A Phase 3, Randomized Study of Amivantamab and Lazertinib Combination Therapy Versus Osimertinib Versus Lazertinib as First-Line Treatment in Patients With EGFR-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer.
Phase: PHASE3
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Janssen Research & Development, LLC

CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved, Date: 14 November 2023
Janssen Research & Development *
Clinical Protocol
Protocol Title
A Phase 3, Randomized Study of Amivantamab and Lazertinib Combination Therapy
Versus Osimertinib Versus Lazertinib as First-Line Treatment in Patients with
EGFR-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer
MARIPOSA
Protocol 73841937NSC3003;Phase 3
AMENDMENT 4
JNJ-61186372(amivantamab) and JNJ-73841937 (lazertinib)
*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.
United States (US)sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
Regulatory Agency Identifier Numbers:
IND: 
146319
EudraCT NUMBER: 
2020-000743-31
EU Trial NUMBER: 
2023-506576-27
Status: 
Approved
Date: 
14 November 2023
Prepared by: Janssen Research & Development, LLC
EDMS number: 
EDMS-ERI-205634811, 5.0
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.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved, Date: 14 November 2023
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 4 
14-Nov-2023
Amendment 3 
22-Aug-2022
Amendment 2  
23-Sep-2021
Amendment 1 
22-Apr-2021
Original Protocol 
05-Jun-2020
Amendment 4 (14 November 2023)
Overall Rationale for the Amendment:
To continue collecting data of clinical relevance/importance while reducing the burden on participants after
the primary progression-free survival (PFS) analysis and unblinding, an open-label extension (OLE) Phase,
with reduced protocol-required visits and assessments, is being added to the study. Of note, all efficacy and
key safety assessments continue during the OLE phase of the study. After completion of the OLE Phase, a
long-term extension (LTE) Phase is also being added, to continue providing access to study treatment..
Additional changes related to the Urgent Safety Measure (venous thromboembolic events [VTE] risk with
combination of amivantamab and lazertinib) and changes related to the management of
pneumonitis/interstitial lung disease (ILD) have also been added to the protocol to optimize patient safety.
Changes related to the transition to the European Union (EU)/European Economic Area (EEA) Clinical
Trial Regulations (CTR) have also been added to the protocol.
The changes made to the clinical protocol 73841937NSC3003 as part of Protocol Amendment 4 are listed
below, including the rationale of each change and a list of all applicable sections. When changes are
provided verbatim, deleted text is shown as strikethrough, and added text is shown as bold font. Changes
made in previous protocol amendments are listed in Section 10.16 Appendix 16: Protocol Amendment
History.
Section Number 
and Name
Description of Change 
Brief Rationale
Changes related to adding an OLE Phase and an LTE Phase to the study.
1.1. Synopsis (Overall 
Design); 
4.1.4. Open-label
Extension Phase and Long-
term Extension Phase (new
subheading)
A description of the new OLE and LTE phases was
added, with cross-references to the newly added
appendices.
To add the new OLE and
LTE phases to the overall
study design.
1.2. Schema, Figure 1 
(Schematic Overview of 
the Study)
The schematic was revised to add the new OLE and
LTE phases.
To add the 2 new phases
(OLE and LTE) to the study
design.
1.3. Schedule of Activities 
(SoA): Table 1 
Added text to the title to indicate that the Schedule
of Activities for the OLE and LTE phases are
provided in Table 16 and Table 17, respectively.
To distinguish the
Schedules of Activities in
the main study from those in
the OLE and LTE phases.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved, Date: 14 November 2023
Section Number
and Name
Description of Change 
Brief Rationale
1.3. Schedule of Activities
(SoA): Table 2
Added text to the title to indicate that this Schedule 
of Activities is not applicable to the OLE and LTE 
phases. 
Pharmacokinetic and
immunogenicity samples are
not collected in OLE and
LTE phases.
6.3. Measures to Minimize
Bias: Randomization and
Blinding
The text below was added under the subheading for 
Blinding. 
The study may be unblinded after the primary
analysis for PFS.
Clarification following
addition of the new OLE
and LTE phases to the
overall study design.
6.7. Continued Access to
Study Treatment After the
End of the Study
Text referring to the OLE and LTE phases was 
added. 
For guidance on details
related to continued access
to study treatment for
participants who are still
benefiting from study
treatment.
10.7. Appendix 7: Clinical
Laboratory Tests
Text referring to the Schedule of Activities during 
the OLE Phase was added. 
To distinguish clinical
laboratory tests performed
during the OLE Phase from
those performed in the main
study.
10.13. Appendix 13:
Anticipated Events
The text shown below was added under the 
subheading for Safety Assessment Committee 
(SAC). 
The review of anticipated events will be stopped
after the OLE Phase has started. Following the
cessation of SAC reviews of anticipated events, the
anticipated events will be evaluated as part of the
ongoing medical review.
To transition anticipated
events review from SAC to
ongoing medical review.
10.14. Appendix 14: Open-
label Extension Phase (new
appendix)
The study design was modified to include a new 
study phase (an OLE Phase), to collect data of 
clinical relevance/importance while reducing the 
burden on participants after the primary PFS 
analysis is complete, and other endpoints are still
being evaluated.
Instructions on study treatment administration,
study procedures, and a Schedule of Activities for
the OLE Phase are provided in the new appendix.
During the OLE Phase, patient-reported outcomes
(PROs) will be collected during treatment phase and
then additionally for 1 year after end of treatment.
During the 1 year after  end of treatment,   data
collection frequency is reduced from every
3 months to every 6 months.
To provide detailed
information on study
conduct during the OLE
Phase.
10.15. Appendix 15: Long-
term Extension Phase (new
appendix)
The study design was modified to include a new 
study phase (an LTE Phase), whose purpose is to 
continue providing participants access to study 
treatment while further reducing the burden on 
participants after the final analysis for overall
survival is complete.
To provide detailed
information on study
conduct during the LTE
Phase.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved, Date: 14 November 2023
Section Number
and Name
Description of Change 
Brief Rationale
During the LTE Phase, PROs will not be collected.
Changes related to the risk of VTE for the combination of amivantamab and lazertinib.
6.6.1. Withholding 
Treatment 
A new bullet (shown below) has been added under
the subheading for combination treatment in Arm A
(amivantamab and lazertinib).
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 study treatment can be
resumed at the discretion of the investigator.
Table 7; Footnote “d” has been updated as shown
below for VTE in participants being treated with the
combination of amivantamab and lazertinib.
No dose reduction required for VTE events.
Study treatment initially held for stable,
treated pulmonary embolism and deep vein
thrombosis ≤Grade 3 can be resumed at the
discretion of the investigator. For VTE events
associated with clinical instability (eg,
respiratory failure or cardiac dysfunction)
in participants being treated with the
combination of amivantamab and
lazertinib, study treatment should be held
until the participant recovers from the
event. Thereafter, the study treatment can
be resumed at the discretion of the
investigator.
Table 8; Footnote “d” (shown below) has been
deleted.
No dose reduction required for VTE events.
Study treatment initially held for stable,
treated pulmonary embolism and deep vein
thrombosis ≤Grade 3 can be resumed at the
discretion of the investigator.
To clarify and align with the
latest recommendations for
VTE risk mitigation and
management.
6.6.3.12. Venous 
Thromboembolic Events 
Section for VTE updated with:
Recommendations for further imaging studies in
case of persistent symptoms of VTE or worsening
VTE.
Mitigations in case VTE events are associated with
clinical instability.
Recommendation if there is a recurrent VTE while
on therapeutic anticoagulation therapy.
To clarify and align with the
latest recommendations for
VTE risk mitigation and
management.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved, Date: 14 November 2023
Section Number 
and Name
Description of Change 
Brief Rationale
Changes related to the
management of
pneumonitis/ILD.
6.6.3.6. Pulmonary 
Toxicity  
The section for Pulmonary Toxicity was updated to 
add the text shown below. 
Study treatment should not be restarted until
pneumonitis/ILD is ruled out.
To clarify actions for
managing pneumonitis/ILD.
Changes related to the EU CTR transition, and other template-specific changes.
Cover page 
The EU Trial number was added. 
To comply with the EU
CTR transition.
1.1. Synopsis 
The IND number, EudraCT number, and EU Trial 
number were added. 
To comply with the EU
CTR transition.
1.1. Synopsis (Benefit Risk 
Assessment) (new section) 
A summary of the benefit-risk assessment for the 
study was added. 
To comply with the EU
CTR transition.
5.1 Inclusion Criteria 
Criterion 10.2
Text has been updated as shown below. 
A woman participant of childbearing potential
must have a negative serum pregnancy test at
screening and within 72 hours of the first dose of
study treatment and must agree to further serum or
urine pregnancy tests during the study.
To make language more
inclusive and gender-
neutral.
