Clinical trial NCT05020275: Resistance to the Tyrosine Kinase Inhibitor Osimertinib and Pharmacokinetics in Non-small Cell Lung Cancer
Official title: Relationship Between Resistance to the Tyrosine Kinase Inhibitor Osimertinib and Pharmacokinetics in Non-small Cell Lung Cancer: Toward an Individualization of the Treatment (RESISTYR)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Lung Cancer
Keywords: Non-small Cell Lung cancer
Osimertinib
Resistance
Pharmacokinetics
Lead sponsor: Rennes University Hospital
Sponsor class: OTHER
First posted: 2021-08-25
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
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.

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: relationship between plasma exposure to osimertinib and response to treatment assessed by progression-free survival
timeFrame: at 18 months follow-up
Secondary outcomes:
measure: Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)
timeFrame: Days 15
measure: Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)
timeFrame: Month 1
measure: Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)
timeFrame: Month 2
measure: Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)
timeFrame: Month 3
measure: Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)
timeFrame: Month 6
measure: Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)
timeFrame: Month 9
measure: Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)
timeFrame: Month12
measure: Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)
timeFrame: Month 15
measure: Longitudinal correlation between the plasma concentration of osimertinib and the concentration of ctDNA (liquid biopsy)
timeFrame: Month18
measure: Correlation between the trough plasma concentration of osimertinib and the time to onset of acquired molecular resistance mutations to osimertinib (identified on ctDNA)
timeFrame: Days 15
measure: Correlation between the trough plasma concentration of osimertinib and the time to onset of acquired molecular resistance mutations to osimertinib (identified on ctDNA)
timeFrame: At desease progression
measure: Correlation between the trough plasma concentration of osimertinib and the acquired clinical resistance
timeFrame: Days 15
measure: Correlation between the trough plasma concentration of osimertinib and the acquired clinical resistance
timeFrame: At desease progression
measure: Correlation between the concentration of ctDNA and acquired clinical resistance
timeFrame: Days 15
measure: Correlation between the concentration of ctDNA and acquired clinical resistance
timeFrame: At desease progression
measure: Study the concentration-toxicity correlation of osimertinib
timeFrame: untill Month 18
measure: Influence of genetic polymorphisms on the plasma concentration of osimertinib (CYP3A4 and ABCB1)
timeFrame: Days 0
measure: the inter-individual variability of osimertinib plasma concentration
timeFrame: Days 15
measure: the inter-individual variability of osimertinib plasma concentration
timeFrame: Month 1
measure: the inter-individual variability of osimertinib plasma concentration
timeFrame: Month 2
measure: the inter-individual variability of osimertinib plasma concentration
timeFrame: Month 3
measure: the inter-individual variability of osimertinib plasma concentration
timeFrame: Month 6
measure: the inter-individual variability of osimertinib plasma concentration
timeFrame: Month 9
measure: the inter-individual variability of osimertinib plasma concentration
timeFrame: Month 12
measure: the inter-individual variability of osimertinib plasma concentration
timeFrame: Month 15
measure: the inter-individual variability of osimertinib plasma concentration
timeFrame: Month 18
measure: the intra-individual variability of osimertinib plasma concentration
timeFrame: Days 15
measure: the intra-individual variability of osimertinib plasma concentration
timeFrame: Month 1
measure: the intra-individual variability of osimertinib plasma concentration
timeFrame: Month 2
measure: the intra-individual variability of osimertinib plasma concentration
timeFrame: Month 3
measure: the intra-individual variability of osimertinib plasma concentration
timeFrame: Month 6
measure: the intra-individual variability of osimertinib plasma concentration
timeFrame: Month 9
measure: the intra-individual variability of osimertinib plasma concentration
timeFrame: Month 12
measure: the intra-individual variability of osimertinib plasma concentration
timeFrame: Month 15
measure: the intra-individual variability of osimertinib plasma concentration
timeFrame: Month 18
Other outcomes:
Locations:
city: Lorient
country: France
facility: CH Bretagne Sud (Site du Scorff)
city: Rennes
country: France
facility: Chu de Rennes (Service Pneumologie)
city: Saint Malo
country: France
facility: CH Saint Malo (Service de Pneumologie)
city: Vannes
country: France
facility: CH Bretagne Atlantique
Study officials:
affiliation: Rennes University Hospital
name: Camille TRON, MD
role: PRINCIPAL_INVESTIGATOR
References: