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
Phase: PHASE3
Conditions: Non-Small Cell Lung Cancer
Sponsor: Yuhan Corporation

Confidential 
Study No.: YH25448-301 
Protocol Ver2
PROTOCOL 
Study Number: YH25448-301 
Protocol Title: 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 
Short Title: Lazertinib vs Gefitinib as First-Line Treatment in Patients with 
EGFRm+ Locally Advanced or Metastatic NSCLC (LASER301) 
Investigational Product: 
Lazertinib 
Phase: 
III 
Protocol Version: 
2 
Date:  
03Sep2020 
This document is a confidential communication of Yuhan Corporation. Acceptance of this document constitutes 
an agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without Yuhan Corporation’s prior written approval, except that this document may be disclosed to appropriate 
Institutional Review Committees so long as they are requested to keep it confidential. 

Confidential 
Study No.: YH25448-301 
Protocol Ver2
SOP-CD-03-Form2 Ver2 
SIGNATURE PAGE 
SPONSOR SIGNATORY 
INVESTIGATOR SIGNATORY 
I agree to conduct this clinical study in accordance with the design outlined in this protocol and 
to abide by all provisions of this protocol. 
Printed Name: 
Title: 
Signature: 
Date: 
PPD 

Confidential 
Study No.: YH25448-301 
Protocol Ver2
Page 3 of 127 
SOP-CD-03-Form2 Ver2 
DOCUMENT HISTORY 
Document 
Date of Issue 
Summary of Change 
Ver1 
18Oct2019 
Not Applicable 
Ver2 
03Sep2020 
•
Added 
the 
exclusion 
criteria 
related 
to 
prior/concomitant therapy
•
Changed the exclusion criteria for brain 
metastases, the criteria for restart study treatment
and the allowed window for PK blood samples at 
pre-dose
•
Removed the measurement of metabolite 
YH26334
•
Others including word correction etc.

Confidential 
Study No.: YH25448-301 
Protocol Ver2
Page 4 of 127 
SOP-CD-03-Form2 Ver2 
SYNOPSIS 
TITLE OF STUDY: 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 
SPONSOR : Yuhan Corporation (74, Noryangjin-ro, Dongjak-gu, Seoul, Republic of Korea) 
PHASE OF DEVELOPMENT: Phase III 
OBJECTIVES: 
Primary Objective 
Endpoint 
To assess the efficacy of lazertinib 
compared with gefitinib as measured by 
progression-free survival (PFS). 
PFS 
according 
to 
RECIST 
v1.1 
by 
Investigator assessment. 
Secondary Objectives 
Endpoints 
To further assess the efficacy of lazertinib 
compared with gefitinib. 
•
Objective Response Rate (ORR)
•
Duration of Response (DoR)
•
Disease Control Rate (DCR)
•
Depth of Response
•
Time to Response
All according to RECIST v1.1 by Investigator 
assessments. 
To assess overall survival of lazertinib 
compared with gefitinib. 
•
Overall survival (OS)
To characterize the pharmacokinetics 
(PK) of lazertinib. 
•
Plasma concentrations of lazertinib at 
pre-dose, 1 to 3 hours, and 4 to 6 hours 
post-dose
•
Cerebrospinal fluid (CSF) concentrations 
of lazertinib
To assess the impact of lazertinib 
compared with gefitinib on patient’s 
disease-related symptoms and Health 
Related Quality of Life (HRQoL). 
Change from baseline in : 
•
European Organization for Research and 
Treatment of Cancer Quality of Life 
Questionnaire – Core 30 items (EORTC 
QLQ-C30)
•
European Organization for Research and 
Treatment of Cancer Quality of Life 
Questionnaire – Lung Cancer 13 items 
(EORTC QLQ-LC13)
•
Euro-Quality of Life-5 Dimension-5 
level (EQ-5D-5L)
Safety Objectives 
Endpoints 
To assess the safety and tolerability profile 
of lazertinib compared with gefitinib. 
•
Adverse events graded by Common 
Terminology Criteria for Adverse Event 
(CTCAE) version 5.0
•
Clinical chemistry, hematology, and 
urinalysis

Confidential 
Study No.: YH25448-301 
Protocol Ver2
Page 5 of 127 
SOP-CD-03-Form2 Ver2 
•
Vital signs (pulse, blood pressure, body 
temperature), physical examination, body 
weight
•
Electrocardiogram (ECG)
•
Left 
Ventricular 
Ejection 
Fraction 
(LVEF)
•
World Health Organization (WHO) 
Performance Status
•
Ophthalmologic assessment
Exploratory Objectives 
Endpoints 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Confidential 
Study No.: YH25448-301 
Protocol Ver2
Page 6 of 127 
SOP-CD-03-Form2 Ver2 
NUMBER OF PATIENTS : Approximately 380 patients 
METHODOLOGY: 
This study is a randomized, double-blind, multinational phase III to assess the efficacy and 
safety of lazertinib 240 mg administered once daily orally compared with gefitinib 250 mg 
administered once daily orally in treatment-naïve patients with EGFR mutation positive 
(exon 19-deletion [Ex19del] or exon 21 [L858R] substitution), locally advanced or metastatic 
non-small cell lung cancer (NSCLC). 
At screening period, up to 28 days prior to randomization, patients will be assessed for 
eligibility. Approximately 380 patients will be randomized in a 1:1 ratio to either lazertinib 
(n=190) or gefitinib (n= 190). Randomization will be stratified by race (Asian vs. non-Asian) 
and mutation status (Ex19del vs. L858R). 
Eligible patients will be administered an investigational product (IP) orally once daily with 
or without food. A cycle of treatment is defined as 21 days. Patients should continue on their 
randomized treatment until RECIST v1.1 defined progression or until a treatment 
discontinuation criterion is met. However, patients may continue to receive their randomized 
CCI
CCI
CCI
CCI

Confidential 
Study No.: YH25448-301 
Protocol Ver2
Page 7 of 127 
SOP-CD-03-Form2 Ver2 
treatment beyond RECIST v1.1 defined progression as long as patients continue to show 
clinical benefit, as judged by the investigator.  
Efficacy assessments according to RECIST v1.1 are to be performed every 6 weeks for the 
first 18 months and then every 12 weeks relative to date of randomization using the RECIST 
v1.1 until objective disease progression. Patients will be followed for survival every 6 weeks 
following objective disease progression. 
Adverse events (AEs) are graded according to National Cancer Institute (NCI) CTCAE v5.0. 
For patients who cannot tolerate the protocol-specified dosing schedule due to drug related 
toxicities, dose interruptions and/or reductions are recommended in order to allow patients 
to continue the treatment. If, due to study treatment related toxicity, a patient requires a dose 
interruption of > 21 days from the intended day of the next scheduled dose, then the patient 
must be discontinued from the study treatment.  
Patients who were randomized to the gefitinib arm will have the option to receive treatment 
with open-label lazertinib 240 mg following objective disease progression according to 
RECIST v1.1, as per BICR, and a T790M mutation positive result. Determination of T790M 
mutation positive status may be performed locally, or centrally for those patients unable to 
be tested locally (plasma or tissue testing). 
SAMPLE SIZE DETERMINATION: 
To provide 90% power at a two-sided 5% significant level, approximately 207 progression-
free survival events will be required to detect a hazard ratio of 0.64 (for median PFS of 16.5 
months in lazertinib and 10.5 months in gefitinib). The primary analysis is expected to 
conduct at around 27 months, assuming approximately 380 patients are randomized over a 
period of 18 months. 
CRITERIA FOR INCLUSION/EXCLUSION 
Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply: 
Age and Sex 
1.
Male or female patients must be ≥ 18 years of age and satisfy the legal age of consent in 
the jurisdiction in which the study is being conducted.
Type of Patient and Disease Characteristics 
2.
Patients with pathologically confirmed adenocarcinoma of the lung (e.g., 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). Patients with mixed histology are 
eligible if adenocarcinoma is the predominant histology.
3.
Patients with locally advanced or metastatic NSCLC, not amenable to curative surgery 
or radiotherapy. 
4.
Patients with 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, assessed in tissue biopsy by an accredited local laboratory based on 
the Qiagen- Therascreen® EGFR Mutation Detection Kit RGQ (Scorpions ARMS), the 

Confidential 
Study No.: YH25448-301 
Protocol Ver2
Page 8 of 127 
SOP-CD-03-Form2 Ver2 
Amoy Diagnostics-the AmoyDx® EGFR Mutation Test Kit, the PANAGENE-
PANAMutyperTM or the Roche Diagnostics-Cobas® EGFR Mutation Test v2, or by 
central testing in a designated laboratory. 
5.
Mandatory provision of an unstained, archived tumor tissue sample in a quantity 
sufficient to allow for central analysis of EGFR mutation status for patients.
6.
Patients must be treatment-naïve for locally advanced or metastatic NSCLC. (Note: Prior 
adjuvant and neo-adjuvant therapy (e.g., chemotherapy, radiotherapy, investigational 
products) for early stage disease is permitted if completed > 12 months prior to 
randomization provided all other entry criteria are satisfied)
7.
Patients must have a WHO performance status score of 0 to 1 with no clinically 
significant deterioration over the previous 2 weeks before randomization.
8.
Patients must have at least 1 measurable lesion, not previously irradiated and not chosen 
for biopsy during the study Screening period, that can be accurately measured at baseline 
as ≥10 mm in the longest diameter (except lymph nodes which must have a short axis of 
≥15 mm) with computerized tomography (CT) or magnetic resonance imaging (MRI), 
and which is suitable for accurate repeated measurements. If only 1 measurable lesion 
exists, it is acceptable to be used (as a target lesion) as long as it has not been previously 
irradiated and baseline tumor assessment scans are done at least 2 weeks after the 
screening biopsy is performed. 
Male Patients 
9.
A male patient who has not undergone a vasectomy must agree to follow the 
contraceptive guidance in Appendix 3 of this protocol during the study treatment period 
and for at least 24 weeks after the last dose of study treatment and refrain from donating 
sperm during this period.
Female Patients 
10. A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at 
least one of the following conditions applies:
•
Not a woman of childbearing potential (WOCBP) as defined in Appendix 3.
OR 
•
A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 from the 
time of screening until 24 weeks after the last dose of study treatment.
•
A WOCBP must have a negative serum pregnancy test (beta human chorionic 
gonadotropin) at screening.
Informed Consent 
11. Patient must sign an informed consent form (ICF) prior to any study specific procedures 
which includes compliance with the requirements and restrictions listed in the ICF and 
in this protocol.
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1.
Symptomatic and unstable brain metastases. Patients with asymptomatic and stable brain 
metastases may participate in this study. If treatment is required, these patients must have 
completed any planned radiation therapy and/or surgery, are not on steroids, for >2

Confidential 
Study No.: YH25448-301 
Protocol Ver2
Page 9 of 127 
SOP-CD-03-Form2 Ver2 
weeks prior to randomization, and remain asymptomatic. Patients must be 
neurologically stable, having no new neurologic deficits on clinical examination, and no 
new findings on central nervous system (CNS) imaging. 
restrictions, and requirements, as determined by the Investigator.
Prior/Concomitant Therapy 
16. Prior treatment with any systemic antineoplastic therapy for locally advanced or 
metastatic NSCLC (Stage IIIB/C or Stage IV) including chemotherapy, biological 
therapy, immunotherapy, or any investigational drug. 

Confidential 
Study No.: YH25448-301 
Protocol Ver2
Page 10 of 127 
SOP-CD-03-Form2 Ver2 
17. Any prior treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor 
(EGFR-TKI).
18. Major surgery (excluding placement of vascular access) within 4 weeks of 
randomization.
19. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of 
radiation within 4 weeks of randomization.
20. Patients currently receiving (or unable to stop use for an appropriate washout period 
prior to randomization) medications or herbal supplements known to be potent CYP3A4 
inhibitors or inducers (Appendix 6).
21. Patients currently receiving the unstable doses of warfarin as an anticoagulant.
22. Patients who have been treated with alternative anti-cancer treatment within 5 half-lives 
of the treatment or within 4 weeks (whichever is longer) prior to randomization.
23. Any unresolved toxicities from prior therapy, greater than CTCAE grade 1 at 
randomization, with the exception of alopecia and grade 2, prior chemotherapy-induced 
neuropathy.
Prior/Concurrent Clinical Study Experience 
24. Patients who have been treated with an investigational drug within 5 half-lives of the 
compound or within 4 weeks (whichever is longer) prior to randomization.
Diagnostic Assessments 
25. Patient has any of following cardiac criteria:
•
Any clinically important abnormalities in rhythm, conduction, or morphology of 
resting ECG (e.g., complete left bundle branch block, third degree heart block, 
second degree heart block, PR interval >250msec).
•
Mean resting QTc >470 msec obtained from 3 electrocardiograms (ECGs), using the 
screening ECG machine derived QTc value.
•
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, hypokalemia, congenital long QT syndrome, family history of 
long QT syndrome, or unexplained sudden death under 40 years of age in first degree 
relatives or any concomitant medications known to prolong QT interval or induce 
Torsades de Pointes (Appendix 6).
•
Left ventricular ejection fraction <50%
26. Inadequate bone marrow reserve or organ function as demonstrated by any of the 
following laboratory values:
•
Absolute neutrophil count <1.5 x 109/L.
•
Platelet count <100 x 109/L.
•
Hemoglobin <90 g/L.
•
Alanine aminotransferase >2.5 times the upper limit of normal (ULN) if no 
demonstrable liver metastases, or >5x ULN in presence of liver metastases.
•
Aspartate aminotransferase >2.5x ULN if no demonstrable liver metastases or >5x 
ULN in the presence of liver metastases.
•
Total bilirubin >1.5x ULN if no liver metastases or >3x ULN in the presence of 
documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver 
metastases.

Confidential 
Study No.: YH25448-301 
Protocol Ver2
Page 11 of 127 
SOP-CD-03-Form2 Ver2 
•
Serum creatinine >1.5x ULN concurrent with creatinine clearance < 50 ml/min 
measured by the study site’s standard method (e.g., Cockcroft and Gault equation). 
Confirmation of creatinine clearance is only required when creatinine is >1.5x ULN.
TREATMENTS: 
Investigational products (IPs): 
Treatment 
Formulation 
Dose 
Route of administration 
Lazertinib 
Tablet 
240 mg (80 mg x 3 tablets) 
160 mg (80 mg x 2 tablets) 
Oral 
Gefitinib 
Capsulea,b 
250 mg 
Oral 
Lazertinib-
matching 
placebo 
Tablet 
Not applicable 
Oral 
Gefitinib-
matching 
placebo 
Capsuleb 
Not applicable 
Oral 
a Gefitinib tablet is over encapsulated. 
b Appearance of all capsules used for encapsulation is identical. 
STATISTICAL METHODS: 
The analyses of data will be based on different analysis population according to the purpose 
of the analyses. Analysis populations are described below:  
-
Full analysis set (FAS): All randomized patients. The FAS will be the primary analysis 
set for all efficacy analyses.
-
Safety analysis set: All patients who received at least one dose of study treatment
-
Pharmacokinetic analysis set: Patients who have at least 1 measurable concentration 
collected post-dose, supported by the relevant date and time of sample collection; and 
the relevant dosing date and time on the day of PK sampling and immediately before 
pre-dose PK sampling.
Efficacy: 
Primary Efficacy Analysis: 
Progression free survival (PFS) 
PFS is defined as the time from randomization until the date of objective disease progression 
or death (by any cause in the absence of progression) whichever comes first based on 
investigator assessment using RECIST v1.1. Patients who have not progressed or died at the 
time of analysis will be censored at the time of the latest date of assessment from their last 
evaluable RECIST v1.1 assessment.  
PFS in the FAS will be analyzed using a log rank test stratified by mutation type (Ex19del 
versus L858R) and race (Asian versus non-Asian) using the Breslow approach for handling 
ties. PFS will be displayed using Kaplan-Meier plot by treatment group. The number of 
events, medians and 95% confidence intervals of the medians (calculated from the Kaplan-
Meier estimate), and proportion of patients without an event at 12, 18 and 24 months will be 
summarized for each treatment group. Additionally, the hazard ratio for PFS will be 

Confidential 
Study No.: YH25448-301 
Protocol Ver2
Page 12 of 127 
SOP-CD-03-Form2 Ver2 
calculated, along with its 95% confidence interval, from a stratified Cox model using the 
same stratification factors as for the log-rank test. 
Secondary Efficacy Analysis: 
Objective response rate (ORR) 
ORR is defined as the percentage of patients with measurable disease with at least one visit 
response of complete response (CR) or partial response (PR). 
ORR will be analyzed using a logistic regression stratified by mutation type (Ex19del versus 
L858R) and race (Asian versus non-Asian). The results of the analysis will be presented in 
terms of an odds ratio together with its associated 95% profile likelihood confidence interval. 
Duration of Response (DoR) 
DoR is defined as the time from the date of first documented response until the date of 
documented progression or death whichever comes first. 
DoR in responding patients will be summarized and the number of responding patients with 
a duration of response (>6; >9; >12; >15 months) will be presented by treatment group. A 
Kaplan-Meier plot and median DoR with 95% CI (calculated from the Kaplan-Meier 
estimate) will be presented by treatment group. DoR will be analyzed using the same method 
as the analysis of PFS. 
Disease control rate (DCR) 
DCR is defined as the percentage of patients who have a best overall response of CR or PR 
or stable disease (SD).  
DCR will be analyzed using the same method as the analysis of ORR.  
Depth of response 
Depth of response will be determined for patients with measurable disease at baseline and is 
derived at each visit by the percentage change in the sum of the diameters of target lesions in 
the absence of new lesions or progression of non-target lesions compared to baseline. The 
absolute change and percentage change from baseline in the sum of tumor size at each 
assessment will be calculated.  
The effect of lazertinib on best percentage change in tumor size will be estimated from an 
analysis of covariance (ANCOVA) model with treatment group as a fixed effect and baseline 
sum of target lesion diameter as a covariate. The number of patients, unadjusted mean, and 
least square means for each treatment group will be presented, together with the difference 
in least squares means, 95% CI and corresponding p-value. 
Time to response (TTR) 
TTR is defined as the time from the date of randomization until the date of first documented 
response. A summary statistics will be produced for TTR, by treatment group. 
Overall survival (OS) 
OS is defined as the time from the date of randomization until the date of death due to any 
cause. Any patient not known to have died at the time of analysis will be censored based on 
the last recorded date on which the patient was known to be alive.  
OS will be analyzed using the same methodology and model as for the analysis of PFS 
provided there are sufficient events available for a meaningful analysis (>20 deaths. if not, 

Confidential 
Study No.: YH25448-301 
Protocol Ver2
Page 13 of 127 
SOP-CD-03-Form2 Ver2 
descriptive summaries will be provided). As appropriate, summaries of the number and 
percentage of patients who have died, are still in survival follow-up, are lost to follow-up and 
have withdrawn consent will be presented for each treatment group.  
The final analysis of OS will be performed after approximately 45 months survival follow-
up from the first patient randomized. Approximately 200 deaths will be anticipated at this 
time. 
HRQoL (Patient Reports Outcomes) 
The following variables will be summarized as appropriate and further details will be 
provided in the statistical analysis plan: 
-
EORTC QLQ-C30
-
EORTC QLQ-LC13
-
EQ-5D-5L
Safety: 
Safety analysis: All patients who receive at least one dose of IP will be included in the 
assessment of the safety profile (safety analysis set). At the end of the study, appropriate 
summaries of all safety data will be produced, as defined below. 
The safety parameters are AEs, clinical laboratory parameters, vital signs, ECG parameters 
and physical examination. For each safety parameter, the last non-missing safety assessment 
made before the date of the first administration of study treatment will be used as the baseline 
for all analyses of that safety parameter. Continuous variables will be summarized by number 
of patients, mean, SD, median, minimum, and maximum values. Categorical variables will 
be summarized by frequency distribution (number and percentage of patients). 
All adverse events will be standardized by systemic organ class and preferred term and 
summarized by each treatment group. Serious adverse events and adverse events with a 
causal relationship to the study treatment will be described for each treatment group. ECGs, 
vital signs, physical examinations and clinical laboratory test results at each observed time 
point will be summarized and listed by each treatment group. 
Pharmacokinetics: 
Plasma concentrations of lazertinib will be summarized by nominal sampling time. CSF 
concentrations of lazertinib will also be summarized. The summary statistics will be 
presented by number of patients, arithmetic mean, standard deviation, arithmetic coefficient 
of variation, median, minimum, maximum, geometric mean, and geometric coefficient of 
variation. 

Confidential 
Study No.: YH25448-301 
Protocol Ver2
Page 14 of 127 
SOP-CD-03-Form2 Ver2 
TABLE OF CONTENTS 
SIGNATURE PAGE ........................................................................................................................... 2 
DOCUMENT HISTORY ................................................................................................................... 3 
SYNOPSIS 
4 
TABLE OF CONTENTS ................................................................................................................. 14 
LIST OF TABLES ............................................................................................................................ 18 
LIST OF FIGURES .......................................................................................................................... 18 
1.
INTRODUCTION AND STUDY RATIONALE ................................................................. 19 
1.1. 
INTRODUCTION ............................................................................................................. 19 
1.2. 
SUMMRY OF NONCLINICAL STUDIES .................................................................... 19 
1.3. 
SUMMARY OF CLINICAL STUDIES .......................................................................... 20 
1.4. 
STUDY RATIONALE ...................................................................................................... 21 
1.5. 
DOSE SELECTION RATIONALE ................................................................................. 21 
1.6. 
OVERALL RISK/BENEFIT ASSESSMENT ................................................................. 22 
1.6.1. Potential Benefit ........................................................................................................... 22 
1.6.2. Potential Risks .............................................................................................................. 22 
1.6.3. Overall Benefit-Risk and Ethical Assessment ............................................................ 22 
2.
STUDY OBJECTIVES AND ENDPOINTS......................................................................... 23 
3.
ETHICS
25 
3.1.
INDEPENDENT ETHIC COMMITTEES / INSTITUTIONAL REVIEW BOARD . 25 
3.2. 
ETHICAL CONDUCT OF THE STUDY ....................................................................... 25 
3.3. 
PATIENT INFORMATION AND CONSENT ............................................................... 25 
4.
INVESTIGATIONAL PLAN ................................................................................................ 25 
4.1. 
STUDY DESIGN ............................................................................................................... 25 
4.1.1. Overall Design ............................................................................................................... 25 
4.1.2. Scientific Rationale for Study Design ......................................................................... 27 
4.2. 
STUDY POPULATION .................................................................................................... 27 
4.2.1. Inclusion Criteria ......................................................................................................... 28 
4.2.2. Exclusion Criteria ......................................................................................................... 29 
4.2.3. Screening Failures ........................................................................................................ 31 
4.2.4. Discontinuation of Patient from Study ....................................................................... 31 
4.2.4.1. 
Discontinuation of Study Treatment ..................................................................... 32 
4.2.4.2. 
Patient Discontinuation/Withdrawal from the Study .......................................... 33 
4.2.4.3. 
Lost to Follow-Up ................................................................................................... 33 
4.2.4.4. 
Procedures for Study Treatment Discontinuation ............................................... 34 
5.
TREATMENTS ...................................................................................................................... 34 
5.1. 
STUDY TREATMENT ..................................................................................................... 34 
5.1.1. Investigational Product ................................................................................................ 34 
5.1.2. Non-investigational Product ........................................................................................ 34 
5.1.3. Code, Description and Composition of Investigational Products ............................ 35 
5.1.4. Packaging and Labeling ............................................................................................... 35 
5.1.5. Handling and Dispensing ............................................................................................. 35 
5.2. 
METHOD OF ASSIGNING PATIENTS TO A TREATMENT ................................... 36 
5.3. 
METHOD OF ADMINISTRATION ............................................................................... 36 
5.3.1. Treatment in Main Study ............................................................................................ 36 
5.3.2. Open-label Lazertinib Treatment in Cross-Over Study ........................................... 37 
5.4. 
DOSE MODIFICATION .................................................................................................. 37 
5.4.1. General Dose Adjustments for Adverse Events ......................................................... 37 
5.4.1.1. 
Corneal Ulceration ................................................................................................. 40 
5.4.1.2. 
Interstitial Lung Disease ........................................................................................ 40 
5.4.1.3. 
Cardiac Dysfunction ............................................................................................... 40 
5.4.1.4. 
Rash-related adverse events .................................................................................. 40 

Confidential 
Study No.: YH25448-301 
Protocol Ver2
Page 15 of 127 
SOP-CD-03-Form2 Ver2 
5.4.1.5. 
Diarrhea .................................................................................................................. 42 
5.4.1.6. 
Liver Chemistry Abnormalities ............................................................................. 43 
5.5. 
BLINDING / UNBLINDING ............................................................................................ 45 
5.5.1. Methods for Ensuring Blinding ................................................................................... 45 
5.5.2. Methods for Unblinding ............................................................................................... 45 
5.6. 
CONCOMITANT TREATMENTS ................................................................................. 45 
5.6.1. Permitted Treatments .................................................................................................. 46 
5.6.2. Prohibited Treatments ................................................................................................. 46 
5.6.3. Other Restrictions and Precautions ............................................................................ 47 
5.7. 
TREATMENT COMPLIANCE ....................................................................................... 47 
6.
STUDY ASSESSMENTS AND PROCEDURES ................................................................. 47 
6.1. 
SCREENING PERIOD ..................................................................................................... 60 
6.1.1. Written informed consent ............................................................................................ 60 
6.1.2. Assignment of Patient Screening/Randomization Number ...................................... 60 
6.2. 
TREATMENT PERIOD ................................................................................................... 60 
6.3. 
FOLLOW-UP PERIOD .................................................................................................... 61 
6.3.1. Discontinuation Visit .................................................................................................... 61 
6.3.2. 28-Day Safety Follow-up Visit ..................................................................................... 61 
6.3.3. Progression Follow-up Visit......................................................................................... 61 
6.3.4. Survival Follow-up Visit .............................................................................................. 61 
6.4. 
CROSS-OVER TO OPEN-LABEL LAZERTINIB ....................................................... 62 
6.4.1. Central Confirmation of Disease Progression............................................................ 62 
6.4.2. T790M Testing .............................................................................................................. 62 
6.4.3. Unblinding ..................................................................................................................... 62 
6.4.4. Open-label Treatment with Lazertinib....................................................................... 63 
6.5. 
End of Study Definition ..................................................................................................... 63 
6.6. 
STUDY MATERIALS ...................................................................................................... 63 
6.7. 
SAFETY ASSESSMENTS ................................................................................................ 63 
6.7.1. Adverse Events (AEs) ................................................................................................... 63 
6.7.2. 12-lead Electrocardiograms ......................................................................................... 64 
6.7.3. Physical Examinations ................................................................................................. 64 
6.7.4. Vital Signs ..................................................................................................................... 64 
6.7.5. Laboratory Test Assessment ....................................................................................... 65 
6.7.6. Other Safety Assessments ............................................................................................ 66 
6.8. 
EFFICACY ASSESMENTS ............................................................................................. 67 
6.8.1. RECIST v1.1 Assessments ........................................................................................... 67 
6.8.2. Blinded Independent Central Review ......................................................................... 68 
6.8.3. Assessment of PFS after Next-line treatment (PFS2) ................................................ 69 
6.8.4. Mandatory Tumor Biopsy Sample for Central Mutation Analysis ......................... 69 
6.9. 
OTHER ASSESSMENTS ................................................................................................. 69 
6.9.1. WHO Performance Status ........................................................................................... 69 
6.9.2. Concomitant Medication Use ...................................................................................... 70 
6.9.3. Anti-cancer and Surgical Treatments ........................................................................ 70 
6.9.4. Patient-Reported Outcomes (PROs) ........................................................................... 70 
6.9.4.1. 
EORTC QLQ-C30 and EORTC QLQ-LC13 ....................................................... 70 
6.9.4.2. 
EQ-5D-5L ................................................................................................................ 71 
6.9.5. Health Resource Use Module ...................................................................................... 71 
6.10. PHARMACOKINETIC ASSESSMENTS ...................................................................... 72 
6.10.1. Collection of PK Samples ............................................................................................. 72 
6.10.2. Determination of Drug Concentration in PK Samples ............................................. 72 
6.10.3. Storage and Destruction of PK Samples .................................................................... 73 
6.11. PHARMACODYNAMICS ASSESSMENTS .................................................................. 73 

