In a phase III trial reported in the Journal of Clinical Oncology, George D. Demetri, MD, of Harvard Medical School and Dana-Farber Cancer Institute, Boston, and colleagues found that treatment with trabectedin (Yondelis) significantly improved progression-free survival vs dacarbazine in patients with advanced liposarcoma or leiomyosarcoma after prior conventional chemotherapy.1 On the basis of this phase III trial, on October 23, 2015, the U.S. Food and Drug Administration approved trabectedin as a treatment option for patients with metastatic and/or unresectable leiomyosarcomas and liposarcomas.
Interim analysis of overall survival, the primary endpoint of the trial, showed a nonsignificant improvement with trabectedin.
Trabectedin is a marine-derived drug that causes both cell-cycle arrest and induction of p53-independent apoptosis and affects the tumor microenvironment via cytotoxicity against tumor-associated macrophages and tissue-resident histiocytes.
Study Details
The open-label NCT01343277 trial enrolled patients aged ≥ 15 years with locally advanced or metastatic disease from 85 sites in four countries between May 2011 and September 2013 (cutoff for interim analysis of overall survival). A total of 518 patients were randomly assigned 2:1 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-treated 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 was overall survival. The published report presented the final analysis of progression-free survival, performed at the first interim analysis of overall survival. Enrollment in the trial was targeted at 570 patients.
The trabectedin and dacarbazine groups were generally balanced for age, sex, body mass index, histology, Eastern Cooperative Oncology Group performance status, best response to last line of prior chemotherapy, prior surgery, prior radiotherapy, time from initial diagnosis, and time from last progression.
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). Hazard ratios 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, hazard ratios for progression-free survival favored trabectedin across all 19 preplanned subgroups examined; hazard ratios 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 survival rates were 56% vs 34% at 3 months and 37% vs 14% at 6 months.
Objective response rates were 9.9% in the trabectedin group vs 6.6% in the dacarbazine group (P = .33), and median duration of response was 6.5 vs 4.2 months (P = .14). Furthermore, 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 vs the dacarbazine group (median = 12.4 vs 12.9 months, HR = 0.87, P = .37). Fewer trabectedin-treated patients received subsequent anticancer therapy (47% vs 56%) 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% vs 28%), 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 alanine transaminase (ALT; 45% vs 6%), and vomiting (44% vs 21%); the most common events 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 aspartate transaminase (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 the start of treatment occurred in 7.1% of the trabectidin vs 5.8% of the dacarbazine arm, 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 vs 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.” ■
Disclosure: 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.
Reference
1. Demetri GD, von Mehren M, Jones RL, et al: Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: Results of a phase III randomized multicenter clinical trial. J Clin Oncol. September 14, 2015 (early release online).
