In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On January 28, 2016, eribulin mesylate (Halaven) was approved for treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen.1,2 Eribulin was previously approved for treatment of patients with metastatic breast cancer who have received at least two chemotherapeutic regimens for metastatic disease and prior treatment with an anthracycline and a taxane in the adjuvant or metastatic setting.
Supporting Efficacy Data
Approval was based on an open-label trial in which 446 patients with unresectable locally advanced or metastatic liposarcoma or leiomyosarcoma who had received at least two prior systemic therapies including an anthracycline and had disease progression within the past 6 months were randomized to receive eribulin at 1.4 mg/m2 on days 1 and 8 of a 21-day cycle (n = 225) or dacarbazine at 850, 1,000, or 1,200 mg/m2 (selected by investigator) on day 1 of a 21-day cycle.2 Treatment was continued until disease progression or unacceptable toxicity.
The trial excluded patients with preexisting grade ≥ 3 peripheral neuropathy, known central nervous system metastasis, elevated serum bilirubin or significant chronic liver disease, history of myocardial infarction within 6 months, history of New York Heart Association class II or IV heart failure, or cardiac arrhythmia requiring treatment. In the entire group, median age was 56 years (range = 24–83 years); 67% were female; 73% were white; Eastern Cooperative Oncology Group (ECOG) performance status was 0 for 44% and 1 for 53%; 47% had received more than two prior systemic therapies; and 68% had leiomyosarcoma, and 32% had liposarcoma.
Median overall survival in the entire population, the primary endpoint, was 13.5 months in the eribulin group vs 11.3 months in the dacarbazine group (hazard ratio [HR] = 0.75, P = .011). There were no differences in progression-free survival (2.6 vs 2.6 months, HR = 0.86, 95% confidence interval [CI] = 0.69–1.06) or confirmed objective response rate (4.0% vs 5.0%).
The treatment effect benefit of eribulin was limited to the 143 patients with liposarcoma, including 71 in the eribulin group and 72 in the dacarbazine group. Among these patients, median age was 55 years (range = 32–83 years); 62% were male; 72% were white; ECOG performance status was 0 for 41% and 1 for 53%; 44% had received more than two prior therapies; and histologic subtypes were dedifferentiated in 45%, myxoid/round cell in 37%, and pleomorphic in 18%. Among these patients, median overall survival was 15.6 vs 8.4 months (HR = 0.51, 95% CI = 0.35–0.75), and median progression-free survival was 2.9 vs 1.7 months (HR = 0.52, 95% CI = 0.35–0.78). Among patients with leiomyosarcoma, median overall survival was 12.8 vs 12.3 months (HR = 0.90, 95% CI = 0.69–1.18), and median progression-free survival was 2.2 vs 2.6 months (HR = 1.05, 95% CI = 0.81–1.35).
How It Works
Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and apoptotic cell death after prolonged mitotic blockage.
Eribulin treatment of human breast cancer cells results in changes in morphology and gene expression and in decreased migration and invasiveness in vitro. In xenograft models of breast cancer, eribulin was associated with increased vascular perfusion and permeability in tumor cores, resulting in reduced tumor hypoxia and changes in the expression of genes in tumor specimens associated with a change in phenotype.
How It Is Given
The recommended dose of eribulin is 1.4 mg/m2 given intravenously over 2 to 5 minutes on days 1 and 8 of a 21-day cycle. The recommended dose is 1.1 and 0.7 mg/m2 on the same schedule in patients with mild and moderate hepatic impairment, respectively, and 1.1 mg/m2 on the same schedule in patients with moderate to severe renal impairment.
Expanded Indication for Eribulin Mesylate
Eribulin mesylate (Halaven) was approved for treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen. It was previously approved for treatment of patients with metastatic breast cancer. The recommended dose of eribulin is 1.4 mg/m2 given intravenously over 2 to 5 minutes on days 1 and 8 of a 21-day cycle.Patients should be assessed for peripheral neuropathy and complete blood cell counts prior to each dose. Eribulin should not be given on day 1 or 8 for absolute neutrophil count (ANC) < 1,000/mm3, platelet count < 75,000/mm3, or grade 3 or 4 nonhematologic toxicities. The dose on day 8 may be delayed for a maximum of 1 week: The dose should be omitted if toxicities do not resolve or improve to grade ≤ 2 by day 15; if toxicities resolve or improve to grade ≤ 2 by day 15, eribulin should be given at a reduced dose, and the next cycle can be started no sooner than 2 weeks later.
After dose delay for toxicity and recovery to grade ≤ 2, the dose should be permanently reduced to 1.1 mg/m2 if toxicity consisted of ANC < 500/mm3 for > 7 days, ANC < 1,000 /mm3 with fever or infection, platelets < 25,000/mm3, platelets < 50,000/mm3 requiring transfusion, or nonhematologic grade 3 or 4 toxicities or if the dose on day 8 in the previous cycle was omitted or delayed for toxicity. The dose should be reduced to 0.7 mg/m2 for any adverse event requiring permanent dose reduction while receiving 1.1 mg/m2, and treatment should be permanently discontinued for any event requiring permanent dose reduction while receiving 0.7 mg/m2.
Safety Profile
Among all patents in the randomized trial, the most common adverse events of any grade in the eribulin group were asthenia/fatigue (62%) and nausea (41%). The most common adverse events occurring at a frequency ≥ 5% higher vs the dacarbazine group were alopecia (35% vs 3%), constipation (32% vs 26%), peripheral neuropathy (29% vs 8%), abdominal pain (29% vs 23%), and pyrexia (28% vs 14%). Grade 3 or 4 peripheral neuropathy occurred in 3.1% vs 0.5%. The most common grade 3 or 4 laboratory abnormalities were neutropenia (32% vs 9%), hypokalemia (5.4% vs 2.8%), and hypocalcemia (5.0% vs 1.4%). The most common serious adverse events in the eribulin group were neutropenia (4.9 %) and pyrexia (4.5%). Febrile neutropenia occurred in 0.9% and fatal neutropenic sepsis occurred in 0.9% of eribulin patients. Adverse events led to dose reduction of eribulin in 26% of patients, with the most common reasons being neutropenia (18%) and peripheral neuropathy (4.0%), and to discontinuation of treatment in 8%, with the most common reasons being fatigue and thrombocytopenia (0.9% each).
Eribulin carries warnings/precautions for neutropenia, neuropathy, embryofetal toxicity, and prolongation of the QT interval. Blood cell counts should be monitored regularly. Patients should be monitored for signs of neuropathy. Monitoring for QT prolongation should be performed in patients with congestive heart failure, bradyarrhythmia, and electrolyte abnormalities and in those taking drugs known to prolong the QT interval. Eribulin should be avoided in patients with congenital long QT syndrome. Women of reproductive potential should be advised of the potential risk to the fetus and to use effective contraception while taking eribulin. ■
References
1. U.S. Food and Drug Administration: Eribulin. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ ApprovedDrugs/ucm483795.htm. Accessed February 22, 2016.
2. Halaven (eribulin mesylate) injection, for intravenous use prescribing information, Eisai Inc., January 2016. Available at http://www.halaven.com/Pdfs/HALAVEN-Full-Prescribing-Information-2015.pdf. Accessed February 22, 2016.
