HELIOS Klinikum Berlin-Buch, Berlin, Germany.
Sana Klinikum, Offenbach, Germany.
Lancet Oncol. 2016 Mar;17(3):345-356. doi: 10.1016/S1470-2045(15)00542-2. Epub 2016 Feb 8.
In metastatic breast cancer, nab-paclitaxel has been shown to significantly increase progression-free survival compared with solvent-based paclitaxel. The GeparSepto (GBG 69) trial assessed whether weekly nab-paclitaxel could increase the proportion of patients achieving pathological complete response compared with weekly solvent-based paclitaxel, both followed by epirubicin plus cyclophosphamide as neoadjuvant treatment.
In a phase 3 randomised trial, we enrolled patients with previously untreated unilateral or bilateral primary invasive breast cancer and randomly assigned them in a 1:1 ratio using dynamic allocation and Pocock minimisation by breast cancer subtype, Ki67 and SPARC expression. Patients were treated for 12 weeks with either intravenous nab-paclitaxel 150 mg/m(2) (after study amendment, 125 mg/m(2)) on days 1, 8, and 15 for four 3-week cycles, or solvent-based intravenous paclitaxel 80 mg/m(2) on days 1, 8, and 15 for four 3-week cycles. Taxane treatment was followed in both groups by intravenous epirubicin 90 mg/m(2) plus intravenous cyclophosphamide 600 mg/m(2) on day 1 for four 3-week cycles. Patients with HER2-positive tumours received concurrent trastuzumab 6 mg/kg (loading dose 8 mg/kg) and pertuzumab 420 mg (loading dose 840 mg) on day 1 of every 3-week cycle. Trastuzumab and pertuzumab were given every 3 weeks concomitantly with chemotherapy for all cycles. This report is the final analysis of the primary endpoint, pathological complete response (ypT0 ypN0), analysed for all patients who started treatment (modified intention to treat). We used a closed test procedure to test for non-inferiority, with the nab-paclitaxel group calculated as non-inferior to the solvent-based paclitaxel group if the lower 95% CI for the OR was above 0·858 (OR equivalent to pathological complete response [33%] minus a 10% non-inferiority margin [3·3%]; 29·7%). We planned to test for superiority only in case of a positive non-inferiority test, using an α of 0·05. Safety was assessed in all patients who received study drug. The trial is registered with ClinicalTrials.gov, number NCT01583426.
Between July 30, 2012, and Dec 23, 2013, we randomly assigned 1229 women, of whom 1206 started treatment (606 with nab-paclitaxel and 600 with solvent-based paclitaxel). The nab-paclitaxel dose was reduced after enrolment of 464 participants to 125 mg/m(2) due to increased treatment discontinuation and sensory neuropathy in this group. Pathological complete response occurred more frequently in the nab-paclitaxel group (233 [38%, 95% CI 35-42] patients) than in the solvent-based paclitaxel group (174 [29%, 25-33] patients; OR 1·53, 95% CI 1·20-1·95; unadjusted p=0·00065). The incidence of grade 3-4 anaemia (13 [2%] of 605 patients in the nab-paclitaxel group vs four [1%] of patients in the solvent-based paclitaxel group; p=0·048) and peripheral sensory neuropathy grade 3-4 (63 [10%] patients receiving any nab-paclitaxel dose; 31 [8%] of patients starting with 125 mg/m(2) and 32 [15%] of patients starting with 150 mg/m(2); vs 16 [3%] in the solvent-based paclitaxel group, p<0·001) was significantly higher for nab-paclitaxel than for solvent-based paclitaxel. Overall, 283 (23%) patients were noted to have at least one serious adverse event (based on study drug received), 156 (26%) in the nab-paclitaxel group and 127 (21%) in the solvent-based paclitaxel group (p=0·057). There were three deaths (during epirubicin plus cyclophosphamide treatment) in the nab-paclitaxel group (due to sepsis, diarrhoea, and accident unrelated to the trial) versus one in the solvent-based paclitaxel group (during paclitaxel treatment; cardiac failure).
Substituting solvent-based paclitaxel with nab-paclitaxel significantly increases the proportion of patients achieving a pathological complete response rate after anthracycline-based chemotherapy. These results might lead to an exchange of the preferred taxane, solvent-based paclitaxel, for nab-paclitaxel in therapy for primary breast cancer.
