Inclusion Criteria:
- - Male or female subjects aged >=18 and <=80 years old.
- - Patients with histologically or cytologically confirmed NSCLC with adenocarcinoma or
adenocarcinoma components predominant, and with central nervous system metastases
(with measurable lesions).
- - The tissue or blood sample is determined to be EGFR positive (including rare EGFR
mutations) by testing by a tertiary Class A hospital or a qualified testing
institution, and the tissue submitted for testing cannot be from a tumor lesion that
has been treated with radiation, but can be used for a new lesion after local
treatment.
- - Patients who had not previously received systemic anti-tumor therapy for locally
advanced or metastatic non-small cell lung cancer (patients who had received
first-line chemotherapy but had not received TKIs could be enrolled).
Patients who
have undergone radical surgery, radical chemo-radiotherapy, or adjuvant therapy
(chemotherapy, radiation) for early NSCLC may be enrolled if they later develop
disease recurrence or metastasis.
- - Stable brain metastases that do not require local treatment of brain metastases either
immediately or planned during the study period.
- - According to RECIST v1.1, enrolled patients should have at least one tumor lesion in
all tumors that can meet the following requirements: they have not been treated with
local therapy such as radiotherapy in the past, and can be accurately measured at
baseline, and the longest diameter at baseline is ≥10mm (in the case of lymph nodes,
the short diameter is ≥15mm).
Lesions that have previously received local treatment
(radiotherapy or other treatment) can only be measured if disease progression occurs
more than 6 months after the end of treatment.
- - ECOG PS 0-1, and with no deterioration during the first 2 weeks of the study and
expected survival time of no less than 3 months.
- - Patients should have sufficient bone marrow reserve function, and no liver, kidney,
coagulation dysfunction, laboratory test values must meet the following conditions:
1.
Absolute neutrophil count ≥ 1.5×109/L, and white blood cell count ≥3×109/L;
2. PLT ≥100×109/L;
3. Hb ≥90g/L;
4. Serum Cr ≤1.5×ULN and eGFR ≥50 mL/min;
5. AST and ALT≤2.5×ULN (or AST and ALT≤5×ULN for patients with liver metastasis)
6. In the absence of proven liver metastasis, TB ≤1.5×ULN (or TB ≤3×ULN for patients
with liver metastasis or Gilbert syndrome;
7. INR ≤1.5, and APTT ≤1.5×ULN.
- - Male patients and female patients of reproductive age should take adequate
contraceptive measures within 3 months after signing the study informed consent to the
last study drug treatment; In women of childbearing age, pregnancy test results are
negative within 7 days before the first dose.
- - All previous treatment-related toxicities (except alopecia and grade 2 neurotoxicity
associated with previous platinum chemotherapy) had been recovered (to ≤ grade 1)
before first administration of the investigational drug.
- - The subject is able to understand and voluntarily sign a written informed consent
(which must be signed prior to performing any procedure specified in the study
protocol).
- - Be able to voluntarily complete the study procedures and follow-up examinations as
required by the study protocol.
Exclusion Criteria:
- - Patients with the following treatments:
1.
Previous use of any EGFR TKIs therapy;
2. Previously received systemic antitumor therapy (such as targeted therapy,
biotherapy, immunotherapy, etc.) for advanced/metastatic non-small cell lung
cancer;
3. Standard chemotherapy within 28 days before the first administration of the study
drug; The study received anti-tumor therapy with traditional Chinese medicine
within 7 days before the first administration of the drug;
4. Previous WBRT; Had received >30% of bone marrow radiotherapy or extensive
radiotherapy within 28 days prior to the first dose of the study drug; Local
radiotherapy (e.g., thoracic and rib radiotherapy) or palliative radiotherapy for
bone metastases within 7 days prior to initial administration of the study drug;
5. Uncontrolled pleuroperitoneal effusion and pericardial effusion;
6. Uncontrollable cancerous pain; Anesthetic painkillers did not reach a stable dose
at the time of enrollment;
7. Study major surgery within 28 days before the first administration of the drug (
major surgery refers to grade 3 and grade 4 surgery in Measures for the Clinical
Application of Medical Technology in China, on May 1, 2009 );
8. Has received a strong inducer or suppressor of CYP3A4 within 14 days prior to
initial administration of the investigatory drug or requires continued treatment
during the study period (including Chinese herbal medicine, see Appendix for a
list of drugs);
9. Patients who are receiving and require continued treatment during the study with
drugs known to prolong the QTc interval or that may cause tip torsion ventricular
tachycardia (see Appendix for a list of drugs);
10. Participants who have participated in other clinical trials within 28 days prior
to the first administration of the investigational drug (except
non-interventional drug trials);
- - Patients with primary malignant brain tumors and unstable brain metastases.
