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Treatment with doxorubicin plus trabectedin (Yondelis), followed by trabectedin maintenance, improved overall survival (OS) and progression-free survival (PFS) in patients with metastatic or unresectable uterine or soft-tissue leiomyosarcoma compared with doxorubicin alone, a randomized phase III trial showed.

Among 150 patients, median OS was 33 months in the combination group versus 24 months in the doxorubicin-alone group (adjusted HR 0.65, 95% CI 0.44-0.95), and the median PFS was 12 versus 6 months, respectively (aHR 0.37, 95% CI 0.26-0.53), reported Patricia Pautier, MD, of the Institut Gustave-Roussy in Villejuif, France, and colleagues.

The 2-year OS rates were 68% in the doxorubicin-trabectedin group and 49% in the doxorubicin-alone group, and the 2-year PFS rates were 30% and 3%, respectively, they noted in the .

"The trial results support the use of doxorubicin plus trabectedin for the first-line treatment of advanced or metastatic leiomyosarcomas, offering hope for improved outcomes in this challenging disease area," wrote Pautier and colleagues.

Soft-tissue sarcomas are rare, with about , and leiomyosarcomas account for 10% to 20% of cases.

The authors explained that leiomyosarcomas vary in terms of their clinical behavior and individual genetic variants, but despite this heterogeneity, "the systemic chemotherapy regimen for metastatic soft-tissue sarcoma subtypes has remained largely unchanged, with doxorubicin monotherapy continuing as the standard first-line treatment since its efficacy was ."

Moreover, they pointed out that trials evaluating various drug combinations -- including those with doxorubicin -- in soft-tissue sarcomas have failed to demonstrate an OS benefit greater than that seen with doxorubicin alone, with trials over the past decade showing a median OS of approximately 20 months.

In a, Robert S. Benjamin, MD, of the University of Texas MD Anderson Cancer Center in Houston, observed that this trial addresses the obstacles to success in previous soft-tissue sarcoma trials -- namely those of diversity and small numbers.

"This trial focused on a single histologic subset of sarcomas, leiomyosarcoma, appropriately addressing the known diversity of behavior within that group on the basis of the site of the primary tumor, and enough patients were enrolled in the trial for a meaningful difference to be detected," Benjamin wrote. "Finally, after more than 50 years of single-agent doxorubicin, a true step forward has been taken, and antiquated single-agent chemotherapy is no longer needed. The importance of this trial by Pautier and colleagues cannot be overemphasized, and the investigators should be congratulated."

Benjamin also cautioned that time may be working against the launch of similar trials involving trabectedin in other sarcomas.

"Given how long it took to get to this point ... the E.U. period of orphan medicinal product exclusivity has already lapsed, and the U.S. patent on trabectedin is set to expire in 2028," he wrote. "Thus, neither PharmaMar, the manufacturer in Spain, nor Janssen, the company licensed to sell trabectedin in the United States, has the financial incentive to support such trials, even to merely provide the drug or to modify the label such that insurance will cover the drug costs for future development."

In this , 150 patients with metastatic or unresectable leiomyosarcoma and no previous chemotherapy were randomized to 6 cycles of doxorubicin plus trabectedin with continued maintenance trabectedin in those who did not have disease progression or to 6 cycles of doxorubicin alone.

Of these patients, 67 had uterine leiomyosarcoma, and 83 had soft-tissue leiomyosarcoma. Median age was 59 years in the combination group and 64 years in the doxorubicin-alone group, and about three-quarters were women.

In the doxorubicin-alone group, 37% of patients received trabectedin as second-line treatment, with an additional 17 patients receiving trabectedin in subsequent lines of therapy. Despite these interventions, the time to second disease progression was longer in the doxorubicin-trabectedin group than the doxorubicin group (26 vs 13 months; HR 0.46, 95% CI 0.32-0.65).

"The longer time to second disease progression with the combination therapy than with monotherapy, despite a substantial percentage of patients in the doxorubicin group receiving trabectedin after disease progression (59% of the patients in the context of second-line or subsequent treatment), reinforces the potential benefits of using an effective combination therapy as early as possible in the disease course rather than waiting for sequential treatment to manage progressing sarcoma," Pautier and colleagues noted.

The incidence of grade 3 or 4 adverse events was significantly higher with the combination than doxorubicin alone (97% vs 56%). Serious adverse events occurred more often in the doxorubicin-trabectedin group (37 patients) compared with the doxorubicin group (20 patients).

The percentages of patients with neutropenia, anemia, thrombocytopenia, and febrile neutropenia were notably higher in the doxorubicin-trabectedin group than in the doxorubicin-alone group. Almost half (46%) of patients in the combination group had grade 3 or 4 hepatic cytolysis, but it reversed to a maximum of grade 2 (to grade 0 in 79% of patients, grade 1 in 15%, and grade 2 in 3%). No chronic liver dysfunction has been reported.

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