Lazertinib in Patients With NSCLC With Asymptomatic or Mild Symptomatic Brain Metastases After Failure of EGFR TKI.

Study Overview
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Brief Summary
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This is an open-label, single-intervention, multicenter clinical trial in patients with non-small cell lung cancer with asymptomatic or mildly symptomatic brain metastases after failure of EGFR TKI treatment. The objective of this study is as follows. Primary objective : intracranial objective response rate (iORR) with RECIST 1.1 Secondary objectives : intracranial progression free survival(iPFS), Intracranial objective response rate in T790M negative, isolated CNS progression patient group, overall Objective Rsponse Rate(ORR), duration of response(DoR), disease control rate(DCR), treatment failure pattern): intracranial progression or extracranial progression or both, salvage intracranial treatment rate, safety and tolerability

Detailed Description
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Patients who eligible the inclusion/exclusion criteria should take lazertinib 240 mg (80 mg, 3 tablets) once a day at the same time as possible on an empty stomach before meals. One cycle of treatment is defined as 42 days of continuous administration, and the tumor response by RECIST 1.1 will be evaluated every 1 cycle for the 1st, 2nd, 3rd, and 4th evaluation, and every 2 cycles from the 5th evaluation thereafter. . If the investigator decides to reduce the dose due to an adverse drug reaction during the administration of lazertinib 240 mg, the dose may be reduced to 160 mg (80 mg, 2 tablets) of lazertinib. Efficacy and safety will be evaluated by administering lazertinib 240 mg to patients with measurable brain metastasis or newly confirmed metastatic non-small cell lung cancer after failure of treatment with gefitinib, erlotinib, or afatinib after EGFR mutation is confirmed.

Official Title
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Lazertinib in Patients With Epidermal Growth Factor Receptor Sensitizing Mutation Positive, Metastatic Non-Small Cell Lung Cancer With Asymptomatic or Mild Symptomatic Brain Metastases After Failure of EGFR Tyrosine Kinase Inhibitor

