Phase Ib study of a high potent PI3K-mTOR dual inhibitor WX390 combined with toripalimab in patients with advanced solid tumors.

e14627 Background: WX390 is a high potent PI3K-mTOR dual inhibitor targeting pan-PI3K and mTOR. It modulates the tumor immune microenvironment by decreasing tumor Treg and myeloid-derived suppressor cells (MDSC) and improves the immune response to checkpoint inhibitors (CPI) in preclinical models. Methods: The Phase Ib study was designed to evaluate safety, pharmacokinetics (PK), and preliminary clinical activity, to determine recommended phase 2 dose (RP2D) of WX390 combined with Toripalimab in patients with advanced solid tumors. WX390 was administered orally daily at escalating doses of 0.7 mg, 0.9mg and 1.1mg, with Toripalimab at 240 mg IV every 3 weeks until confirmed progressive disease, intolerable toxicity or withdrawal of consent. Plasma PK samples were collected up to 24 hours after the first dose at C1D1, and up to 24 hours before and after the morning dose at C1D21. Results: As of December 31, 2023, total 18 patients had been treated in 3 WX390 cohorts: 0.7 mg (n = 3), 0.9 mg (n = 3), and 1.1 mg (n = 12) once daily (QD). No dose limit toxicity (DLT) was observed, and the RP2D of WX390 in combination was 1.1 mg QD, which was consistent with the single agent RP2D. The treatment related adverse events (TRAEs) (≥20%) included hyperglycemia (17/18, 94.4%), creatinine increased (12/18, 66.7%), weight loss (10/18, 55.6%), diarrhea (9/18, 50%), proteinuria (9/18, 50%), nausea (7/18, 38.9%), lymphocytopenia (7/18, 38.9%), vomiting (7/18, 38.9%), rash (7/18, 38.9%), decreased appetite (6/18, 33.3%), hypokalemia (6/18, 33%), fatigue (5/18, 27.8%), hyponatremia (4/18, 22.2%), and thrombocytopenia (4/18, 22.2%). Grade 3 TRAEs included hyperglycemia (5/18), lymphocytopenia (4/18), rash (2/18), weight loss (2/18), leukopenia (1/18), infusion-related reaction (1/18), nausea (1/18), and stomatitis (1/18). There was no TRAE leading to treatment permanent discontinuation and no grade 4/5 TRAE were observed. PK of WX390 in combination showed similar PK profile with the single agent. Among the 16 efficacy-evaluable patients with cervical (N=8), head and neck (N=5), and urothelial cancer (N=3), 5 patients (31.3%) previously received immune checkpoint inhibitors. 3 of 5 (60%) cervical cancer patients at RP2D and 2 of 5 head and neck cancer patient (40%) have achieved confirmed partial response (PR). In addition, 3 cervical patients who were treated with 0.7 or 0.9mg QD and 1of 3 urothelial carcer patients experienced tumor shrinkage (SD). The medium progression free survival (PFS) was 5.49 months (95% CI: 2.53, 6.37). Conclusions: WX390 in combination with Toripalimab had a manageable safety profile and encouraging antitumor effects in patients with advanced solid tumors. An RP2D of 1.1 mg qd of WX390 in combination was selected to be explored in further phase II study, which is ongoing in different tumor types. Clinical trial information: NCT06117566 .