Adapted from the NCI Cancer Bulletin.
Treatment with eribulin (Halaven™) improved overall survival in women with metastatic breast cancer whose disease progressed despite multiple rounds of prior chemotherapy, according to the results of a phase III clinical trial called EMBRACE. Based on these findings, the FDA approved eribulin last November for women with metastatic disease who have already undergone at least two previous chemotherapy regimens.
The study results were published online March 2, 2011, in The Lancet.
The improvement in overall survival makes the findings “clinically meaningful,” wrote the study’s lead author, Javier Cortes, M.D., of the Vall d'Hebron Institute of Oncology in Barcelona, Spain, and his colleagues. “To our knowledge, EMBRACE is the first major single-agent study of a cytotoxic or biological agent to show significantly increased survival in patients with such heavily pretreated metastatic breast cancer.”
Eribulin is a laboratory-made form of halichondrin B, a substance derived from a sea sponge. Similar to some other chemotherapy drugs, it targets the protein tubulin in cells, although it binds to tubulin in a different way, interfering with cancer cell division and growth.
In the trial—funded by Eisai Co., Ltd., which manufactures eribulin—762 patients were randomly assigned to receive either eribulin or the treating physicians’ choice of therapy. Prior to enrolling, trial participants had received, on average, four previous chemotherapy regimens. Because there is no standard of care for women with progressive metastatic breast cancer, the treatments eribulin was compared with “[reflect] real-life choices made by oncologists and their patients,” the researchers wrote.
Women who received eribulin, on average, lived 2.5 months longer than those treated with their physician’s choice (13.1 months versus 10.6 months). Progression-free survival was similar between the groups. Overall, serious side effects were roughly equal in women in both trial arms, although women treated with eribulin had more serious cases of neutropenia, leukopenia, and peripheral neuropathy.
“EMBRACE provides much needed, high-level evidence for chemotherapy use in patients with heavily pretreated breast cancer,” wrote Nancy Lin, M.D., and Harold Burstein, M.D., Ph.D., of Dana-Farber Cancer Institute, in an accompanying editorial. But a number of important questions remain about the use of eribulin in this group of patients, they noted, including whether there is a subgroup that is more likely to respond to the drug.
“The clinical gains from EMBRACE are sufficiently narrow,” the study authors continued, “that a better understanding of the relation between treatment, symptom control, and quality of life in study participants remains crucial.”
Eribulin Improves Survival of Women with Metastatic Breast Cancer - National Cancer Institute
eribulin mesylate
The mesylate salt of a synthetic analogue of halichondrin B, a substance derived from a marine sponge (Lissodendoryx sp.) with antineoplastic activity. Eribulin binds to the vinca domain of tubulin and inhibits the polymerization of tubulin and the assembly of microtubules, resulting in inhibition of mitotic spindle assembly, induction of cell cycle arrest at G2/M phase, and, potentially, tumor regression. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)
Synonym: halichrondrin B analog
Code names: B1939
E7389
ER-086526
Chemical structures: (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-2- [(2S)-3-amino-2-hydroxypropyl]-3-methoxy-26-methyl-20,27-dimethylidenehexacosahydro- 11,15:18,21:24,28-triepoxy-7,9-ethano-12,15-methano-9H,15H-furo[3,2- i]furo[2',3':5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one methanesulfonate (salt)
11,15:18,21:24,28-Triepoxy-7,9-ethano-12,15-methano-9H,15H-furo[3,2- i]furo[2',3':5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one, 2-[(2S)-3- amino-2-hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-, 2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-, methanesulfonate (salt)
Lancet. 2011 Mar 12;377(9769):914-23. Epub 2011 Mar 2.
Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study.
Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Diéras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, Twelves C; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389) investigators.
Source
Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain. c.j.twelves@leeds.ac.uk
c.j.twelves@leeds.ac.uk
Abstract
BACKGROUND: Treatments with survival benefit are greatly needed for women with heavily pretreated metastatic breast cancer. Eribulin mesilate is a non-taxane microtubule dynamics inhibitor with a novel mode of action. We aimed to compare overall survival of heavily pretreated patients receiving eribulin versus currently available treatments.
METHODS: In this phase 3 open-label study, women with locally recurrent or metastatic breast cancer were randomly allocated (2:1) to eribulin mesilate (1·4 mg/m(2) administered intravenously during 2-5 min on days 1 and 8 of a 21-day cycle) or treatment of physician's choice (TPC). Patients had received between two and five previous chemotherapy regimens (two or more for advanced disease), including an anthracycline and a taxane, unless contraindicated. Randomisation was stratified by geographical region, previous capecitabine treatment, and human epidermal growth factor receptor 2 status. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00388726.
FINDINGS: 762 women were randomly allocated to treatment groups (508 eribulin, 254 TPC). Overall survival was significantly improved in women assigned to eribulin (median 13·1 months, 95% CI 11·8-14·3) compared with TPC (10·6 months, 9·3-12·5; hazard ratio 0·81, 95% CI 0·66-0·99; p=0·041). The most common adverse events in both groups were asthenia or fatigue (270 [54%] of 503 patients on eribulin and 98 [40%] of 247 patients on TPC at all grades) and neutropenia (260 [52%] patients receiving eribulin and 73 [30%] of those on TPC at all grades). Peripheral neuropathy was the most common adverse event leading to discontinuation from eribulin, occurring in 24 (5%) of 503 patients.
INTERPRETATION: 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.
FUNDING: Eisai.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Comment in
Lancet. 2011 Mar 12;377(9769):878-80.
PMID:21376385[PubMed - indexed for MEDLINE]
Lancet. 2011 Mar 12;377(9769):878-80. Epub 2011 Mar 2
EMBRACE, eribulin, and new realities of advanced breast cancer.
Lin NU, Burstein HJ.
Source
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Comment on
Lancet. 2011 Mar 12;377(9769):914-23.
PMID:21376386[PubMed - indexed for MEDLINE]
EMBRACE, eribulin, and new realities of advanced breast cancer.
Lin NU, Burstein HJ.
Source
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Comment on
Lancet. 2011 Mar 12;377(9769):914-23.
PMID:21376386[PubMed - indexed for MEDLINE]
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