依维莫司可降低乳腺癌的骨骼效应

BOLERO-2研究的探索性分析结果显示，对于非甾体类芳香化酶抑制剂难治的雌激素受体阳性晚期乳腺癌，在依西美坦基础上加用依维莫司(Afinitor)有助于改善骨转换率和乳腺癌的骨骼进展。此外，分析也显示，依维莫司在绝经后女性(包括老年人)的耐受性较好。

该研究纳入经非甾体类芳香化酶抑制剂后出现复发或进展的雌激素受体阳性乳腺癌绝经后女性患者。患者随机接受依维莫司(10 mg，口服，1次/d)+依西美坦(25 mg，1次/d)或安慰剂+依西美坦(25 mg，1次/d)。加用依维莫司使中位无进展生存期延长4.2个月，该组的中位无进展生存期为7.8个月，是安慰剂组(3.2个月)的2倍以上。基于这些结果，7月份美国食品药品管理局(FDA)批准将该药用于治疗晚期激素受体阳性乳腺癌，使其成为获批治疗此适应证的首个mTOR抑制剂。

为了评价依维莫司的骨相关效应，研究者分析了基线时存在骨转移的患者(安慰剂组184例，依西美坦组370例)的骨转换标志物水平和乳腺癌的骨骼进展情况。

结果显示，6周和12周随访时，依维莫司/依西美坦组的骨骼特异性碱性磷酸酶、1型胶原氨基末端前肽和1型胶原C末端交联后肽水平相对基线降低，而在这两个时间点，安慰剂组这些标志物的水平相对基线均升高(J. Clin. Oncol. 2012;30[suppl. 27; abstr. 102])。

依维莫司组60天时乳腺癌骨骼进展性病变累积发生率低于安慰剂组(3.03% vs. 6.16%)，并且这一趋势持续6个月以上。

该分析所纳入的患者发生的骨骼相关不良事件为1/2级，两组的发生率相似(安慰剂组2.9%，治疗组3.8%)。

对依维莫司的安全性和耐受性进行两项额外探索性分析发现，在中位随访12.5个月期间，依维莫司在治疗组492例绝经后患者中的耐受性普遍较好。与安慰剂组238例患者相比，治疗组所有等级的显著不良事件包括口炎(59% vs. 12%)、皮疹(39% vs. 7%)、肺炎(16% vs. 0%)和高血糖(14% vs. ＜1%)。，显著3/4级事件包括口炎(8% vs. ＜1%)、贫血(7% vs. ＜1%)、高血糖(5% vs. ＜1%)、肺炎(3% vs. 0)和皮疹(1% vs. 0)。这些不良事件经适当处置均得到控制(J. Clin. Oncol. 2012;30[suppl. 27; abstr. 103])。

研究方案允许在出现不良事件的情况下降低剂量或中断治疗，对治疗方案的抗肿瘤作用进行观察发现，接受时间平均剂量＜7.5 mg/d的患者的结果与接受时间平均剂量＞7.5 mg/d的患者一致(风险比分别为0.4和0.45)。对于发生口炎的患者，使用局部皮质类固醇和/或含非甾体抗炎药的漱口水或麻醉药进行处置，对于发生非感染性肺炎的患者，暂停原有治疗，然后进行放射学检查，并使用口服皮质类固醇进行处置。

≥65岁亚组患者的不良事件发生率等同于或稍低于整个人群的发生率。依维莫司组≥65岁患者的口炎、皮疹、肺炎和高血糖发生率分别为52%、32%、15%和13%。仅见于依维莫司组≥70岁患者的3/4级不良事件包括疲劳(10%)、贫血(10%)、高血糖(9%)、口炎(8%)、腹泻(7%)、肺炎(5%)、中性粒细胞减少(3%)和高血压(3%)(J. Clin. Oncol. 2012;30[suppl. 27; abstr. 104])。

依维莫司/依西美坦联合治疗在总人群和老年患者中的耐受性均较好，3/4级不良事件较为少见且通常可以控制。未观察到新的安全性信号。研究者表示，对不良事件处置策略的熟练掌握有助于优化耐受性和患者预后。

BOLERO-2研究获诺华公司资助。研究者声明与多家药企存在联系。

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By: SHARON WORCESTER, Oncology Practice

Adding everolimus to exemestane for the treatment of estrogen receptor–positive advanced breast cancer that is refractory to nonsteroidal aromatase inhibitors has beneficial effects on bone turnover and breast cancer progression in bone, according to an exploratory analysis of data from the BOLERO-2 trial.

Additional exploratory analyses demonstrate that everolimus (Afinitor) is well tolerated among postmenopausal women – including the elderly.