Confidential 
Study No.: YH25448-301 
Protocol Ver2
Page 16 of 127 
SOP-CD-03-Form2 Ver2 
6.12. PHARMACOGENOMIC/PHARMACOGENETIC ASSESSMENTS ........................ 73 
6.12.1. Pharmacogenetics: Collection and Processing ........................................................... 73 
6.12.2. Pharmacogenetic Sample Analyses ............................................................................. 73 
6.13. EXPLORATORY ASSESSMENT ................................................................................... 73 
7.
ADVERSE EVENTS .............................................................................................................. 74 
7.1. 
DEFINITIONS ................................................................................................................... 74 
7.1.1. Adverse Events ............................................................................................................. 74 
7.1.2. Serious Adverse Events ................................................................................................ 74 
7.1.3. Adverse Events of Special Interest .............................................................................. 74 
7.2. 
INTENSITY AND CAUSALITY ..................................................................................... 74 
7.3. 
COLLECTION AND REPORTING ............................................................................... 75 
7.3.1. Adverse Events ............................................................................................................. 75 
7.3.2. Serious Adverse Events ................................................................................................ 75 
7.3.3. Adverse Events of Special Interest .............................................................................. 76 
7.4. 
ADVERSE EVENTS BASED ON EXAMINATIONS AND TESTS ............................ 76 
7.4.1. Adverse events based on Potential Hy’s Law Criteria .............................................. 76 
7.5. 
ADVERSE EVENTS BASED ON DISEASE PROGRESSION .................................... 76 
7.6. 
ADVERSE EVENTS BASED ON NEW CANCERS ..................................................... 77 
7.7. 
OVERDOSE ....................................................................................................................... 77 
7.8. 
PREGNANCY.................................................................................................................... 77 
7.9. 
STANDARD TREATMENT AFTER STUDY COMPLETION .................................. 78 
7.10. OTHER SAFETY CONSIDERATION ........................................................................... 78 
8.
STATISTICAL CONSIDERATIONS .................................................................................. 78 
8.1. 
SAMPLE SIZE DETERMINATION .............................................................................. 78 
8.2. 
POPULATIONS FOR ANALYSES................................................................................. 79 
8.3. 
PATIENT DISPOSITION ................................................................................................ 79 
8.4. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ...................... 79 
8.5. 
PRIOR AND CONCOMITANT MEDICATION AND CONSERVATIVE 
TREATMENT ............................................................................................................................... 80 
8.6. 
ASSESSMENT OF TREATMENT COMPLIANCE ..................................................... 80 
8.7. 
ANALYSES ........................................................................................................................ 80 
8.7.1. Calculation or Derivation of Variables ....................................................................... 80 
8.7.1.1. 
Investigator RECIST v1.1-based Assessments ..................................................... 80 
8.7.1.2. 
BICR of RECIST v1.1-based Assessments ........................................................... 81 
8.7.2. Efficacy Analyses .......................................................................................................... 81 
8.7.2.1. 
Primary Efficacy Analysis...................................................................................... 81 
8.7.2.2. 
Secondary Efficacy Analyses ................................................................................. 82 
8.7.3. Exploratory Analyses ................................................................................................... 84 
8.7.4. Pharmacokinetic Analyses ........................................................................................... 86 
8.7.5. Pharmacodynamic Analyses ........................................................................................ 87 
8.7.6. Pharmacogenomic / Pharmacogenetic Analyses ........................................................ 87 
8.7.7. Biomarkers Analyses .................................................................................................... 87 
8.7.8. Safety Analyses ............................................................................................................. 87 
8.7.8.1. 
Adverse Events ....................................................................................................... 87 
8.7.8.2. 
Clinical Laboratory Parameters ........................................................................... 88 
8.7.8.3. 
Vital Signs................................................................................................................ 88 
8.7.8.4. 
12-lead Electrocardiogram .................................................................................... 88 
8.7.8.5. 
Physical Examination ............................................................................................. 88 
8.7.9. Subgroup Analyses ....................................................................................................... 89 
8.7.10. Multiple Testing Strategy ............................................................................................ 89 
8.7.11. Independent Data Monitoring Committee (IDMC) .................................................. 90 
8.7.12. Sensitivity Analyses ...................................................................................................... 90 
9.
ADMINISTRATIVE SECTION ........................................................................................... 90 

Confidential 
Study No.: YH25448-301 
Protocol Ver2
Page 17 of 127 
SOP-CD-03-Form2 Ver2 
9.1. 
COMPLIANCE ................................................................................................................. 90 
9.1.1. Compliance with the Protocol and Protocol Revisions ............................................. 90 
9.1.2. Monitoring .................................................................................................................... 90 
9.1.3. Investigational Site Training ....................................................................................... 91 
9.2. 
RECORD RETENTION ................................................................................................... 91 
9.2.1. Data on Electronic Data Capture System................................................................... 91 
9.2.2. Investigational Product Records ................................................................................. 91 
9.3. 
RETURN AND DESTRUCTION OF INVESTIGATIONAL PRODUCT .................. 92 
9.3.1. Return of Investigational Product .............................................................................. 92 
9.3.2. Destruction of Investigational Product ....................................................................... 92 
9.4. 
RETENTION AND DESTRUCTION OF HUMAN BIOLOGIC MATERIALS ....... 92 
9.5. 
PUBLICATIONS ............................................................................................................... 92 
10.
GLOSSARY OF TERMS ....................................................................................................... 93 
11.
LIST OF ABBREVIATIONS ................................................................................................ 95 
12.
REFERENCES LIST ............................................................................................................. 98 
Appendix 1. 
Regulatory, Ethical, and Study Oversight Considerations ........................... 101 
Appendix 2. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .............................................................................................................. 106 
Appendix 3. 
Contraceptive Guidance and Collection of Pregnancy Information ........... 112 
Appendix 4. 
Pharmacogenetic Research ............................................................................. 115 
Appendix 5. 
Algorithm for Continuation, Dose Modification, or Discontinuation of Study 
Treatment Based on Increases of LVEF Assessment................................................................... 116 
Appendix 6. 
Guidance on Concomitant Medications regarding Drug Interaction with 
Study Treatment 117 
Appendix 7. 
International 
Airline 
Transportation 
Association 
(IATA) 
Guidance 
Document 
122 
Appendix 8. 
EORTC QLQ C-30 .......................................................................................... 123 
Appendix 9. 
EORTC QLQ LC-13 ........................................................................................ 125 
Appendix 10. 
Euro-Quality of Life-5 Dimension-5 Level (EQ-5D-5L) ............................... 126 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 18 of 127 
SOP-CD-03-Form2 Ver2 
LIST OF TABLES 
Table 1. Summary of Preliminary Tumor Response (Independent Central Review) from study 
YH25448-201/ 73841937NSC2001...................................................................................................... 22 
Table 2. Investigational Products Description .......................................................................................... 35 
Table 3. Dose Modification Level ............................................................................................................... 37 
Table 4. Stepwise Algorithm for Management of Rash ........................................................................... 42 
Table 5. Schedule of Activities .................................................................................................................... 49 
Table 6. Schedule of Activities for Post-Progression Cross-Over to Lazertinib from Gefitinib Arm .. 55 
Table 7. Blood Sample Volumes ................................................................................................................. 59 
Table 8. Protocol-Required Safety Laboratory Assessments .................................................................. 66 
LIST OF FIGURES 
Figure 1. Study Design ................................................................................................................................ 27 
Figure 2. Dose Modification for AEs Related to Study Treatment ......................................................... 39 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 19 of 127 
SOP-CD-03-Form2 Ver2 
1. INTRODUCTION AND STUDY RATIONALE
1.1. 
INTRODUCTION  
Lung cancer is a leading cause of cancer death worldwide, causing 1.4 million deaths annually 
(1Torre et al, 2015). The discovery of somatic sensitizing epidermal growth factor receptor 
(EGFR) gene mutations such as exon 19-deletion [Ex19del] or exon 21 [L858R] substitution 
as targets for tyrosine kinase inhibitors (TKIs) has changed the paradigm of care for advanced 
non-small cell lung cancer (NSCLC) patients. Based on superior efficacy compared to 
chemotherapy, first and second generation EGFR TKIs such as erlotinib, gefitinib, afatinib, or 
dacomitinib are approved for their use in first-line settings for patients with advanced NSCLC 
harboring sensitizing EGFR mutations. However, patients with advanced NSCLC treated with 
first and second generation EGFR TKIs invariably develop acquired resistance. The most 
common mechanism of acquired resistance is a threonine-to-methionine substitution (T790M) 
secondary mutation at exon 20 in EGFR which develops in 50-60% of treated patients (2Pao W 
et al, 2010; 3Gazdar AF et al, 2009). This led to the development of third generation EGFR 
TKIs such as osimertinib, rociletinib, and olmutinib that are specifically designed to target 
T790M and EGFR TKI sensitizing mutations with more selectivity over the wild type form 
(4Juchum M et al, 2015; 5Engel J et al, 2016). Recently, osimertinib showed also a significant 
longer progression-free survival (PFS) compared to standard EGFR-TKI (gefitinib or erlotinib) 
as first-line treatment in NSCLC patients with EGFR mutations (6Soria JC et al, 2018).  
In addition, approximately half of patients with EGFR-mutated NSCLC develop brain 
metastasis (BM) within 3 years of diagnosis. Currently available EGFR TKIs show limited 
efficacy for the treatment of BM. The hypothesis behind this phenomenon is that due to limited 
blood-brain barrier (BBB) penetration of first and second generation TKIs, these drugs can 
neither effectively treat central nervous system (CNS) metastases nor prevent development of 
CNS metastases (7Engel J et al, 2015; 8Rangachari D et al, 2015). 
Lazertinib (YH25448) is an oral, highly potent, mutant-selective and irreversible EGFR TKI 
that targets both the T790M mutation and activating EGFR mutations while sparing wild type-
EGFR. In addition, nonclinical data suggest that lazertinib may be capable of crossing the blood 
brain barrier and potentially may offer better exposure in this anatomically protected location. 
Lazertinib will provide clinical benefit to the NSCLC patients with either activating EGFR 
mutations or T790M mutation based on the non-clinical and clinical results of lazertinib. This 
phase 3 study is designed to evaluate the efficacy and safety of lazertinib as first-line treatment 
in locally advanced or metastatic NSCLC patients with EGFR mutations. 
1.2. 
SUMMRY OF NONCLINICAL STUDIES 
Lazertinib selectively inhibits EGFR single- or double-mutant kinase activity compared to wild 
type-EGFR. IC50 of lazertinib was              for L858R/T790M,            for Ex19del, and   　                  
　  for wild type EGFR. In cell proliferation assays, GI50 values for lazertinib were    　　 for 
H1975 cells (L858R/T790M),　 　    for PC9 (Ex19del) cells, and     　 　 for wild type H2073 
cells, demonstrating potent and selective activity. Lazertinib inhibited human tumor growth in 
multiple xenograft mouse models, with more potent activity in models with EGFR mutations 
compared to models with wild-type EGFR. In a brain metastasis model, in which H1975 cells 
were implanted into brain parenchyma of nude mice, lazertinib achieved significant, complete 
tumor growth inhibition. Dose-dependent inhibition of phosphorylated-EGFR (p-EGFR) 
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 20 of 127 
SOP-CD-03-Form2 Ver2 
clinical study results are provided in the investigator brochure (IB). 
1.3. 
SUMMARY OF CLINICAL STUDIES 
The details for clinical study results are provided in the IB. 
CCI
CCI
CCI
CCI
CCI

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 21 of 127 
SOP-CD-03-Form2 Ver2 
1.4. 
STUDY RATIONALE 
1.5. 
DOSE SELECTION RATIONALE 
CCI
CCI

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 22 of 127 
SOP-CD-03-Form2 Ver2 
1.6. 
OVERALL RISK/BENEFIT ASSESSMENT 
 
CCI
1.6.3. Overall Benefit-Risk and Ethical Assessment 
1.6.2. Potential Risks 
CCI
CCI
CCI

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 23 of 127 
SOP-CD-03-Form2 Ver2 
END
POINTS
Primary Objective 
Endpoint 
To assess the efficacy of lazertinib 
compared with gefitinib as measured by 
progression-free survival (PFS). 
PFS according to RECIST v1.1 by Investigator 
assessment 
Secondary Objectives 
Endpoints 
To further assess the efficacy of lazertinib 
compared with gefitinib. 
•
Objective Response Rate (ORR)
•
Duration of Response (DoR)
•
Disease Control Rate (DCR)
•
Depth of Response
•
Time to Response
All according to RECIST v1.1 by Investigator 
assessments. 
To assess overall survival of lazertinib 
compared with gefitinib 
•
Overall survival (OS)
To characterize the pharmacokinetics (PK) 
of lazertinib. 
•
Plasma concentrations of lazertinib at pre-
dose, 1 to 3 hours, and 4 to 6 hours post-
dose
•
Cerebrospinal fluid (CSF) concentrations 
of lazertinib
To assess the impact of lazertinib compared 
with gefitinib on patient’s disease-related 
symptoms and Health Related Quality of 
Life (HRQoL). 
Change from baseline in : 
•
European Organization for Research and 
Treatment of Cancer Quality of Life 
Questionnaire – Core 30 items (EORTC 
QLQ-C30)
•
European Organization for Research and 
Treatment of Cancer Quality of Life 
Questionnaire – Lung Cancer 13 items 
(EORTC QLQ-LC13)
•
Euro-Quality of Life-5 Dimension-5 level 
(EQ-5D-5L)
Safety Objectives 
Endpoints 
To assess the safety and tolerability profile 
of lazertinib compared with gefitinib. 
•
Adverse events graded by Common 
Terminology Criteria for Adverse Event 
(CTCAE) version 5.0
•
Clinical 
chemistry, 
hematology, 
and 
urinalysis
•
Vital signs (pulse, blood pressure, body 
temperature), physical examination, body 
weight
•
Electrocardiogram (ECG)
CCI

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 24 of 127 
SOP-CD-03-Form2 Ver2 
•
Left Ventricular Ejection Fraction (LVEF)
•
World 
Health 
Organization 
(WHO) 
Performance Status
•
Ophthalmologic assessment
Exploratory Objectives 
Endpoints 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 25 of 127 
SOP-CD-03-Form2 Ver2 
3. ETHICS 
3.1. INDEPENDENT 
ETHIC 
COMMITTEES 
/ 
INSTITUTIONAL 
REVIEW BOARD 
The protocol, protocol amendments, ICF, investigator brochure (IB), and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the Investigator, or on 
the Investigators behalf, and reviewed and approved by the IRB/IEC before the study is initiated. 
A detailed instruction is provided in Appendix 1. 
3.2. ETHICAL CONDUCT OF THE STUDY 
This study will be conducted in accordance with the protocol, consensus ethical principles (e.g., 
Declaration of Helsinki), guidelines (e.g., ICH GCP), applicable laws, and regulations. A 
detailed instruction is provided in Appendix 1. 
3.3. PATIENT INFORMATION AND CONSENT 
Freely given written informed consent must be obtained from every patient (or in situations 
where consent cannot be given by patients, their legally acceptable representative) prior to 
clinical study participation. A detailed instruction is provided in Appendix 1. 
4. INVESTIGATIONAL PLAN
4.1. STUDY DESIGN 
4.1.1. Overall Design 
This study is a randomized, double-blind, multinational phase III to assess the efficacy and 
safety of lazertinib 240 mg administered once daily orally compared with gefitinib 250 mg 
administered once daily orally in treatment-naïve patients with EGFR mutations (Ex19del or 
L858R substitution), locally advanced or metastatic NSCLC.  
During screening, a period up to 28 days prior to randomization, patients will be assessed for 
eligibility. Patients will be enrolled based on either a locally available EGFR mutation result, 
which has been performed in an accredited local laboratory based on the Qiagen-Therascreen® 
EGFR Mutation Detection Kit RGQ (Scorpions ARMS), the Amoy Diagnostics-the AmoyDx® 
EGFR Mutation Test Kit, the PANAGENE-PANAMutyperTM or the Roche Diagnotics-Cobas® 
EGFR Mutation Test v2, or by testing performed at a designated central laboratory. All patients 
who are enrolled based on locally available EGFR mutation results, will be required to provide 
biopsy tissue and blood for central testing of the two most common EGFR mutations known to 
be associated with EGFR-TKI sensitivity (Ex19del and L858R). 
Approximately 380 patients will be randomized in a 1:1 ratio to either lazertinib (n=190) or 
gefitinib (n= 190). Randomization will be stratified by race (Asian vs. non-Asian) and mutation 
CCI
CCI

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 26 of 127 
SOP-CD-03-Form2 Ver2 
status (Ex19del vs. L858R). 
Eligible patients will be administered an investigational product (IP) orally once daily with or 
without food. A cycle of treatment is defined as 21 days. Patients should continue on their 
randomized treatment until RECIST version 1.1 (v1.1) defined progression or until a treatment 
discontinuation criterion is met. However, patients may continue to receive their randomized 
treatment beyond RECIST v1.1 defined progression as long as patients continue to show 
clinical benefit, as judged by the investigator.  
Efficacy assessments according to RECIST v1.1 are to be performed every 6 weeks for the first 
18 months and then every 12 weeks relative to date of randomization using the RECIST v1.1 
until objective progression. Patients will be followed for survival every 6 weeks following 
objective disease progression. 
Adverse events (AEs) are graded according to National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0.  
For patients who cannot tolerate the protocol-specified dosing schedule due to drug related 
toxicities, dose interruptions and/or reductions are recommended in order to allow patients to 
continue the treatment. If, due to study treatment related toxicity, a patient requires a dose 
interruption of > 21 days from the intended day of the next scheduled dose, then the patients 
must be discontinued from the study treatment.  
Patients who were randomized to the gefitinib arm may have the option to receive open-label 
lazertinib 
following 
objective 
disease 
progression 
according 
to 
RECIST v1.1, as per investigator assessment, provided ALL the following criteria are met, and 
should the patient wish to do-so: 
•
Disease progression confirmed by blinded independent central review (BICR) which
must be established prior to a patient being unblinded. (Note: if disease progression is
not centrally confirmed, the patient is not eligible to be considered for cross-over.
Should it be in the patients best interests, they may continue to receive randomized
treatment and submit the next scan for central imaging review according to the study
schedule.)
•
Tumor confirmed as T790M mutation positive by means of plasma or tissue testing
(local or central) following disease progression which must be established prior to a
patient being unblinded.
•
The patient cannot cross-over if they have received intervening therapy following
discontinuation of randomized treatment.
•
Any unresolved toxicities from prior therapy should be controlled, and be no greater
than CTCAE grade 1 (with the exception of alopecia) at the time of starting open-label
lazertinib treatment.
Provided all of the above criteria have been met, and the patient was randomized to the gefitinib 
arm, the patient may commence open-label lazertinib. If the patient has been unblinded and 
they are not eligible for cross-over or choose not to cross-over, they cannot recommence or 
continue on their randomized treatment. After IDMC, in consultation with sponsor and 
regulators determine the primary endpoint of PFS has been achieved, all patients determined 
to have objective disease progression according to RECIST v1.1 as per Investigator’s 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 27 of 127 
SOP-CD-03-Form2 Ver2 
assessment and T790M mutation positive will be given the opportunity to begin treatment with 
open-label lazertinib, if eligible for the criteria above described; central blinded confirmation 
of disease progression will no longer be required. See Table 6 and Section 6.4 for further details 
on post progression cross-over to lazertinib. 
Figure 1. Study Design 
4.1.2. Scientific Rationale for Study Design 
The design of this study follows the recommendations of the Food and Drug Administration 
guidance documents, “Guidance for Industry: Clinical Trial Endpoints for the Approval of 
Cancer Drugs and Biologics”, “Guidance for Industry: Clinical Trial Endpoints for the Approval 
of Non-Small Cell Lung Cancer Drugs and Biologics”, and the European Medicines Agency 
guidance document, “Guideline on the evaluation of anticancer medicinal product in man”. The 
purpose of this study is to evaluate the efficacy and safety of lazertinib in patients with 
EGFRm+, locally advanced or metastatic NSCLC as first-line treatment. Eligible patients will 
be randomized to either lazertinib or gefitinib. Gefitinib is approved for the first-line treatment 
of EGFRm+ NSCLC in many countries. Gefitinib has been chosen as a comparator as it is the 
agent most often used in NSCLC patients with activating EGFR mutations in the regions where 
the present study will be conducted. The primary efficacy endpoint is PFS by Investigator 
assessment. PFS is a recommended endpoint to support drug approval in the guidelines. PFS is 
also an acceptable surrogate for overall survival in patients with NSCLC (10Laporte S et al, 
2013).  
Preclinical and clinical data of lazertinib demonstrate promising anti-tumor efficacy and 
favorable safety profile in patients with EGFRm+ NSCLC. 
4.2. STUDY POPULATION 
The study population will consist of male and female patients at least 18 years of age with 
EGFRm+ (Ex19del or L858R) locally advanced or metastatic NSCLC. Patients must be able to 
provide written consent and meet all the inclusion criteria and none of the exclusion criteria. 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 28 of 127 
SOP-CD-03-Form2 Ver2 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
4.2.1. Inclusion Criteria  
Patients are eligible to be included in the study only if all of the following criteria apply: 
Age and Sex 
1.
Male or female patients must be ≥ 18 years of age and satisfy the legal age of consent in 
the jurisdiction in which the study is being conducted.
Type of Patient and Disease Characteristics 
2.
Patients with pathologically confirmed adenocarcinoma of the lung (e.g., 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). Patients with mixed histology are eligible if 
adenocarcinoma is the predominant histology.
3.
Patients with locally advanced or metastatic NSCLC, not amenable to curative surgery or 
radiotherapy. 
4.
Patients with 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, assessed in tissue biopsy by an accredited local laboratory based on the 
Qiagen-Therascreen® EGFR Mutation Detection Kit RGQ (Scorpions ARMS), the Amoy 
Diagnostics-the AmoyDx® EGFR Mutation Test Kit, the PANAGENE-PANAMutyperTM
or the Roche Diagnostics-Cobas® EGFR Mutation Test v2 or by central testing in a 
designated laboratory.
5.
Mandatory provision of an unstained, archived tumor tissue sample in a quantity sufficient 
to allow for central analysis of EGFR mutation status for patients.
6.
Patients must be treatment-naïve for locally advanced or metastatic NSCLC. (Note: Prior 
adjuvant and neo-adjuvant therapy (e.g., chemotherapy, radiotherapy, investigational 
products) for early stage disease is permitted if completed > 12 months prior to 
randomization provided all other entry criteria are satisfied)
7.
Patients must have a WHO performance status score of 0 to 1 with no clinically significant 
deterioration over the previous 2 weeks before randomization.
8.
Patients must have at least 1 measurable lesion, not previously irradiated and not chosen 
for biopsy during the study Screening period, that can be accurately measured at baseline 
as ≥10 mm in the longest diameter (except lymph nodes which must have a short axis of 
≥15 mm) with computerized tomography (CT) or magnetic resonance imaging (MRI), and 
which is suitable for accurate repeated measurements. If only 1 measurable lesion exists, 
it is acceptable to be used (as a target lesion) as long as it has not been previously irradiated 
and baseline tumor assessment scans are done at least 2 weeks after the screening biopsy 
is performed. 
Male Patients 
9.
A male patient who has not undergone a vasectomy must agree to follow the contraceptive 
guidance in Appendix 3 of this protocol during the study treatment period and for at least 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 29 of 127 
SOP-CD-03-Form2 Ver2 
24 weeks after the last dose of study treatment and refrain from donating sperm during this 
period. 
Female Patients 
10. A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at 
least one of the following conditions applies:
•
Not a woman of childbearing potential (WOCBP) as defined in Appendix 3.
OR 
•
A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 from the 
time of screening until 24 weeks after the last dose of study treatment.
•
A WOCBP must have a negative serum pregnancy test (beta human chorionic 
gonadotropin) at screening.
Informed Consent 
11. Patient must sign an ICF prior to any study specific procedures which includes compliance 
with the requirements and restrictions listed in the ICF and in this protocol.
4.2.2. Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1.
Symptomatic and unstable brain metastases. Patients with asymptomatic and stable brain 
metastases may participate in this study. If treatment is required, these Patients must have 
completed any planned radiation therapy and/or surgery, are not on steroids, for >2 weeks 
prior to randomization, and remain asymptomatic. Patients must be neurologically stable, 
having no new neurologic deficits on clinical examination, and no new findings on central 
nervous system (CNS) imaging.
2.
Leptomeningeal metastases
3.
Symptomatic spinal cord compression. If steroid treatment is not required within at least 
2 weeks prior to randomization then the patient may be enrolled.
4.
History of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which 
required steroid treatment, or any evidence of clinically active ILD.
5.
Any medical conditions requiring chronic continuous oxygen therapy.
6.
History of any malignancy other than the disease under study within 3 years before 
randomization (exceptions are squamous and basal cell carcinomas of the skin and 
carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, 
with concurrence with the medical monitor, is considered cured, or with minimal risk 
of recurrence within a year from screening).
7.
Any evidence of severe or uncontrolled systemic diseases, including uncontrolled 
hypertension and active bleeding diatheses, which in the Investigator’s opinion makes it 
undesirable for the patient to participate in the study, or which would jeopardize 
compliance with the protocol. 
8.
Any cardiovascular disease as follows: 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 30 of 127 
SOP-CD-03-Form2 Ver2 
•
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.
and requirements, as determined by the Investigators.
Prior/Concomitant Therapy 
16. Prior treatment with any systemic antineoplastic therapy for locally advanced or metastatic 
NSCLC (Stage IIIB/C or Stage IV) including chemotherapy, biological therapy, 
immunotherapy, or any investigational drug.
17. Any prior treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor 
(EGFR-TKI).
18. Major surgery (excluding placement of vascular access) within 4 weeks of randomization.
19. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of 
radiation within 4 weeks of randomization.
20. Patients currently receiving (or unable to stop use for an appropriate washout period prior 
to randomization) medications or herbal supplements known to be potent CYP3A4 
inhibitors or inducers (Appendix 6).
21. Patients currently receiving the unstable doses of warfarin as an anticoagulant.
22. Patients who have been treated with alternative anti-cancer treatment within 5 half-lives of 
the treatment or within 4 weeks (whichever is longer) prior to randomization.
23. Any unresolved toxicities from prior therapy, greater than CTCAE grade 1 at 
randomization, with the exception of alopecia and grade 2, prior chemotherapy-induced 
neuropathy.
Prior/Concurrent Clinical Study Experience 
24. Patients who have been treated with an investigational drug within 5 half-lives of the 
compound or within 4 weeks (whichever is longer) prior to randomization.
Diagnostic Assessments 
CCI

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 31 of 127 
SOP-CD-03-Form2 Ver2 
25. Patient has any of following cardiac criteria:
•
Any clinically important abnormalities in rhythm, conduction, or morphology of 
resting ECG (e.g., complete left bundle branch block, third degree heart block, second 
degree heart block, PR interval >250msec).
•
Mean resting QTc >470 msec obtained from 3 electrocardiograms (ECGs), using the 
screening ECG machine derived QTc value.
•
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, hypokalemia, congenital long QT syndrome, family history of 
long QT syndrome, or unexplained sudden death under 40 years of age in first degree 
relatives or any concomitant medications known to prolong QT interval or induce 
Torsades de Pointes (Appendix 6).
•
Left ventricular ejection fraction <50%
26. Inadequate bone marrow reserve or organ function as demonstrated by any of the following 
laboratory values:
•
Absolute neutrophil count <1.5 x 109/L.
•
Platelet count <100 x 109/L.
•
Hemoglobin <90 g/L.
•
Alanine aminotransferase >2.5 times the upper limit of normal (ULN) if no 
demonstrable liver metastases, or >5x ULN in presence of liver metastases.
•
Aspartate aminotransferase >2.5x ULN if no demonstrable liver metastases or >5x 
ULN in the presence of liver metastases.
•
Total bilirubin >1.5x ULN if no liver metastases or >3x ULN in the presence of 
documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver 
metastases.
•
Serum creatinine >1.5x ULN concurrent with creatinine clearance <50 ml/min 
measured by the study site’s standard method (e.g., Cockcroft and Gault equation). 
Confirmation of creatinine clearance is only required when creatinine is >1.5x ULN.
4.2.3. Screening Failures 
Screening failures are defined as patients who consent to participate in the clinical study but are 
not subsequently randomly assigned to study treatment/entered in the study. A minimal set of 
screening failure information is required to ensure transparent reporting of screen failure 
patients to meet the Consolidated Standards of Reporting Trials publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screening failure details, eligibility criteria, and any AEs or serious adverse events (SAEs).  
If a patient is a screening failure, but at some point in the future is believed to meet all of the 
eligibility criteria, the patient may be rescreened after a new informed consent has been 
obtained (only once). Patients who are rescreened will be assigned a new screening number and 
will start a new screening phase. If the patient already has EGFR sensitizing mutation positive 
test result at previous screening, the EGFR sensitizing mutation re-test is not required. 
4.2.4. Discontinuation of Patient from Study 
Refer to the Schedule of Activities (Table 5 and Table 6) for data that are to be collected at the 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 32 of 127 
SOP-CD-03-Form2 Ver2 
time of study discontinuation, during follow-up, and for any further evaluations that are to be 
completed. 
4.2.4.1. 
Discontinuation of Study Treatment 
For all patients in the study, discontinuation from study treatment will not result in automatic 
withdrawal from the study. In the absence of treatment delays, study treatment should continue 
until one of the following criteria applies: 

Objective disease progression as per RECIST v1.1 or patient is no longer receiving 
clinical benefit.
o
If there is radiographic evidence of progressive disease by the Investigator, 
however the Investigator believes the patient is continuing to derive clinical benefit 
(asymptomatic and/or without worsening of performance status or overall health) 
from study treatment, and an increase in tumor burden is not likely to affect vital 
organ function, the patient may remain on study treatment.
o
In the rare event that progressive disease suspected on initial assessment is not 
confirmed on subsequent scan by the Investigator or central reviewer, the patient 
may continue in the study.
o
The Investigator should make every effort to immediately submit radiographic 
assessments for central review when progressive disease is either suspected or 
confirmed, or uncertainty exists.
o
The central review must provide confirmation of progression prior to discontinuing 
study treatment for progression.
o
In the case of progressive disease determined by the Investigator that is not 
confirmed by the central reviewer, and the patient is progressing clinically and 
requires new anti-cancer treatment immediately, the patient should be discontinued.

