Accepted July 28, 2017.// Copyright ©2017, American Association for Cancer Research.
Amy Barone, Dow-Chung Chi, Marc R. Theoret, Huanyu Chen, Kun He, Dubravka Kufrin, Whitney S. Helms, Sriram Subramaniam, Hong Zhao, Anuja Patel, Kirsten B. Goldberg, Patricia Keegan and Richard Pazdur
Abstract
On October 23, 2015, the U.S. Food and Drug Administration approved trabectedin, a new molecular entity for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen.
Approval was based on results of a single, randomized, active-controlled, 518-patient, multicenter study comparing the safety and efficacy of trabectedin 1.5 mg/m2 as a 24-hour continuous intravenous (i.v.) infusion once every 3 weeks to dacarbazine 1000 mg/m2 i.v. once every 3 weeks.
Treatment with trabectedin resulted in a statistically significant improvement in progression-free survival (PFS) of 4.2 months and 1.5 months for trabectedin and dacarbazine, respectively. (HR= 0.55; 95% CI: 0.44, 0.70; unstratified log-rank test p = 0,001 .
The most common adverse reactions ( 20%) were nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache.
Serious adverse reactions included anaphylaxis, neutropenic sepsis, rhabdomyolysis, hepatotoxicity, cardiomyopathy, and extravasation resulting in tissue necrosis.
A post-marketing trial was required to evaluate the serious risk of cardiomyopathy. This approval provides another treatment option in a setting where no drug has been shown to improve overall survival.
A key regulatory consideration during review of this application was use of PFS as an endpoint to support regular approval of trabectedin.