Regulatory Approval Sought for Eribulin in Soft Tissue Sarcoma

Patrick Schöffski, MD, MPH

An application has been submitted to the FDA for eribulin mesylate (Halaven) as a treatment for patients with soft tissue sarcoma following an anthracycline and at least one other regimen, based on an extension in overall survival (OS) with the microtubule dynamics inhibitor compared with dacarbazine in the phase III Study 309 trial.

Findings from the open-label Study 309 trial were presented at the 2015 ASCO Annual Meeting by Patrick Schöffski, MD, MPH, and represented the first phase III analysis to show an OS improvement for patients with soft tissue sarcoma. In the study, patients with intermediate- and high-grade leiomyosarcoma (LMS) or adipocytic sarcoma (ADI) experienced a median OS with eribulin of 13.5 months compared with 11.5 months for dacarbazine, representing a 23% reduction in the risk of death (HR = 0.768; 95% CI, 0.618-0.954; P = .0169).

Regulatory filings have also been submitted to the European Medicines Agency and the Ministry of Health, Labour, and Welfare in Japan, according to the drug's developer, Eisai. The FDA will review the application within 60 days, at which point the agency will assign a review deadline under the Prescription Drug User Fee Act.

"This is the very first phase III trial investigating patients with soft tissue sarcoma to demonstrate an overall survival benefit of a new agent compared with an active agent," Schöffski, said during a press briefing at the 2015 ASCO Annual Meeting. "This is a clinically meaningful result given the high unmet medical need in this rare, hard-to-treat family of diseases."

In the study, 452 patients with advanced soft tissue sarcoma were randomized to receive eribulin (n = 228) or dacarbazine (n = 224). Eribulin was administered at 1.4 mg/m² on days 1 and 8 and dacarbazine was administered at 850, 1000, or 1200 mg/m² on day 1 of each 21-day cycle.

Patients enrolled had high- or intermediate-grade sarcoma and the majority had received 2 or more prior therapies. The primary endpoint of the study was OS, with secondary outcomes focused on progression-free survival (PFS) and safety.

The median OS in patients with the ADI subtype was 15.6 months with eribulin (n = 75) compared with 8.4 months with dacarbazine (n = 78; HR = 0.511; 95% CI, 0.346-0.753). In the LMS group, patients treated with eribulin (n = 152) had a median OS of 12.7 versus 13 months with dacarbazine (n = 145; HR = 0.927; 95% CI, 0.714-1.203).

Median PFS was 2.6 months in both arms of the study (HR = 0.877; 95% CI, 0.710-1.085; P = .2287). The 12-week PFS rate was 33% with eribulin and 28.6% with dacarbazine; however, this difference was not deemed statistically significant (odds ratio = 1.3; P = .253).

The objective response rate (all partial responses) was 3.9% with eribulin versus 4.9% with dacarbazine. The stable disease rate with eribulin was 52.2% compared with 47.8% with dacarbazine.

All-grade adverse events (AEs) were seen in almost all patients in the study. The most common AEs in the eribulin arm were neutropenia (43.8%), fatigue (43.8%), nausea (40.3%), alopecia (35%), and constipation (31.4%). With dacarbazine, the most common AEs were nausea (47.3%), fatigue (38.4%), anemia (30.8%), thrombocytopenia (27.7%), and constipation (25.9%).

Grade ≥3 treatment-related AEs were reported in 67.3% of patients treated with eribulin compared with 56.3% with dacarbazine. The most common grade ≥3 AEs with eribulin were neutropenia (35.4%) and anemia (7.1%) versus neutropenia (15.6%), anemia (12.1%), and thrombocytopenia (15.2%).

"We looked at the safety profile of the drugs that we used in this trial and we found that the safety findings matched our experience with these two drugs in other settings of oncology," Schöffski said. "There were no new safety findings. There were only two treatment-related deaths in this study, both occurring in the eribulin arm."

The FDA initially approved eribulin in 2010 for the treatment of patients with metastatic breast cancer. This approval was based on a 2.5-month extension in OS experienced by patients treated with eribulin compared with physician's choice of treatment in the phase III EMBRACE trial. The treatment continues to be assessed in clinical trials across a variety of settings.

Schöffski P, Maki RG, Italiano A, et al. Randomized, open-label, multicenter, phase III study of eribulin versus dacarbazine in patients (pts) with leiomyosarcoma (LMS) and adipocytic sarcoma (ADI). J Clin Oncol. 2015;(suppl; abstr LBA10502).