Unacceptable toxicity

General or specific changes in the patient’s condition that render the patient
unacceptable for further treatment in the judgment of the investigator

The patient becomes pregnant

Intercurrent illness that prevents further administration of study treatment

Patient refuses further administration of study treatment

The patient receives concurrent (non-protocol) systemic anticancer treatment

Severe noncompliance with study treatment or procedure requirements as judged by 
the Investigator and/or the Sponsor
Where a patient meets one of aforementioned criteria, the Investigator should inform the 
Sponsor immediately, and a discussion and an agreement should occur between the Sponsor 
and the Investigator regarding whether to continue or discontinue the patient from treatment.  
All adverse events, whether serious or non-serious, will be reported from the time a signed and 
dated ICF is obtained until 28 days following the last dose of study treatment. Adverse events 
occurring after 28 days following the last dose of study treatment should also be reported, if 
considered related to study treatment. All adverse events reported must be followed up until 
recovery to baseline or Grade ≤ 1 or until deemed irreversible, and must be recorded. (See 
Section 7.3). 
If a clinically significant finding is identified, the Investigator or qualified designee will 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 33 of 127 
SOP-CD-03-Form2 Ver2 
determine if the patient can continue in the study and if any change in patient management is 
needed. 
4.2.4.2. 
Patient Discontinuation/Withdrawal from the Study 
A patient may withdraw from the treatment period and/or follow-up period of the study at any 
time at his/her own request, or may be withdrawn at any time at the discretion of the Investigator 
for safety, behavioral, or administrative reasons. The reason should be recorded in the patient’s 
medical record/EDC. 
The Sponsor may retain and continue to use any data collected before such a withdrawal of 
consent if the patient withdraws consent for disclosure of future information. If a patient 
withdraws from the study, he/she may request destruction of any samples taken and not 
analyzed/tested, and the Investigator must document this in the site study records. If samples 
are already analyzed/tested, the Sponsor is not obliged to destroy the results of this research. 
If the patients wish to withdraw his/her consent to the participation in the study, they should be 
asked if he/she is willing to continue with both progression follow-up (if applicable) and 
survival follow-up or only survival follow-up. In addition, they should be also asked if he/she 
wishes to entirely withdraw his/her consent to any further participation in the study including 
even survival follow-up. All this should be clearly documented in the patient notes and in the 
clinical study database. 
The status of ongoing, withdrawn (from the study), and lost to follow-up patients at the time of 
the data cut-off for each analysis of survival (i.e., at the time of primary PFS analysis and final 
OS analysis) should be obtained by the site personnel by checking the patients notes, hospital 
records, contacting the patients current physician, and checking publicly available death 
registries. In the event that the patient has actively withdrawn consent to the processing of their 
personal data, the vital status of the patient can be obtained by site personnel from publicly 
available resources where it is possible to do so under applicable local laws. 
Withdrawn patients will not be replaced. 
4.2.4.3. 
Lost to Follow-Up 
A patient will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the study site for a required 
study visit: 
•
The study site must attempt to contact the patient and reschedule the missed visit as 
soon as possible (and within the visit window, where one is defined) and counsel the 
patient on the importance of maintaining the assigned visit schedule and ascertain 
whether or not the patient wishes to and/or should continue in the study.
•
In cases in which the patient is deemed lost to follow-up, the Investigator or designee 
must make every effort to regain contact with the patient. These contact attempts should 
be documented in the patient’s medical record/EDC.
•
Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study.

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 34 of 127 
SOP-CD-03-Form2 Ver2 
4.2.4.4. 
Procedures for Study Treatment Discontinuation 
At any time, patients are free to discontinue study treatment or withdraw from the study without 
prejudice to further treatment. A patient who decides to discontinue study treatment will be 
asked for the reason(s) for discontinuation and the presence of any AEs. At discontinuation visit, 
they will be seen and assessed by the Investigator(s). Also, 28-day safety F/U visit will be made 
via at least a telephone contact. The Investigator will follow up on any AEs that are unresolved 
at the patient’s 28-day safety F/U visit. (See Section 7.3.1 and Appendix 2). The patient or 
his/her representative will return all unused study treatments. 
Any patient who discontinues study treatment for reasons other than objective disease 
progression should have tumor assessments performed as scheduled in the protocol (See Table 
5 and Table 6) until objective disease progression as per RECIST v1.1, unless consent is 
withdrawn. 
Note: Some assessments, e.g., further anti-cancer treatment, should continue beyond first 
objective progression (according to RECIST v1.1) throughout the survival assessment period 
(See Table 5 and Table 6). 
Upon discontinuation of study treatment, patients will be treated in accordance with the 
regional standard of care (SoC). Patients who were randomized to the gefitinib arm following 
objective disease progression according to RECIST v1.1, as per investigator assessment, may 
have the option to receive open-labeled lazertinib provided the specific criteria are met, should 
the patient wish to do so. For further details on post-progression cross-over to lazertinib please 
refer to Table 6 and Section 6.4. 
5. TREATMENTS
5.1. STUDY TREATMENT 
Study treatment is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study patient according to the study 
protocol. 
5.1.1. Investigational Product 

Test product: Lazertinib

Comparator: Gefitinib

Placebo: Lazertinib-matching placebo, Gefitinib-matching placebo
5.1.2. Non-investigational Product 
Not Applicable

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 35 of 127 
SOP-CD-03-Form2 Ver2 
5.1.3. Code, Description and Composition of Investigational Products 
Table 2. Investigational Products Description 
Study treatment 
Test product 
Comparator 
Placebo 
Lazertinib 
Gefitinib 
Lazertinib-
matching 
placebo 
Gefitinib-
matching 
placebo 
Dosage 
Formulation 
Tablet 
Capsulea,b 
Tablet 
Capsuleb 
Unit Dose 
Strengths 
80 mg 
250 mg 
Not applicable 
Dosage Levels 
2 levels 
‐ 
240 mg (3 tablets 
of lazertinib 80 
mg)* 
‐ 
160 mg (2 tablets 
of lazertinib 80 
mg) 
1 level 
‐ 
250 mg gefitinib 
(1 
capsule 
of 
gefitinib 
250 
mg)* 
Not applicable 
Route of 
Administration 
Oral 
Dosing 
Instructions 
Once daily 
*Initial Dose
a Gefitinib tablet is over encapsulated. 
b Appearance of all capsules used for encapsulation is identical.
5.1.4. Packaging and Labeling 
Study treatment will be provided in bottle. Each bottle will be labeled as required per country’s 
regulations. 
5.1.5. Handling and Dispensing 
The Investigator or qualified designee(s) must maintain a log to confirm appropriate 
temperature conditions have been maintained during transit for all study treatment received and 
any discrepancies are reported and resolved before use of the study treatment. 
Only patients enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized site staff. 
The Investigator, study site, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records).  
Study treatment will be dispensed at the study visits summarized in the SoA (See Table 5 and 
Table 6). Returned study treatment should not be re-dispensed to the patients. 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 36 of 127 
SOP-CD-03-Form2 Ver2 
5.2. METHOD OF ASSIGNING PATIENTS TO A TREATMENT 
All patients will be centrally randomized using an Interactive Response Technology (IRT). Each 
patient will be assigned a unique number (randomization number) that encodes the patient’s 
assignment to 1 of the 2 arms of the study, according to the randomization schedule generated 
by the Sponsor or designated CRO using a validated computer program. Details of the 
procedure are described in the IRT manual provided to all sites.  
Patients will be randomly assigned in a 1:1 ratio to receive study treatment (lazertinib or 
gefitinib), using permuted blocked randomization. Patients will be stratified at randomization 
based on EGFR mutation (Ex19del or L858R) and race (Asian or Non-Asian). 
5.3. METHOD OF ADMINISTRATION 
5.3.1. Treatment in Main Study  
At each dispensing visit, sufficient study treatment will be dispensed as follow: 
•
Cycle 1 to Cycle 4: 21 days plus the quantity covering the duration of visit window
•
Cycle 5 onwards: 42 days plus the quantity covering the duration of visit window
Individual bottles of study treatment will be distributed in accordance with the medication 
identification numbers provided by the IRT. 
Patients should swallow 3 tablets and 1 capsule once daily, commencing on Cycle 1 Day 1. 
Tablets/capsule of study treatment should be taken whole with water. Study treatment (i.e., 
lazertinib and gefitinib) can be taken with or without food.  
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 circumstances described in Section 
5.4. The initial dose for gefitinib (250 mg once daily) cannot be reduced to a lower dose. The 
dose of gefitinib may be withheld or discontinued if clinically indicated at the discretion of the 
Investigator.  
On site visit days on which PK samples are scheduled to collect, study treatment should be 
administered at the study site after pre-dose PK blood samples has been collected. It should be 
collected dosing date/time and meal consumption on the day of PK sampling; and dosing 
date/time immediately before pre-dose PK sampling to ensure that an appropriate dosing 
interval (ideally 24 hours) is reached. For ECGs recorded in parallel with PK sampling, the PK 
blood samples should be collected subsequently after the triplicate ECGs have been performed. 
Study treatments should be taken at a similar time each day, approximately 24 hours apart, if 
possible. Doses should not be missed. If a patient misses taking a scheduled dose, within a 
window of 12 hours, it is acceptable to take the dose. If it is more than 12 hours after the 
scheduled dose time, the missed dose should not be taken, and patients should be instructed to 
take the next dose at the next scheduled time. If a patient vomits after taking his/her study 
treatment, he/she should not make up for this dose, but should take the next scheduled dose. 
The time of vomiting should be captured in source document.  
Any change from the dosing schedule, dose interruptions, or dose reductions should be recorded 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
 
 
Page 37 of 127 
SOP-CD-03-Form2 Ver2 
 
in the EDC. 
5.3.2. Open-label Lazertinib Treatment in Cross-Over Study 
For the gefitinib arm patients who are eligible and choose to cross-over to open-label lazertinib, 
lazertinib will be supplied at each visit as tablets for oral administration as a single daily dose 
of 240 mg sufficient amount for 21 days treatment plus coverage (cycle 1-4) and 42 days 
treatment plus coverage (cycle 5 and onwards). Individual bottles of study treatment will be 
distributed in accordance with the medication identification numbers provided by the IRT. 
Patient in the cross-over study should swallow 3 tablets of lazertinib once daily. Tablets should 
be taken whole with water. The initial dose of lazertinib 240 mg once daily can be reduced to 
160 mg once daily under the circumstances described in Section 5.4.1. 
5.4. DOSE MODIFICATION 
The initial dose of lazertinib 240 mg once daily can be reduced to 160 mg once daily under the 
circumstances described in Section 5.4.1. The initial dose of gefitinib 250 mg once daily cannot 
be reduced to a lower dose. The dose of gefitinib may be withheld or discontinued if clinically 
indicated, at the discretion of the Investigator.  
Where dose modification (e.g., interruption, restart reduced dose or same dose, and 
discontinuation, etc.) may be considered, the Investigator should inform the Sponsor 
immediately, and a discussion and an agreement should occur between the Sponsor and the 
Investigator regarding dose modification.  
Table 3. Dose Modification Level 
Dose level 
Lazertinib 
Gefitinib 
Starting  
dose 
240 mg/Day 
(3 tablets of 80 mg lazertinib) 
/ 
1 capsule of gefitinib-matching 
placebo 
250 mg/Day  
(1 capsule of 250mg gefitinib) 
/ 
3 tablets of lazertinib-matching 
placebo 
Reduced  
dose 
160 mg/Day 
(2 tablets of 80 mg lazertinib) 
/ 
1 capsule of gefitinib-matching 
placebo 
250 mg/Day  
(1 capsule of 250 mg gefitinib) a 
/ 
2 tablets of lazertinib-matching 
placebo 
a No dose reduction for gefitinib is actually possible. Reduced dose for gefitinib is the same as the starting dose as 250 mg are the lowest dose 
available. 
5.4.1. General Dose Adjustments for Adverse Events 
If a patient experiences a CTCAE grade 3 or higher and/or unacceptable toxicity (any grade) 
not attributable to the disease or disease-related processes under investigation, where the 
Investigator considers the AE of concern to be specifically associated with the study treatment, 
dosing will be interrupted and supportive therapy will be administered as required in accordance 
with local practice/guidelines. 
If the toxicity resolves or reverts to ≤CTCAE grade 1 or back to baseline status within 3 weeks 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 38 of 127 
SOP-CD-03-Form2 Ver2 
of onset, study treatment may be restarted at the same dose (starting dose) or be reduced using 
the dose reduction levels in Table 3. Dose modification will follow the rules illustrated in Figure 
2 and may be agreed upon between the Investigator and the medical monitor as needed. If 
restarting at the same dose level, patients should be closely monitored for 3 days following the 
restart of treatment. If within 3 days there is recurrence of same toxicity, a dose reduction should 
be considered at the Investigator’s discretion. 
If the toxicity does not resolve to ≤CTCAE grade 1 or back to baseline status after 3 weeks, 
then the patient should be withdrawn from the study treatment and the toxicity should be 
followed (See Section 7.3.1). There will be no individual modifications to treatment schedule 
in response to toxicity, only potential dose reduction or dose interruption. 
If a new as well as recurrent AE subsequently requires dose interruption, study treatment may 
restart at the same dose or the reduced dose, on resolution/improvement of the AE at the 
discretion of the investigator as described above.

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
 
 
Page 39 of 127 
SOP-CD-03-Form2 Ver2 
 
Figure 2. Dose Modification for AEs Related to Study Treatment 
 
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events. 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 40 of 127 
SOP-CD-03-Form2 Ver2 
5.4.1.1. 
Corneal Ulceration 
Any patient developing corneal ulceration will be permanently discontinued from study 
treatment and should be followed regularly until resolution of the event. 
5.4.1.2. 
Interstitial Lung Disease 
Patients with a past medical history of interstitial lung disease, drug-induced interstitial lung 
disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically 
active interstitial lung disease will be excluded from participation in this study.  
Patients with any grade of interstitial lung disease (ILD) will permanently discontinue study 
treatment and be treated as medically indicated.  
If new or worsening pulmonary symptoms (e.g., dyspnoea) or radiological abnormality 
suggestive of interstitial lung disease is observed, an interruption in study treatment dosing is 
recommended, and the Sponsor and/or designated CRO should be informed. Investigator will 
perform a full diagnostic workup (including high-resolution computed tomography (HRCT), 
blood and sputum culture, haematological parameters, bronchoscopy with biopsy as needed) 
to exclude alternative causes such as lymphangitic carcinomatosis, infection, allergy, 
cardiogenic edema, or pulmonary hemorrhage. In the presence of confirmatory HRCT scans 
where other causes of respiratory symptoms have been excluded, a diagnosis of interstitial lung 
disease should be considered and study treatment permanently discontinued. In the absence of 
a diagnosis of interstitial lung disease, study treatment may be restarted after documentation of 
radiographic resolution following the agreement with the medical monitor. 
5.4.1.3. 
Cardiac Dysfunction 
Patients with confirmed symptomatic cardiac dysfunction (symptoms at rest or with minimal 
activity) or ≥ Grade 3 left ventricular systolic dysfunction (resting ejection fraction (EF) 39-
20%; ≥ 20% drop from baseline) as defined by CTCAE will be discontinued from study 
treatment.  
Asymptomatic declines in LVEF will be handled with the process described in detail in 
Appendix 5. If the LVEF is reported as a range, the average should be taken. If the Investigator 
is concerned that an adverse event may be related to cardiac dysfunction, an additional LVEF 
measurement may be performed. LVEF will be monitored at screening and every 12 weeks (-
7 days, +3 days) after randomization, and at discontinuation visit.  
Patients with QTc prolongation (i.e., confirmed QTc prolongation to >500 msec absolute or a 
>60 msec increase from baseline) should have study treatment interrupted and regular ECGs
performed until resolution to baseline. If the QTc prolongation toxicity does not resolve to ≤
grade 1 within 3 weeks, the patient will be permanently withdrawn from study treatment.
5.4.1.4. 
Rash-related adverse events 
Prophylactic treatment 
Starting at the initiation of study treatment dosing and continuing during dosing patients are to 
be instructed to: 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 41 of 127 
SOP-CD-03-Form2 Ver2 
•
use a thick, alcohol-free emollient cream (e.g., glycerin and cetomacrogol cream) to 
prevent dry skin and pruritus.
•
avoid immersion in hot water / detergent / solvents.
•
avoid exposure to sunlight.
•
use broad-spectrum sunscreen (containing titanium dioxide or zinc oxide) with a skin
protection factor (SPF) ≥15 if sunlight exposure cannot be avoided.
Reactive management 
The following interventions and the stepwise algorithm shown in Table 4 are to be used for 
EGFR inhibitor-induced rash  
•
Topical corticosteroids (e.g., hydrocortisone 2.5% cream) 
•
Topical antibiotics (e.g., clindamycin 1% gel) 
•
Topical corticosteroids and systemic antibiotics (minocycline 100 mg bid or first 
generation cephalosporine (avoid CYP3A4 inhibitors)). 
•
For pruritic lesions, the use of cool compresses and oral antihistamine agents may be 
helpful.  
•
For fissuring, the use of Monsel’s solution (ferric subsulfate solution), silver nitrate, or 
zinc oxide cream is advised.  
•
For desquamation, thick emollients and mild soap are recommended.  
•
For paronychia, antiseptic soaks and local potent corticosteroids in addition to oral 
antibiotics are recommended and, if no improvement is seen, a dermatology or surgery 
consultation is recommended.  
•
For infected lesions, bacterial and fungal culturing followed by the appropriate 
culture-driven systemic or topical antibiotics is indicated.
•
Consult with a dermatologist if the rash is severe, atypical in appearance, or distribution, 
or does not improve within 2 weeks of treatment.

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 42 of 127 
SOP-CD-03-Form2 Ver2 
Table 4. Stepwise Algorithm for Management of Rash 
Step Rash 
gradinga 
Management of Rash 
Dose Adjustmentb 
1 
1 
Initiate prophylactic regimen if 
not already started and add 
reactive therapies as above. 
Continue current dose. 
Reassess after 2 weeks; if rash 
worsens or does not improve, 
proceed to Step 2 
Reassess after 2 weeks; if rash 
does not improve, proceed to Step 
2 
2 
2 
Initiate prophylactic regimen if 
not already started, including 
topical corticosteroids and 
systemic antibiotics as above.c 
Consider reducing dose by one 
dose level 
Reassess after 2 weeks; if rash 
does not improve, proceed to Step 
3 
Reassess after 2 weeks; if rash does 
not improve, proceed to Step 3 
3 
3 or 
intolerable 
Grade 2 
Initiate prophylactic regimen if 
not already started, moderate 
strength topical corticosteroids 
and systemic antibiotics as above 
plus prednisone (0.5 mg/kg) for 7 
days. Consider low doses of 
isotretinoin (20-30 mg/day). 
Temporarily interrupt treatment 
until rash improves ≤ Grade 2 or 
resolves, then follow steps 
outlined for the appropriate 
grading. 
Consider obtaining dermatology 
consultation and manage rash per 
dermatologist’s recommendation. 
Reassess after 2 weeks; if rash 
worsens or does not improve, 
permanently discontinue 
treatment. 
a Grading per NCI CTCAE (Version 5.0) 
b Resolution defined as: ≤Grade 1 non-hematologic toxicity or back to baseline 
c For example, hydrocortisone 2.5% cream or fluticasone propionate 0.5% cream 
5.4.1.5. 
Diarrhea 
If patients experience diarrhea, they should be encouraged to drink 8 to 10 large glasses (2 liter 
(L)) of clear liquids per day while on study in order to maintain adequate hydration. 
Maintenance of electrolyte balance using electrolyte containing drinks, broth, and clear juices 
should be considered. If an infectious cause of the diarrhea is suspected, perform stool testing 
and administer antibiotic therapy (avoid CYP3A4 inhibitors) as appropriate.  
General dietary measures to limit impact of diarrhea include: 
•
Stop all lactose-containing products in patients with evidence of lactose intolerance
•
Eat frequent small meals if experiencing increased frequency of stools
•
Consider low-fat regimen enriched with bananas, rice, applesauce, and toast

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
 
 
Page 43 of 127 
SOP-CD-03-Form2 Ver2 
 
Diarrhea management guideline follows:  
CTCAE version 5.0 Grade 1  
• Management:  
o Loperamide (4 mg at first onset, then 2 mg every 2-4 hours until symptom free 
for 12 hours).  
o Fluid intake of at least 2 L as described above.  
• Study treatment: should be continued at the same dose. 
CTCAE version 5.0 Grade 2  
• Management:  
o Loperamide (4 mg at first onset, then 2 mg every 2-4 hours until symptom free 
for 12 hours), or consider diphenoxylate and atropine formulations (e.g., 
Lomotil®).  
o Fluid intake of at least 2 L as described above. Monitor patient closely and 
consider intravenous hydration.  
• Study treatment: If not improved to Grade ≤1 within 24 hours despite use of loperamide, 
hold treatment until Grade ≤1. If diarrhea of Grade >1 recurs after initial improvement, 
consider reduction by one dose level 
CTCAE version 5.0 Grade 3:  
• Management:  
o Oral therapy with diphenoxylate and atropine formulations (eg, Lomotil®), or 
tincture of opium.  
o Fluid intake of at least 2 L should be maintained as described above, 
intravenously if necessary.  
o Consider use of octreotide (Sandostatin®) 100-150 microgram (μg) 
subcutaneously twice daily with escalation to 500 μg three times daily.  
o Consider hospitalization if does not improve to Grade ≤2 within 24 hours, or in 
presence of fever, abdominal pain, etc.  
• Study Treatment: Hold therapy. Upon resolution to Grade ≤1, resume therapy with 
consideration of reduction by one dose level. 
CTCAE version 5.0 Grade 4:  
• Management: Maximal inpatient fluid and nutritional support, antibiotics as indicated 
in judgment of investigator for fever, leucocytosis, marked dehydration, etc.  
• Study Treatment: Hold until Grade ≤1. Mandatory dose reduction by one dose level.  
5.4.1.6. 
Liver Chemistry Abnormalities 
Liver chemistry stopping criteria have been established to provide safety to the patients and to 
better assess the etiology of a liver event during the development of new investigational products. 
Liver chemistry should be monitored according to the schedule in SoA (See Table 5 and Table 
6). The liver chemistry stopping criteria include any of the following: 
 
1. Patients with AST and ALT and total bilirubin baseline values within the normal range: ALT 
or AST ≥3x ULN and bilirubin ≥2x ULN (and >35% direct bilirubin) (or ALT ≥3x ULN and 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
 
 
Page 44 of 127 
SOP-CD-03-Form2 Ver2 
 
INR >1.5, if INR measured) with no evidence of hemolysis and an alkaline phosphatase ≤ 
2x ULN or not available. 
2. Patients with pre-existing AST or ALT or total bilirubin values above ULN:  
1) For patients with pre-existing AST or ALT baseline values above the normal range: AST 
or ALT ≥ 2x the baseline value and ≥ 3x ULN, or ≥ 8x ULN (whichever smaller).  
concurrent with 
 
2) For patients with pre-existing value of total bilirubin above the normal range: Total 
bilirubin of ≥ 2 times ULN and increased by >1 time the ULN or ≥ 3 times ULN 
(whichever is smaller) with no evidence of hemolysis and an alkaline phosphatase ≤ 2 
times ULN or not available. 
Note: Exception to the bilirubin elevation is made if the subject has Gilbert’s disease and the 
elevated bilirubin is predominantly unconjugated. 
This event should be reported as an SAE. 
 
Study treatment should be interrupted, and the medical monitor must be notified as soon as 
possible if any stopping criterion is met. Liver chemistry should be repeated within 1-3 days. If 
any of the chemistry stopping criteria are confirmed upon repeat, then assessments listed below 
should be considered. 
Liver Event Follow-Up Requirements 
The following follow-up assessments should be considered for any subject meeting liver 
chemistry stopping criteria: 
 
Monitor liver chemistries (ALT, AST, ALP, bilirubin, including bilirubin fractions, and INR), 
creatinine phosphokinase, and lactate dehydrogenase, 1 to 2 times per week until resolution, 
stabilization, or return to subject’s baseline values 
 
Monitor clinical condition closely 
 
Draw blood samples for unscheduled PK analysis at timepoints when liver chemistry is 
assessed 
 
Record use of concomitant medications, acetaminophen, herbal remedies, other over-the-
counter medications, or known hepatotoxins 
 
Record alcohol use in the CRF 
 
Check the viral hepatitis serology as appropriate and include: 
o Hepatitis A IgM antibody 
o Hepatitis B surface antigen and Hepatitis B core antibody (IgM) 
o Hepatitis C RNA 
o Hepatitis E IgM antibody 
o Cytomegalovirus IgM antibody 
o Epstein-Barr viral capsid antigen IgM antibody (or equivalent test) 
 
Assess anti-nuclear antibody, anti-smooth muscle antibody, and type 1 anti-liver kidney 
microsomal antibodies 
 
Conduct liver imaging (ultrasound, magnetic resonance imaging [MRI], or computerized 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
 
 
Page 45 of 127 
SOP-CD-03-Form2 Ver2 
 
tomography [CT]) to evaluate liver disease 
 
Refer to a specialist as appropriate 
Rechallenge Criteria 
Resumption of study drug administration may be considered if the following criteria are met: 
 
A reversible underlying cause not associated with study treatments (eg, alcohol use or 
concomitant medication) is clearly identified and agreed upon in consultation with the  
medical monitor 
 
Liver chemistry abnormalities have resolved or values have returned to baseline 
 
5.5. BLINDING / UNBLINDING 
5.5.1. Methods for Ensuring Blinding 
Investigational product (IP, also referred to as ‘study treatment’ in this protocol) will be 
labelled using a unique material pack code, which is linked to the randomization code. The 
IRT will assign the bottles of IP to be dispensed to each patient. This is a double-blind study 
wherein each patient will receive either the active lazertinib plus over encapsulated gefitinib-
matching placebo or over encapsulated active gefitinib plus lazertinib-matching placebo. The 
active and placebo tablets/capsules will be identical and presented in the same packaging to 
ensure blinding of the medication. 
5.5.2. Methods for Unblinding 
Individual treatment codes, indicating the treatment randomization for each randomized 
patient, will be available to the Investigators or pharmacists from the IRT. Routine procedures 
for this will be described in the IRT user manual that will be provided to each site. 
The treatment code may be broken in only medical emergencies except for the circumstance 
where it determined for the patient to receive open-label lazertinib in cross-over arm. The 
Investigator documents and reports the action to the Sponsor and/or designated CRO, without 
revealing the treatment given to patient to the Sponsor and/or designated CRO staff. 
The Sponsor retains the right to break the code for serious adverse events (SAEs) that are 
unexpected and are suspected to be causally related to an IP and that potentially require 
expedited reporting to regulatory authorities. Treatment codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
patient have been made and documented. 
Should there be a requirement to unblind a patient for reasons other than to determine 
suitability for cross-over to lazertinib, central confirmation of RECIST v1.1 disease 
progression is not required. See Table 6 and Section 6.4 for further details of requirements for 
the post-progression cross-over to lazertinib. 
5.6. CONCOMITANT TREATMENTS 
All prior medications administered up to 28 days before randomization must be recorded at 
screening.  

