George D. Demetri, MD
Trabectedin demonstrated superior disease control compared with dacarbazine in heavily pretreated patients with advanced soft tissue sarcoma, according to findings from a phase III trial published in the Journal of Clinical Oncology
In the final analysis of progression-free survival (PFS), there was a 45% reduction in the risk of disease progression or death with trabectedin compared with dacarbazine. The median PFS with trabectedin was 4.2 months compared with 1.5 months with dacarbazine (HR, 0.55; 95% CI, 0.44-0.70; P
At this interim analysis, 64% of events were available for the primary endpoint of overall survival (OS). In this group, there was a trend toward a 13% reduction in the risk of death for patients treated with trabectedin, although it was not statistically significant (HR, 0.87; P
= .37). The median OS with trabectedin was 12.4 versus 12.9 months with dacarbazine. A final analysis of OS will be presented at the 2015 European Cancer Congress, later this month.
“The interim analysis of OS, the primary endpoint of this study, demonstrated a statistically nonsignificant 13% reduction in risk of death that favored the trabectedin group,” wrote the authors of the study, which was led by George D. Demetri, MD. “Of note, the median OS in the dacarbazine arm was statistically equivalent to the trabectedin group and exceeded the predefined statistical assumption of 10 months; this may reflect the use of subsequent therapies, including pazopanib, which was approved by regulatory agencies for STS during the conduct of this trial.”
Demetri, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute, presented findings from the phase III study at the 2015 ASCO Annual Meeting. Based on an earlier assessment of the data from the trial, an application for trabectedin was submitted to the FDA for patients with advanced soft tissue sarcoma who received prior chemotherapy. A final approval decision is expected from the FDA later this year.
In the open-label trial, 518 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. Patients in the trabectedin arm received 20 mg of IV dexamethasone as a premedication. The study enrolled participants across a variety of soft tissue sarcoma histologies, including leiomyosarcoma, nonuterine, uterine, liposarcoma, dedifferentiated, myxoid, and pleomorphic.
The median number of treatment cycles was two in the dacarbazine arm and four in the trabectedin group. The median duration of response with trabectedin was 6.5 months compared with 4.2 months with dacarbazine (HR, 0.47; P
= .14). The objective response rates were 9.9% versus 6.9% and the clinical benefit rate (response plus stable disease rate) was 34% and 19%, for trabectedin and dacarbazine, respectively.
The PFS rate at 3 months was 56% versus 34% for trabectedin and dacarbazine, respectively. By 6 months, the PFS rate was 37% with trabectedin and 14% with dacarbazine. PFS was improved across all histologies in the study, and were confirmed by independent radiographic assessment (HR, 0.54; 95% CI, 0.41 to 0.71).
Following the study, subsequent therapies were less frequently administered to those in the trabectedin arm versus dacarbazine (47% vs 56%). Additionally, following study entry, subsequent therapies were delayed significantly longer for participants in the trabectedin arm versus dacarbazine (6.9 vs 3.7 months; HR, 0.47; 95% CI, 0.36-0.61; P
The study recruited participants between May 27, 2011, and September 16, 2013. During this timeframe, the angiogenesis inhibitor pazopanib (Votrient) was approved as a treatment for patients with soft tissue sarcoma following prior chemotherapy—an event that may have confounded the OS analysis, according to the authors. In fact, 18% of patients in the trabectedin arm received subsequent pazopanib compared with 28% in the dacarbazine arm. Crossover between the dacarbazine and trabectedin arms was not allowed.
“Trabectedin is confirmed as an important treatment option for relapsed/refractory patients with advanced leiomyosarcoma and liposarcoma,” Demetri said when presenting the results at ASCO. “There was a clinically relevant improvement in progression-free survival observed with trabectedin that is superior to the active comparator, dacarbazine.”
The most commonly reported all-grade adverse events with trabectedin versus dacarbazine were nausea (73% vs 49%), fatigue (67% vs 51%), neutropenia (49% vs 29%), increased ALT levels (45% vs 6%), vomiting (44% vs 21%), anemia (39% vs 29%), constipation (36% vs 28%), increased AST levels (35% vs 5%), and diarrhea (34% vs 23%).
Grade 3 AEs with the highest frequency in the trabectedin arm were increased ALT levels (25% vs 1%), neutropenia (21% vs 11%), anemia (14% vs 11%) and increased AST levels (12% vs 0%). Sixteen percent of patients receiving trabectedin had grade 4 neutropenia compared with 10% in the dacarbazine group.
Treatment-related discontinuation rates were 7.7% and 12.6% in the dacarbazine and trabectedin arms, respectively. There were treatment-associated deaths within 30 days of the last dose among 2.1% of patients receiving trabectedin compared with none in the dacarbazine arm. These were related to sepsis/septic shock (n = 3), rhabdomyolysis/sepsis (n = 1), renal failure (n = 1), renal failure/cardiac arrest (n = 1), or multiorgan failure (n = 1).
“In soft tissue sarcomas, disease stabilization is an important metric for evaluating treatment success in patients with advanced disease,” Demetri said in a statement when the data were presented. “The safety data from this trial were consistent with the well-defined adverse events observed in previous clinical trials of trabectedin and in clinical use outside the United States where trabectedin has been approved to treat these aggressive diseases.”
During the FDA’s review period, patients with soft tissue sarcoma who are unlikely to benefit from available therapies and who cannot participate in a clinical trial can apply to receive trabectedin through an FDA expanded access program (NCT00210665).
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 [Published online before print September 14, 2015]. J Clin Oncol. doi: 10.1200/JCO.2015.62.4734