Safety, efficacy, and pharmacokinetics of XNW28012, a tissue factor antibody-drug conjugate (ADC) with topoisomerase 1 inhibitor (TOP1i) payload, in patients with advanced solid tumors: Results from a phase I/II study.

Abstract

3040 Background: Tissue factor (TF) is overexpressed in a broad range of solid tumors including pancreatic ductal adenocarcinoma (PDAC). XNW28012 is the first TF ADC with a novel TOP1i payload. Here we report the safety and PK of XNW28012 in patients (pts) with solid tumors, and the efficacy in PDAC from a Phase I/II study. Methods: Eligible pts who failed standard therapy received XNW28012 Q3W. TF expression was not required for enrollment. The primary endpoints for dose escalation and expansion were safety and ORR, respectively. BOIN design was used for dose escalation. Eligible pts with PDAC and other solid tumors were enrolled at 2.0 and 2.4 mg/kg for dose expansion. Results: As of Nov. 21, 2025, 313 pts were enrolled (escalation: 16; expansion: 297), with median age of 56.3 yrs; 77.0% of ECOG 1; and 56.9% received ≥2 lines of prior systemic therapy. TEAEs in ≥20% pts were anemia (62.0%), stomatitis (60.1%), nausea (49.5%), WBC count decreased (47.0%), appetite decreased (43.1%), neutrophil count decreased (39.9%), vomiting (39.6%), asthenia (35.5%), weight decreased (30.7%), conjunctivitis (29.4%), rash (28.1%), hypokalemia (23.3%), hyponatremia (21.4%), and hypoalbuminemia (21.1%). ≥Grade 3 TEAEs in ≥5% pts were stomatitis (17.6%), neutrophil count decreased (14.4%), WBC count decreased (12.8%), anemia (11.5%), and lymphocyte count decreased (8.3%). Dose interruption, reduction and discontinuation due to TEAE occurred in 60.7%, 22.0%, and 3.8% of the pts, respectively. Grade 3 conjunctivitis was reported in 2.9% pts across the doses. Most common bleeding AE was epistaxis (12.1%), all grade 1/2. 1 pt at 3.6 mg/kg experienced DLT (grade 4 neutropenia, grade 3 stomatitis). 16 pts were enrolled in dose escalation from 0.6 to 3.6 mg/kg. ORR and DCR were 46.7% and 100%, respectively in 15 evaluable pts including PDAC, ovarian cancer, cervical cancer, and head and neck squamous cell carcinoma. In dose expansion, 45 and 48 PDAC pts were efficacy evaluable at 2.0 and 2.4 mg/kg, with a median follow up of 4.4 m and 6.0 m, respectively. Efficacy data in PDAC pts in dose expansion were summarized in the Table. PK data showed dose proportionality and very low payload exposure in the system indicating stable linker. Conclusions: XNW28012 demonstrated a manageable safety profile in heavily treated advanced solid tumor pts and promising anti-tumor activity in PDAC patients. The data support further development of XNW28012 in a broad range of solid tumors including PDAC. Clinical trial information: NCT06799637 . Prior line 2.0 mg/kg, 1L(N=25) 2.0 mg/kg, 2L+(N=20) 2.4 mg/kg, 1L(N=21) 2.4 mg/kg, 2L+(N=27) ORR, n (%) 7 (28.0%) 3 (15.0%) 10 (47.6%) 7 (25.9%) DCR, n (%) 23(92.0%) 18(90.0%) 19 (90.5%) 23 (85.2%) mPFS, (months) 4.2 4.5 6.4 5.2 mOS, (months) NC 10.7 14.6 9.0 KM OS rate at 9m (%) 64.5% 51.6% 54.2% 50.5% KM OS rate at 12m (%) NC NC 54.2% 22.9% NC: Not Calculated.