In an open-label, randomised SU2C-SARC032 clinical trial, conducted by the Sarcoma Alliance for Research through Collaboration (SARC), that enrolled patients at 20 participating academic institutions in Australia, Canada, Italy, and the USA, the researchers showed a clinically meaningful improvement in disease-free survival (DFS) with addition of preoperative and postoperative pembrolizumab to preoperative radiation therapy and surgical resection for patients with stage III undifferentiated pleomorphic sarcoma or liposarcoma in the extremity or limb girdle.
Concurrent pembrolizumab and radiation therapy were tolerated with an acceptable level of toxicity, and major surgical complications were low. The findings were published by Prof. David G Kirsch of the Princess Margaret Cancer Centre, University Health Network in Toronto, ON, Canada and colleagues on 12 November 2024 in The Lancet.
The authors wrote in the background that stage III soft tissue sarcomas of the extremity and limb girdle are a diverse group of mesenchymal malignancies treated with surgery and radiation therapy. Approximately 50% of patients with large (greater than 5 cm), high-grade, localised (stage III) soft tissue sarcomas develop metastatic disease. Patients with metastases receive chemotherapy, leading to a median survival of 12–24 months.
Objective responses to pembrolizumab occurred in 23% of patients with metastatic undifferentiated pleomorphic sarcoma and 10% with pleomorphic or dedifferentiated liposarcoma in the SARC028 study. Based on these results and data suggesting radiation therapy can act synergistically with immune checkpoint blockade to improve local and distant tumour response, the SU2C-SARC032 study team hypothesised that the addition of pembrolizumab to preoperative radiation therapy and surgery would improve DFS for patients with stage III undifferentiated pleomorphic sarcoma or liposarcoma.
Patients were randomly assigned to preoperative radiotherapy then surgery (control group) or preoperative pembrolizumab with radiotherapy (initiated 1–14 days after the first dose of pembrolizumab) then surgery and postoperative pembrolizumab (experimental group). Pembrolizumab 200 mg intravenously every 3 weeks was administered as three neoadjuvant cycles (before, during, and after) radiotherapy and 14 or less adjuvant cycles. Primary endpoint was DFS.
Between 18 November 2017 and 14 November 2023, 143 participants were randomly assigned to treatment. A modified intention-to-treat (ITT) analysis of 127 patients with median follow-up of 43 months showed that 64 patients in the experimental group had significantly longer DFS than 63 patients in the control group (hazard ratio [HR] 0.61, 90% confidence interval [CI] 0.39–0.96; log-rank one-sided p = 0.035). The 2-year DFS increased by 15% with addition of pembrolizumab: 52% (90% CI 42–64) and 67% (90% CI 58–78) for the control and experimental groups, respectively. DFS was similarly improved with pembrolizumab for the ITT patient population (HR 0.61, 90% CI 0.39–0.95).
Grade 3 or higher adverse events occurred more frequently in the experimental group (56%) than the control group (31%).
The authors commented that the outcomes for these patients have not markedly changed over several decades. For patients with resectable, intermediate-grade or high-grade undifferentiated pleomorphic sarcoma or liposarcoma measuring more than 5 cm, SU2C-SARC032 establishes pembrolizumab as a new treatment option.
In an accompanied comment, Prof. Antoine Italiano of the Department of Medicine, Institut Bergonié and Faculty of Medicine, University of Bordeaux in Bordeaux, France wrote that the most valuable insight from this trial is that it is the first to rigorously evaluate the potential of immunotherapy in the perioperative setting for soft tissue sarcomas within a randomised controlled trial framework.
However, the inclusion of both undifferentiated pleomorphic sarcoma and liposarcoma in the same trial could obscure subtype-specific benefits of perioperative immunotherapy which underscores the need for further research to refine patient selection and optimise treatment strategies for high-risk soft tissue sarcomas. Another limitation of the study is the inclusion of both grade 2 and grade 3 tumours, despite existing evidence that perioperative chemotherapy primarily benefits patients with grade 3 disease.
The study also highlights a key challenge in sarcoma research, namely patient recruitment. Despite the involvement of 20 centres, it took 7 years to enrol just 143 patients. This small sample size reduced the study’s ability to thoroughly explore how sarcoma subtypes, tumour grades, or other prognostic factors influence treatment outcomes. This underscores the need for innovative trial designs, such as umbrella trials, which could improve recruitment efficiency and use surrogate endpoints, such as histological response, to identify the most promising therapeutic strategies for specific sarcoma subtypes.
Combining immune checkpoint inhibitors with anthracycline-based neoadjuvant chemotherapy could be more effective than either treatment alone. Whether such a combination is synergistic in the neoadjuvant setting is currently being explored in an ongoing randomised phase II study for high-grade undifferentiated pleomorphic sarcoma. Furthermore, using molecular residual disease to identify patients with soft tissue sarcomas who are more likely to benefit from adjuvant immunotherapy is currently being investigated in a randomised phase III trial.
The study was funded by Stand Up to Cancer (SU2C) and Merck Sharp & Dohme.
References
- Mowery YM, Ballman KV, Hong AM, et al. Safety and efficacy of pembrolizumab, radiation therapy, and surgery versus radiation therapy and surgery for stage III soft tissue sarcoma of the extremity (SU2C-SARC032): an open-label, randomised clinical trial. The Lancet; Published Online 12 November 2024: DOI: https://doi.org/10.1016/S0140-6736(24)01812-9
- Italiano A. Perioperative immunotherapy in soft tissue sarcomas. The Lancet; Published Online 12 November 2024. DOI: https://doi.org/10.1016/S0140-6736(24)02252-9