Subcutaneous Methotrexate, Oral Dexamethasone or Oral Montelukast for the Prevention of Infusion Related Reaction Associated With Amivantamab, an EGFR-MET Bispecific Antibody, Among Post-osimertinib Treated EGFRm NSCLC; SKIPPirr, a Phase 2 Study
Phase: PHASE2
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Janssen Research & Development, LLC

CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved, Date: 21 August 2023
Janssen Research & Development *
Clinical Protocol
Protocol Title
Subcutaneous Methotrexate, Oral Dexamethasone or Oral Montelukast for the Prevention
of Infusion Related Reaction Associated with Amivantamab, an EGFR-MET bispecific
antibody, Among Post-osimertinib Treated EGFRm NSCLC; SKIPPirr, a Phase 2 Study
Protocol 61186372NSC2005; Phase 2
Amendment 4
JNJ-61186372 (amivantamab)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries/territories. Therefore, the legal entity acting as the sponsor for Janssen Research &
Development studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP;
Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term
“sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
At sites in the United States (US), this study will be conducted under US Food & Drug
Administration Investigational New Drug (IND) regulations (21 CFR Part 312).
Regulatory Agency Identifier Number:
IND: 146319
EudraCT Number: 2022-000974-25
EU Trial Number: 2023-506578-11
Status: 
Approved
Date: 
21 August 2023
Prepared by: Janssen Research & Development LLC
EDMS number: 
EDMS-RIM-499919, 6.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT05663866

JNJ-61186372 (amivantamab)    
Clinical Protocol 61186372NSC2005 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved, Date: 21 August 2023
PROTOCOL AMENDMENT SUMMARY OFCHANGES TABLE
DOCUMENT HISTORY
Document 
Country/Territory Affected  
Date
Amendment 4 
All 
21-Aug-2023
Amendment 3 
All 
27-Apr-2023
Amendment 2 
All 
12-Dec-2022
Amendment 1 
All 
29-Aug-2022
Original Protocol 
All 
29-Jun-2022
Amendment 4 (21-Aug-2023)
Overall Rationale for the Amendment: The overall rationale of this amendment is to add Cohort A2
with increased dose of dexamethasone based on emerging data, and also to incorporate new dose
formulation for methotrexate due to supply issues. This amendment also serves to clarify some procedures
related to VTE on the SoA, as well as to correct some errors, and add in EU CTR specific requirements.
The changes made to the clinical protocol 61186372NSC2005 as part of Protocol Amendment 4 are listed
below, including the rationale of each change and a list of all applicable sections. Changes made in previous
protocol amendments are listed in Section 10.7 Appendix 7: Protocol Amendment History.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1. Synopsis (Overall
Design),
1.2 Schema
1.3. Schedule of
Activities (SoA),
4.1. Overall Design,
6.1. Study Treatment(s)
Administered Table
and Suggested Order of
Administration in
Cohort A2 Table
Added Cohort A2: Oral
Dexamethasone (8 mg) BID (16
mg total daily dose) on Cycle 1
Day -2 and -1, and 1 dose (8 mg)
approximately 1 hour prior to the
start of the infusion of IV
amivantamab on C1D1
Emerging data suggest that extended
administration of a higher dose of dexamethasone
prevented IRR in participants receiving IV
amivantamab.
6.1. Study Treatment(s)
Administered Table
Added new dose formulation for
methotrexate:
5mL/vials, 1mL/10mg
To incorporate new dose formulation for
methotrexate due to supply issues
1.3. Schedule of
Activities (SoA)
6.1. Study Treatment(s)
Administered
Added footnote 'a' to the IV
amivantamab in case if dose is
missed and defined it in the table
footnote as below:
A missed dose is defined as
failure to administer IV
amivantamab within 1 day of the
scheduled dosing date in Cycles
1 (except C1D1) and 2, or failure
to administer IV amivantamab
within 3 days of the scheduled
dosing date in Cycle 3 and
beyond. If a dose is missed, as
defined above, it will not be
made up. Administration may
resume at the next planned
To provide a criterion to follow in case an IV
amivantamab dose is missed.

JNJ-61186372 (amivantamab)    
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Status: Approved, Date: 21 August 2023
Section Number 
and Name
Description of Change 
Brief Rationale
dosing date. If the first dose in
Cycle 2 is delayed, then the dates
of all subsequent doses must be
maintained as originally
scheduled based on Cycle 1 Day
1. All other assessments in SoA
should be performed relative to
actual IV amivantamab
administration, not on the
originally scheduled
administration day.
1.3. Schedule of 
Activities (SoA) 
A new row for VTE prophylaxis 
was added in order to emphasize 
the recommended prophylactic
dose anticoagulation during the
first 4 months of treatment for
participants receiving the
combination of IV amivantamab
and oral lazertinib.
To reinforce the VTE prophylaxis
recommendation.
3. Objectives and 
Endpoints 
Updated the language of the 
secondary objective in bold: 
To evaluate incidences and
severity of individual IRR signs
and symptoms such as chills,
dyspnea, flushing, nausea, chest
discomfort, vomiting,
tachycardia, hypotension, or
fever.
To indicate this is not an all-inclusive list of all
signs and symptoms associated with IRRs.
1.1. Synopsis (Overall 
Design), 
4.1. Overall Design  
Updated text that ‘Up to 126 
participants are planned to be 
treated with amivantamab and 
lazertinib in the study. For each 
cohort, the study will have 2
stages treating up to 16
participants (6 at stage 1 and 10
at stage 2) and an expansion
stage that can treat up to 24
additional participants. First
Cohort A will treat up to 6
participants in Stage 1.
Then cohort B will be activated
to treat up to 6 participants in
Stage 1. Then cohort C will be
activated to treat up to 6
participants in Stage 1. Cohort
A2 will be then activated in
Stage 1.
If both Cohorts A and A2 have
positive results in Stage 1, only
one cohort with dexamethasone
(Cohort A or A2) would move
on to subsequent stages as
determined by the SET. For
To adjust for the inclusion of Cohort A2, to allow
for alternative sequential enrollment orders for
operational optimization, and to delete redundant
text not required by Simon’s 2 stage design.

JNJ-61186372 (amivantamab)    
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Status: Approved, Date: 21 August 2023
Section Number 
and Name
Description of Change 
Brief Rationale
Cohort A2 Stage 1, all cohorts in
Stage 2 and expansion phase, the
sequential enrollment will be
maintained, however the order
will be defined by SET
considering data availability and
other operational definitions.
Added the following text:
In the event of scheduling
conflicts or screen failures at the
end of cohort enrollment leading
to an insufficient number of
participants in a cohort, a
previous cohort can be
backfilled.
1.3. Schedule of 
Activities (SoA 
[Background-Anti - 
Cancer Treatment 
Administration for IV 
Amivantamab]) 
6.1. Study Treatment 
Administered Tables 
Added the following text for the 
IV amivantamab (Cohorts A, 
A2, B, and C) dosage level: 
Based on positive study results
in Stages 1 and 2, full dose may
be administered on Cycle 1 Day
1 in expansion phase after
consultation with the sponsor.
To provide flexibility to investigator on the
expansion cohort, if the prophylactic regimen
shows efficacy in the first 2 stages.
10.2. Appendix 2: 
Clinical Laboratory 
Tests
Added urinalysis. 
Urinalysis was inadvertently excluded from
Appendix 2 in the previous version of the protocol
1.3. Schedule of 
Activities (SoA 
[Hematology, Serum
chemistry])
Deleted collection on Cycle 1 
Day 2.
To correct an error
2.2 Background 
Added reference 
Reference to new data regarding dexamethasone
as a prophylactic for IRR
2.2 Background 
Added new text: 
in addition to an increased IV 
dose pre-infusion (20 mg IV) 
To accurately describe the pre-infusion regimen
and total dexamethasone dose used in PAPILLON
trial.
5.2. Exclusion Criteria 
Added a new exclusion criteria 
number 14: 
Participant previously enrolled in
the Sponsor’s studies
73841937NSC3003
(NCT04487080) or
61186372NSC3002
(NCT04988295).
To avoid bias on a key endpoint of other sponsor's
studies.
5.2. Exclusion Criteria, 
6.9.1. Prohibited or 
Restricted Concomitant 
Therapy/Drug 
Interaction  
Added following, a new 
exclusion criteria number 10a; 
and text for prohibited restricted
concomitant therapy:
Participants who are taking
systemic steroids, methotrexate
or montelukast for other
conditions are excluded (inhaled
and/or nasal steroids are
allowed), regardless of cohort
assignment.
To reduce potential bias by limiting confounding
factors for IRR prevention.

JNJ-61186372 (amivantamab)    
Clinical Protocol 61186372NSC2005 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 21 August 2023
Section Number 
and Name
Description of Change 
Brief Rationale
5.2. Exclusion Criteria 
(Note) 
Added following text: if there is 
no interference with the time 
between prophylactic treatment 
and Cycle 1 Day 1
To clarify the allowance of supportive care to meet
eligibility criteria, but not to allow interference
with dosing schedule.
6.9.1. Prohibited or 
Restricted Concomitant 
Therapy/Drug 
Interaction  
Updated following text: 
potent inducer or inhibitory  
effects on CYP3A4/A5 activity
should be avoided. Drugs that
are potent inhibitors of CYP3A4
activity are prohibited and must
have been discontinued for an
appropriate period before
administration of lazertinib.
Drugs that are potent inhibitors
of CYP3A4 activity are
restricted and should be avoided,
when possible, or used with
caution.
Restricted Medications and
Therapies
The following concomitant
medications and therapies are
restricted during the study and
should be avoided, when
possible, or used with caution.
substrates of P-gp, MRP4,
BCRP, or OCT1 are not
recommended and if necessary,
should be used with caution.
Concomitant use of CYP34A
substrate drugs must should be
discontinued before
administration of lazertinib.
avoided. If no other alternatives
exist monitor participants more
closely for adverse reactions.
Guidance on CYP3A4 substrates
that are prohibited require close
monitoring.
Updated to align with currently available drug-
drug interaction data.
7.1. Discontinuation of 
Study Treatment 
(Dexamethasone, 
Montelukast or
Methotrexate)
Deleted the following text: 
Additional participants will not 
be entered in the study.
To correct an error, participants need to be
replaced for robust analysis.
1.1 Synopsis, 
4.1 Overall Design  
9.2 Sample Size
Determination
Revised term “enroll” or 
“enrolled” to “treat” or “treated” 
throughout section. 
Revised term “Enroll” to “Treat”
To clarify that participants must be treated with
amivantamab and lazertinib to be included into the
primary analysis

JNJ-61186372 (amivantamab)    
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Status: Approved, Date: 21 August 2023
Section Number 
and Name
Description of Change 
Brief Rationale
 Stage 1: Enroll Treat up
to 6 participants.
 Stage 2: Enroll Treat up
to 10 additional
participants.
9.3 Populations for
Analysis Sets
Revised Population “Enrolled”
with description “All participants
who sign the ICF” to Population
“Screened”.
To clarify that participants that sign the ICF are
considered screened, not enrolled.
9.5. Interim Analysis 
Updated that one interim
analysis will occur after all
participants from stage 1
complete Cycle 1 Day 1
and added the following text:
Another interim analysis will
take place after all participants
from stage 2 complete Cycle 1
Day 1.
Deleted the following text:
of dosing. Incidences of IRRs on
Cycle 1 Day 1 will be assessed
and if 4 or more of these 6
patients experience IRRs,
enrollment to the cohort will be
stopped.
To clarify that two interim analyses are planned.
The deleted text is redundant. The content is
covered in section 9.2 Sample size determination.
Throughout the 
protocol 
Minor grammatical, formatting,
or spelling changes were made.
Minor errors were noted

JNJ-61186372 (amivantamab)    
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Status: Approved, Date: 21 August 2023
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 7
LIST OF IN-TEXT TABLES AND FIGURES.............................................................................................. 10
1. 
PROTOCOL SUMMARY................................................................................................................... 11
1.1. 
Synopsis......................................................................................................................................... 11
1.2. 
Schema.......................................................................................................................................... 16
1.3. 
Schedule of Activities (SoA)........................................................................................................... 17
2. 
INTRODUCTION................................................................................................................................ 22
2.1. 
Study Rationale.............................................................................................................................. 22
2.2. 
Background.................................................................................................................................... 23
2.3. 
Benefit-Risk Assessment............................................................................................................... 25
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 29
4. 
STUDY DESIGN ................................................................................................................................ 30
4.1. 
Overall Design................................................................................................................................ 30
4.2. 
Scientific Rationale for Study Design............................................................................................. 31
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 31
4.3. 
End of Study Definition................................................................................................................... 31
5. 
STUDY POPULATION ...................................................................................................................... 32
5.1. 
Inclusion Criteria............................................................................................................................ 32
5.2. 
Exclusion Criteria........................................................................................................................... 35
5.3. 
Lifestyle Considerations................................................................................................................. 38
5.4. 
Screen Failures.............................................................................................................................. 38
6. 
STUDY TREATMENT AND CONCOMITANT THERAPY ................................................................ 39
6.1. 
Study Treatment(s) Administered .................................................................................................. 39
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 47
6.3. 
Assignment to Study Intervention .................................................................................................. 48
6.4. 
Blinding, Masking........................................................................................................................... 48
6.5. 
Treatment Compliance................................................................................................................... 48
6.5.1. 
IV Amivantamab and Oral Lazertinib Treatment Compliance .................................................... 49
6.6. 
Dose Modification........................................................................................................................... 49
6.6.1. 
Infusion-related Reactions.......................................................................................................... 51
6.6.2. 
Liver Chemistry Abnormalities.................................................................................................... 52
6.6.3. 
Rash-related Adverse Events..................................................................................................... 53
6.6.4. 
Pulmonary Toxicity ..................................................................................................................... 57
6.6.5. 
Venous Thromboembolic Events................................................................................................ 58
6.7. 
Continued Access to Lazertinib and IV Amivantamab After the End of the Study ........................ 58
6.8. 
Treatment of Overdose .................................................................................................................. 59
6.9. 
Prior and Concomitant Therapy..................................................................................................... 60
6.9.1. 
Prohibited or Restricted Concomitant Therapy/DRUG INTERACTIONS................................... 60
7. 
DISCONTINUATION OF DEXAMETHASONE, MONTELUKAST, METHOTREXATE,
ORAL LAZERTINIB, AND IV AMIVANTAMAB AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 63
7.1. 
Discontinuation of Study Treatment (Dexamethasone, Montelukast or Methotrexate)................. 63
7.2. 
Discontinuation of Anti-cancer Background Regimen (Oral lazertinib, and
IV amivantamab ............................................................................................................................. 63
7.3. 
Participant Discontinuation/Withdrawal From the Study................................................................ 64
7.3.1. 
Withdrawal From the Use of Research Samples ....................................................................... 64
7.4. 
Lost to Follow-up............................................................................................................................ 64

JNJ-61186372 (amivantamab)    
Clinical Protocol 61186372NSC2005 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 21 August 2023
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 65
8.1. 
Study Assessments........................................................................................................................ 66
8.2. 
Safety Assessments....................................................................................................................... 67
8.2.1. 
Physical Examinations................................................................................................................ 68
8.2.2. 
Vital Signs................................................................................................................................... 68
8.2.3. 
Electrocardiograms..................................................................................................................... 69
8.2.4. 
Clinical Safety Laboratory Assessments .................................................................................... 69
8.2.5. 
Pregnancy Testing...................................................................................................................... 69
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 69
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 70
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 70
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 70
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 71
8.3.5. 
Pregnancy................................................................................................................................... 71
8.3.6. 
Disease-Related Events and Disease-Related Outcomes Not Qualifying as Adverse
Events or Serious Adverse Events............................................................................................. 71
8.3.7. 
Adverse Events of Special Interest............................................................................................. 71
8.4. 
Pharmacokinetics........................................................................................................................... 72
8.5. 
Pharmacodynamics........................................................................................................................ 72
8.6. 
Genetics and Pharmacogenomics................................................................................................. 72
8.7. 
Biomarkers..................................................................................................................................... 72
8.8. 
Immunogenicity Assessments ....................................................................................................... 72
8.9. 
Medical Resource Utilization and Health Economics .................................................................... 72
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 72
9.1. 
Statistical Hypotheses.................................................................................................................... 72
9.2. 
Sample Size Determination ........................................................................................................... 72
9.3. 
Populations for Analysis Sets ........................................................................................................ 73
9.4. 
Statistical Analyses ........................................................................................................................ 73
9.4.1. 
General Considerations.............................................................................................................. 73
9.4.2. 
Primary Endpoint ........................................................................................................................ 73
9.4.3. 
Secondary Endpoints.................................................................................................................. 74
9.4.4. 
Safety Analyses.......................................................................................................................... 74
9.4.5. 
Other Analyses ........................................................................................................................... 75
9.5. 
Interim Analysis.............................................................................................................................. 75
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 76
10.1. 
Appendix 1: Abbreviations and Definitions .................................................................................... 76
10.2. 
Appendix 2: Clinical Laboratory Tests ........................................................................................... 78
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 79
10.3.1. 
Regulatory and Ethical Considerations ...................................................................................... 79
10.3.2. 
Financial Disclosure.................................................................................................................... 82
10.3.3. 
Informed Consent Process ......................................................................................................... 82
10.3.4. 
Recruitment Strategy.................................................................................................................. 83
10.3.5. 
Data Protection ........................................................................................................................... 83
10.3.6. 
Committees Structure................................................................................................................. 84
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data............................................................ 84
10.3.8. 
Data Quality Assurance.............................................................................................................. 86
10.3.9. 
Case Report Form Completion................................................................................................... 86
10.3.10. Source Documents ..................................................................................................................... 87
10.3.11. Monitoring ................................................................................................................................... 87
10.3.12. On-Site Audits............................................................................................................................. 88
10.3.13. Record Retention........................................................................................................................ 88
10.3.14. Study and Site Start and Closure ............................................................................................... 89
10.4. 
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting................................................................................................................................. 90

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10.4.1. 
Adverse Event Definitions and Classifications ........................................................................... 90
10.4.2. 
Attribution Definitions.................................................................................................................. 91
10.4.3. 
Severity Criteria.......................................................................................................................... 91
10.4.4. 
Special Reporting Situations ...................................................................................................... 92
10.4.5. 
Procedures ................................................................................................................................. 92
10.4.6. 
Product Quality Complaint Handling........................................................................................... 94
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality............................................. 95
10.5. 
Appendix 5: Contraceptive and Barrier Guidance ......................................................................... 96
10.6. 
Appendix 6: Study Conduct During a Natural Disaster.................................................................. 99
10.7. 
Appendix 7: Protocol Amendment History................................................................................... 100
11. REFERENCES................................................................................................................................. 110
ATTACHMENTS....................................................................................................................................... 112
INVESTIGATOR AGREEMENT............................................................................................................... 117

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Status: Approved, Date: 21 August 2023
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Dose Modifications for Oral lazertinib and IV amivantamab..................................................... 50
Table 2: 
Management of Infusion-related Reactions.............................................................................. 50
Table 3: 
Suggested Algorithm for Management of Rash........................................................................ 56
Table 4: 
Volume of Blood to be Collected From Each Participant Through Cycle 3.............................. 65
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 16

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Status: Approved, Date: 21 August 2023
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
Subcutaneous Methotrexate, Oral Dexamethasone or Oral Montelukast for the Prevention of Infusion
Related Reaction Associated with Amivantamab, an EGFR-MET bispecific antibody, Among Post-
osimertinib Treated EGFRm NSCLC; SKIPPirr, a Phase 2 Study
Amivantamab is a bispecific EGF receptor-directed and MET receptor-directed antibody with immune cell
directing activity, which has received accelerated approval for the treatment of adult patients with locally
advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, after progression  on or after
platinum-based chemotherapy. Among patients with locally advanced or metastatic NSCLC (CHRYSALIS
study) who received IV amivantamab, IRRs were reported in 66% of treated participants (Amivantamab-
vmjw. Package insert. Janssen Biotech, Inc; 2021.), which are primarily limited to the first infusion on
Cycle 1 Day 1, with dramatically reduced risk on subsequent infusions. The median time to onset was 1
hour after start of infusion, with the most common signs and symptoms of IRR including dyspnea, flushing,
fever, chills, nausea, chest discomfort, hypotension, and vomiting. Translational studies conducted to
understand the underlying mechanisms contributing to amivantamab IRRs, failed to elucidate the
underlying mechanism, but have ruled out cytokine release syndrome, mast cell degranulation, and
complement-mediated etiologies for amivantamab-related IRRs, and the dramatically lowered risk after
initial infusion is inconsistent with an IgE-mediated mechanism. Standard premedication with
antihistamines, antipyretics, and glucocorticoids is recommended immediately prior to the IV amivantamab
initial doses (Week 1, Days 1 and 2).
In general, systemic IRRs, including severe reactions, which occur with the introduction of a new protein
therapeutic infusion are frequently observed but the mechanisms inducing the reactions are varied. There
is emerging data to suggest that the addition of methotrexate, montelukast or oral dexamethasone to a
premedication regimen can lower the signs and symptoms associated to infusion therapy, including the
incidence of IRRs.
Infliximab, a monoclonal antibody targeting Tumor Necrosis Factor (TNF), is associated with early IRRs
which are similar to amivantamab. Vermeire et al. 2007 found infliximab treated patients not taking
concomitant Immunosuppressive (IS) therapy of either methotrexate (MTX) or azathioprine (AZA) more
often experienced infusion reactions compared with patients taking concomitant IS treatment. There was
no difference in infusion reactions between patients treated with AZA compared with patients receiving
concomitant MTX. In addition, to infliximab, the anti-CD38 monoclonal antibody daratumumab is also
associated with this type of IRR.
Other reports have suggested that premedication with montelukast, a leukotriene receptor antagonist known
to reduce asthma attacks and allergic rhinitis, may reduce the IRR rate associated with monoclonal
antibodies, and this observation was also reported by investigators in the phase 1/2 study that resulted in
the initial approval of daratumumab.
Use of extended steroid pre-medications have also been utilized to reduce reactions to IV anti-cancer
therapies such as pemetrexed and docetaxel and are now standard pre-medications for regimens including
these agents.
The aim of this study is to determine whether premedication with dexamethasone, montelukast or
methotrexate can act as a prophylaxis of amivantamab-related IRRs.
Amivantamab plus lazertinib is the background anti-cancer regimen in this protocol and is not the primary
focus of this study. Lazertinib is a third-generation EGFR TKI approved in the Republic of Korea for the
treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC  who
have progressed on or after EGFR TKI therapy. The combination of lazertinib plus IV amivantamab has
been investigated in the CHRYSALIS study and is being further evaluated in the CHRYSALIS-2 study

JNJ-61186372 (amivantamab)    
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Status: Approved, Date: 21 August 2023
where the incidence of IRR was 67% with the majority being grade 1 or 2 and a 9% incidence of grade ≥3
IRR. The safety profile of the combination was consistent with the individual components. Furthermore,
the incidence of IRR with oral lazertinib plus IV amivantamab in CHRYSALIS-2 (67%) was similar to the
incidence of IRR with IV amivantamab monotherapy previously (66%) suggesting that addition of oral
lazertinib to IV amivantamab is not expected to impact the rate of IRRs associated with IV amivantamab.
BENEFIT-RISK ASSESSMENT
Combining amivantamab and lazertinib may lead to improved treatment outcomes through synergistic
antiEGFR activity, prevention of EGFR- or MET-based resistance to a third-generation EGFR TKI, and
potential recruitment of Fc-bearing immune cells in the antitumor response. Previous studies have shown
robust and durable antitumor activity with favorable confirmed ORR, prolonged median duration of
response, and high clinical benefit rate. IV amivantamab is FDA approved for the treatment of adult patients
with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an
FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. Lazertinib is
approved in the Republic of Korea for the treatment of patients with locally advanced or metastatic EGFR
T790M mutation-positive NSCLC who have progressed on or after EGFR TKI therapy. At the time of the
initiation of this study, the combination of oral lazertinib plus IV amivantamab is considered investigational
for the treatment of lung cancer. Amivantamab given IV can cause IRRs and the incidence of IRR in the
CHRYSALIS-2 study was 67% with the majority being grade 1 or 2 and a 9% incidence of grade ≥3 IRR.
There is emerging data in amivantamab and other monoclonal antibodies to suggest that the addition of
enhanced dexamethasone, methotrexate or montelukast to a premedication regimen can lower the signs and
symptoms associated to infusion therapy, including the overall incidence of IRRs. These prophylactic
regimens are being implemented to further optimize the benefit-risk profile for participants receiving
treatment with IV amivantamab.

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OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 
To separately assess the potential of dexamethasone,
montelukast and methotrexate administration, prior to
IV amivantamab infusion, to decrease the incidence
and/or severity offirst dose IRRs.
 
Rate of IRRs occurring on Cycle 1
Day 1 following administration of
oral lazertinib and IV amivantamab
combination therapy, which is
defined as IRR events with onset time
within 24 hours of the start of the first
amivantamab infusion and prior to
the start of amivantamab infusion on
Cycle 1 Day 2.
Secondary
 
To evaluate incidences and severity of individual IRR
signs and symptoms such as chills, dyspnea, flushing,
nausea, chest discomfort, vomiting, tachycardia,
hypotension, or fever.
 
Rates and severity of these individual
AEs during Cycle 1 Day 1.
 
Rates and severity of these individual
AEs 
following 
subsequent
administrations up to the end of the
third cycle.
 
