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

  • STATUS
    Recruiting
  • End date
    Jul 23, 2024
  • participants needed
    66
  • sponsor
    Nantes University Hospital
Updated on 23 January 2021
tyrosine
carcinoma
growth factor
kinase inhibitor
lung adenocarcinoma
pemetrexed
erlotinib
epidermal growth factor receptor
EGFR
follicle stimulating hormone
epidermal growth factor
gefitinib
advanced lung cancer
stage iv non-small cell lung cancer
osimertinib
lung carcinoma
egfr t790m

Summary

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.

Details
Condition Non-Small Cell Lung Cancer, nsclc
Treatment Tumor biopsies, ctDNA analysis, TAGRISSO® 80mg (Osimertinib)
Clinical Study IdentifierNCT03865511
SponsorNantes University Hospital
Last Modified on23 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Male or female, aged at least 18 years
Informed consent signed prior to any study specic procedures, sampling, and analyses
Pathologically conrmed 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 rst-line treatment with osimertinib
Subjects affiliated to an appropriate health insurance
World Health Organization Performance Status of 0 to 1 with no clinically signicant 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 rst dose of study drug; or female patients must have an evidence of non-child-bearing potential by fullling one of the following criteria at screening
Post-menopausal dened 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

Exclusion Criteria

Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site)
Previous enrolment in the present study
Treatment with any of the following
Prior treatment with any systemic anti-cancer therapy for advanced NSCLC including standard chemotherapy, biologic therapy, immunotherapy, or any investigational drug
Prior treatment with an EGFR-TKI. including osimertinib
Major surgery (excluding placement of vascular access) within 4 weeks of the rst dose of study drug
Radiotherapy treatment to more than 30% of the bone marrow or with a wide eld of radiation within 4 weeks of the rst dose of study drug
Treatment with an investigational drug within ve half-lives of the compound or any of its related material, if known
Any concurrent and/or other active malignancy that has required systemic treatment within 2 years of rst dose of study drug
Any unresolved toxicities from prior systemic therapy (e. g., adjuvant chemotherapy) greater than CTCAE grade l at the time of starting study drug with the exception of alopecia, prior platinum-therapy related neuropathy grade 2
Spinal cord compression, symptomatic and unstable brain metastases except for those patients who have completed definitive therapy, and have had a stable neurological status for at least 2 weeks after completion of definitive therapy. Patients may be on corticosteroids to control brain metastases if they have been on a stable dose for 2 weeks (14 days) prior to the start of study treatment and are clinically asymptomatic
Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the Investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol; or active infection including hepatitis B, hepatitis C and human immunodeciency virus (HIV). Screening for chronic conditions is not required
Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous signicant bowel resection that would preclude adequate absorption of osimertinib
Any of the following cardiac criteria
Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value
Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG, e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval >250 msec
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events suchas heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in rst-degree relatives or any concomitant medication known to prolong the QT interval
Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD
Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values
Absolute neutrophil count <1.5 x 109/L
Platelet count <100 x 109/L
Haemoglobin <90 g/L
Alanine aminotransferase (ALT) >2.5x the upper limit of normal (ULN) if no demonstrable liver metastases or >5 x ULN in the presence of liver metastases
Aspartate aminotransferase (AST) >2.5 x ULN if no demonstrable liver metastases or >5xULN in the presence of liver metastases
Total bilirubin >1.5 x ULN if no liver metastases or >3 x ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver metastases
Creatinine >1.5 x ULN concurrent with creatinine clearance <50 mL/min (measured or calculated by Cockcroft and Gault equation); conrmation of creatinine clearance is only required when creatinine is >1.5 x ULN
Women who are breast feeding
History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib
Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements
Adults under a legal protection regime (guardianship, trusteeship, judicial safeguard)
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