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 46 of 127 
SOP-CD-03-Form2 Ver2 
Concomitant treatments must be recorded beginning at screening and continuing until 28 days 
after the last dose of study treatment. Concomitant treatments should be also recorded beyond 
28 days after the last dose of study treatment in conjunction with the following situations: 

Adverse events reported after 28 days following the last dose of study treatment, if 
considered related to study treatment
The sponsor and/or designated CRO should be contacted if there are any questions regarding 
concomitant or prior treatments. The sponsor and/or designated CRO must be notified 
immediately if prohibited therapies are administered. 
All medications taken by a patient (prescription or nonprescription, including vaccines, 
vitamins, and herbal/natural supplements) that are not the study treatment must be documented 
in the CRF. Modification of an effective preexisting therapy should not be made for the explicit 
purpose of entering a patient into the study. Nonpharmacologic therapies such as electrical 
stimulation, acupuncture, special diets, and exercise regimens should also be recorded in the 
CRF. 
5.6.1. Permitted Treatments 

Symptomatic treatment:
o
Supportive care, such as, antibiotics, analgesics, anticoagulants (e.g., warfarin, etc.), 
transfusions, diet, etc. 
o
Concomitant medications, for the symptomatic treatment of related toxicities (Grade 
1-4), may be administered according to the standard of care at the site, and at the 
treating physician’s discretion, as clinically indicated.

Prophylactic medications:
o
Appropriate prophylactic antiemetic regimens, if required, in accordance with 
institutional practice and/or current European Society of Medical Oncology guidelines
o
Treatment with corticosteroids and/or bisphosphonates for the treatment of bone 
metastases
‐ 
Patients may also receive palliative radiotherapy for painful bony metastases, as 
long as it will not affect the target and non-target lesions being assessed.
o
Rash prophylaxis, as described in Section 5.4.1.4 and/or in accordance with 
institutional practice
Note: Due to the potential for hypomagnesemia associated with EGFR inhibitors, concomitant 
medications that may decrease serum magnesium should be avoided if possible. In addition, 
patients taking warfarin should be monitored regularly for changes in prothrombin time or 
international normalized ratio. 

Localized, limited radiotherapy of short duration (e.g., 5 days) for palliative purposes may 
be permitted but only after discussion with and approval by the sponsor’s medical monitor.
Women using hormonal contraceptives as a means of birth control must continue to use the 
same hormonal contraceptives throughout the study (See Appendix 3).
5.6.2. Prohibited Treatments 
The sponsor must be notified in advance, or as soon as possible thereafter, of any instances in 
which prohibited therapies were administered.  

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 47 of 127 
SOP-CD-03-Form2 Ver2 
The following concomitant medications and treatments are prohibited during the study. 

Any chemotherapy, anticancer therapy (other than study treatment[s]), or experimental 
therapy

Radiotherapy to target lesions prior to disease progression
In addition, following drugs and/or ingestions of food must have been discontinued for an 
appropriate period prior to randomization and for a period of 3 weeks after the last dose of study 
treatment, and should be prohibited during the study (See Appendix 6). 

Medications, herbal supplements and/or foods with known potent inducer or inhibitory 
effects on CYP3A4 activity or known to or may possibly prolong QT interval or induce 
Torsades de Pointes
Following concomitant use of medications, herbal supplements and/or foods are not 
recommended, if possible. However, if medically necessary, these concomitants may be 
allowed with close monitoring for change in safety (See Appendix 6). 

Substrates of Breast Cancer Resistance Protein (BCRP), P-glycoprotein (P-gp) and/or 
multi-drug resistance protein 4 (MRP4)

Drugs affecting gastric pH (e.g., proton pump inhibitors, H2-receptor antagonists, and 
antacids)
However, patients may receive local standard of care as permitted by protocol for treatment of 
comorbidities and/or management of adverse events. 
5.6.3. Other Restrictions and Precautions 

For WOCBP: Should use reliable methods of contraception from the time of screening until 
24 weeks after discontinuing study treatment. In addition, female patients must refrain from 
donating ovum from randomization until 24 weeks after the last dose of study treatment 
(See Appendix 3 for more information).

For male patients who have not undergone a vasectomy: Should use reliable methods of 
contraception during sex with all partners from randomization until 24 weeks after 
discontinuing study treatment. Patients should refrain from donating sperm from 
randomization until 24 weeks after discontinuing study treatment. If male patients wish to 
father children during aforementioned period, they should be advised to arrange for 
freezing of sperm samples prior to randomization (See Appendix 3 for more information).
5.7. TREATMENT COMPLIANCE 
Patients will be required to return any unused study treatment tablets/capsules at the start of 
their next cycle of treatment. Unused tablets/capsules will be counted and recorded by study 
site personnel to assess study treatment compliance. Reason for dose interruption, reduction, or 
omission will also be recorded in the electronic data capture system. This information plus drug 
accountability for all study treatments at every cycle will be used to assess compliance with the 
treatment. 
6. STUDY ASSESSMENTS AND PROCEDURES
The overall study duration and procedure will vary for patients due to disease progression, 
withdrawal, and/or death, but would generally include procedures, as follows: 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
 
 
Page 48 of 127 
SOP-CD-03-Form2 Ver2 
 
 
Up to 28 days for screening and baseline testing 
 
21-day treatment cycles 
 
Discontinuation visit 
 
28-day safety follow-up visit (after last dosing of study treatment) 
 
Progression follow-up visit (for patients who discontinue study treatment for reasons 
other than objective disease progression) 
 
Survival follow-up visits until death or study withdrawal 
Study procedures and their timing are summarized in the SoA (See Table 5 and Table 6).  
Adherence to the study design requirements, including those specified in the SoA (Table 5, 
Table 6), is essential and required for study conduct. As protocol waivers or exemptions are not 
allowed with the exception of immediate safety concerns, these should be discussed with the 
Sponsor and/or designated CRO immediately upon occurrence or awareness to determine if the 
patient should continue or discontinue study treatment. In exceptional circumstances such as 
COVID-19 pandemic, protocol-specified visits and treatment can be conducted by the local 
regulation. 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 49 of 127 
SOP-CD-03-Form1 Ver2 
Table 5. Schedule of Activities 
Activities 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
onward1 
Unsched
uled 
visit2 
Disconti
nuation3 
28-day
Safety
F/U4
Pro- 
gression 
F/U5 
Survival 
F/U6 
Visit 
1 
2 
3 
4 
5 
6 
7 
After 8 
Cycle7 / Day 
NA 
Cycle 1 / 
Day 1 
Cycle 1 / 
Day 8 
Cyc1e 1 / 
Day 15 
Cycle 2 / 
Day 1 
Cycle 3 / 
Day 1 
Cycle 4/ 
Day 1 
Cycle 5 / 
Day 1 
Day 
-28
1 
8 
15 
22 
43 
64 
85 
Visit window8 
0 
± 2 
± 2 
-2 ~ +3
-7 ~ +3
-7 ~ +3
-7 ~ +3
NA 
+ 7
+ 7
± 7 
± 7 
Informed consent9 
X 
Demographics & baseline 
characteristics including 
current/historical smoking 
status  
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
Medical and surgical history 
X 
Inclusion/Exclusion criteria 
X 
X 
EGFR mutation test10 
(Tissue biopsy) 
X 
Tumor and blood  
samples for central 
laboratory11 
X 
Physical examination12 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
WHO Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
Vital signs13 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
Hepatitis and HIV screen14 
X 
12-lead ECG15
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
Ophthalmologic assessment 
X 
As clinically required 
Echocardiography/MUGA 
X 
Every 12 weeks relative to date of randomization 
X 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 50 of 127 
SOP-CD-03-Form1 Ver2 
Activities 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
onward1 
Unsched
uled 
visit2 
Disconti
nuation3 
28-day
Safety
F/U4
Pro- 
gression 
F/U5 
Survival 
F/U6 
Visit 
1 
2 
3 
4 
5 
6 
7 
After 8 
Cycle7 / Day 
NA 
Cycle 1 / 
Day 1 
Cycle 1 / 
Day 8 
Cyc1e 1 / 
Day 15 
Cycle 2 / 
Day 1 
Cycle 3 / 
Day 1 
Cycle 4/ 
Day 1 
Cycle 5 / 
Day 1 
Day 
-28
1 
8 
15 
22 
43 
64 
85 
Visit window8 
0 
± 2 
± 2 
-2 ~ +3
-7 ~ +3
-7 ~ +3
-7 ~ +3
NA 
+ 7
+ 7
± 7 
± 7 
scan (for LVEF)16 
Laboratory tests17 
Clinical chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
Pregnancy test (WOCBP 
only)18 
X 
Every 6 weeks relative to date of randomization, if needed by local health authorities-
specific requirement or guidance 
(X) 
X 
PK assessment 
PK blood samples19 
X 
X 
X 
cfDNA and blood-borne 
biomarkers assessment 
Blood samples for cfDNA and 
blood-borne biomarkers20 
X 
Every 6 weeks for the first 18 months and then every 12 weeks relative to date of randomization 
Tumor assessment 
RECIST v1.1 assessment21 
X 
Every 6 weeks for the first 18 months and then every 12 weeks relative to date of randomization 
(Per local standard practice following objective disease progression) 
Questionnaires22 
EORTC QLQ C-30 
X 
X 
Every 6 weeks relative to date of randomization 
EORTC QLQ LC-13 
X 
X 
EQ-5D-5L 
X 
X 
Health resource use module 
Health resource use module 
X 
X 
Every 6 weeks relative to date of randomization 
Other sampling (Optional) 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
 
  
Page 51 of 127 
SOP-CD-03-Form1 Ver2 
 
Activities 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
onward1 
Unsched
uled 
visit2 
Disconti
nuation3 
28-day 
Safety 
F/U4 
Pro- 
gression 
F/U5 
Survival 
F/U6 
Visit 
1 
2 
3 
4 
5 
6 
7 
After 8 
 
 
 
 
 
Cycle7 / Day 
NA 
Cycle 1 / 
Day 1 
Cycle 1 / 
Day 8 
Cyc1e 1 / 
Day 15 
Cycle 2 / 
Day 1 
Cycle 3 / 
Day 1 
Cycle 4/ 
Day 1 
Cycle 5 / 
Day 1 
 
 
 
 
 
Day 
-28 
1 
8 
15 
22 
43 
64 
85 
 
 
 
 
 
Visit window8 
0 
± 2 
± 2 
-2 ~ +3 
-7 ~ +3 
-7 ~ +3 
-7 ~ +3 
NA 
+ 7 
+ 7 
± 7 
± 7 
Genetic consent 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
Blood samples for genetic 
assay 
 
(X) 
 
 
 
 
 
 
 
(X) 
 
 
 
CSF (BM only)23 
 
 
 
 
 
 
 
(X) 
(once) 
 
 
 
 
 
Tumor or blood samples upon 
disease progression for 
confirmation of T790M 
mutation status24  
 
 
(X) 
 
Tumor or blood samples upon 
disease progression for 
exploratory research 
 
 
(X) 
 
Randomization/Study 
treatment supply/dispensing 
 
Randomization25 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense study treatment 
 
X 
 
 
X 
X 
X 
X 
(X) 
 
 
 
 
Dose with study treatment26 
 
Daily dosing 
 
 
 
Study treatment return 
 
 
 
 
X 
X 
X 
X 
(X) 
X 
 
 
 
Safety assessment 
 
Adverse events27 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
(X) 
Prior/concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
(X) 
Survival follow-up 
 
Survival and anti-cancer  
therapy survey 
 
 
 
 
 
 
 
 
 
 
 
X 
X 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 52 of 127 
SOP-CD-03-Form1 Ver2 
Activities 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
onward1 
Unsched
uled 
visit2 
Disconti
nuation3 
28-day
Safety
F/U4
Pro- 
gression 
F/U5 
Survival 
F/U6 
Visit 
1 
2 
3 
4 
5 
6 
7 
After 8 
Cycle7 / Day 
NA 
Cycle 1 / 
Day 1 
Cycle 1 / 
Day 8 
Cyc1e 1 / 
Day 15 
Cycle 2 / 
Day 1 
Cycle 3 / 
Day 1 
Cycle 4/ 
Day 1 
Cycle 5 / 
Day 1 
Day 
-28
1 
8 
15 
22 
43 
64 
85 
Visit window8 
0 
± 2 
± 2 
-2 ~ +3
-7 ~ +3
-7 ~ +3
-7 ~ +3
NA 
+ 7
+ 7
± 7 
± 7 
Subsequent 
response/progression data 
X 
Abbreviations: BM = brain metastasis; cfDNA = circulating cell-free deoxyribonucleic acid; CSF = cerebrospinal fluid; ECG = electrocardiogram; EGFR = epidermal 
growth factor receptor; EORTC QLQ  = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, C-30 = Core 30 items, 
LC-13 = Lung Cancer 13 items; EQ-5D-5L = Euro-Quality of Life-5 Dimension-5 level; F/U = follow-up; HIV = human immunodeficiency virus; LVEF 
= left ventricular ejection fraction; MUGA = multiple gated acquisition; NA = not applicable; PK = pharmacokinetics; RECIST = Response Evaluation 
Criteria in Solid Tumors; T790M = threonine-to-methionine substitution; WHO = World Health Organization; WOCBP = woman of childbearing potential. 
1
Study visits will occur on Day 1 of every other cycle from Cycle 5 onwards (C5D1, C7D1, C9D1, C11D1, C13D1, C15D1…). 
2
Unscheduled visits can be arranged if necessary. Study procedures will be performed at the discretion of the investigator. 
3
All patients will attend a discontinuation visit within 7 days of permanent discontinuation of study treatment, where all procedures for the discontinuation visit 
will be performed. The discontinuation visit should occur before the start of any new treatment and the reason should be documented on the electronic Case 
Report Form. 
4
28-day safety F/U will be made via at least a telephone contact within 28 days (+7 days) after permanent discontinuation of study treatment.
5
If patients discontinue study treatment for reasons other than objective disease progression, Progression F/U will be made every 6 weeks. Tumor assessment per 
RECIST v1.1 for the Progression F/U should be continued every 6 weeks for the first 18 months and then every 12 weeks relative to date of randomization until 
objective disease progression.
6
All patients will be followed for survival, disease progression (per local standard practice) and any post-study anticancer treatment via at least a telephone contact 
every 6 weeks relative to date of randomization following discontinuation of study treatment, until lost to follow up, the withdrawal of consent, or death 
(whichever is earlier). However, the patients who discontinue study treatment for reasons other than objective disease progression will conduct survival follow-up 
following confirmation of objective disease progression.
7
A cycle is defined as 21-day treatment period.
8
Visit window is calculated based on the date of randomization. 
9
Signed informed consent must be obtained before the patient undergoes any study-specific procedures.
10
Tumor samples for screening EGFR mutations test should be assessed by an accredited local laboratory, or by central testing in a designated laboratory. If
screening EGFR mutations test is performed at an accredited local laboratory, only 4 types of the mutations kits are allowed such as: the Qiagen-Therascreen®

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 53 of 127 
SOP-CD-03-Form1 Ver2 
EGFR Mutation Detection Kit RGQ (Scorpions ARMS), the Amoy Diagnostics-the AmoyDx® EGFR Mutation Test Kit, the PANAGENE-PANAMutyperTM or 
the Roche Diagnotics-Cobas® EGFR Mutation Test v2. 
11
Collected tumor (Formalin-Fixed Paraffin-Embedded Tissue) and blood samples must be submitted to central laboratory. 
12
May include neurologic examination, if required. 
13
Vital signs (heart rate, blood pressure and body temperature) will be obtained after the patient has rested for 10 minutes. The date and time of the assessment 
should be recorded. 
14
Hepatitis B (HBV) surface antigen (HBsAg) and hepatitis C antibody (anti-HCV) test will be performed. Additional hepatitis examination could be conducted if 
required. Evaluation for HIV seropositivity will be performed, and, if positive, further tests can be determined at the discretion of the Investigator, if needed. 
Appropriate counseling will be made available by the Investigator in the event of a positive finding. Notification of regional and/or national authorities, if required 
by law, will be the responsibility of the Investigator. 
15
All ECG data will be collected digitally and transferred electronically for central analysis. A set of triplicate 12-lead ECGs, approximately 2 minutes apart, will be 
performed as scheduled with reading by a cardiologist. For ECGs recorded in parallel with PK sampling at pre-dose, 1 to 3 hours, and 4 to 6 hours post-dose on 
Day 1 of Cycles 1, 2, 5, 9, and 13, the PK blood samples should be collected subsequently after the triplicate ECGs have been performed. Other ECGs will not be 
time-matched and can be performed regardless of dosing time. 
16
LVEF will be assessed using an echocardiogram or MUGA scan at screening and every 12 weeks (-7 days, +3 days) relative to date of randomization until 
discontinuation visit. Additional assessments may be performed if clinically indicated. For any patient who has at least one echocardiogram or MUGA that is 
considered abnormal by local assessment, the Sponsor will collect all echocardiograms or MUGA scans (obtained at Screening and all subsequent assessments) 
for the purpose of a central read. 
17
Clinical laboratory tests are not required at Cycle 1 Day 1 if acceptable screening is performed within 7 days prior to randomization, unless the patient’s clinical 
condition has changed significantly, otherwise clinical laboratory tests should be performed at Cycle 1 Day 1 before randomization. In addition, clinical 
laboratory test at Cycle 1 Day 1 can be performed within 7 days prior to randomization. If needed, any clinical laboratory tests may also be performed for safety 
evaluation of patients. 
18
At screening and discontinuation visit, all WOCBP should complete a serum pregnancy test per the practice of the site. Repeat as necessary during the treatment 
period if clinically indicated. In addition, it can be performed every 6 weeks relative to date of randomization considering the local health authorities-specific 
requirement or guidance. At other times during study, a serum or urine pregnancy test may be performed as indicated. 
19
Plasma PK samples will be collected at pre-dose, 1 to 3 hours, and 4 to 6 hours post-dose on Day 1 of Cycles 1, 2, 5, 9, and 13. 
20
Blood samples for cfDNA and blood-borne biomarkers analysis will be collected on the same day of any scheduled and unscheduled tumor assessments, if 
possible. 
21
Baseline tumor assessment during screening must be performed within 28 days before randomization. The patient must have at least 1 lesion, not previously 
irradiated, that can be accurately measured. If there is only 1 measurable lesion and it is chosen for biopsy, tumor assessment should be performed after at least 14 
days following the biopsy. Follow-up tumor assessments will be performed every 6 weeks (-7 days, +3 days) for the first 18 months and then every 12 weeks (-7 
days, +3 days) relative to date of randomization using the RECIST v1.1 until objective disease progression. 
Tumor assessment will be performed using computed tomography (CT) or magnetic resonance imaging (MRI) of the chest and abdomen (including liver and 
adrenal glands). Any other sites where disease is suspected or known at baseline must also be imaged. Specifically, patients with confirmed BM at screening 
should be followed up on study with repeated MRI assessment at the same frequency as the other RECIST v1.1 assessments. The same modality for MRI should 
be used for a patient throughout the study. 
Images will be sent to central reading center timely for BICR. Especially, the Investigator should make every effort to immediately submit radiographic 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 54 of 127 
SOP-CD-03-Form1 Ver2 
assessments for central review when progressive disease is either suspected or confirmed, or uncertainty exists. 
22
Questionnaires should be completed prior to any visit-specific procedures. All questionnaires will be performed at Cycle 1 Day 1, Cycle 2 Day 1 (-2 days, +3 
days) and then every 6 weeks (-7 days, +3 days) relative to date of randomization until 28-day safety F/U visit or progression F/U visit (whichever is later).  
23
One CSF sample will be collected at any time from Cycle 5 Day 1 onwards. If possible, the CSF sample should be taken on the same day as planned PK samples. 
24
Determination of T790M mutation positive status by means of plasma or tissue testing may be performed locally, or centrally for those patients unable to be 
tested locally by the discretion of investigator.   
25
Randomization procedures should be performed following completion of all eligibility assessments and determination of patient eligibility prior to the initiation 
of assigned study treatment (i.e., All screening procedures and tests (including Cycle 1 Day 1 procedures and laboratory results for eligibility assessment) must be 
completed and reviewed before randomization.). 
26
Once randomized, the first dose should be administered on the randomization day. If not possible even though it has made every effort to be taken the first dose 
on the randomization day, the first dose must be administered within a maximum of 3 days following randomization. Study treatment should be taken orally once 
daily at approximately the similar time with a glass of water. Patients may continue study treatment following objective disease progression if patient is receiving 
clinical benefit, as judged by the investigator. 
27
All adverse events and special reporting situations, whether serious or non-serious, will be reported from the time a signed and dated ICF is obtained until 28 
days following the last dose of study treatment. Adverse events occurring after 28 days following the last dose of study treatment should also be reported, if 
considered related to study treatment. Reported all AEs must be followed until recovery to baseline or Grade ≤1 or until deemed irreversible, and all relevant 
information must be recorded on the eCRF.  

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 55 of 127 
SOP-CD-03-Form2 Ver2 
Table 6. Schedule of Activities for Post-Progression Cross-Over to Lazertinib from Gefitinib Arm 
Activities 
Pre-
Crossover 
Screening1 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Onward
2
Unsched
uled 
visit3 
Disconti
nuation4 
28-day
Safety
F/U5
Progress
ion F/U6 
Survival 
F/U7 
Visit 
1 
2 
3 
4 
5 
6 
7 
After 8 
Cycle8 / Day 
NA 
Cycle 1 / 
Day 1 
Cycle 1 / 
Day 8 
Cyc1e 1 / 
Day 15 
Cycle 2 / 
Day 1 
Cycle 3 / 
Day 1 
Cycle 4 / 
Day 1 
Cycle 5 / 
Day 1 
Day 
-28
1 
8 
15 
22 
43 
64 
85 
Visit window9 
0 
± 2 
± 2 
-2 ~ +3
-7 ~ +3
-7 ~ +3
-7 ~ +3
NA 
+ 7
+ 7
± 7 
± 7 
Informed consent10 
X 
Eligibility assessment 
Submit plasma samples for 
central laboratory with 
optional tumor tissue sample 
11 
X 
Confirmation of T790M 
mutation positive upon 
progression12 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
WHO Performance Status 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
Vital signs13 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
12-lead ECG14
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
Ophthalmologic assessment 
As clinically required 
Echocardiography/MUGA 
scan (for LVEF)15 
Every 12 weeks relative to date of lazertinib first-dosing 
X 
Laboratory tests16 
Clinical chemistry 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
Pregnancy test (WOCBP 
X 
Every 6 weeks relative to date of first-dosing, if needed by local health authorities-
(X) 
X 

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
Page 56 of 127 
SOP-CD-03-Form2 Ver2 
Activities 
Pre-
Crossover 
Screening1 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Onward
2
Unsched
uled 
visit3 
Disconti
nuation4 
28-day
Safety
F/U5
Progress
ion F/U6 
Survival 
F/U7 
Visit 
1 
2 
3 
4 
5 
6 
7 
After 8 
Cycle8 / Day 
NA 
Cycle 1 / 
Day 1 
Cycle 1 / 
Day 8 
Cyc1e 1 / 
Day 15 
Cycle 2 / 
Day 1 
Cycle 3 / 
Day 1 
Cycle 4 / 
Day 1 
Cycle 5 / 
Day 1 
Day 
-28
1 
8 
15 
22 
43 
64 
85 
Visit window9 
0 
± 2 
± 2 
-2 ~ +3
-7 ~ +3
-7 ~ +3
-7 ~ +3
NA 
+ 7
+ 7
± 7 
± 7 
only)17 
specific requirement or guidance 
cfDNA and blood-borne 
biomarkers assessment 
Blood samples for cfDNA 
and blood-borne biomarkers
18
X 
Every 6 weeks for the first 12 months and then every 12 weeks relative to date of lazertinib first-dosing 
Tumor assessment 
RECIST v1.1 assessment19 
X 
Every 6 weeks for the first 12 months and then every 12 weeks relative to date of lazertinib first-dosing 
Questionnaires20 
EORTC QLQ C-30 
X 
X 
Every 6 weeks relative to date of lazertinib first-dosing 
EORTC QLQ LC-13 
X 
X 
EQ-5D-5L 
X 
X 
Health resource use module 
Health resource use module 
X 
X 
Every 6 weeks relative to date of lazertinib first-dosing 
Other sampling (Optional) 
Genetic consent 
(X) 
Blood samples for genetic 
assay 
(X) 
(X) 
Tumor or blood samples upon 
disease progression for 
exploratory research 
(X) 
Study treatment 
supply/dispensing 
Dispense lazertinib 
X 
X 
X 
X 
X 
(X)

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
 
 
Page 57 of 127 
SOP-CD-03-Form2 Ver2 
 
Activities 
Pre-
Crossover 
Screening1 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Onward
2 
Unsched
uled 
visit3 
Disconti
nuation4 
28-day 
Safety 
F/U5 
Progress
ion F/U6 
Survival 
F/U7 
Visit 
1 
2 
3 
4 
5 
6 
7 
After 8 
 
 
 
 
 
Cycle8 / Day 
NA 
Cycle 1 / 
Day 1 
Cycle 1 / 
Day 8 
Cyc1e 1 / 
Day 15 
Cycle 2 / 
Day 1 
Cycle 3 / 
Day 1 
Cycle 4 / 
Day 1 
Cycle 5 / 
Day 1 
 
 
 
 
 
Day 
-28 
1 
8 
15 
22 
43 
64 
85 
 
 
 
 
 
Visit window9 
0 
± 2 
± 2 
 -2 ~ +3 
-7 ~ +3 
-7 ~ +3 
-7 ~ +3 
NA 
+ 7 
+ 7 
± 7 
± 7 
Dose with lazertinib21 
 
Daily dosing 
 
 
 
Lazertinib return 
 
 
 
 
X 
X 
X 
X 
(X) 
X 
 
 
 
Safety assessment 
 
Adverse events22 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
(X) 
Prior/concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
(X) 
Survival follow-up 
 
Survival and anti-cancer  
therapy survey 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations: BM = brain metastasis; cfDNA = circulating cell-free deoxyribonucleic acid; ECG = electrocardiogram; EGFR = epidermal growth factor receptor; 
EORTC QLQ  = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, C-30 = Core 30 items, LC-13 = Lung Cancer 
13 items, EQ-5D-5L = Euro-Quality of Life-5 Dimension-5 level; F/U = follow-up; LVEF = left ventricular ejection fraction; MUGA = multiple gated 
acquisition; NA = not applicable; RECIST = Response Evaluation Criteria in Solid Tumors; T790M = threonine-to-methionine substitution; WHO = World 
Health Organization; WOCBP = woman of childbearing potential.  
1 
Pre-crossover screening visit may occur on the same day of discontinuation visit of main study. 
2 
Study visits will occur on Day 1 of every other cycle from Cycle 5 onwards (C5D1, C7D1, C9D1, C11D1, C13D1, C15D1…). 
3 
Unscheduled visits can be arranged if necessary. Study procedures will be performed at the discretion of the investigator. 
4 
All patients will attend a discontinuation visit within 7 days of permanent discontinuation of open-label lazertinib, where all procedures for the discontinuation 
visit will be performed. The discontinuation visit should occur before the start of any new treatment and the reason should be documented on the electronic Case 
Report Form. 
5 
28-day safety F/U will be made via at least a telephone contact within 28 days (+7 days) after permanent discontinuation of lazertinib. 
6 
If patients discontinue lazertinib for reasons other than objective disease progression, Progression F/U will be made every 6 weeks. Tumor assessment per 
RECIST v1.1 for the Progression F/U should be continued every 6 weeks for the first 12 months and then every 12 weeks relative to date of lazertinib first-dosing 
until objective disease progression. 
7 
All patients will be followed for survival and any post-study anticancer treatment via at least a telephone contact every 6 weeks relative to date of lazertinib first-

