Abstract
Purpose Patients with advanced papillary renal cell carcinoma (PRCC) have limited therapeutic options. PRCC may involve activation of the MET pathway, for example, through gene amplification or mutations. Savolitinib (AZD6094, HMPL-504, volitinib) is a highly selective MET tyrosine kinase inhibitor. We report results of a single-arm, multicenter, phase II study evaluating the safety and efficacy of savolitinib in patients with PRCC according to MET status. Patients and Methods Patients with histologically confirmed locally advanced or metastatic PRCC were enrolled and received savolitinib 600 mg orally once daily. MET-driven PRCC was defined as any of the following: chromosome 7 copy gain, focal MET or HGF gene amplification, or MET kinase domain mutations. Efficacy was assessed according to MET status. Safety, toxicity, and patient-reported health-related quality-of-life outcomes were assessed in all patients. Results Of 109 patients treated, PRCC was MET driven in 44 (40%) and MET independent in 46 (42%); MET status was unknown in 19 (17%). MET-driven PRCC was strongly associated with response; there were eight confirmed partial responders with MET-driven disease (18%), but none with MET-independent disease ( P = .002). Median progression-free survival for patients with MET-driven and MET-independent PRCC was 6.2 months (95% CI, 4.1 to 7.0 months) and 1.4 months (95% CI, 1.4 to 2.7 months), respectively (hazard ratio, 0.33; 95% CI, 0.20 to 0.52; log-rank P < .001). The most frequent adverse events associated with savolitinib were nausea, fatigue, vomiting, and peripheral edema. Conclusion These data show activity and tolerability of savolitinib in the subgroup of patients with MET-driven PRCC. Furthermore, molecular characterization of MET status was more predictive of response to savolitinib than a classification based on pathology. These findings justify investigating savolitinib in MET-driven PRCC.
Highlights
Renal cell carcinoma (RCC) is a heterogeneous disease comprising several histologic subtypes with different genetic and biochemical characteristics; clear cell RCC is the most frequent, accounting for 75% to 90% of renal malignancies.[1]
Median progression-free survival for patients with MET-driven and MET-independent papillary RCC (PRCC) was 6.2 months and 1.4 months, respectively
Molecular characterization of MET status was more predictive of response to savolitinib than a classification based on pathology
Summary
Renal cell carcinoma (RCC) is a heterogeneous disease comprising several histologic subtypes with different genetic and biochemical characteristics; clear cell RCC is the most frequent, accounting for 75% to 90% of renal malignancies.[1] Of the non–clear cell renal carcinomas, papillary RCC (PRCC) is the most common, with a recent study of patients with metastatic non– clear cell RCC reporting 40% as papillary by histology, followed by chromophobe RCC (# 5%) and other less common subtypes.[1,2,3] In 2017, it is estimated 64,000 new cases of RCC will be diagnosed in the United States, equating to up to 6,400 cases of PRCC.[4]. Somatic PRCC is conventionally classified into two histologic subtypes (type 1 and type 2), with a worse prognosis reported for type 2.5-9 Molecular profiling of PRCC corroborates disease linkage demonstrated by studying rare hereditary syndromes that lead to RCC. Two recent cohorts of molecular analyses of PRCC have confirmed the utility of molecular features to reclassify this disease.[11,12]
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