The MET/VEGFR inhibitor foretinib induces tumor reduction and partial responses in PRCC.
Major finding: The MET/VEGFR inhibitor foretinib induces tumor reduction and partial responses in PRCC.
Approach: Patients enrolled in a phase II trial were stratified retrospectively by MET mutation type.
Impact: Foretinib may be particularly effective in PRCC associated with germline MET mutations.
Papillary renal cell carcinoma (PRCC) is the most common type of non-clear cell RCC, accounting for 10 to 15% of RCC cases overall. Activating germline mutations of MET, encoding the hepatocyte growth factor receptor tyrosine kinase, are associated with hereditary PRCC and occur in approximately 10% of sporadic PRCCs. Widespread or focal gain of chromosome 7, including the MET locus, is also found in the vast majority of sporadic PRCCs, providing additional rationale for the evaluation of MET inhibitors in PRCC. Choueiri and colleagues conducted a multicenter, nonrandomized, open-label phase II trial of foretinib, an oral multikinase inhibitor primarily targeting MET and VEGF receptors (VEGFR), in 74 patients with hereditary or sporadic PRCC. Of the enrolled patients, 67 were also stratified retrospectively based on their MET mutational status. The primary endpoint was an overall response rate of 25%, and safety, progression-free survival, and overall survival were also evaluated. Partial responses were observed in 10 patients (13.5%), and 50 of 68 (73.5%) evaluable patients experienced tumor reduction. The overall median progression-free survival was 9.3 months, and the median overall survival had not yet been reached after 1 year. Strikingly, the presence of a germline MET mutation was specifically and highly predictive of a response, with 5 of 10 patients (50%) harboring germline mutations experiencing a partial response compared with 5 of 57 (8.8%) lacking a germline mutation. Only 1 of 5 patients with a somatic mutation and 1 of 18 patients with chromosome 7 gain had partial responses. The most common adverse events were manageable and similar to those seen with anti-VEGFR therapy, including hypertension, diarrhea, fatigue, and nonfatal pulmonary emboli. Although this trial failed to meet its primary endpoint, other clinical end points suggest that foretinib possesses antitumor activity, particularly in hereditary PRCC associated with germline MET mutations.