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Trabectedin improves PFS, not OS, in liposarcoma, leiomyosarcoma
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The antitumor drug trabectedin demonstrated superior disease control compared with conventional chemotherapy among patients with advanced liposarcoma and leiomyosarcoma who failed after prior chemotherapy, according to the results of a phase 3 randomized controlled trial.
However, the study failed to meet its primary endpoint of OS.
George D. Demetri
“After gastrointestinal stromal tumors, leiomyosarcomas and liposarcomas are the most common subtypes of soft tissue sarcomas, a heterogeneous group of malignancies that arise from tissues of mesenchymal origin and together compose approximately 1% of all solid tumors,” George D. Demetri, MD, professor of medicine at Harvard Medical School, as well as senior vice president for experimental therapeutics and director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute, and colleagues wrote. “The prognosis for patients with advanced or metastatic soft tissues sarcoma is poor. … Treatment is palliative in nature, and the goal is delay of the progression and severe morbidity that can arise when tumor growth compromises organ function.”
Demetri and colleagues compared trabectedin (Yondelis; Janssen, PharmaMar) with dacarbazine for treatment of advanced liposarcoma or leiomyosarcoma, soft tissue sarcomas that are difficult or impossible to remove surgically or that have metastasized.
The analysis included 518 patients previously treated with anthracycline and at least one other prior systemic regimen.
The researchers randomly assigned 345 patients (median age, 57 years; 31% male) to IV trabectedin every 3 weeks. The other 173 patients (median age 56 years; 27% male) received dacarbazine.
Eighty-eight percent of patients had at least two prior lines of therapy and more than 90% had prior surgical treatment. In both groups, the median time from last disease progression was less than 1 month.
OS served as the primary endpoint. Secondary endpoints included PFS, time to progression, objective response rate and duration of response.
In the final PFS analysis — performed after 329 PFS events — the researchers observed a 45% reduction in risk for disease progression or death with trabectedin (median PFS, 4.2 months vs. 1.5 months; HR = 0.55; 95% CI, 0.44-0.7). The benefits extended across all subgroups and the two sarcoma subtypes.
In an interim OS analysis — performed after a median follow-up of 8.6 months and after 50% of the required events had occurred — trabectedin conferred a 13% reduction in risk for death, which did not meet statistical significance (median OS, 12.4 vs. 12.9 months; HR = 0.89).
Patients assigned trabectedin remained on treatment twice as long as patients assigned dacarbazine (median number of cycles, 4 vs. 2).
Although no complete responses occurred in either group, partial responses occurred more frequently in the trabectedin arm. Researchers reported objective response rates of 9.9% with trabectedin vs. 6.9% with dacarbazine.
Safety profiles appeared consistent with the well-characterized toxicities of both agents. Myelosuppression and transient elevation of transaminases were the most common grade 3 to grade 4 adverse events observed in the trabectedin arm.
All treatment-related deaths (n = 7) occurred in the trabectedin arm, with sepsis/septic shock the most frequent cause (n = 3).
“Although the study continued per protocol for the final analysis of OS, the results of two recently reported phase 3 studies have illustrated the difficulty in prolonging OS, despite robust improvements in PFS, even when the control arm involves a placebo,” Demetri and colleagues wrote. “The results of this large, randomized trial support the activity of trabectedin as an effective anticancer agent in this population of patients who have rare but life-threatening malignancies.”
Gary K. Schwartz
The FDA used data from this study as the basis for its decision in October to approve trabectedin for treatment of patients with liposarcoma and leiomyosarcoma who underwent prior anthracycline-based chemotherapy. The agent became the first treatment specifically approved for liposarcoma in the United States in 3 decades.
Because few drugs are available for patients with sarcoma and the toxicity of trabectedin is manageable, one could argue the drug merited approval from U.S. regulators, Gary K. Schwartz, MD, chief of the division of hematology and oncology at Columbia University Medical Center, wrote in an accompanying editorial.
However, Schwartz questioned the overall magnitude of the data.
“With trabectedin, we are left knowing what we originally suspected a decade ago,” Schwartz wrote. “The drug shows clinical benefit in patients with leiomyosarcoma and myxoid liposarcoma. As we have seen with other sarcoma drugs, this has the ability to improve PFS without an OS benefit.
“We still do not know the overall clinical benefits in other sarcoma subtypes, including synovial cell sarcoma or other translocation sarcomas,” Schwartz added. “Although trabectedin activity tends to favor well-differentiated/dedifferentiated [leiomyosarcoma and liposarcoma] subtypes, the benefits here still seem small, and it remains unclear whether the data are now sufficient to make trabectedin the standard of care for all patients with [leiomyosarcoma and liposarcoma], especially those with the well-differentiated/dedifferentiated subtype.” – by Cameron Kelsall
Disclosure: Demetri reports consultant roles with, institutional research funding from and payment for expert testimony provided to Janssen Pharmaceuticals, as well as other financial relationships with multiple pharmaceutical companies. Please see the full study for a list of all other researchers’ relevant financial disclosures. Schwartz reports honoraria and travel expenses from and consultant roles with AstraZeneca, Boehringer Ingelheim and Novartis, as well as a patent pending regarding the development of PNAs for targeted cancer therapy.
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