TY-9591 in the Patients With EGFR Mutations in Advanced NSCLC With Brain Metastases

This study is to evaluate the efficacy and safety of TY-9591 in first-line treatment of patients with EGFR-sensitive mutation-positive non-small cell lung cancer with brain metastases compared to Osimertinib.

This is an open label, multi-center phase II study to compare the efficacy and safety with Osimertinib in EGFR mutated NSCLC patients with brain metastases. Participants will be randomly assigned to one of the TY-9591 group (160mg orally, once daily) or Osimertinb group (80mg orally, once daily) . Participants can continue to receive study treatment as long as disease progression, meeting criteria for discontinuation of treatment, withdrawal criteria, or study termination (whichever occurred first).

Eligibility Criteria:
Inclusion Criteria:

1. Male or female aged ≥18 years and \<80 years.
2. Patients diagnosed with NSCLC by histology or cytology, with brain metastases.
3. Presence of an activating EGFR-sensitive mutations (including exon 19 deletions, L858R, the above mentioned mutations alone or co-existed with other EGFR-mutated sites).
4. No prior systemic antitumor therapy for locally advanced or metastatic NSCLC.
5. Stable brain metastases that do not require immediate or planned local treatment for it during the study period.
6. At least one measurable lesion according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.
7. The ECOG score is 0-1, and there is no deterioration 2 weeks before the study, and the expected survival is not less than 3 months.
8. Adequate bone marrow reserve function, and no liver, kidney and coagulation dysfunction.
9. Male patients and female patients of reproductive age should take adequate contraceptive measures from signing informed consent to 3 months after the last study drug treatment; Women of childbearing age have negative pregnancy test results within 7 days of the first dose.
10. Patients 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) before first dose of study treatment.
11. Patients can understand and voluntarily sign the informed consent form.
12. Patient able to comply with study requirements.

Exclusion Criteria:

1. Any of the following treatment:

   1. Previous treatment with EGFR inhibitor;
   2. Previous treatment with Systematic antitumor therapy (including targeted therapy, biotherapy and immunodrug therapy, etc.)；
   3. Previous treatment with standard chemotherapy with 28 days before the first dose of the study drug, and traditional Chinese medicine antitumor therapy within 7 days before the first dose of the study drug;
   4. Previous whole brain radiation therapy (WBRT); Receiving radiation to more than 30% of the bone marrow or with a wide field of radiation that had to be completed within 28 days of the first dose of study treatment; Radiotherapy with a limited field of radiation within 7 days of the first dose of study treatment or palliative radiation therapy for bone metastasis;
   5. Uncontrollable or poorly controlled pleural, abdominal and pericardial effusion;
   6. Uncontrollable cancerous pain; Anesthetic painkillers did not reach a stable dose at the time of enrollment;
   7. Major surgery within 28 days of the first dose of study treatment;
   8. Patients currently receiving (or at least within 14 days prior to receiving the first dose )medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 isoenzyme (CYP)3A4;
   9. Patients who are receiving and need to continue receiving medications during the study that are known to prolong the QTc interval or may cause tachycardia;
   10. Participants in other clinical trials (other than non-interventional clinical trials) within 28 days prior to the first administration of the investigational drug.
2. Patients with primary malignant brain tumors and unstable brain metastases.
3. 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).
4. The patient had symptoms of spinal cord compression caused by the tumor.
5. Clinically severe gastrointestinal dysfunction may affect the ingestion, transport or absorption of the study drugs.
6. Cardiac function and disease are consistent with the following:

   1. Corrected QT interval(QTc)\> 470 milliseconds from 3 electrocardiograms (ECGs);
   2. Any clinically important abnormalities in rhythm;
   3. Any factors that increase the risk of QTc prolongation;
   4. Left ventricular ejection fraction (LVEF) \<50%.
7. Active human immunodeficiency virus (HIV), syphilis, hepatitis c virus (HCV) or hepatitis b virus (HBV) infection, with the exception of asymptomatic chronic hepatitis b or hepatitis c carriers.
8. Previous history of interstitial lung disease(ILD) or drug-induced ILD or radiation pneumonitis require steroid treatment, or any evidence of clinically active ILD diseases.
9. Previous allogeneic bone marrow transplant.
10. Pregnant or lactating women.
11. Any other disease or medical condition that is unstable or may affect the safety or study compliance.
12. Hypersensitivity to TY-9591 or similar compounds or excipients.