Long-term therapy with trabectedin appeared well tolerated among patients with soft tissue sarcoma, according to retrospective study results presented at Connective Tissue Oncology Society Annual Meeting.
Cumulative toxicity often limits long-term systemic therapy for patients with soft tissue sarcoma, according to study background.The FDA approved trabectedin (Yondelis; Janssen, PharmaMar) — an antitumor chemotherapy drug derived from the Caribbean sea squirt — for treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who underwent prior treatment with an anthracycline-containing regimen.
Through an expanded access program, researchers conducted a multicenter, open-label, single-arm phase 2 study to evaluate trabectedin for patients with locally advanced or metastatic soft tissue sarcoma who underwent prior conventional therapies.
Elizabeth J. Davis, MD, assistant professor of medicine in the division of hematology/oncology at Vanderbilt University School of Medicine, and colleagues subsequently conducted a retrospective analysis on the efficacy and safety on expanded access program enrollees who received long-term trabectedin treatment, defined as 6 months or longer.
The analysis included patients with multiple histologies of pretreated relapsed or refractory soft tissue sarcoma. All participants received at least 6 months of trabectedin, administered at 1.5 mg/m2 IV every 3 weeks.
Davis and colleagues compared efficacy and safety outcomes of patients who received 6 to 12 months of treatment with those of patients who received more than 12 months of treatment.
A total of 1,803 patients received treatment through the expanded access program from 2005 to 2010. The majority were women (58.5%) and aged younger than 65 years (80.5%). Most patients had baseline ECOG performance status of 0 or 1 (94.3%), and had either leiomyosarcoma or liposarcoma (61.1%).
Approximately one in five patients (n = 401; 21.6%) remained on treatment for at least 6 months, 268 (14.5%) remained on treatment for 6 to 12 months; and 133 (7.2%) remained on treatment for more than 12 months.
Median OS was 11.9 months in the entire cohort, 18.14 months (95% CI, 15.51-21.16) among patients treated for 6 to 12 months, and 47.01 months (95% CI, 36.7-not estimable) among patients treated for more than 12 months.
Clinical benefit rate — defined as complete response plus partial response plus stable disease — was 41.2% in the entire cohort, 47.4 (95% CI, 41.3-53.6) among those who received treatment for 6 to 12 months, and 38.3% (95% CI, 30.1-47.2) among those who received treatment for more than a year.
Among patients treated for 6 to 12 months, one (0.4%) achieved complete response, 20 (7.5%) achieved partial response, 106 (39.6%) achieved stable disease and 20 (7.5%) experienced progressive disease. Among patients treated for more than 12 months, three (2.3%) achieved complete response, six (4.5%) achieved partial response, 42 (31.6%) achieved stable disease and 12 (9%) experienced progressive disease.
Incidence of treatment-emergent adverse events appeared similar between those treated for 6 to 12 months and those treated longer than 12 months (84% vs. 89.5%). The most common treatment-emergent adverse events were nausea (40.7% vs. 48.1%), neutropenia (39.6% vs. 47.4%), fatigue (36.6% vs. 39.1%), blood alkaline phosphatase increase (32.8% vs. 37.6%), alanine aminotransferase increase (26.9% vs. 32.3%), anemia (23.9% vs. 27.1%), vomiting (25.7% vs. 19.5%), thrombocytopenia (20.5% vs. 21.8%) and constipation (17.2% vs. 30.1%).
Patients treated for more than 12 months appeared more likely than those treated for 6 to 12 months to require treatment cycle delays (61.7% vs. 57.5%) or dose reductions (78.2% vs. 64.2%).
They also were more likely to experience serious treatment-emergent adverse events (35.3% vs. 32.8%), or grade 3/grade 4 adverse events (26.3%) vs. 25%).
Sixteen patients — 12 (4.5%) of those treated for 6 to 12 months, and four (3%) of those treated for more than 12 months — terminated treatment due to treatment-emergent adverse events.
The majority of patients in both groups discontinued treatment (95.1% for 6 to 12 months; 77.4% for more than 12 months). Most patients discontinued treatment due to disease progression.
One patient with synovial sarcoma remained on treatment for 55 months (64 cycles), and another patient with uterine leiomyosarcoma remained on treatment for 54 months (73 cycles).
“Improved median OS may be achieved in patients who experience prolonged disease stabilization; however, adjustments in the trabectedin dose or schedule are frequently required,” Davis and colleagues wrote. “Trabectedin is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen. However, there is a cohort of [patients with other sarcoma histologies) who derive prolonged benefit.” – by Mark Leiser