To evaluate incidence and severity of IRR on 
subsequent cycles. 
 
Rates of IRR following subsequent
administrations.
 
Severity 
of 
infusion-related
reactions.
 
To evaluate incidences non-IRR AEs. 
 
Incidence of other adverse events.
 
To measure IV amivantamab infusion related times. 
 
Duration of infusion time for pre-
amivantamab infusion medications,
IV amivantamab infusion, and post-
amivantamab infusion medications
on C1D1.
 
Percent of participants completing
amivantamab infusion within 4 hours
on C1D1.
 
To estimate the anti-tumor activity of IV amivantamab
and oral lazertinib following pre-medication with study
treatment
 
Overall response rate (ORR) and
duration of response (DOR) as
determined 
by 
investigator,
according to the Response Criteria in
Solid Tumors (RECIST) v1.1.
Hypothesis
Through prophylactic treatment with methotrexate, montelukast, or dexamethasone pre-treatment, the
incidence of IRRs on Cycle 1 Day 1 will be lower than 67%.

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OVERALL DESIGN
This is a proof-of-concept, open-label, multicenter study in participants with EGFR exon 19 deletion or
L858R mutated NSCLC who have progressed on or after prior osimertinib and on or after platinum
chemotherapy, who may benefit from IV amivantamab + oral lazertinib combination therapy. In the study,
all participants will receive standard prophylaxis with antihistamine, antipyretic, and glucocorticoid as used
in clinical trials of amivantamab.
There are 4 cohorts in the study.
 
Cohort A: Participants will be administered oral dexamethasone (4 mg) twice a day (8 mg total daily
dose) on Day -1 (Cycle 1) prior to the first dose oforal lazertinib and IV amivantamab combination
therapy.
 
Cohort A2: Participants will be administered oral dexamethasone (8 mg) twice a day (16 mg total daily
dose) on Day -2 and -1 (Cycle 1) and 8 mg approximately 1 hour prior to the start of the infusion of
IV amivantamab on Cycle 1 Day 1.
 
Cohort B: Participants will be administered oral montelukast (10 mg) in the morning on Days -4, -3, -2,
-1, and C1D1 (5 doses total) prior to the first dose oforal lazertinib and IV amivantamab combination
therapy.
 
Cohort 
C: 
Participants 
will 
be 
administered 
a 
single 
dose 
of 25 
mg SC
methotrexate between Day -7 and Day -3 (Cycle 1) prior to the first dose of oral lazertinib and IV
amivantamab combination therapy
Study treatments will be administered in addition to all other standard premedication.
Up to 126 participants are planned to be treated with amivantamab and lazertinib in the study. For each
cohort, the study will have 2 stages treating up to 16 participants (6 at stage 1 and 10 at stage 2) and an
expansion stage that can treat up to 24 additional participants. First cohort A will treat up to 6 participants
in Stage 1. Then cohort B will be activated to treat up to 6 participants in Stage 1. Then cohort C will be
activated to treat up to 6 participants in Stage 1. Cohort A2 will be then activated in Stage 1. In the event
of scheduling conflicts or screen failures at the end of cohort enrollment leading to an insufficient number
of participants in a cohort, a previous cohort can be backfilled.
A Study Evaluation Team (SET) will be commissioned for this study. After cohorts A, A2, B and C have
each treated up to 6 participants, SET will evaluate individually which cohort(s) may move onto Stage 2
and this process will repeat for Stage 2 to select possible expansion phase cohorts. If both Cohorts A and
A2 have positive results in Stage 1, only one cohort with dexamethasone (Cohort A or A2) would move on
to subsequent stages as determined by the SET. For Cohort A2 Stage 1, all cohorts in Stage 2 and expansion
phase, the sequential enrollment will be maintained, however the order will be defined by SET considering
data availability and other operational definitions.
NUMBER OF PARTICIPANTS Up to 126 participants (n=6 in Stage 1 per cohort with an expansion
option of up to 34 more participants added per cohort if there is evidence of reduced IRR rate).
TREATMENT GROUPS AND DURATION
EGFR exon 19 or L858R mutated advanced NSCLC with disease progression on or after osimertinib and
doublet platinum chemotherapy and will proceed with the treatment of IV amivantamab + oral lazertinib as
determined by investigator.

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Description of Study treatments
Dexamethasone
Dexamethasone is a synthetic adrenocortical steroid available in oral and IV formulations for allergic states.
IV dexamethasone (10 mg) is a standard premedication administered prior to all participants receiving IV
amivantamab.
Montelukast
Montelukast, a highly selective leukotriene receptor antagonist, is an oral treatment for chronic asthma and
prophylaxis and the prevention of exercise-induced bronchoconstriction.
Montelukast inhibits the mast cell mediated release of leukotrienes and may be used to reduce inflammation
and bronchoconstriction.
Methotrexate
Methotrexate (MTX) is an anti-metabolite, commonly used in chemotherapy and immunosuppressant in
auto-immune diseases; it may affect immune function.
EFFICACY EVALUATION
The primary objective is to separately assess the potential of dexamethasone, montelukast and methotrexate,
administration, prior to IV amivantamab infusion, to decrease the incidence and/or severity of first dose
IRRs. Investigator reported adverse events of IRR and associated symptoms and severity will be assessed.
Investigator assessed tumor response and duration of response will be collected as secondary endpoints.
Response assessment will be determined for all participants in accordance with RECIST v1.1. Disease will
be assessed at baseline, 6 weeks (+1 week) after Cycle 1 Day 1 (ie, Day 42-Day 49) for the first assessment,
and then every 6 (±1) weeks relative to Cycle 1 Day 1, until disease progression by imaging, start of new
anti-cancer therapy, or withdrawal of consent. Scheduled disease assessments for participants who have
completed 12 cycles and are clinically stable (both clinical symptoms and radiographical assessments), may
be extended to 12-week intervals at the discretion of the investigator, after confirmation with medical
monitor.
SAFETY EVALUATIONS
The safety ofthe study treatments (dexamethasone, montelukast, and methotrexate) and ofthe background
anti-cancer therapy (IV amivantamab and oral lazertinib) will be assessed by physical examinations, clinical
laboratory tests, vital signs, monitoring of adverse events (AEs), and concomitant medication usage.
STATISTICAL METHODS
The null hypothesis that the true IRR rate is 0.67 or higher will be tested against a one-sided alternative for
each prophylaxis treatment. Simon's two-stage design (Simon, 1989) will be used separately for each
cohort. In the first stage, 6 participants will be accrued. If there are 4 or more participants with IRR out of
these 6 participants, the cohort will be stopped. Otherwise, second stage of the cohort will be initiated with
accrual of 10 additional participants for a total of 16. The null hypothesis will be rejected if 8 or less
participants with IRR are observed in 16 participants; the cohort will be concluded to be promising in
lowering IRR. The cohort can then be expanded by adding up to 24 additional participants (up to 40
participants total per expanded cohort) for a more precise estimation of the rate of IRR.
The Simon’s two-stage design yields a Type I error rate (one sided) of 0.04 and power of 0.8 when the true
IRR rate is 0.34 (50%reduction in IRR).

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Study Period 
Screening
Prophylaxis
Administration
Treatment (28 days/cycle)
End of
Study
Notes
Cycle 1 
Cycle 2
Cycle 3 (and
all cycles
thereafter)
Up to 30
days after
last dose
Cycle Day
-7 to -3
before 
C1D1
-4 
-3 
-2 
-1 
1 
2 
8 
15 
22 
1 
15 
1 
15
Visit Window
(Days)
-28 to -8 
-7 to -3 
- 
±1 
±2 
±1 
±1 
±1 
±3 
±3 
0
Disease
assessment/Tumor
response evaluation
X 
X
Disease assessments and evaluations as outlined in
Section 8.1 (CT scan with contrast agent and/or
MRI scan should be performed for all active disease
sites documented at Screening, 6 weeks (+1 week)
after Cycle 1 Day 1(ie, Day 42 Day 49) for the
first assessment, and then every 6 (±1) weeks
relative to Cycle 1 Day 1. Scheduled disease
assessments for participants who have completed 12
cycles, and are clinically stable (both clinical
symptoms and radiographical assessments), may be
extended
to 12 week intervals at the discretion of the
investigator, after confirmation with Medical
Monitor. Results will be recorded in the CRF. The
same methodology should be used throughout the
study. Tumor response evaluation will be assessed
by the investigator according to RECIST v1.1.
Results of the assessment should be available prior
to the next scheduled dose.
C cycle; D day; ECOG Eastern Cooperative Oncology Group; EGFR epidermal growth factor receptor; min minute(s); IV intravenous; PO orally.
a A missed dose is defined as failure to administer IV amivantamab within 1 day of the scheduled dosing date in Cycles 1 (except C1D1) and 2, or failure to administer IV amivantamab
within 3 days of the scheduled dosing date in Cycle 3 and beyond. If a dose is missed, as defined above, it will not be made up. Administration may resume at the next planned dosing date.
If the first dose in Cycle 2 is delayed, then the dates of all subsequent doses must be maintained as originally scheduled based on Cycle 1 Day 1. All other assessments in SoA should be
performed relative to actual IV amivantamab administration, not on the originally scheduled administration day.
bFor participants receiving the combination of amivantamab and lazertinib, evaluate for early signs and symptoms of venous thromboembolic (VTE). A focused physical examination of
extremities and evaluation of respiratory status (including pulse oximetry) should be performed.

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2. 
INTRODUCTION
For the most comprehensive nonclinical and clinical information regarding dexamethasone,
montelukast and methotrexate refer to the product labeling. For the most comprehensive
nonclinical and clinical information regarding IV amivantamab, and lazertinib refer to the latest
version of the Investigator's Brochure (IB) and Addenda for IV amivantamab and oral lazertinib.
The term “study treatment” throughout the protocol, refers to study drug as defined in Section 6.1,
Study Treatment(s) Administered.
The term "sponsor" used throughout this document refers to the entities listed in the Contact
Information page(s), which will be provided as a separate document.
2.1. 
Study Rationale
Systemic IRRs, including severe reactions, upon the introduction of a new protein therapeutic
infusion are frequently observed but the mechanisms inducing the reactions are varied (Cáceres
2019; Matucci 2016). There is emerging data to suggest that the addition of methotrexate or
montelukast to a premedication regimen can lower the signs and symptoms associated to infusion
therapy, including incidence of IRRs.
Similar to amivantamab, infliximab also causes IRR, the etiology of which is unknown. Vermeire
et al. 2007 found infliximab treated patients not taking concomitant Immunosuppressive (IS)
therapy of either methotrexate (MTX) or azathioprine (AZA) more often experienced infusion
reactions (40%) compared with patients taking concomitant IS treatment (16%; p  0.04). There
was no difference in infusion reactions between patients treated with AZA (18%) compared with
patients receiving concomitant MTX (14%; p  NS).
Other reports have suggested that premedication with montelukast, a leukotriene receptor
antagonist known to reduce asthma attacks and allergic rhinitis, may reduce the IRR rate associated
with monoclonal antibodies, (Arora 2015; Lebel 2016; Lokhorst 2015; Moreau 2016; Quercia
2011) and this observation was also reported by investigators in the Phase 1/2 study that resulted
in the initial approval of daratumumab. (Chari 2018) A multicenter, open‐label treatment protocol
provided early access to daratumumab for patients who had progressive MM after they received
≥3 prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent or
if they were refractory to both a proteasome inhibitor and an immunomodulatory agent. Patients
received daratumumab 16 mg/kg weekly for 8 weeks, every other week for 16 weeks, and monthly
until they developed disease progression, unacceptable toxicity, or 60 days after the drug gained
US approval. Three hundred forty‐eight patients were enrolled at 39 US sites between June and
December 2015. Infusion reactions occurred in 56%, 2%, and 2% of patients during the first,
second, and all subsequent infusions, respectively; respiratory symptoms (cough, dyspnea, throat
irritation, nasal congestion) were common.
Sixty patients (17%) received montelukast 10 mg before at least 1 infusion. Of these, 50 patients
(14%) at 2 study sites received montelukast before the first daratumumab infusion, 49 of whom

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received montelukast on same day more than 30 minutes before daratumumab infusion. Based on
those 50 patients, the IRR rates at first infusion were 38% and 59% (respiratory symptoms, 20%
and 33%), respectively, in those who did or did not receive montelukast. Furthermore, the
incidence of grade 3 or 4 IRRs was 2% and 9% in patients who did (n  60) or did not (n 298)
receive montelukast, respectively. The median duration of the first daratumumab infusion was 6.7
hours (range, 1.0‐10.7 hours) for the 50 patients who received montelukast before their first
infusion versus 7.6 hours (range, 1.4‐24.0 hours) for those who did not.
2.2. 
Background
Amivantamab given IV can cause IRRs. Amivantamab is a bispecific EGF receptor-directed and
MET receptor-directed antibody FDA approved for the treatment of adult patients with locally
advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an
FDA -approved test, whose disease has progressed on or after platinum-based chemotherapy.
Lazertinib is a potent, irreversible, and brain-penetrant third-generation EGFR TKI approved in
the Republic of Korea for the treatment of patients with locally advanced or metastatic EGFR
T790M mutation-positive NSCLC who have progressed on or after EGFR TKI therapy. The
combination of oral lazertinib plus IV amivantamab has been investigated in the CHRYSALIS
study where a total of 45 patients with EGFR exon 19 deletion- or L858R mutation-positive
metastatic NSCLC who had progressed on prior osimertinib received the combination of IV
amivantamab 1050/1400 mg (IV QW in C1; Q2W thereafter) plus oral lazertinib 240 mg (po QD).
The incidence of IRR was 78%, and other common AEs included rash (acneiform dermatitis, 51%
+ rash, 27%), and paronychia (49%) with the majority being grade 1-2. Treatment-related grade
≥3 AE occurred in 16% of patients, treatment-related discontinuations occurred in 4% and
treatment-related dose reductions occurred in 18% of patients. At a median follow up of 11 months,
an ORR of 36% was observed with a median duration of response of 9.6 months. (Bauml ASCO
2021).
The investigational regimen of oral lazertinib plus IV amivantamab is being further evaluated in
Cohort A of the CHRYSALIS-2 study, where a total of 136 patients with EGFR
exon 19deletion -or L858R mutation-positive metastatic NSCLC who had progressed on prior
osimertinib, and prior platinum-based chemotherapy received the same combination of oral
lazertinib plus IV amivantamab. The incidence of IRR was 67% with the majority being grade 1
or 2 and a 9% incidence of grade ≥3 IRR. The safety profile was consistent with previously
reported experience. Furthermore, the incidence of IRR with oral lazertinib plus IV amivantamab
in CHRYSALIS-2 (67%) was similar to the incidence of IRR with IV amivantamab monotherapy
(66%) suggesting that addition of oral lazertinib to IV amivantamab is not expected to impact the
rate of IRRs associated with IV amivantamab. (Shu ESMO 2021).
More detailed information about the known and expected benefits and risks of dexamethasone,
montelukast, and methotrexate may be found in the respective product labeling. More detailed
information about the known and expected benefits and risks of lazertinib and IV amivantamab
may be found in the respective IBs.

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IV amivantamab can cause IRR; signs and symptoms of IRR include dyspnea, flushing, fever,
chills, nausea, chest discomfort, hypotension, and vomiting. Among 302 patients with locally
advanced or metastatic NSCLC who received IV amivantamab at RP2D as a single-agent in the
CHRYSALIS study, the most common (≥20%) adverse reactions were rash, IRR, paronychia,
musculoskeletal pain, dyspnea, nausea, edema, cough, fatigue, stomatitis, constipation, vomiting
and pruritus.  Patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the
incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and
cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1-2, 2.2%
were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 hour (range 0.1 to 18
hours) after start of infusion. The incidence of infusion modifications due to IRR was 62% and
1.3% of patients permanently discontinued IV amivantamab due to IRR.
Studies conducted on a subset of patients to understand the underlying mechanisms contributing
to IRRs failed to distinguish a pattern between patients with and without IRR. No correlation
between IRR and cytokine release, mast cell degranulation, tumor lysis syndrome, or complement
activation was observed; the underlying mechanism(s) of IRRs require further studies.
(Park ESMO 2021)
Standard premedication with antihistamines, antipyretics, and glucocorticoids is recommended,
including premedication with dexamethasone 10 mg IV required at IV amivantamab initial dose
(Week 1, Days 1 and 2). IV amivantamab is also being investigated in combination with
carboplatin-pemetrexed based chemotherapy in the PAPILLON study. In PAPILLON, the
“enhanced steroid” premedication is aligned with the pemetrexed standard of care. In PAPILLON,
for the carboplatin-pemetrexed based chemotherapy combination with IV amivantamab,
dexamethasone 4 mg twice a day is to be administered orally (PO) the day prior to administration
of pemetrexed/amivantamab (Cycle 1 Day -1), in addition to an increased IV dose pre-infusion
(20 mg IV). It is hypothesized that this “enhanced steroid” use with oral pre-loading the day before
the first IV amivantamab infusion may reduce the incidence of IV amivantamab associated IRRs.
IV amivantamab should be administered via a peripheral line on Week 1 and Week 2, given the
high incidence of IRRs during initial treatment. IV amivantamab may be administered via central
line for subsequent weeks. As a mitigation against the risk of IRRs, the initial dose of IV
amivantamab (Cycle 1, Days 1 and 2), is administered as a split dose over 2 days (eg, Cycle 1
Day 1 [350 mg] and Cycle 1 Day 2 [remainder of dose]). During this initial dose, interruption of
the infusion should be considered even with mild symptoms to prevent more severe manifestations
of IRR. Patients should be monitored for any signs and symptoms of infusion reactions during IV
amivantamab infusion in a setting where cardiopulmonary resuscitation medication and equipment
are available, and the infusion should be interrupted if IRR is suspected and resumed at a reduced
infusion rate for Grade 3 IRR or permanently discontinued for Grade ≥4 and recurrent Grade 3
IRR.
In an updated analysis by Park et al (Park ESMO 2021), among n 380 patients who received IV
amivantamab at the RP2D, IRR was reported in 256 patients (67%) and was mostly grade 1 2
severity except for 8 patients (2%) who had Grade 3 events and 1 patient (0.3%) who had a Grade

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4 event. The patient who had Grade 4 IRR received the C1D1 dose without implementation of IRR
mitigation strategies. IRR typically occurred early; 98% of events occurred on C1D1, and only
5events occurred past cycle 2. The predominance of Grade 2 IRR on C1D1 is consistent with
guideline recommendation to hold infusion at first sign of IRR, even for Grade 1 events, in order
to prevent more serious reactions. Even though the majority of IRRs are Grade 1/2, mostly limited
to the first infusion, and manageable as described above, despite these measures, IRRs do remain
frequent and are associated with a prolonged IV amivantamab infusion. Further measures to reduce
the incidence of IRR are therefore desirable.
The observation by Vermeire et al that methotrexate may reduce infliximab associated infusion
reactions supports the hypothesis that concomitant methotrexate treatment may reduce IRR
associated with  monoclonal antibodies. Other reports have suggested that premedication with
montelukast, a leukotriene receptor antagonist known to reduce asthma attacks and allergic
rhinitis, may reduce the IRR rate associated with monoclonal antibodies. (Arnett 1988; Elkayam
2005; Panayi 1978; Vermeire 2007). Use of extended steroid pre-medications have also been
utilized to reduce reactions to IV anti-cancer therapies such as pemetrexed and docetaxel and are
now standard pre-medications for regimens including these agents. Recent data from a single
investigator practice suggests extended use of oral dexamethasone administered at 8 mg BID for
2 days prior to amivantamab infusion and on the day of infusion was able to prevent all IRRs in a
small patient sample (Chan 2023). Together, this forms the basis for this current study
dexamethasone, montelukast, or methotrexate for the reduction of IV amivantamab  Infusion
Related Reactions. Based on the diverse mechanisms by which dexamethasone, montelukast, and
methotrexate are believed to reduce the incidence monoclonal antibody IRRs and the limited
potential for clinical drug-drug interactions, administering dexamethasone, montelukast, and
methotrexate together may be investigated in this study if administration of these agents alone
prior to lazertinib and IV amivantamab treatment is associated with a reduced rate of IRR.
Please refer to Section 6.6.1 for Infusion-related Reactions.
2.3. 
Benefit-Risk Assessment
The study treatments are dexamethasone, montelukast, or methotrexate (see Section 6.1). IV
amivantamab is FDA approved for the treatment of adult patients with locally advanced or
metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test,
whose disease has progressed on or after platinum-based chemotherapy. Lazertinib is approved in
the Republic of Korea for the treatment of patients with locally advanced or metastatic EGFR
T790M mutation-positive NSCLC who have progressed on or after EGFR TKI therapy. At the
time of the initiation of this study, the combination of oral lazertinib plus IV amivantamab is
considered investigational for the treatment of lung cancer. The study drugs (dexamethasone,
montelukast and methotrexate) that will be investigated in this study are to be given as pre-
medication prior to the administration of this background investigational anti-cancer combination
regimen of oral lazertinib plus IV amivantamab to assess the ability of the study drugs to decrease
the incidence ofIRRs with the anti-cancer treatment.

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Dexamethasone
The safety risk information below is based on prolonged use of dexamethasone and the safety
profile of a limited administration as described in this protocol has not been established. Risks
associated with dexamethasone therapy may include, GI upset, headache, dizziness, insomnia,
depression, anxiety, acne, bruising or infections.
More detailed information about the known and expected benefits and risks of dexamethasone,
montelukast and methotrexate may be found in the respective product labeling.
Montelukast
The safety risk information below is based on prolonged use of montelukast and the safety profile
of a limited administration as described in this protocol has not been established. Serious
neuropsychiatric (NP) events have been reported with the chronic use of montelukast. The types
of events reported were highly variable, and included, but were not limited to, agitation,
aggression, depression, sleep disturbances, suicidal thoughts, and behavior (including suicide).
The mechanisms underlying NP events associated with montelukast use are currently not well
understood. Potential benefits and risks of montelukast should be discussed with patients and
caregivers when montelukast is administered. Patients and/or caregivers should be advised to be
alert for changes in behavior or new NP symptoms when taking montelukast. If changes in
behavior are observed, or if new NP symptoms or suicidal thoughts and/or behavior occur, patients
should be advised to discontinue montelukast and contact a healthcare provider immediately. The
most frequently reported adverse reactions with montelukast include respiratory infection, fever,
headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea,
sinusitis, and otitis.
Methotrexate
The safety risk information below is based on continuous use of methotrexate and the safety profile
of a single, one-time dose of methotrexate has not been established.
Methotrexate should be used only by physicians whose knowledge and experience include the use
of antimetabolite therapy. Patients should be informed by their physician of the risks involved and
be under a physician’s care throughout therapy.
1. Methotrexate has been reported to cause fetal death and/or congenital anomalies. Therefore,
it is not recommended for women of childbearing potential unless there is clear medical
evidence that the benefits can be expected to outweigh the considered risks. Pregnant women
should not receive methotrexate.
2. Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and
gastrointestinal toxicity have been reported with concomitant administration of methotrexate
(usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs).
3. Methotrexate causes hepatotoxicity, fibrosis, and cirrhosis, but generally only after prolonged
use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and
asymptomatic, and also do not appear predictive of subsequent hepatic disease.

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4. Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a
potentially dangerous lesion, which may occur acutely at any time during therapy and has
been reported at low doses. It is not always fully reversible, and fatalities have been reported.
Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of
treatment and careful investigation.
5. Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic
enteritis and death from intestinal perforation may occur.
6. Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with
rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or
alleviate this complication.
7. Severe, occasionally fatal, skin reactions have been reported following single or multiple
doses of methotrexate. Reactions have occurred within days of oral, intramuscular,
intravenous, or intrathecal methotrexate administration. Recovery has been reported with
discontinuation of therapy.
8. Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may
occur with methotrexate therapy.
The most frequently reported adverse reactions with methotrexate injection include ulcerative
stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse effects
are malaise, undue fatigue, chills and fever, dizziness, and decreased resistance to infection.
Background anti-cancer therapy with IV amivantamab plus oral lazertinib
The combination of oral lazertinib and IV amivantamab has been investigated in Cohort E of the
CHRYSALIS study (n 45) and in Cohort A of the CHRYSALIS-2 study (n 136) in patients with
patients with EGFR exon 19 deletion- or L858R mutation-positive advanced NSCLC who had
progressed on prior osimertinib. In CHRYSALIS-2 the most common AEs (≥20%) included IRR,
rash (acneiform dermatitis, rash), paronychia, stomatitis, hypoalbuminemia, vomiting, increased
AST/ALT, and decreased appetite. A total of 37% of patients had treatment-related grade ≥3 AEs.
Four patients (3%) had pneumonitis/ILD. The safety profile was consistent with previously
reported experience with IV amivantamab plus oral lazertinib, and no new safety signals were
identified. IV amivantamab plus oral lazertinib demonstrated antitumor activity in a population
that progressed on both standard of care osimertinib and platinum chemotherapy and for whom
there are no approved targeted therapy treatment options. (Shu ESMO 2021)
Prior to any IV amivantamab infusion, standard premedication with antihistamines, antipyretics,
and glucocorticoids is recommended, including premedication with dexamethasone 10 mg IV
required at initial IV amivantamab doses (Cycle 1, Days 1 and 2). This study will investigate
“enhanced steroid” use in Cohort C with dexamethasone oral pre-loading the day before the first
amivantamab dose to reduce the incidence of IV amivantamab associated IRRs.
At the 20 July 2022 Independent Data Monitoring Committee (IDMC) review of unblinded safety
and efficacy data from another ongoing study of amivantamab and lazertinib combination therapy
(73841937NSC3003), the IDMC confirmed a favorable benefit-risk assessment and therefore
recommended continuation of the study. The IDMC also recommended that additional measures

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be taken to mitigate an observed increase in venous thromboembolic (VTE) events for the
combination that was primarily evident within the first 4 months of initiating therapy. Notably,
based on the VTE search strategy used at the time of IDMC review, no Grade 5 VTE events were
identified, and only 1 participant discontinued study treatment due to VTE events.
The VTE related changes implemented during protocol Amendment 1 for this study are intended
to 1) provide guidance to increase awareness of the potential increased incidence of VTE events
during the first 4 months of treatment with the amivantamab and lazertinib combination,
2) describe measures to increase monitoring for these VTE events, 3) increase data collection
related to all treatment-emergent VTE events to better understand these events and their potential
relatedness to study drugs, and 4) recommend prophylactic anticoagulation during the first
4 months of combination therapy. These measures are being implemented in each study of
amivantamab and lazertinib combination therapy to further optimize the benefit-risk balance for
participants.
More detailed information about the known and expected benefits and risks of lazertinib and IV
amivantamab may be found in the respective IBs.

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3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 
To separately assess the potential of dexamethasone,
montelukast and methotrexate administration, prior to
IV amivantamab infusion, to decrease the incidence
and/or severity of first dose IRRs.
 Rate of IRRs occurring on Cycle 1
Day 1 following administration of
oral lazertinib and IV amivantamab
combination therapy, which is
defined as IRR events with onset
time within 24 hours of the start of
the first amivantamab infusion
and prior to the start of
amivantamab infusion on Cycle 1
Day 2.
Secondary
 
To evaluate incidences and severity of individual IRR
signs and symptoms such as chills, dyspnea, flushing,
nausea, chest discomfort, vomiting, tachycardia,
hypotension, or fever.
 
Rates and severity of these individual
AEs during Cycle 1 Day 1.
 
Rates and severity of these individual
AEs 
following 
subsequent
administrations up to the end of the
third cycle.
 
To evaluate incidence and severity of IRR on 
subsequent cycles. 
 
Rates of IRR following subsequent
administrations.
 
Severity 
of 
infusion-related
reactions.
 
To evaluate incidences non-IRR AEs. 
 
Incidence of other adverse events.
 
To measure IV amivantamab infusion related times. 
 
Duration of infusion time for pre-
amivantamab infusion medications,
IV amivantamab infusion, and post-
amivantamab infusion medications
on C1D1.
 
Percent of participants completing
amivantamab infusion within 4 hours
on C1D1.
 
To estimate the anti-tumor activity of IV amivantamab
and oral lazertinib following pre-medication with
study treatment
 
Overall response rate (ORR) and
duration of response (DOR) as
determined 
by 
investigator,
according to the Response Criteria in
Solid Tumors (RECIST) v1.1.
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.

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HYPOTHESIS
Through prophylactic treatment with  enhanced dexamethasone, montelukast, or methotrexate
pre-treatment, the incidence of IV amivantamab IRRs on Cycle 1 Day 1 will be lower than 67%.
4. 
STUDY DESIGN
4.1. 
Overall Design
This is a proof-of-concept open-label, multicenter study  in participants with EGFR Exon 19
deletion or L858R mutated NSCLC who have progressed on or after osimertinib, and on or after
platinum-based chemotherapy, who may  benefit from oral lazertinib and IV amivantamab
combination therapy. In the study, all participants will receive standard prophylaxis with
antihistamine, antipyretic, and glucocorticoid as used in clinical trials of amivantamab and
lazertinib.
IRRs with IV amivantamab treatment typically occur early. Among 380 participants who received
IV amivantamab at the RP2D, 98% of events occurred on C1D1, and only 5 events occurred past
cycle 2 (Park ESMO 2021). There are four cohorts in the study.
Cohort A: Participants will be administered oral dexamethasone (4 mg) twice a day (8 mg total
daily dose) on Day -1 (Cycle 1) prior to oral lazertinib and IV amivantamab combination therapy
in addition to all other standard premedication.
Cohort A2: Participants will be administered oral dexamethasone (8 mg) twice a day (16 mg total
daily dose) on Day -2 and -1 (Cycle 1) and 8 mg approximately one hour prior to the start of the
infusion ofIV amivantamab on Cycle 1 Day 1.
Cohort B: Participants will be administered oral montelukast (10 mg) in the morning on Days -4,
-3, -2, -1, and C1D1 (5doses total) prior to oral lazertinib  and IV amivantamab combination
therapy.
Cohort C: Participants will be administered a single dose of 25 mg subcutaneous (SC)
methotrexate on any day between Days -7 and Day -3 (Cycle 1) prior to oral lazertinib and IV
amivantamab combination therapy.
Study treatments will be administered in addition to all other standard premedication (See
Section 1.3, Schedule of Activities and Section 6.1, Suggested Order of Administration).
Up to 126 participants are planned to be treated with amivantamab and lazertinib in the study. For
each cohort, the study will have 2 stages treating up to 16 participants (6 at stage 1 and 10 at stage
2) and an expansion stage that can treat up to 24 additional participants. First Cohort A will treat
up to 6 participants in Stage 1. Then Cohort B will be activated to treat up to 6 participants in Stage
1. Then Cohort C will be activated to treat up to 6 participants in Stage 1.Cohort A2 will be then
activated in Stage 1. If both Cohorts A and A2 have positive results in Stage 1, only one cohort
with dexamethasone (Cohort A or A2) would move on to subsequent stages as determined by the
SET. For Cohort A2 Stage 1, all cohorts in Stage 2 and expansion phase, the sequential enrollment

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will be maintained, however the order will be defined by SET considering data availability and
other operational definitions.
In the event of scheduling conflicts or screen failures at the end of cohort enrollment leading to an
insufficient number of participants in a cohort, a previous cohort can be backfilled. If a stop
decision can be made within a cohort before reaching the planned sample size, which is 6 for Stage
1 and 10 additional participants for Stage 2, the enrollment into this cohort will be closed and the
enrollment for the next cohort will start. (see Section 9.2, Sample Size Determination).
A Study Evaluation Team will be commissioned for this study. The Study Evaluation Team will
evaluate which cohort(s) may move onto Stage 2 and this process will be repeated on Stage 2 to
select possible expansion phase cohorts. Refer to Committees Structure in Appendix 3:
Regulatory, Ethical, and Study Oversight Considerations for details.
A diagram of the study design is provided in Section 1.2, Schema (Figure 1).
4.2. 
Scientific Rationale for Study Design
4.2.1. Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study, and, during
the study, participants will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may
be withdrawn at any time with no reason given and without penalty or loss of benefits to which
they would otherwise be entitled. Only participants who are fully able to understand the risks,
benefits, and potential AEs of the study, and provide their consent voluntarily will be enrolled.
The total blood volume to be collected is considered to be an acceptable amount of blood to be
collected over this time period from the population in this study based upon the standard of the
Japanese Red Cross (The Japanese Red Cross Society 2018) and American Red Cross (American
Red Cross 2020).
4.3. 
End of Study Definition
End of Study Definition
The end of study is considered as the last scheduled study assessment shown in the Schedule of
Activities for the last participant in the study. The final data from the study site will be sent to the
sponsor (or designee) after completion of the final participant assessment at that study site, in the
time frame specified in the Clinical Trial Agreement.
Study Completion Definition
A participant will be considered to have completed the study if he or she has died before the end
of the study due to progressive disease or has not prematurely discontinued the study for another
reason (Section 7) by the end of the study. If death occurs for any other reason than progressive
disease, the participant’s status will be categorized as early withdrawal.

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5. 
STUDY POPULATION
Screening for eligible participants will be performed within 28 days before administration of oral
lazertinib and IV amivantamab. Refer to Section 5.4, Screen Failures for conditions under which
the repeat of any screening procedures are allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If
there is a question about these criteria, the investigator must consult with the appropriate sponsor
representative and resolve any issues before enrolling a participant in the study. Waivers are not
allowed.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2,
Sample Size Determination.
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
Age
1. 
Be ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is
taking place) at the time of informed consent.
Type of Participant and Disease Characteristics
2. 
Participant must have advanced or metastatic NSCLC
3. 
Progressed on or after prior treatment with osimertinib and platinum-based chemotherapy.
Prior use of first-or-second generation EGFR TKI is allowed if administered prior to
osimertinib.
4. 
Previously identified EGFR-mutated NSCLC (EGFR Exon19 deletion or L858R)
(identified locally in a Clinical Laboratory Improvement Amendments [CLIA]-certified
laboratory [or equivalent])
5. 
ECOG performance status grade of 0 or 1 (Attachment 1).
6. 
Participant must have organ and bone marrow function as follows:
a) Hemoglobin ≥9g/dL
b) ANC ≥1.5 x 109/L
c) Platelets ≥75 x 10 9/L
d) AST and ALT ≤3 x ULN
e) Total bilirubin ≤1.5 x ULN; participants with Gilbert’s syndrome can enroll if
conjugated bilirubin is within normal limits.
f) Have an estimated glomerular filtration rate (eGFR), based on the Modified Diet
in Renal Disease (MDRD) 4-variable formula (see Attachment 5), of >30 mL/min.

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Sex and Contraceptive/Barrier Requirements
7. 
Male or female (according to their reproductive organs and functions assigned by
chromosomal complement at birth).
8. 
A female participant using oral contraceptives must use an additional barrier
contraceptive method (details in Appendix 5: Contraceptive and Barrier Guidance).
9. 
A female participant must be either of the following (as defined in Appendix 5:
Contraceptive and Barrier Guidance)
a. Not of childbearing potential: premenarchal; postmenopausal (>45 years of age
with amenorrhea for at least 12 months); permanently sterilized (eg, bilateral
tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy);
or otherwise, be incapable of pregnancy.
b. Of childbearing potential and practicing at least 1 highly effective method(s) of
birth control consistent with local regulations regarding the use of birth control
methods for participants participating in clinical studies, as described below:
o Practicing true abstinence (when this is in line with the preferred and usual
lifestyle of the participant), which is defined as refraining from heterosexual
intercourse during the entire period of the study, including up to 6 months
after the last dose of dexamethasone, montelukast, methotrexate, lazertinib
or IV amivantamab is given. Periodic abstinence (calendar, symptothermal,
post-ovulation methods) is not considered an acceptable contraceptive
method.
o Have a sole partner who is vasectomized.
o Practicing 2 methods of contraception, including one highly effective
method (ie, established use of oral, intravaginal, transdermal, injected or
implanted hormonal methods of contraception; placement of an intrauterine
device [IUD] or intrauterine system [IUS], tubal ligation procedures as
consistent with local regulations), AND, a second method, (eg, condom with
spermicidal foam/gel/film/cream/suppository or occlusive cap [diaphragm
or cervical/vault caps] with spermicidal foam/gel/film/cream/suppository).
o Participants must agree to continue contraception throughout the study and
continuing through 6 months after the last dose of dexamethasone,
montelukast, methotrexate, lazertinib or IV amivantamab.
Note: If the childbearing potential changes after start of the study (eg, woman who is not
heterosexually active becomes active, premenarchal woman experiences menarche) the
woman must begin a method of birth control, including 1 highly effective method, as
described above.

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10. 
10.1. 
Criterion modified per Amendment-3
A female participant of childbearing potential must have a negative serum (b-human
chorionic gonadotropin [b-hCG]) at screening (within 72 hours of the first dose of study
treatment administration) and must agree to further serum or urine pregnancy tests during
the study prior to Day 1 of each cycle and at End of Study.
11. 
A female must agree not to donate eggs (ova, oocytes) or freeze for future use for the
purposes of assisted reproduction during the study and for a period of 6 months after
receiving the last dose of study drug, oral lazertinib and IV amivantamab. Female
participants should consider preservation of eggs prior to study treatment as anti-cancer
treatments may impair fertility.
12. 
A male participant must wear a condom when engaging in any activity that allows for
passage of ejaculate to another person during the study and for 3 months after receiving
the last dose of study treatment, oral lazertinib and IV amivantamab.
13. 
If the male participant’s partner is a female of childbearing potential, the male participant
must use condom with or without spermicide and the female partner of the male
participant must also be practicing a highly effective method of contraception (see
Appendix 6: Contraceptive and Barrier Guidance). A male participant who is
vasectomized must still use a condom (with or without spermicide), but the partner is not
required to use contraception.
14. 
A male participant must agree not to donate sperm for the purposes of reproduction during
the study and for 3 months after receiving the last dose of IV amivantamab or lazertinib
or study treatment (whichever comes last). Male participants should consider preservation
of sperm prior to study treatment as anti-cancer treatments may impair fertility.
15. 
A male participant must agree not to plan to father a child while enrolled in this study or
within 3 months after the last dose of IV amivantamab or lazertinib or study treatment
(whichever comes last).
Informed Consent
16. 
16.1. 
Criterion 16 modified per Amendment-3
Each participant, or legally authorized representative, where allowed, must sign an ICF
indicating that the participant understands the purpose of, and procedures required for,
the study and is willing to participate in the study.

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5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
Medical Conditions
1. 
Participant has uncontrolled inter-current illness, including but not limited to:
 Active infection (includes infection requiring treatment with antimicrobial therapy
[participants will be required to complete antibiotics 1 week prior to study
treatment] or diagnosed or suspected viral infection)
 Human immunodeficiency virus-positive participants are eligible if they meet
all of the following:
o 
No detectable viral load (ie, <50 copies/mL) at screening
o 
CD4+ count >300 cells/mm3 at screening
o 
No acquired immunodeficiency syndrome (AIDS)-defining opportunistic
infection within 6 months of screening.
 Receiving highly active antiretroviral therapy (HAART). Any changes in
HAART due to resistance/progression should occur at least 3 months prior to
screening. A change in HAART due to toxicity is allowed up to 4 weeks prior
to screening.
Note: HAART that could interfere with study treatment is excluded (consult
the sponsor for a review of medications prior to enrollment).Poorly controlled
(persistent) hypertension: systolic blood pressure >180 mm Hg; diastolic
blood pressure >100 mm Hg,
o 
Uncontrolled diabetes
o 
Active bleeding diathesis
o 
Impaired oxygenation requiring continuous oxygen supplementation
o 
Refractory nausea and vomiting
o 
Chronic gastrointestinal diseases, inability to swallow the formulated
product, or previous significant bowel resection that would preclude
adequate absorption of study treatment
o 
Any ophthalmologic condition that is either clinically unstable or requires
treatment
o 
Psychiatric illness/social situation that would limit compliance with study
requirements.
o 
Any condition for which, in the opinion of the investigator, participation
would not be in the best interest of the participant (eg, compromise the
well-being) or that could prevent, limit, or confound the
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 Participant has at screening positive hepatitis B (hepatitis B virus [HBV]) surface
antigen (HbsAg)
Note:Participant with a prior history of HBV demonstrated by positive hepatitis B
core antibody are eligible if they have at Screening 1) a negative HbsAg and 2) a
HBV DNA (viral load) below the lower limit of quantification, per local testing.
Participants with a positive HbsAg due to recent vaccination are eligible if HBV
DNA (viral load) is below the lower limit of quantification, per local testing.
 Participant has at screening positive hepatitis C antibody (anti-HCV).
Note: Participants with a prior history of HCV, who have completed antiviral
treatment and have subsequently documented HCV RNA below the lower limit of
quantification per local testing are eligible.
 Other clinically active infectious liver disease.
2. 
Participant has active cardiovascular disease including, but not limited to:
 A medical history of deep vein thrombosis or pulmonary embolism within 1 month
prior to first dose of study drug or any of the following within 6 months prior to the
first dose of study drug: myocardial infarction, unstable angina, stroke, transient
ischemic attack, uncontrolled hypertension, or clinically significant cardiac
arrythmia. Clinically nonsignificant thrombosis, such as nonobstructive
catheter--associated clots, are not exclusionary.
 Prolonged QT interval corrected with Fridericia's formula (QTcF) >470 msec
 Congestive heart failure (CHF), defined as New York Heart Association (NYHA)
class III-IV or hospitalization for CHF (any NYHA class; refer to Appendix: New
York Heart Association Criteria) within 6 months of study Day 1. (Attachment 4)
3. 
Participant has a medical history of ILD, including drug-induced ILD or radiation
pneumonitis.
4. 
Prior treatment with antiPD-1 or antiPD-L1 antibody within 6 weeks of planned first
dose of study treatment or immune-mediated rash from checkpoint inhibitors that has
not resolved prior to enrollment.
5. 
Participant has symptomatic brain metastases. A participant with asymptomatic or
previously treated and stable brain metastases may participate in this study. Participants
who have completed definitive therapy, are not on steroids, and have a stable clinical
status for at least 2 weeks prior to study treatment are allowed. If brain metastases are
diagnosed on Screening imaging, the participant may be enrolled, or rescreened for
eligibility, after definitive treatment if above criteria are met.
6. 
Any toxicities from prior anticancer therapy must have resolved to CTCAE version 5.0
Grade 1 or baseline level (except for alopecia [any grade], Grade ≤2 peripheral
neuropathy, and Grade ≤2 hypothyroidism stable on hormone replacement therapy).

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7. 
Prior treatment with amivantamab or lazertinib.
8. 
8.1 
Criterion modified per Amendment-3
Contraindications, allergies, hypersensitivity, or intolerance to lazertinib, IV
amivantamab, dexamethasone, montelukast, methotrexate or their excipients.
9. 
An invasive operative procedure with entry into a body cavity or major surgery (eg,
requiring general anesthesia), other than placement of vascular access or percutaneous
tumor biopsy, within 4 weeks or without complete recovery before Cycle 1 Day 1.
Thoracentesis, if needed and/or clinically indicated, and percutaneous biopsy for tumor
tissue sample, if needed, may be done less than 4 weeks prior to Cycle 1 Day 1, as long
as the participant has adequately recovered from the procedure prior to the first dose of
study treatment in the clinical judgement of the investigator.
Concomitant Therapy
10. 
Disallowed therapies as noted in Section 6.9, Prior and Concomitant Therapy must be
discontinued at least 3 weeks or 5 half-lives, whichever is shorter, before the first dose
of study treatment. [See Section 6.9.1] for guidance on drugs that are prohibited and
required washout periods].
a. Participants who are taking systemic steroids, methotrexate, or montelukast for
other conditions are excluded (inhaled and/or nasal steroids are allowed),
regardless of cohort assignment.
Prior/Concurrent Clinical Study Experience
11. 
Received an investigational treatment (including investigational vaccines, but not
including anticancer therapy) or used an invasive investigational medical device within
6 weeks before the planned first dose of study treatment.
12. 
Participant with a significant genetic predisposition to venous thromboembolic events
(VTE, such as Factor V Leiden).
13. 
Participant with a prior history of VTE and who are not on appropriate therapeutic
anticoagulation as per the NCCN guidelines or local guidelines.
14. 
Participant previously enrolled in the Sponsor’s studies 73841937NSC3003
(NCT04487080) or 61186372NSC3002 (NCT04988295).
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening
and that the participant continues to meet criteria prior to dosing on Cycle 1 Day1. On Cycle 1
Day 1, the participant’s condition should be consistent with their baseline, and the participant
should have taken regular prescribed medication(s), unless instructed otherwise by the study
physician. If a participant's clinical status changes (including any available laboratory results or

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receipt of additional medical records) after screening but before the first dose of study treatment
is given such that the participant no longer meets all eligibility criteria, supportive treatment may
be administered, if necessary, so that eligibility criteria can be met and laboratory test(s) may be
repeated once, to determine if the participant qualifies for the study, if there is no interference with
the time between prophylactic treatment and Cycle 1 Day 1. If enrollment criteria are not met after
further evaluation, then the participant should be excluded from participation in the study. The
required source documentation to support meeting the enrollment criteria are noted in Appendix 3:
Regulatory, Ethical, and Study Oversight Considerations.
5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the study to be eligible for participation:
1. 
Refer to Section 6.9, Prior and Concomitant Therapy for details regarding prohibited
and restricted therapy during the study.
2. 
Agree to follow all requirements that must be met during the study as noted in the
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
5.4. 
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a screening and enrollment log to permit easy identification
of each participant during and after the study. This document will be reviewed by the sponsor
study site contact for completeness.
The screening and enrollment log will be treated as confidential and will be filed by the investigator
in the study file. To ensure participant confidentiality, no copies will be made. All reports and
communications relating to the study will identify participants by participant identification and
age at initial informed consent. In cases where the participant is not enrolled into the study, the
date seen and age at initial informed consent will be used. Participants who are determined to be
eligible for the study due to changes in their condition after initially failing screening must sign a
new ICF. Rescreening must be discussed with and approved by the Sponsor's medical monitor on
a case-by-case basis.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened. Participants who are rescreened will be assigned a new participant number.

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6. 
STUDY TREATMENT AND CONCOMITANT THERAPY
6.1. 
Study Treatment(s) Administered
Designation 
Product
Investigational Medicinal Product(s) 
Dexamethasone
Montelukast
Methotrexate
Lazertinib
Amivantamab
Authorization status in the EU/EEA:
Authorized 
Dexamethasone
Montelukast
Methotrexate
Amivantamab
Unauthorized 
Lazertinib
The authorized IMPs will not be used in accordance with the
terms of their marketing authorization.
Auxiliary Medicinal Product(s)
(AxMP)
None
Authorization status in the EU/EEA:
Authorized 
Not applicable
Unauthorized 
Not applicable
Study treatment administration must be captured in the source documents, and the case report form
(CRF). Investigational Study Materials (ISM) Dispensing, Accountability, and Reconciliation Log
The study treatments, dexamethasone, montelukast, and methotrexate, will be investigated prior
to administration of the background anti-cancer combination regimen of oral lazertinib plus IV
amivantamab to assess the incidence of IRRs.
Oral dexamethasone, montelukast, and methotrexate, will be provided under the responsibility of
the sponsor. Dexamethasone for injection will be locally sourced and not provided by the sponsor.
Refer to the product labeling for a list of excipients.
Background Anti-Cancer Regimen
Oral lazertinib and IV amivantamab, will be manufactured and provided under the responsibility
of the sponsor. Refer to the IB for a list of excipients. The combination of IV amivantamab plus
oral lazertinib is currently being evaluated in two ongoing phase 3 studies, and additional phase
1/2 studies.

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Status: Approved, Date: 21 August 2023
For a definition of oral lazertinib and IV amivantamab overdose, refer to Section 6.8, Treatment
of Overdose.
A missed dose is defined as failure to administer IV amivantamab within 1 day of the scheduled
dosing date in Cycles 1 (except C1D1) and 2, or failure to administer IV amivantamab within 3
days of the scheduled dosing date in Cycle 3 and beyond. If a dose is missed, as defined above, it
will not be made up. Administration may resume at the next planned dosing date. If the first dose
in Cycle 2 is delayed, then the dates of all subsequent doses must be maintained as originally
scheduled based on Cycle 1 Day 1. All other assessments in SoA should be performed relative to
actual IV amivantamab administration, not on the originally scheduled administration day.

JNJ-61186372 (amivantamab)    
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Status: Approved, Date: 21 August 2023
Group/Arm Name 
Dexamethasone (Cohort
A)
Dexamethasone
(Cohort A2)
Montelukast
(Cohort B)
Methotrexate
(Cohort C)
Lazertinib
(Cohorts A, A2, B,
and C)
IV Amivantamab
(Cohorts A, A2, B,
and C)
Treatment Name 
Dexamethasone Study 
Treatment 
Dexamethasone 
Study 
Treatment 
Montelukast  
Study 
Treatment 
Methotrexate  
Study 
Treatment 
Lazertinib 
Background Anti- 
Cancer Regimen 
IV Amivantamab
Background Anti-
Cancer Regimen
Type 
Drug 
Drug 
Drug 
Drug 
Drug 
Drug
Dose Formulation 
Tablet 
Tablet 
Tablet 
Vial 
Tablet 
Vial
Unit Dose Strength(s) 
4 mg per tablet 
4 mg per tablet 
10 mg per tablet 
25 mg/mL 
2mL/vial and 10 
mg/mL 
5 mL/vial 
80 mg per tablet 
350 mg/vial with
concentration
50 mg/mL in a 7 mL
vial.