Conditions
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Lung Neoplasms

Intervention / Treatment
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* Drug: lazertinib(YH25448)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patients who voluntarily provided written informed consent prior to participation in the clinical trial and genetics and/or exploratory studies Male or female, 20 years of age or older(Female patients must agree to the use of appropriate contraceptive methods and not be lactating, and for women of childbearing age, there must be evidence that the pregnancy test is negative prior to initiation of dosing) Histologically or cytologically confirmed locally advanced or metastatic non-small cell lung cancer patients. This may occur as systemic recurrence after prior surgery for early stage disease or patients may be newly diagnosed with stage IIIB/C or IV disease. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2, with no deterioration in the last 2 weeks Life expectancy judged by the Investigator of at least 3 months Asymptomatic or mild symptomatic brain metastases progressed or newly confirmed patients For one or more intracranial measurable disease, the maximum baseline diameter is measured to be 10mm or more on CT or MRI, and this lesions can be ccurately measured. (The target lesion that has received previous local therapy should not be considered as measurable. However, new CNS lesion after more than 3 months of previous local therapy could be considered as target lesion. ) Confirmed sensitizing EGFR mutation prior to administration of gefitinib, erlotinib, or afatinib (L858R, Exon 19 deletion, G719X and L861Q mutations chould be confirmed as a record) Failure after one regimen of EGFR TKI treatment. Past treatment history for locally advanced or metastatic NSCLC limited to one regimen of EGFR TKI treatment (gefitinib, erlotinib, or afatinib) and/or one palliative cytotoxic chemotherapy regimen. Those who have been confirmed status of T790M mutations in tissues or blood after EGFR TKI failure (T790M positive or negative should be confirmed as a record) Exclusion Criteria Prior treatment with lazertinib Prior treatment with investigational drugs in other clinical trials within 30 days prior to the first administration Patients who received cytotoxic chemotherapy for the treatment of advanced non-small cell lung cancer or other anticancer drugs other than EGFR TKI within 14 days prior to the first administration of the investigational drug Prior local-regional therapy within 4 weeks prior to Day 1 of trial treatment (e.g., major surgery, radiation therapy [with the exception of palliative bone-directed radiotherapy and radiotherapy administered to superficial lesions], hepatic arterial embolization, transcatheter arterial chemoembolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) Patients currently receiving drugs or herbal supplements known as inhibitors or inducers of CYP3A4 or who cannot discontinue use at least 1 week prior to the first dose of lazertinib. Previous anticancer treatment-related toxicities not recovered to baseline or Grade 0-1 (except alopecia) Symptomatic spinal cord compression (However, registration is allowed if steroid treatment is not required within at least 2 weeks before the start of administration of the investigational drug) Symptomatic and unstable central nervous system (CNS) or brain metastasis requiring local treatment at screening. (Asymptomatic or mild symptomatic leptomeningeal metastasis is also permitted to be registered) Symptomatic or intracranial bleeding that needs treatment History of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD Carcinoma other than non-small cell lung cancer, if the investigator is judged to be inadequate to participate in this clinical trial due to evidence of severe or uncontrolled systemic disease, uncontrolled hypertension, or active bleeding tendency, or that it is difficult to follow this protocol. (Screening for chronic disease is not required) Any of the following cardiovascular diaseases: A history of congestive heart failure (CHF) of grade 3 or higher according to the New York Heart Association Classification (NYHA) or cardiac arrhythmia requiring treatment/A History of unstable angina or myocardial infarction experienced within 6 months before the first administration of the investigational drug/Left ventricular ejection fraction <50% on recent echocardiography or MUGA scan Known human immunodeficiency virus (HIV) infection Patient has known active hepatitis B virus(HBV) or hepatitis C virus (HCV) infection Patients with refractory nausea and vomiting, chronic gastrointestinal disorders, inability to swallow the product, or undergoing enterectomy deemed to interfere with the proper absorption of lazertinib. History of hypersensitivity to drugs Clinically significant chronic infection or major medical or mental illness Subjects with any concurrent medical condition or disease that will potentially compromise the conduct of the study at the discretion of the Investigators History of allogeneic hematopoietic stem cell transplantation, history of whole blood transfusions that did not remove leukocytes within 120 days before the date of collection of genetics specimens

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: lazertinib(YH25448)<br>lazertinib 240mg, once a day, oral, before disease progression | Drug: lazertinib(YH25448)<br>* - lazertinib 240mg(3tablets, 80mg/1tablet), once a day, oral, before disease progression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intracranial objective response rates (iORR) (RECIST1.1) | iORR will be evaluated according to RECIST v1.1 after IP administration and Response data will be used for the primary endpoint. | From date of the first administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| intracranial progression free survival, iPFS | the date of onset of objective intracranial disease progression or death of any cause, whichever occurs first. | Up to 2 years | 
| iORR in T790M negative, isolated CNS progression patient group | iORR will be evaluated according to RECIST v1.1 after IP administration | From date of the first administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months | 
| overall ORR | ORR will be evaluated according to RECIST v1.1 after IP administration. | From date of the first administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months | 
| duration of response, DoR | Duration from the date of the first documented confirmatory response(CR or PR) to the date of documented disease progression or death (equivalent to the date of the PFS event) | Up to 2 years | 
| disease control rate, DCR | the percentage of subjects whose response is CR, PR, responding, or SD. | Up to 2 years | 
| overall survival, OS | the period from the first administration of the investigational drug to the date of death from any cause. | Up to 2 years | 
| treatment failure pattern | intracranial progression or extracranial progression or both | From date of the first administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months | 
| salvage intracranial treatment rate | the percentag of subjects who received salvage treatment(surgery or radiation therapy) due to intracranial disease progression. | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, Brain Metastases, Failure of EGFR TKI