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
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.
• Male or female, aged at least 18 years.
• Informed consent signed prior to any study specific procedures, sampling, and analyses.
• Pathologically confirmed adenocarcinoma of the lung (e.g., this may occur as systemic recurrence after prior surgery for early stage disease or patients may be newly diagnosed with Stage lIIB/ IV disease). Patients with mixed histology are eligible if adenocarcinoma is the predominant histology.
• Locally advanced or metastatic NSCLC (Non-small-cell lung carcinoma), not amenable to curative surgery or radiotherapy.
• The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19 deletions, L858R), either alone or in combination with other EGFR mutations.
• Patients must be treatment-naive for advanced NSCLC and eligible to receive first-line treatment with osimertinib
• Subjects affiliated to an appropriate health insurance
• World Health Organization Performance Status of 0 to 1 with no clinically significant deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks.
• At least one lesion, not previously irradiated and not chosen for biopsy during the study screening period, that can be accurately measured at baseline as 10 mm in the longest diameter (except lymph nodes which must have a short axis of 15 mm) with computerized tomography (CT) or magnetic resonance imaging (MRI), and which is suitable for accurate repeated measurements.
⁃ Female patients should be using adequate contraceptive measures, should not be breast feeding, and must have a negative pregnancy test prior to first dose of study drug; or female patients must have an evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
∙ Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments.
‣ Women under 50 years old would be consider postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution.
‣ Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation.
⁃ Male patients should be willing to use barrier contraception, i.e., condoms