The addition of radium-223, an alpha-emitting bone-seeking radioisotope, to cabozantinib, a tyrosine kinase inhibitor, did not improve skeletal-related outcomes in patients with metastatic renal cell carcinoma and bone metastases, according to findings from the randomized phase II RADICAL trial (Alliance A031801) published in the Journal of Clinical Oncology.
Median overall survival did favor the combination arm, though, and the regimen did show a manageable safety profile.
“RADICAL is the first randomized trial of a radiopharmaceutical in kidney cancer, and it tells us several important things,” said lead author Rana R. McKay, MD, Professor of Medicine at UC San Diego Health and principal investigator for the study. “Skeletal complications were low across the board, which speaks to the effectiveness of modern bone-protective care, that in itself is reassuring news for patients.
"Radium-223 did not further reduce skeletal complications, but we did see numerically longer survival with the combination of radium-223 and cabozantinib. This finding is hypothesis-generating and needs further investigation. Together with a tolerable side-effect profile showing these agents can be safely combined, it tells us that radiopharmaceuticals deserve continued, careful study in kidney cancer.”
Study Methods
The phase II RADICAL trial explored the use of a radiopharmaceutical in combination with cabozantinib in patients with metastatic renal cell carcinoma and bone metastases. The study enrolled patients with metastatic renal cell carcinoma of any histology and at least one bone metastasis.
Patients were randomly assigned 1:1 to receive either cabozantinib with radium-223 or cabozantinib monotherapy; they were stratified by osteoclast-targeted therapy, prior therapy, opioid use, and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk.
The primary end point was symptomatic skeletal event–free survival, and secondary endpoints included safety, objective response rate, progression-free survival, and overall survival.
The study was designed with a target of 124 evaluable patients for the analysis and an interim futility analysis at 50% of expected symptomatic skeletal event–free survival events, whereby the trial would then stop if the stratified hazard ratio (sHR) was above 1.0.
Key Findings
The prespecified interim analysis was conducted after 90 were enrolled and had crossed the futility boundary. The study was closed after 98 patients were enrolled after showing that radium-223 was unlikely to significantly impact the primary endpoint.
Patients were followed for a median of 13.1 months.
Median symptomatic skeletal event–free survival for the combination regimen was 16.7 months vs 7.6 months for cabozantinib monotherapy (stratified hazard ratio [sHR] = 1.46; 90% confidence interval [CI] = 0.86–2.51).
Median overall survival was 28.3 months with cabozantinib plus radium-223 vs 19.7 months with cabozantinib alone (sHR = 1.40; 95% CI = 0.70–2.79), which was considered hypothesis-generating because overall survival was a secondary endpoint. The objective response rate was 19.4% with the combination vs 25% with monotherapy (P = .78).
The rate of grade 3 or higher adverse events was similar between the two arms (69.6% vs 75.5%).
DISCLOSURES: The RadiCaL trial was sponsored by National Cancer Institute (NCI) and conducted by the Alliance for Clinical Trials in Oncology. For full disclosures of the study authors, visit ascopubs.org.
