A Single-Arm Phase II Exploratory Study of Neoadjuvant Immunotherapy Plus Chemotherapy Plus SBRT Triplet Therapy and Postoperative Stratified Maintenance Therapy for Undifferentiated Pleomorphic Sarcoma

Undifferentiated pleomorphic sarcoma (UPS) accounts for 5-10% of soft tissue sarcomas. For localized high-risk UPS of the extremities, the standard of care is preoperative radiotherapy plus radical surgery; however, even with R0 resection, the risk of distant metastasis is 30-40% and 2-year disease-free survival is approximately 50%. The SARC028 study showed an objective response rate of 23% in UPS with pembrolizumab, and SU2C-SARC032 demonstrated that adding perioperative pembrolizumab to preoperative radiotherapy improved 2-year DFS (67% vs 52%, HR 0.61). Preclinical and clinical data suggest that stereotactic body radiotherapy (SBRT) with high dose per fraction better synergizes with immune checkpoint blockade than conventional fractionation; sparing the tumor-draining lymph nodes is critical for preserving immune priming.

This phase II study evaluates the triplet neoadjuvant regimen of SBRT, reduced-dose anthracycline chemotherapy, and toripalimab followed by postoperative stratified maintenance in patients with localized high-risk UPS. The fixed treatment schedule is: weeks 1-3 SBRT (8-10 Gy in 5 fractions, on alternate days or consecutively) plus first dose of toripalimab; week 4 first chemotherapy cycle plus second dose of toripalimab; weeks 5-6 recovery; week 7 second chemotherapy cycle plus third dose of toripalimab; weeks 8-9 recovery and response assessment; weeks 10-12 radical surgery. Postoperative maintenance begins within 4-8 weeks after surgery. Patients achieving MPR or HPR receive toripalimab monotherapy 240 mg every 3 weeks for up to 14 cycles; patients not achieving MPR/HPR receive toripalimab for 14 cycles combined with liposomal doxorubicin (2-4 cycles; 2 cycles for HPR >30%).

The sample size uses Simon's two-stage Minimax design with one-sided alpha of 0.05 and 80% power, assuming P0 = 60% and P1 = 80%. The first stage enrolls 13 patients (stop if <=8 responders); the second stage expands to 35 patients total (declare regimen ineffective if <=25 responders overall). Allowing for a 10% dropout rate, the planned total enrollment is 39 patients.

Efficacy assessment: pathologic response (MPR defined as <=10% residual viable tumor cells; HPR defined as >30% hyalinization) is evaluated using a standardized pathology SOP, with confirmation by an independent central pathology laboratory. Radiologic response is evaluated by RECIST v1.1 every 12 weeks. Safety: adverse events are graded per NCI CTCAE v5.0; all adverse events are recorded up to at least 100 days after the last dose. Major wound complications are monitored within 90 days after surgery. Follow-up: visits at 30 days and 84 days after surgery, then every 3 months for survival; imaging every 12 weeks in the first year, every 24 weeks in the second year, and every 6-12 months in years 3-5; ctDNA and peripheral blood immune monitoring every 3 months for at least 2 years.