Confidential 
Study No.: YH25448-301 
Protocol Ver2 
 
 
Page 58 of 127 
SOP-CD-03-Form2 Ver2 
 
dosing following discontinuation of open-label lazertinib, until lost to follow up, the withdrawal of consent, or death (whichever is earlier). However, the patients 
who discontinue open-label lazertinib for reasons other than objective disease progression will conduct survival follow-up following confirmation of objective 
disease progression. 
8 
A cycle is defined as a 21-day treatment period. 
9 
Every visit window is calculated based on the date of first dose of open-label lazertinib. 
10 
Signed informed consent for optional cross-over study must be obtained before the patient undergoes any new study-specific procedures. 
11 
Plasma sample at progression must be submitted to central laboratory for central testing of T790M mutation. Tumor (Formalin-Fixed Paraffin-Embedded Tissue) 
sample collected at progression may be submitted for central testing of T790M mutation (Optional).   
12 
Confirmation of T790M mutation test result is required. The sample that is used to test for the mutation to be eligible to go on to the cross-over arm, can be the 
same as the optional sample at progression. 
13 
Vital signs (heart rate, blood pressure, and body temperature) will be obtained after the patient has rested for 10 minutes. The date and time of the assessment 
should be recorded. 
14 
All ECG data will be collected digitally and transferred electronically for central analysis. A set of triplicate 12-lead ECGs, approximately 2 minutes apart, will be 
performed as scheduled with reading by a cardiologist. 
15 
LVEF will be assessed using an echocardiogram or MUGA scan at pre-crossover screening and every 12 weeks (-7 days, +3 days) relative to date of first-dosing 
until discontinuation visit. Additional assessments may be performed if clinically indicated. For any patient who has at least one echocardiogram or MUGA that 
is considered abnormal by local assessment, the Sponsor collects all echocardiograms or MUGA scans (obtained at pre-crossover screening and all subsequent 
assessments) for the purpose of a central read. 
16 
If needed, any clinical laboratory tests may also be performed for safety evaluation of patients. 
17 
At pre-crossover screening and discontinuation visit, all WOCBP should complete a serum pregnancy test per the practice of the site. Repeat as necessary during 
the treatment period if clinically indicated. In addition, it can be performed every 6 weeks relative to date of first-dosing considering the local health authorities-
specific requirement or guidance. At other times during study, a serum or urine pregnancy test may be performed as indicated. 
18 
Blood samples for cfDNA and blood-borne biomarkers analysis will be collected on the same day of any scheduled and unscheduled tumor assessments, if 
possible. 
19 
Baseline tumor assessment during pre-crossover screening must be performed within 28 days before first-dosing of open-label lazertinib. Follow-up tumor 
assessments will be performed every 6 weeks (-7 days, +3 days) for the first 12 months and then every 12 weeks (-7 days, +3 days) relative to date of first-dosing 
of open-label lazertinib using the RECIST v1.1 until objective disease progression. Tumor assessment will be performed using computed tomography (CT) or 
magnetic resonance imaging (MRI) of the chest and abdomen (including liver and adrenal glands). Any other sites where disease is suspected or known at 
baseline must also be imaged. Images will be sent to central reading center timely for BICR.  
20 
Questionnaires should be completed prior to any visit-specific procedures. All questionnaires will be performed at Cycle 1 Day 1, Cycle 2 Day 1 (-2 days, +3 
days) and then every 6 weeks (-7 days, +3 days) relative to date of first-dosing until 28-day safety F/U visit or progression F/U visit (whichever is later). 
21 
Lazertinib should be taken orally once daily at approximately the similar time with a glass of water. Patients may continue lazertinib following objective disease 
progression if patient is receiving clinical benefit, as judged by the investigator. 
22 
All adverse events and special reporting situations, whether serious or non-serious, will be reported from the time a signed and dated ICF is obtained until 28 
days following the last dose of lazertinib. Adverse events occurring after 28 days following the last dose of lazertinib should also be reported, if considered 
related to lazertinib. Reported all AEs must be followed until recovery to baseline or Grade ≤1 or until deemed irreversible, and all relevant information must be 
recorded on the eCRF. 
 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 59 of 127 
SOP-CD-03-Form2 Ver2 
Table 7. Blood Sample Volumes 
The estimated volume of blood samples required in screening and the first 15 weeks is 248 mL 
in maximum. Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
Visit 
Safety (mL)1 
PK analysis (mL)2 
Others 
(mL)3 
PGx (mL) 
Screening 
15 
NA 
40 
NA 
Cycle 1 
45 (3 * 15 mL)4 
6 (3 * 2 mL) 
20 
10 (optional)5 
Cycle 2 
15 
6 (3 * 2 mL) 
NA 
NA 
Cycle 3 
15 
NA 
20 
NA 
Cycle 4 
15 
NA 
NA 
NA 
Cycle 5 
15 
6 (3 * 2 mL) 
20 
NA 
Subtotal at 
Cycle 5 
120 
18 
100 
10 
Abbreviations: NA = not applicable; PGx =pharmacogenetics; PK=pharmacokinetics. 
1 Sample tubes and sample sizes may vary depending on laboratory method used and routine practice at the site. 
The number of samples/blood volumes is therefore subject to site-specific change. 
2 Only taken at pre-dose, 1 to 3 hours, and 4 to 6 hours post-dose on Day 1 of Cycles 1, 2, 5, 9, and 13.  
3 Included samples for mutation confirmation, cfDNA and blood-borne biomarkers. 
4 Patients attend visits every week within Cycle 1. A cycle is defined as a 21-day treatment period. 
5 If for any reason the sample is not drawn prior to dosing, it may be taken at any visit until the last study visit. 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 60 of 127 
SOP-CD-03-Form2 Ver2 
and 
to be taken the first dose on the randomization 
CCI

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 61 of 127 
SOP-CD-03-Form2 Ver2 
day, the first dose must be administered within a maximum of 3 days following randomization. 
A cycle of treatment is defined as 21 days. Patients will be randomized and receive once daily 
treatment with either lazertinib or gefitinib. Patients will continue study treatment until 
objective disease progression or beyond RECIST v1.1 defined progression if patient is 
receiving clinical benefit, as judged by the Investigator, and in the absence of discontinuation 
criteria. Patients who continue to receive treatment following objective progression due to 
clinical benefit will have tumor assessments as per standard local practice. 
Detailed study treatment schedule is shown in the SoA (See Table 5). 
If disease progression assessed by the Investigator according to RECIST v1.1 is confirmed by 
BICR, and T790M mutation positive, it will be given the opportunity of open-label lazertinib 
treatment to the patient who randomized to the gefitinib. For further details on post-progression 
cross-over to open-label lazertinib please refer to Section 6.4 and Table 6. 
6.3. FOLLOW-UP PERIOD 
Post study treatment assessment will be initiated at the time study treatment is permanently 
discontinued (See Table 5). This may include: 
6.3.1. Discontinuation Visit 
A Discontinuation visit will be performed at the time the study treatment is permanently stopped. 
Refer to the SoA for details (See Table 5). 
6.3.2. 28-Day Safety Follow-up Visit 
28-Day safety follow-up should be made with the patient 28 + 7 days following the 
discontinuation of study treatment to collect new AEs and follow up on any ongoing AEs and 
concomitant medications (including any subsequent cancer therapy). Refer to Appendix 2 for 
full details on AE recordings during follow up.
6.3.3. Progression Follow-up Visit 
If patients discontinue study treatment for reasons other than objective disease progression, 
Progression F/U will be made every 6 weeks. Tumor assessment per RECIST v1.1 for the 
Progression F/U will be continued every 6 weeks for the first 18 months and then every 12 
weeks (relative to randomization) until objective progression (See Table 5). 
6.3.4. Survival Follow-up Visit 
All patients will be followed for survival, disease progression (per local standard practice) and 
any post-study anticancer treatment via at least a telephone contact every 6 weeks relative to 
date of randomization following discontinuation of study treatment, until lost to follow up, the 
withdrawal of consent, or death (whichever is earlier). However, in the case which patients who 
discontinue study treatment for reasons other than objective disease progression will conduct 
survival follow-up following confirmation of objective disease progression. 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 62 of 127 
SOP-CD-03-Form2 Ver2 
In addition to the survival status, the following assessments are also required post progression: 
•
Anti-cancer therapy and surgery collected every 6 weeks.
•
Subsequent response/progression data every 6 weeks until the first confirmed disease
progression on a subsequent treatment.
Patient should be contacted in the week following the data cut-off for each analysis of survival 
(i.e., at the time of primary PFS analysis and final OS analysis) to provide complete survival 
data. 
6.4. CROSS-OVER TO OPEN-LABEL LAZERTINIB 
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. The following steps must be performed as specified for a patient to be 
able to receive open-label lazertinib. 
6.4.1. Central Confirmation of Disease Progression 
Should the investigator determine the patient to have progressed according to RECIST v1.1, 
images must be sent for central confirmation of disease progression. Progression must be 
confirmed centrally in order for a patient to be eligible to receive open-label lazertinib. If 
progression is not confirmed centrally, the patient may continue to receive randomized 
treatment (should it be in their interests to do so) and have progression assessed by BICR at a 
future time point. 
After IDMC in consultation with sponsor and regulators determine the primary endpoint of PFS 
has been achieved, all patients determined to have objective disease progression as per 
Investigator’s assessment and have T790M mutation positive, will be given the opportunity to 
begin treatment with open-label lazertinib, if eligible; central confirmation of disease 
progression will no longer be required. 
6.4.2. T790M Testing 
In order to be eligible to receive open-label lazertinib, the patient’s tumor must have been 
confirmed as T790M mutation positive by means of plasma or tissue collected post-progression. 
Determination of tumor T790M mutation positive status may be performed locally (without the 
requirement for a central test), or centrally for those patients unable to be tested locally.  

For local determination of T790M status, a laboratory report confirming tumor T790M
status performed in an accredited, certified or quality assured clinical laboratory as
required by country-specific guidelines, using an appropriately validated test must be
provided.

For central determination, patients are required to provide tumor tissue or blood from 
a sample taken at progression (Specific instructions regarding the preparation and 
shipment of these tumor samples will be provided in the Laboratory manual).
6.4.3. Unblinding 
Following central confirmation of objective disease progression according to RECIST v1.1 and 
T790M mutation positive, the patient may then be unblinded to establish randomized treatment. 
If randomized to the gefitinib treatment arm, the patient may be a candidate to receive open-

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 63 of 127 
SOP-CD-03-Form2 Ver2 
label lazertinib. Patients who have been unblinded prior to central confirmation of progression 
are not able to receive open-label lazertinib. 
6.4.4. Open-label Treatment with Lazertinib 
Any unresolved toxicities from prior therapy should be controlled, and be no greater than 
CTCAE grade 1 (with the exception of alopecia) at the time of starting open-label lazertinib 
treatment. The patient cannot cross-over if they have received intervening therapy following 
discontinuation of randomized treatment. The disease assessment which documents progression 
will serve as the new baseline for the cross-over portion of the study. The investigator will 
reevaluate the patient for target and non-target lesions, according to RECIST v1.1, based on the 
disease assessment scans showing the initial progression. A cross-over patient need not repeat 
imaging assessments before cross-over Cycle 1, Day1, unless the disease assessment is 
incomplete, or occurred >28 days prior to cross-over Cycle 1, Day 1 (in which case, disease 
assessments must be repeated and will serve as the new baseline). If the disease assessment is 
incomplete, the site will obtain any missing radiographic imaging (e.g. MRI of the brain) prior 
to initiation of treatment with lazertinib. 
Patients who are eligible and choose to cross-over to open-label lazertinib treatment will be 
dispensed bottles of lazertinib. For details on lazertinib please refer to Section 5.1.3. 
6.5. End of Study Definition 
The end of the study is defined as ‘the last visit of the last patient undergoing the study.’ 
The study may be terminated at individual study sites if the study procedures are not being 
performed according to GCP, or if recruitment is slow. The Sponsor may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study with 
lazertinib. 
6.6. STUDY MATERIALS 
Study specific guidelines (e.g., Study reference manual) and materials (e.g., laboratory kit) will 
be provided by the Sponsor or designated CRO/third party. 
6.7. SAFETY ASSESSMENTS 
Planned time points for all safety assessments are provided in the SoA (See Table 5 and Table 
6). Adverse events will be reported throughout the study as described in Appendix 2.  
6.7.1. Adverse Events (AEs) 
6.7.1.1. 
Adverse Events of Special Interest (AESI) 
Not Applicable 
6.7.1.2. 
Adverse Events (AEs) and Serious Adverse Events (SAEs) 
The definitions and other details of AEs and SAEs can be found in Section 7 and Appendix 2. 
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 64 of 127 
SOP-CD-03-Form2 Ver2 
patient's legally authorized representative). 
The Investigator and any qualified designee(s) are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for following 
up the AE or SAE. (See Section 7.3).  
Care will be taken not to introduce bias when detecting AEs/SAEs. Open-ended and non- 
leading verbal questioning of the patient is the preferred method to inquire about AE occurrence. 
6.7.2. 12-lead Electrocardiograms 

Twelve-lead ECGs will be obtained after the patient has been resting semi-supine for at 
least 10 minutes prior to times indicated. For each time point, the ECG should be taken 
three times at about 2 minutes-interval.

ECGs should be obtained immediately before PK blood sampling at pre-dose, 1 to 3 hours, 
and 4 to 6 hours post-dose on Day 1 of Cycles 1, 2, 5, 9, and 13. Other ECGs will not be 
time-matched and can be performed regardless of dosing time.

A standardized ECG machine should be used and the patient should be examined using the 
same machine throughout the study if possible. Triplicate 12-lead ECG will be obtained 
using an ECG machine that automatically calculates the heart rate and measures PR, QRS, 
QT intervals and QTc. 

All ECG data will also be collected digitally and will be transferred electronically for 
central analysis as described in the study specific ECG manual. Heart rate, PR, RR, QRS 
and QT intervals will be determined and reviewed by an external cardiologist. (Central 
confirmed ECG results at screening will not be used in eligibility assessment).

After paper ECGs have been recorded, the Investigator or designated physician will review 
each ECGs and may refer to a local cardiologist if appropriate for immediate management 
of the patient. Each ECGs review should be performed before the next cycle of treatment 
is administered. A paper copy and centrally confirmed results should be filed in the patient’s 
medical records. For all ECGs details of rhythm, ECG intervals and an overall evaluation 
will be recorded.
6.7.3. Physical Examinations 

Height (at screening only) and weight will be measured and recorded.

The physical examination includes an assessment of general appearance and a review of 
systems (e.g., dermatologic, head, eyes, ears, nose, mouth/throat/neck, thyroid, lymph 
nodes, 
respiratory, cardiovascular, gastrointestinal, 
extremities, 
musculoskeletal,
neurologic, and psychiatric systems, etc.).

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
6.7.4. Vital Signs 

Assessment and measurement of vital signs (seated systolic and diastolic blood pressure, 
pulse rate, and body temperature) will be performed at the time points indicated in the SoA 
(See Table 5 and Table 6). 

Measurement of vital signs should be made in the same arm of the patient at each visit.

The method used to measure body temperature at screening should be maintained 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
 
 
Page 65 of 127 
SOP-CD-03-Form2 Ver2 
 
throughout the study for each patient, and should be indicated (e.g., ear, mouth, or armpit, 
etc.). 
 
6.7.5. Laboratory Test Assessment 
 
Refer to the SoA for the timing and frequency of all protocol-required laboratory 
assessments (See Table 5 and Table 6).  
 
The tests detailed in Table 8 will be performed by the local laboratory.  
 
Protocol-specific requirements for inclusion or exclusion of patients are detailed in Section 
4.2.1 and Section 4.2.2 of the protocol. Additional tests may be performed at any time 
during the study as determined necessary by the Investigator or required by local 
regulations. 
 
The Investigator must review the laboratory test report, document this review, and record 
any clinically relevant changes occurring during the study in EDC. The laboratory reports 
must be filed with the source documents. Clinically relevant abnormal laboratory findings 
are those which are not associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the patient's condition. 
 
All laboratory tests with values considered clinically abnormal during participation in the 
study should be repeated until the values return to normal or baseline. If such values do not 
return to normal/baseline within a period of time judged reasonable by the Investigator, the 
etiology should be identified, where possible, and the Sponsor notified. 
 
If laboratory values from laboratory assessments not specified in the protocol and 
performed at the institution’s local laboratory result in the need for a change in patient 
management or are considered clinically relevant by the Investigator (e.g., are considered 
to be an SAE or an AE or require dose modification, etc.), then the results must be recorded 
in EDC. 
 
Laboratory values that meet the criteria for CTCAE grade 3 or higher and/or have changed 
significantly from baseline and are considered to be of clinical concern will be 
repeated/confirmed within 7 days and followed up as appropriate. 
 
If a patient demonstrates a concomitant elevation of AST or ALT and total bilirubin that 
meet the liver chemistry stopping criteria in Section 5.4.1.6 (which may be an indicator of 
Hy’s law or potential hepatotoxicity), it must be reported to the Sponsor and/or designated 
CRO within 24 hours (see Section 7. 4.1). The Investigator will need to follow liver studies 
more frequently, may need to perform additional examinations, and confirm the results 
with the medical monitor. Investigators must document their review of each laboratory 
safety report. Details of identification of potential Hy’s Law cases and actions to take are 
detailed in Section 5.4.1.6.

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 66 of 127 
SOP-CD-03-Form2 Ver2 
Table 8. Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Hematocrit 
Hemoglobin 
Platelet Count 
RBC Count 
WBC Count 
RBC Indices: 
%Reticulocytes 
WBC differential count: 
Basophils 
Eosinophils 
Lymphocytes 
Neutrophils 
Monocytes 
Clinical 
Chemistry 
Albumin 
BUN 
Creatinine 
Potassium 
Sodium  
Magnesium 
Total and direct bilirubin 
Total Protein  
Uric acid 
ALT 
AST 
Alkaline phosphatase 
Calcium 
γGTP 
Glucose, fasting 
Routine 
Urinalysis 
Protein (albumin) 
Glucose 
Blood (RBC) 
WBC by dipstick 
Other Tests 
Serum hCG pregnancy test at screening and discontinuation. Additional 
testing may be performed if needed in WOCBP. At other times during study, 
a serum or urine pregnancy test may be performed as indicated 
Serology (anti-HIV, HBsAg, and hepatitis C antibody) (Screening Visit 
only) 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea 
nitrogen; γ-GTP = gamma guanosine-5’-triphosphate; HbsAg = hepatitis B virus surface antigen; hCG = 
human chorionic gonadotropin; HIV = human immunodeficiency virus; RBC = red blood cell; WBC= white 
blood cell; WOCBP = women of childbearing potential. 
6.7.6. Other Safety Assessments 
6.7.6.1. 
Ophthalmologic Assessment 
An ophthalmic assessment, including slit lamp examination, fundoscopic examination, visual 
acuity test and other tests at the discretion of the Investigator will be performed at screening 
and should be repeated if a patient experiences any visual symptoms (including blurring of 
vision), with additional tests if clinically indicated. Any clinically significant findings, 
including those confirmed by the ophthalmologist must be reported as an AE. Photographs 
should be performed to record any clinically significant findings. These photographs should be 
available for review by the medical monitor if necessary. Ophthalmology examination results 
should be recorded in EDC. 
6.7.6.2. 
Echocardiography or Multiple Gated Acquisition Scan 
Echocardiography (or multiple gated acquisition scan) to assess left ventricular ejection fraction 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 67 of 127 
SOP-CD-03-Form2 Ver2 
will be conducted at screening, every 12 weeks (-7 days, +3 days) after randomization, and at 
discontinuation visit. Additional assessments can be conducted at the discretion of the 
Investigator. The modality of the cardiac function assessments must be consistent within a 
patient (i.e., if echocardiography is used for the screening assessment then echocardiography 
should also be used for subsequent scans). The patients should also be examined using the same 
machine and operator whenever possible. For any patient who has at least one echocardiogram 
or MUGA scan that is considered abnormal by local assessment, the Sponsor and/or designated 
CRO will collect all echocardiograms or MUGA scans (obtained at Screening and all 
subsequent assessments).  
6.8. EFFICACY ASSESMENTS 
6.8.1. RECIST v1.1 Assessments 
The imaging modalities used for RECIST v1.1 assessments will be CT or MRI scans of the 
chest and abdomen (including liver and adrenal glands). The methods used at baseline for 
assessment of tumor burden (CT or MRI) must be used at each subsequent follow-up 
assessment. Any other sites where disease is suspected or known at baseline must also be 
imaged, and additional sites of disease, confirmed at baseline not covered by the 
protocol-specified anatomy, should be followed at the same scheduled visits as the other 
RECIST v1.1 assessments. 
Specifically, patients with confirmed BM at screening should be followed up on study with 
repeated CT or MRI assessment at the same frequency as the other RECIST v1.1 assessments. 
The same modality for MRI should be used for a patient throughout the study.  
Baseline assessments should be performed within 28 days prior to randomization. Subsequent 
assessments are to be performed every 6 weeks (-7 days, +3 days) for the first 18 months and 
then every 12 weeks (-7 days, +3 days) relative to randomization until objective disease 
progression as per RECIST v1.1. Patients who discontinue study treatment for reasons other 
than objective disease progression will continue RECIST v1.1 assessments every 6 weeks (-7 
days, +3 days) for the first 18 months and then every 12 weeks (-7 days, +3 days) relative to 
randomization until objective disease progression, even if a patient receives other anti-cancer 
treatment. It is important to follow the assessment schedule as closely as possible. If scans are 
performed outside of the scheduled timepoint and the patient has not progressed, every attempt 
should be made to perform the subsequent scans at the next scheduled time points, relative to 
the date of randomization. Any other sites at which new disease is suspected should also be 
appropriately imaged during the study. In general, scans should be performed after PRO 
assessments, when possible. 
Imaging assessments including unscheduled visit scans should be collected on an ongoing basis 
and sent to the designated CRO or third party to enable independent central analyses. Following 
objective disease progression, per RECIST v1.1, patients should have tumor assessments 
performed as per standard local practice to assess time to second progression. These post 
RECIST v1.1 progression local-practice scans should not be sent to the designated CRO or third 
party which is performing the independent RECIST v1.1 assessments. However for patients 
that discontinue study treatment due to reasons other than objective disease progression should 
have tumor assessment performed according to RECIST v1.1 and the images submitted to the 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 68 of 127 
SOP-CD-03-Form2 Ver2 
designated CRO or third party to enable independent central analyses until objective disease 
progression. 
For Investigator assessment, RECIST v1.1 criteria will be used to assess each patient’s tumor 
response to treatment and allow calculation of PFS, ORR, DoR, DCR, depth of response and 
time to response. Measurable, non-measurable, target and non-target lesions, and the objective 
tumor response criteria (complete response, partial response, stable disease, or progression of 
disease) are followed the RECIST v1.1 guidelines (11Eisenhauer et al, 2009). 
If the Investigator is in doubt as to whether progression has occurred, particularly with response 
to non-target lesions (NTLs) or the appearance of a new lesion, it is advisable to continue 
treatment until the next scheduled assessment (or sooner if clinically indicated) and reassess the 
patient’s status. If the repeated scans confirm progression, then the date of the initial scan should 
be declared as the date of progression. 
To achieve “unequivocal progression” on the basis of NTLs, there must be an overall substantial 
worsening in NTLs such that, even in the presence of stable disease or partial response in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. 
A modest “increase” in size of 1 or more NTLs is usually not sufficient to qualify for 
unequivocal progression status. 
Categorization of objective tumor response assessment at each visit will be based on the 
RECIST v1.1 criteria of response: complete response, partial response, stable disease, and 
progression of disease. Target lesion progression will be calculated in comparison to when the 
tumor burden was at a minimum (i.e., smallest sum of diameters previously recorded on study). 
In the absence of progression, tumor response (complete response, partial response, or stable 
disease) will be calculated in comparison to the baseline tumor measurements obtained before 
starting treatment. 
The primary analysis for this study will be based on the tumor assessments using investigator 
assessment according to RECIST v1.1 and the management of patients will be based solely 
upon the results of the RECIST v1.1 assessment conducted by the Investigator. 
6.8.2. Blinded Independent Central Review 
All protocol required imaging assessments, including unscheduled visit scans, will be 
duplicated and collected on an ongoing basis and sent to the designated CRO or third party to 
enable central analysis for BICR. The results of this independent central review will not be 
communicated to the investigational site and the management of patients will be based on the 
result of RECIST v1.1 assessments conducted by the investigator. 
However, in case of patients whose tumor have progressed, as assessed by the Investigator, the 
central review must provide confirmation of progression, prior to cross-over receiving open-
label lazertinib, or prior to discontinuing study treatment for progression.  

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 69 of 127 
SOP-CD-03-Form2 Ver2 
6.8.3. Assessment of PFS after Next-line treatment (PFS2) 
Following objective disease progression per RECIST v1.1, patients will have their progression 
status recorded every 6 weeks to assess second progression (PFS2). Second progression is 
considered as an event of subsequent progressive disease, post initiation of subsequent anti-
cancer therapy, or death. A patient’s progression status is defined according to the local standard 
clinical practice and may involve any of the following: objective radiological progression 
(preferred), symptomatic progression, or death. Scans will be performed according to the local 
practice and formal RECIST v1.1 measurements will not be collected for assessment of PFS2. 
The date of PFS2 assessment and Investigator opinion of progression status (progressed or 
non-progressed) at each assessment will be recorded in EDC. 
6.8.4. Mandatory Tumor Biopsy Sample for Central Mutation Analysis 
Tumor tissue sample must be formalin-fixed and paraffin embedded (Specific instructions 
regarding the preparation and shipment of these tumor samples will be provided in the 
Laboratory manual). Biopsy samples taken from bone metastasis and cytology samples are 
unsuitable for testing and should not be provided. Samples may be collected from primary or 
metastatic tumor deposits. Study sites personnel should ship the tumor sample to the sponsor-
designated testing laboratory following patient consent. Blocks must be provided wherever 
possible. Mandatory provision of an unstained, archived tumor tissue sample in a sufficient 
quantity to allow for central analysis of EGFR mutation status should be required. 
The mandatory screening tumor biopsy sample must not be taken from a previously irradiated 
lesion. The biopsy must not be taken from the lesion(s) selected for Inclusion criterion # 8 
(unless only 1 measurable lesion exists, in which case the baseline tumor assessment scans are 
to be done at least 14 days after the screening biopsy). This biopsy sample is not subject to the 
28-day screening window; for patients with systemic recurrence after prior surgery for early 
stage disease, any fresh tumor tissue taken since such recurrence will be acceptable; for newly 
diagnosed patients with locally advanced or metastatic NSCLC, any tumor tissue since the 
initial diagnosis will be acceptable as long as no chemotherapy or radiotherapy (adjuvant or 
neo-adjuvant) are intercalated between the biopsy and screening; if tissue is already available 
from a biopsy sample taken since confirmation of disease progression to Stage IIIB/C or Stage 
IV, then there is no need for a further biopsy as this sample can be submitted for EGFR mutation 
status including Ex19del , L858R, T790M testing. If the first biopsy submitted for central 
testing is not confirmed as EGFR mutation positive (i.e., due to test failure), a further biopsy 
sample may be submitted for central testing. Central re-tests on a new sample can only be 
performed if the original testing failed; re-tests are not permitted if the central EGFR testing 
result is EGFR mutation negative, or does not report an EGFR eligible mutation (Ex19del or 
L858R). Patients who have been locally tested as EGFR mutation negative may submit their 
tissue biopsy sample for testing at the central laboratory at the discretion of the Investigator.
6.9. OTHER ASSESSMENTS 
6.9.1. WHO Performance Status 
Performance status will be assessed at the scheduled visits indicated in the SoA according to 
WHO criteria as follows (See Table 5 and Table 6): 

0 = Fully active, able to carry out all pre-disease activities without restrictions.

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 70 of 127 
SOP-CD-03-Form2 Ver2 

1 = Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, (e.g., light housework, office work).

2 = Ambulatory and capable of self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours.

3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours.

4 = Completely disabled, cannot carry on self-care, totally confined to bed or chair.

