Eribulin Mesylate

A Novel Halichondrin B Analogue for the Treatment of Metastatic Breast Cancer

Ali McBride, Pharm.D., M.S., BCPS; Sara K. Butler, Pharm.D., BCPS, BCOP

Disclosures

Am J Health Syst Pharm. 2012;69(9):745-755. 

In This Article

Clinical Efficacy in Locally Advanced or Metastatic Breast Cancer

Preclinical studies have demonstrated eribulin to inhibit breast, colon, prostate, lung, bladder, and melanoma cancer cell lines in vitro.[11] Importantly, eribulin's potency seems to be superior to that of vinblastine and paclitaxel. Eribulin has also exhibited in vivo inhibitory antitumor effects in several human tumor xenografts such as melanoma, breast, ovarian, and colon. Eribulin has also inhibited tumor growth in taxane-resistant human ovarian cancer cell lines.[11]

Phase I clinical trials with eribulin have been completed using an accelerated dose-escalation schedule to determine the drug's pharma-cokinetics and maximum tolerated dose. Two studies investigated the maximum tolerated dose, toxicity profile, preliminary anticancer activity, and pharmacokinetics of a one-hour infusion of eribulin administered on days 1, 8, and 15 of a 28-day cycle (weekly administration) and on day 1 of a 21-day cycle (three-week schedule, respectively.[24,25] In the weekly administration study, 32 patients received eribulin mesylate doses ranging from 0.25 to 1.4 mg/m2, with the dose-limiting toxicity (DLT) of neutropenia occurring in 2 patients (1 with associated grade 3 fatigue) at the highest dose.[25] Thus, the maximum tolerated dose was 1 mg/m2, a dose at which only 1 of 6 evaluable patients experienced a DLT. In the study of the three-week eribulin mesylate schedule, 21 patients received doses ranging from 0.25 to 4 mg/m2, with neutropenia occurring in all 3 patients receiving the 4-mg/m2 dose and in 2 of the 3 patients receiving 2.8 mg/m2 (Table 2).[24] The maximum tolerated dose in this study was 2 mg/m2, a dose at which only 1 of 6 evaluable patients experienced a DLT. Both trials followed an accelerated dose-escalation strategy, allowing 1 patient per group per site. This design allowed rapid escalation of the dose and the 1 (or 2) patient cohort strategy was appropriately maintained in the weekly schedule; however, two dose levels had to be reduced with the three-week schedule because of reversible toxicity.[24,25]

Two recent single-group, open-label, Phase II clinical trials have demonstrated eribulin's activity and manageable safety profile in patients with refractory metastatic breast cancer. In the study conducted by Vahdat and colleagues,[26] 103 heavily pretreated patients (median of four prior regimens) were given eribulin mesylate (1.4 mg/m2) as a two- to five-minute i.v. infusion on days 1, 8, and 15 of a 28-day cycle. Because of the occurrence of neutropenia at day 15, an alternative regimen of eribulin on days 1 and 8 of a 21-day cycle was used. All of the patients had received prior treatment with an anthracycline and a taxane. In the per-protocol group (n = 87), patients receiving eribulin achieved an independently reviewed objective response rate of 11.5% (all partial responses) and a clinical benefit rate (partial responses plus stable disease for at least 6 months) of 17.2%. This resulted in a median duration of response of 5.6 months, median progression-free survival of 2.6 months, and median overall survival of 9 months. The most common treatment-related grade 3 or 4 toxicities were neutropenia, leukopenia, fatigue, peripheral neuropathy, and febrile neutropenia (Table 2).

In the Phase II study conducted by Cortes and colleagues,[27] 291 patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine were given eribulin mesylate 1.4 mg/m2 as a two- to five-minute i.v. infusion on days 1 and 8 of a 21-day cycle. The objective response rate was 9.3% by independent review and 14.1% by investigator review (all partial responses); the stable disease rate was 46.5%, and the clinical benefit rate was 17.1%. This resulted in a median duration of response of 4.1 months, median progression-free survival of 2.6 months, and median overall survival of 10.4 months. Similar to the previously reported Phase I and II trials, the most common treatment-related grade 3 or 4 toxicities were neutropenia (54%), leukopenia (14.1%), asthenia or fatigue (10%), neuropathy (6.9%), and febrile neutropenia (5.5%) (Table 2).

