异环磷酰胺和依托泊苷（IE）的组合通常用于治疗复发或难治性骨肉瘤；然而，不同指南的二线治疗建议有所不同。旨在评估 IE 中添加仑伐替尼 (LEN-IE) 是否可以改善患有复发性或难治性骨肉瘤的儿童和年轻人的预后。OLIE II 期、开放标签、随机临床试验是在欧洲、亚洲和太平洋地区以及北美等全球范围内进行的。从2020年3月22日到2021年11月11日，该试验招募了年龄为2至25岁的重度骨肉瘤患者，根据实体瘤疗效评估标准1.1版（RECIST 1.1）和1至2版可测量或可评估疾病先前的系统治疗线。数据分析是在2020年3月22日（第一位患者）和2022年6月22日（主要分析的数据截止日期）和2023年9月29日（研究最终数据库锁定结束）之间进行的。OLIE试验评估了疗效和仑伐替尼（每天口服一次 14 mg/m2）联合最多 5 个周期的异环磷酰胺（静脉注射 3000 mg/m2）和依托泊苷（静脉注射 100 mg/m2）（每个周期的第 1 至 3 天）与单独使用 IE 相比的安全性相同的剂量。通过独立影像学审查，随机接受 IE 的患者可以在疾病进展时交叉接受乐伐替尼。主要终点是独立影像学审查根据 RECIST 1.1 得出的无进展生存期 (PFS)。 Kaplan-Meier 方法用于估计 PFS 分布，通过分层对数秩检验预先指定单侧显着性阈值 0.025。次要终点包括 4 个月时的 PFS 率和总生存期。使用描述性统计数据总结不良事件。 共有 81 名患者入组（中位 [IQR] 年龄，15.0 [12.0-18.0] 岁；46 名男性 [56.8%]），其中 LEN-IE 组 40 名，对照组 41 名。即臂。 LEN-IE 组的中位 PFS 为 6.5 个月（95% CI，5.7-8.2 个月），IE 组为 5.5 个月（95% CI，2.9-6.5 个月）（风险比 [HR]，0.54；95% CI） ，0.27-1.08；1边P = .04)。 LEN-IE 组 4 个月时的 PFS 率为 76.3%（95% CI，59.3%-86.9%），IE 组为 66.0%（95% CI，47.7%-79.2%）。 LEN-IE 组的中位总生存期为 11.9 个月（95% CI，10.1 个月至不可估计），而 IE 组的中位总生存期为 17.4 个月（95% CI，14.2 个月至不可估计）（HR，1.28；95% CI，0.60-2.70； 1 面标称 P = .75)。 LEN-IE 组 39 名患者中有 35 名患者 (89.7%) 发生了 3 级或以上治疗相关不良事件，IE 组 39 名患者中有 31 名患者 (79.5%) 发生了 3 级或以上治疗相关不良事件。与 IE 相比，PFS 得到改善，这项研究证明了国际合作和随机临床试验对复发或难治性骨肉瘤患者的重要性，并可能为未来的试验设计提供信息。ClinicalTrials.gov 标识符：NCT04154189。

The combination of ifosfamide and etoposide (IE) is commonly used to treat relapsed or refractory osteosarcoma; however, second-line treatment recommendations vary across guidelines.To evaluate whether the addition of lenvatinib to IE (LEN-IE) improves outcomes in children and young adults with relapsed or refractory osteosarcoma.The OLIE phase II, open-label, randomized clinical trial was conducted globally across Europe, Asia and the Pacific, and North America. From March 22, 2020, through November 11, 2021, the trial enrolled patients aged 2 to 25 years with high-grade osteosarcoma, measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), and 1 to 2 prior lines of systemic treatment. The data analyses were performed between March 22, 2020 (first patient in) and June 22, 2022 (data cutoff for the primary analysis), and September 29, 2023 (end of study final database lock).The OLIE trial assessed the efficacy and safety of lenvatinib (14 mg/m2 taken orally once daily) combined with up to 5 cycles of ifosfamide (3000 mg/m2 intravenously) and etoposide (100 mg/m2 intravenously) on days 1 to 3 of each cycle vs IE alone at the same doses. Patients randomized to IE could cross over to receive lenvatinib upon disease progression by independent imaging review.The primary end point was progression-free survival (PFS) per RECIST 1.1 by independent imaging review. The Kaplan-Meier method was used to estimate the PFS distribution, with a prespecified 1-sided significance threshold of .025 by stratified log-rank test. Secondary end points included PFS rate at 4 months and overall survival. Adverse events were summarized using descriptive statistics.A total of 81 patients were enrolled (median [IQR] age, 15.0 [12.0-18.0] years; 46 males [56.8%]), with 40 in the LEN-IE arm and 41 in the IE arm. Median PFS was 6.5 months (95% CI, 5.7-8.2 months) for the LEN-IE arm and 5.5 months (95% CI, 2.9-6.5 months) for the IE arm (hazard ratio [HR], 0.54; 95% CI, 0.27-1.08; 1-sided P = .04). The rate of PFS at 4 months was 76.3% (95% CI, 59.3%-86.9%) in the LEN-IE arm and 66.0% (95% CI, 47.7%-79.2%) in the IE arm. Median overall survival was 11.9 months (95% CI, 10.1 months to not estimable) with LEN-IE and 17.4 months (95% CI, 14.2 months to not estimable) with IE (HR, 1.28; 95% CI, 0.60-2.70; 1-sided nominal P = .75). Grade 3 or higher treatment-related adverse events occurred in 35 of 39 patients (89.7%) in the LEN-IE arm and 31 of 39 patients (79.5%) in the IE arm.Although LEN-IE did not meet prespecified statistical significance for improved PFS vs IE, this study demonstrates the importance of international collaboration and randomized clinical trials in patients with relapsed or refractory osteosarcoma and may inform future trial design.ClinicalTrials.gov Identifier: NCT04154189.