Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Japan.
Clin Cancer Res. 2021 Dec 15;27(24):6709-6715. doi: 10.1158/1078-0432.CCR-21-1929. Epub 2021 Sep 30.
This is a phase Ib trial of TAS-116, an oral HSP90 inhibitor, plus nivolumab for colorectal cancer and other solid tumors.
Enrolled patients received TAS-116 plus nivolumab in a dose-finding part to estimate the recommended dose. Additional patients were enrolled in a dose-expansion part. TAS-116 monotherapy (orally once daily, 80-160 mg) was administered for 2 weeks followed by the combination with nivolumab (intravenously every 2 weeks, 3 mg/kg). The primary endpoint was dose-limiting toxicities (DLT). We also conducted biomarker research using paired samples from repeated blood collections and tumor biopsies.
A total of 44 patients with colorectal cancer ( = 29), gastric cancer ( = 8), sarcoma ( = 5), non-small cell lung cancer ( = 1), and melanoma ( = 1) were enrolled. Eleven patients had previously received immune-checkpoint inhibitors. No DLTs were observed at all dose levels, and TAS-116 160 mg was determined as recommended dose. The common grade 3 or worse treatment-related adverse events included liver transaminase increased (7%), creatinine increased (5%), and platelet count decreased (5%). Objective tumor response was observed in 6 patients, including 4 microsatellite stable (MSS) colorectal cancers, 1 microsatellite instability-high colorectal cancer, and 1 leiomyosarcoma, resulting in an objective response rate of 16% in MSS colorectal cancer without prior immune-checkpoint inhibitors. Biomarker analysis showed that TAS-116 inhibited the activity of regulatory T cells in peripheral blood mononuclear cells and tumor-infiltrating lymphocytes.
TAS-116 160 mg plus nivolumab had manageable safety profiles and antitumor activity, especially for MSS colorectal cancer patients.
这是一项 TAS-116（一种口服 HSP90 抑制剂）联合纳武利尤单抗治疗结直肠癌和其他实体瘤的 Ib 期临床试验。
入组患者在剂量确定部分接受 TAS-116 联合纳武利尤单抗治疗，以评估推荐剂量。另外还招募了部分患者进入剂量扩展部分。TAS-116 单药治疗（口服，每日一次，80-160mg）持续 2 周，然后联合纳武利尤单抗（每 2 周静脉输注一次，3mg/kg）。主要终点为剂量限制性毒性（DLT）。我们还使用重复采血和肿瘤活检的配对样本进行了生物标志物研究。
共入组 44 例结直肠癌患者（29 例）、胃癌患者（8 例）、肉瘤患者（5 例）、非小细胞肺癌患者（1 例）和黑色素瘤患者（1 例）。11 例患者既往接受过免疫检查点抑制剂治疗。所有剂量水平均未观察到 DLT，确定 TAS-116 160mg 为推荐剂量。常见的 3 级或更高级别的治疗相关不良事件包括肝转氨酶升高（7%）、肌酐升高（5%）和血小板计数降低（5%）。6 例患者观察到客观肿瘤缓解，包括 4 例微卫星稳定（MSS）结直肠癌、1 例微卫星不稳定高结直肠癌和 1 例平滑肌肉瘤，使既往未接受免疫检查点抑制剂治疗的 MSS 结直肠癌的客观缓解率达到 16%。生物标志物分析表明，TAS-116 抑制外周血单核细胞和肿瘤浸润淋巴细胞中调节性 T 细胞的活性。
TAS-116 160mg 联合纳武利尤单抗具有可管理的安全性和抗肿瘤活性，特别是对 MSS 结直肠癌患者。
