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

• Male or female, aged ≥18 years.
• Histologically or cytologically confirmed NSCLC with EGFR sensitizing mutations (including L858R or Exon 19Del), ineligible for curative surgery or radiotherapy.
• CNS metastases diagnosed as brain metastases (BM) and/or leptomeningeal metastases (LM) by imaging and/or cerebrospinal fluid pathological examination.
• Planning to receive zorifertinib (zorifertinib group) or other anti-tumor treatments (other treatment group) as first-line treatment.
• Voluntarily agreeing to participate in this study and signing the informed consent form.

Exclusion criteria

• Currently participating or planning to participate in any interventional clinical study for first-line treatment (patients who have participated in non-interventional, real-world studies may still be included).
• Other reasons that, in the Investigator's opinion, make the patient unsuitable for this 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:

• . No prior treatment with chemotherapy, EGFR-TKIs, biological therapy, immunotherapy, or any investigational drug that is considered first line treatment for advanced NSCLC.
• . Eligible patients are not candidates for definitive surgical resection or radiation of all lesions in the opinion of the treating physician.
• . All patients must be stable without any systemic (oral or parenteral) corticosteroid or anticonvulsant therapy for at least 2 weeks prior to study treatment. Inhaled non-absorbable and topical corticosteroid use are permitted as indicated.
• . Patients may have prior placement of a properly functioning CNS shunt or Ommaya reservoir.
• . ECOG performance status 0 or 1, with no deterioration over the past 2 weeks, and expected survival time ≥ 3 months.
• . Women of child-bearing potential (WOCBP) and male patients should agree to take medically acceptable contraception measures while on study treatment and for 3 months following completion of study treatment. All WOCBP must have a negative pregnancy test at screening.
• . 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 repeated measurements. Measurable extracranial lesions are not required. Patients with non-measurable CNS lesions must have at least one extracranial lesion, which has not been previously irradiated, can be accurately measured at baseline as ≥ 10 mm in the longest 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:

• . 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 the following requirements: >6 months for Cohort A, and >3 months for Cohorts B and C).
• . Positive for T790M mutation documented by central or local laboratory using an approved or validated test method, or documented positive KRAS or cMET.
• . Patients who have received any investigational drug, biological therapy, or immunotherapy for their malignant tumors within the past 21 days.
• . Patients who have had a major surgical procedure (excluding the need for placement of vascular access or a CNS shunt), or significant traumatic injury within 4 weeks of the first dose of study treatment, or have an anticipated need for major surgery during the study.
• . Presence of only leptomeningeal metastases (LM) disease confirmed by MRI and/or positive cerebrospinal fluid (CSF) pathology, with no brain metastases (BM).
• . Prior radiation therapy for CNS metastases that involves measurable or non-measurable sites of disease to assess efficacy.
• . Patients who have received radiation to more than 30% of the bone marrow within 2 weeks before the first dose of study treatment.
• . Patients currently receiving (or unable to stop use at least 1 week prior to receiving the first dose of study treatment) certain medications or herbal supplements that are known to be potent inhibitors or inducers of CYP3A4/5 (see Appendix A).
• . Unmanageable nausea and vomiting, chronic gastrointestinal diseases, or prior gastric resection or surgical procedure that may interfere with adequate absorption of study drug.
• . History of concurrent and/or other active malignant tumors requiring treatment within 5 years of study treatment, excluding prior treated squamous cell carcinoma or basal cell carcinoma or carcinoma in situ.
• . History of any type of documented interstitial lung disease or radiation pneumonitis.
• . Presence of any severe or uncontrolled systemic disease or condition, including: (i) uncontrolled hypertension or diabetes; (ii) serious cardiac, pulmonary or renal disorders; (iii) active bleeding diatheses; (iv) any active type of bacterial, viral, fungal or other infection that would pose a significant risk to the patient in the opinion of the Investigator; or (v) active hepatitis B virus positive (defined as hepatitis B surface antigen (HBsAg) positive or hepatitis B core antibody (HBcAb) positive, and hepatitis B DNA positive (or detectable) or above the cut-off value) or positive HCV antibodies or positive HIV test result.
• . Women who are pregnant or lactating. WOCBP and fertile men with a WOCBP-partner not using adequate contraception measures.
• . Patients with unstable and symptomatic metastases: Any unstable and symptomatic CNS or distant metastasis that is not symptomatically controlled by prior surgery, radiotherapy or corticosteroid therapy within 2 weeks of initial study treatment.
• . Any unresolved toxicities from prior therapy, greater than Common Terminology Criteria for Adverse Events (CTCAE 5.0) Grade 1 at the time of starting study treatment, with exception of alopecia.
• . Patients with a significant cardiovascular disorder or condition, including any of the following:

• Congestive heart failure (CHF) currently requiring treatment and patients with New York Heart Association (NYHA) Class III/IV CHF (see Appendix B).
• Need for antiarrhythmic drug therapy for a ventricular arrhythmia or patients with uncontrolled or unstable arrhythmias.
• Severe conduction disturbance (e.g., second- or third-degree AV block).
• Angina pectoris requiring treatment.
• QTc interval > 450 msec (males) or > 470 msec (females).
• History of congenital long QT syndrome, congenital short QT syndrome, Torsades de Pointes, or Wolff Parkinson White syndrome.
• Left ventricular ejection fraction (LVEF) <50% as determined by echocardiography or MUGA scan.
• Myocardial infarction diagnosed within the past 6 months.
• . Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

• Absolute neutrophil count <1.5 × 109/L.
• Platelet count <100 × 109/L (Transfusion-dependent patients are excluded from this study).
• Hemoglobin <90 g/L.
• Alanine aminotransferase (ALT) > 2.5 times the upper limit of normal (ULN) in the absence of documented metastases to liver or > 5 times the ULN in the presence of metastases to liver.
• Aspartate aminotransferase (AST) > 2.5 times the ULN in the absence of documented metastases to liver or > 5 times the ULN in the presence of metastases to liver.
• Total bilirubin > 1.5 times the ULN in the absence of metastases to liver or >3 times the ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or metastases to liver.
• Creatinine >1.5 times the ULN concurrent with creatinine clearance <50 mL/min (measured or calculated by Cockcroft-Gault equation). Confirmation of creatinine clearance is only required when creatinine is >1.5 times the ULN.
• If bone metastases are present and liver function is otherwise considered adequate by the Investigator, then isolated elevated alkaline phosphatase (ALP) is not an exclusion criterion.
• . History of hypersensitivity to active or inactive excipients of the study drug or drugs with a similar chemical structure or class to the study drug.
• . Judgment by the Investigator that the patient should not participate in the study if the patient is unwilling to comply with all study procedures and treatment.
• . History of recent stroke (<6 months), or prior central nervous system injury that has persistent neurologic deficits that would affect neurologic assessments.
• . Significant medical or psychiatric illness that would interfere with the compliance to the protocol and ability to tolerate treatment.
• . Patients who have received any anti-neoplastic herbal medicines for their malignant tumors within the past 2 weeks.