Ignite Creation Date:
2024-05-06 @ 4:33 PM
Last Modification Date:
2024-10-26 @ 2:12 PM
Study NCT ID:
NCT05020275
Status:
RECRUITING
Last Update Posted:
2024-04-16
First Post:
2021-07-13
Brief Title:
Resistance to the Tyrosine Kinase Inhibitor Osimertinib and Pharmacokinetics in Non-small Cell Lung Cancer
Sponsor:
Rennes University Hospital
Organization:
Rennes University Hospital
Study Overview
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
Status:
RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
RESISTYR
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 treatmentIn 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
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
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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None