5.1 Inclusion Criteria 
Criterion 11.2
Text has been updated as shown below. 
A woman participant must be (as defined in
Appendix 4: Contraceptive Guidance and
Collection of Pregnancy Information) either of the
following:
• Note: If the childbearing potential changes after
start of the study (eg, woman participant who is
not heterosexually active becomes active,
premenarchal woman experiences menarche) the
woman participant must begin birth control, as
described above.
To make language more
inclusive and gender-
neutral.
5.1 Inclusion Criteria
Criterion 12.1
Text has been updated as shown below. 
A woman participant must agree not to donate
eggs (ova, oocytes) for the purposes of assisted
reproduction during the study and for 6 months
after receiving the last dose of study treatment.
To make language more
inclusive and gender-
neutral.
5.1 Inclusion Criteria
Criterion 13.1
Text has been updated as shown below. 
To make language more
inclusive and gender-
neutral.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved, Date: 14 November 2023
Section Number 
and Name
Description of Change 
Brief Rationale
A man participant must wear a condom when
engaging in any activity that allows for passage of
ejaculate to another person during the study and for
6 months after receiving the last dose of study
treatment. A man participant who is sexually
active with a woman person of childbearing
potential must agree to use a condom with
spermicidal foam/gel/film/cream/suppository and
his the partner must also be practicing a highly
effective method of contraception (ie, established
use of oral, injected, or implanted hormonal
methods of contraception; placement of an
intrauterine device [IUD] or intrauterine hormone-
releasing system [IUS]).
If the participant isA vasectomized participant, he
must still use a condom (with or without
spermicide) for prevention of passage of exposure
through ejaculation, but his female the partner is
not required to use contraception.
5.1 Inclusion Criteria 
Criterion 14.1
Text in strikethrough was deleted. 
A male participant must agree not to donate sperm
for the purpose of reproduction during the study and
for a minimum of 6 months after receiving the last
dose of study treatment.
To make language more
inclusive and gender-
neutral.
5.4. Screen Failures 
Added the text shown below under Participant 
Identification, Enrollment, and Screening Logs 
This study will use IWRS. The investigator will
generate screening and enrollment logs directly
from IWRS.
To comply with the current
protocol template.
6.1. Study Treatments 
Administered 
Added text related to study treatment and a new 
table categorizing the study treatments as 
investigational medicinal products (IMPs) or non- 
investigational medicinal products
(NIMPs)/auxiliary medicinal products (AxMPs),
and some associated text.
To comply with the current
protocol template and with
EU CTR guidance.
8.3.4. Regulatory 
Reporting Requirements
for Serious Adverse Events
Text was revised as shown below. 
For the purposes of this study, anticipated events
are discussed will be periodically analyzed as
specified in Appendix 13: Anticipated Events.
To comply with the current
protocol template.
8.3.5. Pregnancy  
Text was revised as shown below. 
All initial reports of pregnancy in female
participants or their partners of male participants
(through sperm of participant/from sexual
intercourse and if appropriate consent is given)
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
To make language more
inclusive and gender-
neutral.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved, Date: 14 November 2023
Section Number 
and Name
Description of Change 
Brief Rationale
form.
10.2.4. Recruitment 
Strategy (new subheading) 
Added text indicating that the study has completed 
its planned enrollment. 
To comply with EU CTR
guidance.
10.2.5. Data Protection 
Minor changes were made to text. 
To comply with the current
protocol template.
Text related to measures by the sponsor to mitigate 
possible adverse effect in the event of a data 
security breach was added.
To comply with the EU
CTR transition.
10.2. Appendix 2: 
Regulatory, Ethical, and 
Study Oversight
Considerations;
10.2.5. Data Protection
Replaced “country” with “country/territory”. 
To comply with the current
protocol template.
10.2.8. Publication 
Policy/Dissemination of 
Clinical Study Data
Minor changes were made to text. 
To comply with the current
protocol template.
10.3.4. Special Reporting 
Situations
Text was revised as shown below. 
Participant-specific special reporting situations
should be recorded in the eCRF.
To comply with the current
protocol template.
10.4. Appendix 4 
Contraceptive Guidance
and Collection of
Pregnancy Information
Text was revised to replace “woman / women” with 
“participant(s)”. 
To make language more
inclusive and gender-
neutral.
10.4. Appendix 4 
Contraceptive Guidance 
and Collection of 
Pregnancy Information
Text was revised as follows: 
• permanently sterile absence of reproductive
potential (for the purpose of this study)
- Has undergone a procedure that precludes
reproductive potential.
- Has a congenital abnormality that precludes
reproductive potential.
Permanent sterilization methods include
hysterectomy, bilateral salpingectomy, bilateral
tubal occlusion/ligation procedures, and bilateral
oophorectomy.
To comply with the current
protocol template.
10.4. Appendix 4 
Contraceptive Guidance 
and Collection of 
Pregnancy Information 
Text was revised as follows: 
(eg, a woman participant who is not heterosexually
active becomes sexually active where pregnancy
can occur)
To make language more
inclusive and gender-
neutral.
10.4. Appendix 4 
Contraceptive Guidance
and Collection of 
Pregnancy Information 
Text was revised in the section on “Examples of 
Contraceptives” as follows: 
• Sexual abstinence from intercourse where
pregnancy could occur
(Sexual abstinence is considered a highly effective
method only if defined as refraining from
heterosexual intercourse where the possibility of
To make language more
inclusive and gender-
neutral.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
8
Status: Approved, Date: 14 November 2023
Section Number
and Name
Description of Change 
Brief Rationale
pregnancy exists during the entire period of risk
associated with exposure to 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.)
Other miscellaneous changes.
4.2. Scientific Rationale 
for Study Design  
Text under the subheading Clinical Pharmacology 
Assessments was revised as shown below. 
Blood samples will be analyzed for amivantamab
serum and lazertinib plasma concentrations, and
estimation of basic PK parameters.
Because of sparse PK
sample collection for
amivantamab and lazertinib,
PK parameters will not be
estimated.
8.5.3. Pharmacokinetic 
Parameters and 
Evaluations
Text in this section was revised as shown below. 
Pharmacokinetic analysis of serum/plasma
concentration data for amivantamab and lazertinib
will be performed. Serum (amivantamab) and
plasma (lazertinib) concentrations and PK
parameters will be listed and summarized by
sampling interval.
Because of sparse PK
sample collection for
amivantamab and lazertinib,
PK parameters will not be
estimated.
9.4.3. Secondary Endpoints The definition for time to symptomatic progression 
and the analysis set for intracranial progression-free 
survival were revised, for consistency with changes 
in Addendum 1 of the statistical analysis plan (SAP) 
for the study. 
Death was inadvertently
omitted from the definition
of TTSP in the protocol.
Because of the sparse
intracranial disease
evaluation schedule (every
24 weeks) for participants
without a history of brain
metastasis at screening, the
intracranial PFS may not be
adequately assessed for
these participants.
10.1. Appendix 1: 
Abbreviations 
New abbreviations used during Amendment 3 were 
added. 
Abbreviations not used in the protocol were deleted.
To provide an updated list
of abbreviations.
Throughout the protocol 
The words “female” and “male” were removed. 
The following text was updated as follows 
“FemaleParticipant of childbearing potential” and
“FPOBCP”
To make the protocol more
inclusive and gender-
neutral.
Throughout the protocol 
Minor editorial and formatting changes were made. 
Minor errors, discrepancies,
or omissions were noted.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
9
Status: Approved, Date: 14 November 2023
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 9
LIST OF IN-TEXT TABLES AND FIGURES.............................................................................................. 13
1. 
PROTOCOL SUMMARY................................................................................................................... 14
1.1. 
Synopsis......................................................................................................................................... 14
1.2. 
Schema.......................................................................................................................................... 19
1.3. 
Schedule of Activities (SoA)........................................................................................................... 20
2. 
INTRODUCTION................................................................................................................................ 26
2.1. 
Standard of Care for NSCLC With EGFR Activating Mutations .................................................... 27
2.2. 
Amivantamab (JNJ-61186372): A Bispecific Antibody for Both EGFR and MET.......................... 28
2.3. 
Lazertinib: A Third-Generation EGFR TKI..................................................................................... 30
2.4. 
Amivantamab and Lazertinib Combination .................................................................................... 31
2.5. 
Study Rationale.............................................................................................................................. 33
2.6. 
Benefit-Risk Assessment............................................................................................................... 33
2.6.1. 
Risks for Study Participation....................................................................................................... 34
2.6.2. 
Benefits for Study Participation .................................................................................................. 34
2.6.3. 
Benefit-Risk Assessment for Study Participation ....................................................................... 34
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 36
4. 
STUDY DESIGN ................................................................................................................................ 37
4.1. 
