Effects of denosumab in patients with bone metastases with and without previous bisphosphonate exposure
Tóm tắt
Bone metastases place patients at increased risk of skeletal-related events (SREs), including pathologic fractures, spinal cord compression, severe pain requiring radiotherapy or surgery, and hypercalcemia, because of increased osteoclast-mediated bone resorption. Denosumab, a fully human monoclonal antibody, decreases bone resorption by inhibiting RANKL, which mediates osteoclast activity. We compared the effects of denosumab in two phase 2 studies in patients with bone metastases naive to intravenous bisphosphonate therapy (IV BP; n = 255) and those with elevated levels of the bone resorption marker urinary N-telopeptide (uNTX) despite ongoing IV BP treatment (n = 111). Patients were randomized to receive IV BP every 4 weeks or subcutaneous denosumab every 4 weeks (30/120/180 mg) or every 12 weeks (60/180 mg). Patients treated with denosumab experienced a rapid and sustained reduction in bone turnover regardless of prior IV BP exposure. After 25 weeks, the median uNTX reduction was 75% (IV BP-naive) and 80% (prior IV BP) after denosumab treatment and 71% (IV BP-naive) and 56% (prior IV BP) in the IV BP arms. Denosumab patients with prior IV BP exposure had marked suppression of the osteoclast marker TRAP-5b (median reduction: denosumab 73%, IV BP 11%). SRE incidence was low across both studies. In patients previously treated with BPs, the rate of first on-study SRE was lower in the denosumab groups (8%) than the IV BP group (17%). Denosumab appeared to be well tolerated in both studies. Denosumab suppresses bone resorption markers independently of prior BP treatment, even in patients who appear to respond poorly to BPs. © 2010 American Society for Bone and Mineral Research.
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Tài liệu tham khảo
Coleman, 1997, Skeletal complications of malignancy, Cancer, 80, 1588, 10.1002/(SICI)1097-0142(19971015)80:8+<1588::AID-CNCR9>3.0.CO;2-G
Coleman, 1998, Clinical course and prognostic factors following bone recurrence from breast cancer, Br J Cancer, 77, 336, 10.1038/bjc.1998.52
Aapro, 2008, Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel, Ann Oncol, 19, 420, 10.1093/annonc/mdm442
Rosen, 2004, Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial, Cancer, 100, 2613, 10.1002/cncr.20308
Rosen, 2004, Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion, Cancer, 100, 36, 10.1002/cncr.11892
Saad, 2004, Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer, J Natl Cancer Inst, 96, 879, 10.1093/jnci/djh141
Fuller, 1998, TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts, J Exp Med, 188, 997, 10.1084/jem.188.5.997
Lacey, 2000, Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo, Am J Pathol, 157, 435, 10.1016/S0002-9440(10)64556-7
Lacey, 1998, Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation, Cell, 93, 165, 10.1016/S0092-8674(00)81569-X
Bekker, 2004, A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women, J Bone Miner Res, 19, 1059, 10.1359/JBMR.040305
Body, 2006, A study of the biological receptor activator of nuclear factor-κB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer, Clin Cancer Res, 12, 1221, 10.1158/1078-0432.CCR-05-1933
Ellis, 2008, Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer, J Clin Oncol, 26, 4875, 10.1200/JCO.2008.16.3832
Brown, 2005, Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors, J Natl Cancer Inst, 97, 59, 10.1093/jnci/dji002
Coleman, 2005, Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid, J Clin Oncol, 23, 4925, 10.1200/JCO.2005.06.091
Costa, 2002, Prospective evaluation of the peptide-bound collagen type I cross-links N-telopeptide and C-telopeptide in predicting bone metastases status, J Clin Oncol, 20, 850, 10.1200/JCO.2002.20.3.850
Lipton, 2007, Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases, J Clin Oncol, 25, 4431, 10.1200/JCO.2007.11.8604
Fizazi, 2009, A randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasm after intravenous bisphosphonates, J Clin Oncol, 27, 1564, 10.1200/JCO.2008.19.2146
Lipton, 2008, Extended efficacy and safety of denosumab in breast cancer patients with bone metastases not receiving prior bisphosphonate therapy, Clin Cancer Res, 14, 6690, 10.1158/1078-0432.CCR-07-5234
Morony, 2005, The inhibition of RANKL causes greater suppression of bone resorption and hypercalcemia compared with bisphosphonates in two models of humoral hypercalcemia of malignancy, Endocrinology, 146, 3235, 10.1210/en.2004-1583
Tometsko, 2006, RANKL inhibition causes a greater suppression of tumor-induced osteoclastogenesis than zoledronate treatment in vivo and RANKL rescues osteoclasts from zoledronate killing in vitro [Abstract M076 and Poster], Am Soc Bone Miner Res, 21, S346
Roudier, 2008, Histopathological assessment of prostate cancer bone osteoblastic metastases, J Urol, 180, 1154, 10.1016/j.juro.2008.04.140
Fizazi, 2009, A prospective phase II trial of consolidation docetaxel and samarium-153 in patients with bone metastases from castration-resistant prostate cancer, J Clin Oncol, 27, 2429, 10.1200/JCO.2008.18.9811