EMILIA研究：T-DMI可延长无进展和总生存

随机开放标记Ⅲ期EMILIA研究的首项计划内期中分析显示，与卡培他滨/拉帕替尼(XL)联合治疗相比，试验性新药曲妥珠单抗emtansine(T-DM1)在978例HER2阳性转移性乳腺癌患者中的耐受性较好，并可显著延长无进展生存及总生存(J. Clin. Oncol. 30, 2012 [suppl 27 abstr 98])。

该研究纳入既往接受曲妥珠单抗和紫杉烷类药物治疗的确诊HER2阳性转移性乳腺癌的女性患者。患者被随机分成两组。一组接受3.6 mg/kg T-DMI静脉治疗，每3周为1个周期。另一组接受卡培他滨/拉帕替尼(XL)联合治疗，卡培他滨在第1~4天给药，剂量为1,000 mg/m²，每日口服2次，每3周为1个周期；拉帕替尼剂量为1,240 mg，每日口服1次。T-DM1组和XL组的中位随访时间分别为12.9个月和12.4个月。无进展生存通过独立审查确定。

结果显示，T-DM1组的中位无进展生存期为9.6个月，而XL组为6.4个月(分层风险比=0.65)，差异兼具统计学显著性(P＜0.0001)和临床意义。

T-DM1组和XL组的1年总生存率分别为84.7%和77%，2年总生存率分别为65.4%和47.5%，客观应答率分别为43.6%和30.8%，客观应答者的中位应答持续时间分别为12.6个月和6.5个月。

T-DM1的耐受性良好；未观察到非预期的安全性信号。T-DM1组最常见的≥3级不良事件为血小板减少(T-DM1组12.9% vs. XL组0.2%)、AST升高(4.3% vs. 0.8%)和ALT 升高(2.9% vs. 1.4%)，最常见的不良事件为腹泻(1.6% vs. 20.7%)、手足综合征(0% vs. 16.4%)和呕吐(0.8% vs. 4.5%)。

T-DM1组有16.3%的患者需降低剂量，XL组有27.3%的患者需降低拉帕替尼剂量，53.4%的患者需降低卡培他滨剂量。

在上述分析中，T-DM1组的总生存率高于XL组(分层风险比=0.621；P＜0.0005)，但差异无统计学显著性。但最新的总生存率分析结果显示，T-DM1在总生存方面的优势具有统计学显著性。这一最新的详细分析结果将在10月1日举行的欧洲肿瘤内科学会2012年会上首次公布。T-DM1生产商罗氏/基因泰克公司2010年曾向美国食品药品管理局递交该药的加快审批申请，但被拒绝，目前已再次递交包含最新总生存分析结果的申请材料。

EMILIA研究获基因泰克公司资助。研究者声明与多家药企存在联系。

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By: SHARON WORCESTER, Ob.Gyn. News Digital Network

The investigational drug trastuzumab emtansine, or T-DM1, was well tolerated and was associated with significantly prolonged progression-free survival compared with combination capecitabine/lapatinib (XL) treatment in 978 patients with HER2-positive metastatic breast cancer.

The antibody-drug conjugate, which combines the antitumor activity of the monoclonal antibody trastuzumab with the cytotoxic effects of the maytansine derivative DM1, also improved overall survival.

The median progression-free survival among those randomized to receive T-DM1 was 9.6 months, compared with 6.4 months for those treated with XL (stratified hazard ratio, 0.65) – a difference that was both statistically significant (P less than .0001) and clinically meaningful, said Dr. Mark D. Pegram of Stanford (Calif.) University’s Stanford Cancer Institute.

The findings were noted in the first planned interim analysis of the randomized, open-label, phase III EMILIA study. Overall survival at 1 year was 84.7% and 77% in the T-DM1 and XL groups, respectively, and overall survival at 2 years was 65.4% and 47.5% for the groups, respectively (J. Clin. Oncol. 30, 2012 [suppl 27 abstr 98]). The objective response rate was 43.6% vs. 30.8%, and the duration of response among those with an objective response was a median of 12.6 months vs. 6.5 months, Dr. Pegram said.

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

The findings with respect to overall survival, based on this analysis, showed a trend in favor of T-DM1 (stratified hazard ratio, 0.621; P less than .0005), but the difference between the two treatment groups did not technically achieve statistical significance, Dr. Pegram said.

However, the overall survival analysis was recently updated, and the latest findings did demonstrate a statistically significant overall survival advantage with T-DM1 treatment, he noted.

The detailed findings from that latest analysis will be reported publicly for the first time at the European Society for Medical Oncology 2012 Congress to be held Oct. 1. Roche/Genentech Inc., maker of T-DM1, resubmitted to the Food and Drug Administration an application for accelerated approval of the agent. The company has said it plans to provide the FDA, which refused to file the initial application for accelerated approval submitted in 2010, with the updated overall survival analysis data when the agency reviews the application.

EMILIA participants were women with confirmed HER2-positive metastatic breast cancer who had been treated previously with trastuzumab and a taxane. They were randomized to receive 3.6 mg/kg of intravenous T-DMI every 3 weeks, or combination therapy with an oral twice-daily dose of 1,000 mg/m2 of capecitabine on days 1-4 every 3 weeks and an oral dose once daily of 1,240 mg of lapatinib; the XL combination treatment is currently the only approved combination treatment for trastuzumab-refractory HER2-positive metastatic breast cancer.

Patients in the T-DM1 and XL groups were followed for a median of 12.9 and 12.4 months, respectively, and progression-free survival was determined by independent review.

T-DM1 was well tolerated; no unexpected safety signals emerged. The most common grade 3 or higher adverse events in the T-DM1 patients were thrombocytopenia (12.9% vs. 0.2% of T-DMI vs. XL patients), increased AST (4.3% vs. 0.8%), and increased ALT (2.9% vs. 1.4%). The most common adverse events in the XL patients were diarrhea (20.7% vs. 1.6% of the XL vs. T-DM1 patients), palmar plantar erythrodysesthesia (16.4% vs. 0), and vomiting (4.5% vs. 0.8%).

Dose reductions were required in 16.3% of T-DM1 patients, whereas lapatinib doses were reduced in 27.3% of the XL patients, and capecitabine doses were reduced in 53.4% of the XL patients.

The EMILIA trial is sponsored by Genentech. Dr. Pegram reported serving as a consultant or adviser for Takeda, receiving honoraria from AstraZeneca and GlaxoSmithKline, receiving research funding from Sanofi, providing expert testimony for Novartis, and receiving other remuneration from Bristol-Myers Squibb, Pfizer, and Roche/Genentech.