(P 364) A PHASE 1B TRIAL OF PREOPERATIVE ERIBULIN AND RADIATION FOR RETROPERITONEAL LIPOSARCOMA

Objective: The complex anatomy of the retroperitoneum and frequent large tumor size make management of retroperitoneal liposarcomas (RPLPS) particularly challenging, and despite aggressive surgical resections, rates of locoregional recurrence remain high. An international, randomized, phase 3 trial comparing preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (EORTC-62092: STRASS) failed to demonstrate significant improvement from radiation alone, although some benefit in liposarcomas was seen. Therefore, we wished to evaluate a preoperative chemoradiotherapy approach with potential to both enhance local efficacy of radiation and control micrometastatic disease. Eribulin is a cytotoxic microtubule inhibitor FDA-approved for the treatment of advanced liposarcoma and is predicted to be a radiosensitizing agent based on mechanism of action. The aim of this study was to assess the safety and tolerability of preoperative eribulin in combination with radiation in patients with RPLPS.

Methods: In this open-label dose-finding study, patients with primary or recurrent resectable RPLPS received preoperative eribulin and intensity-modulated radiation therapy (IMRT). Eribulin was administered for three 21-day cycles at a starting dose of 1.1 mg/m2, with escalation dose of 1.4 mg/m2. Concurrent radiation to 50.4 Gy began during cycle 1. Surgical resection occurred 3-10 weeks after completion of chemoradiation. The primary endpoint was determination of the recommended phase 2 doses (RP2D) of concurrent eribulin and radiation. Secondary endpoints included rate of R0 resection, pathologic response, objective response rate (ORR), recurrence free survival (RFS), and overall survival (OS) rates. Patient-reported questionnaires (PROMIS) were completed at four time-points before and after surgery to monitor the overall well-being of patients.

Results: Between 2018 and 2023, fifteen patients with resectable retroperitoneal liposarcoma were enrolled. Seven patients were female (46.7%), with ages between 44 and 79 years (median age 62). Both well-differentiated (40%) and de-differentiated (60%) liposarcoma subtypes were included. Seven (46.7%) patients had T4 tumors (>15 cm). Thirteen patients were evaluable for dose-determination. Four patients treated at starting dose level had no dose-limiting toxicities (DLTs), while two of nine treated at escalation dose level had DLTs. The RP2D was established as eribulin 1.4 mg/m2 and IMRT 50.4 Gy. The most frequent treatment-related adverse events were hematologic, including grade 3-4 lymphopenia and anemia, as well as grade 1-2 nausea, diarrhea and fatigue. Eleven patients were evaluable for secondary efficacy endpoints. The median RFS was 30.4 months (95% CI 12.0-NR) and the median OS was 54.1 months (95% CI 9.5-NR). Patient reported outcome data did not show any significant changes in global physical health or gastrointestinal belly pain over the study period.

Conclusion: A preoperative chemoradiation protocol of eribulin in combination with IMRT showed a manageable safety profile and warrants additional prospective evaluation for treatment of RPLPS. (This investigator-initiated trial was supported by Eisai Inc.; ClinicalTrials.gov number, NCT03361436.)