Biomarker-Based Phase II Trial of Savolitinib in Patients With Advanced Papillary Renal Cell Cancer

Abstract
Purpose
Patients with advanced papillary renal cell carcinoma (PRCC) face limited treatment options. PRCC may involve activation of the MET pathway through mechanisms such as gene amplification or mutations. Savolitinib (AZD6094, HMPL-504, volitinib) is a highly selective MET tyrosine kinase inhibitor. This single-arm, multicenter, phase II study evaluates the safety and efficacy of savolitinib in PRCC patients based on their MET status.

Patients and Methods
Patients with histologically confirmed locally advanced or metastatic PRCC were enrolled to receive savolitinib 600 mg orally once daily. MET-driven PRCC was defined by the presence of chromosome 7 copy gain, focal MET or HGF gene amplification, or MET kinase domain mutations. Efficacy was assessed based on MET status, while safety, toxicity, and health-related quality-of-life outcomes were evaluated in all participants.

Results
Of the 109 patients treated, 44 (40%) had MET-driven PRCC, 46 (42%) had MET-independent disease, and 19 (17%) had unknown MET status. MET-driven PRCC was strongly associated with treatment response, with eight confirmed partial responses (18%) in MET-driven cases and none in MET-independent cases (P = .002). Median progression-free survival (PFS) was 6.2 months (95% CI, 4.1–7.0) for MET-driven PRCC and 1.4 months (95% CI, 1.4–2.7) for MET-independent PRCC (hazard ratio, 0.33; 95% CI, 0.20–0.52; log-rank P < .001). Common adverse events included nausea, fatigue, vomiting, and peripheral edema.

Conclusion
Savolitinib demonstrated efficacy and tolerability in patients with MET-driven PRCC. Molecular characterization of MET status proved to be a stronger predictor of response to savolitinib than histopathological AZD6094 classification. These findings support further investigation of savolitinib in MET-driven PRCC.