NOMAD-GI: Molecular-guided Non-operative Management and Organ Preservation Strategy After Precision Therapy in Gastrointestinal Cancers

N/ANot Yet RecruitingNCT07775859

Peking University Cancer Hospital & Institute200 enrolled

Overview

The NOMAD-GI study is a single-center, bidirectional cohort study designed to evaluate the safety and efficacy of molecular biomarker-guided non-operative management (NOM) and organ preservation strategies after precision therapy in patients with gastrointestinal cancers. Patients with actionable molecular biomarkers, including dMMR/MSI-H, POLE mutation, PD-L1 high expression, tumor mutational burden-high (TMB-H), Epstein-Barr virus positivity (EBV+), HER2 positivity, CLDN18.2 positivity, and other actionable genomic alterations, will be enrolled. After immune checkpoint inhibitor or targeted therapy, patients achieving favorable clinical responses will undergo multidisciplinary team (MDT) evaluation and receive either non-operative management, local treatment, or radical surgery according to individualized treatment decisions. The study aims to establish a molecular-driven organ preservation paradigm for gastrointestinal cancers and evaluate whether NOM can provide comparable oncological outcomes while improving functional outcomes and quality of life.

The NOMAD-GI study is a single-center, bidirectional cohort study designed to evaluate the safety and clinical effectiveness of molecular biomarker-guided precision therapy followed by non-operative management (NOM) or organ-preservation strategies in patients with gastrointestinal cancers. The central hypothesis of the study is that a subset of gastrointestinal cancers with favorable molecular characteristics may achieve a deep and durable tumor response after appropriately selected precision therapy. In carefully selected patients with a complete or near-complete clinical response, a multidisciplinary team (MDT) may identify patients in whom radical surgery can potentially be avoided while maintaining acceptable oncological safety and preserving organ function. The study is designed to investigate a treatment paradigm in which molecular characteristics are integrated with treatment response and clinical characteristics to support individualized treatment decisions. Molecular biomarkers are therefore considered part of a multidimensional decision-making framework rather than isolated determinants of treatment allocation. Molecular biomarkers in this study are used primarily to guide the selection of precision therapy rather than to directly determine eligibility for non-operative management. The molecular profile may include immune-related biomarkers, such as mismatch repair deficiency or microsatellite instability-high status, pathogenic POLE or POLD1 alterations, high tumor mutational burden, programmed death ligand 1 combined positive score, and Epstein-Barr virus positivity, as well as biomarkers associated with targeted treatment, such as HER2, CLDN18.2, FGFR2, MET, NTRK, KRAS G12C, and other clinically actionable molecular alterations. The specific precision therapy received by each participant will be determined according to tumor type, disease stage, molecular characteristics, approved indications, contemporary clinical practice, and the treating multidisciplinary team. Precision therapy may include immune checkpoint inhibitors, targeted therapies, chemotherapy combined with immunotherapy or targeted therapy, or other clinically appropriate systemic treatment approaches. After precision therapy, treatment response will be evaluated using appropriate clinical, radiological, endoscopic, and pathological assessments according to the primary tumor site. Patients with a favorable response, including clinical complete response or near-complete response, may undergo MDT evaluation for potential non-operative management or organ-preservation treatment. The MDT decision will consider tumor response, primary tumor location, baseline disease characteristics, molecular profile, treatment history, imaging findings, endoscopic findings, pathological findings when available, patient preferences, expected functional consequences of radical surgery, and the feasibility of intensive surveillance. Patients considered suitable for non-operative management may undergo a structured watch-and-wait or active surveillance strategy. Selected patients with residual or near-complete response may undergo local treatment, including endoscopic resection or local excision, when clinically appropriate. Patients who do not meet criteria for safe organ preservation, who have persistent or progressive disease, or who require radical treatment based on MDT assessment will undergo radical surgery according to standard clinical practice. The study includes both a retrospective cohort and a prospective cohort. The retrospective cohort will include eligible patients treated before initiation of prospective enrollment for whom sufficient clinical, molecular, treatment, response, and follow-up data are available. The prospective cohort will include eligible participants enrolled after ethics approval and informed consent, followed according to the predefined study surveillance protocol. The primary research objective is to evaluate the proportion of patients who achieve successful organ preservation without radical surgery after molecular biomarker-guided precision therapy and MDT-directed NOM or organ-preservation treatment. Secondary objectives include evaluation of disease-free survival, overall survival, local tumor regrowth, salvage radical surgery, permanent stoma, treatment-related morbidity, and patient-reported quality of life and organ function. The study is observational. Treatment selection, including the choice of precision therapy, NOM, organ-preservation treatment, or radical surgery, will be based on clinical decision-making and will not be assigned randomly by the study. The presence of an actionable molecular biomarker alone does not constitute an indication for non-operative management. Non-operative management or organ-preservation treatment will only be considered after appropriate precision therapy and comprehensive response assessment, and will require MDT evaluation confirming that the anticipated oncological risk is acceptable and that intensive surveillance is feasible.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Adults aged 18 years or older at the time of study enrollment. 2. Histologically confirmed gastrointestinal malignancy, including gastric cancer, gastroesophageal junction cancer, esophageal cancer, or colorectal cancer. 3. Presence of at least one molecular biomarker that may support selection of precision therapy, including but not limited to: * Mismatch repair deficiency or microsatellite instability-high (dMMR/MSI-H); * Pathogenic or likely pathogenic POLE or POLD1 mutation; * High programmed death ligand 1 combined positive score (PD-L1 CPS), when applicable to the tumor type and treatment strategy; * Tumor mutational burden-high (TMB-H); * Epstein-Barr virus-positive status (EBV-positive), when applicable; * Human epidermal growth factor receptor 2 (HER2) positivity; * Claudin 18.2 (CLDN18.2) positivity; * Fibroblast growth factor receptor 2 (FGFR2) alteration; * Mesenchymal-epithelial transition factor (MET) amplification or other actionable MET alteration; * Neurotrophic tyrosine receptor kinase (NTRK) gene fusion; * Kirsten rat sarcoma viral oncogene homolog G12C (KRAS G12C) mutation; * Other clinically actionable molecular alterations recognized according to contemporary clinical practice. 4. Receipt of molecular biomarker-guided precision therapy before assessment for non-operative management or organ-preservation strategy. Precision therapy may include immune checkpoint inhibitor therapy, targeted therapy, or a combination of systemic therapies according to the participant's tumor type, molecular profile, clinical stage, and standard clinical practice. 5. After completion or adequate exposure to precision therapy, achievement of a favorable clinical response that may support consideration of non-operative management or organ-preservation strategy, including clinical complete response (cCR), near-complete response (near-cCR), major tumor regression, or other predefined favorable response categories. 6. Multidisciplinary team (MDT) evaluation has been performed to determine whether non-operative management, local treatment, organ-preservation strategy, or radical surgery is appropriate. 7. Adequate clinical information is available for assessment of treatment response, including appropriate imaging, endoscopic evaluation, pathological evaluation, or other clinically indicated examinations. 8. Ability and willingness to comply with the predefined surveillance and follow-up schedule. 9. For the prospective cohort, written informed consent is obtained before enrollment and study-specific data collection. 10. For the retrospective cohort, eligible clinical data are available in the institutional medical records and may be used according to institutional ethics approval and applicable regulations. Exclusion Criteria: 1. Uncontrolled progressive metastatic disease or clinical deterioration that precludes evaluation for the study treatment strategy. 2. Patients who are unable to undergo appropriate clinical, radiological, endoscopic, or pathological assessment required for response evaluation or follow-up. 3. Previous treatment history or concurrent medical conditions that, in the judgment of the multidisciplinary team, preclude reliable assessment of tumor response or implementation of the predefined surveillance strategy. 4. Severe comorbidities or medical conditions that make continued follow-up or additional treatment evaluation clinically inappropriate. 5. Inability or unwillingness to comply with the predefined follow-up schedule. 6. Withdrawal of informed consent for prospective participants. 7. Insufficient clinical information to determine eligibility, treatment response, treatment strategy, or follow-up outcomes. 8. Patients with conditions that require immediate radical surgery or other urgent treatment according to multidisciplinary clinical assessment and who cannot safely undergo the predefined study evaluation.

