Lancet Oncol：阿西替尼可作为转移性肾细胞癌患者的二线治疗方案

在一项3期临床研究中，研究者们比较了阿西替尼和索菲拉尼作为二线治疗方案对转移性肾细胞癌患者的疗效，其结果提示应用阿西替尼治疗的患者其无进展生存期更长。在本研究中，来自美国纽约纪念Sloan-Kettering肿瘤中心的Robert J Motzer等报道了上述研究的总体生存期结果，以及更新了研究中与治疗有效性、生活质量和安全性相关的部分结果，他们将上述内容发表在Lancet Oncol 4月最新的在线期刊上。

本研究所纳入的受试者为透明细胞转移性肾细胞癌患者、在经过系统的全身治疗后出现疾病进展，并且其东部肿瘤协作组织一般状态分级（ECOG PS）为0-1。共有723名受试者被纳入研究，研究者根据受试者的ECOG PS和既往所接受过的治疗对其进行分层，并将其按照1:1的比例随机分为两组，361名受试者接受阿西替尼治疗，方案为每日2次，每次5mg，另有362名受试者接受索菲替尼治疗，方案为每日2次，每次400mg。本研究的主要终点是受试者的疾病无进展生存期（PFS），由一组独立的放射学审查委员会对PFS进行评估，该审查委员会的成员不知晓受试者所接受的具体治疗方案。研究者采用问卷评估了患者自我报道的预后情况。研究者将受试者在入组时的特点和在治疗过程中针对高血压进行的治疗作为预后评估因素。研究者采用意向治疗分析法对研究的有效性结果进行分析，在至少接受过一个治疗剂量药物的受试者中进行与安全性相关的评估。本研究尚在进行之中，研究已在ClinicalTrials.gov进行注册，注册号为NCT00678392。

在阿西替尼组和索菲拉尼组中受试者的中位总体生存期分别为20.1月和19.2月，95%可信区间分别为16.7至23.4月和17.5至22.3月，两组差异不具有显著统计学意义。研究者所评估的中位PFS在阿西替尼组和索菲拉尼组分别为8.3月和5.7月，95%可信区间分别为6.7至9.2月和4.7至6.5月，两组差异具有显著统计学意义。在入组时两组受试者所汇报的预后评分相似，在治疗期间上述评分未出现显著变化，但是在治疗结束时该评分出现降低。在研究中，研究者所观察到阿西替尼组（359人）中常见的3级或以上与治疗相关的不良反应事件是高血压（17%）、腹泻（11%）和疲劳（10%），而在索菲拉尼组（355人）中所观察到的常见的3级或以上与治疗相关的不良反应事件是手足综合征（17%）、高血压（12%）和腹泻（8%）。12周的事后分析显示，与舒张压在90mmHg以下的受试者相比，舒张压在90mmHg及以上的受试者的中位总体生存期更长，在阿西替尼组为12.9月（<90mmHg）和20.7月（90mmHg及以上），在索菲拉尼组为14.8月（<90mmHg）和20.2月（90mmHg及以上），上述差异都具有显著统计学意义。

本研究结果指出，虽然研究的次要终点——总体生存期——在两个治疗组间并没有显示出显著差异，但是，研究者发现与索菲拉尼组的受试者相比，阿西替尼组的受试者预测PFS更长。这些结果提示对于转移性肾细胞癌患者而言，阿西替尼治疗可作为二线治疗方案。

与肾细胞癌相关的拓展阅读：

• JNCI：血浆25-羟维生素D浓度影响肾细胞癌发病风险
• BJU Int：新研究可预测转移性肾细胞癌预后
• JCO：Foretinib用于乳头状肾细胞癌疗效显著
• MCP：定量蛋白质组学确定转移性肾细胞癌的生物标志物
• ESMO年会：抗肾细胞癌疫苗研究取得进展
• ASCO 2012：转移性肾细胞癌的治疗若干进展
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Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial.
BACKGROUND
In a phase 3 trial comparing the efficacy and safety of axitinib versus sorafenib as second-line treatment for metastatic renal cell carcinoma, patients given axitinib had a longer progression-free survival (PFS). Here, we report overall survival and updated efficacy, quality of life, and safety results.
METHODS
Eligible patients had clear cell metastatic renal cell carcinoma, progressive disease after one approved systemic treatment, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. 723 patients were stratified by ECOG PS and previous treatment and randomly allocated (1:1) to receive axitinib (5 mg twice daily; n=361) or sorafenib (400 mg twice daily; n=362). The primary endpoint was PFS assessed by a masked, independent radiology review committee. We assessed patient-reported outcomes using validated questionnaires. Baseline characteristics and development of hypertension on treatment were studied as prognostic factors. Efficacy was assessed in the intention-to-treat population, and safety was assessed in patients who received at least one dose of the study drug. This ongoing trial is registered on ClinicalTrials.gov, number NCT00678392.
FINDINGS
Median overall survival was 20·1 months (95% CI 16·7-23·4) with axitinib and 19·2 months (17·5-22·3) with sorafenib (hazard ratio [HR] 0·969, 95% CI 0·800-1·174; one-sided p=0·3744). Median investigator-assessed PFS was 8·3 months (95% CI 6·7-9·2) with axitinib and 5·7 months (4·7-6·5) with sorafenib (HR 0·656, 95% CI 0·552-0·779; one-sided p<0·0001). Patient-reported outcomes scores were similar in the treatment groups at baseline, were maintained during treatment, but decreased at end-of-treatment. Common grade 3 or higher treatment-related adverse events were hypertension (60 [17%]), diarrhoea (40 [11%]), and fatigue (37 [10%]) in 359 axitinib-treated patients and hand-foot syndrome (61 [17%]), hypertension (43 [12%]), and diarrhoea (27 [8%]) in 355 sorafenib-treated patients. In a post-hoc 12-week landmark analysis, median overall survival was longer in patients with a diastolic blood pressure of 90 mm Hg or greater than in those with a diastolic blood pressure of less than 90 mm Hg: 20·7 months (95% CI 18·4-24·6) versus 12·9 months (10·1-20·4) in the axitinib group (p=0·0116), and 20·2 months (17·1-32·0) versus 14·8 months (12·0-17·7) in the sorafenib group (one-sided p=0·0020).
INTERPRETATION
Although overall survival, a secondary endpoint for the study, did not differ between the two groups, investigator-assessed PFS remained longer in the axitinib group compared with the sorafenib group. These results establish axitinib as a second-line treatment option for patients with metastatic renal cell carcinoma.