Everolimus and zoledronic acid in patients with renal cell carcinoma with bone metastases: a randomized first-line phase II trial

Clin Genitourin Cancer. 2015 Feb;13(1):50-8. doi: 10.1016/j.clgc.2014.07.002. Epub 2014 Jul 15.

Abstract

Background: Bone metastases from renal cell carcinoma (RCC) are a major cause of morbidity. Post hoc analysis has suggested that bone turnover markers can identify patients at risk of skeletal-related events (SREs) among those receiving zoledronic acid. This study sought to evaluate the effect on bone metastases of everolimus alone compared with everolimus plus zoledronic acid.

Patients and methods: Thirty treatment-naive patients with RCC and ≥ 1 bone metastases were randomized 1:1 to everolimus (10 mg daily) versus everolimus plus zoledronic acid (4 mg intravenously 4-weekly). Bone-specific assessments were performed at baseline and at weeks 1, 4, 8, and 12. Treatment was continued on allocated arm until progression per RECIST 1.1 (Response Evaluation Criteria in Solid Tumors, version 1.1). The primary outcome measure was urine N-telopeptide (uNTX) level, with secondary measures of plasma C-telopeptide (CTX), quality of life (Functional Assessment of Cancer Therapy-Bone Pain [FACT-BP], Brief Pain Inventory [BPI]), progression-free survival (PFS), SREs, and safety.

Results: After 12 weeks, reduction in mean uNTX and CTX on everolimus plus zoledronic acid relative to everolimus was 68.4% (95% CI, 60.1%-74.9%; P < .0001) and 76.2% (95% CI, 67.3%-82.7%; P < .0001), respectively. There was no evidence of a difference for FACT-BP (P = .5), but evidence was favorable for BPI Severity (P = .05) and BPI Interference (P = .06). Median PFS was 7.5 months (95% CI, 3.4-11.2) on everolimus plus zoledronic acid and 5.4 months (95% CI, 3.2-6.3) on everolimus (P = .009). Median time to first SRE was 9.6 months (95% CI, 4.3-15.5) on everolimus plus zoledronic acid and 5.2 months (95% CI, 1.6-8.2) on everolimus (P = .03).

Conclusion: In this RCC population, the addition of zoledronic acid to everolimus significantly reduced bone resorption markers and may prolong tumor control.

Keywords: Bisphosphonates; Neoplasm metastasis; Randomized controlled trial; Skeletal-related events; Targeted therapy.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Bone Density Conservation Agents / administration & dosage*
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / secondary
  • Carcinoma, Renal Cell / blood
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / urine
  • Collagen Type I / blood
  • Collagen Type I / urine
  • Diphosphonates / administration & dosage*
  • Everolimus
  • Female
  • Humans
  • Imidazoles / administration & dosage*
  • Kidney Neoplasms / blood
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / urine
  • Male
  • Middle Aged
  • Peptides / blood
  • Peptides / urine
  • Prospective Studies
  • Sirolimus / administration & dosage
  • Sirolimus / analogs & derivatives*
  • Treatment Outcome
  • Zoledronic Acid

Substances

  • Antineoplastic Agents
  • Bone Density Conservation Agents
  • Collagen Type I
  • Diphosphonates
  • Imidazoles
  • Peptides
  • collagen type I trimeric cross-linked peptide
  • Zoledronic Acid
  • Everolimus
  • Sirolimus

Associated data

  • ANZCTR/ACTRN12609000980235