Tislelizumab in previously treated, locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors
Jian Li, Ye Xu, Aimin Zang, Yunong Gao, Quanli Gao, Yanqiao Zhang, Dong Wang, Jianming Xu, Ying Yuan, Haiping Jiang, Jieer Ying, Chunmei Shi, Yanhong Deng, Jing Wang, Tianshu Liu, Yi Huang, Xiaoping Qian, Yue-Yin Pan, Ying Cheng, Sheng Hu, Jin Wang, Mengyue Shi, Ke Wang, Han Hu, Lin Shen
Abstract
<sec><b>Objective</b>The open-label, phase II RATIONALE-209 study evaluated tislelizumab (anti-programmed cell death protein 1 antibody) as a tissue-agnostic monotherapy for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) tumors. </sec><sec><b>Methods</b>Adults with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled. Patients received tislelizumab 200 mg intravenously every 3 weeks. Objective response rate (ORR; primary endpoint), duration of response (DoR), and progression-free survival (PFS) were assessed by independent review committee (Response Evaluation Criteria in Solid Tumors v1.1). </sec><sec><b>Results</b>Eighty patients were enrolled and treated; 75 (93.8%) patients had measurable disease at baseline. Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease (n=79; 98.8%). At primary analysis (data cutoff July 8, 2021; median follow-up 15.2 months), overall ORR [46.7%; 95% confidence interval (95% CI), 35.1−58.6; one-sided P<0.0001] and ORR across tumor-specific subgroups [colorectal (n=46): 39.1% (95% CI, 25.1–54.6); gastric/gastroesophageal junction (n=9): 55.6% (95% CI, 21.2−86.3); others (n=20): 60.0% (95% CI, 36.1−80.9)] were significantly greater with tislelizumab <i>vs.</i> a prespecified historical control ORR of 10%; five (6.7%) patients had complete responses. Median DoR, PFS, and overall survival were not reached with long-term follow-up (data cutoff December 5, 2022; median follow-up 28.9 months). Tislelizumab was well tolerated with no unexpected safety signals. Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 53.8% of patients; 7.5% of patients discontinued treatment due to TRAEs. </sec><sec><b>Conclusions</b>Tislelizumab demonstrated a significant ORR improvement in patients with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.</sec>