SAN ANTONIO (EGMN) – Denosumab proved superior to zoledronic acid in delaying or preventing complications from bone metastases in breast cancer patients in a large phase III clinical trial.
Denosumab also showed significantly less toxicity than zoledronic acid, the current standard treatment for bone metastases. Particularly noteworthy was the substantially lower rate of renal toxicity with denosumab; there is no need to monitor serum creatinine in patients on denosumab, unlike with the bisphosphonate, Dr. Alison Stopeck noted at the San Antonio Breast Cancer Symposium.
Denosumab is an investigational fully humanized monoclonal antibody targeting RANK ligand (RANKL), the primary mediator of osteoclast formation, function, and survival. Metastatic cancer cells stimulate RANKL activity, resulting in increased bone resorption and destruction, explained Dr. Stopeck of the University of Arizona Cancer Center, Tucson.
She reported on 2,046 breast cancer patients with confirmed bone metastases. Participants were randomized double-blind to denosumab at 120 mg given once monthly by subcutaneous injection or to 4 mg of zoledronic acid given intravenously on an individualized dosing schedule governed by serum creatinine level in accord with the product labeling.
The primary study end point was the time to the first on-study skeletal-related event (SRE), consisting of fracture, radiation to bone for pain control, surgery, or spinal cord compression. There was a highly significant (P =.0001) 18% relative risk reduction favoring denosumab. The median time to the first SRE was 26.5 months in the zoledronic acid arm; it has not yet been reached in the denosumab arm.
At 34 months of follow up, 30.7% of patients on denosumab and 36.5% on zoledronic acid had experienced at least one SRE, for a 16% relative reduction with the RANKL inhibitor. The difference between the two therapies grew in magnitude over time: The relative risk reduction favoring denosumab was 5.6% at 12 months and 11.5% at 18 months, Dr. Stopeck continued.
A total of 608 SREs occurred in the zoledronic acid group, compared with 474 with denosumab, a 23% reduction.
The time to experiencing moderate or severe pain was a secondary study outcome – and the most important end point of all from most patients’ perspectives. A score greater than 4 on the 11-point validated Brief Pain Inventory occurred for the first time at a median 64 days in the zoledronic acid group compared with 88 days in the denosumab arm, translating to a 23% advantage favoring the investigational agent (P = .009).
Flu-like acute phase reactions in conjunction with administration of therapy occurred in 27.3% of patients in the zoledronic acid arm compared with 10.4% on denosumab. Adverse events related to renal toxicity occurred in 8.5% of the zoledronic acid group and 4.9% with denosumab; severe renal toxicity occurred in 1.5% of the zoledronic acid-treated patients compared to 0.2% of those on denosumab.
Osteonecrosis of the jaw (ONJ) occurred in 1.4% of patients on zoledronic acid and a statistically similar 2.0% of those on denosumab. More than 80% of cases of ONJ were associated with dental extractions, poor oral hygiene, or use of a dental appliance.
Dr. Theresa Guise, professor of medicine at Indiana University, Indianapolis, commented that it wasn’t clear prior to this trial whether ONJ was an adverse event limited to bisphosphonate therapy. These data indicate that it is more globally a side effect associated with inhibiting bone resorption.
Dr. Stopeck said that, interestingly, some cases of ONJ in denosumab-treated patients have turned out to be reversible. She speculated that this may be a function of the monoclonal antibody’s limited duration of activity in bone, in contrast to the bisphosphonates, which remain present in bone for years.
There is great interest in testing denosumab in the adjuvant setting in patients with early stage breast cancer because of theoretic reasons that RANKL inhibition should curb development of breast cancer, according to Dr. Stopeck.
Asked how she’ll incorporate denosumab into her own clinical practice if the agent receives marketing approval for treatment of bone metastases, Dr. Stopeck replied, “I’m going to incorporate it rather quickly, assuming the price isn’t exorbitant, since it shows better efficacy, it’s easier to give by subcutaneous injection, I don’t have to monitor the serum creatinine, and it has less toxicity.”
In October the U.S. Food and Drug Administration held up Amgen’s application for marketing approval for denosumab pending more information. In an interview, a company spokesperson said Amgen plans to resubmit to the FDA, and file for marketing approval in Europe sometime in 2010, armed with these updated data from the breast cancer trial, the findings from another phase III trial involving patients with various solid organ cancers or multiple myeloma, and the results of a third phase III trial in men with prostate cancer, which is expected to report results in the first quarter of 2010. Collectively the three studies total roughly 6,000 cancer patients.
Dr. Stopeck serves as a consultant to Amgen and Novartis and is on the speakers bureau for Novartis, which markets zoledronic acid.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
圣安东尼奥(EGMN)——一项大规模III 期临床试验表明，在延迟或预防乳腺癌患者出现骨转移并发症方面，狄诺塞麦(denosumab)优于唑来膦酸。
在美国圣安东尼奥乳腺癌会议上，Alison Stopeck博士指出，狄诺塞麦的药物毒性也显著低于唑来膦酸，唑来膦酸是目前公认的骨转移标准治疗药物。尤其值得注意的是，狄诺塞麦治疗组肾毒性的发生率大大低于唑来膦酸治疗组；与双膦酸盐类药物不同，采用狄诺塞麦治疗则无需监测患者的血清肌酐水平。
美国亚利桑那大学癌症中心的Stopeck博士解释说，狄诺塞麦是一种研究中的新药，是以RANK 配体(RANKL)为靶点的完全人源性单克隆抗体，RANKL是破骨细胞形成、功能作用以及存活的主要调节因子。转移性癌细胞可刺激RANKL的活性，从而加快骨吸收与骨破坏。
该试验纳入了2,046例被确诊为乳腺癌骨转移的患者。试验采用了双盲法，将受试者随机分为两组，分别接受狄诺塞麦120 mg，皮下注射，每月1次；或唑来膦酸4 mg，静脉滴注，依照产品说明书，根据血清肌酐水平制定个性化的给药方案。
主要试验终点为试验期间出现首例与骨骼相关事件(SRE)的时间，这类事件包括骨折、需采用骨转移放射治疗以镇痛、手术治疗或脊髓受压。狄诺塞麦治疗组的相对风险下降18%，具有统计学意义(P = 0.0001)。唑来膦酸组出现首例SRE的中位时间为26.5个月，而狄诺塞麦组尚未达到这一终点。
Stopeck博士报告称，随访34个月后发现，狄诺塞麦组30.7%的患者以及唑来膦酸组36.5%的患者至少出现了1例SRE，作为RANKL抑制剂的狄诺塞麦使相对风险下降了16%。随着时间的推移，两个治疗组的差异逐渐扩大：12个月时狄诺塞麦组的相对风险下降5.6%，18个月时下降11.5%。
唑来膦酸组共出现了608例SRE，而狄诺塞麦组仅474例，下降了23%。
该试验的次要结局指标为出现中度或重度疼痛的时间，这也是大部分患者公认的最重要的终点。基于总分为11分的经确证的简易疼痛量表，唑来膦酸组首次出现评分大于4分的中位时间为64天，而狄诺塞麦组为88天，提示这种研究中新药可将风险降低23% (P = 0.009)。
唑来膦酸组和狄诺塞麦组分别有27.3%和10.4%的患者出现了与药物治疗相关的流感样急性期反应。唑来膦酸组和狄诺塞麦组分别有8.5%和4.9%的患者出现了与肾毒性相关的不良事件。唑来膦酸组和狄诺塞麦组分别有1.5%和0.2%的患者出现了重度肾毒性。
唑来膦酸组和狄诺塞麦组分别有1.4%和2.0%的患者出现了颌骨坏死(ONJ)，差异无统计学意义。80%以上的ONJ病例都与拔牙、口腔卫生差或使用了牙科材料有关。
美国印第安纳大学医学教授Theresa Guise博士评论道，在此之前并不清楚ONJ是否为只有双膦酸盐类药物治疗才会导致的不良事件。该试验数据表明，ONJ是与骨吸收抑制剂相关的较为普遍的副反应。
Stopeck博士指出，有意思的是，狄诺塞麦治疗组的部分ONJ病例病情是可逆的。她推测，这可能是由于单克隆抗体作用于骨骼的活性的持续时间有限，而双膦酸盐类药物对骨骼的影响则可持续数年之久。
Stopeck博士表示，从理论上讲，抑制RANKL应该能阻碍乳腺癌的进展，因此将来的研究可在早期乳腺癌患者中评价狄诺塞麦作为辅助治疗药物的疗效。
当被问及如果狄诺塞麦获准上市用于骨转移的治疗，你将在临床实践中如何使用该药时，Stopeck博士回答：“只要药价不是太高，我将立即把该药应用于临床，因为其疗效佳，副作用小，皮下注射也更简便，并且还无需监测患者的血清肌酐水平。”
今年10月，美国食品药品管理局驳回了安进(Amgen)公司提交的狄诺塞麦上市申请，要求其提供更多的信息。安进公司的发言人在采访中表示，基于以上来自乳腺癌试验的最新数据，另一项以各种实体器官癌或多发性骨髓瘤患者为研究对象的III 期试验的结果，还有一项在前列腺癌男性患者中开展的III 期试验的结果，安进公司计划于2010年再次向FDA提交申请，并同时向欧盟提交上市申请。III 期试验的结果计划于2010年第1个季度发表。这3项试验共纳入约6,000例癌症患者。
Stopeck博士任安进公司和诺华公司的顾问，也是诺华公司的讲演团成员。诺华公司是唑来膦酸产品的生产商。
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