Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Medicine, Weill Cornell Medical College, New York, New York.
Clin Cancer Res. 2023 Jun 1;29(11):2043-2051. doi: 10.1158/1078-0432.CCR-22-3911.
Epacadostat, an indole 2,3 dioxygenase 1 (IDO1) inhibitor, proposed to shift the tumor microenvironment toward an immune-stimulated state, showed early promise in melanoma but has not been studied in sarcoma. This study combined epacadostat with pembrolizumab, which has modest activity in select sarcoma subtypes.
This phase II study enrolled patients with advanced sarcoma into five cohorts including (i) undifferentiated pleomorphic sarcoma (UPS)/myxofibrosarcoma, (ii) liposarcoma (LPS), (iii) leiomyosarcoma (LMS), (iv) vascular sarcoma, including angiosarcoma and epithelioid hemangioendothelioma (EHE), and (v) other subtypes. Patients received epacadostat 100 mg twice daily plus pembrolizumab at 200 mg/dose every 3 weeks. The primary endpoint was best objective response rate (ORR), defined as complete response (CR) and partial response (PR), at 24 weeks by RECIST v.1.1.
Thirty patients were enrolled [60% male; median age 54 years (range, 24-78)]. The best ORR at 24 weeks was 3.3% [PR, n = 1 (leiomyosarcoma); two-sided 95% CI, 0.1%-17.2%]. The median PFS was 7.6 weeks (two-sided 95% CI, 6.9-26.7). Treatment was well tolerated. Grade 3 treatment-related adverse events occurred in 23% (n = 7) of patients. In paired pre- and post-treatment tumor samples, no association was found between treatment and PD-L1 or IDO1 tumor expression or IDO-pathway-related gene expression by RNA sequencing. No significant changes in serum tryptophan or kynurenine levels were observed after baseline.
Combination epacadostat and pembrolizumab was well tolerated and showed limited antitumor activity in sarcoma. Correlative analyses suggested that inadequate IDO1 inhibition was achieved.
Epacadostat 是一种吲哚 2,3 双加氧酶 1（IDO1）抑制剂，旨在使肿瘤微环境向免疫刺激状态转变，在黑色素瘤中显示出早期疗效，但尚未在肉瘤中进行研究。本研究将 Epacadostat 与帕博利珠单抗联合使用，后者在某些肉瘤亚型中具有适度的活性。
这项 II 期研究纳入了晚期肉瘤患者，分为五个队列，包括（i）未分化多形性肉瘤（UPS）/黏液纤维肉瘤，（ii）脂肪肉瘤（LPS），（iii）平滑肌肉瘤（LMS），（iv）血管肉瘤，包括血管肉瘤和上皮样血管内皮细胞瘤（EHE），以及（v）其他亚型。患者接受 Epacadostat 100mg 每日两次，联合帕博利珠单抗 200mg/dose 每 3 周一次。主要终点是 24 周时通过 RECIST v.1.1 评估的最佳客观缓解率（ORR），定义为完全缓解（CR）和部分缓解（PR）。
共纳入 30 例患者[60%为男性；中位年龄 54 岁（范围，24-78）]。24 周时的最佳 ORR 为 3.3%（PR，n=1[平滑肌肉瘤]；双侧 95%CI，0.1%-17.2%]）。中位无进展生存期（PFS）为 7.6 周（双侧 95%CI，6.9-26.7）。治疗耐受性良好。23%（n=7）的患者出现 3 级治疗相关不良事件。在配对的治疗前后肿瘤样本中，未发现治疗与 PD-L1 或 IDO1 肿瘤表达或 RNA 测序的 IDO 通路相关基因表达之间存在关联。在基线后未观察到血清色氨酸或犬尿氨酸水平的显著变化。
Epacadostat 联合帕博利珠单抗治疗肉瘤耐受性良好，且具有有限的抗肿瘤活性。相关分析表明，IDO1 抑制作用不足。