JNJ-61186372 (amivantamab)    
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Status: Approved, Date: 21 August 2023
Group/Arm Name 
Dexamethasone (Cohort
A)
Dexamethasone
(Cohort A2)
Montelukast
(Cohort B)
Methotrexate
(Cohort C)
Lazertinib
(Cohorts A, A2, B,
and C)
IV Amivantamab
(Cohorts A, A2, B,
and C)
Dosage Level(s) 
4 mg oral twice a day (8 
mg total daily dose) on 
Cycle 1 
Day -1. May be taken 
without regard to food or 
meals. 
8 mg oral twice a 
day (16 mg total 
daily dose) on 
Cycle 1 
Day -2 and -1, 
and 8 mg 
approximately1 
hour prior to the 
start of the 
infusion of IV 
amivantamab on 
Cycle 1 Day 1. 
May be taken 
without regard to 
food or meals. 
10 mg oral in the 
morning on days 
-4, -3, -2, -1 and 
C1D1 (5 doses 
total). may be 
taken without 
regard to food or 
meals. 
2mL/vial 
1 mL/25mg or 
5mL vials, 
1mL/10mg 
subcutaneous, 
single-dose, 
between D-7 and 
D-3 before Cycle
1. 
Oral 240 mg once 
daily  
1050 mg (for
participants <80 kg) or
1400 mg (for
participants ≥80 kg)
once weekly for 4
weeks, then every
2 weeks thereafter.
Initial dose of IV
amivantamab (Cycle 1,
Days 1 and 2), is
administered as a split
dose over 2 days (eg,
Cycle 1 Day 1
[350 mg] and Cycle 1
Day 2 [remainder of
dose]).
Based on positive study
results in Stages 1 and
2, full dose may be
administered on Cycle
1 Day 1 in expansion
phase after consultation
with the sponsor.
Route of Administration Oral 
Oral 
Oral 
SC Injection  
Oral 
IV infusion diluted to
final volume of 250
mL in 5% dextrose or
0.9% sodium chloride
Use 
Experimental 
Experimental 
Experimental 
Experimental 
Background 
treatment
Background treatment
Investigational 
Medicinal Product
(IMP)
Yes 
Yes 
Yes 
Yes 
Yes 
Yes

JNJ-61186372 (amivantamab)    
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Status: Approved, Date: 21 August 2023
Group/Arm Name 
Dexamethasone (Cohort
A)
Dexamethasone
(Cohort A2)
Montelukast
(Cohort B)
Methotrexate
(Cohort C)
Lazertinib
(Cohorts A, A2, B,
and C)
IV Amivantamab
(Cohorts A, A2, B,
and C)
Non-Investigational 
Medicinal
Product/Auxiliary
Medicinal Product
(NIMP/AxMP)
IMP  
IMP  
IMP  
IMP  
IMP  
IMP
Sourcing 
depending on regional 
requirements, 
dexamethasone may be 
sourced centrally or 
locally  
depending on 
regional 
requirements, 
dexamethasone
may be sourced
centrally or
locally
Provided 
centrally by the 
Sponsor 
Provided 
centrally by the 
Sponsor
Provided centrally
by the Sponsor
Provided centrally by
the Sponsor
Packaging and Labeling
(Labels will contain
information to meet the
applicable regulatory
requirements.)
Bulk. 4 mg tablets 
Not Child resistant
Bulk. 4 mg 
tablets 
Not Child
resistant
Bulk. 10 mg 
tablets
Not Child
resistant
Bulk. 2mL/vial.
Or
Bulk. 5mL/vial.
Not Child
resistant
Bulk. 80 mg tablets
Not Child resistant
Bulk. 350 mg/vial with
concentration
50 mg/mL in a 7 mL
vial.
Not Child resistant
Delivery Instructions 
Do not crush tablets 
Do not crush
tablets
Do not crush
tablets
2mL/vial.
Administer
1mL/25mg SC in
the abdomen or
the thigh.
Or
5mL/vial:
Administer
1mL/10mg SC in
the abdomen or
thigh.
Do not crush
tablets
For IV administration.
Do not mix or dilute
with other drugs.
Required preinfusion
medications (a
corticosteroid, an
antihistamine, and an
antipyretic) must be
administered as
described in
Section 1.3

JNJ-61186372 (amivantamab)    
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Status: Approved, Date: 21 August 2023
Group/Arm Name 
Dexamethasone (Cohort
A)
Dexamethasone
(Cohort A2)
Montelukast
(Cohort B)
Methotrexate
(Cohort C)
Lazertinib
(Cohorts A, A2, B,
and C)
IV Amivantamab
(Cohorts A, A2, B,
and C)
Food/Fasting
Requirement
May be taken without
regard to food or meals.
May be taken
without regard to
food or meals.
May be taken
without regard to
food or meals.
N/A  
May be taken
without regard to
food or meals.
N/A
Current/Former Name(s)
or Alias(es) (Not an all-
inclusive list of Former
or Alias names)
Decadron
(dexamethasone)
Decadron
(dexamethasone)
Singulair
(montelukast)
Rasuvo
(methotrexate)
Laclaza (lazertinib) 
Rybrevant (IV
amivantamab)

JNJ-61186372 (amivantamab)    
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Status: Approved, Date: 21 August 2023
Suggested Order of Administration in Cohort A
Medication 
Dose 
Route of 
Administration
Recommended Dosing Window
Study 
Treatment 
Dexamethasone 4 mg
twice a day (8 mg total
daily dose)
Oral 
1 day before the first amivantamab infusion in Cycle 1 
Glucocorticoid 
Days 1 and 2 of Cycle 1: 
Dexamethasone 10 mg
IV  
Start 60 90 minutes before amivantamab infusion
Antipyretic 
Paracetamol 
(acetaminophen) 650 to
1000 mg (or equivalent)*
IV or oral 
Start 15 30 minutes before amivantamab infusion
Antihistamine 
Diphenhydramine 25 mg 
or equivalent*
IV or oral
Background 
anti cancer 
treatment 
Lazertinib 240 mg 
Oral 
Lazertinib should be dosed no more than 15 minutes
before the start of each amivantamab infusion. Lazertinib
should be taken at approximately the same time each day,
approximately 24 hours apart, if possible
Background 
anti cancer 
treatment 
Amivantamab  
IV  
1050 mg (for participants <80 kg) or 1400 mg (for
participants ≥80 kg) once weekly for 4 weeks, then every
2 weeks thereafter.
Initial dose of IV amivantamab (Cycle 1, Days 1 and 2),
is administered as a split dose over 2 days (eg, Cycle 1
Day 1 [350 mg] and Cycle 1 Day 2 [remainder of dose]).
Based on positive study results in Stages 1 and 2, full
dose may be administered on Cycle 1 Day 1 in
expansion phase after consultation with the sponsor.
*required premedication for amivantamab
Suggested Order of Administration in Cohort A2
Medication 
Dose 
Route of 
Administration
Recommended Dosing Window
Study 
Treatment 
Dexamethasone 8 mg 
twice a day (16 mg total
daily dose) on Cycle 1 
Days 2 and 1 and 8 mg 
approximately one hour
prior to start of the
infusion of IV
amivantamab on Cycle 1
Day 1
Oral 
2 days before the first amivantamab infusion in Cycle 1
C1D1 oral dose 60 90 minutes before strat of first
amivantamab infusion
Glucocorticoid 
Days 1 and 2 of Cycle 1: 
Dexamethasone 10 mg
IV  
Start 60 90 minutes before amivantamab infusion
Antipyretic 
Paracetamol 
(acetaminophen) 650 to
1000 mg (or equivalent)*
IV or oral 
Start 15 30 minutes before amivantamab infusion
Antihistamine 
Diphenhydramine 25 mg 
or equivalent*
IV or oral
Background 
anti cancer 
treatment 
Lazertinib 240 mg 
Oral 
Lazertinib should be dosed no more than 15 minutes
before the start of each amivantamab infusion. Lazertinib
should be taken at approximately the same time each day,
approximately 24 hours apart, if possible
Background 
anti cancer 
treatment 
Amivantamab  
IV  
1050 mg (for participants <80 kg) or 1400 mg (for
participants ≥80 kg) once weekly for 4 weeks, then every
2 weeks thereafter.
Initial dose of IV amivantamab (Cycle 1, Days 1 and 2),
is administered as a split dose over 2 days (eg, Cycle 1
Day 1 [350 mg] and Cycle 1 Day 2 [remainder of dose]).

JNJ-61186372 (amivantamab)    
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Status: Approved, Date: 21 August 2023
Based on positive study results in Stages 1 and 2, full
dose may be administered on Cycle 1 Day 1 in
expansion phase after consultation with the sponsor.
Suggested Order of Administration in Cohort B
Medication 
Dose 
Route of 
Administration
Recommended Dosing Window
Study 
Treatment 
Montelukast 10 mg 
Oral 
Montelukast taken in the morning on
days -4, -3, -2, -1 and C1D1 (5 doses total).
Montelukast should be taken at approximately the
same time each day, approximately 24 hours apart,
if possible
Glucocorticoid Days 1 and 2 of Cycle 
1: Dexamethasone 10
mg
IV  
Start 60-90 minutes before amivantamab infusion
Antipyretic 
Paracetamol 
(acetaminophen) 650
to 1000 mg (or
equivalent)*
IV or oral 
Start 15-30 minutes before amivantamab infusion
Antihistamine 
Diphenhydramine 25 
mg or equivalent*
IV or oral
Background 
anti-cancer 
treatment 
Lazertinib 240 mg 
Oral 
Lazertinib should be dosed no more than 15 minutes
before the start of each amivantamab infusion.
Lazertinib should be taken at approximately the
same time each day, approximately 24 hours apart,
if possible
Background 
anti-cancer 
treatment 
Amivantamab 
IV  
1050 mg (for participants <80 kg) or 1400 mg (for
participants ≥80 kg) once weekly for 4 weeks, then
every 2 weeks thereafter.
Initial dose of IV amivantamab (Cycle 1, Days 1 and
2), is administered as a split dose over 2 days (eg,
Cycle 1 Day 1 [350 mg] and Cycle 1 Day 2
[remainder of dose]).
Based on positive study results in Stages 1 and 2,
full dose may be administered on Cycle 1 Day 1 in
expansion phase after consultation with the
sponsor.
*required premedication for amivantamab
Suggested Order of Administration in Cohort C
Medication 
Dose 
Route of 
Administration
Recommended Dosing Window
Study treatment 
Methotrexate 25 mg 
SC 
Single dose on any day between
Days 7 and Day 3 (Cycle 1) prior to oral Lazertinib and
IV amivantamab combination therapy.
Glucocorticoid 
Days 1 and 2 of Cycle 1: 
Dexamethasone 10 mg
IV  
Start 60 90 minutes before amivantamab infusion
Antipyretic 
Paracetamol 
(acetaminophen) 650650
to 1000 mg (or
equivalent)*
IV or oral 
Start 15 30 minutes before amivantamab infusion
Antihistamine 
Diphenhydramine 25 mg 
or equivalent*
IV

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Status: Approved, Date: 21 August 2023
*required premedication for amivantamab
6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study treatments (dexamethasone, montelukast, methotrexate) and background anticancer
therapy (oral lazertinib, and IV amivantamab) must be stored at controlled temperatures according
to the requirements on the drug product label and protected from light prior to use.
Refer to the Site Investigational Product Procedures Manual (SIPPM) for additional guidance on
dexamethasone, montelukast, methotrexate, lazertinib, and IV amivantamab preparation, handling,
and storage.
Accountability
The investigator is responsible for ensuring that all dexamethasone, montelukast, methotrexate,
lazertinib, and IV amivantamab received at the site is inventoried and accounted for throughout
the study. The dexamethasone, montelukast, methotrexate, lazertinib, and IV amivantamab
administered to the participant must be documented on the Investigational Study Materials (ISM)
Dispensing, Accountability, and Reconciliation Log. All dexamethasone, montelukast,
methotrexate, lazertinib, and IV amivantamab  will be stored and disposed of according to the
SIPPM. Study  site personnel must not combine contents of the dexamethasone, montelukast,
methotrexate, lazertinib, and IV amivantamab containers.
Dexamethasone, montelukast, methotrexate, lazertinib, and IV amivantamab must be handled in
strict accordance with the protocol and the container label and must be stored at the study site in a
limited-access area or in a locked cabinet under appropriate environmental conditions. Unused
dexamethasone, montelukast, methotrexate, lazertinib, and IV amivantamab must be available for
verification by the sponsor's study site monitor during on-site monitoring visits. The return to the
sponsor of unused dexamethasone, montelukast, methotrexate, lazertinib, and IV amivantamab,
will be documented on the treatment return form. When the study site is an authorized destruction
unit and dexamethasone, montelukast, methotrexate, lazertinib, and IV amivantamab supplies are
destroyed on-site, this must also be documented on the treatment return form.
Background 
anti cancer
treatment 
Lazertinib 240 mg 
Oral 
Lazertinib should be dosed no more than 15 minutes
before the start of each amivantamab infusion. Lazertinib
should be taken at approximately the same time each day,
approximately 24 hours apart, if possible
Background
anti cancer
treatment
Amivantamab  
IV  
1050 mg (for participants <80 kg) or 1400 mg (for
participants ≥80 kg) once weekly for 4 weeks, then every
2 weeks thereafter.
Initial dose of IV amivantamab (Cycle 1, Days 1 and 2),
is administered as a split dose over 2 days (eg, Cycle 1
Day 1 [350 mg] and Cycle 1 Day 2 [remainder of dose]).
Based on positive study results in Stages 1 and 2,
full dose may be administered on Cycle 1 Day 1 in
expansion phase after consultation with the
sponsor.

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Status: Approved, Date: 21 August 2023
Potentially hazardous materials containing hazardous liquids, such as used ampules, needles,
syringes and vials, must be disposed of immediately in a safe manner and therefore will not be
retained for treatment accountability purposes.
Dexamethasone, montelukast, methotrexate, lazertinib, and IV amivantamab should be dispensed
under the supervision of the investigator or a qualified member of the study site personnel, or by
a hospital/clinic pharmacist. Dexamethasone, montelukast, methotrexate, lazertinib, and IV
amivantamab will be supplied only to participants participating in the study. Returned
dexamethasone, montelukast, methotrexate, lazertinib, and IV amivantamab must not be dispensed
again, even to the same participant. Dexamethasone, montelukast, methotrexate, lazertinib, and IV
amivantamab may not be relabeled or reassigned for use by other participants. The investigator
agrees neither to dispense the dexamethasone, montelukast, methotrexate, lazertinib, and IV
amivantamab from, nor store it at, any site other than the study sites agreed upon with the sponsor.
Further guidance and information for the final disposition of unused dexamethasone, montelukast,
methotrexate, lazertinib, and IV amivantamab are provided in the SIPPM.
6.3. 
Assignment to Study Intervention
Treatment Allocation
Procedures for Randomization
Not Applicable
6.4. 
Blinding, Masking
As this is an open-label study, blinding procedures are not applicable.
6.5. 
Treatment Compliance
The study personnel at the study site will account for all dexamethasone, montelukast,
methotrexate, dispensed and for appropriate return or destruction, if approved by the sponsor. The
certificates of delivery, return, and/or destruction should be signed and filed in the Investigator
Site File.
Dexamethasone, montelukast, methotrexate, are to be prescribed only by the principal investigator
or a qualified physician listed as a sub investigator. Dexamethasone, montelukast, methotrexate,
may not be used for any purpose other than that outlined in this protocol, including other human
studies, animal investigations, or in vitro testing. Methotrexate will be administered as a single
dose of 25 mg SC between Day -7 and Day -3 (Cycle 1) prior to oral lazertinib and IV
amivantamab  combination therapy by qualified study site personnel and the details of
administration will be recorded in the electronic case report form (eCRF) (including date, start,
and stop times of the participant visit and volume administered). Dispensing of all dexamethasone,
montelukast, methotrexate, must also be recorded in the participant’s source documents.

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Status: Approved, Date: 21 August 2023
6.5.1. IV Amivantamab and Oral Lazertinib Treatment Compliance
The study personnel at the study site will account for all oral lazertinib and IV amivantamab
dispensed and for appropriate return or destruction, if approved by the sponsor. The certificates of
delivery, return, and/or destruction should be signed and filed in the Investigator Site File.
Oral lazertinib and IV amivantamab are to be prescribed only by the principal investigator or a
qualified physician listed as a subinvestigator. Oral lazertinib, and IV amivantamab may not be
used for any purpose other than that outlined in this protocol, including other human studies,
animal investigations, or in vitro testing. IV amivantamab will be administered as an IV infusion
by qualified study site personnel and the details of each administration will be recorded in the
electronic case report form (eCRF) (including date, start, and stop times of the IV infusion and
volume infused). Dispensing of all oral lazertinib, and IV amivantamab must also be recorded in
the participant’s source documents.
Administration of pre-infusion medications will be documented in the source documents and
eCRF.
6.6. 
Dose Modification
Dose modifications are not allowed for study treatments dexamethasone, montelukast or
methotrexate,
Adverse Events of Clinical Interest
Dexamethasone
Not Applicable.
Montelukast
The safety risk information is based on prolonged use ofmontelukast, and the safety profile of a
limited administration as described in this protocol has not been established. Neuropsychiatric
events have been reported in participants receiving montelukast. These events have been noted in
adults, teenagers, and younger participants, and include among others: anxiety, depression,
aggressiveness, agitation, attention, and memory impairment, sleeping disorders (insomnia,
somnambulism, dream anomalies), seizures, paresthesia, hypoesthesia, as well as suicidal thoughts
and behavior. (Farah 2018)
Methotrexate
Participants should be monitored for bone marrow, liver, lung and kidney toxicities as described
in the Schedule of Assessments following the single dose of methotrexate.
Any dose/dosage adjustment for IV amivantamab or oral lazertinib should be overseen by
medically qualified study site personnel (principal or sub investigator unless an immediate safety
risk appears to be present).

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Status: Approved, Date: 21 August 2023
When dose modification is required, modification should occur as listed below. (Table 1)
If the experienced toxicity is felt to be attributable to either IV amivantamab or oral lazertinib, then
the dose of the responsible agent should be preferentially modified.
Table 1: 
Dose Modifications for Oral lazertinib and IV amivantamab
Combination dosing level 
Dose oforal lazertinib (mg) 
Dose ofIV amivantamab (mg) IV
(dose <80 kg/dose ≥80kg)
1 
240 
1050/1400
2 
160 
1050/1400
3 
160 
700/1050
4 
80 
700/1050
5 
Discontinue 
1050/1400
If holding of oral lazertinib or IV amivantamab is considered clinically indicated, the decision to
hold oral lazertinib or IV amivantamab dosing should be guided by the experienced toxicity and
the likelihood of either treatment contributing to the toxicity, based upon the safety profile of both
treatments (Refer to the respective IBs or consult with the Sponsor).
If both treatments are held, and are to be restarted, oral lazertinib should be restarted first and
dosed for approximately 7 days prior to the next infusion of IV amivantamab.
Treatment of Infusion-related Reactions
Participants who experience early symptoms of IRRs, manifesting as, but not limited to, chills,
nausea, dyspnea, flushing, chest discomfort, vomiting, or any other symptoms during the time of
the infusion, should have their infusions interrupted, if indicated, and the symptoms managed
according to the recommendations provided in Table 2. With the initial dose of IV amivantamab
(Cycle 1, Days 1 and 2), interruption of the infusion should be considered even with mild
symptoms to prevent more severe manifestations of IRR. All NCI-CTCAE Grade 3 or 4
infusion-related reactions should be reported within 24 hours to the Sponsor.
Table 2: 
Management of Infusion-related Reactions
Toxicity Grade* 
Treatment 
Premedication at all
subsequent dosing
Grade 1 or 2
Grade 1: 
Mild reaction 
 Interrupt IV amivantamab infusion if IRR is 
suspected and monitor participant until 
reaction symptoms resolve.
 Resume the infusion at 50% of the infusion 
rate at which the reaction occurred. 
 If there are no additional symptoms after
30 minutes, the infusion rate may be 
escalated. 
 Include corticosteroid with premedications 
for subsequent dose.
Antihistamine, antipyretic,
and glucocorticoid
Grade 2: 
Mild to moderate reaction; 
therapy or infusion interrupted 
but responds promptly to 
symptomatic treatment 
Antihistamine, antipyretic,
and glucocorticoid
Consider 
meperidine 
if
participant 
experiences
chills and rigors.
Grade 3 
Severe reaction 
Grade 3: prolonged (ie, not 
rapidly responsive to 
Based 
on 
severity 
of
symptoms, 
consider
permanent discontinuation
of 
IV 
amivantamab.
Discussion with Sponsor

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Status: Approved, Date: 21 August 2023
Toxicity Grade* 
Treatment 
Premedication at all
subsequent dosing
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates) 
 Interrupt IV amivantamab infusion and 
administer supportive care medications. 
Monitor participant until reaction symptoms
resolve.
 Resume the infusion at 50% of the infusion
rate at which the reaction occurred.
 If there are no additional symptoms after
30 minutes, the infusion rate may be
escalated.
 Include corticosteroid with premedications
for subsequent dose. For recurrent Grade 3,
permanently discontinue IV amivantamab.
required before continuing
with subsequent dosing.
Grade 4: life-threatening; 
pressor or ventilator support
indicated
Permanently discontinue IV amivantamab
General 
Prophylactic medications (after initial event)
may be used as described in the IV amivantamab
product label. Appropriate personnel and
appropriate resuscitation equipment should be
available in or near the infusion room and a
physician should be readily available during the
infusion of IV amivantamab
*Per NCI CTCAE Version 4.03
6.6.1. Infusion-related Reactions
Infusion-related reactions have been observed during treatment with other monoclonal anti-EGFR
antibodies. The severity of infusion reactions has been variable. Refer to Summary of Data and
Guidance for Investigators in the current version of the IV amivantamab Investigator’s Brochure.
Signs and symptoms of IRR include chills, dyspnea, flushing, nausea, chest discomfort, vomiting,
tachycardia, hypotension, and fever.
During the IV  amivantamab infusion, participants should be clinically monitored at regular
intervals (including an assessment prior to the start of infusion). The monitoring should include
heart rate, blood pressure, temperature, respiratory rate, and oxygen saturation measurements.
Participants must remain at the infusion center for monitoring for at least 2 hours after the end of
the first dose of IV amivantamab (Cycle 1 Day 1), and at least 1 hour after Cycle 1 Day 2, after
which time, vital signs should be obtained (See SOA).
Participants should be closely monitored for early signs and symptoms indicative of an acute
infusion reaction. If clinically indicated, even with mild symptoms, the IV amivantamab infusion
should be interrupted immediately, as described in Table 2. Trained clinical personnel should be
prepared to intervene in the event of infusion-related reactions. Resources necessary for
resuscitation (ie, agents such as epinephrine, aerosolized bronchodilator, IV antihistamines, IV
corticosteroids; medical equipment such as oxygen, airway management equipment including
suction, and a defibrillator) should be readily available.

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Pre-infusion Medications for IV amivantamab
Required pre-infusion medications (a corticosteroid, an antihistamine, and an antipyretic) must be
administered as described in Section 6.1 (Suggested Order of Administration) and Section 1.3
(Schedule of Activities).
6.6.2. Liver Chemistry Abnormalities
Liver chemistry stopping criteria have been established to provide safety to the participants and to
better assess the etiology of a liver event during the development of new investigational products.
Liver chemistry should be monitored as part of serum chemistry laboratory tests according to the
Schedule of Activities (Section 1.3) and Appendix 2: Clinical Laboratory Test. The liver chemistry
stopping criteria include any of the following:
1. ALT or AST ≥3×ULN (if baseline was normal; ≥3×baseline if baseline was abnormal) and
bilirubin ≥2×ULN (if baseline was normal; ≥2 x baseline if baseline was abnormal) (>35%
direct bilirubin) (AST or ALT ≥3×ULN [if baseline was normal; ≥3×baseline if baseline was
abnormal] and INR >1.5, if INR measured).
a) Exception to the bilirubin elevation is made if the participant has Gilbert’s disease and the
elevated bilirubin is predominantly unconjugated.
b) This event, if confirmed upon repeat, should be reported as an SAE.
2. ALT or AST 5×ULN (if baseline was normal; ≥5×baseline if baseline was abnormal) for
2 weeks or ALT or AST >8×ULN (if baseline was normal; ≥8×baseline if baseline was
abnormal).
3. ALT or AST ≥3×ULN (if baseline was normal; ≥3×baseline if baseline was abnormal) if
associated with the appearance or worsening of symptoms of liver injury, hepatitis or
hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness,
fever, rash, or eosinophilia.
4. Persistent elevation of ALT or AST ≥3×ULN (ifbaseline was normal; ≥3×baseline if baseline
was abnormal) for ≥4 weeks. The sponsor’s medical monitor should be consulted for
participants with baseline ALT and/or AST near 3×ULN (if baseline was normal; ≥3×baseline
if baseline was abnormal).
Liver chemistry should be repeated within 1 to 3 days. If any of the chemistry stopping criteria are
confirmed upon repeat, then assessments listed below should be conducted. If no alternative
etiology of liver toxicity is identified, oral lazertinib and IV amivantamab treatment should be
permanently discontinued.
Liver Event Follow-up Requirements
The following follow-up assessments should be conducted for any participant meeting liver
chemistry stopping criteria:
 Monitor liver chemistries (ALT, AST, ALP, bilirubin, and INR), creatinine phosphokinase,
and lactate dehydrogenase, 1 to 2 times per week until resolution, stabilization, or return to
participant’s baseline values.

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 Monitor clinical condition closely.
 Record use of concomitant medications, acetaminophen, herbal remedies, other
over-the-counter medications, or known hepatotoxins.
 Record alcohol use in the eCRF.
 Check the viral hepatitis serology as appropriate and include:
 Hepatitis A immunoglobulin M (IgM) antibody
 Hepatitis B surface antigen and Hepatitis B core antibody (IgM)
 Hepatitis C ribonucleic acid (RNA)
 Hepatitis E IgM antibody
 Cytomegalovirus IgM antibody
 Epstein-Barr viral capsid antigen IgM antibody (or equivalent test)
 Assess antinuclear antibody, anti-smooth muscle antibody, and type 1 anti-liver kidney
microsomal antibodies.
 Conduct liver imaging (ultrasound, magnetic resonance imaging [MRI], or computerized
tomography [CT]) to evaluate liver disease.
 Refer to a specialist as appropriate.
Resumption of oral lazertinib and IV amivantamab administration may be considered if the
following criteria are met:
 Drug-related hepatotoxicity has been excluded.
 A reversible underlying cause not associated with oral lazertinib and IV amivantamab (eg,
alcohol use or concomitant medication) is clearly identified and agreed upon in consultation
with sponsor’s medical monitor.
 Liver chemistry abnormalities have resolved, or values have returned to baseline.
6.6.3. Rash-related Adverse Events
The prevention and management of EGFR inhibitor-induced rash-related TEAEs can be conducted
in accordance with local institutional guidelines, or according to the recommendations below. For
participants receiving oral lazertinib  and IV  amivantamab  combination, more proactive
management of rash is warranted, given the anticipated synergistic anti-EGFR activity.
Prophylaxis Recommendations
The prophylactic regimen can be managed according to local practice and guidelines; however,
these should include the following:
 Avoid exposure to sunlight.
 Wear protective clothing (including hat, sunglasses, etc.).

