Abstract CT276: Liberty-201: Maintenance fluoropyrimidine (FP) and bevacizumab with or without anti-lymphocyte activation gene-3 (LAG-3) antibody LBL-007 plus anti-programmed cell death protein-1 (PD-1) antibody tislelizumab (TIS) for patients (pts) with metastatic or unresectable microsatellite stable (MSS)/mismatch repair proficient (pMMR) colorectal cancer (CRC)

Abstract Background: LBL-007 is a monoclonal antibody targeting LAG-3, a receptor expressed on immune cells that negatively regulates T-cell proliferation and effector T-cell function. LAG-3 is frequently co-expressed with PD-1 on tumor-infiltrating T cells, and dual inhibition of LAG-3/PD-1 synergistically prevents tumor growth in mouse models. CRC is the second-highest cancer-related cause of death worldwide; pts diagnosed with metastatic CRC have a 5-year survival rate of 14%. Immunotherapy (IO) has only demonstrated clinical benefit in pts with microsatellite instability-high/MMR-deficient CRC, which accounts for 5% of CRC pts; however, improved therapy options for patients with MSS CRC remain limited. The combination of anti-LAG-3 + anti-PD-1 IO is currently being tested in clinical trials in pts with MSS CRC. Methods: This is a phase 1b/2, randomized, open-label study (NCT05609370). Pts with unresectable or metastatic CRC with locally or centrally confirmed pMMR or MSS status and no disease progression after induction treatment in first-line therapy are eligible. A maximum of 36 pts will be enrolled in phase 1b (safety run-in) to determine the recommended phase 2 dose. All pts will receive intravenous dual IO (LBL-007 + TIS) in combination with maintenance backbone (FP + bevacizumab). The dose of LBL-007 will be escalated from 150 mg every 3 weeks (Q3W) to 600 mg Q3W/400 mg Q2W using a Bayesian optimal interval design with informative prior. In phase 2, ~130 pts will be enrolled in the programmed death-ligand 1 (PD-L1) -positive group (tumor area positivity TAP ≥1%) and 60 patients in the PD-L1-negative group (TAP 1%). Pts with a PD-L1-positive status will be randomized 2: 1: 2 to receive dual IO + maintenance backbone (Arm A), LBL-007 + maintenance backbone (Arm B), or maintenance backbone only (Arm C). Pts with a PD-L1-negative status will be randomized 1: 1 to receive dual IO + maintenance backbone (Arm D) or maintenance backbone only (Arm E). Treatment will continue until disease progression or unacceptable toxicity. The primary endpoint is safety in phase 1b and investigator-assessed progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) v1. 1 in phase 2. Secondary endpoints include overall survival, PFS2, overall response rate, duration of response, safety, pharmacokinetics, and immunogenicity. Exploratory endpoints include potential biomarkers (including but not limited to PD-L1 and LAG-3). Citation Format: Heinz-Josef Lenz, Ying Yuan, Vivian Li, Juan Zhang, Lubna Jamal, Xiao Lin, Fuxiang Zhu, John H. Strickler. Liberty-201: Maintenance fluoropyrimidine (FP) and bevacizumab with or without anti-lymphocyte activation gene-3 (LAG-3) antibody LBL-007 plus anti-programmed cell death protein-1 (PD-1) antibody tislelizumab (TIS) for patients (pts) with metastatic or unresectable microsatellite stable (MSS) /mismatch repair proficient (pMMR) colorectal cancer (CRC) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr CT276.