Background
LMS-04 — Phase III multicentre, open-label, randomised controlled trial. N=150 patients with metastatic or surgically unresectable uterine or soft-tissue leiomyosarcoma (LMS), previously untreated with systemic therapy for advanced disease. Enrolled at 26 French institutions 2016–2020. Hypothesis: combining doxorubicin with trabectedin followed by trabectedin maintenance would improve outcomes in LMS based on trabectedin's unique mechanism (minor groove DNA binding, interaction with transcription-coupled nucleotide excision repair) and prior phase II evidence of trabectedin activity in LMS. Registration NCT02997358.
Interventions and follow up
Arm A: Doxorubicin 75 mg/m² + trabectedin 1.1 mg/m² q3w × 6 cycles → trabectedin maintenance until progression
Arm B: Doxorubicin 75 mg/m² q3w × 6 cycles
Primary endpoint: Progression-free survival (PFS, initial Lancet Oncol 2022); Overall survival updated in NEJM 2024
mFollow up: Updated analysis with mature OS data (NEJM 2024)
Arm B: Doxorubicin 75 mg/m² q3w × 6 cycles
Primary endpoint: Progression-free survival (PFS, initial Lancet Oncol 2022); Overall survival updated in NEJM 2024
mFollow up: Updated analysis with mature OS data (NEJM 2024)
Results
mPFS: 12 months (dox + trab) vs 6 months (dox alone); HR 0.37 (95% CI 0.26–0.53), P<.0001
mOS: 33 months (dox + trab) vs 24 months (dox alone); HR 0.65 (95% CI 0.44–0.95), P<.05
mOS: 33 months (dox + trab) vs 24 months (dox alone); HR 0.65 (95% CI 0.44–0.95), P<.05
Adverse events
Main adverse events: Grade ≥3 AEs more frequent with combination: neutropenia, nausea, elevated liver transaminases, fatigue. Dose reductions more frequent in combination arm. No unexpected safety signals beyond known trabectedin toxicity profile. Hepatotoxicity (reversible transaminase elevation) is characteristic of trabectedin and was managed with dose modifications.
Conclusions
Doxorubicin + trabectedin followed by trabectedin maintenance significantly improved both PFS (12 vs 6 months, HR 0.37) and OS (33 vs 24 months, HR 0.65) compared with doxorubicin alone in first-line metastatic or unresectable LMS. This is the first phase III trial to demonstrate an OS benefit over doxorubicin monotherapy for LMS, establishing this combination as a new standard of care for first-line metastatic/unresectable LMS.
Key Limitations
Single-country trial (France) limiting generalisability. N=150 is modest for a phase III trial, though the effect size was robust. Trabectedin requires prolonged IV infusion and has a complex drug interaction profile. No BRCA or HRD biomarker stratification — subgroup analyses were exploratory. Both uterine and soft-tissue LMS were included; subtype-specific effects are not fully characterised. Trabectedin is not approved in all countries for first-line LMS. The LMS04 regimen is more intensive than doxorubicin alone and requires experienced clinical management.
Clinical Context
LMS04 changes first-line practice for metastatic/unresectable LMS in countries where trabectedin is available. ESMO and NCCN are expected to update guidelines to include dox+trabectedin → trabectedin maintenance as a preferred first-line option for LMS. Trabectedin is already EMA-approved for advanced STS after failure of anthracyclines (EU). The LMS-04 Lancet Oncol 2022 initial publication reported PFS improvement; the NEJM 2024 update confirmed the OS benefit. Gemcitabine + docetaxel remains an alternative second-line option. First-line immunotherapy combinations for LMS remain investigational.
Arm A (dox + trabectedin, n=75): Doxorubicin 75 mg/m² IV + trabectedin 1.1 mg/m² IV (24h infusion) q3w × 6 cycles, then trabectedin maintenance 1.5 mg/m² IV q3w until PD or unacceptable toxicity
Arm B (doxorubicin alone, n=75): Doxorubicin 75 mg/m² IV q3w × 6 cycles, then follow-up
Arm A (dox + trabectedin, n=75): Doxorubicin 75 mg/m² IV + trabectedin 1.1 mg/m² IV (24h infusion) q3w × 6 cycles, then trabectedin maintenance 1.5 mg/m² IV q3w until PD or unacceptable toxicity
Arm B (doxorubicin alone, n=75): Doxorubicin 75 mg/m² IV q3w × 6 cycles, then follow-up