First-Line Doxorubicin Plus Trabectedin Vs Alone Yielded Improved PFS in Metastatic or Unresectable Leiomyosarcomas

Patients with metastatic unresectable leiomyosarcoma in the first line benefitted more from doxorubicin and trabectedin compared with doxorubicin alone.

First-line treatment with doxorubicin and trabectedin (Yondelis) vs doxorubicin alone yielded significantly improved progression-free survival (PFS) in patients with metastatic or unresectable leiomyosarcomas, according to findings from a phase 3 LMS-04 trial (NCT02997358).

The median follow-up was 38.8 months in the combination arm vs 36.9 months in the single-agent arm. The median PFS was 12.2 months (95% CI, 10.1-15.6) in the combination cohort compared with 6.2 months (95% CI, 4.1-7.1) in the monotherapy cohort (HR, 0.41; 95% CI, 0.29-0.58; P <.0001). The 12- and 24-month PFS rates were 16.0% (95% CI, 9.4%-25.9%) and 5.3% (95% CI, 2.1% vs 12.9%) in the monotherapy group compared with 50.7% (95% CI, 39.5%-61.9%) and 30.2% (95% CI, 20.9%-41.5%), respectively, in the combination group.

Patients enrolled on the multicenter, open-label, randomized trial across 20 institutions of the French Sarcoma Group. Disease needed to be histologically confirmed and patients needed to have at least 1 measurable lesion by RECIST 1.1. Patients also needed to be 18 years or older and have an ECOG performance status of 0 or 1. Adequate hematologic, liver, and cardiac function were also required. Exclusion criteria included those with centra nervous system metastases or who had a history of disease followed by complete remission for less than 3 years.

Patients were randomly assigned 1:1 to monotherapy consisting of 75 mg/m2 of doxorubicin once every 3 weeks for up to 6 cycles followed by subcutaneous granulocyte-colony stimulation factor from day 3 to 9 or combination therapy of 60 mg/m2 of doxorubicin and 1.1 mg/m2 of trabectedin on day 1. Patients in this cohort also received pretreatment with 20 mg of dexamethasone 30 minutes prior to receiving trabectedin. Additionally, 6 mg of pegfilgrastim was given on day 2. Although the single-agent arm did not receive maintenance therapy, those in the combination arm who hadn’t progressed after 6 cycles of treatment with doxorubicin and trabectedin were given 1.1 mg/m2 of maintenance trabectedin every 3 weeks until progression or up to 12 months.

The study’s primary end point was PFS, with key secondary end points including disease control rate, response rate, duration of response, safety, and overall survival.

A total of 150 patients were included in the study, of whom 67 had uterine leiomyosarcoma and 83 had soft tissue leiomyosarcoma. Seventy-six patients were included in the monotherapy arm and 74 were included in the combination arm. The median age was 61 years and nearly all patients had metastatic disease (90%). A total of 149 patients underwent at least 1 cycle of treatment with a median of 6 cycles of therapy and 10 cycles of maintenance. Moreover, 14% of patients received surgery, including 20% of patients in the combination group vs 8% of those in the single-agent group.

Partial responses (PRs) were reported in 13% of patients in the single-agent group compared with 36% of those in the combination group, which included 3 complete responses and 24 PRs. Those with uterine leiomyosarcoma treated with the experimental and control regimens, respectively, had response rates of 36% vs 15% and rates of 37% vs 12% were reported in the soft tissue leiomyosarcoma subgroup. The median durations of response in the experimental and control groups, respectively, were 12.7 months and 5.6 months. The disease control rate was 78.9% in the single-agent arm vs 91.9% in the combination arm.

In terms of safety, dose reductions were necessary in 24% of those in the control arm vs 42% of those in the experimental arm. Additionally, 4% of those in the single-agent arm discontinued treatment compared with 23% in the combination arm. Grade 3/4 adverse effects (AEs) were more common in the combination group (96%) vs the monotherapy group (52%). The most common high-grade hematologic AEs in the single-agent and combination groups, respectively, were neutropenia (13% vs 59%), anemia (5% vs 31%), thrombocytopenia (0% vs 47%), and febrile neutropenia (9% vs 28%). Moreover, 9 serious AEs compared with 15 were reported in the monotherapy and combination arms, respectively. Only 1 death was reported, occurring only in the control arm due to cardiac failure.


Pautier P, Italiano A, Piperno-Neumann S, et al. 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. Lancet Oncol. 2022;23(8):1044-1054. doi:10.1016/S1470-2045(22)00380-1