Overall Design................................................................................................................................ 37
4.1.1. 
Screening Phase ........................................................................................................................ 37
4.1.2. 
Treatment Phase ........................................................................................................................ 37
4.1.3. 
Follow-up Phase......................................................................................................................... 38
4.1.4. 
Open-label Extension Phase and Long-term Extension Phase ................................................. 38
4.2. 
Scientific Rationale for Study Design............................................................................................. 39
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 40
4.3. 
Justification for Dose...................................................................................................................... 41
4.4. 
End of Study Definition................................................................................................................... 41
5. 
STUDY POPULATION ...................................................................................................................... 42
5.1. 
Inclusion Criteria............................................................................................................................ 42
5.2. 
Exclusion Criteria........................................................................................................................... 45
5.3. 
Lifestyle Considerations................................................................................................................. 49
5.3.1. 
Activity......................................................................................................................................... 49
5.4. 
Screen Failures.............................................................................................................................. 50
6. 
STUDY MEDICATION AND CONCOMITANT THERAPY................................................................ 50
6.1. 
Study Treatments Administered..................................................................................................... 50
6.1.1. 
Amivantamab.............................................................................................................................. 51
6.1.2. 
Lazertinib .................................................................................................................................... 52
6.1.3. 
Osimertinib.................................................................................................................................. 53
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 53
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 54
6.4. 
Study Treatment Compliance ........................................................................................................ 55
6.5. 
Concomitant Therapy..................................................................................................................... 56
6.5.1. 
Recording Prestudy and Concomitant Therapies....................................................................... 56
6.5.2. 
Amivantamab Pre-infusion and Post-infusion Medications ........................................................ 56
6.5.3. 
Permitted Medications and Therapies........................................................................................ 58
6.5.3.1. 
Supportive Care....................................................................................................................... 58
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Status: Approved, Date: 14 November 2023
6.5.3.2. 
Radiotherapy ........................................................................................................................... 58
6.5.3.3. 
Hormonal Contraception.......................................................................................................... 58
6.5.3.4. 
Prophylactic Medications......................................................................................................... 58
6.5.4. 
Prohibited or Restricted Medications and Therapies.................................................................. 58
6.6. 
Dose Modification Guidance.......................................................................................................... 59
6.6.1. 
Withholding Treatment................................................................................................................ 59
6.6.2. 
Dose Reduction .......................................................................................................................... 61
6.6.3. 
Dose Modifications and Management of Specific Adverse Events ............................................ 62
6.6.3.1. 
Infusion-Related Reactions (Arm A only) ................................................................................ 63
6.6.3.2. 
Rash-Related Adverse Events ................................................................................................ 65
6.6.3.3. 
Pruritus .................................................................................................................................... 68
6.6.3.4. 
Paronychia............................................................................................................................... 69
6.6.3.5. 
Oral Mucositis.......................................................................................................................... 69
6.6.3.6. 
Pulmonary Toxicity .................................................................................................................. 70
6.6.3.7. 
Cardiac Adverse Events.......................................................................................................... 71
6.6.3.8. 
Liver Chemistry Abnormalities................................................................................................. 72
6.6.3.9. 
Diarrhea................................................................................................................................... 72
6.6.3.10. 
Ocular Toxicity......................................................................................................................... 73
6.6.3.11. 
Paresthesia.............................................................................................................................. 73
6.6.3.12. 
Venous Thromboembolic Events............................................................................................. 74
6.7. 
Continued Access to Study Treatment .......................................................................................... 75
7. 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 75
7.1. 
Discontinuation of Study Treatment............................................................................................... 75
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 76
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 76
7.3. 
Lost to Follow-up............................................................................................................................ 76
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 77
8.1. 
Efficacy Assessments .................................................................................................................... 78
8.1.1. 
Disease Assessments ................................................................................................................ 78
8.1.2. 
Symptomatic Progression........................................................................................................... 81
8.1.3. 
Patient-Reported Outcomes....................................................................................................... 81
8.2. 
Safety Assessments....................................................................................................................... 81
8.2.1. 
Physical Examinations................................................................................................................ 82
8.2.2. 
Vital Signs................................................................................................................................... 82
8.2.3. 
Electrocardiograms..................................................................................................................... 83
8.2.4. 
Left Ventricular Ejection Fraction................................................................................................ 83
8.2.5. 
Ophthalmologic Assessment...................................................................................................... 83
8.2.6. 
ECOG Performance Status ........................................................................................................ 84
8.2.7. 
Clinical Safety Laboratory Assessments .................................................................................... 84
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 84
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 84
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 85
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 85
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 85
8.3.5. 
Pregnancy................................................................................................................................... 86
8.3.6. 
Disease-Related Events and Disease-Related Outcomes Not Qualifying as Adverse
Events or Serious Adverse Events............................................................................................. 86
8.3.7. 
Adverse Events of Special Interest............................................................................................. 86
8.4. 
Treatment of Overdose .................................................................................................................. 87
8.5. 
Pharmacokinetics........................................................................................................................... 87
8.5.1. 
Evaluations ................................................................................................................................. 87
8.5.2. 
Analytical Procedures................................................................................................................. 87
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JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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8.5.3. 
Pharmacokinetic Parameters and Evaluations........................................................................... 88
8.6. 
Pharmacogenomics ....................................................................................................................... 88
8.7. 
Biomarkers..................................................................................................................................... 88
8.8. 
Immunogenicity Assessments ....................................................................................................... 89
8.9. 
Medical Resource Utilization and Health Economics .................................................................... 90
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 90
9.1. 
Statistical Hypotheses.................................................................................................................... 90
9.2. 
Sample Size Determination ........................................................................................................... 91
9.3. 
Populations for Analyses Sets ....................................................................................................... 91
9.4. 
Statistical Analyses ........................................................................................................................ 91
9.4.1. 
General Considerations.............................................................................................................. 91
9.4.2. 
Primary Endpoint ........................................................................................................................ 92
9.4.3. 
Secondary Endpoints.................................................................................................................. 92
9.4.4. 
Exploratory Endpoints................................................................................................................. 94
9.4.5. 
Safety Analyses.......................................................................................................................... 94
9.4.6. 
Other Analyses ........................................................................................................................... 95
9.5. 
Interim Analysis.............................................................................................................................. 96
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 98
10.1. 
Appendix 1: Abbreviations ............................................................................................................. 98
10.2. 
Appendix 2: Regulatory, Ethical, and Study Oversight Considerations....................................... 100
10.2.1. 
Regulatory and Ethical Considerations .................................................................................... 100
10.2.2. 
Financial Disclosure.................................................................................................................. 103
10.2.3. 
Informed Consent Process ....................................................................................................... 103
10.2.4. 
Recruitment Strategy................................................................................................................ 104
10.2.5. 
Data Protection ......................................................................................................................... 104
10.2.6. 
Long-Term Retention of Samples for Additional Future Research .......................................... 105
10.2.7. 
Committees Structure............................................................................................................... 105
10.2.8. 
Publication Policy/Dissemination of Clinical Study Data.......................................................... 106
10.2.9. 
Data Quality Assurance............................................................................................................ 107
10.2.10. Case Report Form Completion................................................................................................. 107
10.2.11. Source Documents ................................................................................................................... 108
10.2.12. Monitoring ................................................................................................................................. 109
10.2.13. On-Site Audits........................................................................................................................... 109
10.2.14. Record Retention...................................................................................................................... 110
10.2.15. Study and Site Start and Closure ............................................................................................. 110
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting............................................................................................................. 112
10.3.1. 
Adverse Event Definitions and Classifications ......................................................................... 112
10.3.2. 
Attribution Definitions................................................................................................................ 113
10.3.3. 
Severity Criteria........................................................................................................................ 113
10.3.4. 
Special Reporting Situations .................................................................................................... 114
10.3.5. 
Procedures ............................................................................................................................... 114
10.3.6. 
Contacting Sponsor Regarding Safety, Including Product Quality........................................... 115
10.3.7. 
Product Quality Complaint Handling......................................................................................... 115
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information......................... 117
10.5. 
Appendix 5: Eastern Cooperative Oncology Group (ECOG) Performance Status...................... 120
10.6. 
Appendix 6: New York Heart Association Criteria....................................................................... 121
10.7. 
Appendix 7: Clinical Laboratory Tests ......................................................................................... 122
10.8. 
Appendix 8: Prohibited and Restricted Medications and Therapies That Induce, Inhibit, or
Are Substrates of CYP3A4/5 ....................................................................................................... 123
10.9. 
