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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Sarcoma therapy is a challenge for oncologists. Soft-tissue sarcomas encompass more than 50 different histologies, resulting in limited familiarity of management for many treating physicians. In addition, there have been few available effective therapies. The phase III trial of eribulin (Halavan) compared with dacarbazine for the treatment of advanced leiomyosarcomas and liposarcomas by Schöffski and colleagues—reviewed in this issue of The ASCO Post—provided data that led to the U.S. Food and Drug Administration approval of eribulin, but only for the treatment of liposarcoma.1 So, what do the data show?
The study randomized adult patients with advanced liposarcoma and leiomyosarcoma with evidence of disease progression within the past 6 months who were not candidates for curative therapy with surgery or radiation—thus, a population of patients requiring palliative therapy. All patients had received at least two prior regimens of therapy, including one containing an anthracycline—the most active class of agents in this disease.
The patients were randomized to receive eribulin at 1.4 mg/m2 given on days 1 and 8 of every 21-day cycle or dacarbazine on day 1 of a 21-day cycle at one of three doses (850, 1000, or 1,200 mg/m2) predetermined by the treating physician. A total of 63% of patients randomized to dacarbazine received 1,000 mg/m2, with 850 mg/m2 being the second most common dosage, used in 21% of the patients.
The objective response rates were low in both treatment groups. There were no complete responses to either drug, with partial response rates of 4% and 5% to eribulin and dacarbazine, respectively. In the preceding phase II trial of eribulin, 1 complete and 1 partial response were seen in 32 adipocytic sarcomas (6%), but there were no responses in any of the 38 patients with leiomyosarcoma.2
Comparative Study Results
Dacarbazine for sarcoma treatment has been assessed in a limited number of studies. The earliest report of its use in sarcomas utilized 250 mg/m2 intravenously (IV) daily for 5 days, with a response rate of 17%.3 A subsequent phase I study tested doses of 850 to 1,980 mg/m2 IV every 21 days and determined that the maximum tolerated dose was 1,980 mg/m2.4
The European Organisation for Research & Treatment of Cancer conducted a phase II study of dacarbazine at 1,200 mg/m2 IV every 3 weeks in soft-tissue sarcomas, demonstrating an 18% response rate utilizing the World Health Organization criteria.5 More recently, a randomized phase II trial of gemcitabine with dacarbazine vs dacarbazine alone demonstrated a 4% response rate to the single agent using 1,200 mg/m2 every 3 weeks, with responses seen only in patients with leiomyosarcoma.6
Lastly, the phase III trial of trabectedin (Yondelis) vs dacarbazine, which was accruing patients with leiomyosarcoma and liposarcoma during a similar time frame, yielded a response rate of 6.9% utilizing the 1,000 mg/m2 dose.7 Thus, the phase III data for response rate are consistent for eribulin, and although lower than older phase II trials for dacarbazine, the response rate is on a par with that seen in the concurrent phase III trial in the same patient population.
The eribulin study met its primary endpoint. It improved median overall survival compared with dacarbazine—13.5 months vs 11.5 months (hazard ratio [HR] = 0.77, P = .0169). This finding is in contrast to the median progression-free survival, which was 2.6 months for both groups (HR = 0.88, P = .23). This suggests that the impact of eribulin manifests itself over the long term, unless there was a significant difference in the patients discontinuing treatment with dacarbazine for reasons other than disease progression or in post-study therapies. The number of patients discontinuing eribulin or dacarbazine due to an adverse event was comparable at 6.2% and 4.5%, as was the percent of patients choosing to stop therapy, at 2.2 % and 4.4%.
Review of the subsequent therapies showed 69.3% of the eribulin cohort and 62.9% of the dacarbazine cohort had chemotherapy, with a similar percentage receiving one to more than four lines of therapy. There were more patients receiving dacarbazine in the eribulin cohort, as would be expected (34.2% vs 7.6%). Disparities in subsequent therapies appear minor, but those with more than a 3% difference between eribulin and dacarbazine cohorts include doxorubicin (11.4% vs 7.1%), trabectedin (15.8% vs 12.1%), and other (3.5% vs 7.6%).
