A Prospective Cohort Study of Zorifertinib as a First-line Treatment in Patients With Epidermal Growth Factor Receptor-mutant Advanced Non-small Cell Lung Cancer With Central Nervous System (CNS) Metastases

Inclusion criteria:

1. Male or female, aged ≥18 years.

2. Histologically or cytologically confirmed NSCLC with EGFR sensitizing mutations (including L858R or Exon 19Del), ineligible for curative surgery or radiotherapy.

3. CNS metastases diagnosed as brain metastases (BM) and/or leptomeningeal metastases (LM) by imaging and/or cerebrospinal fluid pathological examination.

4. Planning to receive zorifertinib (zorifertinib group) or other anti-tumor treatments (other treatment group) as first-line treatment.

5. Voluntarily agreeing to participate in this study and signing the informed consentform.

Exclusion criteria:

1. Currently participating or planning to participate in any interventional clinicalstudy for first-line treatment (patients who have participated innon-interventional, real-world studies may still be included).

2. Other reasons that, in the Investigator's opinion, make the patient unsuitable forthis study.

For patients in Cohort A of the zorifertinib group, the following inclusion/exclusion criteria of the EVEREST study must also be met:

Inclusion Criteria A:

1. . No prior treatment with chemotherapy, EGFR-TKIs, biological therapy,immunotherapy, or any investigational drug that is considered first line treatmentfor advanced NSCLC.

2. . Eligible patients are not candidates for definitive surgical resection orradiation of all lesions in the opinion of the treating physician.

3. . All patients must be stable without any systemic (oral or parenteral)corticosteroid or anticonvulsant therapy for at least 2 weeks prior to studytreatment. Inhaled non-absorbable and topical corticosteroid use are permitted asindicated.

4. . Patients may have prior placement of a properly functioning CNS shunt or Ommayareservoir.

5. . ECOG performance status 0 or 1, with no deterioration over the past 2 weeks, andexpected survival time ≥ 3 months.

6. . Women of child-bearing potential (WOCBP) and male patients should agree to takemedically acceptable contraception measures while on study treatment and for 3months following completion of study treatment. All WOCBP must have a negativepregnancy test at screening.

7. . Patients with measurable CNS lesions must have at least one site of CNS lesion,which has not been previously irradiated, can be accurately measured at baseline as ≥ 10 mm in the longest diameter by MRI, and is suitable for accurate repeatedmeasurements. Measurable extracranial lesions are not required. Patients withnon-measurable CNS lesions must have at least one extracranial lesion, which has notbeen previously irradiated, can be accurately measured at baseline as ≥ 10 mm in thelongest diameter (except for lymph nodes which must have a short diameter ≥ 15 mm)by CT/MRI, and is suitable for accurate repeated measurements.

Exclusion Criteria A:

1. . Prior treatment with EGFR-TKIs (if EGFR-TKIs were used as adjuvant therapy,patients may be enrolled if the time from discontinuation to relapse meets thefollowing requirements: >6 months for Cohort A, and >3 months for Cohorts B and C).

2. . Positive for T790M mutation documented by central or local laboratory using anapproved or validated test method, or documented positive KRAS or cMET.

3. . Patients who have received any investigational drug, biological therapy, orimmunotherapy for their malignant tumors within the past 21 days.

4. . Patients who have had a major surgical procedure (excluding the need for placementof vascular access or a CNS shunt), or significant traumatic injury within 4 weeksof the first dose of study treatment, or have an anticipated need for major surgeryduring the study.

5. . Presence of only leptomeningeal metastases (LM) disease confirmed by MRI and/orpositive cerebrospinal fluid (CSF) pathology, with no brain metastases (BM).

6. . Prior radiation therapy for CNS metastases that involves measurable ornon-measurable sites of disease to assess efficacy.

7. . Patients who have received radiation to more than 30% of the bone marrow within 2weeks before the first dose of study treatment.

8. . Patients currently receiving (or unable to stop use at least 1 week prior toreceiving the first dose of study treatment) certain medications or herbalsupplements that are known to be potent inhibitors or inducers of CYP3A4/5 (seeAppendix A).

9. . Unmanageable nausea and vomiting, chronic gastrointestinal diseases, or priorgastric resection or surgical procedure that may interfere with adequate absorptionof study drug.

