Molecular Markers in Predicting Response to Treatment in FH-deficient RCC Patients

Study Overview
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Brief Summary
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Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare subtype of RCC characterized by germline/somatic mutation of the fumarate hydratase (FH) gene, and is an extremely aggressive tumor, with a propensity to disseminate early even in the setting of a small primary tumor. This project is a real-world exploratory study aiming to explore potential molecular markers detectable at baseline that can enable the prediction of clinical efficacy of systemic treatments in advanced FH-deficient RCC. This project is a real-world exploratory study aiming to explore potential molecular markers detectable at baseline that can enable the prediction of clinical efficacy of immunotherapy combined with target therapy in advanced FH-deficient RCC. This study aims to include a total of 100 patients initially diagnosed with advanced FH-deficient RCC. Paired tissue and blood samples collected from all patients before or/ and after the start of immunotherapy-based treatment (at diagnosis or/ and their change with treatment) will be analyzed. The patient samples will be submitted for molecular analysis, including next-generation sequencing (NGS)-based gene expression profiling (GEP), RNA-sequencing, multiplex immunofluorescence staining and inflammation-related T-cell receptor (TCR) repertoire profiling, ect. The molecular assay results will include but will not be limited to tumor mutation burden (TMB), microsatellite instability (MSI) status, DNA damage repair (DDR)-related gene mutation status, and programmed death-ligand 1 (PD-L1) expression level. Patients will be followed-up for treatment responses until radiological confirmation of disease progression to immunotherapy-based treatment. The molecular assay results will then be analyzed with clinical data including objective responses and progression-free survival outcomes, among others, to identify molecular markers at baseline that are associated with clinical efficacy of immunotherapy-based treatment.

Official Title
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Molecular Markers in Predicting Response to Treatment in FH-deficient RCC Patients

Conditions
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FH-Deficient RCC, Systemic Treatments, Biomarkers

Intervention / Treatment
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* Other: Laboratory analysis of samples


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years old; histopathological evidence of FH-deficient RCC, which was confirmed by Sanger or next-generation sequencing after initial screening by IHC. included patients must be diagnosed with metastatic renal cell carcinoma or have a TNM stage IV (according to 2009 TNM Classification); new FH-deficient RCC patients who has scheduled to start 1st cycle of systemic treatment; ECOG score ≤2; life expectancy ≥ 3 months; sign informed consent, and be able to follow the visit and related procedures stipulated in the program; agree to collect tumor tissue, blood and other specimens required by this study and apply them to relevant studies; Exclusion Criteria: patients with other malignant tumors with different primary sites or histology from the tumor evaluated in this study within 2 years of personal history. major surgery or severe trauma within 4 weeks before enrollment; known or suspected active autoimmune diseases (congenital or acquired), such as interstitial pneumonia, uveitis, enteritis, hepatitis, pituitary inflammation, vasculitis, nephritis, thyroiditis, etc. Patients with type 1 diabetes with good insulin control can also be enrolled. known allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation; allergic to any component of monoclonal antibody; suffering from other uncontrolled serious diseases, including but not limited to: A) severe infection in the active phase or clinically poorly controlled; B) HIV infection (HIV antibody positive); C) acute or chronic active hepatitis b (HBsAg positive and HBV DNA>1*103/ml) or acute or chronic active hepatitis c (HCV antibody positive and HCV RNA>15IU/ml); D) active tuberculosis, etc.; class iii-iv congestive heart failure (New York heart association classification), poorly controlled and clinically significant arrhythmia; uncontrolled arterial hypertension (systolic blood pressure ≥160mmHg or diastolic blood pressure ≥100mmHg); pregnant or lactating women.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with FH-deficient RCC<br>Laboratory analysis of samples | Other: Laboratory analysis of samples<br>* Laboratory analysis of samples<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systemic treatment OS | Systemic treatment OS was defined as the time from the start of systemic treatment to death from any cause, and patients without a recorded death were right censored to the date of last clinical visit or clinical record. | Through study completion, an average of 3 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| First-line PFS | First-line progression free survival (PFS) was defined as the time from the start of first-line systemic treatment to the time of radiographic progression, or death from any cause, whichever occurred first. | Through study completion, an average of 3 year | 
| ORR | Objective response rate (ORR) was defined as complete response (CR)+ partial response (PR) | Through study completion, an average of 3 year | 
| DCR | disease control rate (DCR) was defined as partial response (PR)+complete response (CR)+stable disease (SD) | Through study completion, an average of 3 year |