Almonertinib Combined With Cerebral Radiation Treat Brain Metastases From EGFR Positive NSCLC

Inclusion Criteria:

1. Age 18-75 years old (calculated from the time when the subject signed the informedconsent), both male and female.
2. Confirmed pathology of EGFR mutation positive（exon 19 deletion, L858R, T790M）NSCLCwith brain metastases on enhanced MRI.
3. Subjects had not previously received chemotherapy, EGFR-TKI, biologic orimmunotherapy, or other experimental therapy as first-line treatment for advancedNSCLC.
4. According to RECIST 1.1 criteria, subjects must have a measurable target lesion (maximum diameter under MRI/CT ≥10mm, short diameter of lymph node ≥15mm) that hasbeen examined by CT or MRI.Tumor imaging evaluation was performed within 28 days priorto initial treatment.
5. ECOG PS score: 0-1 points.
6. Must be able to swallow tablets，and expected survival ≥3 months.
7. Clinical diagnosis of Alzheimer's patients who can be treated with radiation therapy.
8. All screening laboratory tests are performed according to protocol and need to beperformed within 14 days prior to the first dose.The values of laboratory testsperformed by screening must meet the following criteria:
9. Routine blood examination :(no blood transfusion, no G-CSF, no drug correctionwithin 14 days before screening)

• Hemoglobin (Hb) ≥90 g/L;
• Absolute neutrophil count (ANC) ≥1.5×109/L;
• Platelet count (PLT) ≥100×109/L;
• White blood cell count (WBC) ≥4.0×109/L and ≤15×109/L;

2. Biochemical test :(no blood transfusion or albumin within 14 days prior toscreening)

• AST and ALT ≤1.5×ULN (such as cancer that has spread to the liver, ≤5×ULN);
• ALP≤2.5×ULN (such as tumor bone metastases, ≤5×ULN);
• TBiL≤1.5×ULN.
• ALB≥30 g/L;
• Cr≤1.5×ULN, while creatinine clearance (CrCL)≥60 mL/min (Cockcroft - Gaultformula);
• APTT≤1.5×ULN, at the same time of INR or PT≤1.5×ULN (without anticoagulationtherapy).

9. Women of childbearing age must have a serum pregnancy test within 3 days prior to thefirst dose and the results are negative.Women of reproductive age subjects and malesubjects whose partners are women of reproductive age must agree to use barriercontraception (i.e., condoms) during the study period and for 180 days after the lastadministration of the study drug.
10. Volunteered to participate in clinical studies and signed informed consent.

Exclusion Criteria:

1. Exclusion criteria for target diseases:
2. Subjects who had previously received anti-EGFR-TKI therapy.
3. Patients with neuromeningeal disease but no intracranial metastases confirmed byMRI and/or CSF malignancy.
4. Previous radiotherapy for CNS metastases, including measurable or unmeasurablesites of the disease for efficacy assessment.
5. Patients who had undergone a major surgical procedure (other than placement ofvascular access or CNS shunt) or had a major traumatic injury or were expected torequire major surgery during the study period within 4 weeks prior to initialdosing.
6. Subject who can be surgically excised or treated with radical radiotherapy.
7. History and complications:
8. The patient is using (or cannot be discontinued for at least 1 week prior to thefirst dosing of the investigational treatment) some drug or herbal supplementknown to be a strong depressant or inducer of CYP3A4/5 (Appendix 8).
9. Excluding uncontrollable nausea and vomiting, chronic gastrointestinal disease,prior gastrectomy or other surgery, may affect the full absorption of the studydrug.
10. exclude the presence of any serious or uncontrolled systemic disease orcondition, including:

• Uncontrolled high blood pressure, diabetes, thyroid disease;
• Severe heart, lung or kidney disease;
• Active bleeding constitution;
• Any bacterial, viral, fungal or other active infection that the Investigatorconsiders to pose a serious risk to the patient;
• Active hepatitis (HBsAg positive or HBcAb positive, HBV DNA positive), orHCV antibody positive or HIV positive.