5 = Death
6.9.2. Concomitant Medication Use 
Information on any treatment within the 4 weeks prior to randomization and all concomitant 
treatments given up to 28 days after discontinuation of study treatment with reasons for the 
treatment, will be recorded in EDC. For additional information, refer to Section 5.6. 
6.9.3. Anti-cancer and Surgical Treatments 
All prior and concomitant anti-cancer and surgical therapies will be collected at screening and 
throughout the study. Subsequent regimens of anti-cancer therapy will be recorded in EDC.  
6.9.4. Patient-Reported Outcomes (PROs) 
Patient-reported outcomes, an umbrella term referring to all outcomes and symptoms, are 
directly reported by the patient. PROs have become a significant endpoint when evaluating 
effectiveness of treatments in clinical trials.  
The following PROs will be administered (Appendix 8, 9 and 10): 

European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire (EORTC-QLQ) Core 30 items (EORTC QLQ-C30);

EORTC QLQ-Lung Cancer 13 items (EORTC QLQ-LC13);

Euro-Quality of Life-5 Dimension-5 level (EQ-5D-5L)
PROs will be collected for all patients throughout the study period. See Table 5 and Table 6 for 
the timing of collection. PROs should be completed prior to any visit-specific procedures. In 
general, the PRO instruments should be administered prior to any and all treatment assessment 
(i.e., including scans for tumor assessment).   
6.9.4.1. 
EORTC QLQ-C30 and EORTC QLQ-LC13 
The EORTC QLQ-C30 was developed by the EORTC Quality of Life Group in 1993. It consists 
of 30 items and measures cancer patients’ functioning (health-related quality of life (HRQoL)) 
and symptoms (12Aaronson NK et al, 1993) 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. The EORTC 
QLQ-C30 is a valid and reliable PRO instrument in this patient population. 
The EORTC QLQ-LC13 is a well-validated complementary module measuring lung cancer 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
 
 
Page 71 of 127 
SOP-CD-03-Form2 Ver2 
 
associated symptoms and side effects from conventional chemotherapy and radiotherapy 
(13Bergman B et al, 1994). 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 (14Fayers PM et al, 2001). 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. 
Both EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires will be administered in those 
countries where a linguistically validated version exists. EORTC QLQ-C30 and EORTC-QLQ 
LC13 will be performed at Cycle 1 Day 1, Cycle 2 Day 1 (-2 days, +3 days) and then every 6 
weeks (-7 days, +3 days) relative to date of randomization until 28-day Safety F/U visit or 
progression F/U visit (whichever is later). 
Note: Signs and symptoms assessed with the EORTC QLQ-C30 and EORTC QLQ-LC13 will 
not be considered AEs. 
6.9.4.2. 
EQ-5D-5L 
The EQ-5D is a standardized measure of health status developed by the EuroQol Group in order 
to provide a simple, generic measure of health for clinical and economic appraisal (15EuroQol 
Group, 1990). The EQ-5D is a disease generic instrument that has been widely used and has 
been found to capture HRQOL changes in NSCLC (16Trippoli S et al, 2001; 17Belani CP et al, 
2006). 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. 
The EQ-5D-5L will be administered in those countries where a linguistically validated version 
exists. EQ-5D-5L will be also performed at Cycle 1 Day 1, Cycle 2 Day 1 (-2 days, +3 days) 
and then every 6 weeks (-7 days, +3 days) relative to date of randomization until 28-day safety 
F/U visit or progression F/U visit (whichever is later). 
6.9.5. Health Resource Use Module 
The Healthcare Resource Use Module will be completed by the investigational site for any 
healthcare resource use between visits. The site will ask patients for any health resource use 
between visits (i.e., excluding routine follow-up clinic visits associated with the clinical trial 
but including both planned and unplanned admissions) at Cycle 1 Day 1, Cycle 2 Day 1 (-2 
days, +3 days) and then every 6 weeks (-7 days, +3 days) relative to date of randomization until 
28-day safety F/U visit or progression F/U visit (whichever is later). 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 72 of 127 
SOP-CD-03-Form2 Ver2 
For the purposes of economic evaluation, it is necessary to capture healthcare resource use 
related to the treatment and the underlying disease. Within the study, the following resource use 
will be captured: 
•
Hospital episodes including the type of contact (hospitalizations, outpatient, day case), 
reason, length of stay (including intensive care unit), and concomitant medications and 
procedures.
•
Symptoms for admission.
The above resource use data will mainly come from the patient’s medical record and will be 
captured by site staff using EDC. 
6.10. PHARMACOKINETIC ASSESSMENTS 
6.10.1. Collection of PK Samples 
Venous blood samples (2 mL each) will be obtained at pre-dose, 1 to 3 hours, and 4 to 6 hours 
post-dose on Day 1 of Cycles 1, 2, 5, 9, and 13. A blood samples taken at pre-dose on Day 1 of 
Cycle 1 can be collected at any time before first dosing on the day, but a -1-hour window will 
be allowed for blood samples taken at pre-dose on Day 1 of Cycles 2, 5, 9, and 13. The pre-dose 
PK blood sample should be taken prior to the administration of study treatment on each PK 
sampling day. Optionally, 1 CSF sample (at least 1-2 mL) will be obtained at any time from 
Cycle 5, Day 1 onwards. If possible, the CSF sample should be taken on the same day as 
planned PK blood samples.  
Dosing date/time and meal consumption on the day of PK sampling and dosing date/time 
immediately before pre-dose PK sampling should be collected. In addition, the date and time 
of collection of each sample (blood and CSF samples) will be collected. The dosing date and 
time, meal consumption and the date and time of collection of each sample will be recorded in 
the EDC. 
Details of PK sample collection, labeling, storage and shipment will be provided in the 
Laboratory manual. 
6.10.2. Determination of Drug Concentration in PK Samples 
Lazertinib concentrations in plasma and CSF will analyzed using an appropriate bioanalytical 
method by the Sponsor’s designated bioanalytical laboratory. Full details of the analytical 
method used will be described in a separate bioanalytical report. All samples within the known 
stability of the analyses of lazertinib at the time of receipt by the bioanalytical laboratory will 
be analyzed. 
In addition, the residual PK samples may be subjected to further analyses by the Sponsor in 
order to future exploratory biomarker research and/or further investigate the presence and/or 
identity of additional drug metabolites. Any results from such analyses will be reported 
separately from the Clinical Study Report. 
Details on sample processing, handling, shipment, and storage will be provided in the 
Laboratory manual. 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 73 of 127 
SOP-CD-03-Form2 Ver2 
6.10.3. Storage and Destruction of PK Samples 
PK samples will be retained for a maximum of 5 years following the finalization of the Clinical 
Study Report.  
Any residual PK samples may be used for future exploratory biomarker research and/or further 
investigate the presence and/or identity of additional drug metabolites. In this case, the residual 
PK samples will be shipped to the Sponsor or the designated bioanalytical laboratory or third 
party, and the residual PK samples will be retained for a maximum of 5 years following the 
finalization of the final Clinical Study Report. 
6.11. PHARMACODYNAMICS ASSESSMENTS 
Not applicable  
6.12. PHARMACOGENOMIC/PHARMACOGENETIC ASSESSMENTS 
6.12.1. Pharmacogenetics: Collection and Processing 
If a patient agrees to participate in the Sponsor’s pharmacogenetics research component of the 
study, a blood sample will be collected (See Appendix 4).  
The 10 mL blood sample for genetic research will be obtained from patients immediately prior 
to randomization. Although genotype is a stable parameter, early sample collection is preferred 
to avoid introducing bias by excluding patients who may withdraw due to an AE. Such patients 
would be important to include in any genetic analysis. If for any reason the sample is not drawn 
prior to dosing, it may be taken at any visit until the last study visit. Only 1 sample should be 
collected per patient for genetics during the study. The samples will be retained for a maximum 
of 15 years following the finalization of the final Clinical Study Report or other period as per 
local regulations. Samples will be collected, labeled, stored, and shipped as detailed in the 
Laboratory manual. 
6.12.2. Pharmacogenetic Sample Analyses 
The results of this pharmacogenetic research will be reported separately and will not be part of 
the Clinical Study Report. Detailed information is provided in Appendix 4. 
6.13. EXPLORATORY ASSESSMENT 
CCI
CCI
CCI

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 74 of 127 
SOP-CD-03-Form2 Ver2 
7. ADVERSE EVENTS
7.1. DEFINITIONS 
7.1.1. Adverse Events 
An AE is any untoward medical occurrence in a clinical study patient, temporally associated 
with the use of a study treatment, whether or not considered related to the medicinal product. A 
detailed explanation is provided in Appendix 2. 
7.1.2. Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that, at any dose: 

Results in death

Is life-threatening

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent disability/incapacity or substantial disruption of the ability to conduct 
normal life functions.

Is or results in a congenital anomaly/birth defect

Is medically important*
* Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention to prevent one of the other outcomes 
listed in the above definition. These events should usually be considered serious. Examples 
of such events include invasive or new malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse, a 
concomitant elevation of AST or ALT and total bilirubin that meet the liver chemistry 
stopping criteria in Section 5.4.1.6 (which may be an indicator of Hy’s law or potential 
hepatotoxicity).
A detailed explanation is provided in Appendix 2. 
7.1.3. Adverse Events of Special Interest 
Not Applicable 
7.2. INTENSITY AND CAUSALITY 
The investigator will assess intensity and causality for each adverse event, and answer ‘yes 
(Certain, Probable/Likely, Possible, Unassessable/Unclassifiable)’ or ‘no (Unlikely, Not 
related)’ to the following question: ‘Do you consider that there is a reasonable possibility that 
the event may have been caused by the investigational product?’ A detailed instruction is 
provided in Appendix 2. 
CCI

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 75 of 127 
SOP-CD-03-Form2 Ver2 
For SAEs causal relationship will also be assessed for other medication and study procedure. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’. 
7.3. COLLECTION AND REPORTING 
7.3.1. Adverse Events 
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until 28 days following the last dose 
of study treatment. All adverse events should be followed until recovery to baseline or Grade 
≤1 or until deemed irreversible.   
Adverse events occurring after 28 days following the last dose of study treatment should also 
be reported, if considered related to study treatment. Aforementioned all adverse events also 
must be followed until recovery to baseline or Grade ≤1 or until deemed irreversible.   
Patients may receive local standard of care as permitted by protocol for treatment of 
comorbidities and/or management of adverse events. 
All adverse events, regardless of seriousness, severity, or presumed relationship to study 
treatment, must be recorded using medical terminology in the source document and the CRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported 
as "upper respiratory infection"). Investigators must record in the CRF their opinion concerning 
the relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions. 
The method of recording, evaluating, and assessing causality of AEs and the procedures for 
completing and transmitting SAE reports are provided in Appendix 2. 
7.3.2. Serious Adverse Events 
The Investigator must report any SAEs to the Sponsor and/or designated CRO within 24 hours 
of becoming aware of the event. A detailed instruction is provided in Appendix 2. 

Prompt notification (within 24 hours, see Appendix 2) by the Investigator to the Sponsor 
and/or designated CRO of an SAE is essential so that legal obligations and ethical 
responsibilities towards the safety of patients and the safety of a study treatment under 
clinical investigation are met.

The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and Investigators.

The Sponsor will report to the investigator (and the head of the investigational institute 
where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate IEC/IRB 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 76 of 127 
SOP-CD-03-Form2 Ver2 
that approved the protocol unless otherwise required and documented by the IEC/IRB. 
7.3.3. Adverse Events of Special Interest 
Not Applicable 
7.4. ADVERSE EVENTS BASED ON EXAMINATIONS AND TESTS 
The results from protocol mandated laboratory tests, vital signs, ECGs and other safety 
assessments will be summarized in the Clinical Study Report. Deterioration as compared to 
baseline in these parameters will therefore only be reported as AEs if they fulfill any of the 
following criteria unless clearly due to progression of disease under study or underlying disease: 

Test results associated with accompanying symptoms that are considered clinically 
significant in the opinion of the investigator.

Test results that require additional diagnostic testing (other than merely repeating an 
abnormal test) or medical/surgical intervention.

Test results that lead to a change in study treatment dosing or discontinuation from the
study, significant additional concomitant drug treatment, or other therapy.

Test results considered to be an AE by the Investigator or Sponsor.
If deterioration in a laboratory value, vital sign, ECG or other safety assessment is associated 
with clinical signs and symptoms, the sign or symptom will be reported as an AE and the 
associated laboratory result or other finding will be considered as additional information. 
Wherever possible the reporting investigator uses the clinical, rather than the laboratory term 
(e.g., anemia versus low hemoglobin value). In the absence of clinical signs and symptoms, 
clinically relevant deteriorations in non-mandated parameters should be reported as AE(s). 
Deterioration of a laboratory value that is unequivocally due to disease progression should not 
be reported as an AE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
7.4.1. Adverse events based on Potential Hy’s Law Criteria 
If a patient demonstrates a concomitant elevation of AST or ALT and total bilirubin that meet 
the liver chemistry stopping criteria in Section 5.4.1.6 (which may be an indicator of Hy’s law 
or potential hepatotoxicity), it must be reported to the Sponsor and/or designated CRO within 
24 hours as an SAE. Prompt reporting of cases meeting potential Hy’s Law criteria is required 
for compliance with regulatory guidelines. Details of identification of potential Hy’s Law cases 
and actions to take are detailed in Section 5.4.1.6. 
7.5. ADVERSE EVENTS BASED ON DISEASE PROGRESSION 
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the study treatment is being studied. It may be an increase in the severity 
of the disease under study and/or increases in the symptoms of the disease. The development 
of new, or progression of existing metastasis to the primary cancer under study should be 
considered as disease progression and not an AE. Events, which are unequivocally due to 
disease progression, should not be reported as an AE during the study. 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 77 of 127 
SOP-CD-03-Form2 Ver2 
Progression of the malignancy under study, including signs and symptoms progression, should 
not be reported as a serious adverse event. Hospitalization due to signs and symptoms of disease 
progression should not be reported as serious adverse event. 
7.6. ADVERSE EVENTS BASED ON NEW CANCERS 
The development of a new cancer should be regarded as an AE and will generally meet at least 
one of the serious criteria. New cancers are those that are not the primary reason for the 
administration of the study treatment and have been identified after the patient’s inclusion in 
this study. They do not include metastases of the original cancer. 
7.7. OVERDOSE 
For this study, any greater dose than intended will be considered an overdose. 
No specific treatment for overdose is known. The treatment given to the patient in case of 
overdose should be symptomatic and supportive.  
In the event of an overdose, the Investigator/treating physician should: 
•
Contact the medical monitor immediately.
•
Closely monitor the patient for AE/SAE and laboratory abnormalities.
•
Obtain a plasma sample for PK analysis within 1 day from the date of the last dose of 
study treatment if requested by the medical monitor (determined on a case-by-case 
basis).
•
Document the quantity of the excess dose as well as the duration of the overdosing in 
EDC.
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the medical monitor based on the clinical evaluation of the patient. 
7.8. PREGNANCY 
All pregnancies occurred throughout the study, from date of randomization until 24 weeks 
following last dosing of study treatment in female patients and female partners of male patients 
should be reported to the medical monitor. A detailed instruction is provided in Appendix 3. 
If a pregnancy is reported, the Investigator should inform the Sponsor and/or designated CRO 
within 24 hours of learning of the pregnancy and should follow the procedures outlined in 
Appendix 3. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered to be SAEs. 
Pregnancy alone is not regarded as an AE unless there is a suspicion that the study treatment 
may have interfered with the effectiveness of a contraceptive medication. 
Elective abortions without complications should not be handled as AEs, unless they were 
therapeutic abortions. Hospitalization for normal delivery of a healthy newborn should not be 
considered a SAE. 
The Investigator must follow-up and document the course and the outcome of all pregnancies 
even if the patient was discontinued from the study or if the study has finished. 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 78 of 127 
SOP-CD-03-Form2 Ver2 
All outcomes of pregnancy must be reported by the Investigator to the Sponsor and/or 
designated CRO on the pregnancy outcome report form within 30 days after he/she has gained 
knowledge of normal delivery or elective abortion. 
Any SAE that occurs during pregnancy (including SAEs occurring after last administration of 
study treatment) must be recorded on the SAE report form (e.g., maternal serious complications, 
spontaneous or therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, congenital 
anomaly, or birth defect) and reported within 24 hours in accordance with the procedure for 
reporting SAEs. 
7.9. STANDARD TREATMENT AFTER STUDY COMPLETION 
Upon discontinuation of study treatment, patients will be treated in accordance with the 
regional standard of care (SoC).  
7.10. OTHER SAFETY CONSIDERATION 
Not Applicable 
8. STATISTICAL CONSIDERATIONS
The statistical considerations summarized in this section outline the plan for data analysis of 
this study. Any deviations from the planned analyses will be described and justified in the final 
integrated study report. 
The aim of the study is to compare the efficacy and safety of lazertinib with gefitinib. 
The primary analysis will be performed when approximately 207 PFS events have occurred. 
The key secondary endpoints of OS in the overall population will be tested after the primary 
PFS analysis in a hierarchical procedure at the time of the PFS analysis. Other secondary 
efficacy endpoints will be analyzed at the time of the PFS analysis, including ORR, DoR, DCR, 
depth of response and time to response at a 2-sided significance level of 5%. 
In addition, a final analysis of OS will be performed at approximately 50% maturity, when 
approximately 200 death events (across both arms) have occurred. The alpha will be split 
between the two analyses to provide strong control of the family-wise error rate (See Section 
8.7.10 for further detail). 
8.1. SAMPLE SIZE DETERMINATION 
The median PFS for gefitinib from the previous conducted randomized phase III study were 9.2 
to 10.9 months (18Mok TS et al, 2009; 19Mitsudomi T et al, 2010; 20Maemondo M et al, 2010; 
21Wu YL et al, 2017). A median PFS of 10.5 months for the gefitinib arm has been assumed. 
To provide 90% power at a two-sided 5% significant level, approximately 207 progression-free 
survival events will be required to detect a hazard ratio of 0.64 (for median PFS of 16.5 months 
in lazertinib and 10.5 months in gefitinib). The primary analysis is expected to conduct at 
around 27 months, assuming approximately 380 patients are randomized over a period of 18 
months with 1:1 ratio.  

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 79 of 127 
SOP-CD-03-Form2 Ver2 
In order to randomize 380 patients, approximately 670 EGFRm+ patients will need to be 
screened. Sample size estimates have been calculated using PASS version 16. 
8.2. POPULATIONS FOR ANALYSES 
The analyses of data will be based on different analyses populations according to the purpose 
of the analyses. 
For purposes of analysis, the following analysis sets are defined: 
c
onfirmed PD by BICR and received at least one dose of lazertinib. 
The FAS will be the primary analysis set for all efficacy analyses. Further details will be 
provided in the Statistical Analysis Plan (SAP). 
8.3. PATIENT DISPOSITION 
The number of patients in the FAS, safety analysis sets, pharmacokinetic analysis set, cEAS, 
iFAS, and cross-over analysis set will be summarized by treatment and by institute. The 
screened set will only be summarized overall. Screening failures (i.e., patients who signed the 
ICF but are not received at least 1 dose of study treatment) and the associated reasons for failure 
will be tabulated overall. 
All randomized patients will be accounted for in the patient disposition table. The number and 
percentage of patients will be presented for discontinued patients, and for each reason for 
discontinuation by treatment. Reasons for discontinuation of study treatment will be listed 
including the study day of treatment discontinuation and will be summarized by treatment. 
8.4. DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographics, baseline characteristics, extent of disease, WHO performance status, and 
smoking status of the patients will be listed for each patients and summarized by treatment for 
the FAS. 
CCI

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 80 of 127 
SOP-CD-03-Form2 Ver2 
Baseline information (e.g., medical and surgical history), prior chemotherapy, prior 
radiotherapy and concomitant medications (baseline and post first dose) will also be listed 
individually for each patient and summarized by treatment.  
8.5. PRIOR 
AND 
CONCOMITANT 
MEDICATION 
AND 
CONSERVATIVE TREATMENT 
Prior and concomitant medications will be presented for the safety analysis set and summarized 
by treatment.  
Prior medication is defined as any medication taken within the period from 28 days before first 
dose of study treatment. Concomitant medication is defined as any medication taken during the 
treatment and until 28 days following the last dose of study treatment. 
Prior and concomitant medications will be coded using latest version of World Health 
Organization Drug Dictionary (WHO-DD).  
Prior and concomitant medications will be summarized separately by ATC level 1, ATC level 
2, and preferred name. A listing will be provided with relevant information for prior and 
concomitant medications for the safety analysis set. 
8.6. ASSESSMENT OF TREATMENT COMPLIANCE 
Exposure to study treatment (i.e., total amount of study treatment received) will be listed for all 
patients. 
Total exposure and total time on study (date of last dose minus date of first dose) will be 
summarized by the following: mean, standard deviation, minimum, maximum, median, and 
number of observations. In addition, the number and percentage of patients with at least 1 dose 
interruption/dose delay and at least 1 dose reduction will be presented separately for the initial 
period defined as 21 days (Cycle 1) and for any time following this initial period of the study. 
8.7. ANALYSES 
The SAP will be developed and finalized around the time of first patient in. Below is a summary 
of planned statistical analyses of the primary and secondary endpoints. Further details are 
presented in the SAP. 
8.7.1. Calculation or Derivation of Variables 
8.7.1.1. 
Investigator RECIST v1.1-based Assessments 
From the investigator review of the imaging scans, the RECIST tumor response data will be 
used to determine each patient visit response according to RECIST v1.1. 
At each visit, patient will be programmatically assigned a RECIST v1.1 visit response of 
complete response, partial response, stable disease, or progressive disease depending on the 
status of their disease compared with baseline and previous assessments. If a patient has had a 
tumor assessment which cannot be evaluated, then the patient will be assigned a visit response 
of not evaluable unless there is any evidence of progression, in which case the response will be 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 81 of 127 
SOP-CD-03-Form2 Ver2 
assigned as progressive disease. 
The data from the investigator’s RECIST v1.1 assessment will be used as a primary analysis. 
8.7.1.2. 
BICR of RECIST v1.1-based Assessments 
The BICR of radiological imaging data will be carried out using RECIST v1.1. All radiological 
scans for all patients (including those at unscheduled visits or outside visit windows) will be 
provided to the BICR. All imaging scans will be reviewed by 2 independent radiologists using 
RECIST v1.1 criteria and will be adjudicated if required. The independent reviewers will be 
blinded to treatment. 
Tumor assessment will be performed using CT or MRI of the chest and abdomen (including the 
liver and adrenal glands) and other regions as clinically indicated. For each patient, the BICR 
will define the overall visit response date (complete response, partial response, stable disease, 
progressive disease, or not evaluable) and the relevant scan dates for each timepoint (i.e., for 
visits where response or progression is not identified). If a patient has had a tumor assessment 
which cannot be evaluated, then the patient will be assigned a visit response of not evaluable 
(unless there is any evidence of progression in which case the response will be assigned as 
progressive disease). Progression-free survival will be derived from the overall visit response 
date and the scan dates. A sensitivity analysis of PFS will be performed based on data assessed 
by BICR for all patients. 
Further details of BICR will be documented in the independent review charter. 
8.7.2. Efficacy Analyses  
8.7.2.1. 
Primary Efficacy Analysis  
Progression free survival (PFS) 
The primary efficacy endpoint is PFS. PFS is defined as the time from randomization until the 
date of objective disease progression or death (by any cause in the absence of progression) 
whichever comes first based on investigator assessment using RECIST v1.1. Patients who have 
not progressed or have not died at the time of analysis will be censored at the time of the latest 
date of assessment from their last evaluable RECIST v1.1 assessment.  
If the patient progresses or dies after 2 or more missed visits, the patient will be censored at the 
time of the last evaluable RECIST v1.1 assessment. If the patient has no evaluable visits or 
does not have baseline data they will be censored at Day 1 unless they die within 2 visits of 
baseline.  
The PFS time will always be derived based on scan/assessment dates not visit dates.  
The primary efficacy endpoint will be analyzed based on the FAS according to the treatment 
group patients were randomized and the strata they were assigned to at randomization. 
PFS in the FAS will be analyzed using a log-rank test stratified by mutation type (Ex19del 
versus L858R) and race (Asian versus non-Asian) using the Breslow approach for handling ties. 
PFS will be displayed using Kaplan-Meier plot by treatment group. The number of events, 
medians, and 95% confidence intervals of the medians (calculated from the Kaplan-Meier 
estimate), and proportion of patients without an event at 12, 18, and 24 months will be 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 82 of 127 
SOP-CD-03-Form2 Ver2 
summarized for each treatment group. Additionally, the hazard ratio for PFS will be calculated, 
along with its 95% confidence intervals, from a stratified Cox model using the same 
stratification factors as for the log-rank test. 
8.7.2.2. 
Secondary Efficacy Analyses 
Objective response rate (ORR) 
ORR is defined as the percentage of patients with measurable disease with at least one visit 
response of complete response (CR) or partial response (PR). 
A visit response of CR is defined when all target lesions (TLs) and non-target lesions (NTLs) 
present at baseline have disappeared (with the exception of lymph nodes which must be <10 
mm to be considered non-pathological) and no new lesions have developed since baseline. A 
visit response of PR is defined when the sum of diameters of the TLs has decreased by 30% or 
more compared to baseline (with no evidence of progression) and the NTLs are at least stable 
with no evidence of new lesions. 
Patients who do not have a tumor response assessment for any reason will be considered non-
responders and will be included in the denominator when calculating the response rate. Data 
obtained up until progression, or last evaluable assessment in the absence of progression, will 
be included in the assessment of ORR. However, any complete response or partial response 
which occurred after a further anticancer therapy was received will not be included in numerator 
of the ORR calculation (where the FAS will be the denominator). 
ORR will be analyzed a logistic regression stratified by mutation type (L858R vs ex19del) and 
race (Asian vs non-Asian). The results of the analysis will be presented in terms of an odds ratio 
together with its associated 95% profile likelihood confidence intervals. 
A summary of all responses will also be presented by treatment group. 
ORR will also be summarized by each stratification factor. 
Duration of Response (DoR) 
DoR is defined as the time from the date of first documented response (CR or PR) until the date 
of documented progression or death, whichever comes first. The end of response should 
coincide with the date of progression or death from any cause used for the PFS endpoint. 
If a patient does not progress following a response, then his/her duration of response will use 
the PFS censoring time.  
The analysis of DoR will be stratified by the same covariates as the primary analysis. 
DoR in responding patients will be summarized and the number of responding patients with a 
duration of response (>6; >9; >12; >15 months) will be presented by treatment group. A 
Kaplan-Meier plot and median DoR with 95% confidence interval (calculated from the Kaplan-
Meier estimate) will be presented by treatment group. 
Disease control rate (DCR) 
DCR is defined as the percentage of patients who have a best overall response of CR or PR or 
stable disease (SD at ≥ 6 weeks, prior to any PD event). The 6 week time point will allow for a 
visit window and be defined as on or after study day 35 (allowing for the visit window). 
DCR will be analyzed using the same method as the analysis of ORR. 
Depth of response 
Depth of response will be determined for patients with measurable disease at baseline and is 
derived at each visit by the percentage change in the sum of the diameters of target lesions in 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 83 of 127 
SOP-CD-03-Form2 Ver2 
the absence of new lesions or progression of non-target lesions compared to baseline. The 
absolute change and percentage change from baseline in the sum of tumor size at each 
assessment will be calculated. 
The best change in tumor size (defined as the maximum reduction from baseline or the minimum 
increase from baseline, in the absence of a reduction) will include all assessments prior to 
progression or start of subsequent anti-cancer therapy. Missing target lesion data at visits may 
be imputed using appropriate imputation rules. 
Depth of response will be examined by summarizing the absolute change in target lesion tumor 
size from baseline, and percentage change in target lesion tumor size from baseline using 
descriptive statistics and presented at each timepoint and by randomized treatment group. 
The effect of lazertinib on best percentage change in tumor size will be estimated from an 
analysis of covariance model with treatment group as a fixed effect and baseline sum of target 
lesion diameter, mutation type (L858R versus Ex19del) and race (Asian versus non-Asian) as a 
covariate. The number of patients, unadjusted mean, and least squares means for each treatment 
group will be presented, together with the difference in least squares means, 95% confidence 
interval, and corresponding p-value. 
Time to response (TTR) 
TTR is defined as the time from the date of randomization until the date of first documented 
response. 
A summary statistics will be produced for TTR, by treatment group.  
Overall survival (OS) 
OS is defined as the time from the date of randomization until the date of death due to any cause. 
Any patient not known to have died at the time of analysis will be censored based on the last 
recorded date on which the patient was known to be alive.  
OS will be analyzed using the same methodology and model as for the analysis of PFS provided 
there are sufficient events available for a meaningful analysis (>20 deaths; if not, descriptive 
summaries will be provided). The number of events, median (calculated from the Kaplan Meier 
estimate), and proportion of patients without an event at 6, 12, 18, 24 and 36 months will be 
summarized by treatment group. As appropriate, summaries of the number and percentage of 
patients who have died, are still in survival follow-up, are lost to follow-up, and have withdrawn 
consent will be presented for each treatment group. 
The analysis of OS will be conducted at 2 time points: 
•
At the time of the primary analysis of PFS
•
After approximately 45 months survival follow-up from the first patient randomized. 
Approximately 200 deaths will be anticipated at this time.
 
