Lorlatinib in Patients With ALK-Positive NSCLC With Brain or Leptomeningeal Metastases

An Open-label, Single-arm, Multicenter, Prospective Study of Lorlatinib in Patients With ALK-Positive NSCLC With Brain or Leptomeningeal Metastases

This study is an investigator-initiated, prospective, open-label, single-arm, multicenter clinical trial aimed at exploring the antitumor activity of Lorlatinib in ALK-positive NSCLC patients with brain/ leptomeningeal metastases.

Study Overview

• Status: Active, not recruiting
• Conditions: Carcinoma, Non-Small-Cell Lung; Brain Metastases; Leptomeningeal Metastasis
• Intervention / Treatment: Drug: Lorlatinib

Detailed Description

Fifty eligible subjects will be divided into a BM cohort (brain parenchymal metastasis only) and an LM cohort (leptomeningeal metastasis ± brain parenchymal metastasis). All subjects will receive Lorlatinib 100 mg once daily on days 1 to 28 of each 28-day cycle.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Dongguan, Guangdong, China, 510080
      • Tenth Affiliated Hospital, Southern Medical University (Dongguan people's hospital)
    • Foshan, Guangdong, China, 510080
      • The First People's Hospital of Foshan
    • Guangzhou, Guangdong, China, 510080
      • Guangdong Provincial Perople's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 years, regardless of sex.
2. Histologically or cytologically confirmed ALK-positive NSCLC.
3. ALK rearrangement positive confirmed by FISH, RT-PCR, IHC Ventana D5F3, or NGS. Patients with other actionable genomic alterations in addition to ALK must be reviewed by the study expert panel to determine eligibility.
4. Patients who have not received prior systemic treatment for advanced NSCLC, or who have experienced disease progression on or intolerance to at least one prior systemic treatment regimen, including an ALK inhibitor, are eligible for enrollment. If the treatment immediately prior to study drug administration was an ALK inhibitor, the washout period may be determined after discussion by the study expert panel.
5. Toxicities related to prior systemic treatment must have recovered to ≤ Grade 1 (CTCAE version 5.0) or to baseline levels, except for adverse events that, in the investigator's judgment, do not pose a safety risk to the subject.
6. At least one CNS lesion meeting one of the following criteria must be present: 1.leptomeningeal metastasis suggested by imaging and/or cerebrospinal fluid findings; cerebrospinal fluid confirmation is not required for imaging-suspected leptomeningeal metastasis; or 2.brain parenchymal metastasis confirmed by magnetic resonance imaging (MRI), with ≥3 brain lesions, or 1-2 lesions that are not suitable for surgery or for which the patient refuses surgery. In patients without leptomeningeal metastasis, at least one measurable brain lesion with a diameter of ≥5 mm is required.
7. Patients with or without symptoms related to brain and/or leptomeningeal metastases are eligible.
8. Life expectancy must be at least 12 weeks.
9. ECOG performance status of 0-2 for patients without leptomeningeal metastasis, and 0-3 for patients with leptomeningeal metastasis.
10. The investigator considers the subject to have generally adequate major organ function, including hematologic, coagulation, hepatic, renal, and pancreatic function.
11. For women of childbearing potential (defined as women who are not postmenopausal for at least 1 year and have not undergone surgical sterilization or hysterectomy), a serum or urine pregnancy test must be performed within 7 days before the first administration of study drug, and the result must be negative. All subjects, male or female, must agree to use adequate contraception throughout the treatment period and for at least 90 days after the last dose of study drug.
12. Subjects must understand and voluntarily sign the written informed consent form, have good compliance, be willing to follow the study treatment plan and visit schedule, and be able to cooperate with safety and efficacy assessments.

Exclusion criteria

1. Prior treatment with the investigational drug, or known hypersensitivity to the active substance or any excipients of the investigational drug.

2. Concurrent participation in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up phase of an interventional study. Subjects who have received any other investigational drug within 28 days before initiation of study treatment are excluded.

