances in molecular profiling of PRCC have identified a segment of PRCC with 10% MET mutation rates (Linehan et al 2016). Chromosome 7 gain is a hallmark of PRCC and thought to occur at 50% frequency in PRCC (Jiang et al 1998). We undertook a retrospective analysis of archival tumors to evaluate MET pathway aberrations for correlation with efficacy in a phase II study of savolitinib (volitinib, AZD6094, HMPL-504) in patients with PRCC (NCT02127710). Archival diagnostic tumor samples were mandated for central confirmation of PRCC diagnosis, histological subtyping, and for exploratory biomarker analysis. Eighty-four archival tumors were obtained and profiled using four methods: H&E stain for PRCC histological subtype, immunohistochemistry (IHC) for c-Met protein expression (Ventana, CONFIRM), fluorescent in situ hybridization (FISH) for MET gene amplification (Abbott, VYSIS), and Next Generation Sequencing (NGS) as an orthogonal method for confirmation of MET amplifications, detection of HGF gene amplifications, MET mutations, chromosome 7 ploidy, and other exploratory genomic biomarkers (Foundation Medicine Inc., T7 panel). Eight patients with a confirmed partial response (PR) to savolitinib were used to define MET-driven PRCC. Retrospective analysis demonstrated that only NGS, not IHC, FISH or histological subtype, identified all PRs. NGS detected any one of the following biomarkers alone or in combination in PRs: chromosome 7 copy number gain, MET or HGF gene focal amplification, MET kinase domain mutations. The frequency of these biomarkers in the phase II population were 31.5%, 10%, 1%, and 7.5%, respectively and captured all responders (18% ORR); however, 42% of non-responders (PD and SD) were also classified as MET-driven by NGS. Focal MET amplifications were confirmed with MET FISH testing, but FISH was unable to identify gains in chromosome 7. IHC was not as sensitive as NGS (57% vs 100%) but had a higher specificity. Molecular characterization of MET status was more predictive of response to savolitinib than a classification based on pathology.