Eribulin Emerges as a Candidate for Earlier Treatment of HER2- Metastatic Breast Cancer

Eribulin mesylate (Halaven) demonstrated efficacy in the first-line for patients with aggressive HER2-negative metastatic breast cancer that have received prior treatment with a taxane in the (neo)adjuvant setting, according to results from the phase II MERIBEL trial.¹

The single agent showed a manageable safety profile, with neutropenia standing out as the most common grade 3/4 treatment-related adverse event (AE), which was associated with improved responses in patients who experienced this toxicity.

Eribulin, a non-taxane microtubule dynamics inhibitor, is currently approved for the treatment of patients with metastatic breast cancer who have previously received at least 2 chemotherapeutic regimens, including prior treatment with an anthracycline and a taxane in either the adjuvant or metastatic setting.

The study authors noted that “anthracyclines and taxanes are being frequently used as (neo)adjuvant therapy, and therefore the number of patients previously exposed to these agents by the time they develop metastatic breast cancer is increasing.”

Yet, preclinical models have shown that taxane-resistance cell lines are still sensitive to treatment with eribulin. Therefore, the investigators aimed to see if patients with HER2-negative metastatic disease who have a short disease-free interval (DFI) and prior use of a taxane in the (neo)adjuvant setting are sensitive to treatment with eribulin and if the regimen is safe in this setting.

The MERIBEL study, which was published in theClinical Breast Cancerjournal by lead study author Vanesa Ortega, MD, of the Hospital General de Granollers and Hospital Vall d’Hebron in Barcelona, Spain, and colleagues, was a single-arm, multicenter phase II trial. Patients on the study were treated with single-agent eribulin given at 1.4 mg/m²in a 2- to 5-minute infusion on days 1 and 8 of a 21-day cycle.

Eligible patients had HER2-negative disease and had never received chemotherapy for metastatic disease, but had received prior taxane treatment for early-stage disease in the neoadjuvant or adjuvant setting and had a DFI of less than 36 months. The DFI criteria was later changed to 48 months. Patients also needed to have an ECOG performance status of 0 or 1 and adequate organ function.

The primary endpoint of the study was time to progression (TTP).

Fifty-three patients enrolled and were treated with at least 1 dose of eribulin. The median age of patients was 47 years (range, 23-82.8).

Patients were split between ECOG performance status scores of 0 and 1. A bit more than half of patients (54.7%) had HR-positive tumors, the rest had triple-negative disease. Among patients with HR-positive disease, 72.4% received endocrine therapy for early disease and 20.7% for advanced disease. Many patients (84.9%) had received a prior anthracycline in addition to taxane therapy, and 39.6% had received prior hormone therapy.

The median DFI was 15.7 months (range, 0.1-46.4) with 34% having a DFI of ≤12 months.

Patients received a median of 6 cycles (range, 1-41) of eribulin. Dose modifications were needed in 9.4% of patients, primarily due to neutropenia toxicity, and schedule modifications were needed in 34%.

After a median follow-up of 12.7 months (range, 0.2-30.5), the median TTP was 4.1 months (range, 0.2-27.8; 95% CI, 3.2-6.2), and at 1 year, the TTP rate was 16.2% (95% CI, 7%-37.5%).

The median overall survival (OS) was not reached, but at 1 year the OS rate was 68.3% (95% CI, 56.5%-82.5%).

The objective response rate (ORR) was 20.8% (95% CI, 9.8%-31.7%), which consisted of 2 complete responses and 9 partial responses. An additional 3 patients experienced stable disease for more than 6 months, amounting to a clinical benefit rate of 26.4% (95% CI, 14.5%-38.3%). The median duration of response was 4.5 months (range, 2.1-20.9; 95% CI, 2.4-12.9).

In exploratory subgroup analyses, the investigators noticed a longer median TTP among patients with HR-positive tumors (6 vs 3.9 months;P= .111) and in patients with a DFI >24 months (6.2 vs 4 months;P= .227), both of which did not achieve statistical significance. Also, the 1-year OS rate was 0 in patients with a DFI of ≤12 months (n = 18).

The investigators also noted an interesting increase in antitumor activity among patients who experienced grade 3/4 neutropenia and had to delay treatment due to toxicity compared with those who did not experience neutropenia. These patients demonstrated an improvement in median TTP (6 vs 3.3 months;P =.013), OS (not reached vs 6.4 months;P= .019), and ORR (38.9% vs 11.4%;P= .01).

“Several studies have also shown a relationship between toxicity and best tumor response in different cancer types. In this way, neutropenia has been identified as a predictive marker of response to chemotherapy in advanced gastric and lung cancers,” the authors wrote in their report. “In this study, time to progression, overall survival, and objective response rate were better in patients with toxicity-related dose delays and grade 3/4 neutropenia. However, it is not clear whether observed toxicity was predictive of response to eribulin, because this finding would suggest that patients benefitting from longer treatment durations are more prone to developing treatment-related adverse events, while patients undergoing lesser treatment exposure due to poor response, or no response, would suffer less treatment-related toxicity. Therefore, caution is needed in the interpretation of subgroup analyses results.”

All-grade AEs were seen in 96.2% of patients, with the most common events including neutropenia, leukopenia, alopecia, nausea, and anemia. Grade 3/4 AEs were observed in 69.8%, which were most commonly neutropenia (35.9%), followed by leukopenia (17%). Serious AEs were seen in 20.8% of patients.

Of note, febrile neutropenia was only observed in 1.9% of patients, and grade 3 neuropathy was seen in 7.5% with no grade 4 incidences. No treatment-related deaths were reported. Seven patients (13.2%) discontinued treatment due to AEs, 2 of which were not treatment-related.

The study authors noted that their results were similar to results of the Study 301 trial which looked at single-agent eribulin in taxane-pretreated patients with metastatic breast cancer in the first line and beyond.²They suggested that this could be because many of the patients in the MERIBEL study had risk factors associated with poor outcomes compared with Study 301.

A phase III trial is currently ongoing looking at eribulin versus paclitaxel in the first or second line for the treatment of patients with HER2-negative locally recurrent or metastatic breast cancer (NCT02037529).

References:

1. Ortega V, Antón A, Garau I, et al. A phase II, multicenter, single-arm trial of eribulin as first-line therapy for aggressive taxane-pretreated HER2-negative metastatic breast cancer patients: the MERIBEL study [published online December 19, 2018].Clin Breast Cancer.doi: 10.1016/j.clbc.2018.12.012.
2. Kaufman PA, Awada A, Twelves C, et al. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane.J Clin Oncol.2015;33(6)594-601. doi: 10.1200/JCO.2013.52.4892.