美国斯隆·凯特琳纪念癌症中心William D. Tap联合英国皇家马斯登NHS基金会信托基金和癌症研究所Robin L. Jones团队近日取得一项新成果。他们探讨了阿霉素+Olaratumab与阿霉素+安慰剂对晚期软组织肉瘤患者生存期的影响。该研究于2020年4月7日发表在《美国医学会杂志》上。

晚期软组织肉瘤（STS）患者的平均总生存期不到2年。在一项临床2期研究中，与仅使用阿霉素相比，向阿霉素中添加Olaratumab可增加患者的总体生存获益。

为了确定阿霉素+Olaratumab对晚期/转移性STS患者的疗效，2015年9月至2018年12月，研究组在25个国家/地区的110个地点进行进行了一项确认性、临床3期、双盲、随机试验，招募了509名未接受过蒽环类药物治疗、不可切除的局部晚期或转移性STS患者。将患者按1：1随机分组，其中258例接受阿霉素+Olaratumab治疗，251例接受阿霉素+安慰剂治疗。

509例患者的平均年龄为56.9岁，女性占58.2%，平滑肌肉瘤（LMS）患者占46.0%，所有患者均纳入初始分析。平均随访31个月后，阿霉素+Olaratumab组总STS的中位总生存期为20.4个月，阿霉素+安慰剂组为19.7个月；阿霉素+Olaratumab组LMS的中位总生存期为21.6个月，阿霉素+安慰剂组为21.9个月，差异均不显著。总STS患者中超过15%的3级以上不良反应为中性粒细胞减少、白细胞减少或高热性中性粒细胞减少。

总之，阿霉素+Olaratumab与阿霉素+安慰剂相比，对总体生存期并无明显影响。

附：英文原文

Title: Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas: The ANNOUNCE Randomized Clinical Trial

Author: William D. Tap, Andrew J. Wagner, Patrick Schffski, Javier Martin-Broto, Anders Krarup-Hansen, Kristen N. Ganjoo, Chueh-Chuan Yen, Albiruni R. Abdul Razak, Alexander Spira, Akira Kawai, Axel Le Cesne, Brian A. Van Tine, Yoichi Naito, Se Hoon Park, Alexander Fedenko, Zsuzsanna Pápai, Victoria Soldatenkova, Ashwin Shahir, Gary Mo, Jennifer Wright, Robin L. Jones

Issue&Volume: 2020/04/07

Abstract: Importance  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.

Objective  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.

Interventions  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.

Main Outcomes and Measures  Dual primary end points were overall survival with doxorubicin plus olaratumab vs doxorubicin plus placebo in total STS and leiomyosarcoma (LMS) populations.

Results  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%).

Conclusions and Relevance  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.

DOI: 10.1001/jama.2020.1707

Source: https://jamanetwork.com/journals/jama/article-abstract/2764181