Appendix 9: Substrates of P-glycoprotein (P-gp), multi-drug resistance protein 4 (MRP4),
and Breast Cancer Resistance Protein (BCRP): Exercise Caution............................................. 125
10.10. Appendix 10: Liver Event Follow-Up and Rechallenge Criteria................................................... 126
10.11. Appendix 11: Cockcroft-Gault Formula for Estimated Creatinine Clearance .............................. 127
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JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
10.12. Appendix 12: Medications With Potential for QT Interval Prolongation....................................... 128
10.13. Appendix 13: Anticipated Events ................................................................................................. 130
10.14. Appendix 14: Open-Label Extension Phase ................................................................................ 132
10.14.1. Eligibility Criteria....................................................................................................................... 132
10.14.2. Study Treatment Administration................................................................................................ 132
10.15. Appendix 15: Long-Term Extension Phase ................................................................................. 137
10.15.1. Eligibility Criteria....................................................................................................................... 137
10.15.2. Study Treatment Administration ............................................................................................... 137
10.15.3. Study Procedures ..................................................................................................................... 137
10.16. Appendix 16: Protocol Amendment History................................................................................. 140
11. REFERENCES................................................................................................................................. 155
INVESTIGATOR AGREEMENT............................................................................................................... 158
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Schedule of Activities (All Arms, Unless Otherwise Indicated)................................................. 20
Table 2: 
Sample Collection Times for Pharmacokinetics and Immunogenicity Samples (Arm A
Only)d ........................................................................................................................................ 25
Table 3: 
Half-Maximal Inhibitory Concentration of Lazertinib or Osimertinib for Kinase Activity
by EGFR Mutation .................................................................................................................... 30
Table 4: 
Initial Dosages for Study Treatment, by Treatment Arm .......................................................... 51
Table 5: 
Pre-Infusion Medications .......................................................................................................... 57
Table 6: 
Post-Infusion Medications......................................................................................................... 57
Table 7: 
Guidance for Withholding Doses for Toxicities Based on Grade (Arm A)................................ 60
Table 8: 
Guidance for Withholding Doses for Toxicities Based on Grade (Arm B or Arm C) ................ 61
Table 9: 
Recommended Dose Reduction for Amivantamab and Lazertinib Combination
Therapy (Arm A) ....................................................................................................................... 62
Table 10: Dose Reduction for Double-Blinded Therapy (Arms B and C)................................................. 62
Table 11: Management of Infusion-Related Reactions ............................................................................ 64
Table 12: Suggested Algorithm for Management of Rash........................................................................ 67
Table 13: Suggested Algorithm for Management of Diarrhea.................................................................. 73
Table 14: Populations for Analyses .......................................................................................................... 91
Table 15: Anticipated Events .................................................................................................................. 130
Table 16: Schedule of Activities in the Open Label Extension Phase (All Arms, Unless
Otherwise Indicated)............................................................................................................... 134
Table 17: Schedule of Activities in the Long-term Extension Phase (All Arms, Unless Otherwise
Indicated) ................................................................................................................................ 139
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 19
Figure 2: Activity of Amivantamab in Combination with Lazertinib in Mice.............................................. 32
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Phase 3, Randomized Study of Amivantamab and Lazertinib Combination Therapy Versus
Osimertinib Versus Lazertinib as First-Line Treatment in Patients with EGFR-Mutated Locally
Advanced or Metastatic Non-Small Cell Lung Cancer
IND: 
146319
EudraCT NUMBER: 
2020-000743-31
EU Trial NUMBER: 
2023-506576-27
Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as
osimertinib are becoming standard of care as first-line therapy for non-small cell lung cancer (NSCLC)
harboring EGFR Exon 19del or L858R mutations. While osimertinib represents a significant advance over
earlier EGFR TKIs, almost all patients eventually relapse. There is an unmet need to improve first-line
therapy to extend progression-free survival (PFS) beyond the median of 19 months seen with osimertinib.
Early data suggest that secondary EGFR mutations such as C797S and mesenchymal-epithelial transition
(MET)activation are among the most frequent mechanisms of resistance in this setting.
Amivantamab (JNJ-61186372) is a low fucose, fully human IgG1-based bispecific antibody directed
against EGFR and MET tyrosine kinase receptors that is being developed for the treatment of solid tumors,
including EGFR-mutated NSCLC. It shows clinical activity against tumors with the primary activating
EGFR mutations Exon 19del and Exon 21 L858R substitution, EGFR Exon 20ins mutations, the EGFR
resistance mutations T790M and C797S, or activation of the MET pathway.
Osimertinib is an oral, highly potent, third-generation, EGFR TKI. It is approved for the treatment of
patients with metastatic NSCLC whose tumors have EGFR Exon 19del or Exon 21 L858R mutations as
detected by a Food and Drug Administration (FDA)-approved test, and for the treatment of patients with
metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease
has progressed on or after EGFR TKI therapy.
Lazertinib (JNJ-73841937; YH-25448), like osimertinib, is an oral, highly potent, third-generation, EGFR
TKI. It selectively inhibits both primary activating EGFR mutations (Exon 19del, Exon 21 L858R
substitution) and the EGFR T790M resistance mutation, while having less activity versus wild-type EGFR.
Nonclinical data suggest lazertinib has in vitro potency, selectivity, and high blood-brain barrier penetration
comparable with osimertinib. Results from participants in early clinical studies of lazertinib are consistent
with the clinical activity previously reported with osimertinib.
This randomized, multicenter, Phase 3 study will compare the efficacy and safety of combining
amivantamab and lazertinib (Arm A) versus single-agent osimertinib (Arm B) as first-line treatment in
participants with EGFR-mutated locally advanced or metastatic NSCLC not amenable to curative therapy.
Combining amivantamab and lazertinib may lead to improved treatment outcomes through synergistic
anti-EGFR activity, prevention of EGFR- or MET-based resistance to a third-generation EGFR TKI, and
potential recruitment of Fc-bearing immune cells in the anti-tumor response. The contribution of
amivantamab to the activity of the combination will be assessed by comparing the efficacy observed in the
amivantamab and lazertinib combination arm (Arm A) with that in a lazertinib monotherapy arm (Arm C).
BENEFIT-RISK ASSESSMENT
The safety and tolerability of amivantamab and lazertinib, as single agents and in combination, have been
shown in Phase 1 studies. The safety and tolerability of amivantamab and lazertinib in combination has also
been shown in a Phase 1 Study. The tolerability of osimertinib was shown in clinical trials.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
15
Status: Approved, Date: 14 November 2023
This study protocol includes elements to mitigate unforeseen safety risks for study participants. In addition
to monitoring participants closely for safety throughout the study, an Independent Data Monitoring
Committee (IDMC) will review safety and tolerability data periodically. Dose modification guidance is
also provided to manage toxicities that occur during the study.
Osimertinib is the standard of care first-line therapy in this patient population. All participants in the study
will accordingly be treated with a third-generation EGFR TKI, consistent with the standard of care.
Amivantamab, lazertinib, and the combination have each demonstrated activity in patients with locally
advanced or metastatic NSCLC with EGFR mutations. Amivantamab, as a monotherapy or in combination
with lazertinib, has demonstrated activity in the osimertinib-relapsed setting. It is anticipated that lazertinib
will have similar benefits to osimertinib in the first-line setting, and that combining the targeted therapies,
amivantamab and lazertinib, will be more effective than either targeted monotherapy for the treatment of
NSCLC with EGFR Exon 19del or L858R mutations, by delaying or preventing the emergence of resistance
to third generation TKI therapy mediated by either the EGFR or MET pathways.
Taking into account the measures taken to minimize risk to participants of this study, the potential risks
identified in association with amivantamab and lazertinib are justified by the anticipated benefits that may
be afforded to participants with treatment naïve, locally advanced or metastatic NSCLC with EGFR Exon
19del or L858R mutations.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
To assess the efficacy of the amivantamab and lazertinib 
combination, compared with osimertinib, in participants with 
EGFR mutation (Exon 19del or Exon 21 L858R substitution)
positive, locally advanced or metastatic NSCLC
PFS (using RECIST v1.1 guidelines), as assessed by
blinded independent central review
Key Secondary
To further assess the clinical benefit achieved using the 
amivantamab and lazertinib combination compared with 
osimertinib in participants with EGFR mutation positive, 
locally advanced or metastatic NSCLC  
Overall survival
Objective response rate
Duration of response
PFS after first subsequent therapy (PFS2)
Time to symptomatic progression
Intracranial PFS
To evaluate the safety and tolerability of the amivantamab 
and lazertinib combination compared with osimertinib 
Incidence and severity of adverse events and laboratory
abnormalities
EGFR
epidermal growth factor receptor; NSCLC
non small cell lung cancer; PFS
progression free survival; RECIST  Response
Evaluation Criteria in Solid Tumors.
Further secondary and exploratory objectives and endpoints are described in the protocol.
Hypothesis
The hypothesis is that the amivantamab and lazertinib combination (Arm A) will demonstrate superior PFS
compared with single-agent osimertinib (Arm B).
