Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
Lancet Oncol. 2013 Nov;14(12):1216-25. doi: 10.1016/S1470-2045(13)70429-7. Epub 2013 Oct 4.
New therapeutic options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor designed to provide prolonged tumour-cell exposure to SN38, the active metabolite. We aimed to assess the efficacy and safety of two etirinotecan pegol dosing schedules in patients with previously treated metastatic breast cancer to determine an optimum dosing schedule for phase 3 trials.
In this randomised, two-stage, open-label phase 2 trial, we recruited patients aged 18 years or older who had received taxane therapy and undergone two or fewer previous chemotherapy regimens for metastatic breast cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from 18 sites in three countries. Eligible patients were randomly assigned (1:1) to etirinotecan pegol 145 mg/m(2) every 14 days or every 21 days. The primary endpoint was the proportion of patients with a confirmed objective response as defined by Response Evaluation Criteria in Solid Tumors version 1.0, analysed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug.
70 patients (35 in each group) were randomly assigned to treatment between Feb 17, 2009 and April 13, 2010. Of the 70 patients, 20 (29%; 95% CI 18·4-40·6) achieved an objective response (two [3%] had a complete response and 18 [26%] had a partial response). Ten patients on the 14-day schedule achieved an objective response (29%; 95% CI 14·6-46·3; eight partial responses, two complete responses) as did ten on the 21-day schedule (29%; 95% CI 14·6-46·3; all partial responses). The most common grade 3 or worse adverse events were delayed diarrhoea (seven [20%] of 35 patients on the 14-day schedule vs eight [23%] of 35 patients on the 21-day schedule), fatigue (five [14%] vs three [9%]), neutropenia (four [11%] vs four [11%]), and dehydration (three [9%] vs four [11%]); 14 [20%] patients discontinued treatment because of drug-related toxicity. There were two possible drug-related deaths (acute renal failure and septic shock) in the 14-day group; other drug-related serious adverse events reported by more than one patient included ten [14%] patients with diarrhoea (six [17%] patients on the 14-day schedule vs four [11%] on the 21-day schedule), six [9%] with dehydration (two [6%] vs four [11%]), two [3%] with nausea (two [6%] vs none), and two [3%] with vomiting (two [6%] vs none).
On the basis of the overall clinical data, pharmacokinetics, and tolerability profile, etirinotecan pegol 145 mg/m(2) every 21 days has been selected for a phase 3 trial against treatment of physician's choice in patients with advanced breast cancer.
对于接受过多线治疗的乳腺癌患者，需要新的治疗方案。埃替拉滨聚乙二醇是一种长效拓扑异构酶 I 抑制剂，旨在使 SN38（活性代谢物）更长时间地暴露于肿瘤细胞。我们旨在评估两种埃替拉滨聚乙二醇给药方案在既往治疗转移性乳腺癌患者中的疗效和安全性，以确定 3 期试验的最佳给药方案。
在这项随机、两阶段、开放标签的 2 期试验中，我们从三个国家的 18 个地点招募了年龄在 18 岁或以上、接受过紫杉烷治疗、且已经接受过两次或两次以下转移性乳腺癌化疗方案的患者，ECOG 体能状态为 0 或 1。符合条件的患者按照 1:1 的比例随机分配（1:1）接受埃替拉滨聚乙二醇 145mg/m²，每 14 天或每 21 天一次。主要终点是根据实体瘤反应评价标准 1.0 确定的客观缓解比例，通过意向治疗进行分析。所有至少接受一剂研究药物的患者均进行安全性评估。
70 例患者（每组 35 例）于 2009 年 2 月 17 日至 2010 年 4 月 13 日期间随机分配接受治疗。70 例患者中，20 例（29%；95%CI 18·4-40·6）达到客观缓解（2 例完全缓解，18 例部分缓解）。14 天方案组有 10 例（29%；95%CI 14·6-46·3；8 例部分缓解，2 例完全缓解），21 天方案组有 10 例（29%；95%CI 14·6-46·3；均为部分缓解）达到客观缓解。最常见的 3 级或更严重的不良事件是延迟性腹泻（14 天方案组 35 例中有 7 例[20%]，21 天方案组 35 例中有 8 例[23%]）、疲乏（5 例[14%] vs 3 例[9%]）、中性粒细胞减少（4 例[11%] vs 4 例[11%]）和脱水（3 例[9%] vs 4 例[11%]）；14 例（20%）患者因药物相关毒性而停止治疗。14 天组有 2 例可能与药物相关的死亡（急性肾衰竭和感染性休克）；其他报告超过 1 例患者的药物相关严重不良事件包括 10 例腹泻（14 天方案组 6 例[17%]，21 天方案组 4 例[11%]）、6 例脱水（21 天方案组 2 例[6%]，14 天方案组 4 例[11%]）、2 例恶心（2 例[6%] vs 无）和 2 例呕吐（2 例[6%] vs 无）。
根据总体临床数据、药代动力学和耐受性特征，埃替拉滨聚乙二醇 145mg/m²，每 21 天给药已被选中用于 3 期试验，与医生选择的治疗方案相比，用于治疗晚期乳腺癌患者。
