A randomized trial of denosumab (AMG 162) versus intravenous (IV) bisphosphonates (BP) in cancer patients (pts) with bone metastases (BM) on established IV BP and evidence of elevated bone resorption.
A randomized trial of denosumab (AMG 162) versus intravenous (IV) bisphosphonates (BP) in cancer patients (pts) with bone metastases (BM) on established IV BP and evidence of elevated bone resorption.
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一项针对骨转移 (BM) 癌症患者 (pts) 进行的狄诺塞麦 (AMG 162) 与静脉注射 (IV) 双磷酸盐 (BP) 对比的随机试验，其中有确定的 IV BP 和骨吸收升高的证据。
DOI：
10.1200/jco.2006.24.18_suppl.8562
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
A. Lipton
中科院分区：
文献类型：
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作者：
T. Suarez;K. Fizazi;Y. Rahim;J. Wilson;M. Fan;S. Jun;A. Lipton
8562背景：骨吸收标志物（尤其是尿N-端肽（uNTx））升高的已建立（≥ 8周）IV BP患者发生骨骼相关事件的风险增加（科尔曼，J Clin Oncol 2005）。Denosumab是一种全人源单克隆抗体，通过结合和中和RANK配体（破骨细胞分化和功能的关键介质）来抑制骨细胞骨吸收。在一项II期、随机化、开放标签、活性对照研究中，在尽管接受了既定IV BP治疗但BM和uNTX水平升高的晚期癌症患者中评价了Denosumab的疗效和安全性。我们报告了第13周对49例患者进行中期分析的初步结果。
方法
合格的患者（≥18岁，患有实体瘤[肺除外]或多发性骨髓瘤[MM];确诊的BM;筛选uNTx > 50 nM BCE/mM肌酐[Cr];随机化前接受IV BP ≥ 8周）按基线uNTx（50-100，>100）和肿瘤类型分层。将患者随机分配至3个治疗组之一：IV BP每4周一次（Q4 W）或180 mg地舒单抗皮下给药Q4 W或Q12 W。主要终点是第13周时uNTx < 50 nM BCE/mM Cr的患者比例（%）。入组正在进行中（计划N = 135）。
结果
分析中所有患者的平均（范围）年龄（地舒单抗组33例; BP组16例）为62.5（39，81）岁; 96%的BM> 2。既往IV BP（主要是唑来膦酸）的中位时间为5.1个月。肿瘤包括前列腺（n = 24）、乳腺（n = 20）、其他/MM（n = 5）。Denosumab组（合并组）第13周uNTx < 50 nM BCE/mM Cr的患者百分比高于IV BP组：分别为76%（95% CI：60.3，91.2）vs 38%（95% CI：18.5，61.4; P = 0.015 Cochran-Mantel-Haenzel）。未报告治疗相关严重不良事件（SAE）。地舒单抗组中经常报告的AE包括恶心、外周水肿、贫血、骨痛和便秘。在数据截止日期，研究期间发生了10例死亡（6/33例地舒单抗，4/16例BP）。
结论
这些中期数据表明，在所有肿瘤类型中，尽管IV BP治疗8周，但在uNTx升高的患者中，地舒单抗使uNTx正常化的频率高于IV BP。地舒单抗的AE特征似乎与接受治疗的癌症患者相似。[表：见正文]。
8562 Background: Pts on established (≥ 8 weeks) IV BP who have elevated bone resorption markers, especially urinary N-telopeptide (uNTx), are at increased risk for skeletal related events (Coleman, J Clin Oncol 2005). Denosumab, a fully human monoclonal antibody, inhibits osteoclastic bone resorption by binding and neutralizing RANK ligand, a key mediator of osteoclast differentiation and function. Denosumab efficacy and safety were evaluated in a phase 2, randomized, open label, active-controlled study in advanced cancer pts with BM and elevated levels of uNTX despite established IV BP therapy. We report preliminary results from an interim analysis of 49 pts at week 13.
METHODS
Eligible pts (≥18 yrs old with solid tumor [except lung] or multiple myeloma [MM]; confirmed BM; screening uNTx > 50 nM BCE/mM creatinine [Cr]; on IV BP for ≥ 8 weeks before randomization) are stratified by baseline uNTx (50-100, >100) and tumor type. Pts are randomized to 1 of 3 arms: IV BP every 4 weeks (Q4W) or 180 mg denosumab given subcutaneously Q4W or Q12W. The primary endpoint is the proportion (%) of pts with uNTx < 50 nM BCE/mM Cr at week 13. Enrollment is ongoing (planned N = 135).
RESULTS
The mean (range) age of all pts in the analysis (33 denosumab; 16 BP) was 62.5 (39, 81) yrs; 96% had > 2 BM. The median time on prior IV BP (mostly zoledronic acid) was 5.1 months. Tumors included prostate (n = 24), breast (n = 20), other/MM (n = 5). The % of pts with uNTx < 50 nM BCE/mM Cr at week 13 was greater with denosumab (pooled arms) than IV BP: 76% (95% CI: 60.3, 91.2) vs 38% (95% CI: 18.5, 61.4; P = .015 Cochran-Mantel-Haenzel), respectively. No treatment-related serious adverse events (SAEs) were reported. Commonly reported AEs in the denosumab arms included nausea, peripheral edema, anemia, bone pain, and constipation. At data cutoff, 10 deaths (6/33 denosumab, 4/16 BP) had occurred on-study.
CONCLUSIONS
These interim data suggest that denosumab normalizes uNTx more frequently than IV BP in pts with elevated uNTx despite 8 weeks of IV BP, across all tumor types. The AE profile of denosumab appeared similar to that of cancer pts undergoing treatment. [Table: see text].