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 (INNOVA-LUNG)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Advanced Non-small Cell Lung Cancer (NSCLC)
• Intervention / Treatment: Diagnostic test: Plasma-based liquid biopsy

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.

• Study Type: Observational
• Enrollment (Estimated): 70

Contacts and Locations

• Study Contact: Name: Maristella Giammaruco, MD; Phone Number: +39 06 5266 5698; Email: maristella.giammaruco@ifo.it
• Study Contact Backup: Name: Simonetta Buglioni, Biology

Study Locations

• Italy
  • RM
    • Roma, RM, Italy, 00144
      • Recruiting
      • IFO-IRE, Istituto Nazionale Tumori Regina Elena
      • Principal Investigator: Federico Cappuzzo, MD
      • Contact: Maristella Giammaruco, MD; Phone Number: +39 06 5266 5698; Email: maristella.giammaruco@ifo.it
      • Contact: Simonetta Buglioni, Biology; Phone Number: +39 06 5266 2923; Email: simonetta.buglioni@ifo.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study population includes adult patients with radiological suspicion of locally advanced lung cancer not suitable for locoregional treatment or metastatic lung cancer. Participants are enrolled before completion of the standard diagnostic pathway, when tissue biopsy or cytological sampling is planned but not yet performed, or has already been performed without an available histopathological diagnosis of NSCLC. Eligible patients are recruited at participating centers during thoracic surgery assessment or the first oncology visit and undergo plasma-based liquid biopsy while continuing the standard diagnostic pathway.

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Prospective Plasma-First NSCLC Cohort; Adult patients with radiological suspicion of locally advanced non-small cell lung cancer (NSCLC) not suitable for locoregional treatment, or metastatic NSCLC, will be enrolled before completion of the standard diagnostic pathway. Participants 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) to evaluate molecular alterations, turnaround time, concordance with tissue-based profiling, and tumor fraction. All participants will continue the standard diagnostic pathway of the enrolling center, including tissue biopsy or cytological sampling, histopathological diagnosis, PD-L1 assessment, and tissue-based molecular testing. No investigational treatment is assigned, and study procedures will not independently determine treatment decisions.

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 the standard diagnostic pathway of the enrolling center, including tissue biopsy or cytological sampling, histopathological diagnosis, PD-L1 assessment, and standard tissue-based molecular testing. The study procedure will not independently determine treatment decisions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of establishing a structured plasma-first molecular profiling dataset	Proportion of enrolled participants with a complete structured dataset including liquid biopsy results, tissue-based diagnostic and molecular profiling results, and relevant clinical data required for the feasibility assessment of the plasma-first approach.	Up to 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Turnaround time for plasma-based molecular profiling	Time in days from peripheral blood collection to availability of the liquid biopsy molecular profiling report.	Up to 7 days from blood collection
Proportion of participants with informative liquid biopsy results	Proportion of enrolled participants in whom plasma-based molecular profiling identifies at least one clinically actionable genomic alteration with established evidence supporting targeted therapy.	Up to 30 days from enrollment
Concordance between plasma-based and tissue-based molecular profiling	Proportion of participants with concordant molecular profiling results between plasma-derived circulating nucleic acids and matched tissue or cytological samples.	Up to 30 days from enrollment
Tumor fraction in plasma samples	Distribution of estimated tumor fraction values in plasma samples and proportion of samples with sufficient circulating tumor DNA concentration for molecular analysis.	Up to 30 days from blood collection
Analytical performance of two NGS-based plasma profiling approaches	Comparison of the ability of amplicon-based and hybrid-capture next-generation sequencing approaches to detect genomic alterations, including low variant allele frequency alterations and gene fusions, in plasma-derived circulating nucleic acids.	Up to 18 months

Collaborators and Investigators

• Sponsor: Regina Elena Cancer Institute
• Investigators: Principal Investigator: Federico Cappuzzo, MD, IFO-IRE, Istituto Nazionale Tumori Regina Elena

Publications and helpful links

General Publications

• 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 of Lung Cancer. J Thorac Oncol. 2021 Oct;16(10):1647-1662. doi: 10.1016/j.jtho.2021.06.017. Epub 2021 Jul 8.
• 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.
• 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.
• 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: 10.1177/17588359221126151. eCollection 2022.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2025
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: June 4, 2026
• First Submitted That Met QC Criteria: June 10, 2026
• First Posted (Actual): June 16, 2026

Study Record Updates

• Last Update Posted (Actual): June 16, 2026
• Last Update Submitted That Met QC Criteria: June 10, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Lung Cancer; NSCLC; Non-small cell lung cancer; Targeted therapy; Biomarkers; Liquid biopsy; ctDNA; NGS; Molecular profiling; Plasma-first approach; ctRNA; Tumor fraction; Actionable genomic alterations
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: RS348/2025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be made publicly available. Study data will be pseudonymized and managed in accordance with applicable data protection requirements. Any data sharing among participating centers will be limited to the purposes of the study and regulated through appropriate data transfer agreements. Study results may be disseminated in aggregated form. Any future reuse or sharing of individual-level data for compatible research purposes would require specific institutional approval and compliance with applicable ethical, legal, and data protection requirements.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No