Impact of Liquid Biopsy on the Therapeutic Pathway for Lung Cancer: Advancing the Molecular Characterization of Patients With Advanced Lung Adenocarcinoma by Integrating Liquid Biopsy Into the Early Stages of the Diagnostic and Therapeutic Pathway

Official title

Impatto Della Biopsia Liquida Sul Percorso Terapeutico Del Tumore al Polmone: Anticipare la Caratterizzazione Molecolare Dei Pazienti Con Adenocarcinoma Del Polmone in Stadio Avanzato Integrando la Biopsia Liquida Nella Fase Iniziale Del Percorso Diagnostico-terapeutico

Overview

This multicenter pilot observational study aims to assess the feasibility of introducing liquid biopsy at an early stage of the diagnostic pathway for patients with suspected advanced non-small cell lung cancer (NSCLC). Liquid biopsy is a minimally invasive blood test that can detect tumor-related genetic alterations in circulating nucleic acids. The study will evaluate whether this approach can provide molecular information more rapidly than standard tissue-based testing and how closely the results obtained from blood samples match those obtained from tumor tissue. Approximately 70 adult patients with radiological evidence of locally advanced or metastatic lung cancer will be enrolled. Participants will undergo a blood draw for liquid biopsy and will continue to follow the standard diagnostic pathway, including tissue biopsy or cytological sampling when indicated. The results generated within the study are intended for research purposes and will not replace standard diagnostic procedures or independently determine treatment decisions. The findings will be used to identify practical and methodological issues and to support the design of future clinical studies on the plasma-first approach.

Detailed description

Molecular characterization is an essential step in the management of advanced non-small cell lung cancer (NSCLC), as the identification of actionable genomic alterations may guide the selection of targeted therapies. However, tissue-based molecular testing may be delayed or limited by insufficient or poor-quality biological material.

Liquid biopsy allows the analysis of circulating tumor-derived nucleic acids from a peripheral blood sample and may provide molecular information earlier in the diagnostic pathway. The plasma-first approach consists of performing liquid biopsy at an early stage, while the patient continues the standard diagnostic process.

This is a multicenter, prospective, non-pharmacological pilot observational study involving adult patients with radiological suspicion of locally advanced NSCLC not suitable for locoregional treatment or metastatic NSCLC. Eligible patients must have a tissue biopsy or cytological sampling planned but not yet performed, or already performed without an available histopathological diagnosis of NSCLC at the time of enrollment.

Each participant will undergo a peripheral blood draw for liquid biopsy within one week of the first clinical assessment. Plasma-derived circulating nucleic acids will be analyzed using next-generation sequencing (NGS). Participants will then continue the standard diagnostic pathway of the enrolling center, including tissue biopsy or cytological sampling, histopathological diagnosis, PD-L1 assessment, and standard tissue-based molecular profiling.

The study will assess the feasibility of the plasma-first approach and will generate a structured dataset to support the design of future prospective studies. Secondary objectives include evaluating:

* the turnaround time of plasma-based and tissue-based molecular testing; * the proportion of informative liquid biopsy results; * the concordance between molecular alterations detected in plasma and tissue samples; * the performance of different NGS-based approaches for the detection of genomic alterations; * the tumor fraction in plasma samples and its relationship with molecular and clinical variables; * the potential organizational and economic implications of integrating liquid biopsy into the diagnostic pathway.

For participants enrolled at the coordinating center, additional exploratory analyses will be performed to estimate tumor fraction and compare two NGS-based analytical approaches.

The results of the liquid biopsy performed within this pilot study are collected for research purposes. They will not replace standard diagnostic procedures and will not independently determine the initiation of treatment. Treatment decisions will remain based on the standard diagnostic and clinical assessment performed according to current clinical practice.

The study plans to enroll approximately 70 participants over a 6-month recruitment period, with an observation period of 12 months and an overall estimated study duration of 18 months.