FDA approval of eribulin was based on results from a Phase III, international, multicenter, open-label, randomized clinical trial (Eribulin Metastatic Breast Cancer Study Assessing Physicians Choice Versus E7389 [EMBRACE]).[28,29] This trial demonstrated a statistically significant improvement in overall survival in patients receiving eribulin compared with those receiving a treatment of their physician's choice (TPC).

In EMBRACE, 762 patients with metastatic or locally recurrent breast cancer were randomized (2:1) to receive eribulin (n = 508) or a TPC determined before randomization (control group, n = 254). The TPC consisted of single-agent chemotherapy agents commonly used to treat metastatic cancer, including vinorelbine (25%), gemcitabine (19%), capecitabine (18%), taxanes (15%), anthracyclines (10%), and less commonly used agents (10%). Supportive care was also considered a treatment option for this group. Hormonal therapy was the TPC in 4% of patients enrolled. Randomization was stratified by geographic region, HER2/neu status, and prior exposure to capecitabine. Patients were required to have received at least two chemotherapeutic regimens for the treatment of metastatic disease but not more than five previous chemotherapy agents and to have experienced disease progression within six months of their last chemotherapeutic regimen. Patients must have had prior anthracycline- or taxane-based chemotherapy in either the adjuvant or metastatic setting (Table 2).[29]

Patient demographic and baseline characteristics were comparable between the treatment groups. The median age was 55 years (range, 27–85 years). Sixty-four percent of patients were enrolled in North America, Western Europe, or Australia; 25% in Eastern Europe or Russia; and 11% in Latin America or South Africa. Ninety-one percent of patients had a baseline Eastern Cooperative Oncology Group performance status of 0 or 1. Tumor prognostic characteristics included estrogen-receptor status (positive, 67%; negative, 28%), progesterone-receptor status (positive, 49%; negative, 39%), HER2/neu-receptor status (positive, 16%; negative, 74%), triple negative status (estrogen receptor-, progesterone receptor-, and HER2/neu-receptor status, 19%), visceral disease (82%), bone disease (61%), and number of sites of metastases (more than two: 50%). Overall, the patients were heavily pretreated, with a median of four previous chemotherapy regimens, and 73% of patients had previously received capecitabine.

Eribulin mesylate 1.4 mg/m2 was administered as an i.v. infusion on days 1 and 8 of a 21-day cycle, with dose delays, dose reductions, or both for prespecified toxicities. In the TPC group, chemotherapy or hormonal therapy was administered according to local practice. Patients received chemotherapy until they demonstrated disease progression, unacceptable adverse effects, or noncompliance or if the patient or physician requested a change in therapy.

The primary endpoint of EMBRACE was overall survival, with secondary endpoints of progression-free survival, objective response rate, and duration of response. A statistically significant prolongation in overall survival was observed in patients randomized to receive eribulin, with a median overall survival of 13.1 months (95% confidence interval [CI], 11.8–14.3 months) versus 10.6 months (95% CI, 9.3–12.5 months) in the eribulin and control groups, respectively (hazard ratio, 0.809; 95% CI, 0.660–0.991; p = 0.041). In patients randomized to receive eribulin, the objective response rate, determined using the Response Evaluation Criteria in Solid Tumors,[30] was 11.0% (95% CI, 8.6–14.3%), and the median response duration was 4.2 months (95% CI, 3.8–5.0 months). The median duration of response did not significantly differ between the two groups. Based on stratification factors, there was a significant improvement in overall survival in patients treated in region 1 (North America, Western Europe, and Australia) compared with regions 2 (Eastern Europe, Russia, and Turkey) (hazard ratio, 1.09; 95% CI, 0.7–1.71) and 3 (Latin America and South Africa) (hazard ratio, 0.91; 95% CI, 0.47–1.78), which could reflect differences in standard practices among regions and a smaller sample size in the latter two populations.

The rates of serious adverse events were similar in the eribulin and TPC groups. The most common adverse reactions associated with eribulin (occurring in at least 25% of patients) were neutropenia, asthenia or fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common grade 3 or 4 adverse reactions related to eribulin (occurring in over 5% of patients) were neutropenia (57%), asthenia or fatigue (10%), and peripheral neuropathy (8%). Febrile neutropenia occurred in 5% of patients receiving eribulin and in 2% of the TPC group. Peripheral neuropathy was the most common toxicity leading to discontinuation of eribulin, with 5% of patients discontinuing therapy.

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