Doxorubicin alone versus doxorubicin with trabectedin followed by trabectedin alone as first-line therapy for metastatic or unresectable leiomyosarcoma (LMS-04): a randomised, multicentre, open-label phase 3 trial.

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/m

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.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests PP has received research funding from PharmaMar, Onxeo (Bristol Myers Squibb [BMS]; all fees to their institution); has received honoraria for lectures and presentations from Merck Shape & Dohme (MSD) and Clovis; has received consultancy fees from MSD, PharmaMar, AstraZeneca, Roche, Onxeo, GlaxoSmithKline (GSK), and Clovis; and has received support for travel or meetings from GSK, PharmaMar, Roche, AstraZeneca, and Amgen. AI has received research funding from AstraZeneca, Bayer, BMS, MSD, Merck, and Roche; and consulting fees from AstraZeneca, Bayer, BMS, MSD, Merck, and Roche. SP-N has received support for travel or attending meetings from PharmaMar. CC has been on a data safety monitoring board or advisory board for Ipsen, Pfizer, ESAI, MSD, and BMS. NF has received support for travel or meetings from PharmaMar. PB-R has received support for travel or attending meetings from Takeda, Pfizer, and Pharmamar; and has received consultancy fees from Ipsen. VL-L has been on a on a data safety monitoring board or advisory board for Ipsen. IR-C has received research funding from BMS, MSD, and GSK; has received honoraria for lectures and presentations from GSK, AstraZeneca, Clovis, Agenus, Deciphera, Mersana, MAcrogenics, Pharmamar, Roche, Novartis, and ESAI; support for attending meetings or travel from AstraZeneca, GSK, Clovis, and Roche; and participated on a data safety monitoring board or advisory board for the Athena trial. EK has received consultancy fees, honoraria for lectures and presentations, support for travel or attending meetings from, and has been on a data safety monitoring board or advisory board for, AstraZeneca, Roche, Sanofi, Tesaro, GSK, and Leopharma. AB has received consultancy fees from Roche. NI has received support for travel or attending meetings from AstraZeneca, Roche, PharmaMar, and Novartis; has been on a data safety monitoring board or advisory board for Ipsen, Daïchi, Senkyo, Transgen, Pfizer, Magen, BMS, and ESAI. All other authors declare no competing interests.