First-in-human phase Ia study of the PI3Kα inhibitor CYH33 in patients with solid tumors

Xiao-Li Wei, Fu-Rong Liu, Ji-Hong Liu, Hong-Yun Zhao, Yang Zhang, Zhi-Qiang Wang, Miao-Zhen Qiu, Fei Xu, Qiu-Qiong Yu, Yi-Wu Du, Yan-Xia Shi, Wang De-Sheng, Feng-Hua Wang and Rui-Hua Xu ()
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Xiao-Li Wei: Sun Yat-sen University Cancer Center, Sun Yat-sen University
Fu-Rong Liu: Sun Yat-sen University Cancer Center, Sun Yat-sen University
Ji-Hong Liu: Sun Yat-sen University Cancer Center, Sun Yat-sen University
Hong-Yun Zhao: Sun Yat-sen University Cancer Center, Sun Yat-sen University
Yang Zhang: Sun Yat-sen University Cancer Center, Sun Yat-sen University
Zhi-Qiang Wang: Sun Yat-sen University Cancer Center, Sun Yat-sen University
Miao-Zhen Qiu: Sun Yat-sen University Cancer Center, Sun Yat-sen University
Fei Xu: Sun Yat-sen University Cancer Center, Sun Yat-sen University
Qiu-Qiong Yu: Haihe Biopharma Co., Ltd
Yi-Wu Du: Haihe Biopharma Co., Ltd
Yan-Xia Shi: Sun Yat-sen University Cancer Center, Sun Yat-sen University
Wang De-Sheng: Sun Yat-sen University Cancer Center, Sun Yat-sen University
Feng-Hua Wang: Sun Yat-sen University Cancer Center, Sun Yat-sen University
Rui-Hua Xu: Sun Yat-sen University Cancer Center, Sun Yat-sen University

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract PIK3CA mutations are highly prevalent in solid tumors. Targeting phosphatidylinositol 3-kinase α is therefore an attractive strategy for treating cancers harboring PIK3CA mutations. Here, we report the results from a phase Ia, open label, dose-escalation and -expansion study (NCT03544905) of CYH33, a highly selective PI3Kα inhibitor, in advanced solid tumors. The primary outcomes were the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of CYH33. The secondary outcomes included evaluation of pharmacokinetics, preliminary efficacy and changes in pharmacodynamic biomarkers in response to CYH33 treatment. The exploratory outcome was the relationship between the efficacy of CYH33 treatment and tumor biomarker status, including PIK3CA mutations. A total of 51 patients (19 in the dose escalation stage and 32 in the dose expansion stage) including 36 (70.6%) patients (4 in the dose escalation stage and 32 in the dose expansion stage) with PIK3CA mutations received CYH33 1–60 mg. The MTD of CYH33 was 40 mg once daily, which was also selected as the RP2D. The most common grade 3/4 treatment-related adverse events were hyperglycemia, rash, platelet count decreased, peripheral edema, and fatigue. Forty-two out of 51 patients were evaluable for response, the confirmed objective response rate was 11.9% (5/42). Among 36 patients harboring PIK3CA mutations, 28 patients were evaluable for response, the confirmed objective response rate was 14.3% (4/28). In conclusion, CYH33 exhibits a manageable safety profile and preliminary anti-tumor efficacy in solid tumors harboring PIK3CA mutations.

Date: 2022
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DOI: 10.1038/s41467-022-34782-9

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