UPDATED January 29, 2016 // Eribulin mesylate (Halaven, Eisai Inc.) has been approved by the US Food and Drug Administration (FDA) for use in the treatment of liposarcomas. This is the first drug to show an improvement in overall survival in this disease, the agency noted.
Eribulin is already approved for the treatment of advanced breast cancer. The new indication is for use in liposarcoma that is unresectable or advanced (metastatic) in patients who have received prior chemotherapy that contained an anthracycline drug.
Liposarcoma is a specific type of soft tissue sarcoma that affects fat cells and can form almost anywhere in the body, but is most common in the head, neck, arms, legs, trunk, and abdomen, the agency notes. An estimated 12,000 cases of soft tissue sarcomas were diagnosed in 2014 in the United States, according to the National Cancer Institute.
The improvement in overall survival for the first time in liposarcoma was reported last year by Medscape Medical News, when it was reported at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting at a session on soft tissue sarcomas.
At the meeting, the data presented came from Study 309, which was conducted in 452 patients with liposarcoma and leiomyosarcoma, which compared eribulin with standard therapy, dacarbazine (DTIC-Dome, Bayer HealthCare Pharmaceuticals). At the ASCO meeting, the results from 452 patients showed an improvement in survival of 2 months; the median overall survival was 13.5 months with eribulin vs 11.5 months with dacarbazine (hazard ratio, 0.768; P = .0169). There was no difference in progression-free survival, which was 2.6 months in both treatment groups.
A preplanned exploratory subgroup analysis of these data showed that the treatment effects of eribulin were limited to patients with liposarcoma, and that there was no evidence of efficacy in patients with advanced or metastatic leiomyosarcoma.
The FDA approval is based on the results from the subgroup of 143 patients with liposarcoma. In this subgroup, the results show a 7-month improvement in survival (15.6 months with eribulin compared with 8.4 months with dacarbazine), which the FDA described as "clinically meaningful." In this subgroup, the median progression-free survival, a secondary end point, was 2.9 months with eribulin vs 1.7 months with dacarbazine.
Discussion of Results
When the results from Study 309, in the total population of patients with liposarcoma and leiomyosarcoma, were reported at the 2015 ASCO meeting, another large phase 3 trial was presented at the same session. That trial showed that trabectedin (Yondelis, PharmaMar) improved progression-free survival in patients with L-sarcomas, but not overall survival. These data on trabectedin led to its approval by the FDA in October 2015 for use in liposarcoma and leiomyosarcoma.
At the meeting, both trials were hailed as positive, and both have now resulted in approvals, and yet they had contrasting results ― eribulin improved overall survival but not progression-free survival, whereas trabectedin improved progression-free survival but not overall survival. Which end point is clinically more meaningful remains an important question, said the discussant for the presentations, Ian Robert Judson, MD, from the sarcoma unit at the Royal Marsden Cancer Hospital in London, United Kingdom.
Dr Judson noted that the results with eribulin in L-sarcomas, as presented at the ASCO meeting, follow the same pattern that was seen with this drug in breast cancer (in the pivotal EMBRACE trial), which also showed an improvement in overall survival of around 2 months, but also no improvement in progression-free survival.
This contrasts with what is usually seen with drugs active against cancer, he commented; usually they prolong progression-free survival and are also shown to improve overall survival. This is the opposite, and "we don't know quite what is going on here," he said, adding that it might be due to a different mechanism of action. Eribulin acts as an inhibitor of microtubule dynamics, and it may be affecting the tumor microenvironment, he suggested. "It does look like a true biological effect," he added.
However, eribulin was more toxic than dacarbazine, Dr Judson noted. Treatment-emergent adverse events (TEAEs) were more frequent in patients treated with eribulin than in those treated with dacarbazine. TEAEs included neutropenia (44% vs 24%), pyrexia (28% vs 14%), peripheral sensory neuropathy (20% vs 4%), and alopecia (35% vs 3%). Also more frequent were TEAEs of grade 3 (63% vs 53%) and grade 4 (26% vs 20%), as well as fatal TEAEs (4% vs 1%), the researchers note.
Dr Judson commented that eribulin was not more active than dacarbazine on conventional measures of efficacy, such as percentage of responses or stable disease, and that it has no apparent effect on disease control. Previous studies have shown that effective chemotherapy improves pain and sleeplessness, but there appeared to be no effect on symptoms with eribulin.
In addition, it is very much more expensive. Eribulin costs $5511 per cycle of treatment, whereas the comparator and standard therapy, dacarbazine, costs $78 per cycle. So there is a question mark over its cost-effectiveness, he said.
In the FDA announcement of the approval, the agency noted that the most common adverse effects seen with eribulin were fatigue, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia. The drugs may also lead to neutropenia or decreased levels of potassium or calcium.
Neutropenia and neuropathy can be serious adverse effects, the agency noted, and added that the drug may be fetotoxic, and may lead to QTc prolongation, which could be fatal.
Eribulin had priority review and also received orphan drug designation for this indication, the FDA noted.
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Cite this: Eribulin Approved for Liposarcoma, Improves Survival - Medscape - Jan 28, 2016.