ctDNA-Guided Immunotherapy for dMMR/MSI-H Colon Cancer

This prospective, multicenter, single-arm phase II study evaluates the clinical utility of longitudinal circulating tumor DNA (ctDNA) monitoring to guide neoadjuvant immunotherapy and surgical decision-making in patients with dMMR/MSI-H colon cancer.

Eligible participants will initially receive neoadjuvant PD-1 inhibitor monotherapy. Peripheral-blood ctDNA will be assessed at baseline and after 3 to 4 treatment cycles. Participants with ctDNA clearance will proceed to curative surgery. Participants with persistent ctDNA positivity will be considered to have potential resistance to PD-1 inhibitor monotherapy and will escalate to combined PD-1 and CTLA-4 inhibitor therapy. ctDNA will be reassessed every 2 cycles during combination therapy. Participants will undergo curative surgery after ctDNA clearance or after no more than 4 cycles of combination treatment, regardless of final ctDNA status.

All participants will undergo postoperative ctDNA/minimal residual disease (MRD) testing 1 month after surgery. The study will evaluate pathological response, survival outcomes, the concordance of ctDNA with pathological and imaging assessments, and treatment- and surgery-related safety.

Inclusion criteria

• Written informed consent obtained before any study-related procedures.
• Age 18 to 75 years, inclusive.
• Histologically confirmed colon adenocarcinoma, mucinous adenocarcinoma, or signet-ring cell carcinoma, with the tumor located at least 15 cm from the anal verge.
• dMMR/MSI-H status confirmed by immunohistochemistry, polymerase chain reaction, or next-generation sequencing.
• Eastern Cooperative Oncology Group performance status of 0 or 1 and an expected survival of at least 3 months.
• Adequate hematologic, hepatic, renal, coagulation, thyroid, and cardiac function, as defined in the protocol.
• Negative pregnancy test for women of childbearing potential; agreement to use highly effective contraception, when applicable.

Exclusion criteria

• Prior treatment with a PD-1 inhibitor, CTLA-4 inhibitor, or other immunotherapy.
• Symptomatic or high-risk bowel obstruction, bleeding, perforation, pneumonitis, or other conditions that may compromise safe study participation.
• Another malignancy diagnosed within 5 years before the first study treatment, except for specified definitively treated low-risk malignancies.
• Current participation in another interventional clinical study, or receipt of another investigational drug or investigational device within 4 weeks before the first study treatment.
• Active autoimmune disease requiring systemic treatment within 2 years before the first study treatment, or recent systemic corticosteroid or other immunosuppressive therapy.
• Uncontrolled pleural effusion or ascites, prior allogeneic organ transplantation (except corneal transplantation), or allogeneic hematopoietic stem cell transplantation.
• Known hypersensitivity to any study drug component.
• Toxicities or complications from prior treatment not recovered to Grade 1 or baseline, except for specified conditions.
• HIV infection, untreated active hepatitis B infection, or active hepatitis C infection.
• Receipt of a live vaccine within 30 days before the first study treatment.
• Pregnancy or breastfeeding.
• Any serious or uncontrolled systemic disease, active infection, clinically significant laboratory abnormality, or other condition that may interfere with study participation or place the participant at unacceptable risk, as judged by the investigator.