Zorifertinib as first-line therapy for EGFR‑mutant advanced lung cancer with brain or leptomeningeal spread

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

This study will try zorifertinib as first treatment for people with EGFR‑mutant advanced non‑small cell lung cancer that has spread to the brain or leptomeninges and compare outcomes with other EGFR‑targeted treatments.

Quick facts

• Study type: Observational
• Enrollment: 800 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Alpha Biopharma (Jiangsu) Co., Ltd. (Industry-sponsored)
• Drugs / interventions: zorifertinib, chemotherapy, immunotherapy, radiation
• Locations: 34 sites (Hefei, Anhui and 33 other locations)
• Trial ID: NCT07143045 on ClinicalTrials.gov

What this trial studies

This is a multi-center, patient-centered prospective cohort that follows two treatment groups (patients receiving zorifertinib versus those receiving other anti-tumor therapies) organized into three cohorts based on central nervous system involvement. Eligible adults have EGFR sensitizing mutations (including L858R or Exon 19 deletions) and radiographic or CSF-confirmed brain and/or leptomeningeal metastases and are starting first-line therapy. The study collects survival and safety data in a real-world, non-interventional setting to compare clinical value across treatments. Sites are tertiary hospitals in China and follow patients over time for intracranial control, overall survival, and adverse events.

Who should consider this trial

Good fit: Adults (≥18) with advanced NSCLC harboring EGFR sensitizing mutations (e.g., L858R or Exon 19 deletions), who are not candidates for curative surgery or radiotherapy and who have imaging- or CSF-confirmed brain and/or leptomeningeal metastases and plan first-line systemic treatment.

Not a fit: Patients without EGFR sensitizing mutations, without CNS metastases, or those currently enrolled in an interventional first-line clinical trial are unlikely to benefit from participation in this observational comparison.

Why it matters

Potential benefit: If successful, zorifertinib could provide better control of brain and leptomeningeal metastases and improve survival with an acceptable safety profile for EGFR‑mutant patients.

How similar studies have performed: Other third-generation EGFR‑TKIs such as osimertinib have shown meaningful intracranial activity and survival benefit, though zorifertinib itself is newer and less extensively studied.

Eligibility criteria

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.

Where this trial is running

Hefei, Anhui and 33 other locations

• The First Affiliated Hospital of Anhui Medical University — Hefei, Anhui, China (Not_yet_recruiting)
• Beijing Tumor Hospital — Beijing, Beijing Municipality, China (Not_yet_recruiting)
• Capital Medical University Affiliated Beijing Chest Hospital — Beijing, Beijing Municipality, China (Recruiting)
• Chongqing University Affiliated Cancer Hospital — Chongqing, Chongqing Municipality, China (Not_yet_recruiting)
• People's Liberation Army Army Specialized Medical Center — Chongqing, Chongqing Municipality, China (Not_yet_recruiting)
• Fujian Cancer Hospital — Fuzhou, Fujian, China (Not_yet_recruiting)
• The First Affiliated Hospital of Xiamen University — Xiamen, Fujian, China (Not_yet_recruiting)
• Foshan First People's Hospital — Foshan, Guangdong, China (Recruiting)
• Heyou Hospital, Shunde District, Foshan City — Foshan, Guangdong, China (Not_yet_recruiting)
• Guangdong Provincial People's Hospital — Guangzhou, Guangdong, China (Recruiting)
• Meizhou People's Hospital — Meizhou, Guangdong, China (Recruiting)
• Affiliated Cancer Hospital of Guangxi Medical University — Nanning, Guangxi, China (Not_yet_recruiting)
• The First Affiliated Hospital of Guangxi Medical University — Nanning, Guangxi, China (Not_yet_recruiting)
• Harbin Medical University Cancer Hospital — Harbin, Heilongjiang, China (Not_yet_recruiting)
• Henan Cancer Hospital — Zhenzhou, Henan, China (Not_yet_recruiting)
• Union Hospital, Tongji Medical College, Huazhong University of Science and Technology — Wuhan, Hubei, China (Not_yet_recruiting)
• Hunan Cancer Hospital — Changsha, Hunan, China (Not_yet_recruiting)
• Xiangya Hospital, Central South University — Changsha, Hunan, China (Not_yet_recruiting)
• Jiangsu Provincial People's Hospital — Nanjing, Jiangsu, China (Not_yet_recruiting)
• Nanjing Chest Hospital — Nanjing, Jiangsu, China (Not_yet_recruiting)
• Northern Jiangsu People's Hospital — Yangzhou, Jiangsu, China (Not_yet_recruiting)
• The First Affiliated Hospital of Nanchang University — Nanchang, Jiangxi, China (Not_yet_recruiting)
• First Hospital of Jilin University — Changchun, Jilin, China (Not_yet_recruiting)
• The First Hospital of China Medical University — Shenyang, Liaoning, China (Not_yet_recruiting)
• Dalian University of Technology Affiliated Central Hospital (Dalian Central Hospital) — Dalian, Shandong, China (Not_yet_recruiting)
• Qingdao University Affiliated Hospital — Qingdao, Shandong, China (Not_yet_recruiting)
• Shanxi Bethune Hospital — Taiyuan, Shanxi, China (Not_yet_recruiting)
• Shenzhen Hospital, Cancer Hospital, Chinese Academy of Medical Sciences — Shenzhen, Shenzhen, China (Not_yet_recruiting)
• Shenzhen Third People's Hospital — Shenzhen, Shenzhen, China (Not_yet_recruiting)
• Chengdu Third People's Hospital — Chengdu, Sichuan, China (Not_yet_recruiting)
• Sichuan Cancer Hospital — Chengdu, Sichuan, China (Not_yet_recruiting)
• Tianjin Cancer Hospital — Tianjin, Tianjin Municipality, China (Not_yet_recruiting)
• Yunnan Cancer Hospital — Kunming, Yunnan, China (Not_yet_recruiting)
• Yunnan Provincial First People's Hospital — Kunming, Yunnan, China (Not_yet_recruiting)

Study contacts

• Principal investigator: Yilong Wu M.D. — Guangdong Provincial People's Hospital
• Study coordinator: John Ge M.D.

Conditions EGFR Mutant Advanced Non-small Cell Lung Cancer; Central Nervous System Metastases