Trabectedin in combination with doxorubicin for first-line treatment of advanced uterine or soft-tissue leiomyosarcoma (LMS-02): a non-randomised, multicentre, phase 2 trial

Background Metastatic leiomyosarcomas of uterine or soft-tissue origin have poor prognosis and moderate chemosensitivity. Trabectedin has shown activity in pretreated leiomyosarcoma. We did a single-group, multicentre, phase 2 trial (LMS-02) to assess the effect of first-line doxorubicin and trabectedin combination on disease control and survival. Methods Adults (18 years to physiological age <= 70 years) with measurable metastatic or unresectable uterine leiomyosarcoma or soft-tissue leiomyosarcoma who had not received any previous chemotherapy were enrolled at 19 centres in France. Treatment consisted of 60 mg/m(2) intravenous doxorubicin followed by 1.1 mg/m(2) trabectedin in a 3 h intravenous infusion on day 1, both by the central venous route, and 6 mg subcutaneous pegfilgrastim on day 2, repeated every 3 weeks for up to six cycles. Surgery for residual disease was permitted. The primary endpoint was the proportion of patients achieving disease control, defined as complete or partial response or stable disease. Stratification was done by anatomical site and analyses were per protocol. This study is registered with ClinicalTrials.gov, number NCT02131480. Findings Between July 28, 2010, and May 10, 2013, 109 patients were enrolled and treated, of whom 108 were assessable for response: 47 in the uterine leiomyosarcoma group and 61 in the soft-tissue leiomyosarcoma group. 32 (68%) patients in the uterine leiomyosarcoma group and 45 (74%) in the soft-tissue leiomyosarcoma group received all six cycles of treatment. Of 47 patients with uterine leiomyosarcoma, 28 (59.6%, 95% CI 44.3-73.6) achieved a partial response and 13 (27.7%, 15.6-42.6) stable disease; 41 (87.2%, 74.3-95.2) patients achieved disease control. Of 61 patients with soft-tissue leiomyosarcoma, two (3.3%, 95% CI 0.4-11.7) achieved a complete response, 22 (36.1%, 25.0-50.8) had a partial response, and 32 (52.5%, 40.8-67.3) had stable disease; 56 (91.8%, 81.9-97.3) of patients achieved disease control. The most common grade 3-4 treatment-associated adverse events were neutropenia (84 [78%] of 108 patients), increased alanine aminotransferase concentration (42 [39%]), thrombocytopenia (40 [37%]), anaemia (29 [27%]), febrile neutropenia (26 [24%]), and fatigue (21 [19%]). Interpretation Despite expected but manageable toxic effects, these results support the activity of doxorubicin plus trabectedin as first-line treatment for uterine leiomyosarcoma and soft-tissue leiomyosarcoma. This combination should be developed further in a phase 3 trial against the present standard of care.