Improved Progression-Free Survival With Trabectedin vs Dacarbazine After Conventional Chemotherapy in Advanced Liposarcoma or Leiomyosarcoma
In a phase III trial reported in the Journal of Clinical Oncology, Demetri et al found that treatment with trabectedin significantly improved progression-free survival vs dacarbazine in patients with advanced liposarcoma or leiomyosarcoma after prior conventional chemotherapy.
Interim analysis of overall survival, the primary endpoint of the trial, showed a nonsignificant improvement with trabectedin.
Study Details
In this open-label trial (NCT01343277), 518 patients aged ≥ 15 years with locally advanced or metastatic disease from 85 sites in four countries were randomly assigned 2:1 between May 2011 and September 2013 (cutoff for interim analysis of overall survival) to receive trabectedin (n = 345) at a starting dose of 1.5 mg/m2 via 24-hour intravenous infusion or dacarbazine (n = 173) at a starting dose of 1 g/m2 via 20- to 120-minute intravenous infusion on day 1 of 21-day cycles.
Trabectedin patients received dexamethasone premedication. Patients were previously treated with at least a combination of an anthracycline and ifosfamide or an anthracycline plus at least one additional cytotoxic chemotherapy regimen. The primary endpoint is overall survival. The current report presents the final analysis of progression-free survival, performed at the first interim analysis of overall survival. Enrollment in the trial is targeted at 570 patients.
The trabectedin and dacarbazine groups were generally balanced for age (median 57 and 56 years, range = 18–81 and 17–79 years), sex (69% and 73% female), body mass index (median 28.21 and 27.05 kg/m2), histology (leiomyosarcoma in 73% in both, including uterine in 39% and 45%; liposarcoma in 27% in both, including dedifferentiated in 13% and 15%), Eastern Cooperative Oncology Group performance status (0 in 50% and 1 in 50% in both), best response to last line of prior chemotherapy (complete response in 1% and 2%, partial response in 8% in both, stable disease in 33% and 30%, and progression in 57% and 60%), prior surgery (95% and 91%), prior radiotherapy (51% and 46%), time from initial diagnosis (median 34 and 27 months), and time from last progression (median 0.85 and 0.82 months).
Improved Progression-Free Survival
Median progression-free survival was 4.2 months in the trabectedin group vs 1.5 months in the dacarbazine group on investigator assessment (hazard ratio [HR] = 0.55, P < .001). HRs were 0.57 (95% confidence interval [CI] = 0.45–0.72) on investigator radiographic assessment, 0.55 (95% CI = 0.40–0.75) on independent review, and 0.54 (95% CI = 0.41–0.71) on radiographic independent review. On subgroup analysis, HRs for progression-free survival favored trabectedin across all 19 preplanned subgroups examined; HRs were 0.50 (95% CI = 0.42–0.73) among patients with leiomyosarcoma and 0.55 (95% CI = 0.34-0.87) among those with liposarcoma. Median time to progression was 4.2 vs 1.5 months (P < .001). Progression-free rates were 56% vs 34% at 3 months and 37% vs 14% at 6 months.
Objective response rates were 9.9% vs 6.6% (P = .33), median duration of response was 6.5 vs 4.2 months (P = .14), 51% vs 35% of patients had stable disease as best response, median duration of stable disease was 6.01 vs 4.17 months (P < .001), and clinical benefit rates were 34% vs 19% (P < .001).
Interim Analysis of Overall Survival
The interim analysis of overall survival (64% censored) indicated a 13% reduction in risk of death in the trabectedin group (median 12.4 vs12.9 months, HR = 0.87, P = .37). Fewer trabectedin patients received subsequent anticancer therapy (47% vs56%) and received such treatment later compared with dacarbazine patients (median time from randomization = 6.9 vs 3.7 months, HR = 0.47, P < .001). The most frequently used treatments were pazopanib (Votrient) (18% vs28%), radiation (10% vs 15%), gemcitabine (9% vs 15%), and dacarbazine (17% vs 6%). At the time of analysis, 28% vs 15% of patients were still receiving study treatment.
Adverse Events
The most common adverse events of any grade in the trabectedin group were nausea (73% vs 49%), fatigue (67% vs 51%), neutropenia (49% vs 29%), increased ALT (45% vs 6%), and vomiting (44% vs 21%); the most common in the dacarbazine group were fatigue and nausea. The most common grade 3 or 4 adverse events were neutropenia (37% vs 21%), increased ALT (26% vs 1%), thrombocytopenia (17% vs 18%), anemia (14% vs 12%), and increased AST (13% vs 0%).
Discontinuation of treatment due to adverse events or death occurred in 12.6% vs 7.7% of patients (and due to withdrawal of consent in 3.2% vs 7.1%). Death within 60 days of start of treatment occurred in 7.1% vs 5.8%, with death considered treatment-related in 2.1% of the trabectedin group (sepsis/septic shock in three patients, rhabdomyolysis/sepsis in one, renal failure in one, renal failure/cardiac arrest in one, and multiorgan failure in one).
The investigators concluded: “Trabectedin demonstrates superior disease control versus conventional dacarbazine in patients who have advanced liposarcoma and leiomyosarcoma after they experience failure of prior chemotherapy. Because disease control in advanced sarcomas is a clinically relevant end point, this study supports the activity of trabectedin for patients with these malignancies.”
George D. Demetri, MD, of Harvard Medical School and Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by Janssen Pharmaceuticals and in part by Adelson Medical Research Foundation. For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
