Neo-adjuvant radiation and intratumoral immunotherapy followed by surgery: The NARIS trial for extremity soft tissue sarcoma.

11566 Background: Patients with STS who failed to respond to standard treatment have limited subsequent treatment options. Radiotherapy combined with immunotherapy has demonstrated efficacy in certain STS subtypes, such as undifferentiated pleomorphic sarcoma (UPS); however, perioperative strategies still require optimization to further improve local control and reduce adverse events, particularly for patients with multiple recurrences yet seeking limb preservation. Methods: Patients with pathologically confirmed extremity STS without metastases were enrolled. Eligible participants received two neoadjuvant cycles administered every three weeks. Each cycle consisted of hypofractionated radiotherapy (a total of 5 Gy × 4 fractions across two cycles) combined with intratumoral injection of a PD-L1 (TQB2450) monoclonal antibody. Results: A total of 15 patients were screened, of whom 11 met the eligibility criteria and provided written informed consent. Except for one patient with disease progression after standard chemoradiotherapy, other patients had recurrent disease following one to three prior curative resections at baseline. The ORR and DCR were 36.4% (95% CI, 10.9–69.2%) and 90.9% (95% CI, 58.7–99.8%), respectively. One patient has not yet undergone surgery. Among the 10 patients who received surgery, one achieved a pCR, and two achieved MPR. All three cases occurred in UPS patients. In the 10 evaluable patients with STS, the median percentage of tumor necrosis and fibrosis was 63.5% (IQR 17.5–88.75%), and the median residual viable tumor percentage was 36.5% (IQR 11.25–82.5%). Subgroup analysis showed that the median percentage of tumor necrosis and fibrosis in UPS patients was 97% (IQR 88–99.25%), compared with 25% (IQR 10–55%) in other histological subtypes. The pCR rate and MPR rate in UPS patients were 25% (1/4) and 75% (3/4), respectively. During the neoadjuvant phase, the main TEAEs were local swelling and decreased lymphocyte counts, which were reversible during treatment intervals. No grade 3 TEAEs or immune-related adverse events were observed. Postoperative complications in the 10 surgical patients were as expected and mainly included local soft tissue edema, pain, local stiffness, and limb numbness. No delayed wound healing or surgical site infections were observed. Conclusions: Compared with current clinical studies in STS that employ conventionally fractionated radical radiotherapy and intravenous immune checkpoint inhibitors, this study utilized a lower total radiation dose delivered in larger fractions combined with intratumoral administration of immunotherapy, achieving comparable disease control with manageable toxicity. It may be clinically valuable for patients with recurrent disease after multiple surgeries or those with prior exposure to local radiotherapy. Clinical trial information: ChiCTR2200060659.