OVERALL DESIGN
The study will include a Screening Phase, a Treatment Phase, and a Follow-up Phase. Participants must
complete screening procedures within 28 days before randomization. To be randomized, all participants
must have been previously diagnosed with NSCLC, characterized by Exon 19del or Exon 21 L858R
substitution EGFR mutations.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
The Treatment Phase for a participant will begin on Cycle 1 Day 1 and continue as 28day- cycles until the
End of Treatment visit, approximately 30 days after discontinuation of study treatment. Participants who
discontinue study treatment for any reason will be followed for survival and symptomatic progression in
the Follow-up Phase. The Follow-up Phase starts after the End of Treatment Visit and continues until the
end of study, death, lost to follow-up, or withdrawal of consent, whichever comes first.
Following the primary PFS analysis for efficacy, the study will transition to an open-label extension (OLE)
Phase (see details provided in Section 10.14 [Appendix 14]). The purpose of the OLE Phase is to continue
to collect data of clinical relevance/importance while reducing protocol-required visit procedures and
assessments and the burden on participants after the primary PFS analysis and unblinding. Unblinding will
occur for blinded Arms B and C. Only active treatment will be provided, without placebo.
Participants will be provided the option to continue their current study treatment in the OLE Phase until the
final analysis for overall survival, after which the study will transition to a long-term extension (LTE)
Phase.
Participants who continue to benefit from study treatment(s), as determined by their investigator, at the time
of completion of the OLE Phase may continue to receive access to study treatment(s) within the study by
transferring to the LTE Phase, where only serious adverse event data and study treatment compliance will
be collected. The LTE Phase will continue to provide participants access to study treatment and further
reduce protocol-required visit procedures and assessments, after the final analysis for overall survival is
complete.
The LTE Phase (see details provided in Section 10.15 [Appendix 15]) will begin after the final analysis for
overall survival, and will continue until the discontinuation criteria described in Section 7.1 are met, or until
4 years after local marketing authorization is obtained for the studied indication, whichever occurs first.
The OLE phase will begin after approval ofAmendment 4 by health authorities of countries/territories in
which this study is being conducted at the time of transition, and by study site Independent Ethics
Committees/Institutional Review Boards (IECs/IRBs). In addition, for transition to the LTE Phase (after
final analysis for overall survival), notification from the sponsor will be provided.
NUMBER OF PARTICIPANTS
Approximately 1000 eligible participants will be randomly assigned to study treatment in a 2:2:1 ratio (Arm
A, B, and C respectively). Randomization will be stratified by mutation type (Exon 19del vs Exon 21
L858R), race (Asian vs non-Asian), and history of brain metastasis (present vs absent).
STUDY TREATMENT GROUPS AND DURATION
Arm A: Approximately 400 participants will be assigned to open-label treatment with the combination
of amivantamab (1050 mg for body weight <80 kg and 1400 mg for body weight ≥80 kg by intravenous
[IV] infusion, once weekly for the first 4 weeks and then once every 2 weeks) and lazertinib (240 mg
orally, once daily).
Arm  B: Approximately 400 participants will receive double-blind treatment with single-agent
osimertinib (80 mg orally, once daily).
Arm C: Approximately 200 participants will receive double-blind treatment with single-agent
lazertinib (240 mg orally, once daily).
Study treatments may be withheld and the dosages may be subsequently modified to manage
treatment-related toxicity. Refer to the protocol for guidance.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
Study treatment should continue until one of the following criteria applies: documented disease progression
using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; withdrawal of consent; the
investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it is in the best interest
of the participant to discontinue study treatment; the participant becomes pregnant; or noncompliance with
study treatment or procedure requirements.
EFFICACY EVALUATIONS
Tumor response will be assessed by blinded independent central review (BICR) according to RECIST v1.1.
Baseline disease assessments, including brain magnetic resonance imaging (MRI) should be performed no
more than 28 days prior to randomization. Repeat imaging will occur at regular intervals, as defined in the
Schedule of Activities, until disease progression.
PHARMACOKINETIC EVALUATIONS
Blood samples will be collected from participants receiving amivantamab for the measurement of serum
amivantamab and plasma lazertinib.
IMMUNOGENICITY EVALUATIONS
Blood samples will be collected and analyzed for antibodies to amivantamab using a validated
immunoassay. Serum samples will be screened for antibodies binding to amivantamab, and other
immunogenicity analyses may be performed to further characterize any immune responses generated.
BIOMARKER EVALUATIONS
Blood samples and tumor tissue collected at Screening and during the study may be evaluated for
biomarkers relevant to cancer to understand the molecular biology of the tumor, efficacy observed with
study treatments, and mechanisms of acquired resistance to study treatments.
SAFETY EVALUATIONS
Safety will be assessed by physical examinations, laboratory tests, vital signs, electrocardiograms, left
ventricular ejection fraction (echocardiogram or multigated acquisition), Eastern Cooperative Oncology
Group (ECOG) performance status, monitoring of adverse events, and concomitant medication usage.
STATISTICAL METHODS
The statistical hypothesis assumes that, compared with single agent osimertinib (Arm B), the amivantamab
and lazertinib combination (Arm A) will prolong median PFS from 19 months to 26 months. Taking account
ofthe accrual period, follow-up, and dropout rate, the sample size needed for the study is approximately
800 participants (400 per Arm A and Arm B). A total of 450 PFS events in Arm A and Arm B combined
will provide approximately 90% power to detect a hazard ratio (HR)of 0.73 with the stratified log-rank test
(2-sided alpha = 0.05).
The primary efficacy endpoint is PFS, defined as the time from randomization until the date of objective
disease progression or death, whichever comes first, based on BICR using RECIST v1.1. The treatment
effect of the combination compared to osimertinib on PFS will be analyzed using a log-rank test stratified
by mutation type (Exon 19del vs Exon 21 L858R), race (Asian vs non-Asian), and history of brain
metastasis (present vs absent). The HR for PFS will be calculated, along with its 95% confidence intervals,
from a stratified Cox model using the same stratification factors as for the log-rank test.
The key secondary endpoint of OS will be analyzed using the same methodology and model as for the
analysis of PFS. A hierarchical testing approach for the primary endpoint and key secondary endpoint will
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
be used: the comparison between the combination and osimertinib for OS will be conducted only if the
comparison for PFS shows statistical significance.
The comparison of the combination of amivantamab and lazertinib therapy (Arm A) versus lazertinib
monotherapy (Arm C) will also be performed to demonstrate the contribution of amivantamab to the activity
of the combination using summary statistics of the primary endpoint and key secondary endpoint (PFS and
OS) along with nominal p-values; there will be no hypothesis testing for this comparison.
A futility analysis based on PFS will be conducted when approximately 150 PFS events have occurred
overall (all treatment arms combined). An Independent Data Monitoring Committee will be commissioned
for this study. Statistical methods for other endpoints will be described in the Statistical Analysis Plan.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
19
Status: Approved, Date: 14 November 2023
1.2. 
Schema
Figure 1: 
Schematic Overview of the Study
EGFR epidermal growth factor receptor; IV intravenous; LTE long term extension; NSCLC non small cell lung cancer;
PFS progression free survival; OLE open label extension; OS overall survival; QD once daily.
*Weight based dosing: <80 kg/≥80 kg
†Cycle 1: Days 1/2 (split dose), 8, 15, 22; Cycles 2+: Days 1, 15
NCT04487080

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NCT04487080

NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
24
Status: Approved, Date: 14 November 2023
BICR
blinded independent central review; C#D# Cycle # Day #; CT computerized tomography; ctDNA circulating tumor deoxyribonucleic acid; ddPCR digital droplet polymerase chain reaction;
ECG electrocardiogram; ECHO echocardiogram; ECOG Eastern Cooperative Oncology Group; EORTC QLQ C30 European Organization for the Research and Treatment of Cancer Quality of Life
Questionnaire Core 30; EQ 5D 5L EuroQol five dimensional descriptive system (5 level version); GSTM 1 glutathione S transferase Mu 1; HBV hepatitis B virus; HCV hepatitis C virus; HIV human
immunodeficiency virus; ICF informed consent form; IV intravenous; MUGA multigated acquisition; MRI magnetic resonance imaging; NSCLC SAQ Non Small Cell Lung Cancer Symptom
Assessment Questionnaire; PD progressive disease; PGIC Patient Global Impression of Change; PGIS Patient Global Impression of Severity; VTE venous thromboembolic; Q12 weeks every 12 weeks.
a. 
If performed within 72 hours before the first dose of study treatment, then the assessment does not need to be repeated at Cycle 1 Day 1.
b. 
With the exception of the end of treatment pregnancy test for participants of childbearing potential, which must occur at least 30 days after the last dose of study treatment, end of treatment procedures
may be conducted before 30 days after last dose of study treatment if new anti cancer therapy is to be initiated.
c. 
