There is a great need for treatments with survival benefit for women with heavily pretreated metastatic breast cancer. Eribulin mesilate (E7389) is a non-taxane inhibitor of microtubule dynamics of the halichondrin class of antineoplastic drugs. It is a structurally modified synthetic analogue of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai.

This phase III open-label study compared the effect of eribulin with currently available treatments on overall survival (primary endpoint) in heavily pretreated women with locally recurrent or metastatic breast cancer. Patients had received between two and five previous chemotherapy regimens (two or more for advanced disease), including an anthracycline and a taxane, unless contraindicated. They were randomised to eribulin mesilate (n= 508, 1.4 mg/m2 IV days 1 and 8 of a 21-day cycle) or treatment of physician's choice (TPC, n= 254,). 

The following findings were reported:

• There were 274 (54%) deaths in the eribulin group and 148 (58%) deaths in the TPC group.

• Overall survival was improved in women assigned to eribulin compared with TPC (median 13.1 months vs. 10.6 months; hazard ratio 0.81, 95% CI, 0.66 to 0.99; p=0.041).

• Median progression-free survival (PFS) was 3.7 months with eribulin and 2.2 months with TPC (0.87; 0.71 to 1.05; p=0.137) in the intention to treat population by independent review. When assessed by the investigator, PFS was similar but the difference between treatment groups was statistically significant (0.76; 0.64 to 0.90; p=0.002).

• The most common adverse events in both groups were asthenia or fatigue (270 [54%] of patients on eribulin and 98 [40%] patients on TPC at all grades) and neutropenia (260 [52%] on eribulin and 73 [30%] on TPC at all grades).

• Peripheral neuropathy was the most common adverse event leading to discontinuation from eribulin, occurring in 24 (5%) patients.

The researchers conclude “Eribulin showed a significant and clinically meaningful improvement in overall survival compared with TPC in women with heavily pretreated metastatic breast cancer. This finding challenges the notion that improved overall survival is an unrealistic expectation during evaluation of new anticancer therapies in the refractory setting.”

An accompanying Comment article notes that the FDA has approved eribulin for refractory breast cancer. It highlights that more information is needed from the study to address the following questions:

• Do some patients or tumour subtypes particularly benefit from ongoing therapy?

• Why is the gain in overall survival better than the improvement in progression-free survival?

• Are there measurable benefits for the patients whose tumours did not respond to therapy, and for those whose tumours did?

• At what point is refractoriness so advanced that ongoing treatment is futile or counterproductive?

• How would eribulin stack up against other new chemotherapeutic agents such as ixabepilone, or new targeted therapies?

The authors conclude that in the interim, “EMBRACE provides much needed, high-level evidence for chemotherapy use in patients with heavily pretreated breast cancer. And that evidence suggests that the methods to treat advanced breast cancer are growing, the treatment challenge in refractory disease is a little bit less daunting, and the treatment results are a little bit better than they were before.”