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Carcinoma, Non-Small-Cell Lung

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Osimertinib

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Tyrosine

Oral administration of TAGRISSO® 80mg (Osimertinib) as a single daily dose until disease progression or unacceptable toxicity.

Tumor biopsies performed at baseline and clinical progression. ctDNA analysis by Collection of plasma (two 10-ml Streck tubes) at each time point indicated in the trial.

Oral administration of TAGRISSO® 80mg (Osimertinib) as a single daily dose until disease progression or unacceptable toxicity.

TAGRISSO® 80mg (Osimertinib)

Tumor biopsies performed at baseline and clinical progression will be processed (fixed) on site, and sent to Nantes University Hospital for analysis.

The following analysis will be performed:

1. Analyses performed on a regular basis, in order to allow subsequent inclusion in other clinical trials :

   * C797S testing (digital PCR)
   * MET amplification (dPCR/FISH)
   * Histological examination of the tissue sample (to identify small cell transformation)
   * Expression of proteins by immunohistochemistry: PD-L1 (Ventana SP263 antibody); CD73 ; CD4; CD8.
2. At the end of inclusions, deep sequencing analysis to identify acquired mutations and copy number variations (amplifications).

Tumor biopsies

ctDNA analysis by Collection of plasma (two 10-ml Streck tubes) at each time point indicated in the trial.

These samples will be sent at room temperature by courier to the central laboratory (Nantes University Hospital). There they will be centrifuged, and plasma will be frozen (-80°C).

Analyses :

* Detection of the EGFR activating mutation in plasma at baseline By dPCR (characterization of patients enrolled)
* Detection of the EGFR activating mutation at d7 and m1 by dPCR (early detection of response to osimertinib)
* Analysis of the plasma samples collected at clinical progression in order to identify acquired mechanisms of resistance by NGS (and comparison with analysis of the biopsies).
* Kinetics studies of the alterations

ctDNA analysis

Jaafar BENNOUNA, MD,PhD

Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer.

The AURA 3 study (T790M-positive advanced non-small-cell lung cancer in progression after first-line EGFR-TKI therapy, shown that the median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months p\<0.001).

In addition, clinical data show that patients with mutated EGFR NSCLC receiving osimertinib in first line, presented an objective response rate of 77 % with a disease control rate of 98 % and a median PFS was 19.3 months.

Finally, The FLAURA study randomized phase 3 study clearly demonstrated the superiority of osimertinib compared with erlotinib or gefitinib in EGFR mutated nonpretreated NSCLC (median PFS of 18.9 months versus 10.2 months).

However, several issues remain unknown or debated :

* What are the mechanisms of resistance to osimertinib prescribed in first-line?
* What are the consequences of prolonged exposure to osimertinib on the expression of markers of response to immunotherapy?
* Is there an association between kinetic parameters of ctDNA (circulating tumor DNA) and prediction of response to osimertinib and/ or and prediction of therapeutic escape under osimertinib? In order to respond to all these questions, this phase II trial will be the first to systemically analyze the mechanisms of resistance to Osimertinib based on the analysis of biopsy, and collection of plasma from all patients during the course of treatment.

MEchanisms of Resistance in EGFR Mutated Nonpretreated Advanced Lung Cancer Receiving OSimErtib

MELROSE: Phase 2 Study Evaluating MEchanisms of Resistance on Tumor Tissue and Liquid Biopsy in Patients With EGFR Mutated Nonpretreated Advanced Lung Cancer Receiving OSimErtinib Until and Beyond Radiological Progression : the MELROSE Trial

Analyze of the proportion of patients with a given genetic marker on tumor biopsy (including, but not limited to, EGFR mutations, HER2 (Human Epidermal Growth factor receptor 2), and cMET expression and/or amplification) at the point of clinical disease progression.

Progression free survival rate at one year defined by time from first study dose to first event between Radiological Progression Disease and death, or one year if no event. The rPFS is defined according to RECIST 1.1.

Radiological Progression Free Survival (rPFS): Time from first study dose to first event between rPFS or death. The rPFS is defined according to RECIST 1.1.

Clinical Progression Free Survival (cPFS): Time from first study dose to off-osimertinib.

Duration of Response (DoR): Disease Control Rate (DCR)

Monitoring of Adverse events (grade 3 and 4)

By the study of the expression of molecules involved in the efficacy of check point inhibitors determined by immunohistochemistry (PD-L1; CD73; CD4; CD8) on tumor tissue collected at progression

Analyze of mutation at progression on tumor tissue and ctDNA

Analyze of the presence of tumors ctDNA at baseline, clinical progression disease

Analyze of absolute quantities of ctDNA molecules presenting the EGFR mutation identified in the tumor, clinical progression disease

Serial monitoring in ctDNA of molecular alterations identified in tissues collected at progression

Analyze of the EGFR mutation identified in the tumor biopsy and in the ctDNA

Analyze of the absolute quantities of ctDNA molecules presenting the EGFR mutation monthly, radiological and clinical progression disease

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
MEchanisms of Resistance in EGFR Mutated Nonpretreated Advanced Lung Cancer Receiving OSimErtib	NCT03865511	Non-small Cell ...	TAGRISSO® 80mg ... Tumor biopsies ctDNA analysis	18 Years -	Nantes University Hospital
MEchanisms of Resistance in EGFR Mutated Nonpretreated Advanced Lung Cancer Receiving OSimErtib	NCT03865511	Non-small Cell ...	TAGRISSO® 80mg ... Tumor biopsies ctDNA analysis	18 Years -	Nantes University Hospital

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