Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China.
Department of Thoracic Oncology, Tianjin Medical University Cancer Hospital, Tianjin, China.
JAMA Oncol. 2018 Nov 1;4(11):1569-1575. doi: 10.1001/jamaoncol.2018.3039.
Anlotinib is a novel multitarget tyrosine kinase inhibitor for tumor angiogenesis and proliferative signaling. A phase 2 trial showed anlotinib to improve progression-free survival with a potential benefit of overall survival, leading to the phase 3 trial to confirm the drug's efficacy in advanced non-small cell lung cancer (NSCLC).
To investigate the efficacy of anlotinib on overall survival of patients with advanced NSCLC progressing after second-line or further treatment.
DESIGN, SETTING, AND PARTICIPANTS: The ALTER 0303 trial was a multicenter, double-blind, phase 3 randomized clinical trial designed to evaluate the efficacy and safety of anlotinib in patients with advanced NSCLC. Patients from 31 grade-A tertiary hospitals in China were enrolled between March 1, 2015, and August 31, 2016. Those aged 18 to 75 years who had histologically or cytologically confirmed NSCLC were eligible (n = 606), and those who had centrally located squamous cell carcinoma with cavitary features or brain metastases that were uncontrolled or controlled for less than 2 months were excluded. Patients (n = 440) were randomly assigned in a 2-to-1 ratio to receive either 12 mg/d of anlotinib or a matched placebo. All cases were treated with study drugs at least once in accordance with the intention-to-treat principle.
The primary end point was overall survival. The secondary end points were progression-free survival, objective response rate, disease control rate, quality of life, and safety.
In total, 439 patients were randomized, 296 to the anlotinib group (106 [36.1%] were female and 188 [64.0%] were male, with a mean [SD] age of 57.9 [9.1] years) and 143 to the placebo group (46 [32.2%] were female and 97 [67.8%] were male, with a mean [SD] age of 56.8 [9.1] years). Overall survival was significantly longer in the anlotinib group (median, 9.6 months; 95% CI, 8.2-10.6) than the placebo group (median, 6.3 months; 95% CI, 5.0-8.1), with a hazard ratio (HR) of 0.68 (95% CI, 0.54-0.87; P = .002). A substantial increase in progression-free survival was noted in the anlotinib group compared with the placebo group (median, 5.4 months [95% CI, 4.4-5.6] vs 1.4 months [95% CI, 1.1-1.5]; HR, 0.25 [95% CI, 0.19-0.31]; P < .001). Considerable improvement in objective response rate and disease control rate was observed in the anlotinib group over the placebo group. The most common grade 3 or higher adverse events in the anlotinib arm were hypertension and hyponatremia.
Among the Chinese patients in this trial, anlotinib appears to lead to prolonged overall survival and progression-free survival. This finding suggests that anlotinib is well tolerated and is a potential third-line or further therapy for patients with advanced NSCLC.
ClinicalTrials.gov identifier: NCT02388919.
安罗替尼是一种新型的多靶点酪氨酸激酶抑制剂，可用于肿瘤血管生成和增殖信号。一项 2 期临床试验表明，安罗替尼可改善无进展生存期，并可能带来总生存期的获益，这促使开展了 3 期临床试验，以确认该药在晚期非小细胞肺癌（NSCLC）中的疗效。
研究安罗替尼对二线或进一步治疗后进展的晚期 NSCLC 患者总生存期的影响。
设计、地点和参与者：ALTER 0303 试验是一项多中心、双盲、3 期随机临床试验，旨在评估安罗替尼在晚期 NSCLC 患者中的疗效和安全性。来自中国 31 家 A 级三级医院的患者于 2015 年 3 月 1 日至 2016 年 8 月 31 日入组。年龄在 18 至 75 岁之间，组织学或细胞学确诊为 NSCLC，且中央型鳞状细胞癌伴空洞特征或脑转移但未得到控制或控制时间少于 2 个月的患者被排除在外。（n = 606）。将（n = 440）名患者按 2:1 的比例随机分配，接受 12 mg/d 的安罗替尼或匹配的安慰剂治疗。所有患者均根据意向治疗原则至少接受一次研究药物治疗。
主要终点为总生存期。次要终点为无进展生存期、客观缓解率、疾病控制率、生活质量和安全性。
共有 439 名患者被随机分组，296 名患者被分配到安罗替尼组（106 名[36.1%]为女性，188 名[64.0%]为男性，平均[标准差]年龄为 57.9[9.1]岁），143 名患者被分配到安慰剂组（46 名[32.2%]为女性，97 名[67.8%]为男性，平均[标准差]年龄为 56.8[9.1]岁）。与安慰剂组（中位，6.3 个月；95%CI，5.0-8.1）相比，安罗替尼组的总生存期明显更长（中位，9.6 个月；95%CI，8.2-10.6），风险比（HR）为 0.68（95%CI，0.54-0.87；P = .002）。与安慰剂组相比，安罗替尼组无进展生存期显著延长（中位，5.4 个月[95%CI，4.4-5.6] vs 1.4 个月[95%CI，1.1-1.5]；HR，0.25[95%CI，0.19-0.31]；P < .001）。与安慰剂组相比，安罗替尼组的客观缓解率和疾病控制率显著提高。安罗替尼组最常见的 3 级或更高级别的不良事件是高血压和低钠血症。
在这项试验中，中国患者中，安罗替尼似乎可延长总生存期和无进展生存期。这一发现表明，安罗替尼具有良好的耐受性，可能是晚期 NSCLC 患者的三线或进一步治疗的潜在选择。
ClinicalTrials.gov 标识符：NCT02388919。
