Overview

This is a non-interventional translational research study aiming to comprehensively characterize the genomic and transcriptomic landscape of patients with non-small cell lung cancer (NSCLC). The study will employ whole-exome sequencing (WES) and RNA sequencing (RNA-seq) on tumor tissue samples and matched germline DNA to identify genomic alterations, mutational signatures, and transcriptomic profiles associated with prognosis and response to immunotherapy.

A total of approximately 300 patients with histologically confirmed NSCLC will be included, comprising both metastatic and early-stage disease. Formalin-fixed paraffin-embedded (FFPE) tumor tissue and, where available, fresh frozen samples will be analyzed. Peripheral blood samples will also be collected for germline DNA assessment. The study aims to identify clinically actionable genomic alterations, measure tumor mutational burden (TMB), characterize immune-related gene expression signatures, and investigate associations between molecular findings and clinical outcomes.

In addition, a pilot sub-study will evaluate circulating tumor DNA (ctDNA) dynamics in approximately 20 patients with unresectable stage III NSCLC treated with concurrent chemoradiation followed by durvalumab maintenance therapy. Longitudinal plasma samples will be collected at predefined timepoints to assess minimal residual disease (MRD), ctDNA kinetics, and correlations with clinical outcomes including progression-free survival (PFS) and overall survival (OS).

The results of this study are expected to improve understanding of tumor biology and immune landscape in NSCLC and support the identification of prognostic and predictive biomarkers for immunotherapy and other treatment strategies.

Eligibility

Main Study:

Diagnosis: Histologically confirmed Non-Small Cell Lung Cancer (NSCLC). Age: ≥18 years. Consent: Signed informed consent for participation in the study.

Patient Cohorts:

Metastatic NSCLC (Stage IV): 150 patients. Must have received immunotherapy from the date of study amendment. Early-stage NSCLC (Stage I-IIIB): 150 patients. Must have received immunotherapy from the date of study amendment. At least 50 patients must be resectable (Stages I, II, selected Stage III) and treated with adjuvant immunotherapy.

Biological Material:

Availability of FFPE tumor tissue collected ≤6 months before study entry. Availability of peripheral blood for germline DNA extraction. Molecular Analysis: Sufficient DNA and RNA for Whole Exome Sequencing (WES) and RNA sequencing (RNA-seq).

Sub - Study:

Participants must be enrolled in the main EXPLORE study. Diagnosis: Histologically confirmed, unresectable Stage III NSCLC. Treatment Plan: Scheduled to receive concurrent chemoradiation (cCRT) followed by Durvalumab maintenance as per standard of care.

Age: ≥18 years. Consent: Signed informed consent for ctDNA sub-study participation. Biospecimens: Willingness to provide longitudinal blood samples (baseline, during Durvalumab cycles, per protocol).