Doxorubicin-trabectedin a ray of hope for advanced or metastatic LMS

In the phase III LMS04 trial, induction therapy with doxorubicin and trabectedin, followed by trabectedin maintenance, improved survival in patients with metastatic or surgically unresectable soft-tissue or uterine leiomyosarcoma (LMS).

The study showed a progression-free survival (PFS) and overall survival (OS) benefit with a doxorubicin-based combination regimen compared with standard doxorubicin monotherapy as first-line (1L) treatment for advanced LMS, said the researchers.

After a median follow-up of 55 months, the median PFS was longer with the combo regimen vs doxorubicin alone (12 vs 6 months). The hazard ratio (HR) for progression or death was 0.37. The 2-year PFS was substantially greater with the former vs the latter (30 percent vs 3 percent). [N Engl J Med 2024;391:789-799]

The median OS was also markedly longer with the combo regimen than with doxorubicin monotherapy (33 vs 24 months). The HR for death was 0.65. OS at 2 years for the respective arms was 68 percent and 49 percent.

“The median OS [in the combo arm] establishes a benchmark,” the researchers said. This could have been driven by the effects of the initial chemo regimen and subsequent treatments, including surgery, and trabectedin maintenance, which allowed for extended disease control. [Lancet Oncol 2022;23:1044-1054]

Compared with doxorubicin alone, the combo regimen was tied to a higher rate of grade 3/4 adverse events (97 percent vs 56 percent; p<0.001). Nearly half of the combo regimen recipients had grade 3/4 cytolysis vs 3 percent with doxorubicin alone. Nonetheless, 79 percent of those in the combination arm with grade 3/4 cytolysis reversed to grade 0, while the rest improved to grade 1 (15 percent) or 2 (3 percent). There were no reports of chronic liver dysfunction.

Bleak prognosis

Prognosis is bleak for individuals with metastatic or locally advanced LMS, the researchers noted. “[T]he systemic chemo regimen for metastatic soft-tissue sarcoma subtypes has remained largely unchanged, with doxorubicin monotherapy continuing as the standard 1L treatment since its efficacy was first shown in 1973, particularly with regard to sarcomas.”

Only a few trials have investigated 1L treatment in cohorts that only included patients with metastatic LMS. Data from the LMS02 trial underlined the potential of the doxorubicin-based combination therapy, with a response observed in 48 percent of patients and with promising survival outcomes despite considerable toxicities. [Lancet Oncol 2015;16:457-464; ESMO Open 2021;6:100209]

As such, the researchers randomized 150 individuals (83 with soft-tissue LMS, 67 with uterine LMS) 1:1 to IV doxorubicin with SC lenograstim* (median age 64 years, 78 percent women) or IV doxorubicin followed by IV trabectedin with SC pegylated filgrastim** (median age 59 years, 72 percent women). In the combination arm, trabectedin 1.1 mg/m² was continued for up to 17 cycles in patients without disease progression.

“LMS04 has confirmed [the LMS02 findings] while also showing the superior efficacy of the combination therapy over doxorubicin alone – given that an objective tumour response was seen in 36 percent of patients in the combination arm, compared with 13 percent of those in the doxorubicin arm, and that the median PFS nearly doubled [with the combo regimen],” the researchers said.

“The results support doxorubicin plus trabectedin as 1L treatment of advanced or metastatic LMS, offering hope for improved outcomes in this challenging disease area,” they concluded.

A true step forward

Given the rarity of sarcomas, large studies are challenging to conduct, and small studies may not be able to show meaningful improvements, pointed out Dr Robert Benjamin from the University of Texas MD Anderson Cancer Center, Houston, Texas, US, in an accompanying editorial. [N Engl J Med 2024;391:854-855]

While few and far between, sarcomas have diverse subtypes and thus varying drug sensitivities, hence the few therapeutic advances, Benjamin added.

“[Hence, the] investigators found a true benefit in OS, a goal that has eluded the sarcoma community for more than 50 years … Finally, after more than 50 years of single-agent doxorubicin, a true step forward has been taken, and antiquated single-agent chemo is no longer needed,” he said.