By Lynda Williams, medwireNews Reporter
medwireNews: LMS-04 trial findings show a significant overall survival (OS) benefit with the use of induction and maintenance trabectedin alongside first-line doxorubicin for patients with inoperable, advanced leiomyosarcoma.
The study findings published in The New England Journal of Medicine also confirm that the previously reported significant improvement in the primary endpoint of progression-free survival (PFS) after a median follow-up of 37 months persisted after a median of 55 months.
“The trial results support the use of doxorubicin plus trabectedin for the first-line treatment of advanced or metastatic leiomyosarcomas, offering hope for improved outcomes in this challenging disease area”, say Patricia Pautier (Institut Gustave-Roussy, Villejuif, France) and co-authors.
For the phase 3 trial, 150 patients with metastatic or unresectable leiomyosarcoma of the uterus or soft tissue who had not previously received chemotherapy for advanced disease were randomly assigned to receive six cycles of doxorubicin 60 mg/m2 for 10–15 min followed by trabectedin 1.1 mg/m2 for 3 hours every 3 weeks (n=74) or to receive doxorubicin 75 mg/m2 for 10–15 mins every 3 weeks (n=76). The patients given combination treatment then received maintenance trabectedin at the same dose for up to 17 cycles or until disease progression.
The doxorubicin plus trabectedin and the doxorubicin-only treatment groups were balanced for age (median 59 vs 64 years), sex (72 vs 78% women), site of primary tumour (45% uterus, 55% soft tissue in both arms), and both the presence of metastatic disease (92 vs 88%) and the proportion of patients who had two or more sites of metastases (81 vs 79%).
After a median 55 months of follow-up, OS was a median 33 months with doxorubicin plus trabectedin versus 24 months with doxorubicin alone, giving a significant hazard ratio (HR) for death of 0.65 after adjusting for tumour origin and disease stage. The 2-year rate of OS in the groups was 68% and 49%, respectively.
PFS remained significantly longer with combination than monotherapy in this later analysis, at a median 12 versus 6 months and an adjusted HR for progression or death of 0.37, report Pautier et al.
Moreover, although 59% of the patients in the control arm went on to receive trabectedin as a second-line or later therapy, the time to second disease progression remained significantly longer with first-line doxorubicin plus trabectedin than doxorubicin alone (26 vs 13 months, HR=0.46).
The investigators found that there was “increased toxicity” with doxorubicin plus trabectedin, citing a significantly higher rate of grade 3–4 adverse events (97 vs 56%). They say that there were “notably higher” rates in the first six cycles of treatment of grade 3–4 neutropenia (77 vs 16%), anaemia (43 vs 12%), thrombocytopenia (47 vs 1%) and febrile neutropenia (19 vs 9%).
Nevertheless, 81% of patients given combination therapy completed all six cycles of treatment compared with 71% of those given doxorubicin alone. There was one treatment-related death in a patient given doxorubicin monotherapy.
Pautier and co-authors believe that their study “establishes a benchmark” for OS, noting that “[t]his outcome may be a result of the efficacy of the initial chemotherapy regimen as well as the effects of subsequent treatments, including surgery, which was more feasible after combination therapy than after monotherapy owing to an apparently higher percentage of patients with a response, and maintenance treatment with trabectedin.”
Specifically, 20% of patients given doxorubicin plus trabectedin received surgery after completing induction therapy compared with just 8% of those given doxorubicin only. This included 15 patients with nonuterine sarcoma and six patients with uterine sarcoma, and complete resection was achieved in seven of the eight patients across the two treatment groups who underwent surgery of their primary tumour.
The researchers emphasize the “importance of studying the effect of continuous treatment in the effective management of advanced sarcomas, given that the contribution of the maintenance phase could have been substantial in the survival results” but admit that “its real effect is unknown.”
News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group
N Engl J Med 2024; doi:10.1056/NEJMoa2403394