Evaluate for early signs and symptoms of VTE. A focused physical examination of extremities and evaluation of respiratory status (including pulse oximetry) should be performed.
d. 
See Section 6.6.3.12 for additional information. Please refer to NCCN Guidelines 22 Version 1.2022 cancer associated venous thromboembolic disease section VTE B for examples of prophylactic dose
anticoagulants in ambulatory cancer patients.
e. 
Study participants who permanently discontinue amivantamab and continue open label lazertinib can follow the visit schedule for Arms B/C if the discontinuation occurs after C1.
NCT04487080

NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
2. 
INTRODUCTION
Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such
as osimertinib are becoming standard of care as first-line therapy for non-small cell lung cancer
(NSCLC) harboring EGFR  Exon 19del or L858R mutations. While osimertinib represents a
significant advance over earlier EGFR TKIs, almost all patients eventually relapse. There is an
unmet need to improve first-line therapy to extend progression-free survival (PFS) beyond the
median of 19months seen with osimertinib. Early data suggest that secondary EGFR mutations
such as C797S and mesenchymal-epithelial transition (MET) activation are among the most
frequent mechanisms of resistance in this setting.
Amivantamab (JNJ-61186372) is a low fucose, fully human IgG1-based bispecific antibody
directed against EGFR and MET tyrosine kinase receptors that is being developed for the treatment
of solid tumors, including EGFR-mutated NSCLC. It shows clinical activity against tumors with
the primary activating EGFR mutations Exon 19del or Exon 21 L858R substitution, EGFR
Exon 20ins mutations, the EGFR resistance mutations T790M or C797S, and activation of the
MET pathway.12
Osimertinib is an oral, highly potent, third-generation, EGFR TKI. It is approved for the treatment
of patients with metastatic NSCLC whose tumors have EGFR Exon 19del or Exon 21 L858R
mutations as detected by a Food and Drug Administration (FDA)-approved test, and for the
treatment of patients with metastatic EGFR T790M mutation-positive NSCLC as detected by an
FDA-approved test, whose disease has progressed on or after EGFR TKI therapy.37
Lazertinib (JNJ-73841937; YH-25448), like osimertinib, is an oral, highly potent,
third-generation, EGFR TKI. It selectively  inhibits both primary activating EGFR mutations
(Exon 19del, Exon 21 L858R substitution) and the EGFR T790M resistance mutation, while
having less activity  versus wild-type EGFR. Nonclinical data suggest lazertinib has in vitro
potency, selectivity, and high blood-brain barrier penetration  comparable with osimertinib.13,39
Results from participants in early clinical studies of lazertinib are consistent with the clinical
activity previously reported with osimertinib.3
This randomized, multicenter, Phase 3 study will compare the efficacy and safety of combining
amivantamab and lazertinib (Arm A) versus single-agent osimertinib (Arm B) as first-line
treatment in participants with EGFR-mutated locally advanced or metastatic NSCLC not amenable
to curative therapy. Both amivantamab and lazertinib are new investigational products. The
contribution of amivantamab to the activity of the combination will be assessed by comparing the
efficacy observed in the amivantamab and lazertinib combination arm (Arm A) with that in the
lazertinib monotherapy arm (Arm C).
The term “study treatment” throughout the protocol, refers to study drug (amivantamab, lazertinib,
or osimertinib), as defined in Section 6.1. The term "sponsor" used throughout this document refers
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
27
Status: Approved, Date: 14 November 2023
to the entities listed in the Contact Information page(s), which will be provided as a separate
document. The term "participant" throughout the protocol refers to the common term "subject".
For the most comprehensive nonclinical and clinical information regarding amivantamab or
lazertinib, refer to the latest version of the Investigator's Brochure (IB).12,13 For additional
information regarding osimertinib, refer to local prescribing information.37
2.1. 
Standard of Care for NSCLC With EGFR Activating Mutations
Worldwide, lung cancer is the most commonly diagnosed cancer (11.6% of total cases) and the
leading cause ofcancer death (18.4% oftotal cancer deaths).8 NSCLC accounts for 80% to 85%
of lung cancers.1 Five-year survival rates for NSCLC depend on the stage at diagnosis, ranging
from 57% for localized cancer to 5% for cancer that has spread to distant locations.36 In patients
with  metastatic NSCLC, clinical guidelines recommend testing for activating mutations.21,27
Among patients with NSCLC, the most prevalent actionable driver mutations are those that result
in the activation of EGFR. These are identified in more than 15% of patients with
adenocarcinoma24 and up to 50% of the corresponding Asian population.14 Approximately 85% to
90% of primary activating EGFR mutations are Exon 19deletions (Exon 19del)or Exon21 L858R
substitutions (L858R).34
Initially, first-generation anti-EGFR TKIs such as erlotinib or gefitinib were the standard of care
as first-line therapy for adenocarcinoma in patients with tumors harboring Exon 19del or L858R
mutations.7,32  First-generation EGFR TKIs demonstrated both improved initial response rates and
prolonged PFS in direct comparisons with combination chemotherapy. Although tumors bearing
Exon 19del or L858R primary activating mutations are initially responsive to first-generation
EGFR TKIs, virtually all of these tumors acquire resistance, with the majority (approximately
60%) acquiring a second-site point mutation, T790M.16,25 Patients with T790M+ NSCLC are
typically treated in second-line with third-generation TKIs (eg, osimertinib), which are active
against T790M+, while patients without this mutation (ie, T790M-negative NSCLC) are treated
with chemotherapy.21,27 Compared with older EGFR TKIs, osimertinib penetrates the blood-brain
barrier better and treats brain metastasis more effectively, which occurs in approximately 10% to
20% of patients with treatment-naïve EGFR-mutated NSCLC.31
More recently, the FLAURA study compared the third-generation EGFR TKI osimertinib versus
a standard EGFR TKI (gefitinib or erlotinib) as first-line therapy for patients with metastatic
NSCLC and Exon 19del or L858R mutations.35 With its demonstrated activity against the EGFR
T790M+ resistance mutation, it was hypothesized that osimertinib as a first-line treatment would
delay the emergence of T790M+  mediated resistance, resulting in improved disease control.
Correspondingly, FLAURA demonstrated a statistically significant improvement in PFS and
overall survival (OS) for participants randomized to osimertinib versus a first-generation EGFR
TKI: median PFS was 18.9 vs 10.2 months, respectively, with a hazard ratio (HR) of 0.46; and
median OS  was 38.6 vs 31.8 months, respectively, with a HR  of 0.80.30,35 This significant
improvement in median PFS with osimertinib treatment was not associated with an improved
response rate, suggesting that the majority of benefit may have been derived from its activity
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
28
Status: Approved, Date: 14 November 2023
against the T790M resistance mutation and improved activity within the central nervous system
(CNS).
Despite the improved initial disease control, however, almost all patients treated with first-line
osimertinib will relapse, and there are no approved targeted therapies for treatment of these patients
once resistance has developed. The mechanisms underlying osimertinib relapse are less well
understood, but early data suggest that secondary EGFR mutations, such  as C797S and MET
activation, are among the most frequent mechanisms of resistance in this setting.9,29 While
osimertinib represents a significant advance over earlier EGFR TKIs, there is a need to improve
on first-line treatment prior to the development of resistance in order to extend PFS beyond the
median of 19months seen with osimertinib monotherapy.
2.2. 
Amivantamab(JNJ-61186372): A Bispecific Antibody for Both EGFR and
MET
Unlike EGFR TKIs, which bind to the intracellular portion of the EGFR, amivantamab is a novel
bispecific antibody that targets the extracellular domain of both EGFR and MET. Nonclinical data
have demonstrated at least 3 potential mechanisms of action, including 1)inhibition of
ligand-dependent signaling, 2)receptor degradation, and 3) initiation of antibody-dependent
cellular cytotoxicity (ADCC).12  It is hypothesized that by targeting the extracellular domain of
EGFR and MET, amivantamab can inhibit tumor growth driven by EGFR and MET receptors,
including tumors that display primary resistance to EGFR TKIs (Exon 20ins) or have acquired
resistance through either EGFR resistance mutations (T790M or C797S) or secondary activation
of the MET pathway (MET amplification).
An ongoing Phase 1 study of amivantamab (Study 61186372EDI1001) enrolled more than
250 participants as of the 30 October 2019 data cutoff date. The recommended Phase 2 dose
(RP2D)was determined to be 1050 mg in participants <80 kg (1400 mg in participants ≥80 kg) by
intravenous (IV) infusion, administered weekly for the first 4 weeks, and then biweekly thereafter.
