Background: Pancreatic cancer is a malignancy with poor prognosis and high mortality ranking 7^th worldwide and with a 5-year survival rate of 10.8%. More than 50% pts are diagnosed at the late stage. The monoclonal antibodies of immune checkpoint inhibitors are also being investigated but has very limit progression free survival (PFS) and overall survival (OS) benefit. KN046, a novel recombinant humanized bispecific antibody, can simultaneously block PD-1/PD-L1 and CTLA-4 pathways and restore T-cell immune response to tumor. KN046 plus nab-paclitaxel/gemcitabine as first-line treatment for unresectable locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) in a phase 2 study arm 2 (NCT04324307) was reported before. Here, we report the efficacy and safety of KN046 as a monotherapy in the 2^nd line and above setting (arm1). Methods: This ongoing phase 2 trial in China enrolled pts with histologically or cytologically confirmed unresectable locally advanced or metastatic PDAC who have ECOG PS of 0-1 and failed to at least one systemic anti-tumor treatment in arm 1. Single agent of KN046 (5mpk, Q2W) were administered until disease progression or intolerable toxicity. Tumor response was assessed according to RECIST 1.1 every 8 weeks. The primary endpoint is investigator-assessed objective response rate (ORR). Secondary endpoints including disease control rate (DCR), PFS, OS and safety, etc. Results: As of Jan 10, 2022, 21pts were enrolled, median (range) age was 57 (51-64) years, 14 (66.7%) pts ECOG 1, 16 (76.2%) pts had distant metastases, and 11 (52,4%) pts had received ≥2 lines systemic treatment. Median KN046 exposure time was 4.1(2.1,6,4) wks. 9 pts were included in the efficacy analysis with 1 PR and 3 SD. 21 pts in the safety analysis. Confirmed ORR was 11.1% (95% CI: 0.28,48.25), and DCR was 44.4% (95% CI: 13.7,78.8). Median PFS was 2.1 months (95% CI:1.61̃7.29), PFS rate in 6 and 9 months were 31.4% and 21%, respectively. Median OS was 7.5months (95% CI:3.02-NR), OS rate in 6 and 9 months were 61.3% and 49.5%, respectively. The incidence of KN046 related treatment-emergent adverse events (TRAE) was 71.4% (15/21), with 14.3% (3/21) ≥grade 3 TRAEs. Two pts experienced TRAE leading to discontinuation. The most common TRAEs (≥10%) were rash (n=6, 28.6%), alanine aminotransferase increased, chills, γ-glutamyl transferase increased and platelet count decreased (n = 3, 14.3%, respectively). No TRAE leading to death occurred. Conclusions: KN046, a bispecific antibody as 2^nd line and above monotherapy for unresectable locally advanced or metastatic PDAC patients demonstrated a good PFS and OS benefit as well as acceptable safety profile, supporting KN046 in combination of chemotherapy as first line treatment. Clinical trial information: NCT04324307.