Eribulin treatment had a manageable safety profile in the both Phase II trials[26,27] and the Phase III EMBRACE trial.[28,29] In EMBRACE, serious adverse events (grade 3 or higher) occurred in 26% of patients, and adverse events leading to discontinuation of treatment were reported in 15% of patients. Adverse events led to dose interruptions, dose delays, and dose reductions in 6%, 49%, and 29% of patients, respectively, in the eribulin group, compared with 9%, 41%, and 26% of patients, respectively, in the TPC group.
Fatal adverse events occurred in 4% of eribulin-treated patients and 7% of patients in the TPC group and were considered treatment related in 1% of patients in each group. Among adverse hematologic events, grade 3 or 4 neutropenia, leukopenia, and febrile neutropenia were much more common among patients treated with eribulin (Figure 2). Among adverse nonhematologic events, grade 3 peripheral neuropathy was more common among eribulin-treated patients compared with those receiving the TPC. The manufacturer has recommended dosage modifications for patients who have toxicities while on eribulin treatment (Table 3).
Rates of adverse events in the Eribulin Metastatic Breast Cancer Study Assessing Physicians Choice Versus E7389 (EMBRACE).29 The most common (≥10%) treatment-related grades 1–4 adverse hematologic and nonhematologic events associated with eribulin monotherapy as reported in EMBRACE (n = 762). Peripheral neuropathy included neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, peripheral sensorimotor neuropathy, demyelinating polyneuropathy, and paraesthesia.
Severe neutropenia (absolute neutrophil count of <500 cells/μL) lasting more than one week occurred in 12% of patients in the Phase III EMBRACE trial, leading to discontinuation in fewer than 1% of patients. Patients with alanine transaminase (ALT) or aspartate transaminase (AST) levels exceeding 3 times the upper limit of normal had higher rates of grade 4 neutropenia and febrile neutropenia than patients with normal ALT and AST levels. Patients with bilirubin levels exceeding 1.5 times the upper limit of normal also had higher rates of grade 4 neutropenia and febrile neutropenia. The most common serious adverse events reported in patients receiving eribulin during the eribulin clinical development program were febrile neutropenia (4%) and neutropenia (2%). However, neutropenia was reported in 82% of patients who received eribulin in the Phase III trial. Grade 3 neutropenia occurred in 45% of patients, and 24% of patients experienced grade 4 neutropenia. Febrile neutropenia occurred in 5% of patients, with two deaths (0.4%) resulting from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% of patients, and discontinuation was required in <1% of patients. Grade 3 or higher thrombocytopenia occurred in 1% of patients. The mean time to nadir within a treatment cycle was 13 days, and the mean time to recovery from severe neutropenia (<500 cells/μL) was approximately 8 days. In EMBRACE, the use of granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) was allowed per American Society of Clinical Oncology guidelines and local practice standards. Prophylactic use of G-CSF or GM-CSF was not required per the study protocol.[28,29]
Therapy with the taxanes as well as with ixabepilone is often limited by the development of peripheral neuropathy. Severe (grade 3 or 4) peripheral neuropathy occurs in up to 30% of patients with breast cancer. Based on results of the clinical trials so far, eribulin seems to be associated with a low rate of neuropathy. For patients who have preexisting peripheral neuropathy before receiving eribulin, the frequency of developing grade 3 or 4 peripheral neuropathy is similar to patients with no preexisting neuropathy.
Patients with preexisting peripheral neuropathy (up to grade 2) were eligible for enrollment in EMBRACE. Worsening of peripheral neuropathy was reported in 29.1% of patients with preexisting grade 1 (n = 87) or grade 2 (n = 16) peripheral neuropathy. This frequency of peripheral neuropathy was similar to that in patients without peripheral neuropathy before eribulin treatment, with 32.9% of the 386 patients experiencing neuropathy. Grade 3 peripheral neuropathy was experienced by 12.6% of patients with preexisting neuropathy and by 7% of patients without peripheral neuropathy at baseline. None of the patients with preexisting peripheral neuropathy experienced grade 4 peripheral neuropathy, compared with 0.5% of patients without peripheral neuropathy at baseline. Therefore, patients with preexisting peripheral neuropathy were no more likely to develop new or worsening symptoms than those who entered the study without the condition.
Q-T Interval Prolongation
In an uncontrolled open-label electrocardiogram (ECG) study of 26 patients, Q-T interval prolongation was observed on day 8 (11.3 milliseconds), independent of eribulin concentration, with no Q-T interval prolongation observed on day 1. ECG monitoring is recommended if eribulin is initiated in patients with congestive heart failure, with bradyarrhythmia, or taking drugs known to prolong the Q-T interval, including class Ia and III antiarrhythmics, and electrolyte abnormalities. Physicians should correct hypokalemia or hypomagnesemia before initiating eribulin and monitor these electrolytes periodically during therapy. Eribulin should be avoided in patients with congenital long Q-T syndrome.
Am J Health Syst Pharm. 2012;69(9):745-755. © 2012 American Society of Health-System Pharmacists
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