KEY TAKEAWAYS
- The LMS-04 phase 3 trial compared the efficacy of combining doxorubicin and trabectedin as first-line therapy versus doxorubicin alone in treating metastatic or unresectable uterine or soft tissue leiomyosarcoma.
- To be eligible for the trial, patients had to be 18 years or older, have an Eastern Cooperative Oncology Group performance status of 0-1, and have leiomyosarcomas that had not been treated with chemotherapy before were either metastatic or unresectable relapsed.
- The trial’s primary objective was to identify and compare progression-free survival between the two groups.
- Combining doxorubicin and trabectedin improved PFS in metastatic leiomyosarcoma as a first-line treatment with manageable toxicity.
Metastatic leiomyosarcomas are associated with a dismal prognosis. Currently, doxorubicin is the standard first-line treatment; however, its efficacy is limited. Combining doxorubicin with trabectedin has demonstrated encouraging results in phase 1 and 2 trials. The study’s objective was to evaluate and contrast the progression-free survival (PFS) of patients diagnosed with metastatic or unresectable uterine or soft tissue leiomyosarcoma who received either doxorubicin alone or a combination of doxorubicin and trabectedin as first-line therapy in a phase 3 trial.
LMS-04 was a phase 3 clinical trial conducted in 20 centers of the French Sarcoma Group, aimed at evaluating the superiority of intravenous doxorubicin alone versus a combination of intravenous doxorubicin and intravenous trabectedin followed by maintenance with trabectedin alone, in patients with metastatic or relapsed unresectable leiomyosarcomas. Patients aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0-1 and no prior chemotherapy treatment were eligible for the study. Patients were assigned to treatment groups randomly using an interactive web response system with different block sizes. One group received intravenous doxorubicin alone at 75 mg/m2 every three weeks for up to six cycles. In contrast, the other group received intravenous doxorubicin at a lower dose (60 mg/m2) combined with intravenous trabectedin (1·1 mg/m2) every three weeks for up to six cycles by maintenance with trabectedin alone. After six treatment cycles, both groups were allowed to undergo surgery for residual disease. Randomization was stratified according to tumor location (uterine vs. soft tissue) and disease status (locally advanced vs. metastatic). The primary outcome was PFS, assessed by a BICR and based on RECIST 1.1 criteria. All randomly assigned patients were included in efficacy analyses based on the intention-to-treat principle, while the safety population comprised those who received at least one treatment cycle.
From January 18, 2017, to March 21, 2019, a total of 150 patients were enrolled in the study, including 67 with uterine leiomyosarcomas and 83 with soft tissue leiomyosarcomas. All patients were included in the intention-to-treat population, with 76 assigned to the doxorubicin alone group and 74 to the doxorubicin plus trabectedin group. The median follow-up duration was 36.9 months (interquartile range [IQR] 30.0-43.2) in the doxorubicin group and 38.8 months (IQR 32.7-44.2) in the doxorubicin plus trabectedin group. The study found that median progression-free survival was significantly longer in the doxorubicin plus trabectedin group compared to the doxorubicin alone group (12.2 months [95% confidence interval (CI) 10.1-15.6] vs. 6.2 months [95% CI 4.1-7.1]; adjusted hazard ratio 0.41 [95% CI 0.29-0.58]; p<0.0001). The most common grade 3-4 adverse events observed were neutropenia (10 [13%] out of 75 patients in the doxorubicin alone group vs. 59 [80%] in the doxorubicin plus trabectedin group), anemia (4 [5%] vs. 23 [31%]), thrombocytopenia (0 vs. 35 [47%]), and febrile neutropenia (7 [9%] vs. 21 [28%]). Serious adverse events occurred in 9 (12%) patients in the doxorubicin alone group and 15 (20%) patients in the doxorubicin plus trabectedin group. One treatment-related death due to cardiac failure was reported in the doxorubicin alone group.
The addition of trabectedin to first-line therapy with doxorubicin significantly improved progression-free survival in patients with metastatic or unresectable leiomyosarcomas compared to treatment with doxorubicin alone. Although the combination treatment was associated with a higher incidence of manageable side effects, it represents a viable option for the initial treatment of metastatic leiomyosarcomas.
Source: https://pubmed.ncbi.nlm.nih.gov/35835135/
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT02997358/
Pautier P, Italiano A, Piperno-Neumann S, Chevreau C, Penel N, Firmin N, Boudou-Rouquette P, Bertucci F, Balleyguier C, Lebrun-Ly V, Ray-Coquard I, Kalbacher E, Bardet A, Bompas E, Collard O, Isambert N, Guillemet C, Rios M, Archambaud B, Duffaud F; French Sarcoma Group. Doxorubicin alone versus doxorubicin with trabectedin followed by trabectedin alone as first-line therapy for metastatic or unresectable leiomyosarcoma (LMS-04): a randomized, multicentre, open-label phase 3 trial. Lancet Oncol. 2022 Aug;23(8):1044-1054. doi: 10.1016/S1470-2045(22)00380-1. Epub 2022 Jul 11. PMID: 35835135.