Definition
of unstable brain metastases: Patients with CNS complications who require emergency
neurosurgical treatment (such as surgery); Patients with an equivalent dose of
dexamethasone or more than 5mg of glucocorticoids, mannitol or diuretics to control
symptoms of brain metastases should be administered within 14 days prior to the first
dose; The first study looked at patients who had received local radiotherapy or gamma
knife treatment within 14 days prior to administration. Patients with meningeal
metastasis were excluded.
- - Patients who have had or have a history of other malignancies within the past 5 years
(except cured basal cell or squamous cell carcinoma of the skin, papillary carcinoma
of the thyroid gland, carcinoma in situ of the cervix, and ductal carcinoma in situ of
the breast).
- - The patient had symptoms of spinal cord compression caused by the tumor.
- - Clinically significant gastrointestinal dysfunction that may affect the intake,
transport, or absorption of investigational drugs, such as inability to take oral
drugs, difficult to control nausea or vomiting, a history of extensive
gastrointestinal resection, Untreated recurrent diarrhea, atrophic gastritis (onset
age less than 60 years), untreated stomach disease requiring long-term use of PPI acid
suppressants, Crohn's disease, ulcerative colitis.
- - Cardiovascular and cerebrovascular diseases/symptoms/indications that meet any of the
following conditions:
1.
Average resting QTc≥470ms (corrected QT interval, calculated according to
Fridericia's formula, see Appendix 18-9), the average QTc of 3 ECG intervals of
more than 5 minutes, and the QT interval should be measured from the beginning of
the QRS complex wave to the end of the T wave;
2. Any abnormalities in rhythm, conduction, or morphology of the clinically
significant resting ECG, such as complete left bundle branch block, 2nd and 3rd
degree heart block, PR interval > 250ms;
3. Any factors that increase the risk of prolonged QTc or arrhythmia, such as heart
failure, hypokalemia, congenital long QT syndrome, family history of long QT
syndrome, or sudden unexplained death in a first-degree relative under the age of
40-year-old, or any combination of medications known to prolong the QT interval;
4. LVEF <50%;
5. Patients with a history of decreased myocardial contractility and related
symptoms in the 6 months prior to study administration, such as chronic
congestive heart failure, pulmonary edema, or decreased ejection fraction;
6. Patients with a history of acute and chronic cardiovascular and cerebrovascular
disease and related symptoms within 6 months prior to study administration, such
as myocardial infarction, severe or unstable angina pectoris, cerebral
infarction, cerebral hemorrhage, or transient ischemic attack.
- - Persons infected with HIV, syphilis, HCV or HBV, meeting the following conditions:
1.
HBs Ag positive and HBV DNA ≥2000cps/ mL (or 500IU/ mL);
2. Anti-HCV antibody and HCV RNA positive;
3. HIV antibody positive.
- - Prior or screening history of interstitial lung disease or ILD, or drug-induced ILD,
or radiation pneumonia requiring hormone therapy, or any evidence of active ILD (such
as acute onset or progressive pneumonia/pulmonary fibrosis at baseline), or pulmonary
symptoms deemed unsuitable for inclusion by the investigator or risk factors deemed
unsuitable for interstitial lung disease.
- - Had previously received allogeneic bone marrow transplantation.
- - Pregnant and lactating women.
- - The patient has any other disease or medical condition that is unstable or may affect
their safety or study compliance, any serious or uncontrolled systemic disease,
including autoimmune disease requiring corticosteroid therapy, uncontrolled
hypertension (SBP ≥150 mmHg or DBP ≥95 mmHg), Uncontrolled diabetes, active bleeding,
eye lesions, and other serious mental, neurological, cardiovascular, or respiratory
diseases.
- - Known or suspected allergy to the investigational drug ingredient or its analogues.
- - The subjects were judged by the investigator to be unfit for this study.