1. In the investigator's judgment, the subject requires urgent local intervention, such as surgery or radiotherapy.
2. Presence of spinal cord compression, unless pain symptoms and neurological function have remained stable or improved for at least 2 weeks prior to enrollment.
3. Open surgery within 14 days prior to enrollment, except for procedures performed for biopsy purposes.
4. Fever >38°C within 1 week prior to enrollment; or clinically significant bacterial, fungal, or viral infection, including but not limited to HIV infection, active HCV infection, or active pulmonary tuberculosis; or infectious complications requiring hospitalization, bacteremia, severe pneumonia, or other clinically significant infections.
5. Clinically significant abnormalities in rhythm, conduction, or morphology on resting electrocardiogram (ECG), such as complete left bundle branch block, second-degree or higher atrioventricular block, clinically significant ventricular arrhythmia, or atrial fibrillation.
6. Current or recent (within 3 months prior to enrollment) unstable angina, congestive heart failure (New York Heart Association Class III or IV), myocardial infarction, coronary artery or peripheral artery bypass grafting, cerebrovascular accident, transient ischemic attack not adequately treated with anticoagulation, or symptomatic pulmonary embolism.
7. Current clinically active interstitial lung disease, or radiation pneumonitis requiring corticosteroid treatment on the day of enrollment.
8. Dysphagia, active gastrointestinal disease, or any other condition that may significantly affect the absorption, distribution, metabolism, or excretion of the investigational drug; or history of major gastric resection.
9. Other acquired or congenital immunodeficiency disorders, or prior solid organ or hematologic transplantation.
10. Evidence of severe or uncontrolled systemic disease, including but not limited to severe psychiatric or neurologic disorders, epilepsy or dementia, unstable or uncompensated respiratory, cardiovascular, hepatic, or renal disease, or uncontrolled hypertension (defined as hypertension that remains at CTCAE version 5.0 Grade 3 or higher despite medical treatment).
11. Use or consumption within 2 weeks prior to enrollment of known strong CYP3A4 inhibitors; use within 2 weeks prior to enrollment of known strong CYP3A4 inducers; or use within 2 weeks prior to enrollment of CYP3A4 substrate drugs with a narrow therapeutic index.
12. Severe acute or chronic psychiatric illness, including recent (within the past year) or active suicidal ideation or behavior.
13. Pregnant or breastfeeding women, or male or female subjects of reproductive potential who refuse to use effective contraception during treatment and for 90 days after the last dose of study drug.
14. In the investigator's judgment, the subject may be unable to complete the study or comply with study requirements.
15. Any other condition that, in the investigator's judgment, would make the subject unsuitable for participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BM/LM cohort; Fifty eligible subjects will be divided into a BM cohort (brain parenchymal metastasis only) and an LM cohort (leptomeningeal metastasis ± brain parenchymal metastasis)	Drug: Lorlatinib; Lorlatinib 100 mg once daily on days 1 to 28 of each 28-day cycle; Other Names: PF-06463922

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
intracranial objective response rate（iORR）	BM Cohort: percentage of participants demonstrating an intracranial complete response or partial response according to modified RECIST v1.1 criteria; LM Cohort: percentage of participants demonstrating an intracranial complete response or partial response according to the imaging criteria of RANO-LM.	From date of the first dose of lorlatinib treatment until the date of last follow up or death, up to 18 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS) and intracranial PFS（iPFS）	PFS defined as time from the first dose of lorlatinib to the first documentation of progression or death from any cause. Specifically, intracranial PFS pertains to the progression of the disease confined within the brain.	From date of the first dose of lorlatinib treatment until the date of last follow up or death, up to 18 months.
Obiective response rate (ORR)	ORR defined as assessed percentage of participants demonstrating a complete response or partial response including central nervous system disease, extracranial disease and overall disease.	From date of the first dose of lorlatinib treatment until the date of last follow up or death, up to 18 months.
Disease control rate (DCR) and intracranial disease control rate (iDCR)	Disease Control Rate, is determined by assessing the percentage of participants who achieve a best response of confirmed Complete Response (CR), confirmed Partial Response (PR), or exhibit stable disease for various disease sites including central nervous system, extracranial, and leptomeningeal involvement, as well as overall disease status. Specifically, intracranial DCR focuses on evaluating the disease control rate within the brain.	From date of the first dose of lorlatinib treatment until the date of last follow up or death, up to 18 months.
Overall survival	Overall survival defined as time from the start of treatment until death or last follow-up	From date of the first dose of lorlatinib treatment until the date of last follow up or death, up to 18 months.
Number of participants with adverse events	Occurrence and severity of adverse events, with severity determined by NCI CTCAE v5.0 criteria.	From date of the first dose of lorlatinib treatment until the date of last follow up or death, up to 18 months.

Collaborators and Investigators

• Sponsor: Guangdong Association of Clinical Trials
• Investigators: Principal Investigator: Jin-Ji Yang, PhD, Guangdong Provincial People's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2024
• Primary Completion (Estimated): April 30, 2026
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: January 30, 2024
• First Submitted That Met QC Criteria: February 21, 2024
• First Posted (Actual): February 28, 2024

Study Record Updates

• Last Update Posted (Actual): April 9, 2026
• Last Update Submitted That Met QC Criteria: April 3, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Brain Metastases; Leptomeningeal Metastasis; ALK-Positive Non-Small-Cell Lung Cancer
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Nervous System Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Meningeal Neoplasms; Central Nervous System Neoplasms; Carcinoma, Non-Small-Cell Lung; Brain Neoplasms; Meningeal Carcinomatosis; lorlatinib
• Other Study ID Numbers: CTONG2303

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No