Outcomes

Primary Outcomes

3-Year Organ Preservation Success Rate Without Radical Surgery

The proportion of participants who remain free from radical surgical resection and maintain the originally targeted organ at 3 years after initiation of the non-operative management or organ-preservation strategy. Organ preservation success will be assessed using clinical records, imaging, endoscopic evaluation, pathological evaluation when applicable, and subsequent treatment records. Measure: Percentage of participants Unit of Measure: Percentage

Time frame: 3 years after initiation of the non-operative management or organ-preservation strategy

Secondary Outcomes

3-Year Disease-Free Survival as Determined by Clinical, Radiological, Endoscopic, and Pathological Evidence of Disease Recurrence

Disease-free survival is defined as the time from initiation of the non-operative management or organ-preservation strategy, or from radical surgery for participants in the radical surgery cohort, to the first documented local regrowth, local recurrence, regional recurrence, distant metastasis, second primary gastrointestinal malignancy, or death from any cause. Participants without an event at the date of last follow-up will be censored at that date. Measure: Time to event. Unit of Measure: Months.

Time frame: 3 years after initiation of the study treatment strategy

3-Year Overall Survival as Determined by All-Cause Mortality

Overall survival is defined as the time from initiation of the non-operative management or organ-preservation strategy, or from radical surgery for participants in the radical surgery cohort, to death from any cause. Participants who are alive at the date of last follow-up will be censored at that date. Measure: Time to event. Events: Months.

Time frame: 3 years after initiation of the study treatment strategy

3-Year Local Regrowth Rate Determined by Imaging, Endoscopy, and Pathological Evaluation

Local regrowth is defined as the reappearance of viable tumor at or adjacent to the primary tumor site after an initial clinical complete response or near-complete response during the non-operative management or organ-preservation surveillance period. Local regrowth will be assessed by magnetic resonance imaging, computed tomography, endoscopy, biopsy, or other clinically indicated diagnostic procedures. Measure: Percentage of participants. Unit of Measure: Percentage.

Time frame: 3 years after initiation of the non-operative management or organ-preservation strategy

3-Year Salvage Radical Surgery Rate After Initial Non-Operative Management

The proportion of participants initially managed with non-operative management or an organ-preservation strategy who subsequently undergo radical surgery because of local regrowth, persistent residual disease, disease progression, inability to achieve or maintain clinical complete response, or other predefined criteria for treatment failure. Measure: Percentage of participants. Unit of Measure: Percentage.

Time frame: 3 years after initiation of the non-operative management or organ-preservation strategy

3-Year Permanent Stoma Rate

The proportion of participants who have a permanent intestinal stoma at 3 years after initiation of the non-operative management or organ-preservation strategy or radical surgery, as applicable. Measure: Percentage of participants. Unit of Measure: Percentage.

Time frame: 3 years after initiation of the study treatment strategy

Global Health Status/Quality of Life Score as Measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)

Global health status and quality of life will be assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). The Global Health Status/Quality of Life scale is transformed to a score ranging from 0 to 100. Higher scores indicate better global health status and quality of life. Measure: Score on a 0 to 100 scale. Unit of Measure: Score.