Importance The combination of ifosfamide and etoposide (IE) is commonly used to treat relapsed or refractory osteosarcoma; however, second-line treatment recommendations vary across guidelines. Objective To evaluate whether the addition of lenvatinib to IE (LEN-IE) improves outcomes in children and young adults with relapsed or refractory osteosarcoma. Design, Setting, and Participants 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). Interventions 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. Main Outcomes and Measures 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. Results 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. Conclusions and Relevance 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. Trial Registration ClinicalTrials.gov Identifier: NCT04154189.

中文翻译：

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Lenvatinib 联合异环磷酰胺和依托泊苷治疗复发性骨肉瘤儿童和年轻人：一项 2 期随机临床试验。


重要性 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，二线治疗建议因指南而异。目的 评价 IE （LEN-IE） 联合 lenvatinib 是否能改善复发或难治性骨肉瘤儿童和年轻人的预后。设计、设置和参与者OLIE II 期、开放标签、随机临床试验在欧洲、亚太地区和北美在全球范围内进行。从 2020 年 3 月 22 日到 2021 年 11 月 11 日，该试验招募了 2 至 25 岁的高级别骨肉瘤患者，根据实体瘤反应评估标准 1.1 版 （RECIST 1.1） 和 1 至 2 线既往全身治疗。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）和 2023 年 9 月 29 日（研究结束最终数据库锁定）期间进行的。干预措施 OLIE 试验评估了乐伐替尼（14 mg/m2，口服，每天一次）在每个周期的第 1 至 3 天联合最多 5 个周期的异环磷酰胺（3000 mg/m2，静脉注射）和依托泊苷（100 mg/m2，静脉注射）与单独使用相同剂量的 IE 的疗效和安全性。随机分配到 IE 的患者可以通过独立的影像学审查在疾病进展时交叉接受 lenvatinib。主要结局和措施 主要终点是独立影像学审查根据 RECIST 1.1 的无进展生存期 （PFS）。采用 Kaplan-Meier 方法估计 PFS 分布，通过分层对数秩检验预先指定的 1 侧显著性阈值为 .025。次要终点包括 4 个月时的 PFS 率和总生存期。 使用描述性统计对不良事件进行总结。结果 共纳入 81 例患者 （中位 [IQR] 年龄，15.0 [12.0-18.0] 岁;46 例男性 [56.8%]），其中 LEN-IE 组 40 例，IE 组 41 例。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 侧 P = .04）。LEN-IE 组 4 个月时的 PFS 发生率为 76.3% （95% CI，59.3%-86.9%），IE 组为 66.0% （95% CI，47.7%-79.2%）。LEN-IE 的中位总生存期为 11.9 个月 （95% CI，10.1 个月至不可估计），IE 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 侧名义 P = .75）。LEN-IE 组 39 例患者中有 35 例 （89.7%） 发生 3 级或更高级别治疗相关不良事件，IE 组 39 例患者中有 31 例 （79.5%） 发生。结论和相关性 尽管 LEN-IE 与 IE 相比没有达到改善 PFS 的预先指定的统计学意义，但本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。试验注册 ClinicalTrials.gov 标识符： NCT04154189.