Improvement in Survival
What is intriguing about the improvement in overall survival with eribulin vs dacarbazine is that it recapitulates what has been seen in advanced breast cancer. A phase III trial randomized eribulin in a 2:1 fashion vs treatment as per physician choice, demonstrating an improvement in overall survival of 13.1 months vs 10.6 months.8 A second phase III trial did not show a benefit when comparing eribulin and capecitabine (15.9 months vs 14.5 months),9 although a pooled analysis of the two studies by Twelves and colleagues demonstrated a median overall survival of 15.2 months in the eribulin groups vs 12.8 months in the control groups (HR = 0.82, P = .002); this difference in survival was established early and persisted.10 Neither of the studies showed an improvement in progression-free survival with eribulin.
Unique Mechanism of Action
How does eribulin work? It functions to bind to microtubules and blocks their growth and the development of mitotic spindles, thus preventing mitosis and leading to apoptosis.11 It also affects the microenvironment, with remodeling of the microvasculature leading to enhanced perfusion.12
Limited data exist for its effects in soft-tissue sarcoma. Preclinical testing for efficacy against pediatric sarcomas in vitro and in vivo demonstrated a high level of activity (51%).13 More relevant to the recent phase III trial in sarcoma, preclinical models in leiomyosarcoma xenografts treated with eribulin demonstrated improved blood perfusion compared with controls.14 In addition, upregulation of genes associated with adipocytic and smooth muscle differentiation were observed.14 These data support the hypothesis that chemotherapy after eribulin may penetrate tumors better and have decreased hypoxia, which is associated with chemotherapy resistance. It also suggests that eribulin may lead to differentiation of sarcomas.
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. The finding that its benefit was limited to liposarcoma in the recent phase III study warrants consideration. For the patient with advanced sarcoma requiring palliation, is there a role for eribulin? That answer lies in a patient-physician discussion reviewing the goals of care in the context of the potential risks and benefit of therapy; no other agent available has been shown to improve overall survival in this patient population. ■
Disclosure: Dr. von Mehren is a member of the scientific steering committee for the phase III trial of trabectedin vs dacarbazine and a member of the data safety monitoring board for the phase III trial of eribulin vs dacarbazine.
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. Schöffski P, Ray-Coquard IL, Cioffi A, et al: Activity of eribulin mesylate in patients with soft-tissue sarcoma: A phase 2 study in four independent histological subtypes. Lancet Oncol 12:1045-1052, 2011.
3. Gottlieb JA, Benjamin RS, Baker LH, et al: Role of DTIC (NSC-45388) in the chemotherapy of sarcomas. Cancer Treat Rep 60:199-203, 1976.
4. Buesa JM, Gracia M, Valle M, et al: Phase I trial of intermittent high-dose dacarbazine. Cancer Treat Rep 68:499-504, 1984.
5. Buesa JM, Mouridsen HT, van Oosterom AT, et al: High-dose DTIC in advanced soft-tissue sarcomas in the adult: A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Ann Oncol 2:307-309, 1991.
6. García-Del-Muro X, López-Pousa A, Maurel J, et al: Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: A Spanish Group for Research on Sarcomas study. J Clin Oncol 29:2528-2533, 2011.
7. Demetri GD, von Mehren M, Jones RL, et al: Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: Results of a phase III randomized multicenter clinical trial. J Clin Oncol 34:786-793, 2016.
8. Cortes J, O’Shaughnessy J, Loesch D, et al: Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): A phase 3 open-label randomised study. Lancet 377:914-923, 2011.
9. Kaufman PA, Awada A, Twelves C, et al: Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 33:594-601, 2015.
10. Twelves C, Cortes J, Vahdat L, et al: Efficacy of eribulin in women with metastatic breast cancer: A pooled analysis of two phase 3 studies. Breast Cancer Res Treat 148:553-561, 2014.
11. Towle MJ, Salvato KA, Wels BF, et al: Eribulin induces irreversible mitotic blockade: Implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions. Cancer Res 71:496-505, 2011.
12. Funahashi Y, Okamoto K, Adachi Y, et al: Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models. Cancer Sci 105:1334-1342, 2014.
13. Kolb EA, Gorlick R, Reynolds CP, et al: Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program. Pediatr Blood Cancer 60:1325-1332, 2013.
14. Kawano S, Asano M, Adachi Y, Matsui J: Antimitoic and non-mitotic effects of eribulin mesilate in soft tissue sarcoma. Anticancer Res 36:1553-1561, 2016.
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 ...