编译：王津京
来源：桓兴医讯
背景（Background）
卡博替尼是一种包括MET、VEGFR和AXL在内的酪氨酸激酶口服抑制剂。这项3期随机METEOR试验在既往VEGFR酪氨酸激酶抑制剂治疗后进展的晚期肾细胞癌患者中，比较了卡博替尼和mTOR抑制剂依维莫司的有效性和安全性。在此，基于一项非计划二次中期分析，我们对这项研究的最终总生存结果予以报告。
Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis.
方法（Methods）
在这项开放标签、3期随机试验中，≥18岁、有可测量病灶的晚期或转移性肾透明细胞癌患者，之前接受过一种或多种VEGFR酪氨酸激酶抑制剂治疗，我们将这些患者随机分组（1:1），接受每天1次60mg卡博替尼或每天1次10mg依维莫司。通过交互式语音和网络反应系统进行随机化。按纪念斯隆凯特琳癌症中心风险分组和之前接受VEGFR酪氨酸激酶抑制剂治疗的次数进行分层。主要终点为无进展生存期，在随机分组的前375名患者中由独立放射学审查委员会进行评估，主要终点既往已报道。次要终点是总生存期和客观缓解率，在所有随机分组患者中通过意向治疗分析进行总生存期和客观缓解评价。所有接受了至少一次剂量研究药物的患者都进行了安全性评估。这项研究入组已结束，但患者治疗和随访仍在进行，以评价长期安全性。这项试验在ClinicalTrials.gov注册，注册号NCT01865747。
In this open-label, randomised phase 3 trial, we randomly assigned (1:1) patients aged 18 years and older with advanced or metastatic clear-cell renal cell carcinoma, measurable disease, and previous treatment with one or more VEGFR tyrosine-kinase inhibitors to receive 60 mg cabozantinib once a day or 10 mg everolimus once a day. Randomisation was done with an interactive voice and web response system. Stratification factors were Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously reported. Secondary endpoints were overall survival and objective response in all randomly assigned patients assessed by intention-to-treat. Safety was assessed per protocol in all patients who received at least one dose of study drug. The study is closed for enrolment but treatment and follow-up of patients is ongoing for long-term safety evaluation. This trial is registered with ClinicalTrials.gov, number NCT01865747.
发现（Findings）
2013年8月8日至2014年11月24日，658名患者随机分配到卡博替尼组（n=330）或依维莫司组（n=328）。卡博替尼组总生存和安全性随访的中位时间为18.7个月(IQR16.1–21.1)，依维莫司组18.8个月(IQR16.0–21.2)。卡博替尼组中位生存期21.4个月（95%CI18.7–不可估计），依维莫司组16.5个月（14.7-18.8）（风险比[HR]0.66[95%CI0.53–0.83]，p=0.00026)。所有随机分组患者每次独立放射性检查表明，卡博替尼治疗还改善了无进展生存率（HR0.51[95%CI0.41–0.62]，p<0.0001）和客观缓解率（卡博替尼组17%[13–22]，依维莫司组3%[2–6]，p<0.0001）。最常见的3、4级不良事件是高血压（卡博替尼组49[15%]对比依维莫司组12[4%]）、腹泻（43[13%]对7[2%]）、疲劳(36[11%]对24[7%])、掌跖红斑综合征（27[8%]对3[1%]）、贫血（19[6%]对53[17%]）、高血糖（3[1%]对16[5%]）及低镁血症（16[5%]对无）。卡博替尼组有130名（39%）患者出现严重3级或更严重不良事件，依维莫司组129名（40%）。卡博替尼组有1名患者出现治疗相关性死亡（死亡未另行说明），依维莫司组2名（1名曲霉菌感染，1名吸入性肺炎）。
Between Aug 8, 2013, and Nov 24, 2014, 658 patients were randomly assigned to receive cabozantinib (n=330) or everolimus (n=328). The median duration of follow-up for overall survival and safety was 18·7 months (IQR 16·1–21·1) in the cabozantinib group and 18·8 months (16·0–21·2) in the everolimus group. Median overall survival was 21·4 months (95% CI 18·7–not estimable) with cabozantinib and 16·5 months (14·7–18·8) with everolimus (hazard ratio [HR] 0·66 [95% CI 0·53–0·83]; p=0·00026). Cabozantinib treatment also resulted in improved progression-free survival (HR 0·51 [95% CI 0·41–0·62]; p<0·0001) and objective response (17% [13–22] with cabozantinib vs 3% [2–6] with everolimus; p<0·0001) per independent radiology review among all randomised patients. The most common grade 3 or 4 adverse events were hypertension (49 [15%] in the cabozantinib group vs 12 [4%] in the everolimus group), diarrhoea (43 [13%] vs 7 [2%]), fatigue (36 [11%] vs 24 [7%]), palmar-plantar erythrodysaesthesia syndrome (27 [8%] vs 3 [1%]), anaemia (19 [6%] vs 53 [17%]), hyperglycaemia (3 [1%] vs 16 [5%]), and hypomagnesaemia (16 [5%] vs none). Serious adverse events grade 3 or worse occurred in 130 (39%) patients in the cabozantinib group and in 129 (40%) in the everolimus group. One treatment-related death occurred in the cabozantinib group (death; not otherwise specified) and two occurred in the everolimus group (one aspergillus infection and one pneumonia aspiration).
解释（Interpretation）
相比依维莫司，卡博替尼治疗延长了总生存期、延缓了疾病进展、提高了客观缓解率。基于这些结果，对于既往治疗过的晚期肾细胞癌，应考虑将卡博替尼作为一种新的治疗标准以供选择。应监测患者不良事件，可能需要调整剂量。
Treatment with cabozantinib increased overall survival, delayed disease progression, and improved the objective response compared with everolimus. Based on these results, cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma. Patients should be monitored for adverse events that might require dose modifications.
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