Single-institution clinical outcomes with pembrolizumab plus neoadjuvant radiation (SARC032 regimen) with or without neoadjuvant doxorubicin/ifosfamide in high grade soft tissue sarcomas.

Abstract

e23552 Background: SARC032 therapy (pembrolizumab plus neoadjuvant XRT, PD-1 + XRT) represents an appealing perioperative option for patients with undifferentiated pleomorphic sarcoma (UPS) or dedifferentiated liposarcoma (dLPS) who are not candidates for doxorubicin/ifosfamide (AI) adjuvant chemotherapy. However, safety and efficacy of PD-1 + XRT in sequence with AI for fit patients deemed high-risk by Sarculator overall survival (OS) predictions has not been studied. Here we report our institution’s experience of PD-1 + XRT treatment with or without neoadjuvant AI in patients with high grade soft tissue sarcomas (STSs). Methods: IRB waiver of consent was obtained to retrospectively review clinical outcomes of patients from 2010 to 2025 receiving neoadjuvant PD-1 + XRT. Patient demographics, disease characteristics, Sarculator estimated OS, and treatment outcomes (including % tumor necrosis at surgery) were obtained from clinical records. Differences between PD-1 + XRT or AI/PD-1 + XRT groups were evaluated using students unpaired t-tests. Results: 18 patients met criteria for evaluation. Represented STS types included UPS (n=9), myxofibrosarcoma (n=3), XRT-associated sarcoma (n=1), pleomorphic liposarcoma (pLPS, n=2), and pleomorphic rhabdomyosarcoma (pRMS, n=3). Represented tumor sites included extremity (n=12), trunk (n=2), intrapelvic (n=3) and retroperitoneal (RP, n=1). 8 patients received 3 or 4 cycles of chemotherapy (AI=7, A/cyclophosphamide=1) followed by PD-1 + XRT (AI/PD-1 + XRT). Significant differences in baseline characteristics between patients that received chemotherapy compared to PD-1 + XRT alone included age (50.5 yrs vs 68.7 yrs, p = <0.01), baseline tumor size (15.5 cm vs 8.8 cm, p = 0.03), and Sarculator ESTS estimated 10-year OS (38% vs 71%, p = 0.02). No difference in Sarculator RPS 5-year OS or % tumor necrosis at resection were seen (61% vs 71%, p=1; 65% vs 75%, p = 0.94). One patient with pRMS had 100% treatment effect at resection with no evidence of residual tumor (AI/PD-1 + XRT). Patients with pLPS had tumor necrosis of 30% (AI/PD-1 + XRT) and 60% (PD-1 + XRT). No additional toxicity with AI/PD-1 + XRT was observed outside of that expected from chemotherapy or PD-1 + XRT alone. Conclusions: Our data suggest feasibility and efficacy with real-world application of XRT/pembrolizumab with or without AI for patients with extremity, intrapelvic, and RP localized high grade STSs, including pLPS and pRMS which were not included in outcomes from SARC032. Significant baseline differences were noted between the AI/PD-1 + XRT and PD-1 + XRT cohorts, driven by clinical judgement and associated with Sarculator high-risk status. This observation warrants consideration in the future design of clinical trials of PD-1 + XRT to assess incorporation of AI chemotherapy.