Trabectedin Extends PFS in Soft Tissue Sarcoma, FDA Approval Pending

George D. Demetri, MD

Second-line treatment with trabectedin (Yondelis) improved progression-free survival (PFS) by 2.7 months compared with dacarbazine in patients with advanced soft tissue sarcoma following prior treatment with an anthracycline, according to results from the phase III ET743-SAR-3007 trial presented at the 2015 ASCO Annual Meeting.

The median PFS was 4.2 months with trabectedin versus 1.5 months with dacarbazine (HR = 0.55; 95% CI, 0.436-0.696;P<.0001). There was also a slight overall survival (OS) trend with trabectedin, but the results were not significant. The 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).

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

Trabectedin is a synthetic derivative of the sea squirtEcteinascidia turbinata. Based on earlier data from the trial, the FDA granted trabectedin a priority review designation as a treatment for patients with advanced soft tissue sarcoma who have previously received chemotherapy that included an anthracycline. A decision is expected from the FDA by early August 2015.

In the open-label phase III SAR-3007 trial, trabectedin was compared 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.

Patients were randomized 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. 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 &ge;6 treatment cycles, with 11% versus 2% of patients receiving &ge;12 cycles.

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. &ldquo;Importantly, as well, the median time from the last disease progression to randomization on this trial was <1 month in both arms,&rdquo; 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.

The 3-month PFS rates were 56% versus 34% for the two arms, respectively, and the 6-month PFS rates were 37% versus 14%. &ldquo;PFS improved across all of the major preplanned subgroups&hellip;including for both leiomyosarcoma and liposarcoma,&rdquo; 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 &ge;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.

In the dacarbazine and trabectedin arms, respectively, 56.1% and 47.0% of patients received postprotocol anticancer treatments. 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.

&ldquo;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,&rdquo; said Demetri.

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%).

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%. 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.

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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).