CCI

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 84 of 127 
SOP-CD-03-Form2 Ver2 
EORTC QLQ-C30, EORTC QLQ-LC13: 
An outcome variable consisting of a score from 0 to 100 will be derived for each of the symptom 
scales/items, the functional scales and the global health status scale in the EORTC QLQ-C30, 
and for each of the symptom scales/items in the EORTC QLQ-LC13 according to the EORTC 
QLQ-C30 scoring manual and EORTC QLQ-LC13 instructions. 
Higher scores on the global health status and functioning scales indicate better health 
status/function. Higher scores on the symptoms scales indicate greater symptom burden.  
Changes in score compared to baseline will be evaluated. A minimum clinically meaningful 
change is defined as a change in the score from baseline of ≥5 for scales/items from the EORTC 
QLQ-LC13 and ≥10 for scales/items from the EORTC QLQ-C30 (22Osoba D et al, 1998). 
At each post-baseline assessment, change in symptoms/functioning from baseline will be 
categorized as improved, stable or worsening. Further details will be provided in the SAP. 
The PRO questionnaire data will be analyzed using a mixed model for repeated measure 
(MMRM) analysis of the change from baseline in PRO score for each visit. The MMRM model 
will include patient as a random effect, treatment, visit, treatment by visit interaction as a fixed 
effects, baseline PRO and baseline PRO score by visit interaction as a covariate. The within-
patient correlation will be modeled using the unstructured covariance matrix in the mixed model. 
The restricted maximum likelihood method will be used. Adjusted mean estimates per treatment 
group and corresponding 95% confidence intervals will be presented along with an estimate of 
the treatment difference, and 95% confidence interval. No p-values will be presented. The 
treatment-by-visit interaction will remain in the model regardless of significance. 
Time to symptom deterioration: 
For each of the symptom scales/items in EORTC QLQ-C30 and EORTC QLQ-LC13 as well as 
global health status, time to symptom deterioration will be defined as the time from 
randomization until the date of first clinically meaningful symptom deterioration or death (by 
any cause) in the absence of a clinically meaningful symptom deterioration.  
Patients whose symptoms have not shown a clinically meaningful deterioration and who are 
alive at the time of the analysis will be censored at the time of their last PRO assessment where 
the symptom could be evaluated. If a patient has no evaluable visits or does not have baseline 
data, they will be censored at Day 1. 
Symptom Improvement Rate: 
The symptom improvement rate will be defined as the percentage of patients with 2 consecutive 
assessments which showed a clinically meaningful improvement in that symptom from baseline. 
The denominator will consist of a subset of the FAS who have a baseline symptom score ≥5 
(EORTC QLQ-LC13) or ≥10 (EORTC QLQ-C30). 
EQ-5D-5L 
The EQ-5D VAS scale will be analyzed using the same method as the analysis of global health 
status in EORTC QLQ-C30. For the EQ-5D health status profiles, descriptive statistics including 
the proportions of patients reported having each response level at each time point will be 
reported.  
8.7.3. Exploratory Analyses 
CCI

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 85 of 127 
SOP-CD-03-Form2 Ver2 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 86 of 127 
SOP-CD-03-Form2 Ver2 
8.7.4. Pharmacokinetic Analyses 
Pharmacokinetic analysis of the plasma and CSF concentration data for lazertinib will be 
performed by the designated bioanalytical laboratory or third party. For each patient, the 
following concentrations will be listed. 

Plasma concentrations of lazertinib at pre-dose, 1 to 3 hours, and 4 to 6 hours post-dose on 
Day 1 of Cycles 1, 2, 5, 9, and 13

CSF concentrations of lazertinib
Plasma concentrations of lazertinib will be summarized by nominal sampling time. CSF 
concentrations of lazertinib will also be summarized. The summary statistics will be presented 
by number of patients, arithmetic mean, standard deviation, arithmetic coefficient of variation, 
CCI
CCI
CCI
CCI
CCI
CCI

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 87 of 127 
SOP-CD-03-Form2 Ver2 
median, minimum, maximum, geometric mean, and geometric coefficient of variation. Further 
details will be provided in the SAP. 
Pharmacokinetic data from this study will be analyzed using a population PK approach, which 
may include exploring the influence of covariates on PK, if the data allow. PK data collected in 
this study may also be combined with similar data from other lazertinib studies and explored 
using population PK and/or pharmacokinetic-pharmacodynamic approach. The results of any 
such analyses will be reported separately from the final Clinical Study Report. 
8.7.5. Pharmacodynamic Analyses 
Not Applicable 
8.7.6. Pharmacogenomic / Pharmacogenetic Analyses 
Refer to Appendix 4. 
8.7.7. Biomarkers Analyses  
The data collected from biomarkers will be analyzed and reported separately. 
8.7.8. Safety Analyses 
All patients who receive at least one dose of study treatment will be included in the assessment 
of the safety profile. All safety analyses will be performed on the safety analysis set. At the end 
of the study, appropriate summaries of all safety data will be produced. 
The safety parameters are AEs, clinical laboratory parameters, vital signs, ECG parameters and 
physical examination. For each safety parameter, the last non-missing safety assessment made 
before the date of the first administration of study treatment will be used as the baseline for all 
analyses of that safety parameter. Continuous variables will be summarized by number of 
patients, mean, SD, median, minimum, and maximum values. Categorical variables will be 
summarized by frequency distribution (number and percentage of patients). 
8.7.8.1. 
Adverse Events 
AEs will be coded using MedDRA. The CTCAE grade will be assigned by the Investigator. 
Severity of all AEs will be graded according to the CTCAE, v5.0.  
Any AE occurring before study treatment will be included in the data listings but will not be 
included in the summary tables of AEs.  
Any AE occurring until 28 days following the last dose of study treatment will be included in 
the AE summaries. Any AEs in this period that occur after a patient has received further 
anticancer therapy (following discontinuation of study treatment) will be flagged in the data 
listings. AEs occurring after 28 days following the last dose of study treatment will be listed 
separately, but not included in the summaries. 
The number and percentage of patients reporting AEs, SAEs including deaths, AEs considered 
related to study treatment, and AEs leading to discontinuation from study treatment will be 
tabulated by treatment, systemic organ class, and preferred term by each treatment group. 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 88 of 127 
SOP-CD-03-Form2 Ver2 
The AEs by maximum severity and relationship will also be tabulated by treatment group, 
system organ class and preferred term. If more than one AE is coded to the same preferred term 
for the same patients, the patients will be counted only once for that preferred term using the 
most severe and most related occurrence for the summarization by severity and by relationship 
to the study treatment. 
Listings of AEs, SAEs, deaths, and AEs leading to discontinuation will be produced by patients. 
8.7.8.2. 
Clinical Laboratory Parameters  
Descriptive statistics for laboratory test results (hematology, clinical chemistry, and urinalysis) 
will be provided for the observed values and changes from baseline and each observed time 
point by treatment group. 
For all laboratory variables, which are included in the CTCAE v5.0, the CTCAE grade will be 
calculated.  
Any qualitative assessments will be summarized for all patients using the number of patients 
with results of negative, trace, or positive. 
A shift table (abnormal low/normal/abnormal high) will be provided for laboratory tests. In 
addition, shifts in toxicity grade from baseline to the worst toxicity grade will be provided for 
safety analysis set. A supportive listing of patients with clinical significant changes in post-
baseline values will be provided, including the patient number, study site and baseline and post 
baseline values. 
8.7.8.3. 
Vital Signs 
Descriptive statistics by treatment group will be provided for the observed values and changes 
from baseline at each observed time point with vital signs assessment. 
8.7.8.4. 
12-lead Electrocardiogram
ECG parameters will be summarized by observed time point using appropriate descriptive 
statistics by treatment group. For all ECG variables, which are included in the CTCAE v5.0, the 
CTCAE grade will be calculated. 
A shift table (abnormal NCS/normal/abnormal CS) will be provided for ECG overall evaluation. 
In addition, shifts in toxicity grade from baseline to the worst toxicity grade will be provided for 
safety analysis set. A supportive listing of patients with clinically significant changes in post 
baseline 12 lead ECG findings will be provided, including the patient number, study site, and 
baseline and post-baseline findings. 
8.7.8.5. 
Physical Examination 
Results of the physical examinations will be summarized by observed time point using 
appropriate descriptive statistics by treatment group. 
The number and percentage of patients with clinically significant changes in post baseline 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 89 of 127 
SOP-CD-03-Form2 Ver2 
physical examination findings will be tabulated by treatment group. A supportive listing of 
patients with clinically significant changes in post baseline physical examination findings will 
be provided, including the patient number, study site, and baseline and post baseline findings. A 
listing of physical examination findings at screening will be provided as part of the medical 
history listing. 
8.7.9. Subgroup Analyses 
The subgroup analysis will be performed by baseline potential prognostic factors by comparing 
PFS between treatment group (i.e., using a Cox-Proportional Hazards Model) including the 
following groups.  

Mutation type (Ex19del versus L858R)

Race (Asian versus Non-Asian)

Brain metastatic at entry

Gender (Male versus Female)

Age at screening (<65 versus ≥65)

Smoking history

WHO Performance Status (0 versus 1)
If there are too few events available for a meaningful analysis of a particular subgroup (it is not 
considered appropriate to present analyses where there are less than 20 events per level in a 
subgroup), the relationship between that subgroup and PFS will not be formally analyzed. In 
this case, only descriptive summaries will be provided. 
No adjustment to the significance level for testing will be made since the subgroup analysis 
may only be supportive of the primary analysis of PFS. Further details will be provided in the 
SAP. 
8.7.10. Multiple Testing Strategy 
In order to provide strong control of the type I error rate, α=0.05 (two-sided), the primary 
endpoint of PFS and secondary endpoints of OS, will be tested in this sequential order. If any 
previous analysis in the sequence is not statistically significant, the alpha will not be transferred 
to subsequent analyses. 
Sequential order of endpoints 
1. PFS
2. OS
One analysis of the primary endpoint (PFS) is planned. 
Two analyses of OS are planned; one interim at the time of PFS and a final analysis. The final 
OS analysis is planned to be conducted when the OS data is approximately 50% mature 
(approximately 200 deaths). 
A 2-sided 5% alpha will be used in all testing, with the exception of OS endpoint. Since two 
analyses of OS are planned, the Lan-DeMets approach with the Pocock-type spending function 
will be used to maintain an overall 2-sided 5% type I error across the two planned analyses of 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 90 of 127 
SOP-CD-03-Form2 Ver2 
 
CCI

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 91 of 127 
SOP-CD-03-Form2 Ver2 
The investigator must notify the Sponsor promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to the Sponsor. 
9.1.3. Investigational Site Training 
Site study personnel involved in the conduct of this study must be qualified by education, 
training, and experience for the appropriate performance of their respective task(s).  
The Sponsor and/or designated CRO will provide appropriate investigational staff training prior 
to study initiation. Training topics will include but are not limited to: ICH-GCP, AE reporting, 
study details and procedure, study documentation, informed consent, and enrollment method.  
For study sites using the EDC system including electronic CRF system provided by The 
Sponsor and/or designated third party, each individual making entries and/or corrections on 
EDC system and/or each individual electronically signing electronic CRFs must meet the 
training requirements offered by the Sponsor and/or designated CRO and must only access the 
EDC system using the unique user account provided by the Sponsor and/or designated third 
party. User accounts are not to be shared or reassigned to other individuals. 
For EDC system, corrections are made through the EDC system provided by the Sponsor and/or 
designated third party that generates an automated audit trail including date and timestamp, full 
name of the person making the correction and original entry. The system also prompts the user 
to document the reason for the change which is also recorded in the audit trail.  
9.2. 
RECORD RETENTION 
Records and documents pertaining to the conduct of this study must be retained by the 
Investigator for 15 years after study completion unless local regulations or institutional policies 
require a longer retention period. A detailed instruction is provided in Appendix 1. 
9.2.1. Data on Electronic Data Capture System 
All patient data relating to the study will be recorded on EDC unless transmitted to the Sponsor 
or designee electronically (e.g., ECG result data). A detailed instruction is provided in Appendix 
1. 
9.2.2. Investigational Product Records 
It is the responsibility of the principal investigator to ensure that a current record of 
investigational product disposition is maintained at each study center where investigational 
product is inventoried and dispensed. Records or logs must comply with applicable regulations 
and guidelines and should include: 

quantity received and placed in storage area 

quantity currently in storage area 

label ID number or batch number and use by date or re-test date 

dates and initials of person responsible for each investigational product inventory 
entry/movement

quantity dispensed to and returned by each patient, including unique patient identifiers

quantity transferred to another areas/centers for dispensing or storage 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 92 of 127 
SOP-CD-03-Form2 Ver2 

any details of non-study use (e.g., lost, wasted, broken, etc.) 

quantity returned to the sponsor 
The Sponsor and/or designated CRO will provide forms to facilitate inventory control if the 
staff at the investigational center does not have an established system that meets these 
requirements. 
9.3. 
RETURN 
AND 
DESTRUCTION 
OF 
INVESTIGATIONAL 
PRODUCT 
9.3.1. Return of Investigational Product 
All unused and/or partially used investigational product must be returned to the Sponsor and/or 
designated CRO. After receiving approval of the Sponsor and/or designated CRO in writing, 
the designated CRO is responsible for returning all unused or partially used study treatment to 
the Sponsor and/or designated third party or for preparing the study treatment for destruction 
via incineration. If required, destruction of study treatment following completion of Sponsor 
confirmed accountability can be proceeded in the site according to the regulation of jurisdiction 
which the study being conducted.  
9.3.2. Destruction of Investigational Product 
The Sponsor and/or designated third party will destroy all used and unused study treatment 
as per their SOP and relative regulation.  
9.4. 
RETENTION AND DESTRUCTION OF HUMAN BIOLOGIC 
MATERIALS 
Human biological materials will be stored at The Sponsor and/or designated third party during 
a specified period as described in the informed consent. At the end of the period, they will be 
destroyed in accordance with their SOP and relative regulation. 
9.5. 
PUBLICATIONS 
The data collected during this study are confidential and proprietary to the Sponsor. Any 
publications or abstracts arising from this study require prior written approval from the Sponsor 
and must adhere to the Sponsor’s publication requirements as set forth in the approved clinical 
trial agreement (CTA). A detailed instruction is provided in Appendix 1. 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 93 of 127 
SOP-CD-03-Form2 Ver2 
10. GLOSSARY OF TERMS
Term 
Definition 
Adverse Event 
Any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a patient for clinical 
investigation administered an investigational (medicinal) 
product and that does not necessarily have a causal 
relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign 
(including an abnormal laboratory findings, for example), 
symptom, or disease temporally associated with the use 
of an investigational product.  
Adverse Drug Reaction 
In the pre-approval clinical experience with a new 
medicinal product or its new usages, particularly as the 
therapeutic dose(s) may not be established: all noxious 
and unintended responses to a medicinal product related 
to any dose should be considered adverse drug reactions. 
The phrase responses to a medicinal product means that a 
causal relationship between a medicinal product and an 
adverse event is at least a reasonable possibility. 
Suspected Unexpected Serious 
Adverse Reactions 
Any Unexpected Adverse Drug Reaction that at any dose: 
•
Results in death
•
Is life-threatening
•
Requires inpatient hospitalization or prolongation of 
existing hospitalization
•
Results 
in 
persistent 
disability/incapacity 
or 
substantial disruption of the ability to conduct normal 
life functions.
•
Is or results in a congenital anomaly/birth defect
•
Is medically important*
* Medical or scientific judgment should be exercised 
in deciding whether SAE reporting is appropriate in 
other situations such as important medical events that 
may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the 
patient or may require medical or surgical 
intervention to prevent one of the other outcomes 
listed in the above definition. These events should 
usually be considered serious. Examples of such 
events include invasive or new malignant cancers, 
intensive treatment in an emergency room or at home 
for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse, a 
concomitant elevation of AST or ALT and total 
bilirubin that meet the liver chemistry stopping 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
 
 
Page 94 of 127 
SOP-CD-03-Form2 Ver2 
 
criteria in Section 5.4.1.6 (which may be an indicator 
of Hy’s law or potential hepatotoxicity). 
Unexpected Adverse Drug  
Reaction 
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (e.g., 
Investigator's Brochure for an unapproved investigational 
product 
or 
package 
insert/summary 
of 
product 
characteristics for an approved product) 
 
 
 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 95 of 127 
SOP-CD-03-Form2 Ver2 
11. LIST OF ABBREVIATIONS
Term 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BBB 
Blood-brain barrier 
BCRP 
Breast cancer resistance protein 
BICR 
Blinded independent central review 
BM 
Brain metastasis 
BUN 
Blood urea nitrogen 
cfDNA 
Circulating cell-free deoxyribonucleic acid 
CFR 
Code of Federal Regulation 
CI 
Confidence interval 
CNS 
Central nervous system 
CR 
Complete response 
CRO 
Contract research organization 
CS 
Clinically significant 
CSF 
Cerebrospinal fluid 
CT 
Computerized tomography 
CTA 
Clinical trial agreement 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DCR 
Disease control rate 
DGR 
Dangerous Goods Regulations 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
ECG 
Electrocardiogram 
(e)CRF
(Electronic) case report form(s) 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EORTC QLQ 
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire 
EQ-5D-5L 
Euro-Quality of Life-5 Dimension-5 level 
Ex19del 
Exon 19-deletion 
FAS 
Full analysis set 
F/U 
Follow-up 
GCP 
Good Clinical Practice 
GTP 
Gamma-glutamyl transpeptidase 
HbsAg 
Hepatitis B virus surface antigen 
hCG 
Human chorionic gonadotropin 
HCl 
Hydrogen chloride 
HCTZ 
Hydrochlorothiazide 
HIV 
Human immunodeficiency virus 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 96 of 127 
SOP-CD-03-Form2 Ver2 
HRQoL 
Health-related quality of life 
HRT 
Hormone replacement therapy 
IATA 
International Airline Transportation Association 
IB 
Investigator’s brochure 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICR 
Independent central review 
iDCR 
Intracranial disease control rate 
IDMC 
Independent data monitoring committee 
iDoR 
Intracranial duration of response 
IEC 
Independent ethics committee 
iFAS 
Intracranial full analysis set 
IgM 
Immunoglobulin M 
ILD 
Interstitial lung disease 
IM 
Intra-muscular 
IND 
Investigational new drug 
iORR 
Intracranial objective response rate 
iPFS 
Intracranial progression-free survival 
IRB 
Institutional review board 
IRT 
Interactive response technology 
L858R 
Leucine-to-arginine substitution in Exon 21 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
m+ 
Mutation positive 
MRI 
Magnetic resonance imaging 
MRP4 
Multidrug resistance-associated protein 4 
MUGA 
Multiple gated acquisition 
NA 
Not applicable 
NCI 
National Cancer Institute 
NCS 
Not clinically significant 
NGS 
Next generation sequencing 
NSCLC 
Non-small cell lung cancer 
NTL 
Non-target lesion 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progression of disease 
PFS 
Progression-free survival 
PFS2 
Time to second progression 
PK 
Pharmacokinetic(s) 
P-gp
p-glycoprotein
PR 
Partial response 
PRO 
Patient-reported outcome(s) 
QD 
Quaque die (daily) 
QTc 
Corrected QT interval 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
 
 
Page 97 of 127 
SOP-CD-03-Form2 Ver2 
 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SoA 
Schedule of activities 
SoC 
Standard of care 
SOP 
Standard operational procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
T790M 
Threonine-to-methionine substitution 
TEAE 
Treatment-emergent adverse event 
TKI 
Tyrosine kinase inhibitor 
TL 
Target lesion 
TTR 
Time to response 
ULN 
Upper limit of normal 
UN number 
United Nations numbers 
US 
United States 
VAS 
Visual analogue scale 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Woman of childbearing potential 
 
 
 
 
 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 98 of 127 
SOP-CD-03-Form2 Ver2 
12. REFERENCES LIST
1
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 
2012. CA Cancer J Clin. 2015;65(2):87-108.
2
Pao W, Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small- 
cell lung cancer. Nat Rev Cancer. 2010;10(11):760-774.
3
Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role 
in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 2009;28 Suppl 1:S24-
31.
4
Juchum M, Günther M, Laufer SA. Fighting cancer drug resistance: opportunities and 
challenges for mutation-specific EGFR inhibitors. Drug Resist Updat. 2015;20:12-28.
5
Engel J, Becker C, Lategahn J, Keul M, Ketzer J, Mühlenberg T, et al. Insight into the 
inhibition of drug-resistant mutants of the receptor tyrosine kinase EGFR. Angew Chem Int 
Ed. 2016;55(36):10909-10912.
6
J.-C. Soria, Y. Ohe, J. Vansteenkiste, T. Reungwetwattana, B. Chewaskulyong, K.H. Lee, A. 
Dechaphunkul, F. Imamura, N. Nogami, T. Kurata, I. Okamoto, C. Zhou, B.C. Cho, Y. 
Cheng, E.K. Cho, P.J. Voon, D. Planchard, W.-C. Su, J.E. Gray, S.-M. Lee, R. Hodge, M. 
Marotti, Y. Rukazenkov, and S.S. Ramalingam, for the FLAURA Investigators. Osimertinib 
in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer. N Engl J Med. 2018 
Jan 11;378(2):113-125.
7
Engel J, Lategahn J, Rauh D. Hope and disappointment: covalent inhibitors to overcome 
drug resistance in non-small cell lung cancer. ACS Med Chem Lett. 2015;7(1):2-5.
8
Rangachari D, Yamaguchi N, VanderLaan PA, Folch E, Mahadevan A, Floyd SR, Uhlmann 
EJ, Wong ET, Dahlberg SE, Huberman MS, Costa DB. Brain metastases in patients with 
EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer. 
2015;88(1):108-111.
9
Ahn MJ, Han JY, Lee KH, Kim SW, Kim DW, Lee YG, Cho EK, Kim JH, Lee GW, Lee JS, 
Min YJ, Kim JS, Lee SS, Kim HR, Hong MH, Ahn JS, Sun JM, Kim HT, Lee DH, Kim SH, 
Cho BC. Lazertinib in patients with EGFR mutation-positive advanced non-small-cell lung 
cancer: results from the dose escalation and dose expansion parts of a first-in-human, open-
label, multicentre, phase 1–2 study. Lancet Oncol. 2019 Oct 3. pii: S1470-2045(19)30504-
2. doi: 10.1016/S1470-2045(19)30504-2.
10 Laporte S, Squifflet P, Baroux N, Fossella F, Georgoulias V, Pujol JL, Douillard JY, Kudoh 
S, Pignon JP, Quinaux E, Buyse M. Prediction of survival benefits from progression-free 
survival benefits in advanced non-small-cell lung cancer: evidence from a meta-analysis of 
2334 patients from 5 randomised trials. BMJ Open. 2013 Mar 13;3(3). pii: e001802. doi: 
10.1136/bmjopen-2012-001802. 
11 Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck 
S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 99 of 127 
SOP-CD-03-Form2 Ver2 
Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.  
12 Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, 
Flechtner H, Fleishman SB, de Haes JC. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical 
trials in oncology. J Natl Cancer Inst. 1993 Mar 3;85(5):365-76. 
13
Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M. The EORTC QLQ-LC13: a 
modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use 
in lung cancer clinical trials. EORTC Study Group on Quality of Life. Eur J Cancer. 
1994;30A(5):635-42. 
14
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of 
the EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). 
Published by: European Organisation for Research and Treatment of Cancer, Brussels 2001. 
15
EuroQol Group, EuroQol-a new facility for the measurement of health-related quality of 
life. Health Policy. 1990 Dec;16(3):199-208. 
16
Trippoli S, Vaiani M, Lucioni C, Messori A. Quality of life and utility in patients with non-
small cell lung cancer. Quality-of-life Study Group of the Master 2 Project in 
Pharmacoeconomics. Pharmacoeconomics. 2001;19(8):855-63. 
17
Belani CP, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, 
Ramlau R, Szczesna A, Fidias P, Millward M, Fossella F; TAX 326 study group. Effect of 
chemotherapy for advanced non-small cell lung cancer on patients' quality of life. A 
randomized controlled trial. Lung Cancer. 2006 Aug;53(2):231-9. 
18 Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, 
Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield 
EL, Watkins CL, Armour AA, Fukuoka M; Gefitinib or carboplatin–paclitaxel in pulmonary 
adenocarcinoma. New England Journal of Medicine 361.10 (2009): 947-957. 
19 Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, 
Tada H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, 
Shimizu E, Saito H, Toyooka S, Nakagawa K, Fukuoka M; Gefitinib versus cisplatin plus 
docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal 
growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. The lancet 
oncology 11.2 (2010): 121-128.  
20 Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Gemma A, Harada M, 
Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, 
Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T; Gefitinib or 
chemotherapy for non–small-cell lung cancer with mutated EGFR. New England Journal of 
Medicine 362.25 (2010): 2380-2388.  
21 Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Tsuji F, Linke R, Rosell R, Corral 
J, Migliorino MR, Pluzanski A, Sbar EI, Wang T, White JL, Nadanaciva S, Sandin R, Mok 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
 
 
Page 100 of 127 
SOP-CD-03-Form2 Ver2 
 
TS; "Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-
positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 
trial." The Lancet Oncology 18.11 (2017): 1454-1466. 
22 Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol. 1998 Jan;16(1):139-44. 
 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 101 of 127 
SOP-CD-03-Form2 Ver2 
Appendix 1. Regulatory, Ethical, and Study Oversight Considerations 

This study will be conducted in accordance with the protocol and with:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines.
o
Applicable International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines.
o
Applicable laws and regulations.

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients.

The Investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC.
o
Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures.
o
Overall conduct of the study at the site and adherence to requirements of 21 Code 
of Federal Regulations (CFR), ICH GCP guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable 
local regulations.
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor and/or designated CRO with 
sufficient, accurate financial information in accordance with local regulations to allow the 
Sponsor and/or designated CRO to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators and sub-
Investigators are responsible for providing information on financial interests during the course 
of the study and for 1 year after completion of the study. 
Informed Consent Process 

The Investigator or his/her representative will explain the nature of the study to the patient
or his/her legally authorized representative and answer all questions regarding the study.

Patients must be informed that their participation is voluntary. Patients will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF.

Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 102 of 127 
SOP-CD-03-Form2 Ver2 
representative. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to 
the protocol. If the ICF is revised, it must be reviewed and approved by the appropriate IEC/IRB, 
and signed by all patients subsequently enrolled in the study as well as those currently enrolled 
in the study. 
Data Protection 

Patients will be assigned a unique identifier by the Sponsor and/or designated CRO. Any 
patient records or datasets that are transferred to the Sponsor and/or designated CRO will 
contain the identifier only; patient names or any information which would make the patient
identifiable will not be transferred.

The patient must be informed that his/her personal study-related data will be used by the 
Sponsor and/or designated CRO in accordance with local data protection law. The level of 
disclosure must also be explained to the patient.

The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor and/or 
designated CRO, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
Committees Structure 
Committees will be organized and operated. Full details regarding committees (e.g., IDMC, 
Steering Committee, BICR, etc.) will be documented in the specific charter prior to the first 
review meeting. 
Dissemination of Clinical Study Data 
When the final Clinical Study Report is completed, the Sponsor and/or designated CRO will 
provide the major findings of the study to the Investigator. A summary of the study results will 
also be posted in a publicly accessible database (e.g., www.ClinicalTrials.gov). The results may 
also be submitted for publication. 
Data Quality Assurance 

All patient data relating to the study will be recorded on EDC unless transmitted to the 
Sponsor or designated third party electronically (e.g., ECG result data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing EDC.

The Investigator must maintain accurate documentation (source data) that supports the 
information entered in EDC.

The Investigator must permit study-related monitoring, audits, IEC/IRB review, and 
regulatory agency inspections and provide direct access to source data documents.

The Sponsor or designated CRO is responsible for the data management of this study 
including quality checking of the data.

Study monitors will perform ongoing source data verification to confirm that data entered 
into EDC by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 103 of 127 
SOP-CD-03-Form2 Ver2 
agreements, ICH GCP, and all applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations 
or institutional policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the Sponsor or designated CRO. 
No records may be transferred to another location or party without written notification to 
the Sponsor or designated CRO.

All data generated by the site personnel will be captured electronically at each study center 
using EDC. Data from external sources (e.g., ECG result data) will be imported into the 
database. Once EDC clinical data have been submitted to the central server at the 
independent data center, corrections to the data fields will be captured in an audit trail. The 
reason for change, the name of the person who performed the change, together with the 
time and date will be logged to provide an audit trail.

If additional corrections are needed, the responsible monitor or data manager will raise a 
query in EDC application. The appropriate staff at the study site will answer queries sent 
to the Investigator. The name of the staff member responding to the query, and time and 
date stamp will be captured to provide an audit trail. Once all source data verification is 
complete and all queries are closed, the monitor will freeze the EDC page.

The specific procedures to be used for data entry and query resolution using the EDC 
system will be provided to study sites in a training manual. In addition, site personnel will 
receive training on the EDC system.
Source Documents 

Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.