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 Use broad-spectrum sunscreen with an SPF of≥30 and reapply as necessary. UVA light can
penetrate glass; therefore, sunscreen should also be worn indoors and in vehicles if exposed
to direct sunlight. Recommended active sunscreen ingredients are zinc oxide and/or titanium
dioxide.
 Apply alcohol-free emollient cream or ointments (eg, glycerin, cetomacrogol, or ceramide-
based cream) or skin moisturizer on dry areas of the body. These topical agents can be
applied on a daily basis starting on Day 1, and more often as needed. Ideal time for application
is after bathing. Creams and ointments are preferred over gels, lotions and oils.
 Alcohol-based (eg, gel formulations) topical agents such as steroids, antibiotics, or hand
sanitizers can dry the skin and should be avoided.
 In addition, for combination therapy, a more proactive approach is recommended, given
the anticipated increase in anti-EGFR activity:
 These participants should have prescriptions (preferably already filled) for topical
antibiotics, oral antibiotics, and topical steroids at the time of initial dosing, to minimize
any delay in reactive management once rash is observed.
 Strongly consider initiating antibiotic therapy on Cycle 1 Day 1 and continuing antibiotic
therapy for the first 8 weeks: either a topical antibiotic (clindamycin, mupirocin, or
fusidic acid) on sun-exposed skin, or an oral antibiotic (such as doxycycline 100 mg once
daily, minocycline 100 mg once daily, or cephalexin 500 mg once daily).
 A topical corticosteroid of medium to low potency twice daily on the face and chest (such
as alclometasone 0.05% or desonide 0.05% cream) may also be considered.
Reactive Management Recommendations
It is strongly recommended that participants who develop rash/skin toxicities receive evaluations
for management on the specific adverse event.
 Consider consultation with a dermatologist, especially if the rash is Grade 3, atypical in
appearance or distribution, or does not improve within 2 weeks (for Grade 2 rash).
 Initiate a topical corticosteroid (cream or ointment) twice daily.
 Examples to use for face: betamethasone valerate 0.05%, hydrocortisone valerate 0.2%
or desonide 0.05%
 Examples to use for body: betamethasone valerate 0.1%, triamcinolone acetonide 0.1%
 If not already initiated for prophylaxis, initiate systemic antibiotic (such as doxycycline
100 mg twice daily, minocycline 100 mg twice daily, or cephalexin 500 mg twice daily), or
increase the dosing if already administered.
 If an associated skin infection is suspected, obtain bacterial and fungal cultures followed by
adjustment of antibiotic or antifungal therapy, based upon culture and susceptibility
determination.
 For reactive management of pruritic lesions, refer to the following recommendations:

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Reactive Management Recommendations for Pruritic Lesions:
Grade 1 pruritus:
 Apply topical low to moderate strength steroid cream (eg, hydrocortisone 2.5%, desonide
0.05%, or betamethasone valerate 0.05%), topical calcineurin inhibitor (eg, tacrolimus or
pimecrolimus), or topical antipruritic containing numbing agent (eg, pramoxine) and menthol.
Grade 2 pruritus:
 Apply topical moderate to high strength steroid cream (eg, betamethasone valerate 0.1%,
triamcinolone acetate 0.1%) or topical antipruritic containing numbing agent (eg, pramoxine)
and menthol.
 Initiate an oral antipruritic (eg, cetirizine, fexofenadine, rupatadine, bilastine) one dose twice
daily. If still pruritic after 2-5 days, may increase to double dose twice daily.
Grade 3 pruritus:
 Initiate an oral antipruritic (as above for Grade 2 pruritus).
 Initiate oral pregabalin or gabapentin.
 Initiate an oral corticosteroid (eg, prednisone 0.5-1.0 mg/kg/day or equivalent for 5 days).
 For skin fissures, use of Monsel’s solution (ferric subsulfate solution), silver nitrate, or zinc
oxide cream is recommended.
 For xerosis, fragrance-free moisturizing creams or sprays are recommended.
 For desquamation, emollients and mild soap are recommended.
 After the rash is controlled, consider gradually tapering the antibiotic.
A suggested algorithm for stepwise management of rash is provided in Table 3.

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Table 3: 
Suggested Algorithm for Management of Rash
Gradea 
Management 
Dose Adjustmentb,c
1 
 
Initiate reactive management as above 
 
Reassess after 2 weeks 
 
Continue current dose(s) of oral
lazertinib and IV amivantamab
2 
 
Initiate reactive management as above 
 
Reassess after 2 weeks 
 
Initiate supportive care management.
 
Reassess after 2 weeks; if rash does not
improve, consider [IV amivantamab]
dose reduction.
3 
 
Initiate reactive management as above
 
Start moderate strength topical corticosteroidsd
and systemic antibiotics as above, plus
systemic prednisone (0.5 mg/kg) for 7 days
 
Consider low doses of acitretin or isotretinoin
(20 30 mg/day)
 
Reassess after 2 weeks
 
Consider dermatology consultation and
manage rash per recommendation
 
Withhold oral lazertinib and IV
amivantamab and initiate supportive
care management.
 
Upon recovery to ≤ Grade 2, resume IV
amivantamab at reduced dose.
 
After consultation with the Medical
Monitor may restart oral lazertinib at
current dose level or consider dose
reduction of oral lazertinib
 
If no improvement within 2 weeks,
permanently discontinue treatment
4 
 
Initiate reactive management as above 
 
Start moderate strength topical corticosteroidsd 
and systemic antibiotics as above, plus 
systemic prednisone (0.5 mg/kg) for 7 days 
 
Consider low doses of acitretin or isotretinoin 
(20 30 mg/day)
 
Reassess after 2 weeks
 
Consider dermatology consultation and
manage rash per recommendation
 
Permanently 
discontinue 
IV
amivantamab and hold oral lazertinib.
 
Consider restarting oral lazertinib per
investigator assessment of causality,
once resolved.
Severe bullous, 
blistering, or 
exfoliating skin
conditions including 
toxic epidermal 
necrolysis (TEN) 
 
Consult dermatologist and manage rash per 
recommendation 
 
Permanently 
discontinue 
IV
amivantamab and hold oral lazertinib
 
Consider restarting oral lazertinib per
investigator assessment of causality,
once resolved
a. Grading per National Cancer Institute - Common Terminology Criteria for Adverse Events (Version 5.0).
b. IfIV amivantamab must be withheld due to toxicity for 2 consecutive doses, then oral lazertinib and IV
amivantamab cannot be restarted without consultation from the Medical Monitor. Participants considered by the
investigator and sponsor to be benefiting from treatment may be continued, potentially at a lower dose upon
satisfactory resolution of the toxicity.
c. Resolution defined as: ≤Grade 1 non-hematologic toxicity or back to baseline.
d. For example, hydrocortisone 2.5% cream or fluticasone propionate 0.5% cream.
Scalp Rash
A typical scalp rash and associated infection may develop over time with the use of EGFR
inhibitors. Treatment options include:
 A topical steroid shampoo (eg, clobetasol 0.05%), or an anti-dandruff shampoo with
anti-inflammatory, antibacterial, and antifungal properties (eg, ketoconazole, selenium sulfide
[Selsun®], zinc pyrithione [Head and Shoulders®], or Ciclopirox). These shampoos should
be used twice/week, massaging into scalp, leaving on for 2-5 minutes, and then rinsing.
 Application of a steroid lotion may also be effective (eg, betamethasone valerate 0.1% lotion,
mometasone furoate 0.1% lotion, or betamethasone dipropionate 0.05% lotion).

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 Initiation of a systemic antibiotic (eg, doxycycline 100 mg twice daily, minocycline 100 mg
twice daily) may also be used to treat acute scalp infection.
Of note, while wearing hats to avoid sun damage to the scalp is suggested in a prophylactic setting,
avoiding any headwear for a participant with established scalp rash is strongly recommended to
prevent further spread of the rash.
6.6.4. Pulmonary Toxicity
Participants with NSCLC are at risk of multiple adverse events affecting pulmonary function,
including disease progression, pulmonary embolus, infectious pneumonias, and more rarely, drug
related Interstitial lung disease (ILD)/pneumonitis. Participant respiratory status should be
assessed at every visit; any clinically significant change in respiratory status, including a change
in radiographic lung images, should prompt immediate investigation into the etiology in
accordance with local practice/guidelines to institute appropriate treatments and to rule out early
ILD/pneumonitis. If new or worsening pulmonary symptoms (eg, dyspnea) or radiological
abnormality suggestive of pulmonary adverse event is observed, including ILD/pneumonitis, oral
lazertinib and IV amivantamab should be withheld, and appropriate treatment management should
be promptly initiated.
Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a
potentially dangerous lesion, which may occur acutely at any time during therapy and has been
reported at low doses. It is not always fully reversible, and fatalities have been reported. Pulmonary
symptoms (especially a dry, nonproductive cough) may require interruption of treatment and
careful investigation.
Oral lazertinib and IV amivantamab can cause ILD/pneumonitis. Participants with a medical
history of ILD, drug induced ILD, radiation pneumonitis that required steroid treatment, or any
evidence of clinically active ILD have not been studied. As of June 2021, 2 fatal events of
pneumonitis have been reported in 351 (0.6%) participants treated with the combination of oral
lazertinib and IV amivantamab. Participants should be monitored for symptoms indicative of
ILD/pneumonitis (eg, dyspnea, cough, fever). If symptoms develop, interrupt treatment with
amivantamab pending evaluation of these symptoms for suspected ILD and initiate appropriate
treatment as necessary. Discontinue amivantamab in participants with confirmed ILD.
The following evaluations are recommended in order to exclude alternative etiologies such as
lymphangitic carcinomatosis, pulmonary embolism, infection, allergy, and cardiogenic edema:
 Detailed focused history reviewing respiratory status and exercise tolerance
 Focused physical examination, including full assessment of vital signs (with pulse oximetry)
 Unscheduled radiological assessment, including CT scan (high-resolution CT is preferred)
 Infectious evaluation, including blood and sputum cultures, atypical pneumonia panels, and
SARS-CoV-2 testing, if indicated
 Hematology and other laboratory tests, including serum albumin levels
 Referral to pulmonologist for evaluation, including bronchoscopy with biopsy, cell counts,
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 Evaluation of cardiac function, if indicated
Documentation of ILD/pneumonitis of any grade should prompt withholding treatment and
contacting the Medical Monitor. Pertinent radiological images and reports should be submitted to
the Sponsor. For symptomatic participants with pneumonitis (Grade 2 and above), treatment with
steroids should be initiated per local guidelines, in addition to withholding of oral lazertinib and
IV amivantamab. Oral lazertinib and IV amivantamab should be discontinued upon confirmation
of ILD/pneumonitis. In the absence of a diagnosis of ILD/pneumonitis, oral lazertinib and IV
amivantamab may be restarted.
6.6.5. Venous Thromboembolic Events
Participants with NSCLC are at risk of developing complications, including VTE events.
Investigators should closely monitor all participants receiving the combination of amivantamab
and lazertinib for signs and symptoms of VTE events, specifically pulmonary embolism and deep
vein thrombosis, throughout the duration of the study. Physical examinations (see Section 8.2.1)
should include focus on signs and symptoms of VTE events, including upper- or lower-extremity
swelling and discoloration. There should be a low threshold to perform additional diagnostic
testing (eg, CT angiogram or lower-extremity ultrasound) for VTE events beyond the scheduled
disease evaluations.
All study participants receiving the combination of amivantamab and lazertinib are recommended
to receive prophylactic-dose anticoagulation as per local guidelines during the first 4 months of
combination therapy. Vitamin K antagonists are not recommended due to numerous drug
interactions. The benefit-risk assessment for participants to tolerate prophylactic-dose
anticoagulation is at the discretion of the treating investigator. Notably, prophylactic-dose
anticoagulation has been found to be safe and effective in multiple prior studies (Carrier 2019,
Rutjes 2020).
If a VTE event is diagnosed, the participant should be treated with treatment-dose anticoagulation
as per local guidelines. Vitamin K antagonists are not recommended because of numerous drug
interactions. For VTE events associated with clinical instability (eg, respiratory failure or cardiac
dysfunction) in participants receiving the combination of amivantamab and lazertinib, study
treatment should be held until the participant recovers from the event. Thereafter, the treatment
can be resumed at the discretion of the investigator. In the case of a recurrent VTE whilst on
therapeutic anticoagulation therapy, the combination of amivantamab and lazertinib should be
permanently discontinued. Participants may continue to receive treatment with either
amivantamab or lazertinib (but not both) at the discretion of the treating investigator. For
participants that have experienced VTE, if symptoms persist or in case of worsening VTE, further
imaging studies (which may include doppler studies) should be performed to assess the resolution
of the event with corrective measures, as per the investigator’s discretion.
6.7. 
Continued Access to Lazertinib and IV Amivantamab After the End of the
Study
At the end of their participation in the study, participants who have completed the main part of the
study (Section 4.3 End of Study Definition) and are benefiting from the IV amivantamab and oral

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lazertinib, as determined by their investigator, will be able to receive continued access via post-
study independent requests from their investigators.
All serious adverse events that occur while the participant is receiving IV amivantamab and/or oral
lazertinib and within 30 days after the last dose of IV amivantamab and/or oral lazertinib or until
the start of subsequent anti-cancer therapy, if earlier, will be collected and reported to the sponsor.
Serious adverse events, including those spontaneously reported to the investigator within 30 days
after the last dose of oral lazertinib and IV amivantamab, must be reported. The sponsor will
evaluate any safety information that is spontaneously reported by an investigator beyond the time
frame specified in the protocol. Please refer to Section 8.3 for the details.
Pregnancy reporting should continue as described in Section 8.3.5.
In instances where the investigator feels a participant may continue to receive clinical benefit from
further treatment with IV amivantamab and oral lazertinib after documented disease progression
(eg, new CNS disease), the case must be discussed with the sponsor’s medical monitor, who in
conjunction with the investigator, will determine if treatment beyond RECIST v1.1 defined
progression is indicated. If the participant is treated beyond documented disease progression,
disease assessments will continue according to the schedule in Section 1.3, and the investigator
and sponsor medical monitor will review clinical benefit after each disease assessment.
6.8. 
Treatment of Overdose
In the event of an overdose of study treatment (dexamethasone, montelukast, methotrexate) or
background anticancer therapy (oral lazertinib and IV amivantamab), the investigator or treating
physician should:
 Contact the Medical Monitor immediately.
 Closely monitor the participant for AE/SAE and laboratory abnormalities.
 Document the quantity of the excess dose as well as the duration of the overdosing in the
eCRF.
Montelukast
No specific information is available on the treatment of overdosage with montelukast. In the event
of overdose, it is reasonable to employ the usual supportive measures, eg, remove unabsorbed
material from the gastrointestinal tract, employ clinical monitoring, and institute supportive
therapy, if required. It is not known whether montelukast is removed by peritoneal dialysis or
hemodialysis.
Methotrexate
Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently
administered overdosages of methotrexate. Leucovorin administration should begin as promptly
as possible. As the time interval between methotrexate administration and leucovorin initiation
increases, the effectiveness of leucovorin in counteracting toxicity decreases. Monitoring of the

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serum methotrexate concentration is essential in determining the optimal dose and duration of
treatment with leucovorin. In cases of massive overdosage, hydration and urinary alkalinization
may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal
tubules. Generally speaking, neither hemodialysis nor peritoneal dialysis has been shown to
improve methotrexate elimination. However, effective clearance of methotrexate has been
reported with acute, intermittent hemodialysis using a high-flux dialyzer (Wall 1996). In
postmarketing experience, overdose with methotrexate has generally occurred with oral and
intrathecal administration, although intravenous and intramuscular overdose have also been
reported.
IV Amivantamab and/or Oral Lazertinib
There are no data on overdose from studies of amivantamab or lazertinib (refer to IB for each
agent).
6.9. 
Prior and Concomitant Therapy
Pre-study therapies administered up to 28 days before first dose of oral lazertinib and IV
amivantamab must be recorded at screening.
Concomitant therapies must be recorded throughout the study beginning at screening and
continuing until 30 days after the last dose of oral lazertinib or IV amivantamab treatment, or until
the end of study visit (whichever is later), or until the start of a subsequent systemic anti-cancer
therapy, if earlier. Concomitant therapies should also be recorded beyond 30 days after the last
dose of oral lazertinib or IV amivantamab in conjunction with the following situations.
 Grade 3 or Grade 4 adverse events being followed per Section 8.3.1
 Adverse events reported after 30 days following the last dose of study drug, oral lazertinib or
IV amivantamab if considered related to study drug, oral lazertinib or IV amivantamab, the
sponsor must be notified.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special
diets, exercise regimens, or other specific categories of interest) different from the study treatment
must be recorded in the CRF.  Modification of an effective preexisting therapy should not be made
for the explicit purpose of entering a participant into the study.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
6.9.1. Prohibited or Restricted Concomitant Therapy/DRUG INTERACTIONS
Disallowed therapies must be discontinued at least 3 weeks or 5 half-lives, whichever is shorter,
before the first dose of study treatment (dexamethasone, montelukast or methotrexate).

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To avoid study bias, participants who are taking systemic steroids, methotrexate, or montelukast
for other conditions are excluded (inhaled and/or nasal steroids are allowed), regardless of cohort
assignment.
Methotrexate
Methotrexate is contraindicated in  pregnancy, alcoholism or liver disease, immunodeficiency
syndromes, preexisting blood dyscrasias, and hypersensitivity to methotrexate (MTX).
NSAIDs, salicylates, TMP, penicillin, warfarin, valproate, proton pump inhibitors, cyclosporin,
cisplatin increases the risk of MTX toxicity in the blood; aminoglycosides, neomycin, probenecid
reduces the absorption of MTX.
Drug Interactions:
 Aspirin, NSAIDs, and steroids: concomitant use may elevate and prolong serum methotrexate
levels and cause increased toxicity.
 Proton pump inhibitors: concomitant use may elevate and prolong serum methotrexate levels
and cause increased toxicity.
 Oral antibiotics
 Hepatotoxins
 Theophylline
 Folic acid and antifolates
 Mercaptopurine
 Nitrous oxide
The most significant and serious interactions are with NSAIDs and proton pump inhibitors (PPIs)
since these are very common therapeutic choices.
As methotrexate is highly plasma protein bound, any drug that displaces methotrexate from
proteins can increase its blood levels.

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Montelukast
Montelukast is contraindicated in participant with a history of hypersensitivity to the drug or its
components. For participants with phenylketonuria (PKU), caution should be exercised with
phenylalanine-containing formulations.
Oral lazertinib and IV amivantamab
Prohibited Medications and Therapies
The following concomitant medications and therapies are prohibited during the study. The Sponsor
must be notified in advance, or as soon as possible thereafter, of any instances in which prohibited
therapies were administered.
 Any chemotherapy, anti-cancer therapy (other than oral lazertinib and IV amivantamab), or
experimental therapy.
 Concomitant use of medications, herbal supplements and/or ingestions of foods with known
potent inducer effects on CYP3A4/A5 activity are prohibited and must have been discontinued
for an appropriate period before administration of lazertinib. Drugs that are potent inhibitors
of CYP3A4 activity are restricted and should be avoided, when possible, or used with caution.
Guidance on drugs that are prohibited, require close monitoring and washout periods is given
in Attachment 2.
Restricted Medications and Therapies
The following concomitant medications and therapies are restricted during the study and should
be avoided, when possible, or used with caution.
 Lazertinib is an inhibitor of P-glycoprotein (P-gp), multi-drug resistance protein 4 (MRP4),
Breast Cancer Resistance Protein (BCRP), and Organic Cation Transporter 1 (OCT1).
Therefore, concomitant administration of medications, herbal supplements and/or ingestions
of foods with that are substrates of P-gp, MRP4, BCRP, or OCT1 are not recommended and
if necessary, should be used with caution. A list of substrates of P-gp, MRP4, and BCRP is
provided in Attachment 3.
 Lazertinib has the potential for reversible and time dependent inhibition of CYP3A4.
Concomitant use of CYP34A substrate drugs should be avoided. If no other alternatives exist
monitor participants more closely for adverse reactions. Guidance on CYP3A4 substrates that
require close monitoring (Attachment 2 require close monitoring).

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7. 
DISCONTINUATION OF DEXAMETHASONE, MONTELUKAST,
METHOTREXATE, ORAL LAZERTINIB, AND IV AMIVANTAMAB AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Treatment (Dexamethasone, Montelukast or
Methotrexate)
A participant's dexamethasone, montelukast or methotrexate treatment must be discontinued if:
 The participant withdraws consent to receive dexamethasone, montelukast or methotrexate
 The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the
best interest of the participant to discontinue dexamethasone, montelukast or methotrexate
 The participant becomes pregnant (refer to Section 10.5, Appendix 5: Contraceptive and
Barrier Guidance)
 Noncompliance with study drug administration or procedure requirements.
Participants refusing the assigned study treatment will withdraw from study and will not be eligible
to receive IV amivantamab and oral lazertinib in this study. Study treatment assigned to the
participant who discontinued study treatment may not be assigned to another participant.
7.2. 
Discontinuation of Anti-cancer Background Regimen (Oral lazertinib, and
IV amivantamab
Study treatment will continue until disease progression or until early discontinuation criteria are
met. A participant's oral lazertinib, and IV amivantamab treatment must be discontinued if:
 The participant withdraws consent to receive oral lazertinib and IV amivantamab
 The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the
best interest of the participant to discontinue oral lazertinib and IV amivantamab
 The participant becomes pregnant (refer to Section 10.5, Appendix 5: Contraceptive and
Barrier Guidance)
 Noncompliance with study drug administration or procedure requirements.
If a participant discontinues oral lazertinib and IV amivantamab for any reason, then the EOS
assessments should be obtained according to the Schedule of Activities. Lazertinib, and IV
amivantamab assigned to the participant who discontinued oral lazertinib, and IV amivantamab
may not be assigned to another participant. Additional participants will not be entered in the study.
In instances where the investigator feels a participant may continue to receive clinical benefit from
further treatment with IV amivantamab and oral lazertinib after documented disease progression
(eg, new CNS disease), the case must be discussed with the sponsor’s medical monitor, who in
conjunction with the investigator, will determine if treatment beyond RECIST v1.1 defined
progression is indicated. If the participant is treated beyond documented disease progression,

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disease assessments will continue according to the schedule in Section 1.3, and the investigator
and sponsor medical monitor will review clinical benefit after each disease assessment.
7.3. 
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:
 Lost to follow-up
 Withdrawal of consent
 Noncompliance with dexamethasone, montelukast or methotrexate administration.
When a participant withdraws before study  completion, the reason for withdrawal is to be
documented in the CRF and in the source document. If the reason for withdrawal from the study
is withdrawal ofconsent [or assent] then no additional assessments are allowed.
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent
form apply (eg, consult with family members, contacting the participant’s other physicians,
medical records, database searches, use of locator agencies at study completion,) as local
regulations permit.
7.3.1. Withdrawal From the Use of Research Samples
Not Applicable
7.4. 
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, attempts should be made
to obtain contact information from each participant, eg, home, work, and mobile telephone
numbers and email addresses for both the participant as well as appropriate family members.
A participant will be considered lost to follow-up if the participant repeatedly fails to return for
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed
lost to follow-up until all reasonable efforts made by the study  site personnel to contact the
participant are deemed futile. The following actions must be taken if a participant fails to return to
the study site for a required study visit:
 The study site personnel must attempt to contact the participant to reschedule the missed visit
as soon as possible, to counsel the participant on the importance of maintaining the assigned
visit schedule, to ascertain whether the participant wishes to or should continue in the study.
 Before a participant is deemed lost to follow up, the investigator or designee must make every
reasonable effort to regain contact with the participant (where possible, 3 telephone calls,
emails, fax, and, if necessary, a certified letter to the participant’s last known mailing address,
or local equivalent methods). These contact attempts should be documented in the
participant’s medical records.

