By Dr. Inas Abuali
Massachusetts General Hospital
There is a paucity of available treatment options for patients with advanced papillary renal cancer (PRC), a disease characterized by aggressive features and a poor prognosis. Currently available therapeutic options are vascular endothelial growth factor (VEGF)–targeted therapies, with confirmed response rates (cRRs) of around 20%. Deoxyribonucleic acid (DNA) alterations to mesenchymal epithelial transition receptors (METs) occur in approximately 30% of patients with PRC. Preclinical data suggest a potentially positive interaction between MET and programmed cell death ligand-1 (PD-L1) inhibition. The single-arm phase II CALYPSO trial tested this combination of a MET inhibitor (savolitinib: 600 mg daily) and a PD-L1 inhibitor (durvalumab: 1,500 mg every 4 weeks) in advanced PRC. 50% was the primary endpoint [1]. Progression-free survival, tolerability, and overall survival were secondary endpoints. Biomarkers were explored from archived tissue (MET-driven status).
41 patients with advanced PRC were enrolled in this study; 63% of whom were Heng intermediate risk score. The cRR was 29% and the trial missed the primary endpoint. The cRR, however, increased to 53% in MET-driven patients and 33% in PD-L1–positive tumors. The median progression-free survival was 4.9 months in the treated population and 12 months in MET-driven patients. The median overall survival was 14.1 months in the treated population and 27.4 months in MET-driven patients. Grade 3 and above treatment-related adverse events occurred in 17 (41%) patients. There was one grade 5 treatment-related adverse event (cerebral infarction).
Although the combination did not reach its primary response endpoint in the treated population, the cRR in MET-driven patients was promising and noted across different efficacy parameters, such as PFS, OS, and duration of response.
This study demonstrated that the combination of savolitinib and durvalumab was tolerable and associated with high cRRs in the exploratory MET-driven subset. SAMETA, a large, ongoing randomized phase III trial (ClinicalTrials.gov identifier: NCT05043090) is formally testing the combination in MET-driven individuals, which may herald a new era of personalized combination therapy in PRC.
References:
- Suárez C, Larkin JMG, Patel P, et al. Phase II study investigating the safety and efficacy of savolitinib and durvalumab in metastatic papillary renal cancer (CALYPSO). J Clin Oncol. Published online February 21, 2023. doi:10.1200/JCO.22.01414
