Resistance to the Tyrosine Kinase Inhibitor Osimertinib and Pharmacokinetics in Non-small Cell Lung Cancer

NCT05020275 | Active Not Recruiting

• 1 other identifier: 35RC20_8892_RESISTYR
• Study Type: observational
• Target: 60
• Locations: 1 country
• Sites: 4

Brief Summary

Osimertinib is a tyrosine kinase (TKI) inhibitor targeting EGF-R (epidermal growth factor receptor) and used in the management of patients with non-small cell lung cancer (NSCLC) with oncogenic drug addiction to EGF-R. The results of the FLAURA study justifies this 3rd generation TKI as the first line TKI of choice since an increase in overall survival of several months has been observed compared to TKIs of previous generations (erlotinib, gefitinib). However, the response to osimertinib is heterogeneous and some patients are poor responder. In addition, even when an initial response to ITK is observed, the natural history of the disease inevitably leads to the appearance of resistance mutations and loss of efficacy of osimertinib after a few months of treatment.In the hypothesis of a concentration-effect relationship, an underexposure (an insufficient plasma concentration) to osimertinib could lead to a suboptimal response by favoring the appearance of molecular resistance. By analogy with the mechanisms of resistance to anti-infectives, the systemic concentration of TKI may have to be maintained above a certain value throughout the treatment to reach an effective concentration in the tumor, in order to to prevent the selection of resistant clones. The value of this approach for optimizing treatment with TKI has been shown for this therapeutic class. This mechanistic hypothesis has been suggested several TKIs. In addition, the association between pharmacokinetics of TKIs and the development of resistance has been reported in several pilot studies for dasatinib, erlotinib. Furthermore, a link between TKI concentration and ctDNA concentration was demonstrated in a pilot study by Garlan et al. in 11 patients treated for melanoma with vemurafenib. The impact of the results of this study is important since the aims are to identify preemptive and predictive biomarkers of drug response and to increase mechanistic knowledge regarding risk factor of resistance to osimertinib. Finally, if the hypotheses evaluated in this translational research study are verified, therapeutic drug monitoring of TKI (and ctDNA analysis) would be immediately applicable in clinical practice since the technical tools are already available in the laboratories of most hospitals centers.

Conditions

Lung Cancer

Keywords

Non-small Cell Lung cancer; Osimertinib; Resistance; Pharmacokinetics

Outcome Measures

Primary Outcomes (1)

• relationship between plasma exposure to osimertinib and response to treatment assessed by progression-free survival

  patients who have not progressed during the first 18 months and those who have progressed during the first 18 months.

  at 18 months follow-up

Secondary Outcomes (35)

• Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)

  Days 15

• Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)

  Month 1

• Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)

  Month 2

• Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)

  Month 3

• Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)

  Month 6

Study Arms (1)

Blood samples

Blood samples for further assays

Diagnostic Test: Blood Samples

Interventions

Blood Samples DIAGNOSTIC_TEST

* Samples for ctDNA blood concentration and osimertinib plasma concentration * Sample for genetic polymorphisms

Blood samples

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patient naïve to any treatment for the metastatic stage, treated with osimertinib as first line treatment (Prior adjuvant or neoadjuvant treatment with chemotherapy, or radiotherapy, are authorized) with a Diagnosis of locally advanced non-small cell bronchial adenocarcinoma, and followed in one of the investigationnal centers.

You may qualify if:

• Age\> 18 years old
• Man or woman
• Diagnosis of locally advanced non-small cell bronchial adenocarcinoma (not eligible for locoregional treatment) or metastatic
• Tumor with an activating mutation of EGF-R (deletion of exon 19 or L858R, L861x, or G719x mutation)
• No one opposed to his participation in the research
• Dated and signed consent form
• Patient in good general condition according to WHO (PS: 0 or 1)

You may not qualify if:

• Previous treatment of NSCLC with an EGF-R tyrosine kinase inhibitor
• Adult persons subject to legal protection (safeguard of justice, curatorship, guardianship), persons deprived of their liberty.
• Treatment with Osimertinib on going
• Co-treatments with a potent enzyme inducing or inhibitor compound within 2 weeks before starting treatment with Osimertinib
• Participation in intervention research on a drug

Sponsors & Collaborators

• Rennes University Hospital: lead

Study Sites (4)

CH Bretagne Sud (Site du Scorff)

Lorient, 56322, France

Location

Chu de Rennes (Service Pneumologie)

Rennes, 35000, France

Location

CH Saint Malo (Service de Pneumologie)

St-Malo, 3500, France

Location

CH Bretagne Atlantique

Vannes, 56017, France

Location

Biospecimen

Retention: SAMPLES WITH DNA

Evaluate the influence of genetic polymorphisms on the plasma concentration of osimertinib (CYP3A4 and ABCB1)

MeSH Terms

Conditions

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Camille TRON, MD

  Rennes University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 13, 2021
• First Posted: August 25, 2021
• Study Start: December 29, 2021
• Primary Completion: March 16, 2026
• Study Completion (Estimated): March 16, 2027
• Last Updated: August 15, 2025

Record last verified: 2025-08

Locations

FR (4)