SAN DIEGO – Among patients with uterine leiomyosarcoma who underwent prior chemotherapy, treatment with trabectedin resulted in superior disease control, with significantly longer progression-free survival, compared with dacarbazine, a phase III trial showed.
“Trabectedin is an important new treatment option for patients with advanced uterine LMS after anthracycline-containing treatment,” lead study author Dr. Martee L. Hensley said at annual meeting of the Society of Gynecologic Oncology.
Trabectedin, which is marketed by Janssen Products and is also known as ET743, has a novel mechanism of action that “distorts DNA structure resulting in the initiation of DNA repair,” explained Dr. Hensley, a surgical oncologist at Memorial Sloan Kettering Cancer Center, New York. “At the same time it binds and inhibits repair mechanisms, thereby activating apoptosis. In addition, trabectedin inhibits transcriptional activation and can modify the tumor microenvironment.”
ET743-SAR-3007 was the largest randomized, phase III study in soft tissue sarcoma. It found that trabectedin demonstrated a statistically significant improvement in progression-free survival (PFS), compared with dacarbazine (4.2 months vs. 1.5 months; hazard ratio = .55; P less than .001). The results led to FDA approval of trabectedin for the treatment of patients with leiomyosarcoma (LMS) or liposarcoma (LPS), after prior anthracycline therapy. In addition, a previously reported subgroup analysis demonstrated equivalent PFS benefit in patients with either LMS (HR = .56) or LPS HR = .55). However, the majority of that study population (73%) had LMS, and most of those (40%) were uterine LMS. The purpose of the current analysis was the subgroup of patients 232 with uterine LMS who were enrolled in ET743-SAR-3007, which was conducted in 90 sites on four different countries.
Dr. Hensley reported that of the 232 women, 144 were randomized to receive a 24-hour infusion of trabectedin 1.5 mg/m2 every three weeks and 88 to receive a 20- to-120-minute infusion of dacarbazine 1 g/m2 every three weeks. “It’s interesting to note that the vast majority of these patients are enrolling in this study for either a third or fourth-line therapy, and nearly 20% are enrolling for fifth-line therapy for metastatic sarcoma,” she said. The primary endpoint was overall survival, while secondary endpoints were progression-free survival, overall response rate, duration of response, safety, and patient-reported outcomes.
The median number of treatment cycles was four in the trabectedin arm, compared with two in the dacarbazine arm. Nearly 40% of patients in the trabectedin arm received at least six cycles of therapy, compared with 19% in the dacarbazine arm. “There is probably a lack of cumulative toxicity that allows patients that have good disease control to remain trabectedin for a prolonged period of time,” Dr. Hensley said.
The researchers found that in patients with uterine LMS, trabectedin significantly improved progression-free survival, compared with those who received dacarbazine (4.01 months vs. 1.54 months, respectively; HR: .57; P = .0012). “Because progression-free survival can be a soft endpoint, the study was designed to collect radiographic images for central review,” Dr. Hensley said. “That was achieved in 60% of the study population in order to corroborate the PFS endpoint.”
The overall survival benefit observed with trabectedin treatment did not differ from that of dacarbazine (a median of 13.4 months vs. 12.9 months, respectively; HR = .89; P = .5107). Dr. Hensley characterized the overall response rate of both agents as “modest” (11% in the trabectedin arm, vs. 9% in the dacarbazine arm; P = .816).
Median time to response was similar between both arms (about three months) as was median duration of response (about four months for the dacarbazine arm vs. six months for the trabectedin arm). However, she pointed out that those two comparisons were based on a total of 22 patients: seven in the dacarbazine arm and 15 in the trabectedin arm.
Grade 3-4 adverse events such as increased ALT and neutropenia were more common in the trabectedin arm, compared with the dacarbazine arm (69% vs. 42%). There were two treatment-related deaths within 30 days of last dose in the trabectedin arm (1.4%) and no deaths on the dacarbazine arm.