Amivantamab has a manageable safety profile up to the dose of 1750 mg, with no dose-limiting
toxicities (DLTs) reported during dose escalation and no maximum tolerated dose (MTD)
identified (see IB).12 The most common treatment-emergent adverse events (TEAEs) in
153 participants treated at the RP2D were infusion-related reactions (IRRs; 61%), rash (31%) and
dermatitis acneiform (29%), paronychia (28%), constipation (22%), dyspnea (21%), fatigue
(20%), and hypoalbuminemia (20%). The majority of TEAEs were of Grade 1-2 severity. TEAEs
of Grade 3 or Grade 4 severity considered by the investigator to be related to amivantamab were
reported in 14 subjects (9%) treated at the RP2D, the most common being rash in 2 (1%) subjects.
Consistent with the overall safety profile at the RP2D, dose reduction and discontinuation of
treatment due to TEAE were infrequent. Eight subjects (5%) treated at the RP2D experienced at
least 1 TEAE considered related to amivantamab that led to dose reduction. These TEAEs included
dermatitis acneiform (2 subjects) and rash, fatigue, edema peripheral, cellulitis, paronychia, and
lactic acid dehydrogenase elevation (1 subject each). Six subjects (4%) treated at the RP2D
experienced at least 1 TEAE leading to discontinuation of amivantamab treatment, with 3 (2%)
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
29
Status: Approved, Date: 14 November 2023
reported as related to amivantamab: these 3 TEAEs leading to discontinuation were IRR
(2 subjects) and paronychia.
Infusion-related reactions have been commonly observed, typically within the first 90 minutes of
beginning the first infusion of amivantamab. Subsequent infusions, including Cycle 1 Day 2, are
associated with dramatically reduced IRR risk, such that predose steroids are not required starting
with Cycle 1 Day 8. As of the 30 October 2019 data cutoff date, 158 of 252 (63%) total treated
subjects experienced at least 1 IRR. Adverse events associated with IRRs that occurred in more
than 10% of all treated subjects included the following: nausea (21%), chills and dyspnea (19%
each), flushing (16%), and chest discomfort (12%). Transient increases in mean blood pressure,
mean pulse rate, and mean respiratory rate, and decreases in mean oxygen saturation were noted
during the first infusion of amivantamab in all dose cohorts. The majority of IRRs were of Grade 2
severity, reflecting the guidance to temporarily interrupt infusion at the first sign of IRR symptoms.
In rare cases, IRRs of Grade 3 severity were reported. Re-occurrence of IRRs on subsequent doses
was infrequent; the occurrence of an IRR  on first infusion should not be considered a
contraindication to further treatment with amivantamab.
Evidence of clinical activity has been observed across patients with diverse EGFR-mutated
disease, including those characterized by primary EGFR L858R, Exon 19del, G719A, and
Exon 20ins disease, as well as EGFR T790M or C797S resistance mutations, and MET-based
EGFR TKI resistance (both MET amplification and MET Exon 14skip mutation).10,12 Based on
interim data for evaluable subjects in the Phase 1 study, 32 of 108 subjects (30%) experienced
tumor best response of partial response (PR), including subjects who were primarily resistant to
third-generation EGFR TKI therapy (including primary EGFR Exon 20ins disease), as well as
EGFR C797S mutation or MET amplification after third-generation EGFR TKI relapse.12  Based
on the preliminary activity observed in the Exon 20ins population, amivantamab was granted
Breakthrough Therapy Designation by the United States (US) FDA for the treatment of patients
with EGFR Exon 20ins disease who have progressed after prior treatment with platinum-based
chemotherapy. Given the monotherapy activity observed with amivantamab in third-generation
EGFR TKI relapsed disease characterized by EGFR C797S  resistance mutation or MET-based
EGFR TKI resistance pathways, it is anticipated that administration of amivantamab in the first-
line setting, in combination with lazertinib, will prolong disease control by suppressing the
emergence of EGFR and MET resistance pathways to third-generation EGFR TKIs.
Amivantamab has also been demonstrated to induce ADCC in nonclinical models, via its Fc
domain that has been optimized for interaction with Fc-bearing immune cells.12 In these models,
treatment with an analogous molecule with a silent Fc domain reduced anti-tumor activity by up
to approximately 50%. These data suggest that inclusion of amivantamab in the first-line setting
provides an opportunity to recruit immune cells in an anti-tumor response, in a disease that is
considered to be relatively resistant to currently approved anti-PD(L)1 agents, due to their inherent
low mutational burden.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
30
Status: Approved, Date: 14 November 2023
2.3. 
Lazertinib: A Third-Generation EGFR TKI
Lazertinib, like osimertinib, is a third-generation, irreversible EGFR TKI that has high affinity for
and inhibits both primary activating Exon 19del or Exon 21 L858R substitution EGFR mutations
and the EGFR T790M+ resistance mutation, while having lower affinity for EGFR wild-type to
minimize EGFR-related toxicities. In cell-free kinase activity studies, lazertinib selectively
inhibited EGFR single- or double-mutant kinase compared with wild-type EGFR (Table 3). In
non-clinical studies, lazertinib exhibited high blood-brain barrier penetration and excellent
therapeutic efficacy against both primary lung tumors and brain metastases in a T790M mutant
NSCLC xenograft model, and achieved cerebrospinal fluid (CSF) concentrations exceeding the
IC50 value for p-EGFR inhibition in vitro.39
Table 3: 
Half-Maximal Inhibitory Concentration of Lazertinib or Osimertinib for Kinase Activity by
EGFR Mutation
EGFR Kinase Genotype 
IC50, nM
Lazertinib 
Osimertinib
Wild-type 
76.0 
54.0
Del19 
5.3 
8.6
L858R  
20.6 
12.2
Del19/T790M  
1.7 
2.2
L858R/T790M  
2.0 
8.0
ErbB2  
364.0 
44.0
ErbB4  
1017.0 
54.0
EGFR=epidermal growth factor receptor; IC50=half-maximal inhibitory concentration.
Adapted from Yun 2019.39
The safety and activity of lazertinib were evaluated in a Phase 1/2 study (73841937NSC2001;
YH25448-201).13 As of the date of data cutoff on 30 September2019, there were 181 subjects who
were evaluable for efficacy  with EGFR-mutated advanced NSCLC that had progressed after
therapy with afirst- or second-generation EGFR TKI.13 Among 162 subjects with T790M+ disease
(n 162), the objective response rate (ORR) was 59% and the median PFS was 10.9 months across
all dose levels, as assessed by independent central review.3,13 These results were comparable to
those of osimertinib in the Phase 1 AURA study, in which  participants with T790M+ disease
showed an ORR of 61% and a median PFS of 9.6 months across all dose levels.15 In the lazertinib
Phase 1/2 study, among 22 subjects with measurable brain lesions the intracranial ORR  by
independent central review and investigator assessment were 55% and 64%, respectively, and
intracranial PFS was not reached at a follow-up of 20.5 months, indicating lazertinib achieves
effective blood-brain barrier penetration.13,26 In 62 subjects with T790M+ disease who received
lazertinib 120 mg, 160 mg, or 240 mg, the median PFS was 12.3 months.3
Lazertinib was well tolerated across all doses (from 20 mg up to 320 mg)in 252 subjects who were
evaluable for safety.3,13 No DLTs occurred in dose escalation. The most commonly reported
TEAEs occurring in  >20% of subjects (any grade) were rash, pruritus, diarrhea, paresthesia,
constipation, upper respiratory infection, and decreased appetite. Grade 3 or 4 events were
observed in  35.3% of subjects. The most commonly reported (>1%) serious TEAEs were
pneumonia, asthenia, dyspnea, and pulmonary embolism. Drug-related serious TEAEs were
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
31
Status: Approved, Date: 14 November 2023
reported in 8 (3.2%) subjects. TEAEs leading to death occurred in 5 subjects (pulmonary embolism
in 2 subjects, death, dyspnea, and atypical pneumonia in 1 subject each) but none were considered
to be possibly related to lazertinib. TEAEs leading to dose reduction or drug discontinuation were
observed in  11.1% and 7.9% of subjects, respectively. Overall, the incidence and severity of
adverse events seen in this study were similar to those of osimertinib in the Phase 1 AURA study.15
However, cardiac safety assessment in these subjects has shown that lazertinib has no clinically
relevant effect on QT interval and left ventricular ejection fraction (LVEF).3
Based on pharmacokinetics (PK), efficacy, and safety, the RP2D for T790M-positive subjects was
selected as 240 mg once daily. Another Phase 3, randomized, double-blind study (YH25448-301;
LASER301) will assess the efficacy and safety of lazertinib versus gefitinib as first-line treatment
in subjects with locally advanced or metastatic NSCLC with EGFR Exon 19del or L858R
mutations.28
2.4. 
