As reported in The New England Journal of Medicine by Pautier et al, the French Sarcoma Group phase III LMS04 trial showed that the addition of trabectedin to doxorubicin significantly improved progression-free and overall survival in the first-line treatment of unresectable or metastatic uterine or soft-tissue leiomyosarcoma.
Study Details
The open-label multicenter trial started enrollment in January 2017, and the final data cutoff for analysis was in January 2023. A total of 150 patients were randomly assigned to receive trabectedin plus doxorubicin (n = 74) or single-agent doxorubicin (n = 76). Single-agent doxorubicin was given at 75 mg/m2 every 3 weeks for six cycles. Treatment with trabectedin plus doxorubicin consisted of doxorubicin at 60 mg/m2 followed by trabectedin at 1.1 mg/m2 every 3 weeks for six cycles. Patients without disease progression received trabectedin maintenance at the same dose for up to 17 cycles. The primary endpoint was progression-free survival; overall survival was a secondary endpoint. A prior report from the study indicated improved progression-free survival with the combination therapy.
Overall and Progression-Free Survival
A total of 21 patients (28%) given trabectedin plus doxorubicin completed trabectedin maintenance. In the doxorubicin group, 28 patients (37%) received trabectedin as second-line treatment.
Median follow-up was 55 months (interquartile range = 49–63 months). Death occurred in 47 patients in the trabectedin/doxorubicin group and 60 patients in the doxorubicin group. Median overall survival was 33 months (95% confidence interval [CI] = 26–48 months) in the trabectedin/doxorubicin group vs 24 months (95% CI = 19–31 months) in the doxorubicin group (adjusted hazard ratio [aHR] = 0.65, 95% CI = 0.44–0.95). Overall survival at 2 years was 68% vs 49%.
KEY POINTS
- The combination of trabectedin and doxorubicin with selective trabectedin maintenance significantly improved overall survival vs doxorubicin alone in patients with metastatic or surgically unresectable uterine or soft-tissue leiomyosarcoma.
- Median overall survival was 33 months vs 24 months.
With extended follow-up, progression-free survival results were consistent with earlier reports. Median progression-free survival was 12 months (95% CI = 10–16 months) in the trabectedin/doxorubicin group vs 6 months (95% CI = 4–7 months) in the doxorubicin group (aHR = 0.37, 95% CI = 0.26–0.53). The median progression-free survival rate at 2 years was 30% vs 3%.
Adverse Events
Grade 3 or 4 adverse events occurred in 97% of the trabectedin/doxorubicin group vs 56% of the doxorubicin group (P < .001), with hematologic adverse events being more common with the combination. Serious adverse events occurred in 50% vs 27% of patients. Completion of six cycles of treatment was achieved in 60 patients (81%) in the trabectedin/doxorubicin group and 54 patients (71%) in the doxorubicin group. One treatment-related death was reported, the result of cardiac failure in a patient in the doxorubicin group.
The investigators concluded: “Combination therapy with doxorubicin and trabectedin induction, followed by trabectedin maintenance, was associated with improved overall survival and progression-free survival, as compared with doxorubicin alone, among patients with metastatic or surgically unresectable uterine or soft-tissue leiomyosarcoma.”
Patricia Pautier, MD, of the Departement de Medecine, Institut Gustave-Roussy, Villejuif, is the corresponding author of The New England Journal of Medicine article.
Disclosure: The study was funded by PharmaMar and others. For full disclosures of the study authors, visit www.nejm.org.
