Background

Metastatic leiomyosarcomas have a poor prognosis, and currently doxorubicin alone is used as the standard first-line treatment. Doxorubicin combined with trabectedin has shown promising results in phase 1 and 2 studies. We aimed to identify and compare the progression-free survival of patients with metastatic or unresectable uterine or soft tissue leiomyosarcoma treated with doxorubicin and trabectedin combined as first-line therapy versus doxorubicin alone in a phase 3 trial.

Methods

LMS-04 was a randomised, multicentre, open-label, superiority phase 3 trial, which included patients from 20 centres of the French Sarcoma Group (anticancer centers or hospitals with an oncological unit) in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0–1, and had metastatic or relapsed unresectable leiomyosarcomas that had not previously been treated with chemotherapy. Patients were randomly assigned (1:1), by means of an interactive web response system (permuted blocks of different sizes from two to six), to receive either intravenous doxorubicin alone (75 mg/m²) once every 3 weeks for up to six cycles or of intravenous doxorubicin (60 mg/m²) plus intravenous trabectedin (1·1 mg/m²) once every 3 weeks up to six cycles followed by maintenance with trabectedin alone. Surgery for residual disease was allowed in both groups after six cycles of treatment. Randomisation was stratified by tumour location (uterine vs soft tissue) and disease (locally advanced vs metastatic). The primary endpoint was progression-free survival assessed by blinded independent central review and according to Response Evaluation Criteria in Solid Tumours 1.1 criteria. Efficacy analyses were performed on all randomly assigned patients, based on the intention-to-treat principle. The safety population included all randomly assigned patients who received at least one cycle of treatment. This trial is registered with ClinicalTrials.gov, NCT02997358, and is closed to enrolment.

Findings

Between Jan 18, 2017, and March 21, 2019, 150 patients were enrolled (67 with uterine leiomyosarcomas and 83 with soft tissue leiomyosarcomas) and included in the intention-to-treat population: 76 in the doxorubicin alone group and 74 in the doxorubicin plus trabectedin group. The median duration of follow-up was 36·9 months (IQR 30·0–43·2) in the doxorubicine group and 38·8 months (32·7–44·2) in the doxorubicin plus trabectedin group. Median progression-free survival was significantly longer with doxorubicin plus trabectedin versus doxorubicin alone (12·2 months [95% CI 10·1–15·6] vs 6·2 months [4·1–7·1]; adjusted hazard ratio 0·41 [95% CI 0·29–0·58]; p<0·0001). The most common grade 3–4 adverse events were neutropenia (ten [13%] of 75 patients in the doxorubicin alone group vs 59 [80%] in the doxorubicin plus trabectedin group), anaemia (four [5%] vs 23 [31%]), thrombocytopenia (0 vs 35 [47%]), and febrile neutropenia (seven [9%] vs 21 [28%]). Nine (12%) patients in the doxorubicin alone group and 15 (201%) patients in the doxorubicin plus trabectedin group has serious adverse events. There was only one treatment-related death, reported in the doxorubicin alone group (cardiac failure).

Interpretation

Doxorubicin plus trabectedin in first-line therapy was found to significantly increase progression-free survival in patients with metastatic or unresectable leiomyosarcomas compared with doxorubicin alone, despite a higher but manageable toxicity, and could be considered an option for the first-line treatment of metastatic leiomyosarcomas.

Funding

PharmaMar.

中文翻译：

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多柔比星单独与多柔比星联合曲贝替定继之以曲贝替定单独作为转移性或不可切除的平滑肌肉瘤的一线治疗 (LMS-04)：一项随机、多中心、开放标签的 3 期试验

背景

转移性平滑肌肉瘤预后较差，目前单用多柔比星作为标准一线治疗。阿霉素联合曲贝替定在 1 期和 2 期研究中显示出可喜的结果。我们的目的是在一项 3 期试验中确定和比较阿霉素和曲贝替定联合一线治疗与阿霉素单独治疗的转移性或不可切除子宫或软组织平滑肌肉瘤患者的无进展生存期。

方法

LMS-04 是一项随机、多中心、开放标签、优效性的 3 期试验，其中包括来自法国法国肉瘤集团 20 个中心（抗癌中心或设有肿瘤科的医院）的患者。符合条件的患者年龄在 18 岁或以上，东部肿瘤协作组体能状态为 0-1，并且患有转移性或复发性不可切除的平滑肌肉瘤，且之前未接受过化疗。患者被随机分配 (1:1)，通过交互式网络响应系统（排列不同大小的块，从 2 到 6），接受每 3 周一次的单独静脉阿霉素 (75 mg/m ² )，持续时间长达六个周期或静脉阿霉素 (60 mg/m ² ) 加静脉曲贝替定 (1·1 mg/m ²) 每 3 周一次，最多六个周期，然后单独使用曲贝替定进行维持。六个疗程后，两组均允许手术治疗残留病灶。随机化按肿瘤位置（子宫与软组织）和疾病（局部晚期与转移）分层。主要终点是无进展生存期，由盲法独立中央审查根据实体瘤反应评估标准 1.1 标准评估。根据意向治疗原则，对所有随机分配的患者进行了疗效分析。安全人群包括所有接受至少一个治疗周期的随机分配患者。该试验已在 ClinicalTrials.gov 注册，编号为 NCT02997358，并且已停止注册。

发现

2017 年 1 月 18 日至 2019 年 3 月 21 日期间，共招募了 150 名患者（67 名子宫平滑肌肉瘤患者和 83 名软组织平滑肌肉瘤患者）并纳入意向治疗人群：阿霉素单独治疗组 76 名，阿霉素治疗组 74 名加上曲贝定组。阿霉素组的中位随访时间为 36·9 个月 (IQR 30·0–43·2)，阿霉素联合曲贝替定组为 38·8 个月 (32·7–44·2)。阿霉素联合曲贝替定组的中位无进展生存期显着长于单用阿霉素组（12·2 个月 [95% CI 10·1–15·6]对比6·2 个月 [4·1–7·1]；调整后的风险比0·41 [95% CI 0·29–0·58]；p<0·0001）。最常见的 3-4 级不良事件是中性粒细胞减少（多柔比星单药组 75 名患者中有 10 名 [13% ]阿霉素加曲贝替定组 59 [80%]）、贫血（4 [5%] vs 23 [31%]）、血小板减少症（0 vs 35 [47%]）和发热性中性粒细胞减少症（7 [9%] vs 21 [28%]）。多柔比星单药组中有 9 名 (12%) 患者和多柔比星联合曲贝替定组中有 15 名 (201%) 患者出现严重不良事件。只有一例与治疗相关的死亡发生在多柔比星单药组（心力衰竭）中。

解释

与单用多柔比星相比，多柔比星加曲贝替定一线治疗可显着延长转移性或不可切除平滑肌肉瘤患者的无进展生存期，尽管毒性较高但可控，可被视为转移性平滑肌肉瘤一线治疗的选择平滑肌肉瘤。

资金

PharmaMar。