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), which has been implicated in resistance to standard endocrine therapy for estrogen receptor–positive breast cancer. Previously reported data from the double-blind, placebo-controlled phase III BOLERO-2 trial showed a significant clinical benefit with respect to the primary end point of progression-free survival when everolimus was added to the steroidal aromatase inhibitor exemestane (Aromasin).

The new findings were presented during poster sessions at the American Society of Clinical Oncology’s 2012 Breast Cancer Symposium.

To evaluate the bone-related effects of everolimus, investigators analyzed bone turnover marker levels and breast cancer progression in bone in BOLERO-2 patients who had bone metastases at baseline, including 184 patients who received placebo and 370 who received exemestane.

They found that active treatment with everolimus and exemestane was associated with improved levels of bone-specific alkaline phosphatase, amino-terminal propeptide of type 1 collagen, and C-terminal cross-linking telopeptide of type 1 collagen at 6- and 12-week follow-up.

The levels of each of these markers had increased at both time points in those receiving placebo, but had decreased in those receiving everolimus, Dr. Lowell L. Hart, a hematologist/oncologist in group practice in Fort Myers, Fla., and his colleagues reported (J. Clin. Oncol. 2012;30[suppl. 27; abstr. 102]).

Also, the cumulative incidence rate of breast cancer progressive disease in bone was lower in those who received everolimus, compared with those who received placebo (3.03% vs. 6.16% at day 60), they said, noting that this trend continued beyond 6 months.

Bone-related adverse events among the patients included in this analysis were grade 1/2, and occurred at a similar frequency in both groups (2.9% for the placebo group and 3.8% for the treatment group).

The safety and tolerability of everolimus were also evaluated in two additional exploratory analyses. In one, everolimus treatment was shown at a median of 12.5 months’ follow-up to be generally well tolerated among 492 postmenopausal women in the treatment group for the study.

Notable adverse events of all grades in those patients, compared with the 238 patients in the placebo group, included stomatitis (59% vs. 12%), rash (39% vs. 7%), pneumonitis (16% vs. 0%), and hyperglycemia (14% vs. less than 1%). Notable grade 3/4 events were stomatitis (8% vs. less than 1%), anemia (7% vs. less than 1%), hyperglycemia (5% vs. less than 1%), pneumonitis (3% vs. 0), and rash (1% vs. 0), reported Dr. Alejandra T. Perez, director of the breast cancer center at Memorial Cancer Institute in Hollywood, Fla.

The adverse events were manageable when patients were treated appropriately, Dr. Perez said (J. Clin. Oncol. 2012;30[suppl. 27; abstr. 103]).

For example, the study protocol permitted dose reduction or interruptions for the management of adverse events, and a look at the antitumor effects of treatment showed that results were consistent in those who received time-averaged doses less than 7.5 mg/day and those who received time-averaged doses greater than 7.5 mg/day (hazard ratios, 0.4 vs. 0.45, respectively). Those who developed stomatitis were treated with topical corticosteroids and/or mouthwashes containing nonsteroidal anti-inflammatories or anesthetics, and those with noninfectious pneumonitis were treated using a combination of radiographic imaging, oral corticosteroids, and temporary cessation of treatment.

Among the subset of study participants aged 65 years and older, the incidences of adverse events were similar or marginally lower than in the entire population, according to Dr. Hope S. Rugo of the University of California, San Francisco, and her colleagues.

For example, stomatitis occurred in 52% of those aged 65 and older who received everolimus, rash occurred in 32%, pneumonitis occurred in 15%, and hyperglycemia occurred in 13%. Grade 3/4 adverse events among those aged 70 years or older and reported only in those receiving everolimus included fatigue in 10%, anemia in 10%, hyperglycemia in 9%, stomatitis in 8%, dyspnea in 7%, pneumonitis in 5%, neutropenia in 3%, and hypertension in 3% (J. Clin. Oncol. 2012;30[suppl. 27; abstr. 104]).

Adding everolimus to exemestane was well tolerated both in the overall population and among elderly patients, and grade 3/4 adverse events were uncommon and manageable, Dr. Rugo noted. No new safety signals emerged.

Dr. Perez added that knowledge of adverse event management strategies is essential for optimizing tolerability and patient outcomes.

BOLERO-2 trial participants were postmenopausal women with estrogen receptor–positive breast cancer who relapsed or progressed on a nonsteroidal aromatase inhibitor. They were randomized to receive a 10-mg oral daily dose of everolimus plus 25 mg of exemestane once daily, or placebo and 25 mg of exemestane daily; treatment with everolimus conferred a median 4.2-month progression-free survival advantage, more than doubling the median progression-free survival from 3.2 months in the placebo group to 7.8 months in the treatment group. Based on these findings, the U.S. Food and Drug Administration approved the drugfor this indication in July, making it the first mTOR inhibitor approved for advanced hormone receptor–positive breast cancer.