RAD001 and zoledronic acid in renal cell carcinoma patients with bone metastases (RAZOR): A randomized phase II trial.
e15054 Background: Bone metastases (BM) from renal cell carcinoma (RCC) are common, cause major morbidity and have been identified as an adverse prognostic feature. Previous trials have not assessed the effects of modern therapies on BM from RCC. Randomized data has demonstrated that zoledronic acid (ZOL) reduces skeletal-related-events (SRE’s) in RCC patients (pts). Bone turnover markers can identify pts at risk of SREs among those receiving ZOL. We sought to evaluate the effect on BM of RAD001 (everolimus) alone compared to RAD001 plus ZOL in the first-line setting. Methods: 30 treatment naïve pts with RCC and ≥ 1 BM were randomized 1:1 to RAD001 10mg daily (Arm A) vs. RAD001 + ZOL 4mg IV 4-weekly (dose adjusted for creatinine clearance [CrCl], Arm B). Key eligibility criteria were ECOG PS ≤ 2, no bisphosphonates or radiotherapy within 4 weeks and CrCl >35ml/min. Bone-specific assessments were performed at baseline, weeks 1,4,8 and12. Treatment was continued on the allocated arm until progression (RECIST 1.1). The primary objective was to assess the difference in bone turnover markers over the first 12-weeks. The primary endpoint was urine N-telopeptide (uNTX) levels with plasma C-telopeptide (CTX) being secondary. Secondary objectives include comparison of quality of life (QoL) and pain (FACT-BP, BPI scores), SREs, safety and efficacy (PFS, RR). Results: Heng prognostic group was poor, intermediate and favorable-risk in; 40.0%, 46.7%, 13.3% respectively in Arm A and 20.0%, 46.7%, 33.3% (Arm B). 53.3% (Arm A) and 60.0% (Arm B) of pts had prior nephrectomy. Over the first 12 weeks, the reduction in mean CTX on Arm B relative to Arm A was 77% (95% CI (68%, 83%); p<0.0001). Median PFS was 7.5mo (95% CI 3.5, 14.7) in Arm B and 5.5mo (95% CI 3.2, 7.2) in Arm A (p=0.11). Data on uNTX, QoL and SREs will be presented. At data cut off, 8 pts in Arm B had stopped ZOL before progression with either a drop in CrCl or hypocalcaemia. No cases of osteonecrosis of the jaw were seen. Conclusions: The addition of ZOL to RAD001 significantly reduced the bone resorption marker CTX in this treatment-naïve RCC population of pts with the adverse prognostic feature of BM.