转移性乳腺癌 贝伐珠单抗+紫杉醇更有效

维也纳——前瞻性Ⅲ期TURANDOT研究结果显示，与贝伐珠单抗(Avastin)/卡培他滨(Xeloda)相比，贝伐珠单抗/紫杉醇联合治疗既往未接受过化疗的HER2阴性乳腺癌女性患者的疗效更佳。

Christoph Zielinski博士

此前的E2100研究显示，贝伐珠单抗联合一线紫杉醇(每周1次)可显著改善无进展生存和总应答率(J. Clin. Oncol. 2009;27:4966-72)，RIBBON-1研究也表明贝伐珠单抗联合卡培他滨时具有同样疗效(J. Clin. Oncol. 2011;29:1252-60)，但尚无研究对贝伐珠单抗/紫杉醇与贝伐珠单抗/卡培他滨进行直接比较。因此维也纳医科大学的Christoph Zielinski博士及其同事开展了TURANDOT这项国际多中心双盲研究，首次前瞻性直接比较了贝伐珠单抗/紫杉醇与贝伐珠单抗/卡培他滨作为不可手术的局部晚期或转移性乳腺癌的一线治疗的疗效。该研究纳入564例既往未接受过化疗的晚期乳腺癌女性(中位年龄59岁)。如果患者入组前曾接受辅助或新辅助的化疗和(或)放疗，则这些治疗需在入组前至少6个月完成。

285例患者接受贝伐珠单抗(10 mg/kg，第1和15天)和紫杉醇(90 mg/m2，第1、8和14天)治疗，每4周为1个周期。其余279例患者接受贝伐珠单抗(15 mg/kg，第1天)和卡培他滨(1,000 mg/m2，第1~14天)，每3周为1个周期。治疗直至出现进展或不可接受的毒性才停止。主要目的是证明贝伐珠单抗/卡培他滨联合治疗方案非劣效于贝伐珠单抗/紫杉醇联合治疗。

贝伐珠单抗/紫杉醇组次要终点无进展生存[11个月vs. 8.1个月，危险比(HR)=1.36，P=0.0052]和客观应答率(44% vs. 27%，P＜0.0001)显著优于贝伐珠单抗/卡培他滨组。两组在主要终点总生存方面无显著差异(HR=1.04)，然而，贝伐珠单抗/紫杉醇组的总生存期为30.5个月，而贝伐珠单抗/卡培他滨组为26个月(HR=1.04，P=0.059)，两组的1年、2年和3年总生存率分别为81%和79%、68%和70%，60%和55%。

安全性人群包括561例女性，紫杉醇组和卡培他滨组停用贝伐珠单抗的患者比例分别为51%和64%，因不良事件而停用贝伐珠单抗的患者比例分别为16%和14%，分别有2例和4例死亡。

贝伐珠单抗/卡培他滨组因疾病进展而停止化疗的患者比例高于贝伐珠单抗/紫杉醇组(63% vs. 32%)，但因不良事件而停止化疗的患者比例低于后组(15% vs. 34%)。两组分别有46%和54%的患者因毒性而需调整化疗。

总生存亚组分析未发现组间差异。最终总生存结果预计将于2014年发表。紫杉醇组至获得应答的时间显著短于卡培他滨组(HR=0.58，P=0.0002),，但两组在至治疗失败时间和应答持续方面方面无显著差异。

不良事件结果与既往研究一致：紫杉醇组的血液学事件和神经病变发生率更高，而卡培他滨组的腹泻、贫血、高血压和手足综合征发生率更高。无进展生存率和应答率也与既往Ⅲ期研究一致。

上述两种联合治疗已在欧洲注册应用，但英国国家健康与临床优化研究所(NICE)拒绝批准这两种方案，因为有证据显示这些治疗无明显的总生存获益和成本效益比。美国食品药品管理局(FDA)在后续临床研究中未能证明E2100研究所观察到的边缘获益，随后撤除了贝伐珠单抗治疗转移性乳腺癌的一个适应证。

随刊述评：紫杉醇活性可能更强

巴塞罗那Vall d’Hebron肿瘤研究所的Javier Cortes博士表示，含贝伐珠单抗的治疗是HER2阴性转移性乳腺癌患者的较好一线治疗方案。贝伐珠单抗/紫杉醇和贝伐珠单抗/卡培他滨在总生存方面的差异较难被发现，但这并不意味两种方案是一样的。

该研究获罗氏资助。Zielinski博士和Javier Cortes均声明从该公司获得酬金。

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By: SARA FREEMAN, Oncology Practice

VIENNA – Paclitaxel may be a better partner for bevacizumab than capecitabine for treating chemotherapy-naive women with HER2-negative breast cancer, the first efficacy results from the prospective phase III TURANDOT trial suggest.

