Final Results of a Randomized Phase II Study comparing Trabectedin and best supportive care (BSC) in patients (pts) with Translocation-related sarcomas (TRS) .
T. Kunisada(1), S. Takahashi(2), N. Araki(3), H. Sugiura(4), T. Ueda(5), T. Yonemoto(6), M. Takahashi(7), H. Morioka(8), H. Hiraga(9), T. Hiruma(10), A. Matsumine(11), A. Kawai(12)
The marine-derived antitumor agent trabectedin binds to the minor groove of DNA and blocks DNA repair machinery leading to inhibition of cell cycle and proliferation. In addition, trabectedin inhibits interactions of transcription factors with DNA. In Japan, a randomized comparative phase II study for TRS pts was conducted and has shown that trabectedin is an active drug in TRS pts pretreated by available chemotherapies (Kawai A, et al. Lancet Oncol 2015). Here we present the final analysis of this study following the primary analysis (8th February 2014).
Material and Methods:
Main inclusion criteria were the following: histologically proven TRS; unresponsiveness or intolerability to standard chemotherapy regimens (pts with extraskeletal Ewing sarcoma (EES), myxoid liposarcoma (ML), or synovial sarcoma (SS) should have received anthracyclines); at least 1 measurable baseline lesion (RECIST v1.1); confirmed disease progression (per RECIST) compared with the image assessment performed during the previous 6 months (m). Pts stratified by subtype (alveolar rhabdomyosarcoma, ESS, ML, SS vs other TRS) were randomly assigned 1:1 to trabectedin (1.2mg/m2 in 24h continuous infusion every 21 days) or BSC. The primary endpoint was PFS by an independent review (IR). This study had 80% power for a one-sided 5% significance level test given a hazard ratio (HR) (trabectedin relative to BSC) of 0.50. Sample size goal was 74 pts with an event goal of 52 events by IR and a total of 60 events by investigator's assessment. PFS and overall survival (OS) were analyzed using a stratified log-rank test.
Results:
A total of 76 pts were enrolled. Number of pts for efficacy analysis was 73 (trabectedin: 37 pts and BSC: 36 pts). Median follow-up was 22.7 m. Median PFS (90% confidence interval (CI) for trabectedin and BSC were 5.6 m (4.1–7.3) and 0.9 m (0.9–1.0), respectively (p 0.0001; HR=0.11, 90% CI: 0.06–0.19). PFR at 3 m was 70.2% in trabectedin and 3.3% in BSC. Objective response rate was 10.8% in trabectedin and 0.0% in BSC. Disease control rate was 70.3% in trabectedin and 2.8% in BSC. Median OS (95%CI) for trabectedin and BSC were 17.7 m (12.8–26.4) and 12.2 m (7.0–24.0), respectively (p=0.397; HR=0.72, 95%CI: 0.40–1.29). 29 pts (80.1%) of BSC crossed over to trabectedin after progressive disease confirmed in this study.
Conclusions:
Final analysis demonstrated significant risk reduction in disease progression by trabectedin. OS for trabectedin was also promising. Therefore, trabectedin could be considered as a new therapeutic treatment option for TRS pts after standard chemotherapy.