• Maximum Tolerated Dose (MTD) [ Time Frame: 21 days ]
  To determine the maximum tolerated dose (MTD) of APG-1252 in subjects with NSCLC
• Recommended Phase 2 dose (RP2D) [ Time Frame: 21 days ]
  Recommended Phase 2 dose (RP2D) of APG-1252 in subjects with NSCLC

This is a multi-center, open-label, Phase 1b study evaluating the adverse events and best dose of the combination of fixed dose AZD9291 with APG-1252 in EGFR-TKI resistant NSCLC patients.

In exploration phase, 3+3 design will be used to determine the MTD/RP2D of the combination of AZD9291 with APG-1252; Dose of AZD9291 will be fixed at 80mg QD, APG-1252 will start with 240mg weekly, then escalate to 320mg weekly and 400mg weekly or decline to 160mg weekly and 80weekly if not tolerate to 240mg weekly dosage.

In expansion phase, IF 1 confirmed PR or CR observed in NSCLC patients who failed 3rd generation EGFR TKI, the exploration of the combination of AZD9291 with APG-1252 in 3rd generation EGFR TKI naïve NSCLC patients will be initiated.

Patients will be treated in 21-day cycles. APG-1252 administered via intravenous infusion for 30 minutes weekly (,Day 1, 8 15), AZD9291 via oral daily with 80mg.

• Drug: APG-1252
  Multiple dose cohorts, 30 minute IV infusion, weekly for 3 weeks of a cycle with 21days.
  Other Name: APG-1252 for injection
• Drug: Osimertinib Mesylate Tablets
  Osimertinib Mesylate Tablets 40mg/80 mg, one time a day until disease progression
  Other Name: AZD9291

Inclusion Criteria:

1. Histologically or cytologically confirmed incurable advanced or metastatic non-small cell lung cancer.
2. At least 1 measurable lesion (RECIST 1.1).
3. Confirmed EGFR mutation positive before start use prior EGFR TKI(s) .
4. Willing to biopsy or to supply achieved tumor sample which biopsy after the most recent treatment.
5. Male or female patients age ≥18 years.
6. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
7. Estimated OS ≥3 months.
8. Adequate hematologic and bone marrow functions.
9. Adequate renal and liver function.
10. Brain metastases with clinically controlled neurologic symptoms.
11. Had recovered from all toxicities related to prior anticancer therapies to grade ≤ 2, except for patients with grade 2 nausea/vomiting and/or grade 2 diarrhea despite optimal supportive therapy who will not be allowed to participate in the study.
12. Willingness to use contraception by a method that is deemed effective by the investigator by both males and female patients of child bearing potential (postmenopausal women must have been amenorrhea for at least 12 months to be considered of non-childbearing potential) and their partners throughout the treatment period and for at least three months following the last dose of study drug.
13. Ability to understand and willingness to sign a written informed consent form (the consent form must be signed by the patient prior to any study-specific procedures).
14. Willingness and ability to comply with study procedures and follow-up examination.

Exclusion Criteria:

1. Received chemotherapy, radiation therapy, surgery, immunotherapy, hormonal therapy, targeted therapy, biologic therapy (hormones for hypothyroidism or estrogen replacement therapy (ERT), anti-estrogen analogs, agonists required to suppress serum testosterone levels are permitted); or any investigational therapy, or has had tumor embolization or tumor lysis syndrome (TLS) within 28 days prior to the first dose of study drug, received TKIs within 14 days.
2. A history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid therapy, or any evidence of clinically active interstitial lung disease.
3. Any of the following cardiac criteria: mean value of QTcB for three resting periods during the screening period > 470 milliseconds; rhythm of resting electrocardiogram (ECG), any clinically important abnormality of conduction or morphology (e.g., complete left bundle branch block, Grade 3 heart block, Grade 2 heart block); family history of congenital long QT prolongation syndrome or long QT syndrome.
4. Evidence of any serious or uncontrolled systemic disease; various chronic active infections such as hepatitis B (HBV-DNA ≥ 104 copy number/ml or 2000 IU/ml), hepatitis C and HIV; uncontrollable Hypertensive patients (requires 2 or more drugs to control blood pressure); unstable angina; angina pectoris within 3 months prior to study; congestive heart failure (NYHA class II or higher); myocardial infarction (NSTEMI or STEMI) history in 6 months before study enrollment; severe arrhythmia requiring medical attention; severe liver, kidney, gastrointestinal or metabolic diseases.
5. Patients who are unable to stop taking the drug or herbal medicine within 1 week before the first study drug treatment and during the treatment phase (these drugs or herbs are known to be effective inducers of cytochrome P450 or effective inhibitors or inducers of CYP3A4); Patients who discontinue use of these compounds at least 1 week prior to receiving this regimen are eligible
6. Hemorrhagic constitution/disease, such as a history of non-chemotherapy-induced thrombocytopenic hemorrhage or a history of ineffective platelet transfusion within 1 year prior to the first dose of study drug; Severe gastrointestinal bleeding occurred within 3 months prior to the first dose of study drug; Active immune thrombocytopenic purpura (ITP), active autoimmune hemolytic anemia (AIHA), etc.
7. Use a therapeutic dose of anticoagulant or antiplatelet agent before the first use of APG-1252 or within 7 days of central catheter placement (if platelet count is stable (≧50×109/L), Subjects who previously received aspirin to prevent thrombosis therapy can reuse low-dose aspirin (i.e., up to 100 mg QD) after 3 weeks of study drug treatment; Decisions regarding anticoagulants and antiplatelet therapy will be determined by the investigator and the sponsor; Allow low-dose anticoagulant drugs to maintain central venous catheters open.
8. Received a biologic (G-CSF, GM-CSF or erythropoietin) within 28 days prior to the first dose of study drug.
9. According to the investigator's judgment, patients who did not fully recover after surgery. Patients who underwent major surgery within 28 days prior to the first study drug and who underwent minor surgery within 7 days prior to the start of the study.
10. Other malignancies have been diagnosed within 5 years prior to the first use of the study drug; except effectively treated skin basal cell carcinoma, cutaneous squamous cell carcinoma, and/or effectively resected orthotopic cervical cancer and/or breast cancer.
11. Female patients during pregnancy or lactation.
12. Previous allergies or intolerance to treatment with osimertinib.
13. A diagnosis of febrile neutropenia within one week prior to the first use of the study drug.
14. Prior treatment with Bcl-2/Bcl-xL inhibitors.
15. Any other condition or circumstance of that would, in the opinion of the investigator, make the patient unsuitable for participation in the study.