To compare efficacy and safety of Abivertinib maleate alone versus standard first-line EGFR-TKIs for the treatment of patients with advanced non-small cell lung cancer with sensitive EGFR mutation

This is a randomized controlled, double-blind, multicenter, phase III clinical study to compare efficacy and safety of Abivertinib maleate versus first-line standard therapy EGFR-TKI for the treatment of patients with advanced non-small cell lung cancer with sensitive EGFR mutation

Inclusion Criteria:

1. Stage IV NSCLC confirmed by histology or cytology, or Stage IIIB-IIIC stage NSCLC not suitable for radical surgery or radiation therapy (eighth edition lung cancer staging criteria of International Association for the Study of Lung Cancer).

2. At least one lesion that can be measured by imaging examinations (CT, MRI) according to Response Evaluation Criteria in Solid Tumors (RECIST) V1.1; the lesion can be accurately and reproducibly measured at baseline. Long diameter of tumor in CT and MRI scan ≥ 10mm, or short diameter of metastatic lymph node ≥15 mm, and the lesion has not undergone radiotherapy or biopsy (if the patient has only one target lesion and requires biopsy, biopsy of the target lesion is allowed, but time interval between biopsy and baseline assessment of tumor during screening period must be ≥2 weeks, and the target lesion after biopsy still meets the definition of target lesion per RECIST); the lesion either has no radiotherapy history or no obvious disease progression after radiotherapy.

3. Patients with or without brain metastases could be enrolled. For patients with symptomatic brain metastases, brain lesions must be stable, and the patients shall not receive hormonal therapy within 2 weeks before start of the study treatment. In addition, the Investigator shall confirm that local treatment for the brain metastases is temporarily not needed, and PS score does not decrease significantly in the last 2 weeks. If the patient has received brain radiotherapy, time interval between end of radiotherapy and start of the study treatment shall exceed 2 weeks, and radiotherapy-related toxicity shall be recovered to less than or equal to grade 1 (CTCAE criteria) (except for hair loss)Investigator.

4. Tumor tissue or cytopathological specimens have any of two common sensitive EGFR mutation (Ex19del or L858R) as confirmed by tests with Cobas (Roche) kit in central lab of this study, which can be combined with other EGFR gene mutations.

5. The patients shall have sufficient vital organ functions during screening, including:

   • Absolute neutrophil count (ANC) ≥ 1.5x10^9/L if no treatment with hematopoietic stimulating factor is performed within 14 days before the first dose
   • Platelet count ≥100×10^9/L if no treatment with hematopoietic stimulating factor or blood transfusion is performed within 14 days before the first dose
   • Hemoglobin >90g/L if no treatment with hematopoietic stimulating factor or blood transfusion is performed within 14 days before the first dose
   • Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5X ULN (ULN = upper limit of normal) for patients without liver metastasis, or aspartate aminotransferase (AST), alanine Acid transaminase (ALT) ≤ 5 X ULN (ULN = upper limit of normal) for patients with liver metastasis
   • Total bilirubin ≤1.5X ULN
   • Coagulation function INR ≤ 1.5
   • Serum creatinine ≤ 1.5 × ULN or creatinine clearance rate (calculated using the Cockcroft and Gault formula) ≥ 50 ml/min

6. Palliative radiotherapy is allowed to be completed before 1 week prior to study enrollment, and radiotherapy-related toxicity shall be recovered to less than or equal to grade 1 (CTCAE 5.0).

7. ECOG score: 0 or 1 point, and no signs of deterioration should be found in the last 2 weeks; expected survival time >12 weeks.

8. Negative results in pregnancy tests (only for women with fertility potential). No fertility potential is defined as at least 1 year after menopause or surgical sterilization or hysterectomy.

9. All enrolled patients (whether male or female) agree to take effective contraceptive measures throughout the treatment period and at least 3 months after the end of treatment.

   For women with fertility potential, effective contraceptive methods include:

   Any combination of the following two methods (a+b or a+c or b+c):

   1. Use of oral, injection or implantable hormonal contraceptive methods or other forms of hormonal contraception with similar efficiency (failure rate ≤ 1%), such as hormone vaginal ring or percutaneous hormonal contraception
   2. implantation of intrauterine device (IUD) or intrauterine system (IUS)
   3. Barrier contraception method: a condom or a cervical cap (diaphragm or cervical cap) coated with spermicidal foam/gel/cream/vaginal suppository Note: Complete abstinence (if it is the patient's preferred and usual lifestyle), periodic abstinence (such as calendar method, ovulation method, symptomatic temperature method and post-ovulation method) and in vitro ejaculation are unacceptable methods of contraception.

