Research on Effective Strategies After Immunotherapy for Mismatch Repair-deficient Early-stage GI Tumors

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).

Patients who demonstrate a complete or near-complete clinical response to ICI and are considered eligible for non-surgical management (based on multidisciplinary evaluation), enter an intensified surveillance program in lieu of immediate surgery (Part B).

The active surveillance includes Clinical assessments, Cross-sectional imaging (e.g., CT or MRI) , Endoscopic evaluations at defined intervals and Facultative ctDNA testing 6 months after completion of immunotherapy (Part B)

Inclusion criteria

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

Exclusion criteria

• 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.