4. Patients with unstable symptomatic metastases: Any unstable and symptomatic CNSor distant metastases that were not controlled by previous surgery, radiotherapy,or corticosteroid treatment within 2 weeks prior to the initial studytreatment.Corticosteroids were used before treatment for CNS symptoms, but thesymptoms were controllable after treatment, and corticosteroids were used duringradiotherapy.
5. Exclude subjects who are participating in other clinical studies or whose firstadministration has been less than 3 weeks (or 5 half-lives of the investigationaldrug) since the end of the previous clinical study (last dosing).
6. Excluding subjects who expected to require any other form of antitumor therapy (including maintenance therapy with other NSCLC drugs, and/or surgical resection)during the study.
7. excluded subjects with high suspicion of interstitial pneumonia; Or subjects thatmay interfere with the detection or management of suspected drug-relatedpulmonary toxicity;Or other moderate to severe lung diseases that seriouslyaffect lung function.
8. Subjects with other active malignancies requiring concurrent treatment wereexcluded.
9. Subjects with a previous history of malignancy were excluded unless they hadachieved a complete response at least 5 years prior to screening and did notrequire or are not expected to require additional treatment during the studyperiod for basal cell carcinoma of the skin, superficial bladder carcinoma,squamous cell carcinoma of the skin, or cervical carcinoma in situ.Rule out with Ⅱ magnitude myocardial ischemia and myocardial infarction, arrhythmia of thesubjects of poor control.
10. Ruled out according to the NYHA standard Ⅲ ~ Ⅳ level cardiac insufficiency orheart colour to exceed examination: LVEF, left ventricular ejection fraction < 50% of the subjects.
11. Patients with significant hemoptysis or hemoptysis of half a teaspoon (2.5ml) ormore per day within 1 month before randomization.
12. Patients with bleeding symptoms of significant clinical significance or withdefinite bleeding tendency, such as gastrointestinal bleeding, hemorrhagicgastric ulcer, or vasculitis, occurred within 1 month prior to randomization.
13. Artery/venous thrombosis events occurred in the first 3 months at random, such ascerebrovascular accidents (including transient ischemic attack, cerebralhemorrhage, cerebral infarction), deep venous thrombosis and pulmonary embolism,etc.
14. Subjects with active tuberculosis (TB) were excluded.In subjects suspected ofactive TB, chest X-rays and sputum should be examined, and clinical signs andsymptoms should be excluded.Subjects with a history of active tuberculosisinfection within the previous 1 year were screened, even if they had beentreated. Subjects with a history of active TB infection more than 1 year agoshould also be excluded unless the course and type of anti-TB treatmentpreviously used is demonstrated to be appropriate.
15. Excluding subjects who were preparing for or had previously received tissue/organtransplants.
16. Subjects who received or will receive live vaccine within 30 days prior to thefirst dose were excluded.
17. Inclusion of subjects with uncontrolled tumor-related pain is notrecommended.Subjects requiring pain medication must have a stable pain controlregimen;Symptomatic lesions suitable for palliative radiotherapy (such as bonemetastases or nerve invasion metastases) should be completed at least 2 weeksbefore inclusion; Asymptomatic metastatic foci whose further growth may result indysfunction or intractable pain (e.g. epidural metastases that do not show spinalcord compression) should be considered for local-regional treatment beforerandomization, if appropriate.
18. Physical examination and laboratory examination
19. A known history of positive human immunodeficiency virus (HIV) tests or a knownhistory of acquired immunodeficiency syndrome (AIDS).
20. Untreated active hepatitis:

• Hepatitis B: HBV surface antigen (HBV sAg) positive and HBV DNA detectionvalue is higher than the upper limit of normal value;
• Hepatitis C: Hepatitis C virus antibody (HCV Ab) positive, HCV RNA positive,and abnormal liver function;
• Complicated with hepatitis B and C co-infection.

3. Exclude subjects with uncontrolled pleural effusion, pericardial effusion, orascites requiring repeated drainage.
4. Allergic reactions and adverse drug reactions:Study drugs with CYP3A4 inhibitionagents, inducers, or drugs with a narrow therapeutic window that are CYP3A4-sensitivesubstrates were used within 7 days before the first administration.
5. Patients receiving concurrent chemotherapy were excluded.
6. Excludes subjects with mental illness, alcoholism, inability to quit smoking, drug orsubstance abuse.
7. At the discretion of the Investigator, exclude subjects with history or currentevidence of any disease, treatment or laboratory anomaly that may confuse studyresults, interfere with subjects' participation in the study procedure, or is not inthe best interest of subjects' participation in the study.