A pair of studies from the 2013 Breast Cancer Symposium delivered promising and preliminary news about the microtubule inhibitor eribulin mesylate.
A phase Ib study of eribulin and cyclophosphamide (CTX) in metastatic breast cancer (MBC) reported significant activity and moderate side effects,1while a lab study found that eribulin inhibited cell growth and Akt activation when applied to triple-negative breast cancer cells.2
The first trial enrolled six patients with MBC (median age, 50 years).1All patients had prior taxane exposure, and four patients had baseline grade 1 peripheral neuropathy. Tumor characteristics included hormone receptor-positive (5 patients), HER2-postive (2 patients), and triple-negative (1 patient). The median number of prior treatments for MBC was five.
Eribulin was administered in two escalating doses on day 1 and day 8 of each 21-day cycle, while 600 mg/m2CTX was given on the first day of each cycle. Patients received a median of 5.5 cycles, with three patients still receiving the treatment.
Toxicities included neutropenia (50%), thrombocytopenia, fatigue, nausea, rash, mucositis, peripheral neuropathy, alopecia (33% each), and elevated liver enzymes (17%). Neutropenia was the only grade 3/4 toxicity.
Responses included two patients with partial remissions and four with stable disease. The two patients who met threshold of >5 CTC/7.5 mL at baseline saw a mean decrease of 90.5% at the start of cycle 2. Phase II trials of the eribulin-CTX combo are already under way in patients with MBC.
“The activity was substantial and the treatment was well tolerated, particularly when compared to the combination of taxane and cyclophosphamide. Half the patients who began the study were still taking the treatment at the end,” said study co-author Hope Rugo, MD, professor of Medicine and director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco.
“In the long run, it may well make medical sense to explore eribulin as a substitute for taxane as a first-line treatment in combination with cyclophosphamide. Taxane produces very severe side effects, and the substitution could save considerable pain, but such a trial would require a huge number of patients studied over a long time period, and the patent on this drug expires relatively soon.”
The second eribulin study, which was conducted at City of Hope Cancer Center-Beckman Research Institute in Duarte, California, was designed to evaluate eribulin’s efficacy in inhibiting PI3K pathway activity and cell growth, both alone and in combination with the mTOR inhibitor RAD001.2
Both MDA468 and SKBR3 cells treated with eribulin in varying concentrations showed inhibition of pAkt expression. Standard dilutions of eribulin in combination with log dilutions of RAD001 resulted in marked synergistic growth inhibition (CI<1) in both MDA468 and BT549 cells. Western blot analysis for MDA468 cells treated with the combination of eribulin and RAD001 showed a dose-related suppression of pAkt along with complete inhibition of pS6K1, while RAD001 alone increased pAkt.
The research team, which was led by David Luyimbazi, MD, concluded that their findings point to a potential role for eribulin and RAD001 in the treatment of refractory triple-negative breast cancer.
Eribulin is a fully synthetic macrocyclic ketone analogue of a natural compound called halichondrin B, which is found in some marine sponges. Halichondrin B and eribulin inhibit microtubule dynamics by binding to a small number of high-affinity sites at the plus ends of existing microtubules. This mitotic roadblock eventually triggers apoptosis in cancer cells.
Eribulin was first approved by the FDA in 2010 for patients with MBC who have received at least two prior chemotherapy treatments for late-stage disease, including both anthracycline- and taxane-based agents.
Eisai Co., which markets eribulin as Halaven, is currently sponsoring nearly a dozen studies to investigate eribulin’s efficacy against other solid tumor types such as non-small cell lung cancer, prostate cancer, and sarcoma.
A phase III study published late last year found that eribulin was not superior to capecitabine in the treatment of previously treated locally advanced or MBC,3but a subgroup analysis presented this summer at the 2013 American Society of Clinical Oncology Annual Meeting showed that certain patientsparticularly those with ER- or triple-negative cancers—may benefit more from eribulin,4and quality of life (QoL) data suggest that patients may prefer eribulin because of a lower frequency of certain adverse events such as cognitive impairment.5
“Overall, eribulin is a pretty interesting compound,” Rugo said. “Its mechanism of action is unique. The side effects tend to be pretty mild. People who treat breast cancer should pay attention to the new research as it comes in.”