Molecular Profiling and Dynamic Changes of ctDNA in Unresectable Locally Advanced NSCLC

Study Overview
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Brief Summary
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Multi-center observational clinical study to evaluate the application value of ctDNA monitoring in efficacy assessment and relapse prediction in patients diagnosed with unresectable, locally advanced NSCLC receiving CRT with or without durvalumab maintenance treatment.

Detailed Description
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Newly diagnosed, histologically confirmed, unresectable stage III NSCLC patients, amenable to receive standard of care chemoradiotherapy with or without durvalumab maintenance, will be enrolled in this study. Whole blood collection will be conducted during the treatment for ctDNA detection in specific time-points of interest. Next-generation sequencing using commercially available panels, and analysis of ctDNA aberrant methylation will be performed. Results will be correlated to patients' recurrence times and survival outcomes.

Official Title
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Molecular Profiling and Dynamic Changes of Circulating Tumor DNA in Unresectable Locally Advanced Non-small Cell Lung Cancer

Conditions
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Lung Cancer, Stage III Lung Cancer, Unresectable Lung Carcinoma

Intervention / Treatment
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* Procedure: Sample collection
* Diagnostic Test: Characterization of the tumoral tissue genomic alterations
* Drug: Chemoradiation treatment regimen and maintenance (if amenable)
* Diagnostic Test: Genomic and methylation analysis in liquid biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with newly diagnosed, histologically confirmed, unresectable locally advanced NSCLC. ≥18 years of age. Ability to understand the written informed consent and willingness to sign it. Exclusion Criteria: Patients who are unwilling to follow-up evaluation of response to therapy. Any condition that, in the opinion of the investigator, would interfere with study results.

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

| Intervention/Treatment |
| --- |
|Procedure: Sample collection|Tumor samples will be collected as standard diagnostic procedure at diagnosis. Plasma samples from whole blood extractions will also be collected at diagnosis, after chemoradiotherapy, and every 3 months from there until completing one year of follow-up.|
|Diagnostic Test: Characterization of the tumoral tissue genomic alterations|Genomic alterations of tumor tissue samples will be analyzed locally by next-generation sequencing when material is adequate, as standard diagnostic procedure.|
|Drug: Chemoradiation treatment regimen and maintenance (if amenable)|Patients will be treated with standard chemotherapy (following the clinical practice at each institution). Radiotherapy will be delivered concurrently when feasible with a total dose of 60-66 Gy. In selected cases, due to frailty of the patient or impaired pulmonary function, radiotherapy will be delivered sequentially. In tumors with positive PD-L1 expression, a year of durvalumab 10 mg/m2 every 2 weeks will be administered if there are no contraindications.|
|Diagnostic Test: Genomic and methylation analysis in liquid biopsy|Blood samples for ctDNA genomic and methylation analysis (4 mL of plasma for each sample) will be sent to the Guardant Health Laboratories in the US and analyzed after Contractual Agreement signature, using the Guardant Reveal test. This liquid biopsy test uses ctDNA to detect presence of MRD and monitor for recurrence after definitive surgical/systemic therapy for patients with cancer. It has been validated in early-stage colorectal cancer and integrates assessment of somatic alterations with an epigenomic cancer signature to identify the presence of methylation signatures associated with cancer versus normal DNA.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantitative variation of aberrant methylated ctDNA concentrations before chemoradiotherapy, after chemoradiotherapy, and every 3 months during 1 year of follow-up. |  | 16 months | 
| Correlation between patients' recurrence or progression, and quantitative detection of circulating tumour DNA (ctDNA) concentration. |  | 2 years | 
| Concordance of ctDNA genomic alterations detected in peripheral blood samples, with those in matched tumour samples. |  | At diagnosis | 
| Correlation between survival outcomes (progression free survival, overall survival) and quantitative detection of ctDNA genomic alterations or methylation status. |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liquid biopsy, ctDNA, Chemoradiotherapy