Background A non-randomised, phase 2 study showed activity and tolerability of eribulin in advanced or metastatic soft-tissue sarcoma. In this phase 3 study, we aimed to compare overall survival in patients with advanced or metastatic soft-tissue sarcoma who received eribulin with that in patients who received dacarbazine (an active control). Methods We did this randomised, open-label, phase 3 study across 110 study sites in 22 countries. We enrolled patients aged 18 years or older with intermediate-grade or high-grade advanced liposarcoma or leiomyosarcoma who had received at least two previous systemic regimens for advanced disease (including an anthracycline). Using an interactive voice and web response system, an independent statistician randomly assigned (1:1) patients to receive eribulin mesilate (1·4 mg/m2 intravenously on days 1 and 8) or dacarbazine (850 mg/m2, 1000 mg/m2, or 1200 mg/m2 [dose dependent on centre and clinician] intravenously on day 1) every 21 days until disease progression. Randomisation was stratified by disease type, geographical region, and number of previous regimens for advanced soft-tissue sarcoma and in blocks of six. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT01327885, and is closed to recruitment, but treatment and follow-up continue. Findings Between March 10, 2011 and May 22, 2013, we randomly assigned patients to eribulin (n=228) or dacarbazine (n=224). Overall survival was significantly improved in patients assigned to eribulin compared with those assigned to dacarbazine (median 13·5 months [95% CI 10·9-15·6] vs 11·5 months [9·6-13·0]; hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·0169). Treatment-emergent adverse events occurred in 224 (99%) of 226 patients who received eribulin and 218 (97%) of 224 who received dacarbazine. Grade 3 or higher adverse events were more common in patients who received eribulin (152 [67%]) than in those who received dacarbazine (126 [56%]), as were deaths (10 [4%] vs 3 [1%]); one death (in the eribulin group) was considered treatment-related by the investigators. Interpretation 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.
Bibliographical noteFunding Information:
The study was funded by Eisai and designed in collaboration with the principal investigator. Eisai also funded the data collection, data analysis, data interpretation, and writing of the report. DD'A and MG are employees of Eisai. The corresponding author had full access to all the data in the study, and, together with all authors, had final responsibility for the decision to submit for publication.
ALC declares personal fees from Novartis, Pharmamar, Pfizer, and GlaxoSmithKline. GD declares grants from Eisai, Pfizer, Threshold Pharmaceuticals, Janssen Oncology, Bayer, Novartis, and GlaxoSmithKline; personal fees from Pfizer, Lilly, EMD Serono, Threshold Pharmaceuticals, Sanofi Oncology, GlaxoSmithKline, Saiichi-Sankyo, Ariad, AstraZeneca, Ziopharm, Polaris Pharmaceuticals, Kolltan Pharmaceuticals, Blueprint Medicines, Caris Life Sciences, Champions Oncology, and Bessor Pharmaceuticals; and has the following declarations: Kolltan Pharmaceuticals (stock options), Blueprint Medicines (stock, stock options, and service on the Board of Directors), Caris Life Sciences (stock options), Champions Oncology (stock options), and Bessor Pharmaceuticals (stock options). SRP is a consultant for Novartis, EMD Serono, Johnson and Johnson, and CytRx; and is the data safety and monitoring committee chair for CytRx. All other authors declare no competing interests. All institutions were compensated for participation in this study.
We thank the patients, their families, the investigators, and the teams who participated in this trial; and Shilpa Aggarwal and Brian Falcone of Oxford PharmaGenesis for providing editorial assistance (funded by Eisai). A complete list of all recruiting sites and the principal investigators is provided in the appendix . Presented in part at the American Society of Clinical Oncology Annual Meeting; May 29–June 2, 2015; Chicago, IL, USA.
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