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 Should the participant continue to be unreachable, they will be considered to have withdrawn
from the study.
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities summarizes the frequency and timing of efficacy  and safety
measurements applicable to this study.
The total blood volume to be collected from each participant depends upon the duration of
participation and the required blood volume for local laboratory assessments, but through 3 cycles
of treatment and the End of Study visit, the total amount of blood drawn from each participant for
the study is approximately 115mL (110 mL for safety and 5mL for pregnancy testing [women
only]). Depending on country-specific regulations, volume requirements at local laboratories, and
availability of blood collection tubes, the total blood volume may vary (see Table 4).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.
Table 4: 
Volume of Blood to be Collected From Each Participant Through Cycle 3
Type of Sample 
Volume per 
Sample (mL) 
No. of Samples 
per Participant 
Approximate
Total Volume of
Blood (mL)[a]
Safety (including screening and post treatment assessments)
Hematology  
5 mL 
10 
50 mL
Serum chemistry  
5 mL 
10 
50 mL
Serology (HIV, hepatitis)b 
5 mL 
1 
5 mL
Serum hCG pregnancy tests 
5 mL 
1 
5 mL
Coagulation (PT/APTT)b 
5 mL 
1 
5 mL
Approximate Total 
115mL
a. Calculated as number of samples multiplied by amount of blood per sample.
b. Additional coagulation and serology tests may be performed as clinically indicated
Note: An indwelling intravenous cannula may be used for blood sample collection.
 hCG  Human chorionic gonadotropin, PT Prothrombin time, APTT activated prothrombin test time
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory
requisition form.
Refer to the Schedule of Activities for the timing and frequency of all sample collections.
Collection, handling, storage, and shipment of samples must be under the specified, and where
applicable, controlled temperature conditions as indicated in the laboratory manual.
Study-Specific Materials
The investigator will be provided with the following supplies:
 Clinical protocol

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 IBs for lazertinib and IV amivantamab and product labeling for dexamethasone, montelukast
and methotrexate,
 IPPI and SIPPM
 NCI-CTCAE, Version 5.0
 Electronic data capture (eDC) manual
 Sample ICF
8.1. 
Study Assessments
The objective of this study is to assess prophylaxis efficiency of dexamethasone, montelukast or
methotrexate prior to oral lazertinib, and IV amivantamab infusion to reduce first-dose IRRs. The
primary endpoint is rate of IRRs occurring on Cycle 1 Day 1 following administration of oral
lazertinib and IV amivantamab combination therapy. Signs and symptoms of IRR include: chills,
dyspnea, flushing, nausea, chest discomfort, vomiting, tachycardia, hypotension, and fever.
Investigator reported adverse events of IRR and associated symptoms and severity will be assessed
(see Section 3, Objectives and Endpoints).
During the IV amivantamab  infusion, participants should be clinically monitored at regular
intervals (including an assessment prior to the start of infusion). Vital signs should be measured
within 30 minutes prior to IV amivantamab administration. On Cycle 1 Day 1, vital signs should
also be measured 2 hours ±15 min after the IV amivantamab administration. The monitoring
should include pulse/heart rate, blood pressure, temperature, respiratory rate, and oxygen
saturation measurements. Participants must remain at the infusion center for monitoring for at least
2 hours after the end of the first dose of IV amivantamab (Cycle 1 Day 1), after which time, vital
signs should be obtained (See Vital Signs row in SOA).
Secondary endpoints are rates and severity of individual AEs associated with  IRR signs and
symptoms (chills, dyspnea, flushing, nausea, chest discomfort, vomiting, tachycardia,
hypotension, fever) as defined by the NCI CTCAE Criteria, Version 5.0 during Cycle 1 Day 1,
rates and severity of these AEs on subsequent administrations up to 3 months, severity of
infusion-related reactions, incidence ofother AEs, and median duration of infusion time for pre-
amivantamab infusion medications, IV amivantamab infusion, post-amivantamab infusion
medications, investigator assessed tumor response and duration of response.
Disease Assessments and Evaluation of Tumor Response
Disease assessments will be performed as scheduled regardless of any dose modifications,
according to the Schedule of Activities (Section 1.3). More frequent radiological assessments are
allowed, if clinically indicated. CT scans of the disease location(s) should be performed with an
IV contrast agent. Participants not able to undergo CT scans with IV contrast (eg, due to allergy
or renal insufficiency) may have non-contrast CT of the thorax and MRI scan of the abdomen and
pelvis with IV contrast at baseline and during the study, if approved by the sponsor.
Contraindications to the CT scan with IV contrast that develop post-baseline should be discussed
with the sponsor medical monitor. MRI should be used to evaluate sites of disease that cannot be

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adequately imaged using CT (eg, brain). Brain MRI is not required at Screening unless clinically
indicated (eg, prior brain metastases or suspicion of brain metastases). Subsequent brain imaging
is allowed per local practice for surveillance. Identical methodology (CT scan with contrast agent
and/or MRI) should be used for disease assessment at baseline, and throughout the course of the
study, to characterize each identified and reported lesion to document disease status. Techniques
other than CT or MRI may be used, based upon investigator judgment, local standard of care, and
RECIST v1.1 guidelines for the use of these alternative techniques. For example, bone
scintigraphy may be used to identify bone lesions at Screening or new bone lesions during
treatment, but bone lesions will not be considered target lesions. Sites will be required to retain
digital copies of radiological images (eg CT, MRI) used for disease assessments for potential
independent review. Assessment of responses for solid tumors will be performed according to
RECIST v1.1 criteria. RECIST assessments at baseline should be representative of all areas
involved with metastases. At any time, disease progression is clinically suspected, tumor
assessments should be performed. Irradiated or partially excised lesions will generally be
considered not measurable at baseline and may be followed as non-target lesions, except for a
lesion that has progressed following local radiation or surgery, provided the investigator and
sponsor medical monitor agree it is measurable and will not confound the efficacy evaluation.
Additionally, a lesion that was biopsied during Screening should only be assessed as a target lesion
if a post-biopsy CT confirms that it still meets measurability criteria and is amenable to accurate
and reproducible measurement. Tumor response will be reported by the investigator in the CRF.
The following response criteria (according to RECIST v1.1) are acceptable: complete response,
partial response, stable disease, progressive disease, unevaluable. A response of partial response
or complete response must be confirmed by repeat assessments ≥4 weeks from the initial
observation. For a response to qualify as stable disease, follow-up measurements must have met
the stable disease criteria at least once at a minimum interval not less than 6 weeks after the first
dose of study agent. If symptomatic deterioration (on the basis of global deterioration of health
status) is recorded as the basis for determining disease progression, then the clinical findings used
to make the determination must be specified in the CRF and documented in the source documents.
Every effort should be made to document radiographic progression even after discontinuation of
treatment for symptomatic deterioration, but prior to subsequent therapy, if possible.
Response assessment will be determined for all participants in accordance with RECIST v1.1.
Disease will be assessed at baseline, 6 weeks (+1 week) after Cycle 1 Day 1 (ie, Day 42-Day 49)
for the first assessment, and then every 6 (±1) weeks relative to Cycle 1 Day 1, until disease
progression by imaging, start of new anti-cancer therapy, or withdrawal of consent. Scheduled
disease assessments for participants who have completed 12 cycles and are clinically stable (both
clinical symptoms and radiographical assessments), may be extended to 12-week intervals at the
discretion of the investigator, after confirmation with Medical Monitor.
8.2. 
Safety Assessments
Details regarding the Study Evaluation Team are provided in Committees Structure in Appendix 3:
Regulatory, Ethical, and Study Oversight Considerations.

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Adverse events will be reported and followed by the investigator as specified in Section 8.3,
Adverse Events, Serious Adverse Events, and Other Safety Reporting, and Appendix 4: Adverse
Events, Serious Adverse Events, Product Quality Complaints, and Other Safety Reporting:
Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event
section of the CRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be
followed by the investigator until resolution or until a clinically stable condition is reached.
The study will include the following evaluations of safety and tolerability according to the time
points provided in the Schedule of Activities.
8.2.1. Physical Examinations
The screening physical examination will include, at a minimum, the participant’s height, weight,
and general appearance and an examination of the skin, ears, nose, throat, lungs, heart, abdomen,
extremities, musculoskeletal system, lymphatic system, and nervous system.
On Day 1 of each cycle, directed physical examinations of involved organs and other body
systems, as indicated, will be performed and participant body weight will be obtained using a
calibrated scale. At all visits (per SoA) after the IV amivantamab administration, participants
should be questioned for skin and eye symptoms, with physical examination as appropriate, and
specialty referral as indicated. In addition, participants receiving the combination of amivantamab
and lazertinib should similarly be questioned for signs and symptoms of VTE events, and a focused
physical examination of extremities and evaluation of respiratory status (including pulse oximetry)
should be performed, particularly during the first 4 months of assigned therapy. Any changes from
baseline should prompt consideration for further diagnostic evaluation, including unscheduled CT
exam or lower-extremity Doppler evaluation.
8.2.2. Vital Signs
Vital sign measurements will include the following assessments as indicated in the Schedule of
Activities. Vital signs should be measured within 30 minutes prior to IV amivantamab
administration. On Cycle 1 Day 1, vital signs should also be measured 2 hours ±15 min after the
IV amivantamab administration. For all visits, collect vital sign measurements ≤30 minutes before
amivantamab infusion, at 30-minute intervals (±5 minutes) during each amivantamab infusion,
and at the end of the infusion (±5 minutes) (See SOA).
Temperature, pulse/heart rate, respiratory rate, O2 saturation, blood pressure will be assessed.
Blood pressure and pulse/heart rate measurements will be assessed in a seated position with a
completely automated device. Manual techniques will be used only if an automated device is not
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Blood pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of rest
in a quiet setting without distractions (eg, television, cell phones).
8.2.3. Electrocardiograms
During the collection of ECGs, participants should be in a quiet setting without distractions (eg,
television, cell phones). Participants should rest in a supine position for at least 5 minutes before
ECG collection and should refrain from talking or moving arms or legs. Only a single ECG tracing
is required unless the result is both abnormal and clinically significant.
If blood sampling or vital sign measurement is scheduled for the same time point as ECG
recording, the procedures should be performed in the following order: ECG(s), vital signs, blood
draw.
If the first ECG tracing is abnormal and clinically significant, triplicate ECGs are required. At each
time point at which triplicate ECGs are required, 3 individual ECG tracings should be obtained as
closely as possible in succession, but no more than 2 minutes apart. The full set of triplicates should
be completed in less than 4 minutes.
The study will also include the following analysis according to the time points provided in the
SoA: urinalysis, Echocardiography/multigated acquisition scan.
8.2.4. Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology will be collected as noted in  Appendix 2,
Clinical Laboratory Tests. The investigator must review the laboratory results, document this
review, and record any clinically relevant changes occurring during the study in the AE section of
the CRF. The laboratory reports must be filed with the source documents.
8.2.5. Pregnancy Testing
Serum pregnancy testing will be performed at screening (within 72 hours prior to the first study
treatment administration) and as clinically indicated for women of childbearing potential only.
A negative serum or urine pregnancy test is required within 72 hours before Day 1 of each cycle,
at the End of Study visit, and as determined necessary by the investigator or required by local
regulation, to establish the absence of pregnancy at any time during the participation in the study.
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs,
and PQCs, from clinical studies are crucial for the protection of participants, investigators, and the
sponsor, and are mandated by regulatory agencies worldwide. The sponsor has established
Standard Operating Procedures in conformity with regulatory requirements worldwide to ensure
appropriate reporting of safety information; all clinical studies conducted by the sponsor or its
affiliates will be conducted in accordance with those procedures.

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Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate,
or the participant's legally acceptable representative) for the duration of the study.
Further details on AEs, SAEs, and PQCs can be found in Appendix 4: Adverse Events, Serious
Adverse Events, Product Quality Complaints, and Other Safety Reporting: Definitions and
Procedures for Recording, Evaluating, Follow-up, and Reporting.
8.3.1. Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from the
time a signed and dated ICF is obtained until 30 days after the last dose of study drug or IV
amivantamab and/or oral lazertinib or until the start of subsequent anti-cancer therapy, if earlier.
Serious Adverse Events
All SAEs, as well as PQCs, occurring during the study must be reported to the appropriate sponsor
contact person by study site personnel within 24 hours of their knowledge of the event.
Serious adverse events, including those spontaneously reported to the investigator within 30 days
after the last dose of oral lazertinib  and IV amivantamab, must be reported. The sponsor will
evaluate any safety information that is spontaneously reported by an investigator beyond the time
frame specified in the protocol.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event
Form and Safety Report Form of the CRF, which must be completed and reviewed by a physician
from the study site andtransmitted to the sponsor within 24 hours. The initial and follow-up reports
of an SAE should be transmitted electronically or by facsimile (fax). Telephone reporting should
be the exception and the reporter should be asked to complete the appropriate form(s) first.
8.3.2. Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading
verbal questioning of the participant is the preferred method to inquire about AE occurrence.
Solicited Adverse Events
Solicited AEs are predefined local at the infusionsite and systemic events for which the participant
is specifically questioned.
Unsolicited Adverse Events
Unsolicited AEs are all AEs for which the participant is not specifically questioned.
8.3.3. Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and evaluations as medically indicated to elucidate the nature and causality of the AE, SAE, or

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PQC as fully as possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other health care professionals.
Adverse events, including pregnancy, will be followed by the investigator as specified in
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting.
8.3.4. Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities.
The sponsor will also report to the investigator (and the head of the investigational institute where
required) all suspected unexpected serious adverse reactions (SUSARs). The investigator must
report SUSARs to the appropriate Independent Ethics Committee/Institutional Review Board
(IEC/IRB) that approved the protocol unless otherwise required and documented by the IEC/IRB.
8.3.5. Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be
reported to the sponsor by the study site personnel within 24 hours of their knowledge of the event
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg,
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are
considered SAEs and must be reported using an SAE reporting form. Any participant who becomes
pregnant during the study must discontinue further study treatment and complete End of Study
assessments.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required.
8.3.6. Disease-Related Events and Disease-Related Outcomes Not Qualifying as
Adverse Events or Serious Adverse Events
All events that meet the definition of an SAE will be reported as SAEs, regardless of whether they
are protocol-specific assessments or disease related. Progression of disease should not be
considered nor should be reported as an adverse event (or serious adverse event). However, signs
and symptoms of disease progression or of clinical sequelae resulting from disease
progression/lack of efficacy that are determined by the investigator to be of clinical significance
should be reported per the usual reporting requirements (refer to Adverse Event Definitions and
Classifications in Appendix 4: Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting).
8.3.7. Adverse Events of Special Interest
Adverse events of special interest are pneumonitis/ILD, rash, IRR, and VTE events. Additional
information will be collected for these events (see Section 6.6). Confirmed cases of
pneumonitis/ILD (regardless of grade) should be reported as serious adverse events (see

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Section 8.3.1). All Grade 3 or 4 IRRs should be reported within 24 hours to the Medical Monitor.
Events of rash and VTE should follow standard reporting guidelines.
8.4. 
Pharmacokinetics
Not Applicable
8.5. 
Pharmacodynamics
Not Applicable
8.6. 
Genetics and Pharmacogenomics
Not Applicable
8.7. 
Biomarkers
Not Applicable
8.8. 
Immunogenicity Assessments
Not Applicable
8.9. 
Medical Resource Utilization and Health Economics
Time and motion studies will evaluate participant chair time, treatment room time, duration of
treatment administration, and active HCP time for drug preparation, treatment administration, and
post-treatment monitoring.
9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the Statistical Analysis Plan.
9.1. 
Statistical Hypotheses
The primary hypothesis ofthis study is that through prophylactic treatment with dexamethasone,
methotrexate or montelukast, the incidence of IV amivantamab IRRs on Cycle 1 Day 1 will be
lower than 67%.
In this study, the null hypothesis that the true IRR rate is 0.67 or higher will be tested against a
one-sided alternative for each prophylaxis cohort.
9.2. 
Sample Size Determination
Simon's two-stage design (Simon, 1989) will be used separately for each cohort. Details of the
design are below.
 Stage 1: Treat up to 6 participants
 If the number of participants with IRR ≥ 4 (out of 6), the cohort stops at Stage 1.

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 Otherwise, move on to Stage 2.
 Stage 2: Treat up to 10 additional participants
 Reject the null hypothesis in that cohort if the number of participants with IRR ≤ 8 (out
of 16), the cohort will be declared promising in lowering IRR.
Each cohort can be expanded by adding up to 24 additional participants (up to 40 participants total
per expanded cohort).
For each cohort, the Simon’s two-stage design was identified as optimal on minimizing the
expected number of participants through PASS 15 given the following assumptions:
 The IRR is 67% without prophylaxis treatment (null hypothesis) and true IRR rate is 34%
 One-sided type-I error controlled within 0.05 and the target power of 80%.
9.3. 
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
Population 
Description
Screened 
All participants who sign the ICF
Randomized 
Not Applicable
Treated Set 
All participants who take at least 1 cycle of oral lazertinib and IV amivantamab combination
therapy preceded by prophylaxis treatment for the given cohort.
9.4. 
Statistical Analyses
This section is a summary of the planned statistical analyses of the most important endpoints
including primary and key secondary endpoints. Detailed specifics and algorithms will be provided
in the Statistical Analysis Plan.
9.4.1. General Considerations
Data will be summarized using descriptive statistics. Categorical values will be summarized using
the number of observations and percentages as appropriate. Where appropriate, two-sided exact
95% confidence intervals will be provided. Continuous variables will be summarized using the
number of observations, mean, standard deviation, coefficient of variation, median, and range as
appropriate.
9.4.2. Primary Endpoint
The primary endpoint is the Rate of IRRs occurring on Cycle 1 Day 1 following administration of
oral lazertinib and IV amivantamab  combination therapy. Primary analysis of IRR rate will be
performed after the last participant receives the first infusion or at the end of study, whichever
comes first. Treated participant population will be used for primary analysis. IRR rate along with
95% confidence interval will be estimated for the cohorts that have moved to second stage of the
trial.

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9.4.3. Secondary Endpoints
Secondary endpoints are rates and severity of individual AE signs and symptoms of IRR (chills,
dyspnea, flushing, nausea, chest discomfort, vomiting, tachycardia, hypotension, fever) occurring
on Cycle 1 Day 1, and on subsequent administrations of IV amivantamab for up to 3 months, the
severity of infusion-related reactions, incidence of other adverse events, rates of IRR following
subsequent administrations, median duration of infusion time for pre-amivantamab infusion
medications, IV amivantamab infusion, and post-amivantamab infusion medications and
investigator assessed ORR and duration of response.
The secondary  endpoint of IRR rate on subsequent administrations of IV amivantamab will be
analyzed similarly  to the primary  endpoint using treated participant population. Infusion time
will be summarized descriptively.
Final analysis of secondary endpoints will be conducted after last participant completes last
scheduled study assessment.
Disease Assessments and Evaluation of Tumor Response
The secondary endpoint of ORR with confirmed best overall responses will be performed
approximately 12 weeks after the last participant receives the first infusion or at the end of study,
whichever comes first. Due to the limited number of participants and the nature of this study, all
anti-tumor analyses are considered descriptive. ORR is defined as the proportion of participants
who achieve either a complete (CR) or partial response (PR) as defined by investigator assessment
using RECIST v1.1. Observed ORR along with their two-sided exact 95% CIs will be presented
for each cohort as appropriate.
Duration of response will be estimatedusing the Kaplan-Meier methodand calculated as time from
initial response of CR or PR to progressive disease (PD) or death due to underlying disease,
whichever comes first, only for participants who achieve CR or PR.
9.4.4. Safety Analyses
All participants who received at least one cycle of IV amivantamab and oral lazertinib combination
therapy preceded by prophylaxis treatment will be included in the safety analysis.
Adverse Events
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the
Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the initial
administration of study treatments (dexamethasone, montelukast or methotrexate) or background
anti-cancer therapy (oral lazertinib and IV amivantamab) through the day of last dose plus 30 days
is considered to be treatment-emergent. All reported treatment-emergent AEs will be included in
the analysis. For each AE, the percentage of participants who experience at least 1 occurrence of
the given event will be summarized by system organ class, preferred term, worst grade experienced
by the participant.

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Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue treatment due to an AE, or who experience a severe or an
SAE.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline and
for observed values and changes from baseline at each scheduled time point. Frequency tabulations
of the laboratory abnormalities will be made. A listing of participants with any laboratory results
outside the reference ranges will be provided. A listing of participants with any markedly abnormal
laboratory results will also be provided.
Electrocardiogram
Electrocardiogram data will only be collected at screening visit and as clinically indicated
thereafter. No analysis is planned for this data.
Vital Signs
The percentage of participants with vital signs values (including temperature, pulse/heart rate,
respiratory rate, and blood pressure [systolic and diastolic]) supine beyond clinically important
limits will be summarized and abnormal changes from baseline will be reported as adverse events.
Physical Examinations
Abnormal changes from baseline in physical examination findings will be reported as adverse
events.
Physical examination findings will be summarized at each scheduled time point. Descriptive
statistics will be calculated at baseline and for observed values and changes from baseline at each
scheduled time point. Frequency tabulations of the abnormalities will be made.
9.4.5. Other Analyses
A Study Evaluation Team (SET) will be established as noted in Committees Structure in
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations.
9.5. 
Interim Analysis
The study has two stages for each cohort using Simon’s 2-stage optimal design to assess the
primary endpoint of incidence of IRRs. One interim analysis will occur after all participants from
stage 1 complete Cycle 1 Day 1.
Another interim analysis will take place after all participants from stage 2 complete Cycle 1 Day
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations and Definitions
AE(s) 
ALT  
ANA  
AST  
adverse event(s)
alanine aminotransferase
antinuclear antibody
aspartate aminotransferase
BCRP  
cMet 
Breast Cancer Resistance Protein
tyrosine-protein kinase mesenchymal epithelial transition
CNS  
central nervous system
CRF  
CT  
case report form(s) (paper or electronic as appropriate for this study)
computerized tomography
CTCAE 
Common Terminology Criteria for Adverse Events
CYP  
DNA  
cytochrome P
deoxyribonucleic acid
ECG  
ECOG  
electrocardiogram
Eastern Cooperative Oncology Group
eDC  
EGF  
electronic data capture
epidermal growth factor
EGFR  
epidermal growth factor receptor
FDA  
GCP  
HAART  
HBV  
Food and Drug administration
Good Clinical Practice
highly active antiretroviral therapy
hepatitis B virus
HBsAb 
hepatitis B surface antibody
HBcAb 
hepatitis B core antibody
HbsAg 
HCV  
hepatitis B surface antigen
hepatitis C virus
HIV  
IB(s) 
human immunodeficiency virus
investigator brochure(s)
ICF  
informed consent form
ICH  
International Council on Harmonisation
IDMC  
Independent Data Monitoring Committee
IEC  
IgM  
ILD  
Independent Ethics Committee
immunoglobulin M
interstitial lung disease
IMP  
INR  
Investigational Medicinal Product
international normalized ratio
IRB  
Institutional Review Board
IRR(s) 
infusion-related reaction(s)
ISM  
IV  
investigational study materials
intravenous
MedDRA  
MET  
Medical Dictionary for Regulatory Activities
mesenchymal epithelial transition
MRP  
multi-drug resistance protein 4
MTX  
NCI 
NP  
NSAIDs 
methotrexate
National Cancer Institute
neuropsychiatric
nonsteroidal anti-inflammatory drugs
NSCLC  
PCC  
non-small cell lung cancer
protocol clarification communication
P-gp 
P-glycoprotein
PKU  
PO 
phenylketonuria
orally
PPI 
PQC(s) 
RA  
proton pump inhibitors
product quality complaint(s)
rheumatoid arthritis

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RP2D  
SAE(s) 
SET  
recommended Phase 2 dose
serious adverse event(s)
study evaluation team
SIPPM  
SoA  
Site Investigational Product Procedures Manual
schedule of activities
TEN  
toxic epidermal necrolysis
TKI 
ULN  
tyrosine kinase inhibitor
upper limit of normal
VTE 
venous thromboembolic

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10.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1. 
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and
country or territory-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study participants are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
Protocol Clarification Communications
If text within a final approved protocol requires clarification (eg, current wording is unclear or
ambiguous) that does not change any aspect of the current study conduct, a protocol clarification
communication (PCC) may be prepared. The PCC Document will be communicated to the
Investigational Site, Site Monitors, Local Trial Managers (LTMs), Clinical Trial Managers
(CTMs), and/or Contract Research Organizations (CROs) who will ensure that the PCC
explanations are followed by the investigators.
The PCC Document may be shared by the sites with independent Ethics Committees/Institutional
Review Boards (IECs/IRBs) per local regulations.
The PCC Documents must NOT be used in place of protocol amendments, but the content of the
PCC Document must be included in any future protocol amendments.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by
the sponsor. All protocol amendments must be issued by the sponsor and signed and dated by the
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or
when the relevant competent authority has raised any grounds for non-acceptance, except when
necessary to eliminate immediate hazards to the participants, in which case the amendment must
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where
required) only needs to be notified.
In situations where a departure from the protocol is unavoidable during the study, the investigator
or other physician in attendance will contact the appropriate sponsor representative listed in the
Contact Information page(s), which will be provided as a separate document. Except in emergency
situations, this contact should be made before implementing any departure from the protocol. In
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and

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agree on an appropriate course of action. The data recorded in the CRF and source documents will
reflect any departure from the protocol, and the source documents will describe this departure and
the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country/territory, if applicable. A study may not be initiated until all local
regulatory requirements are met.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study treatment to
the study site:
 Protocol and amendment(s), if any, signed and dated by the principal investigator
 A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if
applicable, participant compensation programs. This approval must clearly identify the
specific protocol by title and number and must be signed (or sealed, where appropriate per
local regulations) by the chairman or authorized designee.
 Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their
function, with a statement that it is organized and operates according to GCP and the
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a
member of the study site personnel is a member of the IEC/IRB, documentation must be
obtained to state that this person did not participate in the deliberations or in the vote/opinion
of the study.
 Regulatory authority approval or notification, if applicable
 Signed and dated statement of investigator (eg, Form FDA 1572), if applicable
 Documentation of investigator qualifications (eg, curriculum vitae)
 Completed investigator financial disclosure form from the principal investigator, where
required
 Signed and dated clinical trial agreement, which includes the financial agreement
 Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first
participant:
 Completed investigator financial disclosure forms from all subinvestigators
 Documentation of subinvestigator qualifications (eg, curriculum vitae)
 Name and address of any local laboratory conducting tests for the study, and a dated copy of
current laboratory normal ranges for these tests, if applicable

