Trabectedin with concomitant radiotherapy in resectable retroperitoneal L-sarcoma: A multicenter, prospective, phase I/II trial—A collaborative study by the Spanish (GEIS), Italian (ISG), and French (FSG) groups.

11507 Background: Liposarcoma (LPS) and leiomyosarcoma (LMS) account for most retroperitoneal sarcomas. Despite complete resection, local recurrence remains high, particularly in dedifferentiated LPS (DDLPS). While preoperative radiotherapy (RT) may improve local control, optimal multimodal strategies are undefined. Trabectedin (T) is active in L-sarcomas, with emerging clinical evidence supporting its radiosensitizing properties and its efficacy in combination with RT. A preoperative short course of T with concurrent low-dose RT was investigated in a multicenter, phase I/II trial in patients (pts) with centrally confirmed resectable retroperitoneal L-sarcoma (grade 2-3 DDLPS with >30% dedifferentiated component or grade 2-3 LMS). Methods: Pts received 3 cycles of T in combination with RT (45 Gy in 25 x 1.8 Gy). Phase I followed a 3+3 dose-escalation design with T dose levels 1.5 (0), 1.3 (-1), and 1.1mg/m 2 (-2). Dose-limiting toxicity was any grade ≥3 adverse events (excluding neutropenia <5 days, elevated transaminases without treatment delay, and nausea/vomiting due to inadequate prophylaxis). Phase I primary endpoint was safety and the determination of the recommended Phase II dose (RP2D). Phase II primary endpoint was centrally assessed Choi response. Secondary endpoints included relapse-free survival (RFS; from surgery), progression-free survival (PFS; from first T cycle), overall survival (OS), RECIST and pathological response, and treatment-related toxicity according to CTCAE v5.0. Results: From February 2019 to January 2025, 56 pts, 6 in phase I and 50 in phase II, (M/F: 31/25) with a median age of 61 years (range: 19-75) and a median tumor size of 17 cm (range: 12-30) were enrolled. 51 pts had grade 2-3 DDLPS, and 5 pts had grade 2-3 LMS. A T dose of 1.5 mg/m 2 was the RP2D. Per-protocol therapy was completed in 47 pts (84%); discontinuations were due to local progression (N=1), toxicity (N=6), or refusal (N=2). The most common grade 3/4 toxicities were neutropenia (21.4%), leukopenia (8.9%), fatigue (8.9%), and increased ALT, febrile neutropenia, and thrombocytopenia (7.1% each). 51 pts (91%) underwent surgery, with 96% achieving complete resection. According to the central review, Choi (N=45) showed 12 PR (26.7%) and 33 SD (73.3%). RECIST 1.1 (N=53): PR 1 (2%), SD 51 (96%), PD 1 (2%). At a median follow-up of 40 months (95% CI, 36-43), from the start of T (N=53), 3-year PFS was 70% (95 CI, 56-83) and 3-year OS was 85% (95 CI, 75-95). Conclusions: Preoperative concurrent T and RT was feasible and safe for resectable retroperitoneal L-sarcomas, yielding density responses in over 25% of pts and promising survival outcomes. A phase III trial is warranted to compare this regimen against RT alone. Clinical trial information: NCT02275286 .