SAMETA: A Phase III study of savolitinib + durvalumab vs sunitinib and durvalumab monotherapy in patients with MET-driven, unresectable, locally advanced/metastatic papillary renal cell carcinoma

Abstract Background Papillary renal cell carcinoma (PRCC) is the most common subtype of non-clear cell renal cell carcinoma (RCC) and accounts for 10–15% of RCCs. Many PRCC cases are MET-driven, characterized by genomic abnormalities resulting in dysregulation of the MET signaling pathway, making these abnormalities a potential therapeutic target for treatment. The estimated prevalence of MET-driven status is 35−40% in PRCC. Savolitinib is an oral, potent and highly selective MET tyrosine-kinase inhibitor (TKI) demonstrating preliminary clinical activity in advanced solid tumors, including in MET-driven PRCC, defined as presence of any of the following molecular alterations, in the absence of co-occurring fumarate hydratase mutations: chromosome 7 gain, MET amplification, MET kinase domain variations, or hepatocyte growth factor amplification. In the Phase III SAVOIR study, in PRCC, savolitinib monotherapy showed encouraging efficacy vs the multi-targeted TKI, sunitinib. In addition, non-clinical studies suggest a possible synergistic anti-tumor effect of MET-inhibitors and programmed cell death-ligand (PD-L1) inhibitors, such as durvalumab; emerging data from the Phase I/II CALYPSO study investigating savolitinib plus durvalumab shows a notable efficacy signal in patients with MET-driven PRCC. Following these findings, the SAMETA study (NCT05043090) is designed to evaluate the efficacy and safety of savolitinib in combination with durvalumab vs sunitinib and durvalumab monotherapy in PRCC. Trial Schema In this open-label, three-arm, multi-center, Phase III study, adult patients with unresectable, MET-driven and locally advanced/metastatic PRCC are eligible. An estimated 200 patients (25 countries, 165 centers) will be randomized in a 2:1:1 ratio into three treatment arms (A–C) with stratification by International metastatic RCC database consortium risk group & PD-L1 expression tumor status. Arm A: oral savolitinib 600 mg once daily plus intravenous durvalumab 1500 mg every 4 weeks; Arm B: oral sunitinib 50 mg once daily for 4 consecutive weeks, followed by a sunitinib-free interval of 2 weeks every 6 weeks; Arm C: intravenous durvalumab 1500 mg every 4 weeks. Study treatment continues until RECIST 1.1 disease progression, or another discontinuation criterion is met. The primary endpoint is progression-free survival (by Blinded Independent Central Review; Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints include overall survival, objective response rate and duration of response. Safety (adverse events, vital signs, echocardiograms, hematology and biochemistry parameters) will also be reported. Current status The first patient was enrolled onto the study on 28 October 2021. At the early enrollment stage, during the biomarker pre-screening, approximately 29% of patients with PRCC who submitted a sample had eligible MET-driven status and of these patients with MET-driven PRCC, approximately 84% also met other eligibility criteria and were randomized.