Abstract CT029: Preliminary outcomes from a phase 1b/2 study of the highly potent PI3K-mTOR dual inhibitor WX390 combined with toripalimab in patients with advanced cervical cancer

Abstract Background: WX390 is a highly potent PI3K-mTOR dual inhibitor with activity against PI3Kα, PI3Kδ, and PI3Kγ isoforms, which plays key roles in tumor cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs), respectively, within the tumor microenvironment. PI3K inhibition may enhance the anti-tumor efficacy and reverse the immune resistance combined with an anti-PD1 antibody. Preclinical studies showed that WX390 modulated the tumor microenvironment and reversed anti-tumor immune resistance in combination with an anti-PD1 antibody by decreasing the amounts of Tregs and MDSCs in tumors, compared to the formulation control and anti-PD1 group. In addition, a previous clinical study showed WX390 monotherapy in PIK3CA mutated cervical cancer achieved an objective response rate (ORR) of 6.7%. Methods: A multicenter phase 1b/2 trial of WX390 in combination with Toripalimab was conducted for the treatment of advanced or metastatic cervical cancer patients (NCT06117566). The disease must have progressed while on or after receiving at least one line of systemic therapy, and PIK3CA mutation status is not a criterion for enrollment. The phase 2 study was designed to evaluate the preliminary efficacy and the primary endpoint was ORR. WX390 was administered orally at 1.1mg qd, with Toripalimab at 240 mg IV every 3 weeks. Results: As of January 14, 2025, a total of 49 subjects with cervical cancer were enrolled, with a median age of 52 years old (range 34 to 69). Forty-three (43) subjects (87.8%) were diagnosed with squamous cell carcinoma. A total of 43 subjects were efficacy-evaluable, the ORR was 48.8% (21/43), the disease control rate (DCR) was 86.0% (37/43), and median progression-free survival (mPFS) was 6.47 months (95% CI, 3.98 to NE). Among the 23 checkpoint inhibitor (CPI)-naïve subjects, the ORR was 60.9% (14/23), the DCR was 91.3% (21/23), and mPFS was 6.90 months (95% CI, 6.47 to NE). This included 3 subjects with a complete response (CR) and 11 with a partial response (PR). Among the 20 CPI pretreated subjects, the ORR was 35.0% (7/20), the DCR was 80.0% (16/20), and mPFS was 4.17 months (95% CI, 2.27 to NE). This included 1 subject with a CR and 6 with a PR. Median overall survival was not reached. All subjects experienced treatment-related adverse events (TRAEs), with 31 (63.3%) subjects reporting Grade≥3 TRAEs. The most common TRAEs included hyperglycemia (87.8%), diarrhea (44.9%), and hypophosphatemia (34.7%). The most common Grade≥3 TRAEs were hyperglycemia (24.5%) and diarrhea (16.3%). TRAE leading to dose reduction occurred in 9 (18.4%) subjects. Two (4.1%) subjects suffered TRAEs leading to the discontinuation of WX390. No TRAE leading to death was reported. Conclusions: WX390 in combination with Toripalimab had a manageable safety profile and promising efficacy in patients with advanced cervical cancer, including encouraging antitumor effects in CPI-pretreated patients. Citation Format: Guiling Li, Ai Huang, Qin Yang, Yanhua Ding, Dapeng Li, Shuqing Wei, Quan Li, Zhong Zheng, Shuzhen Lai, Hanmei Lou, Yang Sun, Jiaming Huang, Husheng Tan, Xiao Jia, Wei Wei, Yongguo Li, Ye Guo. Preliminary outcomes from a phase 1b/2 study of the highly potent PI3K-mTOR dual inhibitor WX390 combined with toripalimab in patients with advanced cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT029.