Interventions

• Diagnostic test Plasma-based liquid biopsy
  Participants will undergo a peripheral blood draw for plasma-based liquid biopsy within one week of the first clinical assessment. Circulating cell-free nucleic acids extracted from plasma will be analyzed using next-generation sequencing (NGS) to identify molecular alterations and evaluate turnaround time, concordance with tissue-based molecular profiling, and tumor fraction. The liquid biopsy is performed for research purposes within this pilot observational study. Participants will continue

Primary outcome measures

• Feasibility of establishing a structured plasma-first molecular profiling dataset [Time frame: Up to 18 months]

Secondary outcome measures (5)

• Turnaround time for plasma-based molecular profiling [Time frame: Up to 7 days from blood collection]
• Proportion of participants with informative liquid biopsy results [Time frame: Up to 30 days from enrollment]
• Concordance between plasma-based and tissue-based molecular profiling [Time frame: Up to 30 days from enrollment]
• Tumor fraction in plasma samples [Time frame: Up to 30 days from blood collection]
• Analytical performance of two NGS-based plasma profiling approaches [Time frame: Up to 18 months]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years.
• Radiological suspicion of locally advanced lung cancer not amenable to locoregional treatment or metastatic lung cancer (stage III-IV).
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
• Tissue biopsy and/or cytological sampling planned but not yet performed, or already performed without an available histopathological diagnosis of non-small cell lung cancer (NSCLC).
• Written informed consent for study participation and personal data processing obtained before any study-specific procedure.

Exclusion criteria

• Previous or current history of non-small cell lung cancer (NSCLC).
• Histopathological diagnosis of NSCLC already available following tissue biopsy.
• Eligibility for surgical removal of tumor tissue.
• Ongoing or previous systemic oncological treatment for lung cancer.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Italy · 1 center

• IFO-IRE, Istituto Nazionale Tumori Regina Elena — Roma

Publications

• Low SK, Ariyasu R, Uchibori K, Hayashi R, Chan HT, Chin YM, Akita T, Harutani Y, Kiritani A, Tsugitomi R, Manabe R, Ogusu S, Amino Y, Kitazono S, Yanagitani N, Nakamura Y, Nishio M. Rapid genomic profiling of circulating tumor DNA in non-small cell lung cancer using Oncomine Precision Assay with Genexus integrated sequencer. Transl Lung Cancer Res. 2022 May;11(5):711-721. doi: 10.21037/tlcr-21-981 PMID 35693289
• Husain H, Pavlick DC, Fendler BJ, Madison RW, Decker B, Gjoerup O, Parachoniak CA, McLaughlin-Drubin M, Erlich RL, Schrock AB, Frampton GM, Das Thakur M, Oxnard GR, Tukachinsky H. Tumor Fraction Correlates With Detection of Actionable Variants Across > 23,000 Circulating Tumor DNA Samples. JCO Precis Oncol. 2022 Oct;6:e2200261. doi: 10.1200/PO.22.00261. PMID 36265119
• Rolfo C, Mack P, Scagliotti GV, Aggarwal C, Arcila ME, Barlesi F, Bivona T, Diehn M, Dive C, Dziadziuszko R, Leighl N, Malapelle U, Mok T, Peled N, Raez LE, Sequist L, Sholl L, Swanton C, Abbosh C, Tan D, Wakelee H, Wistuba I, Bunn R, Freeman-Daily J, Wynes M, Belani C, Mitsudomi T, Gandara D. Liquid Biopsy for Advanced NSCLC: A Consensus Statement From the International Association for the Study PMID 34246791
• Garcia-Pardo M, Czarnecka K, Law JH, Salvarrey A, Fernandes R, Fan J, Corke L, Waddell TK, Yasufuku K, Donahoe LL, Pierre A, Le LW, Ghumman N, Liu G, Shepherd FA, Bradbury P, Sacher A, Stockley T, Pal P, Rogalla P, Tsao MS, Leighl NB. Plasma-first: accelerating lung cancer diagnosis and molecular profiling through liquid biopsy. Ther Adv Med Oncol. 2022 Sep 20;14:17588359221126151. doi: 10.1177/17 PMID 36158638

Identifiers

NCT: NCT07649629 · RS348/2025

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