STOCKHOLM — Trabectedin, a synthetic version of a compound derived from sea squirts, significantly delayed progression of recurrent ovarian cancer in a large, randomized phase III trial presented at the European Society for Medical Oncology Congress.
When combined with pegylated liposomal doxorubicin (Doxil/Caelyx), the novel drug brought progression-free survival to 7.3 months vs. 5.8 months for a control group treated with pegylated liposomal doxorubicin alone (hazard ratio, 0.79; P = .0190), reported the principal investigator, Dr. Bradley J. Monk of the University of California Irvine Medical Center.
Overall survival results, a secondary end point, were not yet mature, but also suggested the possibility of an advantage with trabectedin (Yondelis). With more than half of 672 women in the trial still alive, overall survival had reached 20.5 months in those given the combination and 19.4 months in the arm that received single-agent care (HR, 0.85; P = .1506).
More patients responded to treatment in the combination arm as well (28% vs. 19%).
Trabectedin is currently approved for treatment of advanced soft-tissue sarcoma in Europe and South Korea. Initially isolated from the marine animal Ecteinascidia turbinate, it binds selectively with the minor groove of DNA, and drives cells to apoptosis by interfering with DNA repair and transcription factors.
Two drug companies, PharmaMar, S.A. in Spain and Johnson & Johnson Pharmaceutical Research and Development in the United States, cosponsored the Ova-301 trial. PharmaMar has announced plans to seek European approval for trabectedin in ovarian cancer, and Johnson & Johnson is expected to seek an indication in the United States, according to Dr. Monk, who disclosed receiving honoraria from Johnson & Johnson.
Noting that numerous other agents are under study for ovarian cancer, he extolled trabectedin as the first to succeed in a phase III study. “The list is short in late-stage development, and many of those late trials are negative,” he said in an interview. “To have a study which is actually positive for its primary end point, and to bring a new drug to cancer patients, is a big deal. And that is why we are so excited.”
Investigators at 124 hospitals in 21 countries completed patient enrollment in the trial on May 29, 2007. Participants had to have measurable epithelial ovarian, epithelial fallopian tube, or primary peritoneal cancer that had progressed after six full cycles of therapy or 6 months after front-line therapy. Only patients with one previous platinum-based front-line therapy were included; women given anthracyclines were excluded as were those who progressed during platinum-based front-line therapy. Maintenance or consolidation therapy was allowed.
The study randomized 335 women to 50 mg/m
The population had a median age of 57 years; more than two-thirds had papillary/serous histology, of which 65% was platinum sensitive based on a platinum-free interval of more than 6 months from first-line therapy.
Dr. Monk reported that trabectedin appeared to be more active in women with platinum-sensitive disease, compared with patients who were platinum resistant. More platinum-sensitive patients responded to the combination than to the single agent (35.3% vs. 22.6%; P = .0042), he said. Response rates in platinum-resistant patients were lower and similar (13.4% and 12.2%, respectively).
Progression-free survival in those who did not have a recurrence for at least 6 months after their initial treatment for ovarian cancer reached 9.2 months with the combination vs. 7.5 months with the standard single-agent regimen (HR 0.73; P = .0170). This same measure was just 4 months and 3.7 months, respectively, in platinum-resistant patients.
Progression-free survival was based on review by an independent radiologist who used RECIST (Response EvaluationCriteria in Solid Tumors).
An analysis of grade 3/4 toxicity in treated patients showed less hand and foot syndrome and mucositis/stomatitis but more vomiting, nausea, and febrile neutropenia (8% vs. less than 3%) in the combination arm. More patients had severe neutropenia (52% vs. 30%) and elevated liver enzymes, but Dr. Monk said the latter were transient and mostly resolved without the need for dose reductions. Cardiac disorders were described as uncommon in both arms.
All told, 11% of patients discontinued treatment because of treatment-related adverse events. In all patients, the median number of completed cycles was five.
Discussant Dr. Cristiana Sessa of the National Cancer Institute in Milan, Italy, said preclinical data show trabectedin has a different mechanism of action from previous drugs and antitumor activity in xenografts. It has not shown significant activity in resistant ovarian disease, she said, but may have “a therapeutic index better than standard therapies in partially platinum-sensitive disease.”
Its role in ovarian cancer will be determined by other studies, she suggested. These include trials comparing pegylated liposomal doxorubicin and trabectedin with paclitaxel and carboplatin, and comparing single-agent pegylated liposomal doxorubicin with single-agent trabectedin.