To assess the efficacy and safety of SH-1028 tablets versus Gefitinib, a standard of care epidermal growth factor receptor tyrosine kinase inhibitor, in patients with locally advanced or Metastatic Non Small Cell Lung Cancer

This is a Phase III, multi-center,double-blind, randomised study assessing the efficacy and safety of SH-1028 tablets (200 mg orally, once daily) versus a standard of care (SoC) Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) ( gefitinib, 250 mg orally, once daily) in patients with locally advanced or metastatic Non-small Cell Lung Cancer (NSCLC) that is known to be EGFR sensitising mutation (EGFRm) positive, treatment-naive and eligible for first-line treatment with an EGFR-TKI.

Inclusion Criteria:

• 1. Male or female, aged at least 18 years.

• 2. Pathologically or cytologically confirmed locally advanced or metastatic NSCLC (e.g. this may occur systemic recurrence after prior surgery for early stage disease or patients may be newly diagnosed with stage IIIB/IV disease). Patients must be treatment-naïve for locally advanced or metastatic NSCLC. Prior adjuvant and neo-adjuvant therapy is permitted (chemotherapy, radiotherapy, investigational agents) provided all other entry criteria are satisfied.

• 3. The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either or in combination with other EGFR mutations assessed by central testing using tumour tissue sample or cytology sample.

• 4. A ECOG performance status equal to 0-1 with a minimum life expectancy of 12 weeks.

• 5. At least 1 lesion that has not previously been irradiated, that has not been chosen for biopsy during the study screening period, and that can be accurately measured at Baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15mm) with computerized tomography (CT) or magnetic resonance imaging (MRI), whichever is suitable for accurately repeated measurements.

• 6. Adequate bone marrow reserve or organ function, as demonstrated by the following laboratory values:

  1. Absolute neutrophil count (ANC）≥1.5×10^9 / L
  2. Platelet count ≥100×10^9 / L
  3. Hemoglobin ≥90 g/L
  4. Alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN) if no demonstrable liver metastases or ≤ 5 × ULN in the presence of liver metastases.
  5. Aspartate aminotransferase (AST) ≤ 2.5 × ULN if no demonstrable liver metastases or ≤ 5 × ULN in the presence of liver metastases.
  6. Total bilirubin (TBL) ≤ 1.5 × ULN if no liver metastases or ≤ 3 × ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases.
  7. Creatinine ≤ 1.5 × ULN concurrent with creatinine clearance ≥ 50 mL/min (measured or calculated by the Cockcroft-Gault equation); confirmation of creatinine clearance is only required when creatinine is ≤ 1.5 × ULN.

• 7. Females of child-bearing potential should be using adequate contraceptive measures throughout the study, should not be breast feeding during the study and until 6 months after completion of study, and must have a negative pregnancy test prior to start of dosing.

• 8. Male patients should be willing to use barrier contraception during the study and until 6 months after completion of study (i.e., condoms).

• 9. Do not participate in other clinical trial (enroll and take medicine) in 1 month prior to start of dosing.

• 10.Patients must sign and date written informed consent prior to admission to the study.

Exclusion Criteria:

• 1. Treatment with any of the following, including any EGFR-TKI, systemic chemotherapy (except for relapsed patients at last 6 months after received post-surgery adjuvant chemotherapy)，immunotherapy, targeted therapy and anti-tumor traditional Chinese medicine therapy.

• 2. Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study drug.

• 3. Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study drug, with the exception of patients receiving radiation to > 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug.

• 4. The patient is currently using (or cannot discontinue at least 1 week before the first dose of study drug) a drug or herbal supplement known as a potent inhibitor or inducer of CYP3A4.

• 5. Treatment with large doses of glucocorticoids (eg, >10 mg/day dexamethasone ) or other immunosuppressive agents within 2 weeks.

• 6. Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE), Grade 1, at the time of starting study treatment with the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy.

• 7. Spinal cord compression, meningeal metastases or brain metastases unless asymptomatic, s table, and not requiring steroids for at least 4 weeks prior to start of study treatment.

• 8. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension or active bleeding diatheses, or which in the Investigator's opinion makes it undesirable for the patient to participate in the trial.

• 9. Active infection (e.g., hepatitis B, hepatitis C or human immunodeficiency virus [HIV]). (HBsAg is positive but HBV-DNA < ULN, and HCVAb is positive but HCV-RNA<ULN can be accepted.）

• 10. Any of the following cardiac criteria:

  1. Mean resting corrected QT interval (QTcF) > 470 msec obtained from 3 electrocardiograms (ECGs), using the Screening clinic ECG machine and Fridericia's formula for QT interval correction.
  2. Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG (e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval >250 msec).
  3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval.
  4. Left ventricular ejection fraction (LVEF) ≤ 40%.

• 11. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.

• 12. History of any other malignant tumor within five years (except clinically cured cervical carcinoma in situ, basal cells or squamous epithelial skin cancer).

• 13. Any seriously abnormal gastrointestinal function would affect uptake, transport and absorption of the drug, such as inability to swallow the study medication, refractory nausea and vomiting, previous significant bowel resection, Recurrent diarrhea, atrophic gastritis (age < 60 years), unhealed serious gastric diseases, Crohn's disease or ulcerative colitis.

• 14. History of hypersensitivity to any active or inactive ingredient of SH-1028 or drug with a similar chemical structure or class to SH-1028.

• 15. Any severe and uncontrolled ocular disease that may, in the Investigator's opinion, present a specific risk to the patient's safety.

• 16. Lactating Women.

• 17. Any disease or condition that, in the opinion of the Investigator, would compromise the safety of the patient or interfere with study assessments.

All trial personnel and participants were masked to treatment allocation, until unblinding due to progression disease or other Criteria of termination.