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

Relationship Between Resistance to the Tyrosine Kinase Inhibitor Osimertinib and Pharmacokinetics in Non-small Cell Lung Cancer: Toward an Individualization of the Treatment (RESISTYR)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Lung Cancer
• Intervention / Treatment: Diagnostic test: Blood Samples

Detailed Description

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.

The occurrence of resistances is a major problem since they lead to treatment failure. Identifying biomarkers predictive of the response and / or the emergence of these mutations of resistance is therefore a research challenge. Indeed, knowing risk factors molecular resistance could help to optimize the treatment.

A first approach to monitor the disease is the measurment of residual disease circulating tumor DNA in the blood of patients (ctDNA). These minimally invasive "liquid biopsies" can be performed iteratively, unlike tissue biopsies. It is a dynamic biomarker with several advantages. On the one hand, it would be a biomarker for monitoring residual disease during treatment. The ctDNA concentration and its kinetics under treatment have also been associated with the clinical outcome. Better overall survival has thus been observed with the first generation molecules in patients with low baseline ctDNA concentration or a rapid decrease in the ctDNA concentration at the start of treatment. On the other hand, the analysis of ctDNA makes it possible to characterize the nature of the acquired resistance mutations appearing during treatment.

In addition, TKI are good candidates for therapeutic drug monitoring (TDM). The objective of TDM is to assess exposure by measuring plasma concentration. TKIs are characterized by interindividual pharmacokinetic (PK) variability. Indeed, taking into account their route of administration (per os) and their metabolism (substrate for CYP450 enzymes), plasma exposure is variable from one patient to another. Thus, at the same dosage, depending on absorption and metabolic capacity, patients are not likely to be exposed to the same plasma concentrations. This PK variability is also observed for osimertinib since interindividual coefficients of variation of plasma exposure of 50 to 60% have been reported.

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.

In NSCLC, it therefore appears relevant and innovative to study the relationship between the plasma concentration of osimertinib and the efficacy of the treatment. In addition, it would be relevant to investigate the correlation between the plasma concentration of osimertinib and ctDNA in order to assess whether osimertinib plasma exposure could be a risk factor of emergence of resistance to anti-EGF treatment. These two minimally invasive biomarkers could be integrated into a dynamic monitoring of the treatment response in a personalized medicine approach.

Results expected, perspectives As this is an observational study, there is no need to add invasive procedure compared to the usual follow-up of patients with NSCLC , the benefit / risk balance is favorable for the participants.

The expected benefit is collective since if the interest of a therapeutic follow-up by pharmacological (and oncogenetic) approach is demonstrated, the clinicians will have at their disposal minimally invasive, longitudinal and follow-up biomarkers, allowing to prevent the emergence of resistance to osimertinib to maintain its effectiveness as longer as possible. It should allow to individualize the dosages for each patient, taking into account their pharmacokinetic profile and the molecular profile of the tumor. This personalized medicine in "2-dimensions" would help to delay tumor progression and would preserve a valuable line of treatment with TKI by optimizing its effectiveness.

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.

• Study Type: Observational
• Enrollment (Actual): 60

Contacts and Locations

Study Locations

• France
  • Lorient, France, 56322
    • CH Bretagne Sud (Site du Scorff)
  • Rennes, France, 35000
    • Chu de Rennes (Service Pneumologie)
  • Saint Malo, France, 3500
    • CH Saint Malo (Service de Pneumologie)
  • Vannes, France, 56017
    • CH Bretagne Atlantique

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• 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.

Description

Inclusion Criteria:

• 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)

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Blood samples; Blood samples for further assays	Diagnostic test: Blood Samples; Samples for ctDNA blood concentration and osimertinib plasma concentration; Sample for genetic polymorphisms

