Trabectedin Extends PFS in Phase III Soft Tissue Sarcoma Study

George D. Demetri, MD

Trabectedin reduced the risk of disease progression by 45% versus dacarbazine in patients with advanced soft tissue sarcoma, according to results from the phase III ET743-SAR-3007 trial presented at the 2015 ASCO Annual Meeting. There was also a slight survival trend with trabectedin, but the results were not significant.

“Trabectedin is confirmed as an important treatment option for relapsed/refractory patients with advanced leiomyosarcoma and liposarcoma,” lead author George D. Demetri, MD, said when presenting the results. “There was a clinically relevant improvement in progression-free survival observed with trabectedin that is superior to the active comparator, dacarbazine,” added Demetri, who is director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute.

Based on the data from the trial, the FDA previously granted trabectedin a priority review designation as a treatment for patients with advanced soft tissue sarcoma, including liposarcoma and leiomyosarcoma subtypes, who have previously received chemotherapy that included an anthracycline. A final approval decision is expected from the FDA by early August.

The open-label, multicenter, phase III SAR-3007 trial compared trabectedin with dacarbazine in 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 Demetri noted that 94% of the patients were enrolled in the United States.

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 median number of treatment cycles was two in the dacarbazine arm and four in the trabectedin group. In the trabectedin versus the dacarbazine arms, 34% versus 17% of patients, respectively, received ≥6 treatment cycles, with 11% versus 2% of patients receiving ≥12 cycles. The maximum numbers of cycles was 28 and 18 in the trabectedin and dacarbazine arms, respectively.

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. “Importantly, as well, the median time from the last disease progression to randomization on this trial was <1 month in both arms,” Demetri noted.

The primary outcome measure of the trial was OS. Secondary outcome measures included PFS, objective response rate (ORR), time to progression, duration of response (DOR), and safety.

At a preplanned interim analysis following 189 OS events, the HR for OS indicated a “trend toward trabectedin…that did not reach statistical significance,” said Demetri. 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).

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, 0.436-0.696; 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%. “PFS improved across all of the major preplanned subgroups…including for both leiomyosarcoma and liposarcoma,” said Demetri. 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 DOR were 3.07 and 6.47 months, respectively, with trabectedin and 2.35 and 4.17 months with dacarbazine.

Postprotocol anticancer treatments were received by 56.1% and 47.0% of patients, respectively, in the dacarbazine and trabectedin arms. 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. “This can confound survival analyses, we know this. There was, however, a prolonged time to the initiation of any postprotocol therapy in the trabectedin arm as one would expect by the progression-free survival benefit,” said Demetri.

“The safety profiles were as we would expect with both of these drugs,” Demetri said. 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% and 10% in the dacarbazine and trabectedin arms, respectively. 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.

The investigational antitumor agent trabectedin was originally derived from the sea squirt, Ecteinascidia turbinate, and is now manufactured synthetically. “Trabectedin has many unique mechanisms of action. It impacts DNA binding repair in many different ways, inhibits transcription, and modifies tumor microenvironment,” said Demetri.

During the FDA’s priority review period, patients with soft tissue sarcoma who are unlikely to benefit from available therapies and who cannot participate in a clinical trial can apply to receive trabectedin through an FDA expanded access program (NCT00210665).

Demetri GD, von Mehren M, Jones RL, et al. A randomized phase III study of trabectedin (T) or dacarbazine (D) for the treatment of patients (pts) with advanced liposarcoma (LPS) or leiomyosarcoma (LMS). J Clin Oncol. 2015;(suppl; abstr 10503).

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