Research on Effective Strategies After Immunotherapy for Mismatch Repair-deficient Early-stage GI Tumors
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 234
- 试验地点
- 3
- 主要终点
- Relapse-Free Survival (RFS)
研究概览
简要总结
This cohort study is divided into two parts:
Part A: Registry Cohort All patients with non-metastatic, MMRd/MSI-H colorectal cancers (and other gastrointestinal cancers for exploratory analysis) who have signed the general research consent will be included in a prospective registry. This includes patients who undergo primary surgical resection (+/- neoadjuvant/adjuvant therapy) or following immunotherapy, regardless of response.
Part A is a multicenter observational registry with both prospective and retrospective enrolment. Prospective enrolment includes eligible patients entered into the registry after activation of the study at the respective participating site. Retrospective enrolment includes eligible patients diagnosed on or after 1 January 2024 whose clinical data were generated prior to registry activation. Both prospectively and retrospectively enrolled patients contribute to the registry analyses.
Part B: Active Surveillance Cohort (Surveillance Study) A subset of patients from Part A who achieve a complete or near-complete response to ICI therapy, wish to avoid surgery, and are deemed appropriate for non-operative management by a multidisciplinary tumor board are offered inclusion in a phase II surveillance study (Part B). Patients enrolled in Part B will be analysed for the primary endpoint.
详细描述
Background and Rationale: Mismatch repair-deficient (MMRd) or microsatellite instability-high (MSI-H) gastrointestinal (GI) cancers represent a distinct molecular subtype characterized by high tumor mutational burden and increased immunogenicity. Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in this population, with recent studies showing high rates of pathological complete response (pCR) when used in the neoadjuvant setting for non-metastatic GI cancers and colorectal cancers in particular. These results raise important questions about the necessity of surgical resection in patients who achieve complete clinical response (cCR) after ICI therapy.
Avoiding surgery in patients with complete response through an active surveillance approach could significantly reduce treatment-related morbidity and improve quality of life for selected patients. However, this strategy remains investigational and robust clinical evidence is lacking regarding its safety, long-term oncologic outcomes and appropriate selection criteria. Our study seeks to address this gap by evaluating response-guided, non-operative management in patients with non-metastatic MMRd/ MSI-H GI tumors treated primarily with immunotherapy.
Objectives: The primary objective of this study is to evaluate 2-year relapse-free survival (RFS) in patients with non-metastatic, mismatch repair-deficient (MMRd) or microsatellite instability-high (MSI-H) in patients with stage II/III colorectal cancer who achieve a complete or near-complete response following primary treatment with immune checkpoint inhibitors (ICIs) who enter Part B of the study (surveillance study).
Method: Eligible patients may receive immune checkpoint inhibitor (ICI) therapy as the primary treatment for mismatch repair-deficient (MMRd) or microsatellite instability-high (MSI-H), locally advanced, non-metastatic gastrointestinal cancer according to local practice. Treatment regimens include PD-(L)1 monotherapy (e.g., pembrolizumab, atezolizumab) or combination ICI therapy (e.g., nivolumab plus ipilimumab), administered at the discretion of the treating oncologist for up to 6 months (in case of near complete response ICI may be continued up to a total of 12 months following multidisciplinary evaluation).
Patients who do not achieve a complete or near-complete clinical response-or who are not eligible or not willing to undergo non-operative management-proceed to standard oncological surgery (with or without neo-/adjuvant systemic therapy), in accordance with clinical guidelines. Postoperatively, they receive routine oncological follow-up per institutional standards and remain in registry cohort (Part A).
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Part A and Part B:
- •Consent and Capacity:
- •Participant is 18 years of age or older.
- •Participant is legally competent and able to provide informed consent.
- •Participant has provided the appropriate written consent
- •Diagnosis: Histologically confirmed gastro-oesophageal, colon or rectum cancer, showing mismatch repair-deficiency (MMRd) by immunohistochemistry (loss of immunoreactivity for at least one of the following proteins: MLH1, PMS2, MSH2 and/or MSH6).
