Colorectal Cancer (MSI-H), Molecular Residual Disease
Conditions
Brief summary
This study aims to evaluate whether plasma molecular residual disease (MRD), assessed using circulating tumor DNA (ctDNA), can help optimize the duration of immunotherapy in patients with metastatic microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) colorectal cancer. Patients with MSI-H/dMMR metastatic colorectal cancer can achieve durable responses to immune checkpoint inhibitors, but the optimal duration of treatment remains uncertain. Prolonged immunotherapy may increase treatment burden and the risk of immune-related adverse events. ctDNA-based MRD testing may provide a sensitive method for detecting residual tumor burden and identifying patients who may be able to safely stop treatment. In this study, patients receiving immunotherapy will undergo serial plasma MRD testing. After completing 1 year of immunotherapy, patients with two consecutive negative MRD results will be randomly assigned to either continue immunotherapy or stop treatment and enter observation. Patients will then be followed every 3 months for 2 years with MRD testing and routine clinical assessments, including imaging and laboratory examinations. The study will compare clinical outcomes between the two groups and evaluate whether serial plasma MRD monitoring can support a more individualized approach to the duration of immunotherapy in MSI-H/dMMR metastatic colorectal cancer.
Interventions
Patients with dMMR/MSI-H metastatic colorectal cancer who achieve an objective response after 1 year of immunotherapy and have two consecutive negative plasma MRD results will be randomized to discontinue immunotherapy. Patients will enter observation and undergo routine clinical and imaging assessments, with plasma MRD testing every 3 months until the study endpoint.
OTHERContinued Immunotherapy
Patients with dMMR/MSI-H metastatic colorectal cancer who achieve an objective response after 1 year of immunotherapy and have two consecutive negative plasma MRD results will be randomized to continue immunotherapy for a total treatment duration of 2 years. Patients will undergo routine clinical and imaging assessments, with plasma MRD testing every 3 months until the study endpoint.
OTHERObservation
Patients who achieve disease control for at least 6 months after immunotherapy will undergo plasma MRD testing and prospective follow-up. The study will not interfere with subsequent treatment decisions, including discontinuation or continuation of immunotherapy, surgery, or local treatment. Patients will undergo routine clinical follow-up and serial MRD monitoring according to the study schedule.
Sponsors
Sun Yat-sen University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Voluntary participation in the study and provision of written informed consent. 2. Age ≥18 years at the time of signing informed consent. 3. Histologically confirmed colorectal adenocarcinoma with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) status. 4. Clinically confirmed stage IV disease. 5. No prior immunotherapy for the current colorectal cancer. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 7. Availability of adequate pretreatment tumor tissue and peripheral blood samples for whole-exome sequencing (WES) and personalized circulating tumor DNA (ctDNA)/MRD analysis. 8. Life expectancy \>12 months. 9. Willing and able to comply with the study procedures and scheduled follow-up.
Exclusion criteria
1. Presence of another malignancy. 2. Prior immunotherapy for the current stage IV colorectal cancer. 3. Organ transplantation within 3 months before enrollment. 4. History of blood transfusion within 3 months before enrollment. 5. Active, known, or suspected autoimmune disease, or evidence of active or chronic infection with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus (HIV). 6. Pregnancy or breastfeeding. 7. Presence of a serious concurrent disease that, in the investigator's judgment, may substantially affect life expectancy or study participation. 8. Failure to provide written informed consent. 9. Any other condition that, in the investigator's judgment, makes the participant unsuitable for enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | From randomization to disease progression, death, or up to 2 years | Progression-free survival is defined as the time from randomization to the first documented disease progression or death from any cause, whichever occurs first. Participants without disease progression or death will be censored at the date of the last disease assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization to death from any cause or up to 3 years | Overall survival is defined as the time from randomization to death from any cause. Participants who are alive at the end of follow-up will be censored at the date they were last known to be alive. |
| Incidence of Immune-Related Adverse Events (irAEs) | From randomization through 2 years of follow-up | The incidence of immune-related adverse events will be assessed during the study. The proportion of participants experiencing immune-related adverse events will be recorded and compared between the treatment-discontinuation and continued-immunotherapy groups. |
Countries
China
Contacts
CONTACTBinyi Xiao, M.D
PRINCIPAL_INVESTIGATORPeirong Ding, M.D.
Sun Yat-Sen University Cancer Center
Outcome results
None listed