Phase III Trial Finds PFS Benefit with Trabectedin in Soft Tissue Sarcoma

Phase III Trial Finds PFS Benefit with Trabectedin in Soft Tissue Sarcoma

In a randomized, open-label phase III trial, trabectedin failed to show an overall survival (OS) improvement over dacarbazine in patients with advanced liposarcoma (LPS) or leiomyosarcoma (LMS), but it did show a significant improvement in progression-free survival (PFS; Abstract 10503). Results of the ET743-SAR-3007 trial were presented by George D. Demetri, MD, of Dana-Farber Cancer Institute and Ludwig Center at Harvard Medical School, during the Sarcoma Oral Abstract Session, on Monday, June 1.

Dr. George D. Demetri

Among 518 patients with previously treated LPS or LMS randomly assigned to receive trabectedin (345 patients) or dacarbazine (173 patients), the median OS was similar across both arms at 12.4 months with trabectedin and 12.9 months with dacarbazine. However, a preplanned PFS analysis showed a significant improvement in median PFS with trabectedin over dacarbazine (4.2 vs. 1.5 months; hazard ratio 0.55, 95% CI [0.436, 0.696]; p < 0.0001).

PFS rates were higher with trabectedin versus dacarbazine at 3 months (56% vs. 34%) and at 6 months (37% vs. 14%). The PFS benefit observed with trabectedin was maintained across subgroups and in both LPS and LMS and was also confirmed in an independent audit.

An analysis of subsequent therapies suggested that the use of post-protocol anticancer therapies may have minimized any survival benefit with trabectedin. Post-protocol anticancer therapies, including pazopanib, dacarbazine, gemcitabine, and radiation, were reported in 47.0% of patients in the trabectedin arm and 56.1% of patients in the dacarbazine arm.

Discussant Ian Judson, MD, FRCP, of the Royal Marsden Hospital, United Kingdom, noted that another possible confounding factor was that the median OS observed with dacarbazine was longer than had been expected.

“We aren’t trying to say we should replace dacarbazine,” Dr. Demetri said in the discussion period. Instead, “the idea is having new active agents that we can have on top of an older active agent.”

Trabectedin is approved for use in Europe, but it is not available in the United States. Of the prior smaller trials that have demonstrated the efficacy of trabectedin in soft tissue sarcoma, several have demonstrated that a subset of patients attains a long duration of benefit with the agent.

The current trial showed a similar trend, with a clinical benefit rate (including patients with objective responses or stable disease for at least 18 weeks) of 34.2% with trabectedin versus 18.5% with dacarbazine (Fisher’s Exact test p = 0.0002). The median time to next anticancer therapy was also significantly longer with trabectedin compared with dacarbazine (6.9 vs. 3.7 months; HR 47, 95% CI [0.358, 0.607], p < 0.0001).

Emphasizing this finding, Dr. Judson noted that every clinical trial of trabectedin in soft tissue sarcoma has revealed a small proportion of patients who experience “prolonged clinical benefit [from trabectedin].” Additional research is needed to identify these patients.

In regards to safety, Dr. Demetri reported that adverse event rates were similar to those reported in previous studies. Nausea, fatigue, neutropenia, and alanine aminotransferase elevations were the most common adverse events with trabectedin; fatigue, nausea, thrombocytopenia, neutropenia, and anemia were the most common with dacarbazine.

Dr. Judson said that estimating the cost effectiveness of trabectedin could be challenging, given that the drug is not commercially available in the United States. 

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