Results from a new randomized, open-label, phase III study showed a two-month increase in median overall survival for patients with advanced liposarcoma or leiomyosarcoma treated with eribulin, compared with patients treated with dacarbazine-which is recommended by clinical practice guidelines as a treatment option for patients with advanced soft tissue sarcomas, and is commonly used for this indication. The data were published online ahead of print in The Lancet (DOI: http://dx.doi.org/10.1016/S0140-6736(15)01283-0).
"While soft tissue sarcomas are relatively rare, there remains an unmet medical need for 50 percent of the patients who fail to respond to initial local treatment, surgery, and first-line anthracycline-based chemotherapy," lead study author Patrick Schoffski, MD, MPH, Head of the Department of General Medical Oncology at University Hospitals Leuven, Belgium, explained in an email. "This is the first data of a single agent therapy to show such a benefit to overall survival-and the survival benefit was demonstrated even when comparing with an active agent."
Eribulin is the most advanced compound in the halichondrin class of microtubule dynamics inhibitors and has a novel mechanism of action, Schoffski added. The drug preferentially suppresses microtubule growth without interfering with microtubule shortening.
The takeaway message for clinicians is that eribulin has a proven overall survival benefit compared with dacarbazine, Schoffski said. "Outcomes for people with advanced sarcomas are poor, with a median survival around one year or less. In this context, a two-month improvement in patient survival, as demonstrated by [this data], is significant and welcomed by the clinical sarcoma community."
Research Details
The study included 452 patients at 110 study sites in 22 countries across North America, Latin America, Europe, Asia, and Australia with histologically confirmed locally recurrent, locally advanced, or metastatic liposarcoma (including de-differentiated, myxoid or round-cell, or pleomorphic liposarcoma) or leiomyosarcoma. Only patients 18 or older were eligible.
Two hundred twenty eight patients were randomized to receive eribulin and 224 were randomized to receive dacarbazine. The eribulin mesylate dose was 1.4mg/m2 given intravenously over 2-5 minutes on day one and day eight of every 21-day cycle. In the case of toxic effects, treatment was delayed or the dose reduced to 1.1mg/m2 or 0.7mg/m2. Dacarbazine was given at a dose of 850mg/m2, 1000mg/m2, or 1200mg/m2 as an IV infusion over 15-60 minutes on day one of every 21-day cycle. Hematological toxicities for treatment with dacarbazine resulted in treatment delays or dose reduction, while clinically relevant hepatic or renal toxicity or hypersensitivity required treatment cessation.
Patients' tumors were assessed with CT, MRI, and bone scans every six weeks from the date of randomization for the first 12 weeks and every nine weeks thereafter, or sooner if clinically indicated, until disease progression was confirmed. Safety monitoring was done periodically by the data monitoring committee at intervals no longer than six months, starting with the recruitment of the first patients, and as determined by the committee.
The data showed the following results:
* Median overall survival for the patients receiving eribulin was 13.5 months, compared with 11.5 months for patients receiving dacarbazine.
* Median progression-free survival was similar in both treatment groups-2.6 months for both.
* The number of patients whose disease had not progressed at 12 weeks was similar for both groups-76 of the patients receiving eribulin (33%) compared with 64 of the patients receiving dacarbazine (29%).
* No patients in either group had a complete response and similar numbers of patients in both groups had partial responses.
* During the treatment period, the overall health-related quality of life (as documented by Global Health Status scores) did not greatly differ between the two treatment groups.
As an eligibility criteria, all patients had disease that was not amenable to curative surgery or radiotherapy; and they had disease progression within six months before being randomized for treatment on the trial and after having received at least two standard systemic regimens for advanced soft-tissue sarcoma, including an anthracycline (unless contraindicated). Previous use of adjuvant and neoadjuvant chemotherapy was allowed, but was only considered as a line of treatment if disease progression had been documented within six months of its completion.
Adverse Events
Treatment-related adverse events led 17 of the patients in the study in the group receiving eribulin to stop treatment (8%) compared with 11 patients in the group receiving dacarbazine (5%); and 58 patients (26%) receiving eribulin had to have their dose reduced because of adverse events compared with 32 patients (14%) in the group receiving dacarbazine.
Grade 3 or higher adverse events were reported in 152 patients (67%) receiving eribulin compared with 126 patients receiving dacarbazine (56%). Neutropenia and leukopenia were the two most common grade 3 or higher adverse events for the patients receiving eribulin. Anemia and thrombocytopenia were the most common grade 3 or higher adverse event for patients receiving dacarbazine.
Making the Drug Available to Patients
In January, the FDA approved eribulin for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing chemotherapy regimen (OT 3/10/16 issue). The drug is marketed with the brand name Halaven by Eisai Co., Ltd.
A type II variation application also has been submitted in the European Union to extend the indication of eribulin for the treatment of patients with unresectable soft tissue sarcoma who have received prior chemotherapy for locally advanced disease.
This recent study was funded by Eisai and was designed in collaboration with the principal investigator. Eisai also funded the data collection, data analysis, data interpretation, and writing of The Lancet paper in which the data were published.
Sarah DiGiulio is a contributing writer.