Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Medicine, Weill Cornell Medical College, New York, New York.
JAMA. 2020 Apr 7;323(13):1266-1276. doi: 10.1001/jama.2020.1707.
Patients with advanced soft tissue sarcoma (STS) have a median overall survival of less than 2 years. In a phase 2 study, an overall survival benefit in this population was observed with the addition of olaratumab to doxorubicin over doxorubicin alone.
To determine the efficacy of doxorubicin plus olaratumab in patients with advanced/metastatic STS.
DESIGN, SETTING, AND PARTICIPANTS: ANNOUNCE was a confirmatory, phase 3, double-blind, randomized trial conducted at 110 sites in 25 countries from September 2015 to December 2018; the final date of follow-up was December 5, 2018. Eligible patients were anthracycline-naive adults with unresectable locally advanced or metastatic STS, an Eastern Cooperative Oncology Group performance status of 0 to 1, and cardiac ejection fraction of 50% or greater.
Patients were randomized 1:1 to receive doxorubicin, 75 mg/m2 (day 1), combined with olaratumab (n = 258), 20 mg/kg in cycle 1 and 15 mg/kg in subsequent cycles, or placebo (n = 251) on days 1 and 8 for up to 8 21-day cycles, followed by olaratumab/placebo monotherapy.
Dual primary end points were overall survival with doxorubicin plus olaratumab vs doxorubicin plus placebo in total STS and leiomyosarcoma (LMS) populations.
Among the 509 patients randomized (mean age, 56.9 years; 58.2% women; 46.0% with LMS), all were included in the primary analysis and had a median length of follow-up of 31 months. No statistically significant difference in overall survival was observed between the doxorubicin plus olaratumab group vs the doxorubicin plus placebo group in either population (total STS: hazard ratio, 1.05 [95% CI, 0.84-1.30], P = .69, median overall survival, 20.4 months vs 19.7 months; LMS: hazard ratio, 0.95 [95% CI, 0.69-1.31], P = .76, median overall survival, 21.6 months vs 21.9 months). Adverse events of grade 3 or greater reported in 15% or more of total patients with STS were neutropenia (46.3% vs 49.0%), leukopenia (23.3% vs 23.7%), and febrile neutropenia (17.5% vs 16.5%).
In this phase 3 clinical trial of patients with advanced STS, treatment with doxorubicin plus olaratumab vs doxorubicin plus placebo resulted in no significant difference in overall survival. The findings did not confirm the overall survival benefit observed in the phase 2 trial.
ClinicalTrials.gov Identifier: NCT02451943.
患有晚期软组织肉瘤（STS）的患者的总体中位生存期不足 2 年。在一项 2 期研究中，与多柔比星单药治疗相比，在该人群中添加奥拉单抗可观察到总体生存获益。
确定多柔比星联合奥拉单抗在晚期/转移性 STS 患者中的疗效。
设计、地点和参与者：ANNOUNCE 是一项在 25 个国家的 110 个地点进行的确认性、3 期、双盲、随机试验；随访的最终日期为 2018 年 12 月 5 日。符合条件的患者为未经蒽环类药物治疗的不可切除的局部晚期或转移性 STS 成人，东部合作肿瘤学组（ECOG）体能状态为 0 至 1，射血分数为 50%或更高。
患者以 1:1 的比例随机接受多柔比星 75mg/m2（第 1 天）联合奥拉单抗（n=258）或安慰剂（n=251），在第 1 天和第 8 天接受多达 8 个 21 天周期的治疗，随后接受奥拉单抗/安慰剂单药治疗。
主要终点是总 STS 和平滑肌肉瘤（LMS）人群中多柔比星联合奥拉单抗与多柔比星联合安慰剂的总生存期。
在 509 名随机分组的患者（平均年龄 56.9 岁；58.2%为女性；46.0%为 LMS）中，所有患者均纳入主要分析，并中位随访 31 个月。在总 STS 和 LMS 人群中，与多柔比星联合奥拉单抗组相比，多柔比星联合安慰剂组的总生存期无统计学差异（总 STS：风险比，1.05[95%CI，0.84-1.30]，P=0.69，中位总生存期，20.4 个月比 19.7 个月；LMS：风险比，0.95[95%CI，0.69-1.31]，P=0.76，中位总生存期，21.6 个月比 21.9 个月）。STS 患者中报告发生率为 15%或以上的 3 级或更高级别的不良事件为中性粒细胞减少症（46.3%比 49.0%）、白细胞减少症（23.3%比 23.7%）和发热性中性粒细胞减少症（17.5%比 16.5%）。
在这项针对晚期 STS 患者的 3 期临床试验中，与多柔比星联合奥拉单抗相比，多柔比星联合安慰剂治疗并未显著改善总体生存期。研究结果并未证实 2 期试验中观察到的总体生存获益。
ClinicalTrials.gov 标识符：NCT02451943。