10. . History of concurrent and/or other active malignant tumors requiring treatmentwithin 5 years of study treatment, excluding prior treated squamous cell carcinomaor basal cell carcinoma or carcinoma in situ.

11. . History of any type of documented interstitial lung disease or radiationpneumonitis.

12. . Presence of any severe or uncontrolled systemic disease or condition, including: (i) uncontrolled hypertension or diabetes; (ii) serious cardiac, pulmonary or renaldisorders; (iii) active bleeding diatheses; (iv) any active type of bacterial,viral, fungal or other infection that would pose a significant risk to the patientin the opinion of the Investigator; or (v) active hepatitis B virus positive (defined as hepatitis B surface antigen (HBsAg) positive or hepatitis B coreantibody (HBcAb) positive, and hepatitis B DNA positive (or detectable) or above thecut-off value) or positive HCV antibodies or positive HIV test result.

13. . Women who are pregnant or lactating. WOCBP and fertile men with a WOCBP-partnernot using adequate contraception measures.

14. . Patients with unstable and symptomatic metastases: Any unstable and symptomaticCNS or distant metastasis that is not symptomatically controlled by prior surgery,radiotherapy or corticosteroid therapy within 2 weeks of initial study treatment.

15. . Any unresolved toxicities from prior therapy, greater than Common TerminologyCriteria for Adverse Events (CTCAE 5.0) Grade 1 at the time of starting studytreatment, with exception of alopecia.

16. . Patients with a significant cardiovascular disorder or condition, including any ofthe following:

17. Congestive heart failure (CHF) currently requiring treatment and patients withNew York Heart Association (NYHA) Class III/IV CHF (see Appendix B).

18. Need for antiarrhythmic drug therapy for a ventricular arrhythmia or patientswith uncontrolled or unstable arrhythmias.

19. Severe conduction disturbance (e.g., second- or third-degree AV block).

20. Angina pectoris requiring treatment.

21. QTc interval > 450 msec (males) or > 470 msec (females).

22. History of congenital long QT syndrome, congenital short QT syndrome, Torsadesde Pointes, or Wolff Parkinson White syndrome.

23. Left ventricular ejection fraction (LVEF) <50% as determined byechocardiography or MUGA scan.

24. Myocardial infarction diagnosed within the past 6 months.

25. . Inadequate bone marrow reserve or organ function as demonstrated by any of thefollowing laboratory values:

26. Absolute neutrophil count <1.5 × 109/L.

27. Platelet count <100 × 109/L (Transfusion-dependent patients are excluded fromthis study).

28. Hemoglobin <90 g/L.

29. Alanine aminotransferase (ALT) > 2.5 times the upper limit of normal (ULN) inthe absence of documented metastases to liver or > 5 times the ULN in thepresence of metastases to liver.

30. Aspartate aminotransferase (AST) > 2.5 times the ULN in the absence ofdocumented metastases to liver or > 5 times the ULN in the presence ofmetastases to liver.

31. Total bilirubin > 1.5 times the ULN in the absence of metastases to liver or >3times the ULN in the presence of documented Gilbert's syndrome (unconjugatedhyperbilirubinemia) or metastases to liver.

32. Creatinine >1.5 times the ULN concurrent with creatinine clearance <50 mL/min (measured or calculated by Cockcroft-Gault equation). Confirmation ofcreatinine clearance is only required when creatinine is >1.5 times the ULN.

33. If bone metastases are present and liver function is otherwise consideredadequate by the Investigator, then isolated elevated alkaline phosphatase (ALP)is not an exclusion criterion.

34. . History of hypersensitivity to active or inactive excipients of the study drug ordrugs with a similar chemical structure or class to the study drug.

35. . Judgment by the Investigator that the patient should not participate in the studyif the patient is unwilling to comply with all study procedures and treatment.

36. . History of recent stroke (<6 months), or prior central nervous system injury thathas persistent neurologic deficits that would affect neurologic assessments.

37. . Significant medical or psychiatric illness that would interfere with thecompliance to the protocol and ability to tolerate treatment.

38. . Patients who have received any anti-neoplastic herbal medicines for theirmalignant tumors within the past 2 weeks.