Trabectedin (Yondelis) improved progression-free survival (PFS) when compared with dacarbazine in women with advanced uterine leiomyosarcoma, according to a subgroup analysis of the phase III SAR-3007 trial.
Patients with uterine leiomyosarcoma who received trabectedin had a median PFS of 4.0 months versus 1.5 months with dacarbazine, almost identical to previously reported results in the overall study population of patients with leiomyosarcoma and liposarcoma. Treatment with trabectedin did not extend overall survival (OS), the trial’s primary endpoint, which was consistent with the overall analysis.
“Trabectedin is an important new treatment option for patients with advanced uterine leiomyosarcoma that has progressed after anthracycline-containing treatment,” lead author Martee L. Hensley, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, said when presenting the results at the meeting.
The open-label, multicenter, phase III SAR-3007 trial compared trabectedin with dacarbazine in 518 patients with advanced liposarcoma and leiomyosarcoma who previously received an anthracycline-containing regimen followed by at least one additional line of chemotherapy.2
Patients were randomized in a 2:1 ratio to 1.5 mg/m2 of trabectedin (n = 345) or 1.0 g/m2 of dacarbazine (n = 173) once every 3 weeks until disease progression or unacceptable toxicity. Trabectedin was administered through a catheter as an IV infusion over 24 hours and patients received dacarbazine as a 20- to 120-minute infusion. Patients in the trabectedin arm received 20 mg of IV dexamethasone as a premedication.
In the overall study population, treatment with trabectedin did not meet the primary endpoint of OS, with a median OS of 13.7 months versus 13.1 months for dacarbazine (HR, 0.93; 95% CI, 0.75-1.15;P= .49). However, patients in the trabectedin group had a significantly improved median PFS of 4.2 months versus 1.5 months for dacarbazine (HR, 0.55; 95% CI, 0.44-0.70;P<.001).
The overall findings from the trial led to FDA approval last year of trabectedin as a second-line therapy for unresectable leiomyosarcoma or liposarcoma following first-line anthracycline therapy.
An initial subgroup analysis showed that patients with leiomyosarcoma or liposarcoma derived similar benefit from trabectedin (HR, 0.56; HR, 0.55, respectively, versus dacarbazine), Hensley noted. Patients with leiomyosarcoma accounted for almost three-fourths of the patients included in the overall analysis. In the leiomyosarcoma subgroup, 40% of patients had uterine leiomyosarcoma.
Hensley reported findings from a subgroup analysis limited to the 232 patients with uterine leiomyosarcoma. Patients in the subgroup had received a median of 3 prior lines of chemotherapy, almost all had undergone surgery, and almost half had received radiation therapy. The 2 treatment groups did not differ significantly with respect to baseline characteristics.
Consistent with the overall analysis, the subgroup showed that median OS did not differ significantly between the treatment groups: 13.4 months with trabectedin and 12.9 months with dacarbazine (HR = 0.89; 95% CI, 0.65-1.24;P= .5107). Three-fourths of patients in each group received subsequent anticancer therapy at progression.
The subgroup analysis confirmed the significant PFS benefit with trabectedin demonstrated in the overall trial. The 2.5-month PFS benefit with trabectedin translated into a 43% reduction in the risk of progression (HR, 0.57; 95% CI, 0.41-0.81;P= .0012).
Comparison of all other secondary endpoints demonstrated numerical advantages for the trabectedin arm, including overall response rate (11.2% vs 9.0%), clinical benefit rate (30.6% vs 17.9%), and median duration of response (6.47 vs 4.07 months). Median time to response was similar, 3.22 months with trabectedin and 2.79 months with dacarbazine.
Trabectedin was associated with higher rates of certain adverse events, including elevated liver enzymes (ALT and AST), anemia, neutropenia, leukopenia, and thrombocytopenia. However, rates of grade 3/4 toxicity were generally low in both groups.
Dose modifications, including dose reductions and cycle delays, occurred more often with trabectedin. However, the differences did not translate into less treatment, as 39% of patients in the trabectedin group completed 6 cycles of therapy as compared with 18% of patients in the dacarbazine arm.
“The lack of cumulative toxicity with trabectedin allowed for prolonged treatment courses, as more than twice as many patients received at least 6 cycles of therapy,” said Hensley.