Background

Approximately half of patients with localised, high-risk soft tissue sarcoma of the extremity develop metastases. We aimed to assess whether the addition of pembrolizumab to preoperative radiotherapy and surgery would improve disease-free survival.

Methods

We completed an open-label, randomised clinical trial in patients with grade 2 or 3, stage III undifferentiated pleomorphic sarcoma or dedifferentiated or pleomorphic liposarcoma of the extremity and limb girdle. Patients were enrolled at 20 academic institutions in Australia, Canada, Italy, and the USA. 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 disease-free survival. This study is registered with ClincialTrials.gov (NCT03092323).

Findings

Between Nov 18, 2017, and Nov 14, 2023, 143 participants were randomly assigned to treatment. A modified intention-to-treat analysis of 127 patients with median follow-up of 43 months showed that the experimental group (n=64) had significantly longer disease-free survival than the control group (n=63; log-rank one-sided p=0·035; hazard ratio [HR] 0·61; 90% CI 0·39–0·96). The 2-year disease-free survival 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. Disease-free survival was similarly improved with pembrolizumab for the intention-to-treat 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%).

Interpretation

Addition of pembrolizumab to preoperative radiotherapy and surgery improves disease-free survival for patients with stage III undifferentiated pleomorphic sarcoma and pleomorphic or dedifferentiated liposarcoma of the extremity, which establishes a promising new treatment option for these patients.

Funding

Stand Up to Cancer and Merck Sharp & Dohme.

中文翻译：

---

帕博利珠单抗、放射治疗和手术与放射治疗和手术治疗 III 期肢体软组织肉瘤 （SU2C-SARC032） 的安全性和有效性：一项开放标签、随机临床试验

 背景

大约一半的肢体局部高危软组织肉瘤患者发生转移。我们旨在评估在术前放疗和手术中加入 pembrolizumab 是否会提高无病生存率。

 方法

我们在 2 级或 3 级、III 期未分化多形性肉瘤或肢体和肢带去分化或多形性脂肪肉瘤患者中完成了一项开放标签、随机临床试验。患者在澳大利亚、加拿大、意大利和美国的 20 个学术机构入组。患者被随机分配到术前放疗组，然后手术组 （对照组） 或术前 pembrolizumab 联合放疗 （在 pembrolizumab 首次给药后 1-14 天开始），然后手术和术后 pembrolizumab 组 （实验组）。Pembrolizumab （200 mg，静脉注射，每 3 周一次） 作为 3 个新辅助周期 （放疗前、放疗期间和放疗后） 和 14 个或更少的辅助周期给药。主要终点是无病生存期。本研究已在 ClincialTrials.gov （NCT03092323） 注册。

 发现

在 2017 年 11 月 18 日至 2023 年 11 月 14 日期间，143 名参与者被随机分配接受治疗。对 127 名中位随访 43 个月患者的改良意向性治疗分析显示，实验组 （n=64） 的无病生存期显著长于对照组 （n=63;对数秩单侧 p=0·035;风险比 [HR] 0·61;90% CI 0·39–0·96）。添加 pembrolizumab 后，2 年无病生存率增加了 15%：对照组和实验组分别为 52% （90% CI 42-64） 和 67% （90% CI 58-78）。对于意向治疗患者群体，帕博利珠单抗组的无病生存率同样得到改善 （HR 0·61 [90% CI 0·39–0·95]）。实验组 （56%） 比对照组 （31%） 更频繁地发生 3 级或更高级别的不良事件。

 解释

在术前放疗和手术中加入 pembrolizumab 可提高 III 期未分化多形性肉瘤和肢体多形性或去分化脂肪肉瘤患者的无病生存率，这为这些患者建立了一个有前途的新治疗选择。

 资金

挺身而出对抗癌症和默克夏普&多姆。