- •Clinical Stage: Non-metastatic, locally advanced disease, defined as:
- •cT2-T4, cN0-2, cM0 for gastro-oesophageal or rectum cancer
- •cT4 and/or cN+, cM0 for colon cancer
- •Therapy with immune checkpoint inhibitor (ICI) as primary treatment, either:
- •Combination ICI therapy (e.g., anti-PD-1 plus anti-CTLA-4 such as nivolumab + ipilimumab) or
- •Single-agent ICI therapy (e.g., pembrolizumab, atezolizumab, or other anti- PD(L)1 agents)
- •Part B only:
- •Patient consents to participate in surveillance study
- •Complete or near complete response (*) to primary ICI treatment, as determined by local multidisciplinary team (MDT) assessment, based on restaging 8 weeks after termination of the ICI treatment:
- •Radiological imaging (CT/MRI/PET-CT),
- •Endoscopic findings, and
- •Clinical parameters (e.g., normalization of tumor markers, absence of symptoms **)
- •Note: in case of near complete response up to a total of 12 months of ICI is allowed following multidisciplinary team (MDT) discussion. After diagnosis of a near-complete response, tumor reassessments should be performed every 3 months up to a total treatment period of 12 months. If a complete tumor response is observed within the 12-month period, it should be recorded as the best overall response.
- •Note: Assessment of complete or near complete response does not incorporate ctDNA test results
排除标准
- •Recurrent Disease: Known history of previously treated gastrointestinal cancer with recurrence at time of inclusion.
- •Metastatic Disease: Evidence of distant metastases (M1) at any point prior to or during ICI therapy.
- •Other Malignancies: Active second malignancy (excluding non-melanoma skiN cancer or in-situ cervical carcinoma) that may interfere with study outcomes or surveillance.
- •Part B only:
- •Inadequate response to ICI: Patients with progressive disease, stable disease, or partial response deemed unsuitable for non-operative management.
- •Prior Treatment: Any prior systemic therapy, radiotherapy or surgery for the current colon cancer diagnosis before ICI treatment (except biopsy)
- •Medical or Psychiatric Conditions: Significant comorbid conditions or psychiatric illness that, in the opinion of the investigator, would impair the patient's ability to comply with protocol requirements, including surveillance.
- •Logistical Barriers: Social, geographic, or organizational factors (e.g., lack of access to regular follow-up care, inability to attend surveillance visits) that would prevent adherence to the active surveillance protocol.
研究组 & 干预措施
Active Surveillance after ICI response instead of surgery
Participants with mismatch repair-deficient (MMRd) or microsatellite instability-high (MSI-H) stage II/III gastrointestinal cancer who achieve a complete or near-complete response after immune checkpoint inhibitor (ICI) therapy enter a structured active surveillance program instead of undergoing immediate surgery. Surveillance includes scheduled radiologic imaging, endoscopic evaluation, clinical assessment, and biomarker monitoring to detect relapse early and allow timely salvage treatment.
干预措施: Active surveillance after complete response to immunotherapy in MMRd GI cancers (Other)
Standard of Care Cohort
Patients that receive an operation to remove the primary tumour after completion of immunecheckpoint therapy for MSI high colorectal cancer (resp. other MSI high GI cancer).
干预措施: Stand of Care (Other)
结局指标
主要结局
Relapse-Free Survival (RFS)
时间窗: 24 months
The proportion of patients with colorectal cancers who remain free from local, regional, or distant recurrence at 24 months after achieving a complete or near-complete clinical response to immune checkpoint inhibitor therapy and undergoing active surveillance. Recurrence is defined as radiologic, endoscopic, or histologic evidence of tumor regrowth requiring salvage surgery or systemic treatment.
次要结局
- Relapse-Free Survival - other GI Cancers(24 months)
- Clinical Complete Response (cCR) Rate(12 months)