SU2C-SARC032

Background

SU2C-SARC032 — Phase II randomised controlled trial. N=143 randomised (127 modified ITT). Patients with stage III undifferentiated pleomorphic sarcoma (UPS) or dedifferentiated or pleomorphic liposarcoma (LPS) of the extremity or trunk undergoing surgical resection at 18 US centres. Enrolled 2019–2023. Hypothesis: perioperative pembrolizumab (PD-1 blockade) added to standard preoperative radiotherapy (RT) and surgery would improve disease-free survival by exploiting RT-induced immunogenic cell death and enhancing T-cell responses in immunogenic STS histotypes. Registration NCT03092323.

Interventions and follow up

Arm A: Preoperative pembrolizumab 200 mg × 3 doses concurrent with RT (50 Gy in 25 fx) → surgery → adjuvant pembrolizumab × 14 cycles
Arm B: Preoperative RT (50 Gy in 25 fx) → surgery (no pembrolizumab)
Primary endpoint: Disease-free survival (DFS)
mFollow up: Not reported (median follow-up)

Results

DFS: HR 0.61 (90% CI 0.39–0.96), P=.035
2-year DFS: 67% (pembro) vs 52% (RT alone)

Adverse events

Main adverse events: Grade ≥3 AEs: 56% (pembro+RT) vs 31% (RT alone). Immune-related AEs consistent with pembrolizumab profile.

Conclusions

Perioperative pembrolizumab added to preoperative RT significantly improved disease-free survival in UPS and dedifferentiated/pleomorphic liposarcoma of the extremity, achieving a 39% relative DFS improvement. This is the first randomised trial to demonstrate improved outcomes with immunotherapy added to perioperative treatment in STS, and establishes proof of concept for checkpoint blockade in immunogenic STS histotypes.

Key Limitations

Phase II trial with 90% CI (not 95%) for the primary endpoint — the wider CI reflects lower statistical certainty. Only two histotypes enrolled (UPS and LPS); does not apply to other STS subtypes. Modified ITT analysis used (n=127 of 143 randomised) — 11% excluded. OS data are immature. Single-country trial (US centres only). The preoperative RT + surgery control arm is standard, but adjuvant therapy details (RT target volumes, dose) were not standardised. Crossover or salvage therapy effects not reported. A confirmatory phase III trial would be needed for practice change.

Clinical Context

SU2C-SARC032 provides the first positive randomised evidence for immunotherapy in the perioperative STS setting. UPS and dedifferentiated LPS are histotypes with higher tumour mutational burden and greater immune infiltration compared to other STS, supporting this approach. These results are likely to be practice-informing for perioperative management of extremity UPS and LPS at specialised centres, although a phase III confirmatory trial is needed before FDA approval. Pembrolizumab is currently approved for second-line+ MSI-H/dMMR sarcomas. TMB-high/MSI sarcomas represent a small subset — the SU2C-SARC032 approach is histotype-driven rather than biomarker-driven.
Arm A (pembro + RT + surgery, n=65 mITT): Pembrolizumab 200 mg IV q3w × 3 cycles (neoadjuvant, concurrent with RT), surgery, then pembrolizumab × 14 additional adjuvant cycles
Arm B (RT + surgery, n=62 mITT): Standard preoperative RT then surgery (no immunotherapy)

References