Clinical Trial of YH25448(Lazertinib) as the First-line Treatment in Patients With EGFR Mutation Positive Locally Advanced or Metastatic NSCLC (LASER301)

Study Overview
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Brief Summary
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This Phase III study will be conducted to evaluate the efficacy and safety of YH25448 as first-line treatment in locally advanced or metastatic Non-small Cell Lung Cancer (NSCLC) patients with EGFR mutations

Detailed Description
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YH25448 is an oral, highly potent, mutant-selective and irreversible EGFR Tyrosine-kinase inhibitors (TKIs) that targets both the T790M mutation and activating EGFR mutations while sparing wild type EGFR. This is a Phase III, Randomized, Double-blind study evaluating the efficacy and safety of YH25448 (240 mg orally, once daily) versus Gefitinib (250 mg orally, once daily) in patients with locally advanced or metastatic NSCLC that is known to be EGFR sensitizing mutation (EGFRm) positive, treatment-naïve and eligible for first-line treatment with an EGFR-TKI.

Official Title
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A Phase III, Randomized, Double-blind Study to Assess the Efficacy and Safety of Lazertinib Versus Gefitinib as the First-line Treatment in Patients With Epidermal Growth Factor Receptor Sensitizing Mutation Positive, Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Lazertinib 240 mg/160 mg
* Drug: Gefitinib 250 mg
* Drug: Lazertinib-matching placebo 240 mg/160 mg
* Drug: Gefitinib-matching placebo 250 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed adenocarcinoma of the lung Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy At least 1 of the 2 common EGFR mutations known to be associated with EGFR TKI sensitivity (Ex19del or L858R), either alone or in combination with other EGFR mutations Treatment-naïve for locally advanced or metastatic NSCLC WHO performance status score of 0 to 1 with no clinically significant deterioration over the previous 2 weeks before randomization At least 1 measurable lesion, not previously irradiated and not chosen for biopsy during the study Screening period Exclusion Criteria: Symptomatic and unstable brain metastases Leptomeningeal metastases Symptomatic spinal cord compression History of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD Any medical conditions requiring chronic continuous oxygen therapy History of any malignancy other than the disease under study within 3 years before randomization Any cardiovascular disease as follows: History of symptomatic chronic heart failure or serious cardiac arrhythmia requiring active treatment History of myocardial infarction or unstable angina within 24 weeks of randomization

