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

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.

Sex

All

Minimum age

18 Years

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