A randomized clinical study comparing trabectedin combined with regional hyperthermia with trabectedin in patients with advanced soft tissue sarcoma: HyperTET, a German Interdisciplinary Sarcoma Group trial

Background The German Interdisciplinary Sarcoma Group (GISG) assessed efficacy and safety of trabectedin plus regional hyperthermia (Tr + RHT) versus trabectedin (Tr) in patients with advanced soft tissue sarcoma (STS). Patients and methods In this randomized, open-label, multicenter study, adults with advanced STS who had progressed after at least one line of anthracycline-based chemotherapy or were unsuited for this treatment were enrolled. Patients were randomly assigned 1 : 1 to receive Tr + RHT or Tr every 3 weeks. Stratification factors included histological subtype, prior surgery (at any time), metastatic status, and Eastern Cooperative Oncology Group performance status. The primary endpoint was progression-free survival (PFS) analyzed in the intention-to-treat (ITT) population. Results Between 19 December 2014 and 7 December 2021, 118 eligible patients from five GISG centers were allocated to Tr + RHT (n = 60) or Tr (n = 58). Patients received a median of three cycles [interquartile range (IQR) 2-6.2 cycles] in the Tr + RHT arm and four cycles (IQR 2-6 cycles) in the Tr arm. Median PFS was 3.0 months [95% confidence interval (CI) 2.5-5.0 months] with Tr + RHT versus 3.5 months (95% CI 2.8-5.9 months) with Tr (stratified HR 0.86, 95% CI 0.57-1.29, P = 0.459). In a Cox proportional hazards model, patients receiving five or more cycles showed a median PFS of 12.8 months (95% CI 9.8-21.0 months) with Tr + RHT versus 7.8 months (95% CI 6.0-12.6 months) with Tr (stratified HR 0.33, 95% CI 0.13-0.86, P = 0.023). Most commonly reported grade 3/4 treatment-related adverse events (AEs) were hematologic, hepatic, and infections. Treatment-related deaths were reported in three patients (5.3%) of the Tr arm. Conclusions Adding RHT to trabectedin did not improve PFS. Although the study was negative, a post hoc exploratory analysis of the subgroup of patients receiving ≥5 cycles of Tr + RHT showed an improvement in PFS. The combination had a manageable safety profile, serving as the basis for a subsequent study on maintenance therapy with trabectedin or lurbinectedin plus RHT in advanced STS.