In the French phase III LMS-04 trial reported in The Lancet Oncology, Pautier et al found that the addition of trabectedin to doxorubicin significantly prolonged progression-free survival as first-line treatment for patients with unresectable or metastatic leiomyosarcoma.

Study Details

In the open-label multicenter trial, 150 patients were randomly assigned between January 2017 and March 2019 to receive doxorubicin at 60 mg/m² plus trabectedin at 1.1 mg/m² every 3 weeks for up to six cycles, followed by trabectedin maintenance at 1.1 mg/m² every 3 weeks until disease progression or for a maximum of 1 year (n = 74) or doxorubicin at 75 mg/m² every 3 weeks for up to six cycles (n = 76). Overall, 45% of patients and 55% of patients in each group had uterine leiomyosarcoma and soft-tissue leiomyosarcoma, respectively, and 90% of all patients had metastatic disease. Surgery for residual disease was allowed in both groups after six cycles of treatment. The primary endpoint was progression-free survival on blinded independent central review.

Progression-Free Survival

Median follow-up was 37 months (interquartile range = 31–44 months). Median progression-free survival was 12.2 months (95% confidence interval [CI] = 10.1–15.6 months) in the doxorubicin/trabectedin group vs 6.2 months (95% CI = 4.1–7.1 months) in the control group (adjusted hazard ratio [HR] = 0.41, 95% CI = 0.29–0.58, P < .0001). Rates at 12 and 24 months were 50.7% vs 16.0% and 30.2% vs 5.3%.

Objective responses were observed in 27 patients (36%) in the combination group, including complete response in 3, and in 10 patients (13%, all partial responses) in the control group (P = .0009). Median duration of response was 12.7 months vs 5.6 months (HR = 0.36, 95% CI = 0.17–0.77, P = .0090). Surgery for residual disease was performed in 20% of patients in the combination group vs 8% of the control group.

Adverse Events

Grade 3 or 4 adverse events occurred in 96% of patients in the combination group vs 52% of the control group; the most common in the combination group were neutropenia (80% vs 13%), anemia (31% vs 5%), thrombocytopenia (47% vs 0%), and febrile neutropenia (28% vs 9%).

Serious adverse events occurred in 15 patients (20%) in the combination group, most commonly febrile neutropenia (n = 7) and in 9 (12%) in the control group, most commonly febrile neutropenia (n = 3). One treatment-related death was reported, due to cardiac failure in a patient in the control group.

The investigators concluded, “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.”

Patricia Pautier, MD, of Institut Gustave-Roussy, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by PharmaMar. For full disclosures of the study authors, visit thelancet.com.