Table3_Activity of PD-1 Inhibitor Combined With Anti-Angiogenic Therapy in Advanced Sarcoma: A Single-Center Retrospective Analysis.docx

Background: Immune checkpoint inhibitors (ICIs) are employed to treat various cancers, including soft tissue sarcomas (STSs), and less than 20% of patients benefit from this treatment. Vascular endothelial growth factor (VEGF) promotes the immunosuppressive tumor microenvironment and contributes to ICI-resistant therapy. Anti-VEGF receptor tyrosine-kinase inhibitors (TKIs) combined with ICIs have shown antitumor activity in patients with alveolar soft-part sarcoma (ASPS). However, they have not been extensively studied to treat other STS subtypes, such as leiomyosarcoma (LMS), dedifferentiated liposarcoma (DDLPS), undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), and angiosarcoma (AS).Methods: In this retrospective study, we collected data from 61 patients who were diagnosed with advanced STS based on imaging and histology, including LMS, DDLPS, and UPS. Among them, 41 patients were treated with ICIs combined with TKIs and 20 patients received ICI therapy. The endpoints of progression-free survival (PFS) and overall response rate (ORR) were analyzed in the two groups, and the overall response [partial response (PR), stable disease (SD), and progressive disease (PD)] of each patient was determined using RECIST 1.1 evaluation criteria.Results: In total, 61 STS patients had the following subtypes: LMS (n = 20), DDLPS (n = 17), UPS (n = 8), ASPS (n = 7), MFS (n = 7), and AS (n = 2). The median PFS (mPFS) was significantly prolonged after ICI treatment in combination with TKIs (11.74 months, 95% CI 4.41–14.00) compared to ICI treatment alone (6.81 months, 95% CI 5.43–NA) (HR 0.5464, p = 0.043). The 12-month PFS rates of patients who received ICI–TKI treatment were increased from 20.26% (95% CI 0.08–0.53) to 42.90% (95% CI 0.27–0.68). In the combination therapy group, 12 patients (30%) achieved PR, 25 patients (62.5%) achieved SD, and 3 patients (7.5%) achieved PD for 3 months or longer. In the non-TKI-combination group, 2 patients (9.5%) achieved PR, 14 patients (66.7%) achieved SD, and 5 patients (23.8%) achieved PD within 3 months. The ORRs in the two groups were 30.0% (ICI–TKI combination) and 9.5% (ICI only), respectively. A notable ORR was observed in the ICI–TKI combination group, especially for subtypes ASPS (66.7%), MFS (42.9%), and UPS (33.3%). The PD-L1 expression (n = 33) and tumor mutation burden (TMB, n = 27) were determined for each patient. However, our results showed no significant difference in PFS or response rates between the two groups.Conclusion: This study suggests that ICI–TKI treatment has antitumor activity in patients with STS, particularly the ASPS and MFS subtypes. Moreover, effective biomarkers to predict clinical outcomes are urgently needed after combination therapy in the STS subtypes.

背景：免疫检查点抑制剂（ICIs）被用于治疗多种癌症，包括软组织肉瘤（STSs），但仅有不到20%的患者从这种治疗中获益。血管内皮生长因子（VEGF）促进免疫抑制性肿瘤微环境，并导致对免疫检查点抑制剂治疗的耐药性。抗VEGF受体酪氨酸激酶抑制剂（TKIs）与免疫检查点抑制剂联合治疗在肺泡性软组织肉瘤（ASPS）患者中显示出抗肿瘤活性。然而，它们尚未被广泛研究以治疗其他STS亚型，如平滑肌肉瘤（LMS）、去分化脂肪肉瘤（DDLPS）、未分化多形性肉瘤（UPS）、黏液纤维肉瘤（MFS）和血管肉瘤（AS）。方法：在本项回顾性研究中，我们收集了61例基于影像学和组织学诊断为晚期STS患者的数据，包括LMS、DDLPS和UPS。其中，41例患者接受了免疫检查点抑制剂联合TKI治疗，20例患者接受了单一免疫检查点抑制剂治疗。分析了两组患者的无进展生存期（PFS）和总缓解率（ORR），并使用RECIST 1.1评估标准确定每位患者的总体缓解情况[部分缓解（PR）、疾病稳定（SD）和疾病进展（PD）]。结果：总共61例STS患者具有以下亚型：LMS（n = 20）、DDLPS（n = 17）、UPS（n = 8）、ASPS（n = 7）、MFS（n = 7）和AS（n = 2）。与单独使用免疫检查点抑制剂治疗相比，免疫检查点抑制剂联合TKI治疗后中位无进展生存期（mPFS）显著延长（11.74个月，95% CI 4.41–14.00），HR 0.5464，p = 0.043。接受免疫检查点抑制剂–TKI治疗的患者12个月PFS率从20.26%（95% CI 0.08–0.53）增加到42.90%（95% CI 0.27–0.68）。在联合治疗组中，12名患者（30%）实现了PR，25名患者（62.5%）实现了SD，3名患者（7.5%）实现了3个月或更长时间的PD。在非TKI联合治疗组中，2名患者（9.5%）实现了PR，14名患者（66.7%）实现了SD，5名患者（23.8%）在3个月内实现了PD。两组的总缓解率分别为30.0%（免疫检查点抑制剂–TKI联合治疗）和9.5%（仅免疫检查点抑制剂），观察到显著的缓解率，尤其是在ASPS（66.7%）、MFS（42.9%）和UPS（33.3%）亚型中。对每位患者进行了PD-L1表达（n = 33）和肿瘤突变负荷（TMB，n = 27）的测定。然而，我们的结果显示，两组在PFS或缓解率方面无显著差异。结论：本研究表明，免疫检查点抑制剂–TKI治疗在STS患者中具有抗肿瘤活性，特别是ASPS和MFS亚型。此外，在STS亚型联合治疗后，迫切需要有效的生物标志物来预测临床结果。