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 consent
form.
Exclusion criteria:
1. 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).
2. 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:
1. . No prior treatment with chemotherapy, EGFR-TKIs, biological therapy,
immunotherapy, or any investigational drug that is considered first line treatment
for advanced NSCLC.
2. . Eligible patients are not candidates for definitive surgical resection or
radiation 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 study
treatment. Inhaled non-absorbable and topical corticosteroid use are permitted as
indicated.
4. . Patients may have prior placement of a properly functioning CNS shunt or Ommaya
reservoir.
5. . ECOG performance status 0 or 1, with no deterioration over the past 2 weeks, and
expected survival time ≥ 3 months.
6. . 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.
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 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:
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 the
following 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 an
approved or validated test method, or documented positive KRAS or cMET.
3. . Patients who have received any investigational drug, biological therapy, or
immunotherapy for their malignant tumors within the past 21 days.
4. . 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.
5. . Presence of only leptomeningeal metastases (LM) disease confirmed by MRI and/or
positive cerebrospinal fluid (CSF) pathology, with no brain metastases (BM).
6. . Prior radiation therapy for CNS metastases that involves measurable or
non-measurable sites of disease to assess efficacy.
7. . Patients who have received radiation to more than 30% of the bone marrow within 2
weeks before the first dose of study treatment.
8. . 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).
9. . Unmanageable nausea and vomiting, chronic gastrointestinal diseases, or prior
gastric resection or surgical procedure that may interfere with adequate absorption
of study drug.
10. . 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.
11. . History of any type of documented interstitial lung disease or radiation
pneumonitis.
12. . 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.
13. . Women who are pregnant or lactating. WOCBP and fertile men with a WOCBP-partner
not using adequate contraception measures.
14. . 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.
15. . 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.
16. . Patients with a significant cardiovascular disorder or condition, including any of
the following:
1. Congestive heart failure (CHF) currently requiring treatment and patients with
New York Heart Association (NYHA) Class III/IV CHF (see Appendix B).
2. Need for antiarrhythmic drug therapy for a ventricular arrhythmia or patients
with uncontrolled or unstable arrhythmias.
3. Severe conduction disturbance (e.g., second- or third-degree AV block).
4. Angina pectoris requiring treatment.
5. QTc interval > 450 msec (males) or > 470 msec (females).
6. History of congenital long QT syndrome, congenital short QT syndrome, Torsades
de Pointes, or Wolff Parkinson White syndrome.
7. Left ventricular ejection fraction (LVEF) <50% as determined by
echocardiography or MUGA scan.
8. Myocardial infarction diagnosed within the past 6 months.
17. . Inadequate bone marrow reserve or organ function as demonstrated by any of the
following laboratory values:
1. Absolute neutrophil count <1.5 × 109/L.
2. Platelet count <100 × 109/L (Transfusion-dependent patients are excluded from
this study).
3. Hemoglobin <90 g/L.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
18. . 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.
19. . 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.
20. . History of recent stroke (<6 months), or prior central nervous system injury that
has persistent neurologic deficits that would affect neurologic assessments.
21. . Significant medical or psychiatric illness that would interfere with the
compliance to the protocol and ability to tolerate treatment.
22. . Patients who have received any anti-neoplastic herbal medicines for their
malignant tumors within the past 2 weeks.
