Overall survival was improved in patients assigned to eribulin compared with those assigned to an active control, suggesting that eribulin could be a treatment option for advanced soft-tissue sarcoma.— Patrick Schöffski, MD, and colleagues
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In a phase III trial reported in The Lancet, Patrick Schöffski, MD, of University Hospitals Leuven, Leuven Cancer Institute, Belgium, and colleagues found that eribulin (Halaven) improved overall survival vs dacarbazine in patients with advanced or metastatic soft-tissue sarcoma who had received at least two prior systemic treatments, including an anthracycline, for advanced disease.1 Outcome in the subgroup of patients with liposarcoma led to U.S. Food and Drug Administration (FDA) approval of eribulin in January 2016, in patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen.1,2
In this open-label trial, 452 patients aged ≥ 18 years from 110 sites in 22 countries with intermediate- or high-grade advanced liposarcoma or leiomyosarcoma were randomly assigned between March 2011 and May 2013 to receive eribulin mesylate at 1.4 mg/m² intravenously on days 1 and 8 every 21 days (n = 228) or dacarbazine at 850 mg/m², 1,000 mg/m², or 1,200 mg/m² intravenously according to center and clinician discretion on day 1 every 21 days until disease progression. The primary endpoint was overall survival in the intent-to-treat population.
In the entire patient population, median age was 56 years (range = 24–83 years), 67% were female, 73% were white, Eastern Cooperative Oncology Group (ECOG) performance status was 0 for 44% and 1 for 53%, and 47% had received more than two prior systemic therapies. The United States or Canada accounted for 38% of patients in both groups; Western Europe, Australia, or Israel accounted for 46% and 47% of patients in the eribulin and dacarbazine groups, respectively; and Eastern Europe, Latin America, or Asia accounted for 15% of patients in both groups.
A total of 152 patients (67%) in the eribulin group and 145 patients (65%) in the dacarbazine group had leiomyosarcoma, while 75 (33%) and 78 (35%) patients in the eribulin and dacarbazine groups, respectively, had liposarcoma. Among patients with liposarcoma, median age was 55 years (range = 32–83 years); 62% were male; 72% were white; ECOG performance status was 0 for 41% and 1 for 53%; 44% had received more than two prior therapies; and histologic subtypes were dedifferentiated in 45%, myxoid/round cell in 37%, and pleomorphic in 18%.
Among all patients, median overall survival was 13.5 months (95% confidence interval [CI] = 10.9–15.6 months) in the eribulin group vs 11.5 months (95% CI = 9.6–13.0 months) in the dacarbazine group (hazard ratio [HR] = 0.77, P = .0169). Median progression-free survival was 2.6 months (95% CI = 1.9–2.8 months) in the eribulin group vs 2.6 months (95% CI = 1.8–2.7 months; HR = 0.88, P = .23) in the dacarbazine group.
Subgroup analysis showed that a significant effect of eribulin on overall survival was limited to patients with liposarcoma. Among these patients, median overall survival was 15.6 months (95% CI = 10.2–18.6 months) in the eribulin group vs 8.4 months (95% CI = 5.2–10.1 months) in the dacarbazine group, with a hazard ratio of 0.51 (95% CI = 0.35–0.75).
The authors noted that “[the] study was not powered to draw definitive conclusions from such subgroup analyses.” Among patients with leiomyosarcoma, median overall survival was 12.7 months (95% CI = 9.8–14.8 months) in the eribulin group vs 13.0 months (95% CI = 11.3–15.1 months) in the dacarbazine group, with a hazard ratio of 0.93 (95% CI = 0.71–1.20).
Use of poststudy chemotherapy was similar in the two groups (69% vs 63%), except for greater use of dacarbazine in the eribulin group (34% vs 8%), as was poststudy use of surgery (16% vs 17%) and radiotherapy (23% vs 20%).
Grade ≥ 3 adverse events were more common in the eribulin group (67% vs 56%), including neutropenia (35% vs 16%) and leukopenia (10% vs 5%). Grade ≥ 3 anemia (12% vs 7%) and thrombocytopenia (15% vs < 1%) were more common in the dacarbazine group. Adverse events led to dose interruption in 33% vs 32% of patients, dose reduction in 26% vs 14%, and treatment discontinuation in 8% vs 5%.
A total of 13 patients died from treatment-related adverse events, including 10 (4%) in the eribulin group and 3 (1%) in the dacarbazine group. Of them, one death in the eribulin group, due to neutropenic sepsis, was considered possibly related to study treatment by investigators. Another death in the eribulin group, due to septic shock, was considered possibly related to treatment by the trial sponsor, but not by investigators.
The investigators concluded: “Overall survival was improved in patients assigned to eribulin compared with those assigned to an active control, suggesting that eribulin could be a treatment option for advanced soft-tissue sarcoma.” ■
Disclosure: The study was funded by Eisai. For full disclosures of the study authors, visit www.thelancet.com.
1. Schöffski P, Chawla S, Maki RG, et al: Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: A randomised, open-label, multicentre, phase 3 trial. Lancet 387:1629-1637, 2016.
2. Halaven (eribulin mesylate) injection prescribing information, January 2016, Eisai Inc. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2016/201532s015lbl.pdf. Accessed March 29, 2016.
Eribulin appears to have a unique mechanism of action, with data suggesting its benefits are due less to direct cytotoxic effects and more to changes in the tumor microenvironment or malignant cells.— Margaret von Mehren, MD
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