Efficacy and safety of XNW27011, a Claudin-18.2 targeted (CLDN18.2) ADC, in advanced pancreatic ductal adenocarcinoma: A phase 2 study.

Abstract

3039 Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a historically poor prognosis, the median overall survival (mOS) for PDAC patients (pts) who received ≥ 1 prior lines of standard treatments is only 6.2 to 7.4 months(mos). XNW27011 is a novel and potent Topoisomerase inhibitor (TOP1i)-based ADC targeting CLDN18.2. In preclinical studies, XNW27011 demonstrated antitumor activities in PDAC, supporting its progression into clinical development. Here, we report results of XNW27011 in pts with PDAC. Methods: The objectives of this phase 2 study were to evaluate the efficacy and safety of XNW27011 in PDAC, and to optimize doses for subsequent confirmatory trials. Pts with PDAC expressing CLDN18.2 (defined as ≥5% tumor cells with ≥2+ IHC staining) who had received prior systemic therapy were treated with XNW27011 at doses from 2.4 - 4.8 mg/kg, Q3W. The primary endpoint was ORR, secondary endpoints included TRAEs for safety, DCR, PFS, OS, and PK parameters. Results: As of Dec 29, 2025, a total of 48 pts had been enrolled with majority of them being enrolled in 3.0 mg/kg group. Among the 48 pts, the ECOG PS was 0 or 1, the median age was 59.0 years. 18 pts (37.5%) had received 1 prior line of systemic therapy. 22 pts (45.8%) had been treated with TOP1i. Efficacy: A total of 30 PDAC pts in the 3.0 mg/kg dose group were evaluable for efficacy. The ORR and DCR was 26.7% and 83.3%, respectively. mPFS and mOS was 4.1 and 10.0 mos, respectively. Among the 13 pts who had received only one prior line of therapy, the ORR was 46.2% and the DCR was 100.0%, mPFS was 4.4 mos, OS was not mature yet. However, the current mOS was 10.1 mos with the median follow-up of 8.1 mos. Detailed efficacy data are presented in the table. Among the pts who were previously treated with TOP1i, the median follow-up was 7.9 mos, the mPFS and mOS were 5.2 and 10.0 mos, respectively. Safety: Among the 48 PDAC pts, the incidence of treatment-related adverse events (TRAEs) was100.0%. The incidence of Grade ≥3 TRAEs and serious TRAEs were 77.1% and 58.3%, respectively. 35.4% and 6.3% of the TRAEs led to dose reduction and discontinuation, respectively. The most common TRAEs included nausea (77.1%), vomiting (64.6%), decreased appetite (64.6%) and anemia (62.5%). Pharmacokinetics: At doses of 0.6-6.0 mg/kg in patients with solid tumors including PDAC, the XNW27011 exposure (C max and AUC 0-∞ ) increased in an approximately dose proportional manner with a half-life of 5~7 days. Across all dose levels, circulating payload blood concentrations were low with 3.3% ADA positive rate. Conclusions: XNW27011 showed a manageable safety profile and encouraging survival outcome in pts with PDAC expressing CLDN 18.2, supporting its further clinical development as a promising therapeutic option for patients with PDAC expressing CLDN 18.2. Clinical trial information: NCT06792435 .