ISY-13-4 - Clinical trials of trabectedin for soft tissue sarcoma

Abstract

Doxorubicin and ifosfamide are the two main effective therapies for STS, but few therapeutic options exist after those two therapies.Trabectedin, a marine-derived anti-tumor agent, exerts its anti-tumor activity by inhibiting DNA repair through its binding to the DNA minor groove, and it also inhibits transcription factors derived from fusion proteins. It is effective for soft tissue sarcomas (STS), especially translocation-related sarcomas (TRS).Pooled analysis from five phase II studies of trabectedin (n = 350, pre-treated in 91%) showed 10% response rate, 28.3% disease-control rate, and OS of 13-14 months.In a randomized phase III study comparing trabectedin or dacarbazine (2:1) for pts with advanced liposarcoma or leiomyosarcoma pretreated with anthracycline and other cytotoxic drug (n = 518), trabectedin showed improvement in PFS (HR 0.55, 4.2M vs 1.5M), but did not show improvement in OS (HR 0.87). Most common Grade 3-4 adverse events were myelosuppression and transient elevation of transaminases.In Japan, randomized open label phase II study comparing trabectedin 1.2mg/m2 versus best supportive care in pts with TRS unresponsive or intolerant to standard chemotherapy, trabectedin showed improvement of PFS (HR 0.07, 5.6M versus 0.9M). Common adverse events were nausea, decreased appetite, decreased neutrophil, increased ALT, common and adverse events of G3 or more were neutrophil decreased (67%), ALT increased (61%), febrile neutropenia (14%). G4 rhabdomyolysis were also seen (3%).From these data, trabectedin was approved for STS in Japan at 2015 and should be considered as a therapeutic option for pretreated STS, especially TRS. Doxorubicin and ifosfamide are the two main effective therapies for STS, but few therapeutic options exist after those two therapies. Trabectedin, a marine-derived anti-tumor agent, exerts its anti-tumor activity by inhibiting DNA repair through its binding to the DNA minor groove, and it also inhibits transcription factors derived from fusion proteins. It is effective for soft tissue sarcomas (STS), especially translocation-related sarcomas (TRS). Pooled analysis from five phase II studies of trabectedin (n = 350, pre-treated in 91%) showed 10% response rate, 28.3% disease-control rate, and OS of 13-14 months. In a randomized phase III study comparing trabectedin or dacarbazine (2:1) for pts with advanced liposarcoma or leiomyosarcoma pretreated with anthracycline and other cytotoxic drug (n = 518), trabectedin showed improvement in PFS (HR 0.55, 4.2M vs 1.5M), but did not show improvement in OS (HR 0.87). Most common Grade 3-4 adverse events were myelosuppression and transient elevation of transaminases. In Japan, randomized open label phase II study comparing trabectedin 1.2mg/m2 versus best supportive care in pts with TRS unresponsive or intolerant to standard chemotherapy, trabectedin showed improvement of PFS (HR 0.07, 5.6M versus 0.9M). Common adverse events were nausea, decreased appetite, decreased neutrophil, increased ALT, common and adverse events of G3 or more were neutrophil decreased (67%), ALT increased (61%), febrile neutropenia (14%). G4 rhabdomyolysis were also seen (3%). From these data, trabectedin was approved for STS in Japan at 2015 and should be considered as a therapeutic option for pretreated STS, especially TRS.