Understanding and Overcoming the Early Adaptive Resistance to EGFR Tyrosine-kinase Inhibitors in Lung Cancer Patients (LUNG-RESIST)

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) are effective therapies for advanced lung cancer patients bearing EGFR-activating mutations, but are not curative due to the invariable apparition of resistances. The investigator team have identified a new phenotype related to drug tolerance after EGFR-TKI treatment that shares several characteristics of a known process of Therapy-Induced Senescence (TIS), which could be a major event of drug tolerance in patients. Using cutting-edge technologies, patient-derived xenografts (PDX) and circulating tumor cells (CTC), the investigator team will perform an exhaustive characterization of the phenotypic and molecular changes associated with this drug-tolerant state in patients. Their results should lead to new therapeutic approaches to eliminate the reservoir of drug-tolerant cells and to prevent emergence of resistance mutations responsible for the relapse of patients.

Study Overview

• Status: Recruiting
• Conditions: Lung Cancer, Nonsmall Cell
• Intervention / Treatment: Other: Blood samples

Detailed Description

LUNG-RESIST is a translational, monocentric and prospective research study on 40 patients whose objective is to characterize Drug Tolerant Cell (DTC) type cells in patients with a NSCLC carrying an EGFR mutation and to discover and monitor potentials biomarkers involved in this mechanism of resistance to osimertinib. The study will be offered to patients, and for whom the therapeutic decision was decided collegially during multidisciplinary molecular meetings (molecular Tumor Board). Following informed consent, patients will be registered in a single cohort. In this study, treatment with osimertinib is not studied and will be delivered according to current recommendations

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Julien MAZIERES, MD; PHD; Phone Number: +33 5 67 77 18 37; Email: mazieres.j@chu-toulouse.fr

Study Locations

• France
  • Occitanie
    • Toulouse, Occitanie, France, 31300
      • Recruiting
      • Toulouse University Hospital
      • Contact: Sandra BERNARD; Phone Number: +33 5 61 77 85 73; Email: bernard.s@chu-toulouse.fr
      • Principal Investigator: Julien MAZIERES, MD; PHD
      • Sub-Investigator: Laurence BIGAY-GAME, MD; PHD
      • Sub-Investigator: Christophe HERMANT, MD; PHD
      • Sub-Investigator: Gavin PLAT, MD; PHD
      • Sub-Investigator: Audrey RABEAU, MD; PHD
      • Sub-Investigator: Nicolas GUIBERT, MD; PHD
      • Sub-Investigator: Myriam DELAUNAY, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patient with non operable and / or metastatic non-small cell lung cancer documented histologically.
• Pathological diagnosis of NSCLC carrying an EGFR activating mutation associated with sensitivity to the tyrosine kinase inhibitors (TKI) (exons 18, 19 and 21).
• Sufficient tissue sample quantity and quality for translational research
• Naïve TKI-treated EGFR patient who can receive first-line treatment with Osimertinib or second-line after chemotherapy

Exclusion Criteria:

• Any patient with an exon 20 EGFR mutation.
• Any disease or pathology that recommend not to perform blood samples collection
• Any psychological, family, geographical or social condition that could potentially, according to the investigator's judgment, prevent the collection of informed consent or interfere with compliance with the study protocol
• Patient with a resistance mutation of EGFR
• Patient under State Medical Assistance
• Patient deprived of liberty on administrative or judicial decision, or patient under guardianship, curatorship or safeguard of justice

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Blood sampling

Other: Blood samples; Each participant will be followed-up regularly as part of the usual practice for imaging and medical consultations. During their visits, from inclusion (T0) to the end of study participation (T progression), each patient will have a blood sampling specifically for the research to analyze tumor DNA and circulating tumor cells: T0, T1month, T3 months, Tn months, T DNA C+, T progression. This research does not include any other act or intervention specifically required for its purposes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of EGFR mutated patients for whom phenotypic characterization of DTC-like and osimertinib-tolerant tumor cells is feasible.	Rate of EGFR mutated patients for whom the DTC phenotype has been characterized at T0 (Baseline), T1 month, T3 month, Tn month, T antideoxyribonuclease (ADN) Circulant+, T progression	Up to one year or progression

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of patients for whom the molecular characterization of DTC-like cells is successfully performed.	This rate id defined by the number of patients who are successful compared to the total number of patients. Failure is defined by a patient with circulating tumor cells for which molecular characterization of DTC-like cells could not be performed at all measurement times.	Up to one year or progression
Progression-free survival (PFS)	PFS is defined as the delay between the date of the patient's inclusion and the date of progression or death. Patients alive and without progression will be censored on the date of last news or on the date of initiation of a new anti-cancer therapy (if applicable).	Up to one year or progression or death

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse
• Collaborators: Institut National de la Santé Et de la Recherche Médicale, France; National Cancer Institute, France
• Investigators: Principal Investigator: Julien MAZIERES, MD; PHD, Toulouse University Hospitals

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2021
• Primary Completion (Anticipated): December 1, 2025
• Study Completion (Anticipated): December 1, 2025

Study Registration Dates

• First Submitted: December 17, 2019
• First Submitted That Met QC Criteria: January 7, 2020
• First Posted (Actual): January 9, 2020

Study Record Updates

• Last Update Posted (Actual): May 12, 2023
• Last Update Submitted That Met QC Criteria: May 11, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Lung cancer; Targeted therapy; resistance
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: RC31/18/0475; Numéro ID RCB : 2019-A02440-57 (Other Identifier: ANSM)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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