RCT: Pembrolizumab with Preoperative Radiotherapy Shows Potential in Stage III Soft Tissue Sarcoma

Background: Patients with locally advanced, high-grade soft tissue sarcomas of the extremity often face a high risk of metastatic disease, despite curative-intent surgery and radiotherapy. Traditional doxorubicin-based chemotherapy provides variable benefits and can cause considerable toxicity, prompting investigations into alternative strategies. Emerging data from smaller trials hinted that immune checkpoint inhibitors might offer targeted benefit in sarcomas, but robust evidence in the neoadjuvant setting remains limited.

Objective: To assess whether adding neoadjuvant and adjuvant pembrolizumab to preoperative radiotherapy and surgical resection could enhance disease-free survival (DFS) in individuals with resectable grade 2 or 3, stage III undifferentiated pleomorphic sarcoma or liposarcoma of the extremity and limb girdle.

Methods: This open-label, randomized trial (SU2C-SARC032) enrolled 143 participants at 20 academic centers in Australia, Canada, Italy, and the USA. Eligible patients were 12 years or older, presented with primary tumors >5 cm, and did not receive chemotherapy as part of this protocol. Participants were randomized 1:1 to standard preoperative radiotherapy (50 Gy/25 fractions) plus surgery (control) or the same radiotherapy combined with pembrolizumab (200 mg every three weeks) in the neoadjuvant setting, followed by up to 14 adjuvant cycles. The primary endpoint was disease-free survival, analyzed in a modified intention-to-treat cohort of 127 evaluable patients, with a median follow-up of 43 months.

Results: The pembrolizumab group demonstrated a higher 2-year DFS rate (67%) compared with controls (52%), suggesting a favorable hazard ratio (0.61) for recurrence or death. Nonetheless, grade 3 or higher adverse events were more common in the pembrolizumab arm (56% vs 31%). Secondary endpoints, including distant disease-free survival and overall survival, also appeared to favor the pembrolizumab arm, but these comparisons were not powered for definitive conclusions.

Conclusions: Neoadjuvant and adjuvant pembrolizumab in combination with radiotherapy and surgery demonstrated a DFS advantage in stage III undifferentiated pleomorphic sarcoma or liposarcoma, reinforcing the potential role of immunotherapy in high-risk settings. However, given the increased incidence of adverse events and the relatively short follow-up for overall survival, cautious interpretation is warranted. Further evidence is required to determine long-term benefits and confirm whether these findings extend to other sarcoma subtypes.

Implications for Practice: These data suggest that incorporating pembrolizumab could be considered in selected patients, particularly those with large, high-grade tumors unresponsive to or unsuitable for traditional chemotherapy. Clinicians must balance the incremental risk of immunotherapy-induced side effects against the observed gains in disease-free survival and the ongoing need for extended follow-up.

Study Strengths and Limitations: Strengths include a multicenter randomized design, focus on a high-risk population, and a robust primary endpoint. Limitations encompass a relatively small sample size, inherent to rare cancers, underpowered subgroup analyses, and absence of long-term survival data. Confirmation of these early signals in larger cohorts and over more extended follow-up periods remains necessary.

Future Research: Additional trials should explore optimal radiotherapy fractionation, potential synergies with cytotoxic or targeted agents, and predictive biomarkers of response. Understanding immune correlates, including circulating tumor DNA and tumor microenvironmental factors, may refine treatment selection and enhance therapeutic outcomes.

Reference: Mowery YM, 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. 2024;404(10467). DOI: http://doi.org/10.1016/S0140-6736(24)01812-9