Medical Oncology, University of Washington, Seattle, Washington.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Clin Cancer Res. 2022 Jun 1;28(11):2306-2312. doi: 10.1158/1078-0432.CCR-22-0240.
Leiomyosarcoma and liposarcoma frequently express PD-L1 but are generally resistant to PD-1/PD-L1 inhibition (immune checkpoint inhibitor). Trabectedin is FDA approved for leiomyosarcoma and liposarcoma. This study aimed to evaluate the safety and efficacy of trabectedin with anti-PD-L1 antibody avelumab in patients with advanced leiomyosarcoma and liposarcoma.
A single-arm, open-label, Phase 1/2 study tested avelumab with trabectedin for advanced leiomyosarcoma and liposarcoma. The phase I portion evaluated safety and feasibility of trabectedin (1, 1.2, and 1.5 mg/m2) with avelumab at standard dosing. Primary endpoint of the phase II portion was objective response rate (ORR) by RECIST 1.1. Correlative studies included T-cell receptor sequencing (TCRseq), multiplex IHC, and tumor gene expression.
33 patients were evaluable: 24 with leiomyosarcoma (6 uterine and 18 non-uterine) and 11 with liposarcoma. In Phase 1, dose-limiting toxicities (DLT) were observed in 2 of 6 patients at both trabectedin 1.2 and 1.5 mg/m2. The recommended Phase 2 dose (RP2D) was 1.0 mg/m2 trabectedin and 800-mg avelumab. Of 23 patients evaluable at RP2D, 3 (13%) had partial response (PR) and 10 (43%) had stable disease (SD) as best response. Six-month PFS was 52%; median PFS was 8.3 months. Patients with PR had higher Simpson Clonality score on TCRseq from peripheral blood mononuclear cells versus those with SD (0.182 vs. 0.067, P = 0.02) or progressive disease (0.182 vs. 0.064, P = 0.01).
Although the trial did not meet the primary objective response rate endpoint, PFS compared favorably with prior studies of trabectedin warranting further investigation.
平滑肌肉瘤和脂肪肉瘤常表达 PD-L1，但通常对 PD-1/PD-L1 抑制（免疫检查点抑制剂）有抗性。曲贝替定已获 FDA 批准用于治疗平滑肌肉瘤和脂肪肉瘤。本研究旨在评估曲贝替定联合抗 PD-L1 抗体avelumab 治疗晚期平滑肌肉瘤和脂肪肉瘤患者的安全性和疗效。
一项单臂、开放标签、1/2 期研究评估了avelumab 联合曲贝替定治疗晚期平滑肌肉瘤和脂肪肉瘤的安全性和有效性。1 期部分评估了标准剂量下曲贝替定（1、1.2 和 1.5mg/m2）联合avelumab 的安全性和可行性。2 期的主要终点是 RECIST 1.1 评估的客观缓解率（ORR）。相关研究包括 T 细胞受体测序（TCRseq）、多重免疫组化和肿瘤基因表达。
33 例患者可评估：24 例平滑肌肉瘤（6 例子宫和 18 例非子宫），11 例脂肪肉瘤。1 期时，在曲贝替定 1.2 和 1.5mg/m2 剂量下，有 2 例患者出现剂量限制毒性（DLT）。推荐的 2 期剂量（RP2D）为曲贝替定 1.0mg/m2 和avelumab 800mg。在 RP2D 可评估的 23 例患者中，3 例（13%）有部分缓解（PR），10 例（43%）有最佳缓解为疾病稳定（SD）。6 个月无进展生存期（PFS）为 52%；中位 PFS 为 8.3 个月。与 SD（0.182 比 0.067，P=0.02）或进展性疾病（0.182 比 0.064，P=0.01）相比，PR 患者外周血单个核细胞 TCRseq 的 Simpson 克隆性评分更高。
尽管该试验未达到主要客观缓解率终点，但与曲贝替定的既往研究相比，PFS 表现较好，值得进一步研究。
