Inclusion Criteria:
1. Provision of informed consent prior to any study specific procedures. 2. Male or female, aged at least 18 years. 3. Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1. 4. Life expectancy of at least 3 months. 5. Histologically or cytologically documented metastatic NSCLC, which are not amenable
to curative surgery or radiotherapy, patients must be classified as stage IIIB-IV.
Staging will be according to the TNM staging system for lung cancer (8th edition)
6. Histologically documented that with sensitizing EGFR mutations(either L858R or
Exon19del)
7. symptomatic brain metastasis, with at least three metastatic lesions in the brain
which need WBI based on investigator's decision. Symptom score 1-6 point.(notes:
Symptomatic definition: Symptoms without acute intervention or hospitalization,
symptoms including but not limited in headache, nausea, dizziness, and sensory
disturbance, but without hospitalization or medical emergency.)
8. HVLT-R score 15 point (Notes: this number is based on the data in a study in Chinese
population)
9. At least 1 measurable lesion in the brain according to RECIST 1.1; At least one
lesion, not previously irradiated, that can be accurately measured at baseline as ≥
10 mm in the longest diameter with computed tomography (CT) or magnetic resonance
imaging (MRI).
10. No previous treatment with EGFR-TKI or other systemic treatment, as well as
radiotherapy for brain metastases.
11. Female subjects should be using highly effective contraceptive measures, 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:
- - 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 considered postmenopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and with LH and 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 Further
information in Appendix E(Definition of Women of Childbearing Potential and
Acceptable Contraceptive Methods)
12.
Male subjects should be willing to agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive measures and agreement to refrain
from donating sperm, as defined below: a. With female partners of childbearing
potential or pregnant female partners, men must remain abstinent or use a condom
during the treatment period and for at least 4 months after the last dose of
Osimertinib. b. Men must refrain from donating sperm during this same period.
Exclusion Criteria:
1. Involvement in the planning and/or conduct of the study (applies to both
Investigator staff and/or staff at the study site)
2. Previous randomisation in the present study or previous treatment with osimertinib. 3. Leptomeningeal met alone or synchronously is not allowed. 4. History of hypersensitivity to active or inactive excipients of Osimertinib or drugs
with similar chemical structure or class to Osimertinib. 5. For patients, inability to collect plasma, CSF and tissue at baseline. 6. 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). Screening for chronic conditions
is not required.
7. Currently receiving (or unable to stop use prior to receiving the first dose of
study treatment) medications or herbal supplements known to be strong inducers of
CYP3A4 (at least 3 week prior) (Appendix D). All patients must try to avoid
concomitant use of any medications, herbal supplements and/or ingestion of foods
with known inducer effects on CYP3A4.
8. 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.
9. Any of the following cardiac criteria:
- - Mean resting corrected QT interval (QTc) > 470 msec obtained from 3
electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc
value (Note: patients with congenital long QT syndrome (CLQTS) are excluded
from this study.
)
- - Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG e.g. complete left bundle branch block, third degree heart block
and second degree heart block.
- - Patient with any factors that increase the risk of QTc prolongation or risk of
arrhythmic events such as heart failure, electrolyte abnormalities (including:
Serum/plasma potassium < LLN; Serum/plasma magnesium < LLN; Serum/plasma
calcium < LLN) , congenital long QT syndrome, family history of long QT
syndrome or unexplained sudden death under 40 years of age in first degree
relatives or any concomitant medication known to prolong the QT interval and
cause Torsades de Pointes.
10. 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.
11. 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 >2.5 x ULN if no demonstrable liver metastases or >5
times ULN in the presence of liver metastases;
- Aspartate aminotransferase >2.5 x ULN if no demonstrable liver metastases or >5
times ULN 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;
- Serum creatinine >1.5 x ULN concurrent with creatinine clearance <50 mL/min
[measured or calculated by Cockcroft and Gault equation]
12.
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.
13. Women who are pregnant or breast-feeding.
