10-Year Trabectedin Real-World Data Demonstrate Efficacy in Sarcoma

Long-term follow-up showed that trabectedin (Yondelis) was associated with high rates of survival and clinical benefit rate for patients with advanced high grade soft tissue sarcomas, especially liposarcoma and leiomyosarcoma.

In a poster presented at the 2017 ASCO Annual Meeting, Sivan Shamai, MD, and Ofer Merimsky, MD, with the Tel Aviv Medical Center and Sackler School of Medicine found that patients with liposarcoma treated with trabectedin had a median overall survival (OS) of 11 months (range, 1-63), and patients with leiomyosarcoma had a median OS of 15 months (range, 1-35).

“In contrast to former trials, our retrospective data represents real-life experience with trabectedin, and includes patients with diverse age, histology, performance status, prior treatments and tumor burden,” wrote Shamai and Merimsky. “Trabectedin is a safe and effective drug in advanced high-grade STS. Further research is needed to identify which patients will benefit most.”

Shamai and Merimsky reviewed real-life experience data on 86 patients with high-grade soft tissue sarcomas collected over 10 years. Patients with liposarcoma (46%) and leiomyosarcoma (43%) were treated with 1.5 mg/m2 of trabectedin once every 3 weeks until progression. Patients received a median of 5 cycles of treatment, with a total of 703 cycles administered.

Trabectedin was delivered as first-line (11.62%), second-line (53.48%), third-line (25.58%), and fourth-line therapy (9.3%). Investigators said there was no statistically significant difference in OS or progression-free survival (PFS), when assessed by treatment line.

The FDA approved trabectedin in 2015 for patients with unresectable or metastatic soft tissue sarcoma who previously received anthracycline-containing chemotherapy. The approval was based on results from the phase III ET743-SAR-3007 trial comparing trabectedin with dacarbazine. Trabectedin was shown to reduce the risk for disease progression by 45% versus dacarbazine in patients with advanced soft tissue sarcoma.

The open-label, multicenter, phase III SAR-3007 trial recruited 518 patients with liposarcoma and leiomyosarcoma who previously received an anthracycline-containing regimen followed by at least one additional line of chemotherapy. The protocol required patients to have an ECOG performance status of 0 or 1. The study was conducted at 85 sites in four different countries, but 94% of the patients were enrolled in the United States.

In the dacarbazine arm, 13.3% of patients (n = 23) had one prior line of chemotherapy, 43.4% (n = 75) had two prior lines, and 43.4% (n = 75) had three or more prior lines. Among patients receiving trabectedin, the rates were 11.0% (n = 38), 46.4% (n = 160), and 42.6% (n = 147), respectively. Additionally, the median time to randomization from the last disease progression was <1 month in both arms.

After 329 PFS events, patients receiving trabectedin had a statistically significant reduction in the risk of disease progression, with a median PFS of 4.2 months versus 1.5 months with dacarbazine (HR, 0.55; 95% CI, 0.44-0.70; P <.001). The 3-month PFS rates were 56% versus 34% for the two arms, respectively, and the 6-month PFS rates were 37% versus 14%. The PFS benefit with trabectedin was observed across preplanned subgroups, including patients with leiomyosarcoma and liposarcoma.

Additionally, the PFS benefit was confirmed by an independent review of radiographic PFS.

ORR was 9.9% with trabectedin and 6.9% with dacarbazine. The clinical benefit rates (partial response, complete response, or stable disease ≥18 weeks) were 34.2% and 18.5% in the two arms, respectively (P = .0002). The median time to response and duration of response were 3.07 and 6.47 months, respectively, with trabectedin and 2.35 and 4.17 months with dacarbazine.

The median OS was 13.7 months with trabectedin versus 13.1 months with dacarbazine (HR, 0.93; 95% CI, 0.75-1.15; P = .49).

About 56% of dacarbazine patients received post-protocol anticancer treatments compared with 47.0% of patients in the trabectedin arm. Several of the treatments, including pazopanib, gemcitabine, docetaxel, and other drugs, as well as radiation and surgery were used more commonly in the dacarbazine arm.

There were no unexpected toxicities with either of the treatments. All-grade adverse-event (AE) rates were 99.1% and 98.1% in the trabectedin versus dacarbazine arms, respectively, with grade 3/4 AE rates of 76.2% versus 51.6%.

The most commonly reported all-grade AEs 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% in the dacarbazine arm and 10% in the trabectedin arms. There were treatment-associated deaths within 30 days of the last dose among 3.2% of patients receiving trabectedin compared with none in the dacarbazine arm.

Shamai S, Merimsky O. Trabectedin for advanced soft tissue sarcoma: Ten-year real-life perspective. J Clin Oncol 35, 2017 (suppl; abstr 11060).