The secondary end points of progression-free survival (11 months vs. 8.1 months, hazard ratio 1.36, P = .0052) and objective response rates (44% vs. 27%, P less than .0001) were significantly better with bevacizumab (Avastin) and paclitaxel than with bevacizumab and capecitabine (Xeloda).

The primary end point of overall survival did not show a statistically significant difference between the combinations (HR 1.04), however. Overall survival was 30.5 months with bevacizumab plus paclitaxel and 26 months with bevacizumab plus capecitabine (HR 1.04, P = .059). The respective overall survival rates were 81% versus 79% at 1 year, 68% versus 70% at 2 years, and 60% versus 55% at 3 years.

"Many agents are available for first-line treatment of HER2-negative inoperable locally advanced or metastatic breast cancer, but currently there is no gold standard," Dr. Christoph Zielinski said Sept. 29 at the European Society for Medical Oncology Congress.

Dr. Zielinski, of the Medical University of Vienna, noted that progression-free survival and overall response rates were significantly improved when bevacizumab was combined with first-line weekly paclitaxel in the E2100 trial (J. Clin. Oncol. 2009;27:4966-72) or with capecitabine in the RIBBON-1 trial (J. Clin. Oncol. 2011;29:1252-60), but there was no head-to-head comparison.

Both combinations have been registered for use in Europe, although the National Institute for Health and Clinical Excellence in the United Kingdom has rejected both on the grounds of no clear overall survival benefit and the cost-to-benefit ratio.

In the United States, the Food and Drug Administration withdrew an indication for bevacizumab in metastatic breast cancer after subsequent clinical trials failed to confirm the margin of benefit seen in E2100.

TURANDOT Offers Direct Comparison

TURANDOT (Capecitabine and Bevacizumab Randomized Against Avastin and Taxol) is the first prospective trial directly comparing bevacizumab and paclitaxel versus bevacizumab and capecitabine as first-line treatment for inoperable locally advanced or metastatic breast cancer.

The international, multicenter, double-blind trial involved 564 women (median age 59 years) who had received no prior chemotherapy in the advanced setting. Prior adjuvant or neoadjuvant chemotherapy, radiotherapy, or both were permitted only if the regimens used had been completed at least 6 months before enrollment.

Women were treated until progression or until unacceptable toxicity, with 285 receiving bevacizumab 10 mg/kg on days 1 and 15 plus paclitaxel 90 mg/m2 on days 1, 8 and 14 of a 4-week cycle. The remaining 279 women received bevacizumab 15 mg/kg on day 1 plus capecitabine 1,000 mg/m2 on days 1-14 of a 3-week cycle. The primary objective was to demonstrate that the latter combination was noninferior to bevacizumab plus paclitaxel.

The safety population included 561 women, with 51% versus 64% of patients discontinuing bevacizumab treatment in the paclitaxel and capecitabine arms, respectively. A similar percentage (16% vs. 14%) discontinued bevacizumab because of adverse events, and two and four patients in each group died.

A higher percentage of patients in the bevacizumab-capecitabine arm than in the bevacizumab-paclitaxel arm discontinued chemotherapy due to disease progression (63% vs. 32%), although there were fewer discontinuations due to adverse events (15% vs. 34%). Chemotherapy had to be modified because of toxicity in 46% and 54% of cases, respectively.

Subgroup analysis of overall survival showed no difference between the two treatment arms. Final overall survival results are expected in 2014.

The time to achieve a response was significantly shorter with the paclitaxel-containing regimen (HR 0.58, P = .0002), although the time to treatment failure and duration of response was not significantly different.