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 Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB
with current and complete copies of the following documents (as required by local regulations):
 Final protocol and, if applicable, amendments
 Sponsor-approved ICF (and any other written materials to be provided to the participants)
 IB (or equivalent information) and amendments/addenda
 Sponsor-approved participant recruiting materials
 Information on compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 Investigator’s curriculum vitae or equivalent information (unless not required, as documented
by the IEC/IRB)
 Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for participants
 Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol,
amendments (if any, excluding the ones that are purely administrative, with no consequences for
participants, data or study conduct, unless required locally), the ICF, applicable recruiting
materials, and participant compensation programs, and the sponsor has received a copy of this
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
 Protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct)
 Revision(s) to ICF and any other written materials to be provided to participants
 If applicable, new or revised participant recruiting materials approved by the sponsor
 Revisions to compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 New edition(s) of the IB and amendments/addenda
 Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 Reports of AEs that are serious, unlisted/unexpected, and associated with the study treatment
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 New information that may adversely affect the safety of the participants or the conduct of the
study
 Deviations from or changes to the protocol to eliminate immediate hazards to the participants
 Report of deaths of participants under the investigator’s care
 Notification if a new investigator is responsible for the study at the site
 Development Safety Update Report and Line Listings, where applicable
 Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct), the amendment and applicable ICF revisions
must be submitted promptly to the IEC/IRB for review and approval before implementation of the
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion (if applicable, the notification will be submitted through the head of
investigational institution).
Country/Territory Selection
This study will only be conducted in those countries/territories where the intent is to launch or
otherwise help ensure access to the developed product if the need for the product persists, unless
explicitly addressed as a specific ethical consideration in Section  4.2.1, Study-Specific Ethical
Design Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
10.3.2. 
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial
information in accordance with local regulations to allow the sponsor to submit complete and
accurate financial certification or disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial interests during the study and
for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
10.3.3. 
Informed Consent Process
Each participant must give written consent according to local requirements after the nature of the
study has been fully explained. The ICF(s) must be signed before performance of any study-related
activity. The ICF(s) that is/are used must be approved by both the sponsor and by the reviewing
IEC/IRB and be in a language that the participant can read and understand. The informed consent

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should be in accordance with principles that originated in the Declaration of Helsinki, current ICH
and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study site personnel
must explain to potential participants the aims, methods, reasonably anticipated benefits, and
potential hazards of the study, and any discomfort participation in the study may entail.
Participants will be informed that their participation is voluntary and that they may withdraw
consent to participate at any time. They will be informed that choosing not to participate will not
affect the care the participant will receive for the treatment of his or her disease. Participants will
be told that alternative treatments are available if they refuse to take part and that such refusal will
not prejudice future treatment. Finally, they will be told that the investigator will maintain a
participant identification register for the purposes of long-term follow up if needed and that their
records may be accessed by health authorities and authorized sponsor personnel without violating
the confidentiality of the participant, to the extent permitted by the applicable law(s) or regulations.
By signing the ICF the participant or legally acceptable representative is authorizing such access,
which includes permission to obtain information about his or her survival status. It also denotes
that the participant agrees to allow his or her study physician to recontact the participant for the
purpose of obtaining consent for additional safety evaluations, and subsequent disease-related
treatments, if needed.
The participant will be given sufficient time to read the ICF and the opportunity to ask questions.
After this explanation and before entry into the study, consent should be appropriately recorded
by means of the participant’s personally dated signature. After having obtained the consent, a copy
of the ICF must be given to the participant.
Participants who are rescreened are required to sign a new ICF.
If the participant is unable to read or write, an impartial witness should be present for the entire
informed consent process (which includes reading and explaining all written information) and
should personally date and sign the ICF after the oral consent of the participant is obtained.
10.3.4. 
Recruitment Strategy
Various resources will be developed to support trial awareness and provide information and
education to potential participants about the trial and clinical trials in general. Materials may
include informational brochures, advertisements, study guides, provider referral materials,
advocacy outreach and diversity resources.
10.3.5. 
Data Protection
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate

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technical and organizational measures to protect the personal data against unauthorized disclosures
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity
of participants confidential.
The informed consent obtained from the participant includes explicit consent for the processing of
personal data and for the investigator/institutionto allow direct access to his or her original medical
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and
regulatory inspection. This consent also addresses the transfer of the data to other entities and to
other countries/territories.
The participant has the right to request through the investigator access to his or her personal data
and the right to request rectification of any data that are not correct or complete. Reasonable steps
will be taken to respond to such a request, taking into consideration the nature of the request, the
conditions of the study, and the applicable laws and regulations.
In the event of a data security breach, the sponsor will apply measures to adequately manage and
mitigate possible adverse effects taking into consideration the nature of the data security breach as
necessary to address other obligations such as notifying appropriate authorities in accordance with
applicable data protection law.
Exploratory research is not conducted under standards appropriate for the return of data to
participants. In addition, the sponsor cannot make decisions as to the significance of any findings
resulting from exploratory research. Therefore, exploratory research data will not be returned to
participants or investigators, unless required by law or local regulations. Privacy and
confidentiality of data generated in the future on stored samples will be protected by the same
standards applicable to all other clinical data.
10.3.6. 
Committees Structure
SET Evaluation Team
A SET Evaluation Team will be established to monitor data at a regular interval. This committee
will consist of at least one medical expert in the relevant therapeutic area and at least one
statistician; committee membership responsibilities, authorities, and procedures will be
documented in its charter. The committee will meet periodically to review interim data. After the
review, the SET Evaluation Team will make recommendations regarding the continuation of the
study.
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data
All information, including but not limited to information regarding IV amivantamab and oral
lazertinib or the sponsor’s operations (eg, patent application, formulas, manufacturing processes,
basic scientific data, prior clinical data, formulation information) supplied by the sponsor to the
investigator and not previously published, and any data, including research data, generated as a
result of this study, are considered confidential and remain the sole property of the sponsor. The
investigator agrees to maintain this information in confidence and use this information only to

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accomplish this study and will not use it for other purposes without the sponsor’s prior written
consent.
The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development ofIV amivantamab and oral lazertinib, and
thus may be disclosed as required to other clinical investigators or regulatory agencies. To permit
the information derived from the clinical studies to be used, the investigator is obligated to provide
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and
will contain data from all study sites that participated in the study as per protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study. Results of analyses
performed after the Clinical Study Report has been issued will be reported in a separate report and
will not require a revision of the Clinical Study Report.
Study participant identifiers will not be used in publication of results. Any work created in
connection with performance of the study and contained in the data that can benefit from copyright
protection (except any publication by the investigator as provided for below) shall be the property
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter)
data and information without approval from the investigator. The investigator has the right to
publish study site-specific data after the primary data are published. If an investigator wishes to
publish information from the study, a copy of the manuscript must be provided to the sponsor for
review at least 60 days before submission for publication or presentation. Expedited reviews will
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow for
filing of a patent application. In the event that issues arise regarding scientific integrity or
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will
not mandate modifications to scientific content and does not have the right to suppress information.
For multicenter study designs and sub-study approaches, secondary results generally should not
be published before the primary endpoints of a study have been published. Similarly, investigators
will recognize the integrity of a multicenter study by not submitting for publication data derived
from the individual study site until the combined results from the completed study have been
submitted for publication, within 18 months after the study end date, or the sponsor confirms there
will be no multicenter study publication. Authorship of publications resulting from this study will
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which
state that the named authors must have made a significant contribution to the conception or design
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content; and given final approval of the
version to be published; and agreed to be accountable for all aspects of the work in ensuring that

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questions related to the accuracy or integrity of any part of the work are appropriately investigated
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law. The disclosure of the final study results will be performed after the end of study in order
to ensure the statistical analyses are relevant.
10.3.8. 
Data Quality Assurance
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study site personnel before the study, and periodic monitoring visits by the sponsor into the
sponsor's data base. Written instructions will be provided for collection, handling, storage, and
shipment of samples.
Guidelines for CRF completion will be provided and reviewed with study site personnel before
the start of the study.
The sponsor may review the CRF for accuracy and completeness during on-site monitoring visits
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or
designee, as appropriate. After upload of the data into the study database they will be verified for
accuracy and consistency with the data sources.
10.3.9. 
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each participant in electronic
format. All data relating to the study must be recorded in the CRF. All CRF entries, corrections,
and alterations must be made by the investigator or authorized study site personnel. The
investigator must verify that all data entries in the CRF are accurate and correct.
The study data will be transcribed by study site personnel from the source documents onto an
electronic CRF, if applicable. Study-specific data will be transmitted in a secure manner to the
sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any
such worksheets will become part ofthe participant's source documents. Data must be entered into
the CRF in English. The CRF must be completed as soon as possible after a participant visit and
the forms should be available for review at the next scheduled monitoring visit.
All participative measurements (eg, pain scale information or other questionnaires) will be
completed by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after
the initial entry into the CRF, this can be done in either of the following ways:

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 Investigator and study site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 Sponsor or sponsor delegate can generate a query for resolution by the investigator and study
site personnel.
10.3.10. 
Source Documents
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
participant identification, eligibility, and study identification; study discussion and date of signed
informed consent; dates of visits; results of safety and efficacy parameters as required by the
protocol; record of all AEs and follow-up of AEs; concomitant and prophylactic medication;
treatment receipt/dispensing/return/destruction records; study treatment, oral lazertinib and IV
amivantamab  administration information; and date of study completion and reason for early
discontinuation of oral lazertinib and IV amivantamab or withdrawal from the study, if applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent document).
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:
 Referral letter from treating physician or
 Complete history of medical notes at the site
 Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by participant interview or other protocol required assessment (eg, physical
examination, laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or
clinic record to document medical care (eg, electronic source documents) as well as the clinical
study-specific data fields as determined by the protocol. This data is electronically extracted for
use by the sponsor. If eSource is utilized, references made to the CRF in the protocol include the
eSource system but information collected through eSource may not be limited to that found in the
CRF.
10.3.11. 
Monitoring
The sponsor will use a combination of monitoring techniques including central, remote, or on-site
monitoring, to monitor this study.

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The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study site visit log that will be kept at the study site. The first
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits,
the monitor may  compare the data entered into the CRF with the source documents
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source
documents will be identified to ensure that all sources of original data required to complete the
CRF are known to the sponsor and study site personnel and are accessible for verification by the
sponsor study site contact. If electronic records are maintained at the study site, the method of
verification must be discussed with the study site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review will
be discussed with the study site personnel. The sponsor expects that, during monitoring visits, the
relevant study site personnel will be available, the source documents will be accessible, and a
suitable environment will be provided for review of study-related documents. The monitor will
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these
remote contacts, study site personnel will be available to provide an update on the progress of the
study at the site.
10.3.12. 
On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. These audits will require access to all study
records, including source documents, for inspection. Participant privacy must, however, be
respected. The investigator and study site personnel are responsible for being present and available
for consultation during routinely scheduled study site audit visits conducted by the sponsor or its
designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
10.3.13. 
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF and
all source documents that support the data collected from each participant, as well as all study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial, and all study documents as specified by the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.

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Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such reports.
10.3.14. 
Study and Site Start and Closure
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study/Site Termination
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 participants by the investigator
 Discontinuation of further oral lazertinib and IV amivantamab development

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10.4. Appendix 4: Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting
10.4.1. 
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a
pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have
a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended
sign (including an abnormal finding), symptom, or disease temporally associated with the use of a
medicinal (investigational or non-investigational) product, whether or not related to that medicinal
(investigational or non-investigational) product. (Definition per International Council on
Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to All Adverse Events
under Section  8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious
Adverse Events Information, for time of last AE recording).
Serious Adverse Event
An  SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for
Human Use is any untoward medical occurrence that at any dose:
 Results in death
 Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.)
 Requires inpatient hospitalization or prolongation of existing hospitalization
 Results in persistent or significant disability/incapacity
 Is a congenital anomaly/birth defect
 Is a suspected transmission of any infectious agent via a medicinal product
 Is Medically Important*.
*Medical and scientific judgment should be exercised in deciding whether expedited reporting
is also 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
participant or may require treatment to prevent one of the other outcomes listed in the
definition above. These should usually be considered serious.

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If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship
between the study treatment, lazertinib or IV amivantamab  and the event (eg, death from
anaphylaxis), the event must be reported as a serious and unexpected suspected adverse reaction
even if it is a component of the study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product
reference safety information. For IV amivantamab and oral lazertinib, the expectedness of an AE
will be determined by whether or not it is listed in the IB.
10.4.2. 
Attribution Definitions
Assessment of Causality
The causal relationship to study treatment, lazertinib or IV amivantamab  is determined by the
Investigator. The following selection should be used to assess all AEs.
Related
There is a reasonable causal relationship between study treatment, lazertinib or IV amivantamab
administration and the AE.
Not Related
There is not a reasonable causal relationship between study treatment, lazertinib or IV
amivantamab administration and the AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
10.4.3. 
Severity Criteria
Adverse event severity is a clinical determination of the intensity of an AE. The severity
assessment for an AE or serious AE should be completed using the NCI-CTCAE, Version 5.0.
Any AE or SAE not listed in the NCI-CTCAE, Version 5.0 will be graded according to the
investigator clinical judgment by using the standard grades as follows:
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only;
treatment not indicated.
 Grade 2: Moderate; minimal, local or noninvasive treatment indicated; limiting age-
appropriate instrumental activities of daily living (ADL)a.
 Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization
or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily
livingb.
 Grade 4: Life-threatening consequences; urgent treatment indicated.
 Grade 5: Death related to AE.

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a Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the
telephone, managing money, etc.
b Self-care ADL refers to bathing; dressing and undressing; feeding self; using the toilet; taking
medications; and not bedridden.
The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the participant (eg, laboratory abnormalities).
10.4.4. 
Special Reporting Situations
Safety events of interest on dexamethasone, montelukast, methotrexate, lazertinib, or IV
amivantamab in an interventional study that may require expedited reporting or safety evaluation
include, but are not limited to:
 Overdose of dexamethasone, montelukast, methotrexate, lazertinib, or IV amivantamab
 Suspected abuse/misuse of dexamethasone, montelukast, methotrexate, lazertinib, or IV
amivantamab
 Accidental or occupational exposure to dexamethasone, montelukast, methotrexate,
lazertinib, or IV amivantamab
 Medication error, intercepted medication error, or potential medication error involving a
Johnson & Johnson medicinal product (with or without participant exposure to the Johnson &
Johnson medicinal product, eg, product name confusion, product label confusion, intercepted
prescribing or dispensing errors)
 Exposure to dexamethasone, montelukast, methotrexate, lazertinib, or IV amivantamab from
breastfeeding.
Special reporting situations should be recorded in the CRF. Any special reporting situation that
meets the criteria of an SAE should be recorded on the SAE page of the CRF.
10.4.5. 
Procedures
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study treatment, lazertinib
or IV amivantamab 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 AE to study therapy. All measures required for AE management
must be recorded in the source document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be
provided with a "wallet (study) card" and instructed to carry this card with them for the duration
of the study indicating the following:

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 Study number
 Statement, in the local language(s), that the participant is participating in a clinical study
 Investigator's name and 24hour contact telephone number
 Local sponsor's name and 24-hour contact telephone number (for medical personnel only)
 Site number
 Participant number
 Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon the
participant's discontinuation from the study, must be followed until any of the following occurs:
 The event resolves
 The event stabilizes
 The event returns to baseline, if a baseline value/status is available
 The event can be attributed to agents other than the study treatment, lazertinib or IV
amivantamab or to factors unrelated to study conduct
 It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during
participation in the study must be reported as an SAE, except hospitalizations for the following:
 Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending
placement in long-term care facility)
 Surgery or procedure planned before entry into the study (must be documented in the CRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be
considered SAEs. Any AE that results in a prolongation of the originally planned
hospitalization is to be reported as a new SAE.
 or convenience the investigator may choose to hospitalize the participant for the duration of
the treatment period.
Expected progression of disease should not be considered or reported as an adverse event (or
serious adverse event).
However, if determined by the investigator to be more likely related to the study treatment,
lazertinib or IV amivantamab  than being expected from the underlying disease, the treatment-
invoked progression (ie, the treatment--invoked signs/symptoms of such progression) should be
reported per the usual reporting requirements (refer to Adverse Event Definitions and
Classifications in Appendix 10.4: Adverse Events, Serious Adverse Events, Product Quality

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Complaints, and Other Safety Reporting: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting).
Death that is attributed by the investigator explicitly to progression of disease should not be
considered nor reported as an adverse event (or serious adverse event).
However, if determined by the investigator to be more likely related to the study treatment,
lazertinib or IV amivantamab  than being expected from the underlying disease, the treatment-
invoked death due to progression should be reported per the usual reporting requirements (refer to
Adverse Event Definitions and Classifications in Appendix 10.4: Adverse Events, Serious Adverse
Events, Product Quality Complaints, and Other Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting).
Progression of disease and death due to disease progression should be documented on the
appropriate eCRF forms (eg, the Disease Progression form and the Death form).
Signs or symptoms of disease progression that are of clinical significance, such as spinal cord
compression, vena cava superior syndrome, major vessel rupture, efflux obstruction or organ
failure, should be documented on the appropriate eCRF forms (eg, the Clinical Progression form).
Information regarding SAEs will be transmitted to the sponsor using an SAE reporting form and
safety report form of the CRF, which must be completed and reviewed by a physician from the
study site andtransmitted in a secure manner to the sponsor within 24 hours. The initial and follow-
up reports of an SAE should be transmitted in a secure manner electronically or by facsimile (fax).
Telephone reporting should be the exception and the reporter should be asked to complete the
appropriate form(s) first.
10.4.6. 
Product Quality Complaint Handling
Definition
A product quality complaint (PQC) is defined as any suspicion of a product defect related to
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality,
durability, reliability, or performance of a distributed product, including its labeling, drug delivery
system, or package integrity. A PQC may have an impact on the safety and efficacy of the product.
In addition, it includes any technical complaints, defined as any complaint that indicates a potential
quality issue during manufacturing, packaging, release testing, stability monitoring, dose
preparation, storage or distribution of the product or the drug delivery system.
Procedures
All initial PQCs must be reported to the sponsor by the study site personnel within 24 hours after
being made aware of the event.
A sample of the suspected product should be maintained under the correct storage conditions until
a shipment request is received from the sponsor.

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10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues, PQC, or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.

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10.5. Appendix 5: Contraceptive and Barrier Guidance
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria.
Pregnancy information will be collected and reported as noted in Section 8.3.5, Pregnancy and
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not ofChildbearing Potential
 premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the
postmenopausal range may be used to confirm a postmenopausal state in women not using
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of
12 months 
of 
amenorrhea, 
a 
single 
FSH 
measurement 
is 
insufficient.
If there is a question about menopausal status in women on HRT, the woman will be required
to use one of the non-estrogen-containing hormonal highly effective contraceptive methods if
she wishes to continue HRT during the study.
 permanently sterile
 Permanent sterilization methods include hysterectomy, or bilateral salpingectomy, or
bilateral oophorectomy.
 Has congenital abnormalities resulting in sterility.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually
active becomes active), a woman must begin a highly effective method of contraception, as
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by men or women should be consistent with local regulations
regarding the acceptable methods of contraception for those participating in clinical studies.
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 participants in
clinical studies.

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Examples of Contraceptives
EXAMPLES OF HIGHLY EFFECTIVE METHODS OF CONTRACEPTIVESa:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used
consistently and correctly.
 Implantable progestogen-only hormone contraception associated with inhibition of ovulationb
 Intrauterine device (IUD)
 Intrauterine hormone-releasing system (IUS)
 Tubal closure (eg, bilateral tubal occlusion, bilateral tubal ligation)
 Azoospermic partner (vasectomized or due to medical cause)
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the
sole sexual partner of the woman of childbearing potential and the absence of sperm has been
confirmed. If not, additional highly effective method of contraception should be used.
Spermatogenesis cycle is approximately 74days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulationb
 oral
 intravaginal
 transdermal
 injectable
 Progestogen-only hormone contraception associated with inhibition of ovulationb
 oral
 injectable
 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 treatment. 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 participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not
considered to be highly effective - failure rate of 1% per year)
 Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary
mode of action.
 Male or female condom with or without spermicidec
 Cap, diaphragm, or sponge with spermicide
 A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)c
 Periodic abstinence (calendar, symptothermal, post-ovulation methods)
 Withdrawal (coitus-interruptus)
 Spermicides alone
 Lactational amenorrhea method (LAM)

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a) 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 participants in
clinical studies.
b) Hormonal contraception may be susceptible to interaction with the study treatment, which may
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception
may interact with the study treatment.
c) Male condom and female condom should not be used together (due to risk of failure with friction).

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10.6. Appendix 6: Study Conduct During a Natural Disaster
GUIDANCE ON STUDY CONDUCT DURING COVID-19 PANDEMIC
It is recognized that the COVID-19 pandemic may have an impact on the conduct of this clinical
study due to, for example, isolation or quarantine ofparticipants and study site personnel; travel
restrictions/limited access to public places, including hospitals; study site personnel being
unavailable, isolated, or reassigned to critical tasks.
The sponsor is providing options for study related participant management in the event of
disruption to the conduct of the study. This guidance does not supersede any local or government
requirements or the clinical judgement of the investigator to protect the health and well-being of
participants and site staff. If, at any time, a participant’s travel to the study site is considered to be
dangerous, study participation may be interrupted, and study follow-up conducted. If it becomes
necessary to discontinue participation in the study, the procedures outlined in the protocol for
discontinuing study treatment will be followed.
If, as a result of the COVID-19 pandemic scheduled visits cannot be conducted in person at the
study site, they will be performed to the extent possible remotely/virtually or delayed until such
time that on-site visits can be resumed. At each contact, participants will be interviewed to collect
safety data. Key efficacy endpoint assessments should be performed if required and as feasible.
Participants will also be questioned regarding general health status to fulfill any physical
examination requirement.
Every effort should be made to adhere to protocol-specified assessments for participants on study
treatment, including follow up. Modifications to protocol-required assessments may be permitted
using the examples contained in this appendix, after consultation with the participant, investigator,
and the sponsor. Missed assessments/visits will be captured in the clinical trial management system
for protocol deviations. Discontinuations of study treatments and withdrawal from the study should
be documented with the prefix “[COVID-19 pandemic]-related” in the CRF.
Ifthe participant has tested positive for the COVID-19 pandemic, the investigator should contact
the sponsor’s responsible medical officer to discuss plans for administration of study treatment,
performing. study assessments, and follow-up. Modifications made to the study conduct as a result
of the COVID-19 pandemic should be summarized in the clinical study report.

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10.7. Appendix 7: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).
All Protocol Amendments
DOCUMENT HISTORY
Document 
Country/Territory Affected  
Date
Amendment 3 
All 
27-Apr-2023
Amendment 2 
All 
12-Dec-2022
Amendment 1 
All 
29-Aug-2022
Original Protocol 
All 
29-Jun-2022
Amendment 3 (27 April 2023)
Overall Rationale for the Amendment:  The overall purpose of this protocol amendment is to incorporate
changes that were recommended by health authorities in response to the Urgent Safety Measure (VTE risk
with combination of amivantamab and lazertinib) released on July 22,2022. This amendment also serves to
provide clarity on the schedule of assessments, objectives, and study procedures.
The changes made to the clinical protocol 61186372NSC2005 as part of Protocol Amendment 3
are listed below, including the rationale of each change and a list of all applicable sections.
Changes made in previous protocol amendments are listed in Section 10.7 Appendix 7: Protocol
Amendment History.
Section Number
and Name
Description of Change 
Brief Rationale
6.5.5. Venous
Thromboembolic
Events
The following text was added: 
If a VTE event is diagnosed, the participant 
should be treated with treatment-dose
anticoagulation as per local guidelines. Vitamin K
antagonists are not recommended because of
numerous drug interactions. For VTE events
associated with clinical instability (eg, respiratory
failure or cardiac dysfunction) in participants
receiving the combination of amivantamab and
lazertinib, study treatment should be held until the
patient recovers from the event. Thereafter, the
treatment can be resumed at the discretion of the
investigator. In the case of a recurrent VTE whilst
on therapeutic anticoagulation therapy, the
combination of amivantamab and lazertinib
should be permanently discontinued. Participants
may continue to receive treatment with either
amivantamab or lazertinib (but not both) at the
discretion of the treating investigator. For
participants that have experienced VTE, if
symptoms persist or in case of worsening VTE,
further imaging studies (which may include
doppler studies) should be performed to assess the
resolution of the event with corrective measures,
as per the investigator’s discretion.
The following text was deleted:
After completion of the duration of treatment for
active VTE events, the investigator may consider
To clarify and align with the VTE
risk mitigation and management.

