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About
Treatment of non-small cell lung cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) mutation is mainly based on tyrosine kinase inhibitors (TKIs) targeting EGFR. 1st or 2nd generation inhibitors have been shown to be superior to chemotherapy in terms of Progression-Free Survival (PFS) when used as 1st line treatment.
In case of progression at several metastatic sites, systemic treatment will be considered and will depend on the presence of the TKI resistance mutation, the T790M mutation. In the presence of the T790M mutation, osimertinib is superior to chemotherapy in terms of progression-free survival, while in the absence of the T790M mutation, platinum salt chemotherapy is recommended. In case of local progression, treatment of the site in progression by radiotherapy and/or surgery is considered. As these local treatments can cause long-term adverse effects, systemic treatments are increasingly being considered in this indication.
Brain and leptomeningeal metastases are the most frequent isolated site of progression in EGFR mutated patients treated with TKI. The high frequency of isolated cerebral and leptomeningeal progression is a consequence of the lower diffusion of 1st and 2nd generation TKIs in the central nervous system (CNS). Osimertinib is a 3rd generation TKI that has the particularity of overcoming the T790M mutation and having greater brain penetration than 1st or 2nd generation TKIs, which could make it an attractive therapeutic option in the event of brain progression or leptomeningeal progression. However, its efficacy in patients with cerebral or leptomeningeal metastases is still poorly understood.
Enrollment
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Inclusion criteria
Patient with NSCLC (histological or cytological diagnosis) stage IV (8th UICC TNM edition, 2017).
Patients with brain and/or leptomeningeal metastases. For cohort 1, the diagnosis of leptomeningeal metastasis requires either 1) detection of cancer cell or EGFR mutation in the CSF, or 2) presence of both clinical and neuro-imaging findings typical of LM, according to EANO-ESMO criteria.
Presence of an activating EGFR mutation. The following mutations are considered to be activating: L858R, exon 19 deletions, exon 19 insertions, L861Q, G719X. The inclusion of patients with other mutations should be discussed on a case-by-case basis with IFCT.
The presence of co-mutations on an oncogenic driver should be discussed with the IFCT before inclusion of the patient.
Testing for T790M mutation in circulating tumour DNA or tumour tissue sample at progression on the last treatment received before inclusion.
Maximum lines of anti-cancer treatment received before inclusion:
In case of previous chemotherapy, a wash-out period of 28 days will be applied. If there was any prior therapy with an investigational agent, a washout period of five half-lives of the compound or 3 months, whichever is greater, is needed.
Patient having recovered from all grade ≤ 1 toxicities related to previous anticancer therapies (CTCAE v 5.0) except for alopecia, platinum-therapy-related neuropathy (where ≤2 is allowed).
Presence of at least one evaluable lesion not previously irradiated according to RECIST 1.1. For cohort 2, presence of one CNS evaluable lesion not previously irradiated according to RECIST 1.1.The radiological assessment has to be done within the timelines indicated.
Age of at least 18 years old. 10. Performance status (PS) 0 to 2 (ECOG) except for patients with leptomeningeal carcinomatosis (cohort 1) a PS 3 is authorised.
Patient with a life expectancy of ≥ 6 weeks for cohort 1 and ≥ 12 weeks for cohort 2.
Haematological function:
Absolute number of neutrophils ≥ 1.5 x 109/L;
Platelets ≥ 100 x 109/L;
Haemoglobin ≥ 9 g/dL (transfusions to maintain or exceed this value are accepted).
Total bilirubin ≤ 1.5 x UNL (Upper Normal Limit) or ≤ 3 x UNL in case of documented Gilbert's syndrome or liver metastases;
AST / ALT < 2.5 x UNL if no liver metastases or < 5 x UNL in case of liver metastases.
International Normalized Ratio (INR) ≤ 1.5 ;
Prothrombin Ratio (PR) ≤ 1.5 x UNL. 16. Patient having signed an informed consent form prior to any study specific procedure 17. Patient able, according to the investigator, to comply with study requirements, 18. Patient covered by a national health insurance 19. Female subjects should be using highly effective contraceptive measures during the study and 2 months after discontinuing osimertinib (highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly), and must have a negative pregnancy test and not be breast-feeding prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
Exclusion criteria
Small cell lung cancer histology (SCLC) or tumours with mixt histology including a SCLC component.
Previous treatment with osimertinib or another 3rd generation EGFR inhibitor.
Previous treatment with any EGFR TKI (cohort 2 only)
Brain progression requiring whole brain radiation without delay.
Local treatments (neurosurgical or stereotactic treatment) for brain metastases performed less than 2 weeks prior to enrolment.
Local brain treatment scheduled during study treatment.
Patient who received radiotherapy including the lung fields ≤ 4 weeks before enrolment or patient who has not recovered from radiotherapy-induced toxicities. For all other body sites (including radiotherapy on thoracic vertebrae and ribs), radiotherapy ≤ 2 weeks before enrolment or who have not recovered from radiotherapy-induced toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks before enrolment is authorised.
Any of the following cardiac criteria:
Active malignant disease other than NSCLC.
Previous or active cancer within the previous 3 years (except for treated carcinoma in situ of the cervix or basal cell skin cancer).
Others on-going anti-cancer treatment (including hormone therapy).
Major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic) during the 4 weeks before enrolment or patient who has not recovered from the side effects of such as procedure.
Current severe infectious disease or fever > 38.5°C or evidence of any other pathology, degradation of organic or neurological functions, result of the physical examination or laboratory tests leading to suspect disease or a condition contra-indicating the use of the study treatment, which can impair the patient's compliance to the protocol conditions or expose to any possible risk of complications related to treatment.
Clinically significant heart disease (e.g. active): stroke or myocardial infarction in the 6 months prior to inclusion, unstable angina, congestive heart failure grade > II according to New York Heart Association (NYHA) parameters, or cardiac arrhythmia requiring specific treatment during the study which could interfere with study compliance or which is not controlled by a treatment.
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 immunodeficiency virus (HIV).Active infection will include any patients receiving treatment for infection. Participants with a resolved or chronic infection HBV are eligible if they are:
Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib
History of hypersensitivity to any of the active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib.
Currently receiving (or unable to stop use at least 3 week prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of CYP3A4 (see Appendix 2). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4.
Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
Patient who is subject to legal protection or who is unable to express his will.
Patient with a deficiency preventing complete understanding of the study requirements.
Patient having already been included and treated in this study or in another clinical trial (except for biological trials consisting of taking samples only).
Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site).
Primary purpose
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Interventional model
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57 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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