January 28, 2016
On January 28, 2016, the U. S. Food and Drug Administration approved eribulin (HALAVEN® injection, Eisai Co., Ltd.) for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen.
The approval was based on an open-label, randomized (1:1), multicenter, active-controlled trial in 446 patients with unresectable, locally advanced or metastatic liposarcoma or leiomyosarcoma who had received at least two prior systemic chemotherapies (one of which must have included an anthracycline) and had experienced disease progression within 6 months of randomization. Patients were randomized to receive either eribulin 1.4 mg/m2 on days 1 and 8 of a 21-day cycle or dacarbazine (at a dose of 850 mg/m2, 1000 mg/m2, or 1200 mg/m2 chosen by the investigator prior to randomization) on day 1 of a 21-day cycle. Treatment was continued until disease progression or unacceptable toxicity. Patients were stratified by histology (liposarcoma vs. leiomyosarcoma), number of prior therapies (2 vs. greater than 2), and geographic region. Patients on the dacarbazine arm were not offered eribulin at the time of progression.
A total of 446 patients were randomized, 225 to eribulin and 221 to dacarbazine. The median age was 56 years (range: 24 to 83); 33% were male; 73% were White; 44% had ECOG performance status (PS) 0 and 53% had ECOG PS 1; 68% had leiomyosarcoma and 32% had liposarcoma; and 47% received more than two prior systemic chemotherapies.
The trial met its primary endpoint based on demonstration of a statistically significant improvement in overall survival (OS) in the eribulin arm compared to the dacarbazine arm with a hazard ratio (HR) of 0.75 (95% CI: 0.61, 0.94; p=0.011). The median OS was 13.5 months in the eribulin arm and 11.3 months in the dacarbazine arm. There was no improvement in progression-free survival (PFS) or confirmed objective response rates in the overall study population.
Treatment effects of eribulin were limited to the stratified subgroup of patients with liposarcoma, observed in pre-planned, exploratory subgroup analyses of OS and PFS. The median OS was 15.6 vs. 8.4 months [HR 0.51 (95% CI: 0.35, 0.75)] and the median PFS was 2.9 vs. 1.7 months [HR 0.52 (95% CI: 0.35, 0.78)] in patients with liposarcoma treated with eribulin compared to dacarbazine, respectively. There was no evidence of efficacy for eribulin in patients with leiomyosarcoma: median OS of 12.8 vs. 12.3 months [HR 0.90 (95% CI: 0.69, 1.18)] and median PFS of 2.2 vs. 2.6 months [HR 1.05 (95% CI: 0.81, 1.35)] in patients with treated with eribulin compared to dacarbazine, respectively.
Safety was evaluated in the 223 patients with liposarcoma and leiomyosarcoma who received eribulin in the trial. The most common (greater than or equal to 25%) adverse reactions were fatigue, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia. The most common (greater than or equal to 5%) grade 3-4 laboratory abnormalities were neutropenia, hypokalemia, and hypocalcemia.
The most common serious adverse reactions were neutropenia (4.9%) and pyrexia (4.5%). Febrile neutropenia occurred in 0.9% and fatal neutropenic sepsis in 0.9% of patients treated with eribulin. The most frequent adverse reactions leading to discontinuation were fatigue (0.9%) and thrombocytopenia (0.9%).
The recommended dose and schedule for eribulin is 1.4 mg/m2 on Days 1 and 8 of a 21-day cycle.
The application was granted a Priority Review. The development program for eribulin for this indication received orphan drug designation. A description of the expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf
Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/201532s015lbl.pdf
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).