A phase II exploratory study of iparomlimab and tuvonralimab (QL1706) combined with bevacizumab in patients with locally advanced or metastatic MSI-H/dMMR colorectal cancer.

Abstract

TPS3677 Background: Microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC) is highly responsive to immune checkpoint inhibitors (ICIs). PD-1 monotherapy or PD-1/CTLA-4 dual blockade are standard options for locally advanced or metastatic disease, but a significant proportion of patients still show no response to these regimens. Evidence suggests that vascular endothelial growth factor (VEGF) signaling mediates an immunosuppressive tumor microenvironment (TME). Combining anti-VEGF agents with ICIs may potentially normalize the inhibitory TME, and thereby could enhance anti-tumor immunity and improve response rates in this population. QL1706 is a novel bifunctional antibody combination targeting PD-1 (iparomlimab) and CTLA-4 (tuvonralimab). This Phase II exploratory study aims to investigate the efficacy and safety of QL1706 in combination with anti-VEGF agent bevacizumab in locally advanced or metastatic CRC patients with MSI-H/dMMR. Methods: This single-arm, open-label, multicenter, Phase II exploratory study is designed to evaluate the efficacy and safety of QL1706 plus bevacizumab in patients with MSI-H/dMMR advanced CRC. Eligible patients are adults aged 18 to 80 years with histologically confirmed locally advanced or metastatic CRC and who have an MSI-H/dMMR status via immunohistochemistry or polymerase chain reaction. Key inclusion criteria include at least one measurable target lesion per RECIST v1.1, an ECOG Performance Status of 0-1, and no prior immunotherapy for advanced disease. The systemic regimen consists of QL1706 (5 mg/kg) and bevacizumab (7.5 mg/kg) administered intravenously every 3 weeks (Q3W). Treatment continues until disease progression, unacceptable toxicity, or a maximum of 2 years. The primary endpoint is the objective response rate (ORR) assessed by investigators per RECIST v1.1. Secondary endpoints include disease control rate, duration of response, progression-free survival, overall survival, and landmark survival rates at 6, 12, and 24 months. Safety is monitored via NCI CTCAE v5.0. Efficacy assessments, including chest CT and enhanced abdominal/pelvic CT/MRI, are performed every 12 weeks. Statistical power is based on an estimated ORR of 80%; with a 95% confidence interval width of 35%, a total of 22 subjects are required (supplemented by a Simon’s two-stage design for the broader cohort if applicable). The study has received ethics committee approval, and patient enrollment is currently ongoing. Clinical trial information: NCT07009145 .