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)	ctDNA blood concentration and osimertinib plasma concentration	Days 15
Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)	ctDNA blood concentration and osimertinib plasma concentration	Month 1
Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)	ctDNA blood concentration and osimertinib plasma concentration	Month 2
Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)	ctDNA blood concentration and osimertinib plasma concentration	Month 3
Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)	ctDNA blood concentration and osimertinib plasma concentration	Month 6
Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)	ctDNA blood concentration and osimertinib plasma concentration	Month 9
Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)	ctDNA blood concentration and osimertinib plasma concentration	Month12
Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)	ctDNA blood concentration and osimertinib plasma concentration	Month 15
Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)	ctDNA blood concentration and osimertinib plasma concentration	Month18
Correlation between the trough plasma concentration of osimertinib and the time to onset of acquired molecular resistance mutations to osimertinib (identified on ctDNA)	Trough osimertinib plasma concentration and emergence of resistance mutation not present at baseline and / or re-appearance of the of EGF-R baseline mutation on ctDNA	Days 15
Correlation between the trough plasma concentration of osimertinib and the time to onset of acquired molecular resistance mutations to osimertinib (identified on ctDNA)	Trough osimertinib plasma concentration and emergence of resistance mutation not present at baseline and / or re-appearance of the of EGF-R baseline mutation on ctDNA	At desease progression
Correlation between the trough plasma concentration of osimertinib and the acquired clinical resistance	Acquired "clinical" resistance (expressed in months) defined as tumor progression (according to RECIST criteria) diagnosed after an initial response period in a patient treated without interruption of osimertinib	Days 15
Correlation between the trough plasma concentration of osimertinib and the acquired clinical resistance	Acquired "clinical" resistance (expressed in months) defined as tumor progression (according to RECIST criteria) diagnosed after an initial response period in a patient treated without interruption of osimertinib	At desease progression
Correlation between the concentration of ctDNA and acquired clinical resistance	Acquired "clinical" resistance (expressed in months) and evolution of the blood ctDNA concentration	Days 15
Correlation between the concentration of ctDNA and acquired clinical resistance	Acquired "clinical" resistance (expressed in months) and evolution of the blood ctDNA concentration	At desease progression
Study the concentration-toxicity correlation of osimertinib	Type and number of grade II to IV adverse events observed under treatment with osimertinib (according to CTCAE V5.0)	untill Month 18
Influence of genetic polymorphisms on the plasma concentration of osimertinib (CYP3A4 and ABCB1)	Concentrations of osimertinib in the groups of patients carrying an allelic variant modifying the activity of CYP3A4/5 and / or ABCB1 versus concentrations in the group of patients of wild-type genotype	Days 0
the inter-individual variability of osimertinib plasma concentration	Coefficient of variation of trough plasma concentrations of osimertinib between subjects	Days 15
the inter-individual variability of osimertinib plasma concentration	Coefficient of variation of trough plasma concentrations of osimertinib between subjects	Month 1
the inter-individual variability of osimertinib plasma concentration	Coefficient of variation of trough plasma concentrations of osimertinib between subjects	Month 2
the inter-individual variability of osimertinib plasma concentration	Coefficient of variation of trough plasma concentrations of osimertinib between subjects	Month 3
the inter-individual variability of osimertinib plasma concentration	Coefficient of variation of trough plasma concentrations of osimertinib between subjects	Month 6
the inter-individual variability of osimertinib plasma concentration	Coefficient of variation of trough plasma concentrations of osimertinib between subjects	Month 9
the inter-individual variability of osimertinib plasma concentration	Coefficient of variation of trough plasma concentrations of osimertinib between subjects	Month 12
the inter-individual variability of osimertinib plasma concentration	Coefficient of variation of trough plasma concentrations of osimertinib between subjects	Month 15
the inter-individual variability of osimertinib plasma concentration	Coefficient of variation of trough plasma concentrations of osimertinib between subjects	Month 18
the intra-individual variability of osimertinib plasma concentration	Coefficient of variation of trough plasma concentrations of osimertinib for the same subject during the follow-up period	Days 15
the intra-individual variability of osimertinib plasma concentration	Coefficient of variation of trough plasma concentrations of osimertinib for the same subject during the follow-up period	Month 1
the intra-individual variability of osimertinib plasma concentration	Coefficient of variation of trough plasma concentrations of osimertinib for the same subject during the follow-up period	Month 2
the intra-individual variability of osimertinib plasma concentration	Coefficient of variation of trough plasma concentrations of osimertinib for the same subject during the follow-up period	Month 3
the intra-individual variability of osimertinib plasma concentration	Coefficient of variation of trough plasma concentrations of osimertinib for the same subject during the follow-up period	Month 6
the intra-individual variability of osimertinib plasma concentration	Coefficient of variation of trough plasma concentrations of osimertinib for the same subject during the follow-up period	Month 9
the intra-individual variability of osimertinib plasma concentration	Coefficient of variation of trough plasma concentrations of osimertinib for the same subject during the follow-up period	Month 12
the intra-individual variability of osimertinib plasma concentration	Coefficient of variation of trough plasma concentrations of osimertinib for the same subject during the follow-up period	Month 15
the intra-individual variability of osimertinib plasma concentration	Coefficient of variation of trough plasma concentrations of osimertinib for the same subject during the follow-up period	Month 18

Collaborators and Investigators

• Sponsor: Rennes University Hospital
• Investigators: Principal Investigator: Camille TRON, MD, Rennes University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 29, 2021
• Primary Completion (Estimated): March 16, 2026
• Study Completion (Estimated): March 16, 2027

Study Registration Dates

• First Submitted: July 13, 2021
• First Submitted That Met QC Criteria: August 18, 2021
• First Posted (Actual): August 25, 2021

Study Record Updates

• Last Update Posted (Estimated): August 15, 2025
• Last Update Submitted That Met QC Criteria: August 14, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Osimertinib; Resistance; Non-small Cell Lung cancer
• 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: 35RC20_8892_RESISTYR

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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