Efficacy and safety of SHR-2554 in advanced epithelioid sarcoma: A phase 2 trial.

person Yan Zhou Shanghai Sixth People's Hospital, Shanghai, China info_outline Yan Zhou, Xiaomin Ding, Yawen Zhang, Jinrong Liang, Hongli Xu, Luyuan Tian, Changhong Zhao, Haiyan Hu

Authors person Yan Zhou Shanghai Sixth People's Hospital, Shanghai, China info_outline Yan Zhou, Xiaomin Ding, Yawen Zhang, Jinrong Liang, Hongli Xu, Luyuan Tian, Changhong Zhao, Haiyan Hu Organizations Shanghai Sixth People's Hospital, Shanghai, China, Jiangsu Hengrui Pharmaceuticals Co. Ltd, Shanghai, China, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China Abstract Disclosures Research Funding Jiangsu Hengrui Pharmaceuticals Co., Ltd. Background: Epithelioid sarcoma (ES) is a rare and aggressive subtype of soft-tissue sarcoma. The loss of SMARCB1 (INI1) expression which leads to oncogenic dependence on the transcriptional repressor EZH2 has been observed in over 90% of ES. Patients (pts) with metastatic ES have a poor prognosis. We investigated the efficacy and safety of SHR-2554, an oral selective EZH2 inhibitor, in pts with refractory ES. Methods: To be eligible for inclusion, pts had to fulfill the following criteria: 8 years or older; histologically confirmed advanced or metastatic ES with loss of INI1 or upregulated mRNA level of EZH2; progressive disease after at least one line of doxorubicin-containing chemotherapy; the presence of measurable disease according to RECIST 1.1; an ECOG performance status of 0-1. Pts received SHR2554 (350 mg, bid, po) until disease progression or unacceptable toxicity. The primary endpoint was progression-free rate at 12 weeks. A Simon two-stage design was applied. If there were 3 pts remaining progression-free at 12 weeks within the first 9 pts, the cohort would expand to 17 pts and the outcome would be positive if more than 7 pts remained progression-free at 12 weeks. Results: Between Jul 2021 and Dec 2023, a total of 17 pts were enrolled and received at least 1 dose of SHR-2554. The median age was 32 years (range 8-57) and 41.2% were males. 9 (52.9%) pts had received immunotherapy targeting PD-1/L1 and 6 (35.3%) pts had received anti-angiogenesis therapy before enrollment. The median line of previous treatment was 2 (range 1-4). Loss of INI1 was confirmed in 14 (82.4%) pts. Tumor response was evaluated in 14 pts at data cutoff. 9 (64.3%) of 14 pts remained progression-free at 12 weeks. The primary endpoint was met. Based on investigator assessment, 3 (21.4%) of 14 pts achieved partial response and 8 (57.1%) pts had stable disease as best response. Adverse events (AEs) were generally mild. The most common treatment-related hematological AEs were anaemia, platelet count decreased and hyperuricaemia. Conclusions: SHR-2554 showed promising efficacy and an acceptable safety profile in pts with refractory ES, warranting further investigation. Clinical trial information: ChiCTR2100046099 .