Radium-223 dichloride in Combination with Vascular Endothelial Growth Factor-Targeting Therapy in Advanced Renal Cell Carcinoma with Bone Metastases

Purpose: This study investigates the biologic activity of radium-223 with vascular endothelial growth factor (VEGF)-targeted therapy in patients with advanced renal cell carcinoma (aRCC) and bone metastases. Experimental Design: Fifteen treatment-naïve patients (n=15) received pazopanib 800 mg orally once-daily and 15 previously-treated patients received sorafenib 400 mg orally twice-daily. Radium-223 55 kilobecquerel/kg was administered concurrently every four weeks for up to 6 infusions in both cohorts. The primary endpoint was decline in bone turnover markers (Procollagen I Intact N-Terminal, N-telopeptide, C-telopeptide, osteocalcin and bone-specific alkaline phosphatase) compared to baseline. Secondary endpoints included safety, rate of symptomatic-skeletal event (SSE) and time to first SSE, objective response rate, change in analgesic use and quality of life. Exploratory analysis of tumor genomic alterations was performed. Results: Of the 30 patients enrolled, 83% had IMDC intermediate- or poor-risk disease, 33% had liver metastases and 83% had a history of SSE prior to enrolment. No dose-limiting toxicity was observed. All bone turnover markers significantly declined from baseline at week 8 and 16. Forty percent of patients experienced treatment-related grade ≥3 adverse events. Response rates were 15% and 18% per RECIST v1.1 and bone response was 50% and 30% per MD Anderson criteria, in the pazopanib and sorafenib cohort, respectively. Median SSE-free interval was 5.8 months and not reached, respectively. Analgesic use remained stable over the study time. Conclusions: Radium-223 combined with VEGF-targeted therapy is biologically active and safe. Randomized-controlled trials are needed to define the role of radium-223 in aRCC with skeletal metastases. NCT02406521

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