FDA Approves Yondelis (trabectedin) for Liposarcoma and Leiomyosarcoma

James Radke, PhD

The FDA has announced they have approved Janssen’s Yondelis (trabectedin) for the treatment of specific soft tissue sarcomas  – unresectable or metastatic liposarcoma and leiomyosarcoma. This treatment is approved for patients who previously received chemotherapy that contained anthracycline.
Soft tissue sarcomas are a type of cancer that originate in muscle, fat, blood vessels, nerves, tendons and/or the lining of joints. Approximately 12,000 people will be diagnosed and approximately 4,870 are expected to die of soft tissue sarcomas in 2015.
 Leiomyosarcoma is an aggressive type of soft tissue sarcoma that occurs in smooth muscles, such as those in the uterus, gastrointestinal tract or lining of blood vessels.
Liposarcoma originates in fat cells and most commonly occurs in the thigh and abdominal cavity
In a press announcement, Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research said,  “The treatment of advanced or metastatic soft tissue sarcoma represents a difficult challenge with few effective therapeutic choices available for patients,” adding, “Today’s approval of Yondelis provides a treatment option for advanced or metastatic liposarcoma and leiomyosarcoma.”

Efficacy of Yondelis

The pivotal study that was reviewed by the FDA was an open-label, multicenter, phase 3  trial comparing trabectedin to dacarbazine in 518 patients with liposarcoma and leiomyosarcoma who previously received an anthracycline-containing regimen followed by at least 1 additional line of chemotherapy.

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. Trabectedin was administered through a catheter as an IV infusion over 24 hours and patients received dacarbazine as a 20- to 120-minute infusion. Patients in the trabectedin arm received 20 mg of IV dexamethasone as a premedication.

The primary outcome measure of the trial was overall survival (OS)and in a preplanned interim analysis following 189 OS events, the hazard ratio (HR) for OS indicated a trend toward trabectedin that did not reach statistical significance. Median OS was 12.4 months with trabectedin versus 12.9 months with dacarbazine (HR, 0.87; 95% CI, 0.644-1.181; P = .3741).

Secondary outcome measures however were more promising. The study found that after 329 progressive-free survival (PFS) 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, 0.436-0.696; P <.0001). 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,  overall response rate (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 DOR were 3.07 and 6.47 months, respectively, with trabectedin and 2.35 and 4.17 months with dacarbazine.

Safety of Yondelis

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.


FDA approves new therapy for certain types of advanced soft tissue sarcoma [news release]. Washington, DC. US Food and Drug Administration; October 23, 2015.
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