Two stage, multi-center trial of cadonilimab and LM-302 for patients with CLDN18.2+ biliary tract cancer (BTC) that failed chemotherapy and PD-(L)1 antibody (ZSAB-Calm).

e16152 Background: BTC is a lethal disease with limited effective treatments, especially for those who have failed immune checkpoint inhibitors (ICIs) plus chemotherapy. Cadonilimab, a tetrameric bispecific antibody targeting PD-1 and CTLA-4, showed promising safety profile and efficacy in several malignant tumors. LM-302 is a novel antibody-drug conjugate targeting CLDN18.2, a tight junction protein expressed on the cell surface of many solid tumors, including BTC. Here, we present preliminary data on the safety and efficacy of cadonilimab plus LM-302 in CLDN18.2+ BTC patients (pts) with prior treatment of ICI and chemotherapy. Methods: This ongoing study is a multicenter, two-stage, randomized phase Ib/II clinical trial. In the dose-escalation phase, 6 pts (no requirement for CLDN18.2) are enrolled, using "3+3" design to determine the RP2D. Pts will receive LM302 (1.6mg/kg or 1.8mg/kg Q2W) and cadonilimab (6mg/kg Q2W). The expansion stage is expected to enroll 90 pts (CLDN18.2 + staining in ≥40% of tumor cells), randomized into 3 arms with 30 patients each. Arm 1: cadonilimab (6mg/kg Q2W), Arm 2: LM-302 (1.8mg/kg, Q2W), Arm 3: cadonilimab (6mg/kg Q2W) and LM-302 (RP2D). The primary endpoints are the safety (CTCAE 5.0) in phase 1b and ORR (RECIST1.1) in phase 2. The secondary endpoints include DCR, PFS, OS and safety. Results: A total of 18 pts were enrolled from Aug 4, 2023 to Jan 15, 2024. Median age was 62 (range: 42-79), 44% were male. 61% have intrahepatic cholangiocarcinoma. 78% pts with distant metastasis were diagnosed as stage IV. In the dose-escalation phase, 7 pts were enrolled. The first pt was discontinued after only one dose due to percutaneous transhepatic cholangiography and drainage catheter infection and gastrointestinal bleeding (unrelated to treatment). No DLTs were observed. 7 (100%) pts experienced TRAEs. The most common TRAEs were bilirubin increase (71.4%) thrombocytopenia (57.1%), neutropenia (57.1%), infusion reactions (rash) (42.9%), leukopenia (42.9%), anemia (28.6%). Only 2 pts had grade 3 TRAEs including anemia(1pt), neutropenia, leukopenia and rash (1pt). There was no grade≥4 TRAE. Of the 6 efficacy-evaluable pts, 3 pts(CLDN18.2 expression in 30%, 40%, 80%)achieved PR resulting in a BOR of 50% in Phase Ib. The RP2D for LM-302 was 1.8mg/kg. In expansion phase, 11 pts with CLDN18.2+ BTC were randomly enrolled. The median number of treatment cycles was 2 (range 1-8), with 4 pts each in Arm 1 and Arm 2, and 3 pts in Arm 3. Among the 11 pts, 5 (45.5%) occurred TRAEs, with 3 pts in Arm 3 and 2 pts in Arm 1. The most common TRAEs were neutropenia (18.2%), neutropenia (18.2%). Only 1 pt in Arm 3 experienced grade 3 neutropenia. One pt had a SAE of myocardial infarction (unrelated to treatment). Conclusions: Cadonilimab combined with LM-302 has manageable safety and promising antitumor activity in CLDN18.2+ BTC. Clinical trial information: NCT05994001 .