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Section Number 
and Name
Description of Change 
Brief Rationale
continuing treatment dose anticoagulation or
transition to prophylactic dose anticoagulation
while continuing the combination of amivantamab
and lazertinib. Dose modification is not required
for a VTE event.
5.2. Exclusion Criteria New criteria added per Amendment-3: 
12. Participant with a significant genetic 
predisposition to venous thromboembolic events
(VTE; such as Factor V Leiden).
13. Participant with a prior history of VTE and
who are not on appropriate therapeutic
anticoagulation as per the NCCN guidelines or
local guidelines.
To clarify and align with the VTE
risk mitigation and management.
Title Page 
The title was updated from: 
Evaluation of Amivantamab Infusion Related 
Reaction Mitigation
to:
Subcutaneous Methotrexate, Oral Dexamethasone
or Oral Montelukast for the Prevention of Infusion
Related Reaction Associated with Amivantamab,
an EGFR-MET bispecific antibody, Among Post-
osimertinib Treated EGFRm NSCLC ; SKIPPirr,
a Phase 2 Study
To reflect the trial objective on the
protocol title.
1.1. Synopsis 
(Objectives and 
Endpoints; Efficacy 
Evaluation)
3. Objectives and
Endpoints
1.1. Synopsis 
(Hypothesis) 
3. Objectives and 
Endpoints
(Hypothesis)
9.1 Statistical
Hypotheses
1.2 Schema 
1.3 SoA (Visit 
Window) 
1.3 SoA (Duration of 
infusion time row) 
1.3 SoA (Weight) 
2.1. Study Rationale 
The following text was removed: 
IRR, when amivantamab is given in combination
with oral lazertinib, to reduce
The following text was updated from
reduced by half, from 67% to 34% to
lower than 67%.
The term C1D-1 was replaced by Day-1.
The visit window for Screening was updated
to -28 to -8
The duration of infusion time collection is not
applicable prior to C1D1, therefore removed from
the prophylaxis administration visit.
The weight assessment is marked at Screening.
The following text was deleted:
The IRR rates at first infusion were 38% and 59%
(respiratory symptoms, 20% and 33%),
respectively, in those who did or did not receive
montelukast.
The text in secondary endpoints was updated from
To correct errors.

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Section Number 
and Name
Description of Change 
Brief Rationale
3. Objectives and 
Endpoints 
5.4. Screen Failures 
6.1. Study 
Treatment(s) 
Administered Table 
‘3 months’ to ‘the end of the third cycle’ and
Median time to complete was updated to Duration
of infusion time
The term randomized was updated to enrolled.
All references to (single dose) auto injectors were
deleted and replaced with 2mL/vial where
applicable for column ‘Methotrexate (Cohort C).
The dosage level for ‘Methotrexate (Cohort C)
was replaced from Administer SC in the abdomen
or the thigh to 1 ml/25mg subcutaneous, single-
dose, between D-7 and D-3 before Cycle 1.
1.1. Synopsis 
(Efficacy Evaluation) 
8.1 Study 
Assessments (Disease 
Assessments and 
Evaluation of Tumor 
Response) 
1.3. SoA (Disease 
assessment/Tumor 
response evaluation) 
The following text was deleted: 
Subjects who permanently discontinue treatment 
for any reason other than radiological disease 
progression or withdrawal of consent will
continue disease assessments per the protocol
schedule until radiological progression is
confirmed, or new anti cancer therapy begins,
whichever comes first.
The following text was deleted:
For subjects who discontinue treatment prior to
disease progression, radiological assessments
should continue to be performed as per the
protocol schedule until disease progression is
documented. If a discontinued subject begins a
new cancer therapy prior to progression, disease
assessment should occur prior to initiation of the
new therapy.
To exclude procedures after end of
study and to align with Schedule
of Assessments.
1.3. SoA (Inclusion/ 
exclusion criteria row) 
The following text was added: 
Rescreening must be discussed with and approved 
by the Sponsor's medical monitor on a case-by-
case basis.
To clarify procedures related to
inclusion/exclusion criteria.
1.3 SoA (Medical 
history row) 
1.3. SoA (Time and 
Motion row) 
1.3. SoA (Safety 
Assessments: 
Hematology  
Serum Chemistry
Coagulation
Urinalysis
Pregnancy test)
1.3. SoA 
(Diphenhydramine 
and paracetamol / 
acetaminophen) 
1.3. SoA Vital signs 
The following text was added: 
Include any planned surgeries. 
The line item for ‘Time and Motion’ was added. 
The following text was added to the column 
‘Notes’:
See Appendix 2.
The pre-infusion medications diphenhydramine 
and paracetamol/acetaminophen are marked for 
Cycle 1, Days 8, 15, and 22. 
The vital signs are marked for Cycle 2 Day 15 and 
Cycle 3 (and all cycles thereafter) Day 15. 
The following text was deleted:
To clarify requirements in medical
history - including planned
surgeries while on study treatment.
To evaluate duration of patient
care.
To clarify required assessments.
To correct an error as
diphenydramine and
paracetamol/acetominphen are to
be used as pre-infusion medication
in all amivantamab infusions.
To correct an error as vital signs
are to be assessed on all visits per
this study.

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Section Number 
and Name
Description of Change 
Brief Rationale
8. Study Assessments 
and Procedures 
(Sample Collection 
and Handling)
8.1. Study 
Assessments 
1.3 SoA (Vital signs) 
8.2.2. Vital Signs 
10.2.Appendix 2: 
Clinical Laboratory 
Tests (Clinical
Chemistry)
Instructions for the collection, handling, storage, 
and shipment of samples are found in the 
laboratory manual that will be provided.
The following text was added:
(See Vital Signs row in SOA) 
The following text was added: 
For all visits, collect vital sign measurements ≤30
minutes before amivantamab infusion, at 30-
minute intervals (±5 minutes) during each
amivantamab infusion, and at the end of the
infusion (±5 minutes). (See SOA).
Serum glutamic-oxaloacetic was replaced by
Serum glutamic-pyruvic transaminase 
The term direct/indirect was deleted. 
To correct an error as this study is
using local labs.
To clarify study procedures related
to vital signs.
To correct an error and to clarify
study procedures.
1.3. SoA (Serology) 
The following text was added to the column 
‘Notes’: 
HIV antibody, HBsAg, HBsAb, HBcAb, anti-HCV
antibody, HBV viral load (if needed) and HCV
viral load (if needed).
To clarify study procedures related
to serology tests.
1.3. SoA (Pregnancy
test)
The following text was added:
Within 72 hours of day 1 of each cycle and at End
of Study
The text in bold was updated to the column
‘Notes’:
Serum test required at screening and urine or
serum test within 72 hours prior to each IV
amivantamab infusion and at End of Study.
To clarify study procedures related
to pregnancy tests.
1.3. SoA (Chest X-
ray)
6.5.4. Pulmonary
Toxicity
8.1. Study
Assessments
8.2.3.
Electrocardiograms
The row for Chest X-ray was deleted
The text ‘chest X ray’ was deleted.
To align with the latest safety
guidance for amivantamab plus
lazertinib.
2.2. Background 
The text was modified as:
the infusion should be interrupted if IRR is
suspected and resumed at a reduced infusion rate
for Grade 3 IRR or permanently discontinued for
Grade ≥4 and recurrent Grade 3 IRR
To correct an error regarding when
the infusion rate should be reduced
versus having the infusion
permanently discontinued based on
IRR grade.
2.2.1. Benefit-Risk
Assessment
Pregnant women with psoriasis or rheumatoid 
arthritis was deleted. 
To clarify the study procedures
regarding treatment received by
pregnant woman.
3. Objectives and
Endpoints
The text in bold was added to primary endpoints: 
Rate of IRRs occurring on Cycle 1 Day 1 following 
administration 
of oral 
lazertinib 
and 
IV
amivantamab combination therapy, which is
defined as IRR events with onset time within 24
To clarify the primary endpoint
timeframe.

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Section Number 
and Name
Description of Change 
Brief Rationale
hours of the start of the first amivantamab
infusion and prior to the start of amivantamab
infusion on Cycle 1 Day 2.
A new secondary objective was added:
To evaluate incidence and severity of IRR on
subsequent cycles.
And the following endpoints were updated from
non-IRR AEs secondary objective to the newly
added secondary objective:
-Rates of IRR following subsequent
administrations.
-Severity of infusion-related reactions.
To clarify a secondary objective
and related endpoints.
4.1. Overall Design  
The following text was added: 
Up to 126 patients could be enrolled in the study.
The study will have 2 stages and an expansion
cohort of that will enroll up to 24 additional
patients.
The following text was deleted and updated to
After cohorts A, B and C have each completed
Stage 1, the Study Evaluation Team will evaluate
which cohort(s) may move onto Stage 2 and this
process will repeat for Stage 2 Similarly in Stage
2, the selected cohorts (if more than one) will be
enrolled sequentially as well. If a stop decision
can be made within a cohort before reaching the
planned sample size, which is 6 for Stage 1 and 10
additional patients for Stage 2, the enrollment into
this cohort will be closed and the enrollment for
the next cohort will start.
The following text was added:
The Study Evaluation Team will evaluate which
cohort(s) may move onto Stage 2 and this process
will be repeated on Stage 2 to select expansion
phase cohorts.
To clarify study enrollment.
4.3. End of Study 
Definition (Study 
Completion 
Definition) 
The following text in bold was added: 
A participant will be considered to have
completed the study if he or she has died before
the end of the study due to progressive disease or
has not prematurely discontinued the study for
another reason (Section 7) by the end of the study.
If death occurs for any other reason, than
progressive disease, the participant’s status will
be categorized as early withdrawal.
To clarify end of study.
5.1. Inclusion Criteria 
The criterion 10 was updated and text in bold was 
added as: 
10. Criterion modified perAmendment-3
10.1. A female participant of childbearing
potential must have a negative serum (b-human
chorionic gonadotropin [b-hCG]) at screening
(within 72 hours of the first dose of study
treatment administration) and must agree to
further serum or urine pregnancy tests during the
To clarify the timing and
frequency of pregnancy test.

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Section Number 
and Name
Description of Change 
Brief Rationale
8.2.5. Pregnancy 
Testing 
study prior to each IV amivantamab infusion
and at End of Study.
The following text was deleted:
Additional serum or urine pregnancy tests may be
performed.
and updated to:
A negative serum or urine pregnancy test is
required within 72 hours before Day 1 of each
cycle, at the End of Study visit
5.1. Inclusion Criteria 
The criterion 16 was updated and text in bold was 
added as: 
16. Criterion 16 modified per Amendment-3 
16.1. Each participant, or legally authorized
representative, where allowed, must sign an ICF
indicating that the participant understands the
purpose of, and procedures required for, the study
and is willing to participate in the study.
For clarification and consistency
with other sections of protocol
regarding the ICF procedure.
5.2. Exclusion Criteria The criterion 8 was updated and text in bold was 
added as: 
8. Criterion modified per Amendment-3 
8.1. Contraindications, allergies, hypersensitivity,
or intolerance to oral lazertinib, IV amivantamab,
dexamethasone, montelukast, methotrexate or
their excipients. Methotrexate is contraindicated
in pregnancy, alcoholism or liver disease,
immunodeficiency syndromes, preexisting blood
dyscrasias, and hypersensitivity to methotrexate.
For clarification on exclusion
criteria for drug interactions
section.
5.4. Screen Failures 
The following texts were added: 
Rescreening must be discussed with and approved
by the Sponsor's medical monitor on a case-by-
case basis.
To clarify rescreening procedure.
6.1. Study 
Treatment(s) 
Administered 
The following text was added to the row 
‘Current/Former Name(s) or Alias (es) as: 
(Not an all-inclusive list of Former or Alias
names).
For clarification of study drug
names.
6.5.1. Infusion-related 
Reactions 
The text in bold was updated in the following 
sentence: 
Subjects must remain at the infusion center for
monitoring for at least 2 hours 1 hour after the
end of the first dose of IV amivantamab (Cycle 1
Day 21), and at least 1 hour after Cycle 1 Day
2, after which time, vital signs should be obtained
(See SOA).
To clarify study procedures related
to post infusion monitoring.
6.5.2. Liver 
Chemistry 
Abnormalities 
The following text was deleted: 
including bilirubin fractions, 
To align with the latest safety
guidance for amivantamab plus
lazertinib.
6.7. Treatment of 
Overdose (IV 
Amivantamab and/or 
Oral Lazertinib 
The following text was updated to: 
There are no data on overdose from studies of 
amivantamab or lazertinib (refer to IB for each 
agent).
from:
No clinical studies have been conducted to assess
a toxic threshold for IV amivantamab. Doses up to
1,750 mg have been assessed without
To clarify and align with the latest
safety guidance for amivantamab
plus lazertinib.

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Section Number 
and Name
Description of Change 
Brief Rationale
identification of a maximum tolerated dose
(MTD). In the event of an overdose, stop
amivantamab, undertake general supportive
measures until clinical toxicity has diminished or
resolved.
Lazertinib: There is no specific antidote designed
for lazertinib overdose. In the event of an acute
overdose, close monitoring and supportive care
should be provided.
7.2. Discontinuation 
of Anti-cancer 
Background Regimen 
(Oral lazertinib, and 
IV amivantamab) 
The following text was added: 
Study treatment will continue until disease 
progression or until early discontinuation criteria
are met.
The text in bold was updated in the following 
sentence: 
If a participant discontinues lazertinib and IV 
amivantamab for any reason before the EOS visit,
then the end of treatment EOS and post treatment
assessments should be obtained according to the
Schedule of Activities and follow up visits should
continue after study treatment is discontinued.
For clarification of treatment
duration.
To clarify study procedures and
align the text with Schedule of
Activities
8. Study Assessments
and Procedures
(Overview)
8. Study Assessments
and Procedures Table
4
The following text in bold w added:
The total blood volume to be collected from each
participant depends upon the duration of
participation and the required blood volume
for local laboratory assessments, but through 3
cycles of treatment and the End of Study visit,
the total amount of blood drawn from each
participant for the study is approximately
115 mL (110 mL for safety and 5mL for
pregnancy testing [women only]). Depending on
country-specific regulations, volume
requirements at local laboratories, and
availability of blood collection tubes, the total
blood volume may vary (see Table 4).
The title of the Table 4 was updated in bold:
Volume of Blood to be Collected From Each
Participant Through Cycle 3
Serology and B HCG were made standalone tests,
Footnote b was deleted:
Serum chemistry includes serology (HIV,
hepatitis) and serum b hCG pregnancy tests
Footnote c was updated to b
The term PTT was updated to APTT
Superscript for chemistry was removed and
superscript for serology and coagulation was
updated.
To clarify the total volume of
blood to be collected.
To correct an error.
8.2.3.
Electrocardiograms
The following text was added:
Only a single ECG tracing is required unless the
result is both abnormal and clinically significant
and
If the first ECG tracing is abnormal and clinically
significant, triplicate ECGs are required.
To align with the latest safety
guidance for amivantamab plus
lazertinib.

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Section Number 
and Name
Description of Change 
Brief Rationale
8.3.5. Pregnancy  
10.2. Appendix 2: 
Clinical Laboratory 
Tests (Other
Screening Tests)
The following text in bold was added: 
Any participant who becomes pregnant during the 
study must discontinue further study treatment
and complete End of Study assessments.
The following text was added:prior to each
amivantamab IV infusion and at the End of Study
To clarify the study procedure for
participants who become pregnant.
8.3.6. Disease-Related 
Events and Disease- 
Related Outcomes 
Not Qualifying as 
Adverse Events or 
Serious Adverse 
Events 
The following text in bold was added: 
All events that meet the definition of an SAE will 
be reported as SAEs, regardless of whether they
are protocol-specific assessments or disease
related. Progression of disease should not be
considered nor should be reported as an
adverse event (or serious adverse event).
However, signs and symptoms of disease
progression or of clinical sequelae resulting
from disease progression/lack of efficacy that
are determined by the investigator to be of
clinical significance should be reported per the
usual reporting requirements (refer to Adverse
Event Definitions and Classifications in
Appendix 4: Adverse Events, Serious Adverse
Events, Product Quality Complaints, and
Other Safety Reporting: Definitions and
Procedures for Recording, Evaluating, Follow-
up, and Reporting).
To clarify the reporting procedure
related to events related to PD.
8.8. Health 
Economics OR  
Medical Resource 
Utilization and Health 
Economics 
N/A was deleted, and the following text was 
added:
Time and motion studies will evaluate participant
chair time, treatment room time, duration of
treatment administration, and active HCP time for
drug preparation, treatment administration, and
post-treatment monitoring.
To clarify study assessments.
9.2. Sample Size 
Determination  
The text in bold was added: 
For each cohort, the Simon’s two-stage design 
was identified as optimal on minimizing the
expected number of subjects through PASS 15
given the following assumptions:
 The IRR is 67% without prophylaxis
treatment (null hypothesis) and true
IRR rate is 34%
 
One-sided type-I error controlled
within 0.05 and the target power of
80%.
and the following text was deleted:
yields a Type I error rate (one sided) of 0.04 and
power of 0.8 when the true IRR rate is 0.34 (50%
reduction in IRR). Under null hypothesis,
expected sample size of the trial (for each cohort)
is estimated to be 9.1 and probability of early
stopping is estimated to be 0.687.
To provide clarification on sample
size calculation.
9.4.4. Safety Analyses The following text in bold was added: 
For clarification.

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Section Number 
and Name
Description of Change 
Brief Rationale
All subjects who received at least one cycle of IV
amivantamab  and oral lazertinib combination
therapy preceded by prophylaxis treatment will be
included in the safety analysis.
Throughout the 
protocol 
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted
Amendment 2 (12 December 2022)
Overall Rationale for the Amendment:
The overall rationale for the amendment is to add regulatory agency identifier numbers.
The changes made to the clinical protocol 61186372NSC2005 as part of Protocol Amendment 2 are listed
below, including the rationale of each change and a list of all applicable sections. Changes made in previous
protocol amendments are listed in Section 10.7 Appendix 7: Protocol Amendment History.
Section Number 
and Name
Description of Change 
Brief Rationale
Title page 
Added the EudraCT and IND numbers 
To add regulatory agency identifier
numbers.
Throughout 
Updated “country” to “country/territory” 
To align with current template
Amendment 1 (29 August 2022)
Overall Rationale for the Amendment: To implement guidance related to participant safety and dose
modification for rash-related adverse events. This amendment also serves to implement safety measures
related to venous thromboembolic events (VTEs).
The changes made to the clinical protocol 61186372NSC2005 as part of Protocol Amendment 1 are listed
below, including the rationale of each change and a list of all applicable sections.
Section Number 
and Name
Description of Change 
Brief Rationale
1.3. Schedule of 
Activities (SoA) 
Venous thromboembolic (VTE)-related footnote 
“a” for physical examination and recommendation 
of prophylactic-dose anticoagulation during the first
4 months of amivantamab and lazertinib treatment
were added.
To implement safety measures
related to VTE.
2.3. Benefit-Risk 
Assessment 
The rationale for and aims of the VTE-related safety
measures were added.
6.5.5. Venous 
Thromboembolic 
Events
A new section to provide guidance on management
of VTE events was added.
8.2.1. Physical 
Examinations 
Additional guidance for detection of VTE through
physical examination was added.
8.3.7. Adverse 
Events of Special 
Interest 
VTE was added to the list of AEs of special interest.
It was noted that events of VTE should follow
standard reporting guidelines.
11. References 
Three new references (Carrier 2019, NCCN 2022,
and Rutjes 2020) were added to the list of references
to support VTE-related information.
6.5.3. Rash-related 
Adverse Events 
The suggested algorithm for management of
Grade 4 rash was modified in Table 3.
To provide specific guidance for
rash-related 
(including 
TEN)

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Section Number 
and Name
Description of Change 
Brief Rationale
Management of severe bullous, blistering, or 
exfoliating 
skin 
conditions 
including 
toxic 
epidermal necrolysis (TEN) was added to Table 3.
adverse events and clarify for the
safety of participants.
10.4.3. Severity 
Criteria 
The following text was removed: 
Any AE will be graded as per the above. Should an 
AE become fatal or have a fatal outcome, the
original grade is not changed but “fatal” shall be
reported as an outcome.
Only in the following cases a Grade 5 event is to be
reported:
• Death NOS: only for deaths due to unknown
reason (pending follow-up information; if further
information becomes available this should be
adapted as adequate)
• Sudden 
death: 
a 
sudden 
(defined 
as
instantaneous or within 1 hour of the onset of
symptoms) cessation of life that cannot be attributed
to a CTCAE term.
To ensure all Grade 5 events are
captured.
5.4. Screen Failures 
The participant number assignment requirement for 
rescreened participants was removed.
To facilitate study operation.
10.1. Appendix 1: 
Abbreviations and 
Definitions 
Abbreviations of Independent Data Monitoring 
Committee, TEN, and VTE were added to the
abbreviation list.
To include minor updates.
Throughout the 
protocol
Minor formatting changes were made. 
Minor errors were noted.

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11. 
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Chan DBY (2023). Prevention of amivantamab infusion related reactions with extended pre-infusion day oral steroid
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Park K (2021), Joshua S, Eric BH, et.al. Management of Infusion-related Reactions (IRRs) in Patients Receiving
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ATTACHMENTS
Attachment 1: Eastern Cooperative Oncology Group (ECOG) Performance Scale
Grade Eastern Cooperative Oncology Group Performance Status
0 
Fully active, able to carry on all pre-disease performance without restriction
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or
sedentary nature, eg, light house work, office work
2 
Ambulatory and capable of all 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 any self-care. Totally confined to bed or chair
5 
Dead
Eastern Cooperative Oncology Group, Robert Comis M.D, Group Chair (Oken, 1982).

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Attachment 2: Listing of Prohibited or Restricted Medications and Therapies for Lazertinib
Medications Inhibiting CYP3A4/5
Contraindicated Drugs 
Withdrawal Period Prior To Lazertinib start
ketoconazole, itraconazole, indinavir,  nelfinavir, atazanavir, 
amprenavir, fosamprenavir, troleandomycin, telithromycin,
fluconazole, nefazodone, cimetidine, aprepitant, miconazole,
fluvoxamine
1 week
Amiodarone 
27 weeks
erythromycin, clarithromycin, verapamil, ritonavir, diltiazem  
2 weeks
Medications Inducing CYP3A4/5
Contraindicated drugs 
Withdrawal Period Prior To Lazertinib start
phenytoin, rifampicin, St. John's Wort, carbamazepine, 
primidone, griseofulvin, barbiturates, troglitazone,
pioglitazone, oxcarbazepine, nevirapine, efavirenz, rifabutin
3 weeks
Phenobarbitone 
5 weeks
Medications that are Substrates of CYP3A4
Abemaciclib, ABT 384, alfentanil, almorexant, alpha  
dihydroergocryptine, atazanavir, avanafil, avapritinib,
brecanavir, buspirone, casopitant, conivaptan, darifenacin,
darunavir, dronedarone, ebastine, elvitegravir, everolimus,
ibrutinib, ivacaftor, lomitapide, lopinavir, lovastatin,
maraviroc, midazolam, midostaurin, naloxegol, nisoldipine,
paritaprevir4, saquinavir, simeprevir, simvastatin, sirolimus,
tacrolimus, tilidine3, tipranavir, triazolam, vardenafil,
voclosporin, zanubrutinib
1 day
This listing is not intended to be exhaustive, and a similar restriction will apply to other agents
known to induce or inhibit CYP3A4/5 activity. Appropriate medical judgment is required, and any
of these medications should be utilized, if clinically indicated, for the treatment of adverse events.
Please contact the medical monitor with any questions.

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Attachment 3: Substrates of P-glycoprotein (P-gp), Multi-drug Resistance Protein 4 (MRP4), and
Breast Cancer Resistance Protein (BCRP)
Transporter 
Substrates
P gp 
Dabigatran etexilate
Digoxin
Fexofenadine
Loperamide
Auinidine
Talinolol
Vinblastine
BCRP  
Rosuvastatin
Sulfasalazine
Coumestrol
Daidzein
Dantrolene
Estrone 3 sulfate
Genistein
Prazosin
MRP4 
acyclovir
ritonavir
adefovir
tenofovir
furosemide
hydrochlorothiazide
ceftizoxime
cefazolin
methotrexate
6 mercaptopurine
6 thioguanine topotecan
olmesartan
para methoxy N ethylamphetamine

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Attachment 4: New York Heart Association Criteria
The following table presents the New York Heart Association classification of cardiac disease:
Class 
Functional Capacity  
Objective Assessment
I 
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence of cardiovascular
disease.
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity results 
in fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of minimal cardiovascular
disease.
III 
Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of moderately severe
cardiovascular disease.
IV  
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or the 
anginal syndrome may be present even at rest. If any physical activity is
undertaken, discomfort is increased.
Objective evidence of severe cardiovascular
disease.
Classification of Functional Capacity and Objective Assessment. Available at
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes of Heart
Failure UCM 306328 Article.jsp Accessed 18 March 2019.

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Attachment 5: MDRD formula for eGFR
Modified Diet in Renal Disease Formula
For standardized serum creatinine (SCr) in mg/dL, the estimated glomerular filtration rate (eGFR) is:
eGFR (MDRD) mL/min per 1.73 m2 = 175 x [standardized SCr (mg⁄dL)]-1.154 x age-0.203 x 1.212if black x
0.742if female
Creatinine levels in µmol/L can be converted to mg/dL by dividing them by 88.4.
creatinine (mg⁄dL) =
creatinine (µmol)⁄L
88.4
Alternatively, for standardized serum creatinine (SCr) in µmol/L, the estimated glomerular filtration rate
(eGFR) is:
eGFR (MDRD) mL/min per 1.73 m2  30,849 x [standardized SCr (µmol)/L)] 1.154) x age 0.203 x
1.212if black x 0.742if female
Sources: Levey (2006)

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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Research & Development
Signature: [electronic signature appended at the end of the protocol] 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD

Signature
User 
Date 
Reason
 
21-Aug-2023
16:49:55
(GMT)
Document Approval
PPD