   If a woman has at least 12 months of natural amenorrhea and meets the clinical criteria for postmenopausal woman or has undergone bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks ago, she is considered a postmenopausal woman and does not have fertility potential.

   Men who have sex shall use condoms during sexual intercourse during the medication and within 3 months after end of treatment, so as not to conceive their sexual partners.

   Men who have vasectomy shall also use condoms to prevent the transmission of drugs through semen.

10. Patients shall voluntarily participate in the study, sign the informed consent form, follow the study treatment plan and visit plan, and be able to cooperate in observation of adverse events and efficacy

Exclusion Criteria:

1. History of systemic chemotherapy or any other systemic treatment for advanced NSCLC, including:

   • Systematic chemotherapy, biotherapy, immunotherapy or any study drug treatment (patients who have previously received preoperative neoadjuvant chemotherapy or postoperative adjuvant chemotherapy or radical chemoradiotherapy can be enrolled if disease progression occurs after one year following the last treatment)
   • Any EGFR TKI drug
   • Any anti-tumor Chinese medicine (the patients who have received no more than 3 doses (1 dose per administration) of Chinese medicine with anti-tumor effects can be enrolled, but the medicine shall be discontinued for at least 2 weeks before treatment with the study drug)

2. The patients who are currently receiving a known strong cytochrome P450 (CYP)3A4 inhibitor or inducer (or the patients who cannot discontinue the drug within 1 week prior to the first dose of study drug);

3. Acute and chronic hepatitis C, HBsAg positive and/or HBV DNA positive;

4. HIV antibody positive, or other acquired, congenital immunodeficiency disease, or a history of organ transplantation;

5. A history of interstitial lung disease, or clinically significant radiation pneumonitis or imaging findings suggesting interstitial pneumonia or radiation pneumonitis;

6. Evidence of severe or uncontrolled systemic diseases (such as severe mental disease, neurological diseases, epilepsy or dementia, unstable or uncompensated diseases in respiratory, cardiovascular, liver, or kidney, uncontrolled hypertension [ CTCAE grade 2 above hypertension after drug treatment];

7. Patients with active bleeding or thrombotic disease who are taking therapeutic anticoagulant drugs or have bleeding tendency.

8. There are clinically significant abnormalities in rhythm, conduction and morphology in resting electrocardiogram, such as complete left bundle branch block, heart block above grade II and PR interval >250 ms; myocardial infarction in the past 6 months; risk factors leading to prolongation of QT interval or increasing risk factors for arrhythmia, such as heart failure, hypokalemia (greater than or equal to CTCAE grade 2), confirmed or suspected congenital long QT syndrome, family history of long QT syndrome or history of sudden death under 40 years old of first-degree relatives; mean QT interval (QTcB) after correction of Bazetts of 3 ECGs: male > 450 milliseconds, female > 470 milliseconds.

9. The Investigator's concerns based on safety or compliance with clinical study process, or conditions that may interfere with interpretation of study results, including but not limited to: active infections/inflammations and any other serious and unstable diseases, intestinal obstruction, inability to swallow drugs, social/psychological issues, etc.

10. In addition to NSCLC, another malignant disease has been diagnosed in the past 5 years (excluding malignant tumors that have been cured, such as completely excised basal cell carcinoma, carcinoma in situ, and thyroid cancer).

11. Patients underwent extensive bone marrow radiation therapy within 4 weeks prior to use of the study drug.

12. Surgery was performed ≤ 28 days before use of the study drug (except for surgery for biopsy).

13. Use of any drugs known to prolong QT interval or incapability to stop using these drugs within 2 weeks before the first dose of study drug;

14. Use of immunosuppressive therapy within 1 month before initiation of study treatment;

15. Patients with previous treatment with this study drug or known to be allergic to the study drug ingredients or excipients cannot be enrolled;

16. Patients who withdrew from the study cannot be enrolled.

17. Pregnant or lactating women;

18. Other potential risks based on which the Investigator believes that the patients are not suitable for participating in this study.

19. Gastrointestinal perforation and/or Keratitis history within 1 year before initiation of study treatment.