Celgene, Roche.
在转移性乳腺癌中，与溶剂型紫杉醇相比，白蛋白结合型紫杉醇显著增加了无进展生存期。GeparSepto（GBG 69）试验评估了每周给予白蛋白结合型紫杉醇是否能比每周给予溶剂型紫杉醇增加更多的患者达到病理完全缓解（ypT0 ypN0），这两种药物均随后接受表柔比星加环磷酰胺作为新辅助治疗。
在一项 3 期随机试验中，我们招募了之前未接受过单侧或双侧原发性浸润性乳腺癌治疗的患者，并使用动态分配和 Pocock 最小化方法，根据乳腺癌亚型、Ki67 和 SPARC 表达情况，将其随机分为 1:1 比例。患者接受静脉注射nab-紫杉醇 150mg/m2（在研究修正案后，剂量为 125mg/m2），在第 1、8 和 15 天使用 4 个 3 周周期，或每周静脉注射溶剂型紫杉醇 80mg/m2，在第 1、8 和 15 天使用 4 个 3 周周期。两组患者均在紫杉醇治疗后，在第 1 天接受静脉注射表柔比星 90mg/m2 和环磷酰胺 600mg/m2，共 4 个 3 周周期。HER2 阳性肿瘤患者在每个 3 周周期的第 1 天接受曲妥珠单抗 6mg/kg（负荷剂量 8mg/kg）和帕妥珠单抗 420mg（负荷剂量 840mg）。所有周期中均同时给予曲妥珠单抗和帕妥珠单抗化疗。本报告是对主要终点（ypT0 ypN0）的最终分析，所有开始治疗的患者（改良意向治疗）均进行了分析。我们使用封闭检验程序来检验非劣效性，nab-紫杉醇组计算为非劣效于溶剂型紫杉醇组，如果 OR 的下 95%CI 大于 0.858（OR 等效于病理完全缓解[33%]减去 10%非劣效性边界[3.3%]；29.7%）。只有在非劣效性检验为阳性的情况下，我们才计划进行优效性检验，α 值为 0.05。所有接受研究药物治疗的患者均进行安全性评估。该试验在 ClinicalTrials.gov 注册，编号为 NCT01583426。
在 2012 年 7 月 30 日至 2013 年 12 月 23 日期间，我们随机分配了 1229 名女性，其中 1206 名开始治疗（606 名接受 nab-紫杉醇治疗，600 名接受溶剂型紫杉醇治疗）。由于这组患者的治疗中断和感觉神经病变增加，在纳入 464 名患者后，nab-紫杉醇的剂量减少至 125mg/m2。nab-紫杉醇组病理完全缓解的发生率高于溶剂型紫杉醇组（233[38%，95%CI 35-42]例患者与 174[29%，25-33]例患者；OR 1.53，95%CI 1.20-1.95；未调整的 p=0.00065）。nab-紫杉醇组贫血（3-4 级）（605 例患者中有 13 例[2%]与溶剂型紫杉醇组的 4 例[1%]；p=0.048）和周围感觉神经病变（3-4 级）（接受任何剂量的 nab-紫杉醇的患者中有 63 例[10%]；起始剂量为 125mg/m2的患者中有 31 例[8%]，起始剂量为 150mg/m2的患者中有 32 例[15%]；溶剂型紫杉醇组为 16 例[3%]；p<0.001）的发生率明显高于溶剂型紫杉醇组。共有 283 名（23%）患者至少出现一次严重不良事件（基于接受的研究药物），nab-紫杉醇组为 156 名（26%），溶剂型紫杉醇组为 127 名（21%）（p=0.057）。nab-紫杉醇组有 3 例（在表柔比星加环磷酰胺治疗期间）死亡（因脓毒症、腹泻和与试验无关的意外事件），而溶剂型紫杉醇组有 1 例（在紫杉醇治疗期间）死亡（心力衰竭）。
用 nab-紫杉醇替代溶剂型紫杉醇可显著增加接受蒽环类药物为基础的化疗后病理完全缓解的患者比例。这些结果可能导致在原发性乳腺癌治疗中，将首选的紫杉烷类药物溶剂型紫杉醇替换为 nab-紫杉醇。
Celgene、Roche。
