白蛋白结合型紫杉醇和伊沙匹隆疗效与安全性并不优于老药紫杉醇

美国临床肿瘤学会(ASCO)年会上公布的一项纳入既往未接受过化疗的局部复发或转移性乳腺癌女性患者的Ⅲ期研究显示，白蛋白结合型紫杉醇(nab-paclitaxel)和伊沙匹隆(ixabepilone)这两种较新且昂贵的乳腺癌治疗药物的有效性和安全性并不高于紫杉醇这种老药。

在这项名为CALGB40502/NCCTGN063H的研究中，加州大学旧金山分校海伦·迪勒家庭综合癌症中心乳腺癌和临床试验教育项目主任HopeS.Rugo博士及其同事将799例患者随机分入3个开放标记一线化疗组：紫杉醇组(90mg/m2，每周1次，最常用的剂量方案)、白蛋白结合型紫杉醇组(150mg/m2，每周1次)和伊沙匹隆组(16mg/m2，每周1次)。所有3组均加用贝伐珠单抗(每2周1次)，均采用给药3周停药1周的方案。治疗6个周期后获得应答或疾病稳定的患者可停止化疗，仅继续接受贝伐珠单抗治疗。

中位随访12个月的结果显示，白蛋白结合型紫杉醇组[9.2个月；危险比(HR)=1.19；P=0.12]和伊沙匹隆组(7.6个月；HR=1.53；P＜0.0001)的无进展生存期均短于紫杉醇组(10.6个月)。紫杉醇组、白蛋白结合型紫杉醇组和伊沙匹隆组≥3级不良事件的总发生率分别为55%、79%和59%。白蛋白结合型紫杉醇组和伊沙匹隆组≥3级非血液学不良事件的发生率显著高于紫杉醇组。白蛋白结合型紫杉醇组和伊沙匹隆组周围神经病变发生率也高于紫杉醇组。白蛋白结合型紫杉醇组≥3级血液学事件的发生率显著高于紫杉醇组，而伊沙匹隆组该发生率则显著低于紫杉醇组。

研究者表示，虽然该研究未设无贝伐珠单抗的对照组，但紫杉醇对照组的无进展生存结果与比较紫杉醇单药治疗与紫杉醇/贝伐珠单抗联合治疗的ECOG2100研究结果基本相同。因此，即使在不使用贝伐珠单抗的情况下重新进行整个研究，所得出的结果也不会与目前的研究结果有很大出入。研究结果表明白蛋白结合型紫杉醇并不优于紫杉醇，但可作为替代性药物用于不适合使用紫杉醇的患者，比如对cremophor(紫杉醇溶剂)过敏的患者或不能耐受激素预处理的糖尿病患者。此外，白蛋白结合型紫杉醇还能有效治疗晚期转移性乳腺癌或经其他紫杉烷类药物治疗后出现进展的癌症患者。最后，在缺乏紫杉醇的情况下，白蛋白结合型紫杉醇无疑也可作为替代药物。然而，需指出的是，有资料表明，在100mg/me2这样的低剂量水平(比本研究所用剂量低1/3)使用白蛋白结合型紫杉醇，毒性较小。因此，在使用白蛋白结合型紫杉醇治疗患者时，应使用100mg/me2剂量。

该研究获美国国立癌症研究所资助。Rugo博士声明从Abraxis BioScience、百时美施贵宝和罗氏/基因泰克公司获得研究资金。

摘要号：CRA1002

题目：CALGB 40502/NCCTG N063H: Randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (Ix) with or without bevacizumab (B) as first-line therapy for locally recurrent or metastatic breast cancer (MBC).

CALGB 40502/NCCTG N063H：紫杉醇周疗(P)对比白蛋白纳米紫杉醇(NP)周疗或伊沙匹隆(Ix)加或不加贝伐单抗作为局部复发或转移性乳腺癌(MBC)一线治疗的随机III期研究

摘要：

Background: Weekly P is superior to q 3 week (wk) dosing, and adding B improves progression free survival (PFS) (E2100). Ix is a potent epothilone that can be effective after microtubule inhibitor resistance. NP is a novel albumin-bound formulation of P with promising activity in the first-line MBC setting. In this phase III trial, the efficacy of weekly Ix or NP is compared to P, in combination with B in patients (pts) with chemotherapy (CTX) na??ve MBC. Toxicity including >Grade 2 sensory neuropathy (SN) is compared to P.

Methods: Pts were randomized 1:1:1 to receive P (90 mg/m2), Ix (16 mg/m2) or NP (150 mg/m2) on a 3 wk on, 1 wk off schedule, stratified by prior adjuvant taxane use and hormone receptor status. B was initially given to all pts, but became optional in 3/2011 and was added to stratification. The primary end point of PFS is defined as time from randomization to progression or all-cause death. With a target N=900 pts, the study was powered to detect a hazard ratio (HR) of 1.36 (median PFS 10 vs 13.6 mos). Eligibility included no prior CTX for MBC, >12 mos from adjuvant P and measurable disease.

Results: 799 pts were enrolled between 11/08-11/11 (283 to P, 271 to NP, 245 to Ix); 98% received B. 72% had ER+ disease, 44% received adjuvant P. At the 1st interim analysis (165 events) the comparison of Ix to P crossed the futility boundary (FB) and accrual to Ix was closed. At the 2nd interim analysis (236 events), NP to P crossed the FB and the study was closed on 11/30/11. Median PFS was 10.4, 9.6 and 7.6 mos for P, NP and Ix, with HRs (95% CIs) of 0.94 (0.73-1.22) and 0.66 (0.51-0.84) for P to NP and Ix respectively. Grade 2+ SN was 48% for NP, 44% for Ix and 37% for P; Grade 3+ hematologic toxicity was 49% for NP, 20% for Ix, and 12% for P.

Conclusions: In pts with CTX naive MBC, both NP and Ix are highly unlikely to be superior to P for PFS (when all are combined with B), and in combination with B, weekly P is the better tolerated drug. Toxicity including SN was greater in each experimental arm compared to P. Updated data will be presented, and correlative studies will be reported at a future date.

编辑: xy 作者:丁香园通讯员

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