Data entered in EDC that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need 
to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available.
Study and Site Closure 
The Sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the Sponsor. Study sites will be closed upon study completion. 
A study site is considered closed when all required documents and study supplies have been 
collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include, but are 
not limited to: 

Failure of the Investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the Sponsor's procedures, or GCP guidelines.

Inadequate recruitment of patients by the Investigator.

Discontinuation of further study treatment development.
Publication Policy 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 104 of 127 
SOP-CD-03-Form2 Ver2 

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows the Sponsor to protect proprietary information and to provide 
comments.

All draft publications, including abstracts or detailed summaries of any proposed 
presentations, must be submitted to the Sponsor at the earliest practicable time for review, 
but in any event not less than 30 days before submission or presentation unless otherwise 
set forth in the CTA. The Sponsor retains the right to delete any confidential or proprietary 
information contained in any proposed presentation or abstract and may delay publication 
for purposes of filing a patent application.

The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be 
approved by the IEC/IRB/Competent Authorities, in accordance with local legal requirements. 
The Sponsor must ensure that all ethical and legal requirements have been met before the first 
patient is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC/Competent Authority 
approval prior to implementation (if appropriate).  
Administrative changes (not affecting the patient benefit/risk ratio) may be made without the 
need for a formal amendment. All amendments will be distributed to all protocol recipients, 
with appropriate instructions. 
Major Protocol Violations Reporting 
All potential major violations must be reported to the Sponsor and/or designated CRO 
immediately. A major violation is a violation of the conditions and principles of GCP in 
connection with the study or the protocol, which is likely to affect, to a significant degree, the 
safety or physical or mental integrity of the patients of the study or the scientific value of the 
study.  
Liability and Insurance 
The Sponsor and/or designated CRO will take out reasonable third-party liability insurance 
cover in accordance with all local legal requirements. The civil liability of the Investigator, the 
persons instructed by him or her and the hospital, practice, or institute in which they are 
employed and the liability of the Sponsor and/or designated CRO with respect to financial loss 
due to personal injury and other damage that may arise as a result of the carrying out of this 
study are governed by the applicable law. 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 105 of 127 
SOP-CD-03-Form2 Ver2 
Access to Source Data 
During the study, a monitor will make site visits to review protocol compliance, compare EDC 
entries and individual patient’s medical records, assess drug accountability, and ensure that the 
study is being conducted according to pertinent regulatory requirements. EDC entries will be 
verified with source documentation. The review of medical records will be performed in a 
manner to ensure that patient confidentiality is maintained. 
Checking of EDC entries for completeness and clarity, and cross-checking with source 
documents, will be required to monitor the progress of the study. Moreover, regulatory 
authorities of certain countries, IRBs, IECs, and/or the Sponsor’s Clinical Quality Assurance 
Group may wish to carry out such source data checks and/or on-site audit/inspections. Direct 
access to source data will be required for these inspections and audits; they will be carried out 
giving due consideration to data protection and medical confidentiality. The Investigator assures 
the Sponsor and/or designated CRO of the necessary support at all times. 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 106 of 127 
SOP-CD-03-Form2 Ver2 
Appendix 2. Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 

An AE is any untoward medical occurrence in a clinical study patient, temporally 
associated with the use of a study treatment, whether or not considered related to the 
medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements) fulfill 
any of the following criteria unless clearly due to progression of disease under study or 
underlying disease:
o
Test results associated with accompanying symptoms that are considered clinically 
significant in the opinion of the investigator.
o
Test results that require additional diagnostic testing (other than merely repeating an 
abnormal test) or medical/surgical intervention.
o
Test results that lead to a change in study treatment dosing or discontinuation from 
the study, significant additional concomitant drug treatment, or other therapy.
o
Test results considered to be an AE by the Investigator or Sponsor.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even though 
it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be considered as an 
AE/SAE. 

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the patient’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the patient’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
 
 
Page 107 of 127 
SOP-CD-03-Form2 Ver2 
 
to the procedure is the AE. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease under study). 
 
An SAE is defined as any untoward medical occurrence that, at any dose: 
Results in death 
Disease progression can be considered as the worsening of a patient’s condition attributable 
to NSCLC. It may be an increase in the severity of the disease under study and/or increases 
in the symptoms of the disease. The development of new, or progression of existing 
metastases from the primary cancer under study should be considered as disease progression 
and not an AE. Death which are unequivocally due to disease progression should not be 
reported as an AE during the study. SAE term should be recorded as immediate cause of 
death, not “Death”. 
Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the patient 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the patient has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AE. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
NOTE:  
The following hospitalizations are not considered SAEs in Sponsor clinical studies: 
 
hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
 
a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an "important medical event" or event life 
threatening)  
 
elective surgery, planned prior to signing consent  
 
admissions as per the protocol for a planned medical/surgical procedure  
 
routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)  
 
medical/surgical admission for purposes other than remedying ill health state and that are 
planned prior to entry into the study. Appropriate documentation is required in these cases 
 
admission due to another life circumstance that carries no bearing on health status and 
requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
care-giver respite, family circumstances, administrative) 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 108 of 127 
SOP-CD-03-Form2 Ver2 
Results in persistent disability/incapacity or substantial disruption of the ability to 
conduct normal life functions. 

The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday
life functions but do not constitute a substantial disruption.
Is or results in a congenital anomaly/birth defect 
Is medically important 

Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.

Examples of such events include invasive or new malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse, a concomitant elevation of AST or ALT and total bilirubin that meet the liver 
chemistry stopping criteria in Section 5.4.1.6 (which may be an indicator of Hy’s law or 
potential hepatotoxicity).
Recording and Follow-up of AE and SAE 
AE and SAE Recording 

When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) related 
to the event.

The Investigator will then record all relevant AE/SAE information in EDC.

It is not acceptable for the Investigator to send photocopies of the patient’s medical 
records in lieu of completion of the AE/SAE EDC page.

There may be instances when copies of medical records for certain cases are requested 
by the Sponsor and/or designated CRO. In this case, all patient identifiers, with the 
exception of the patient number, will be blinded on the copies of the medical records 
before submission to the Sponsor and/or designated CRO.

The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories: 

Grade 1: Mild; Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.

Grade 2: Moderate; Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)*.

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 109 of 127 
SOP-CD-03-Form2 Ver2 

Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care 
ADL**.

Grade 4: Life-threatening consequences; urgent intervention indicated.

Grade 5: Death related to AE.
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
AEs will be graded according to NCI-CTCAE v5.0.
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden.
Assessment of Causality 
The investigator will assess causality for each adverse event, and answer ‘yes (Certain, 
Probable/Likely, Possible, Unassessable/Unclassifiable)’ or ‘no (Unlikely, Not related)’ to the 
following question: ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the investigational product?’ 
The following factors should be considered when deciding if there is a “reasonable 
possibility” that an AE may have been caused by the drug.  

Time Course. Exposure to suspect drug. Has the patient actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? OR could the AE be anticipated from its pharmacological 
properties?

Dechallenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors. 

Rechallenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? The Sponsor would not normally recommend or support a 
rechallenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship?
A “reasonable possibility” could be considered to exist for an AE where one or more of these 
factor exist.  
In contrast, there would not be a “reasonable possibility” of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but any 
Dechallenge (if performed) is negative or ambiguous or there is another more likely cause of 
the AE.  
In difficult cases, other factors could be considered such as: 

Is there a recognized feature of overdose of the drug?

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 110 of 127 
SOP-CD-03-Form2 Ver2 

Is there a known mechanism?
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this.  
Follow-up of AE and SAE 

The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor 
and/or designated CRO to elucidate the nature and/or causality of the AE or SAE as fully 
as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.

If a patient dies during participation in the study or during a recognized follow-up period, 
the Investigator will provide the Sponsor and/or designated CRO with a copy of any post-
mortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

All AEs and special reporting situations, whether serious or non-serious, should be 
reported from the time a signed and dated ICF is obtained until 28 days following the 
last dose of study treatment. All adverse events should be followed until recovery to 
baseline or Grade ≤1 or until deemed irreversible.

AEs occurring after 28 days following the last dose of study treatment should also be 
reported, if considered related to study treatment. Aforementioned all AEs also must be 
followed until recovery to baseline or Grade ≤1 or until deemed irreversible.

The Investigator will submit any updated SAE data to the Sponsor and/or designated 
CRO.
SAE Reporting 
SAE Reporting to the Sponsor and/or designated CRO 

The Investigator must submit the completed SAE form and any supporting 
documentation to the Sponsor and/or designated CRO within 24 hours of becoming 
aware of the event according to the Study reference manual.

The Investigator and the Sponsor and/or designated CRO will review each SAE report 
and the Sponsor and/or designated CRO will evaluate the seriousness and the causal 
relationship of the event to study treatment. In addition, the Sponsor and/or designated 
CRO will evaluate the expectedness according to the reference documents (Investigator’s 
Brochure or package insert/summary of product characteristics for an approved product
for gefitinib). Based on the Investigator and Sponsor’s assessment of the event, a decision 
will be made concerning the need for further action.

SAE reporting process and contact information of the medical monitor can be found in 
the Study reference manual.
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Any AE that is serious, associated with the use of the study treatment, and unexpected (not 
listed in the investigator brochure) (SUSAR) has additional reporting requirements, as 
described below. 

Regulatory authorities, the Investigators and IEC/IRB (if required) will be notified 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
 
 
Page 111 of 127 
SOP-CD-03-Form2 Ver2 
 
within 7 calendar days after the Sponsor and/or designated CRO learns of the event, if 
the SUSAR is fatal or life-threatening, associated with study treatment, and unexpected. 
Additional follow-up (cause of death, autopsy report, and hospital report) information 
should be reported within an additional 8 days (15 days total). 
 
Regulatory authorities, the Investigators and IEC/IRB (if required) will be notified 
within 15 calendar days after the Sponsor and/or designated CRO learns of the event, if 
the SUSAR is not fatal or life-threatening but is otherwise serious, associated with study 
treatment, and unexpected.  
 
The Sponsor and/or designated CRO will also provide annual safety updates to the 
regulatory authorities, the Investigators and IEC/IRB (if required) responsible for the 
study. These updates will include information on SUSARs and other relevant safety 
findings. 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 112 of 127 
SOP-CD-03-Form2 Ver2 
Appendix 3. Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1.1. Premenarchal 
1.2. Premenopausal female with 1 of the following: 
•
Documented hysterectomy
•
Documented bilateral salpingectomy
•
Documented bilateral oophorectomy
•
Documented bilateral tubal occlusion [which includes tubal ligation procedures as 
consistent with local regulations]
NOTE: Documentation can come from the site personnel’s review of the patient’s med
ical records, medical examination, or medical history interview. 
1.3. Post-menopausal female 
•
A post-menopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone level in the post-menopausal range 
may be used to confirm a post-menopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 12 
months of amenorrhea, a single follicle stimulating hormone measurement is 
insufficient.
•
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status before study enrollment.
Contraception Guidance: 
Male Patients: 
Male Patients who have not undergone a vasectomy should use reliable methods of contra
ception from randomization until 24 weeks after discontinuation of study treatment. 
Male Patients with female partners of childbearing potential are eligible to participate i
f they agree to ONE of the following: 
•
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent.
•
Agree to use a male condom plus partner use of a contraceptive method with a failure 
rate of <1% per year as described in the table below when having penile-vaginal 
intercourse with a WOCBP who is not currently pregnant.
In addition, male Patients must refrain from donating sperm from randomization until 2
4 weeks after the last dose of study treatment. 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
 
 
Page 113 of 127 
SOP-CD-03-Form2 Ver2 
 
Male Patients with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile p
enetration from randomization until 24 weeks after the last dose of study treatment. 
 
Female Patients 
Female Patients should use reliable methods of contraception from the time of screeni
ng until 24 weeks after discontinuation of study treatment. 
Female Patients of childbearing potential are eligible to participate if they agree to use
 a highly effective method of contraception consistently and correctly as described in t
he table below.  
In addition, female Patients must refrain from donating ovum from randomization until
24 weeks after the last dose of study treatment. 
 
Highly Effective Contraceptive Methods That Are User Dependent1 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestin-containing) hormonal contraception associated with 
inhibition of ovulation2 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation2 
• 
Oral 
• 
Injectable 
Highly Effective Contraceptive Methods That Are User Independent1 
Implantable contraceptive method2 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner
 is the sole male sexual partner of the WOCBP and the absence of sperm has been confirme
d. If not, an additional highly effective method of contraception should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from
 heterosexual intercourse during the entire period of risk associated with the study treatmen
t. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the
 study and the preferred and usual lifestyle of the patient. 
NOTES: 
1 Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
patients participating in clinical studies. 
2 Hormonal contraception may be susceptible to interaction with the study treatment, which 
may reduce the efficacy of the contraceptive method. In this case, 2 highly effective methods 
of contraception should be utilized from the time of screening until 24 weeks after the last dose 
of study treatment. 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
 
 
Page 114 of 127 
SOP-CD-03-Form2 Ver2 
 
Pregnancy Testing 
• 
WOCBP should only be included after a confirmed a negative serum pregnancy test. 
• 
Additional pregnancy testing may be repeated during the treatment period as necessary 
if clinically indicated. 
• 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
 
Collection of Pregnancy Information 
Male Patients with partners who become pregnant 
• 
The Investigator will attempt to collect pregnancy information on any male patient’s 
female partner who becomes pregnant while the male patient is in the study period, 
from randomization until 24 weeks following last dosing of study treatment. 
• 
This applies only to male patients who are randomized. 
• 
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the appropriate 
form and submit it to the Sponsor and/or designated CRO within 24 hours of learning 
of the partner’s pregnancy. The female partner will also be followed to determine the 
outcome of the pregnancy. Information on the status of the mother and child will be 
forwarded to the Sponsor and/or designated CRO. Generally, the follow up will be no 
longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of fetal status (presence or absence of anomalies) 
or indication for the procedure. 
 
Female Patients who become pregnant 
• 
The Investigator will collect pregnancy information on any female patient who 
becomes pregnant while participating in this study, from randomization until 24 weeks 
following last dosing of study treatment. 
• 
Information will be recorded on the appropriate form and submitted to the Sponsor 
and/or designated CRO within 24 hours of learning of a patient’s pregnancy. The 
patient will be followed to determine the outcome of the pregnancy. The Investigator 
will collect any follow up information on the patient and the neonate and the 
information will be forwarded to the Sponsor and/or designated CRO. Generally, 
follow up will not be required for longer than 6 to 8 weeks beyond the estimated 
delivery date. Any termination of the pregnancy will be reported, regardless of fetal 
status (presence or absence of anomalies) or indication for the procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication will be reported as an AE or SAE. A spontaneous abortion is always 
considered to be an SAE and will be reported as such. Any post-study pregnancy-
related SAE considered reasonably related to study treatment by the Investigator will 
be reported to the Sponsor and/or designated CRO. While the Investigator is not 
obligated to actively seek this information in former study patients, he or she may learn 
of an SAE through spontaneous reporting. 
• 
Any female patient who becomes pregnant while participating in the study will be 
withdrawn from the study treatment. 
 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
 
 
Page 115 of 127 
SOP-CD-03-Form2 Ver2 
 
Appendix 4. Pharmacogenetic Research 
Use/Analysis of DNA 
 
Genetic variation may impact a patient’s response to therapy. Variable response to therapy 
may be due to genetic determinants that impact drug absorption, distribution, metabolism, 
and excretion; mechanism of action of the drug; disease etiology; and/or molecular subtype 
of the disease being treated. Therefore, where local regulations and IRB/IEC allow, a blood 
sample will be collected for DNA analysis. 
 
DNA samples will be used for research related to lazertinib or NSCLC with EGFR mutation 
status and related diseases. They may also be used to develop tests/assays related to 
lazertinib and NSCLC with EGFR mutation status. Genetic research may consist of the 
analysis of one or more candidate genes or the analysis of genetic markers throughout the 
genome or analysis of the entire genome (as appropriate) in relation to lazertinib. 
 
DNA samples will be analyzed for exploratory genetic research. Additional analyses may 
be conducted if it is hypothesized that this may help further understand the clinical data. 
 
The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to lazertinib or drug of this class to understand study disease or 
related conditions. 
 
The results of genetic analyses will be reported separately and will not be part of the 
Clinical Study Report. 
 
The Sponsor or designated CRO/third party will store the DNA samples in a secure storage 
space with adequate measures to protect confidentiality. 
 
The samples will be retained for a maximum of 15 years following the finalization of the 
final Clinical Study Report or other period as per local regulations. 
 
 
 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 116 of 127 
SOP-CD-03-Form2 Ver2 
Appendix 5. Algorithm for Continuation, Dose Modification, or 
Discontinuation of Study Treatment Based on Decreases of LVEF 
Assessment  
CHF = congestive heart failure; LVEF = left ventricular ejection fraction 
a LVEF < 40% can be repeated within 21 days, and study treatment should be discontinued if LVEF < 40% is 
confirmed. Study treatment should be held while the repeat LVEF is obtained. 
b Class ≥ 3 as defined by New York Heart Association (NYHA) classification (2014) 
Class I 
No limitations. Ordinary physical activity does not cause undue fatigue, dyspnoea or 
palpitations (asymptomatic LV dysfunction). 
Class II 
Slight limitation of physical activity. Ordinary physical activity results in fatigue, 
palpitation, dyspnoea or angina pectoris (mild CHF) 
Class III 
Marked limitation of physical activity. Less than ordinary physical activity leads to 
symptoms (moderate CHF). 
Class IV 
Unable to carry on any physical activity without discomfort. Symptoms of CHF 
present at rest (severe CHF) 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 117 of 127 
SOP-CD-03-Form2 Ver2 
Appendix 6. Guidance on Concomitant Medications regarding Drug 
Interaction with Study Treatment 
LAZERTINIB 
Lazertinib is an investigational product that currently has no available data on clinical drug 
interactions. Use of any other medications, folk remedies, natural/herbal products (e.g. Ginseng 
and other Traditional Chinese Medicine) should be discouraged in this study. Use of these folk 
remedies or products, as well as use of all nutritional supplements, vitamins, and all other 
concomitant medications should be recorded in the electronic case report form (eCRF). 
Potent CYP3A4 inhibitors/inducers are prohibited for co-administration 
with lazertinib 
According to in vitro data, the principal cytochrome P450 (CYP) enzyme involved in the 
metabolism of lazertinib is CYP3A4. Therefore, the following concomitants of medications, 
herbal products and/or ingestions of foods with known potent inhibitors/inducers of CYP3A4 
should not be used for any patient receiving lazertinib (Table 1, Table 2). However this list is 
not meant to be exhaustive, and similar restrictions should be applied to other drugs known to 
potently modulate CYP3A4 activity. Appropriate medical judgment is required.  
Table 1. Examples of potent CYP3A4 inhibitor 
Contraindicated drugs 
Washout period prior to 
randomization 
boceprevir, clarithromycin2, cobicistat, conivaptan, 
danoprevir, dasabuvir, diltiazem, elvitegravir, 
indinavir, ketoconazole, nelfinavir, paritaprevir, 
ritonavir1,3, saquinavir1,3, tipranavir,  
2 days 
grapefruit juice, lopinavir1,3, telaprevir, 
telithromycin3, troleandomycin 
4 days 
atazanavir, darunavir, mibefradil, nefazodone, 
ombitasvir ,voriconazole 
1 week 
itraconazole, posaconazole 
2 weeks 
1also see Table 3. 
2also see Table 4. 
3also see Table 5. 
Table 2. Examples of potent CYP3A4 inducer 
Contraindicated drugs 
Washout 
period 
prior 
to 
randomization 
phenytoin, rifapentine, St. John’s wort 
2 weeks 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 118 of 127 
SOP-CD-03-Form2 Ver2 
Table 2. Examples of potent CYP3A4 inducer 
Contraindicated drugs 
Washout 
period 
prior 
to 
randomization 
carbamazepine, phenobarbital, rifabutin, rifampin 
(rifampicin)1 
3 weeks 
1also see Table 3. 
BCRP/P-gp/MRP4 substrates may be allowed with caution 
According to in vitro data, lazertinib has potent inhibitory effect on breast cancer resistance 
protein (BCRP) and weak inhibitory effect on p-glycoprotein (P-gp) and multidrug resistance 
protein 4 (MRP4). Therefore, the bioavailability of BCRP, P-gp or MRP4 substrate may 
increase by lazertinib. Co-administration of the following substrates is allowed with caution, 
and possible drug interaction should be closely monitored for any patient receiving lazertinib 
(Table 3). Please refer to their label before co-administration with lazertinib. However this list 
is not meant to be exhaustive, and similar restrictions should be applied to other drugs known 
to BCRP, P-gp or MRP4 substrate. Appropriate medical judgment is required.  
Table 3. Examples of BCRP, P-gp or MRP4 substrate 
Transporter 
Drugs to use with caution 
BCRP 
abacavir, ciprofloxacin, coumesterol, daidzein, estrone-3-sulfate, 17β-
estradiol sulfate, 17β-estradiol 17-(β-D-glucuronide), folic acid, genistein, 
nitrofurantoin, 
norfloxacine, 
ofloxacin4, 
pitavastatin, 
pravastatin, 
quercetin, resveratrol, rosuvastatin, sulfasalazine, warfarin, zidovudine 
P-gp
aliskiren, ambrisentan, bunitrolol, carvedilol, celiprolol, colchicine, 
cyclosporine A, dabigatran etexilate, digoxin, diltiazem, erythromycin3, 
fentanyl, fexofenadine, ivermectin, loperamide, maraviroc, methadone3, 
morphine, nelfinavir1, posaconazole, ranitidine, ranolazine, rifampin 
(rifampicin)2, ritonavir1,4, saquinavir1,4, saxagliptin, sirolimus, sitagliptin, 
tacrolimus4, talinolol, tolvaptan 
MRP4 
acyclovir, 
adefovir, 
cefazolin, 
ceftizoxime, 
furosemide, 
hydrochlorothiazide4, olmesartan, ritonavir1,4, tenofovir 
1also see Table 1. 
2also see Table 2. 
3also see Table 4. 
4also see Table 5. 
Drugs that are known to or may possibly prolong QT interval or induce 
Torsades de Pointes are prohibited for co-administration with lazertinib 
The following drugs are known to or may possibly prolong QT interval or induce Torsades de 
Pointes should not be used for any patient receiving lazertinib (Table 4, Table 5). However this 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
 
 
Page 119 of 127 
SOP-CD-03-Form2 Ver2 
 
list is not meant to be exhaustive, and similar restrictions should be applied to other drugs 
known to prolong QT interval or induce Torsades de Pointes. Appropriate medical judgment is 
required.  
Table 4. Examples known to prolong QT interval or induce Torsades de Pointes 
Contraindicated drugs 
Washout 
period 
prior 
to 
randomization 
anagrelide, ciprofloxacin, clarithromycin1, cocaine (only medical 
use), 
domperidone, 
droperidol, 
erythromycin2, 
ibutilide, 
levofloxacin, ondansetron, papaverine HCl (intra-coronary), 
procainamide, 
quinidine, 
sulpiride, 
sultopride, 
terlipressin, 
thioridazine 
2 days 
chlorpromazine, cilostazol, disopyramide, dofetilide, dronedarone, 
ibogaine, levosulpiride, moxifloxacin, sotalol 
4 days 
citalopram, escitalopram, flecainide, fluconazole, levomepromazine 
(ethotrimeprazine), roxithromycin, sevoflurane 
1 week 
methadone2, pimozide, terodiline 
2 weeks 
azithromycin, donepezil, propofol 
15 days 
halofantrine, pentamidine 
2 months 
haloperidol 
4 months 
amiodarone, chloroquine 
10 months 
1also see Table 1. 
2also see Table 3. 
 
Table 5. Examples that may possible prolong QT interval or induce Torsades de pointes 
Contraindicated drugs 
Washout 
period 
prior 
to 
randomization 
apomorphine, benperidol, clotiapine, dexmedetomidine, dolasetron, 
eliglustat, encorafenib, gemifloxacin, granisetron, hydrocodone-
ER, isradipine, melperone, nicardipine, ofloxacin2, oxytocin, 
perflutren lipid microspheres, pilsicainide, primaquine phosphate, 
prothipendyl, risperidone, saquinavir1,2, telavancin, tetrabenazine, 
tiapride, tolterodine, tramadol, tropisetron, vardenafil 
2 days 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 120 of 127 
SOP-CD-03-Form2 Ver2 
Table 5. Examples that may possible prolong QT interval or induce Torsades de pointes 
Contraindicated drugs 
Washout 
period 
prior 
to 
randomization 
alfuzosin, 
clozapine, 
cyamemazine 
(cyamepromazine), 
deutetrabenazine, 
dextromethorphan/quinidine, 
ezogabine 
(retigabine), 
lacidipine, 
lopinavir1,2/ritonavir1,2, 
mifepristone, 
moexipril/HCTZ2, 
pasireotide, 
perphenazine, 
promethazine, 
telithromycin1, venlafaxine 
4 days 
asenapine, 
atomoxetine, 
betrixaban, 
felbamate, 
imipramine 
(melipramine), 
ketanserin, 
nortriptyline, 
paliperidone, 
pipamperone, trimipramine, valbenazine, zotepine, zuclopenthixol 
(zuclopentixol, oral) 
1 week 
buprenorphine, delamanid, desipramine, iloperidone, lithium, 
maprotiline, mirabegron, mirtazapine, palonosetron, rilpivirine, 
tacrolimus2, tizanidine 
2 weeks 
aripiprazole, clomipramine, efavirenz, memantine 
3 weeks 
artemether/lumefantrine, sertindole 
1 month 
fingolimod, flupentixol, pimavanserin 
1.5 months 
zuclopenthixol (zuclopentixol, IM injection) 
3.5 months 
artenimol/piperaquine 
6 months 
clofazimine 
12 months 
nusinersen 
15 months 
bedaquiline 
28 months 
1also see Table 1. 
2also see Table 3. 
GEFITINIB 
Gefitinib is an approved drug indicated for the treatment of patients with advanced or metastatic 
non-small-cell lung cancer whose cancer cells have a mutation in the genes that make a protein 
called epidermal-growth-factor receptor (EGFR). In addition to the restrictions imposed by 
lazertinib, the following restrictions apply as prescribed by gefitinib in this study; 
Drugs affecting gastric pH 
Drugs that elevate gastric pH (e.g., proton pump inhibitors, H2-receptor antagonists, and 
antacids) may reduce plasma concentrations of gefitinib. Patients should avoid concomitant use 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
 
 
Page 121 of 127 
SOP-CD-03-Form2 Ver2 
 
of gefitinib with proton pump inhibitors, if possible. If treatment with a proton-pump inhibitor 
is required, Patients could take gefitinib 12 hours after the last dose or 12 hours before the next 
dose of the proton-pump inhibitor. Patients could take gefitinib 6 hours after or 6 hours before 
an H2-receptor antagonist or an antacid. 
 
Hemorrhage in Patients taking Warfarin 
International normalized ratio elevations and/or hemorrhage have been reported in some 
patients taking warfarin while on gefitinib therapy. Patients taking warfarin should be 
monitored regularly for changes in prothrombin time or International normalized ratio.

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 122 of 127 
SOP-CD-03-Form2 Ver2 
Appendix 7. International Airline Transportation Association (IATA) 
Guidance Document 
Labeling and Shipment of Biohazard Samples 
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition (2005).  
Infectious substances are now classified either as Category A, Category B or Exempt.  There 
is no direct relationship between Risk Groups and categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to it 
occurs, is capable of causing permanent disability, life-threatening or fatal disease in otherwise 
healthy humans or animals. Category A pathogens are eg. Ebola, Lassa fever virus 

are to be packed and shipped in accordance with IATA Instruction 602
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are e.g., Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name: 

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens 

Clinical trial samples will fall into Category B or exempt under IATA regulations.

Clinical trial samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging.

Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content.

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable.

Samples routinely transported by road or rail are patient to local regulations which require 
that they are also packed and transported in a safe and appropriate way to contain any risk 
of infection or contamination by using approved couriers and packaging / containment 
materials at all times. The IATA 650 biological sample containment standards are 
encouraged wherever possible when road or rail transport is used.

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 123 of 127 
SOP-CD-03-Form2 Ver2 
Appendix 8. EORTC QLQ C-30 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 124 of 127 
SOP-CD-03-Form2 Ver2 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 125 of 127 
SOP-CD-03-Form2 Ver2 
Appendix 9. EORTC QLQ LC-13 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
 
 
Page 126 of 127 
SOP-CD-03-Form2 Ver2 
 
Appendix 10. Euro-Quality of Life-5 Dimension-5 Level (EQ-5D-5L) 
 

Confidential 
Study No.:YH25448-301 
Protocol Ver2 
Page 127 of 127 
SOP-CD-03-Form2 Ver2