A phase Ib/II trial of radiotherapy combined with doxorubicin and PD-1 antibody for localized high-risk limbs and trunk soft tissue sarcomas.

11568 Background: Localized high-risk soft tissue sarcomas (STSs) presents a therapeutic challenge due to limited preoperative treatment options. Radiotherapy (RT) and Doxorubicin (DOXO) are well-established immunogenic cell death inducers [1-3], which are capable of boosting the effects of immunotherapy even in "cold" tumors. This study aims to evaluate the safety and efficacy of a preoperative triple combination of RT, DOXO, and the PD-1 antibody for STS. Methods: In this Phase Ib/II trial (NCT05774275), up to 52 patients with localized high-risk STSs will be enrolled. Participants will receive RT (BED = 50-60 Gy), combined with DOXO and PD-1 antibody (Sintilimab, SIN 200 mg, Day 1) every three weeks for four cycles prior to surgery. In Phase Ib (3+3 design), patients will receive Pegylated liposomal doxorubicin (PLD, 37.5 mg/m² or 30 mg/m², i.v., Day 1) to establish the recommended Phase 2 dose (RP2D). In Phase II, DOXO will be administered as PLD at RP2D or as Doxorubicin Hydrochloride (Adriamycin, ADM, 75 mg/m² i.v., Day 1). The primary endpoint is the objective response rate (ORR), while secondary endpoints include the rate of pathological complete response (pCR) and near pCR (defined as < 10% viable tumor cells), survival and safety. Results: From September 2022 to January 2025, 33 patients (26 in limbs and 7 in trunks) were enrolled. The median age was 50 years (range 19-75), with 17 males, and 13 patients had prior surgeries. 29 tumors were histological grade 3. No dose-limiting toxicities (DLT) were observed in the first six patients receiving PLD (37.5 mg/m², i.v., Day 1, q3w), confirming the RP2D. Among the 28 radiological evaluable patients, 2 achieved complete response (CR), 12 achieved partial response (PR), and 11 had stable disease, resulting in an ORR of 50.0% and a disease control rate (DCR) of 89.2%. In addition, among 24 pathological assessable patients, 14 (58.3%) achieved pCR or near-pCR. Two patients (9.5%) experienced major wound complications. They underwent secondary operation and readmission to hospital for wound care, respectively. Other serious adverse events (SAE) include Grade 3 dermatitis (17.9%) and Grade 3-4 neutropenia (7.1%). No G5 SAE were reported. Median progression-free survival and overall survival have not yet been reached. Conclusions: The combination of RT, DOXO, and SIN showed potential efficacy and tolerable toxicity in high-risk localized limbs and trunk STS. The trial is still ongoing. Clinical trial information: NCT05774275 .