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Approximately 380 patients will be randomized in a 1:1 ratio to either lazertinib (n=190) or gefitinib (n= 190). Following objective disease progression according to RECIST v1.1, as per investigator assessment, patients who were randomized to gefitinib arm may have the option to receive open-label lazertinib
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lazertinib + Gefitinib-matching placebo<br>Lazertinib (240 mg or 160 mg orally, once daily) plus Gefitinib-matching placebo (250 mg orally, once daily) in accordance with the randomization schedule | Drug: Lazertinib 240 mg/160 mg<br>* The initial dose of lazertinib 240 mg (3 tablets of 80 mg lazertinib) once daily can be reduced to 160 mg once daily (2 tablets of 80 mg lazertinib) under specific circumstances<br>* Other names: YH25448 240 mg/160 mg;Drug: Gefitinib-matching placebo 250 mg<br>* The initial dose for Gefitinib-matching placebo (250 mg once daily) cannot be reduced to a lower dose<br>* Other names: Iressa-matching placebo 250 mg;|
| Active Comparator: Gefitinib + Lazertinib-matching placebo<br>Gefitinib (250 mg orally, once daily) plus Lazertinib-matching placebo (240 mg or 160 mg orally, once daily) in accordance with the randomization schedule | Drug: Gefitinib 250 mg<br>* The initial dose for Gefitinib (250 mg once daily) cannot be reduced to a lower dose<br>* Other names: Iressa 250 mg;Drug: Lazertinib-matching placebo 240 mg/160 mg<br>* The initial dose of lazertinib-matching placebo 240 mg (3 tablets of 80 mg lazertinib-matching placebo) once daily can be reduced to 160 mg once daily (2 tablets of 80 mg lazertinib-matching placebo) under specific circumstances<br>* Other names: YH25448-matching placebo 240 mg/160 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) according to RECIST v1.1 by Investigator assessment | To assess the efficacy of lazertinib compared with gefitinib as measured by PFS | The primary analysis of PFS based on investigator assessment will occur when PFS maturity is observed at approximately 27 months after the first patient is randomized | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) according to RECIST v1.1 by Investigator assessments | To further assess the efficacy of lazertinib compared with gefitinib | ORR analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized | 
| Duration of Response (DoR) according to RECIST v1.1 by Investigator assessments | To further assess the efficacy of lazertinib compared with gefitinib | DoR analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized | 
| Disease Control Rate (DCR) according to RECIST v1.1 by Investigator assessments | To further assess the efficacy of lazertinib compared with gefitinib | DCR analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized | 
| Depth of Response according to RECIST v1.1 by Investigator assessments | To further assess the efficacy of lazertinib compared with gefitinib | Depth of Response analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized | 
| Time to Response according to RECIST v1.1 by Investigator assessments | To further assess the efficacy of lazertinib compared with gefitinib | Time to Response analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized | 
| Overall survival (OS) | To assess OS of lazertinib compared with gefitinib | OS will be analyzed at 2 time points: when PFS maturity is observed at approximately 27 months after the first patient is randomized, and when OS maturity is observed at approximately 45 months after the first patient is randomized | 
| Plasma concentrations of lazertinib | To characterize the pharmacokinetics (PK) of lazertinib | Plasma concentration analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized | 
| Cerebrospinal fluid (CSF) concentrations of lazertinib | To characterize the PK of lazertinib | CSF concentration analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized | 
| Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 items (QLQ-C30) | The EORTC QLQ-C30 consists of 30 items and measures cancer patients' functioning (health related quality of life (HRQoL)) and symptoms for all cancer types. Questions can be grouped into 5 multi item functional scales (physical, role, emotional, cognitive, and social); 3 multi item symptom scales (fatigue, pain, nausea/vomiting); a 2 item global HRQoL scale; 5 single items assessing additional symptoms commonly reported by cancer patients (dyspnea, loss of appetite, insomnia, constipation, diarrhea) and 1 item on the financial impact of the disease. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. a high score for a functional scale represents a high / healthy level of functioning a high score for the global health status / QoL represents a high QoL but a high score for a symptom scale / item represents a high level of symptomatology / problems | EORTC-QLQ-C30 analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaires Lung Cancer 13 items (EORTC QLQ-LC13) | The EORTC QLQ-LC13 includes questions assessing cough, hemoptysis, dyspnea, site specific pain (symptoms), sore mouth, dysphagia, peripheral neuropathy, and alopecia (treatment related side effects), and pain medication. The items on both measures were scaled and scored using the recommended EORTC procedures. Raw scores were transformed to a linear scale ranging from 0 to 100, with a higher score representing a higher level of functioning or higher level of symptoms. Provided at least half of the items in the scale were completed, the scale score was calculated using only those items for which values existed. | EORTC QLQ-LC13 analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized | 
| Change From Baseline in Euro-Quality of Life-5 Dimension-5 level (EQ-5D-5L) | The EQ-5D comprises the following two questionnaires: The EQ-5D comprises 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). Each dimension comprises five levels (no problems, slight problems, moderate problem, severe problem, unable/extreme problems). The EQ VAS records the patients self-rated health status on a vertical graduated (0-100) visual analogue scale. The patient's self-rated health is assessed on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state) by the EQ-VAS. | EQ-5D-5L analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ex19del, Locally Advanced EGFR Sensitizing Mutation, Metastatic EGFR Sensitizing Mutation, EGFR TKI, L858R, First-line, YH25448, Advanced Non-Small Cell Lung Cancer, Adenocarcinoma of lung, Non-squamous carcinoma of lung, Phase III, Lazertinib