In women with uterine leiomyosarcoma, trabectedin (Yondelis), a novel cytotoxic agent, significantly improved progression-free survival, compared with dacarbazine (4.2 vs 1.5 months, hazard ratio [HR] = 0.55, P < .001). According to the study’s authors, a lack of cumulative toxicity allows late-stage patients with good disease control to remain on trabectedin for prolonged periods.1
“Trabectedin represents an important new treatment option for patients with advanced uterine leiomyosarcoma after anthracycline-containing treatment,” said Martee L. Hensley, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, at the recent Society of Gynecologic Oncology Annual Meeting on Women’s Cancer in San Diego.
The drug did not, however, improve overall survival, the study’s primary endpoint. At approximately 13 months in each arm, overall survival did not differ between the two treatment strategies.
As Dr. Hensley explained, trabectedin has a novel mechanism of action as a cytotoxic: It intercalates into the DNA minor groove, distorting the DNA structure and beginning the initiation of DNA-repair mechanisms. At the same time, it binds and inhibits repair mechanisms, thereby activating apoptosis.
Trial Design
ET743-SAR-3007 was the largest phase III trial to date in soft-tissue sarcoma. All 577 patients had histologically proven liposarcoma or leiomyosarcoma, and all had been previously treated with an anthracycline-containing regimen. Patients could also have received any number of prior additional regimens.
Researchers stratified patients by lines of chemotherapy, performance status, and type of sarcoma. They were then randomly assigned 2:1 to either trabectedin (n = 384) or dacarbazine (n = 193). Patients in the trabectedin arm received the drug at 1.5 mg/m2 as a 24-hour infusion. Patients in the other arm received dacarbazine at 1 g/m2 over 20 to 120 minutes every 3 weeks.
The study was conducted at 90 sites in 4 different countries, although the vast majority of patients were treated in the United States (94%). The primary endpoint was overall survival. Secondary endpoints included progression-free survival, response rate, duration of response, safety, and patient-reported outcomes.
As reported in the Journal of Clinical Oncology,2 trabectedin demonstrated a significant improvement in progression-free survival compared to the active comparator dacarbazine (4.2 vs 1.5 months, HR = 0.55 P < .001). These data led to U.S. Food and Drug Administration approval of trabectedin, in October 2015, for the treatment of patients with leiomyosarcoma or liposarcoma who had received a prior anthracycline regimen.
Subgroup Analysis
A previously reported subgroup analysis demonstrated an equivalent progression-free survival benefit in patients with either leiomyosarcoma (HR = 0.56) or liposarcoma (HR = 0.55). For this analysis, Dr. Hensley reported on the subgroup of patients who had uterine leiomyosarcoma (144 patients on trabectedin and 88 on dacarbazine).
According to Dr. Hensley, the majority of these patients were enrolled in the study for either third- or fourth-line therapy, and nearly 20% of patients were enrolled for fifth-line therapy for metastatic sarcoma. All patients had received a prior anthracycline, and nearly all had received prior gemcitabine and docetaxel.
Trabectedin in Leiomyosarcoma
- In patients with uterine leiomyosarcoma, trabectedin significantly improved progression-free survival vs dacarbazine (4.2 vs 1.5 months, HR = 0.55, P < .001).
- The study did not, however, improve the primary endpoint, overall survival.
In terms of treatment exposure, although both agents were able to be delivered for a prolonged number of cycles, the median number of treatment cycles for trabectedin was four, compared with two for dacarbazine. “The higher number of trabectedin cycles reflects the prolonged time of disease control and also the lack of cumulative toxicity,” said Dr. Hensley.
Uterine leiomyosarcoma patients experienced more grade 3 or 4 treatment-emergent adverse events in the trabectedin arm, compared with dacarbazine (69% vs 42%). In addition, there were two treatment-related deaths in the trabectedin arm and none in the dacarbazine arm.
Similar Overall Survival
Median overall survival, the primary endpoint of the study, did not differ between the two arms at approximately 13 months. “Overall survival can be complicated to interpret in randomized trials since one does not control downstream therapy,” Dr. Hensley explained. “When you’re giving cytotoxic agents, it’s also interesting to consider whether patients are able to receive more therapy after they’ve received prolonged exposure to a cytotoxic.”
The median progression-free survival was superior among patients assigned to trabectedin at 4.2 months, vs 1.5 months for dacarbazine.
Finally, said Dr. Hensley, overall response rates were modest with both agents and did not differ between the two arms (9% with dacarbazine and 11% with trabectedin). However, the clinical benefit rate, which incorporated partial response, complete response, and stable disease for at least 18 weeks, was higher among patients assigned to trabectedin, Dr. Hensley concluded. ■
Disclosure: Dr. Hensley has a consulting or advisory role with Janssen Pharmaceuticals and has received research funding from Janssen Research and Development, LLC, and her spouse is employed by Sanofi.
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