Amivantamab and LazertinibCombination
The current clinical experience with lazertinib suggests activity at least equivalent to current
standard of care osimertinib, and clinical experience with amivantamab demonstrates activity in
third-generation EGFR TKI-relapsed disease. Thus, combining these agents in the first-line
treatment of patients with EGFR-mutated NSCLC may lead to improved treatment outcomes
through synergistic anti-EGFR activity, prevention of EGFR- or MET-based resistance to a
third-generation EGFR TKI, and potential recruitment of Fc-bearing immune cells in the
anti-tumor response.
Nonclinical studies have evaluated the efficacy of amivantamab in combination with lazertinib
using a H1975-HGF NSCLC xenograft model in mice.12,19 These xenografts model NSCLC
tumors with an activating EGFR mutation (L858R), a second-site resistance EGFR mutation
(T790M+), and activation of the MET  pathway by autocrine expression of the MET  ligand,
hepatocyte growth factor (HGF). Single-agent treatment with amivantamab or lazertinib resulted
in significant tumor growth inhibition (70% and 75%, respectively) as compared to isotype and
vehicle-treated controls at Day 28 (p 0.0059 and p 0.0030; Figure 2). The combination of
amivantamab with lazertinib resulted in significant tumor growth inhibition (109%) as compared
to isotype- and vehicle-treated controls at Day 28 (p<0.0001). The combination of amivantamab
with lazertinib also demonstrated statistically significant tumor growth inhibition as compared to
single-agent treatment (p<0.0001). These nonclinical data are consistent with the hypothesis that
through their complementary mechanisms of action, the amivantamab and lazertinib combination
can result in significantly better anti-tumor activity than either agent alone in H1975-HGF
xenografts.
NCT04487080

NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
no impact on subsequent dosing. Incidence of diarrhea remains low at 18% and again mostly Grade
1-2. The safety profile indicates amivantamab and lazertinib are combinable.
Of the 91 subjects with EGFR Exon19del or L858R disease treated with the combination,
26 subjects were in the dose escalation cohort, 45 were osimertinib- resistant but chemotherapy-
naïve, and 20 subjects were treatment naïve. In the osimertinib-relapsed but chemotherapy-naïve
cohort (N 45) the combination of lazertinib and amivantamab demonstrated a confirmed ORR of
36% (95% CI, 22%-51%), including 1 complete response and 15 partial responses, and a clinical
benefit rate of 60%. In the 20 patient cohort with treatment-naïve EGFR Exon 19del or L858R
disease, the combination of lazertinib and amivantamab demonstrated an investigator-assessed
confirmed partial response in all 20 subjects, for an ORR of 100% (95% CI, 83%-100%), with a
median time to first response of 1.5 months. After 18 months of follow-up, the median duration of
response was not estimable with 16 of 20 subjects remaining on therapy without progression.
In conclusion, the clinical data from Study 61186372EDI1001 indicate that amivantamab can be
safely combined with lazertinib and suggest that the combination is efficacious in advanced
EGFRm NSCLC including subjects who are treatment naïve.
The combination of amivantamab and lazertinib is being explored further in
Study 73841937NSC1001 in a cohort of patients with either EGFR Exon19del or L858R NSCLC
who have progressed after osimertinib and subsequent platinum-based doublet chemotherapy, or
in patients with other EGFR mutations.
2.5. 
Study Rationale
The FLAURA study has demonstrated that an effective approach to improving treatment outcomes
in EGFR mutation driven NSCLC is to employ first-line therapies with activity against potential
mechanisms of resistance, either through resistance mutations, or via escape through sanctuary
sites such as the CNS. Given the observed broad activity of amivantamab in EGFR- or MET-driven
disease, its use in the first-line setting may provide improved clinical benefit by suppressing the
development of C797S mutations and MET amplification when given together with lazertinib, a
third-generation EGFR TKI with demonstrated CNS activity. In addition, combination of
amivantamab with lazertinib is anticipated to provide synergistic activity against the primary
EGFR activating mutations as demonstrated in nonclinical models (Figure 2). Finally, the
inclusion of amivantamab in the first-line setting may also uniquely recruit immune cells as part
of its anti-tumor response, via its Fc domain designed to maximize affinity with immune cell Fc
receptors. In this manner, the combination of amivantamab and lazertinib has the potential to build
upon the improvements of osimertinib, as demonstrated by the FLAURA study, but also introduce
new anti-tumor mechanisms of anti-tumor activity in the first-line setting.
2.6. 
Benefit-RiskAssessment
More detailed information about the known and expected benefits and risks of amivantamab and
lazertinib may be found in the IB for each product.12,13 Information about the benefits and risks of
osimertinib may be found in the local prescribing information.37
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
34
Status: Approved, Date: 14 November 2023
2.6.1. 
Risks for Study Participation
The safety and tolerability of amivantamab monotherapy  was shown in the Phase 1 Study
61186372EDI1001 (Section 2.2). The safety and tolerability of single-agent lazertinib was shown
in the Phase 1/2 Study 73841937NSC2001 (refer to Section 2.3). The safety and tolerability of
amivantamab and lazertinib in combination was also shown in the Phase 1 Study
61186372EDI1001 (Section 2.4). The tolerability of osimertinib was shown in clinical trials (refer
to local prescribing information37).
Unforeseen safety risks associated with the study treatments are possible. This study protocol
includes the following elements to mitigate risks for study participants:
An Independent Data Monitoring Committee (IDMC)will review safety and tolerability data
periodically and review pre-planned efficacy analyses as per protocol.
Participants will be monitored closely for safety throughout the study (refer to Section 8.2).
Dose modification guidance is provided to manage toxicities that occur during the study (refer
to Section 6.6), including specific guidance for IRRs, rash, pruritus, interstitial lung disease
(ILD), pulmonary toxicity, paresthesia, cardiac adverse events, liver chemistry abnormalities,
oral mucositis, paronychia, diarrhea, ocular toxicity, and venous thromboembolic (VTE)
events.
2.6.2. 
Benefits for Study Participation
Osimertinib is the standard of care first-line therapy in this patient population. All participants in
the study will accordingly be treated with a third-generation EGFR TKI, consistent with the
standard of care.
Amivantamab, lazertinib, and the combination have each demonstrated activity in patients with
locally advanced or metastatic NSCLC with EGFR mutations. Amivantamab, as a monotherapy
or in combination with lazertinib, has demonstrated activity in the osimertinib-relapsed setting. It
is anticipated that lazertinib will have similar benefits to osimertinib in the first-line setting, and
that combining the targeted therapies, amivantamab and lazertinib, will be more effective than
either targeted monotherapy  for the treatment of NSCLC with EGFR Exon 19del or L858R
mutations, by delaying or preventing the emergence of resistance to third-generation TKI therapy
mediated by either the EGFR or MET pathways.
2.6.3. 
Benefit-Risk Assessment for Study Participation
Taking into account the measures taken to minimize risk to participants ofthis study, the potential
risks identified in association with amivantamab and lazertinib are justified by the anticipated
benefits that may be afforded to participants with treatment-naïve, locally advanced or metastatic
NSCLC and EGFR Exon 19del or L858R mutations.
For the duration of this ongoing study, the assessment of risk has been monitored by the IDMC,
who have reviewed unblinded safety data through the protocol-specified futility analysis on
20 July 2022, when the IDMC first reviewed the unblinded safety and efficacy data of
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
1,038 randomized participants in the study. After reviewing the unblinded safety and efficacy data,
the IDMC confirmed a favorable benefit-risk assessment, and therefore recommended
continuation of the study. The IDMC also recommended that additional measures be taken to
mitigate an observed increase in VTE events in Arm A 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.
VTE-related changes implemented during protocol Amendment 3 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 adopted, after IDMC review, to
further optimize the benefit-risk balance for participants in the study.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
36
Status: Approved, Date: 14 November 2023
3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
To assess the efficacy of the amivantamab and lazertinib 
combination, compared with osimertinib, in participants with 
EGFR mutation (Exon 19del or Exon 21 L858R substitution)
positive, locally advanced or metastatic NSCLC
PFS according to RECIST v1.1 by blinded independent
central review
Secondary
To further assess the clinical benefit achieved using the 
amivantamab and lazertinib combination compared with 
osimertinib in participants with EGFR mutation positive, 
locally advanced or metastatic NSCLC  
Overall survival
Objective response rate
Duration of response
PFS after first subsequent therapy
Time to symptomatic progression
Intracranial PFS
To evaluate the safety and tolerability of the amivantamab 
and lazertinib combination compared with osimertinib 
Incidence of severity of adverse events and clinical
laboratory abnormalities, assessment of vital signs, and
physical examination abnormalities
To evaluate pharmacokinetics or immunogenicity for 
amivantamab and pharmacokinetics for lazertinib and assess 
their relationship to selected endpoints (including but not
limited to efficacy, safety, and/or patient reported outcomes)
Serum amivantamab and plasma lazertinib
concentrations, and serum anti amivantamab antibodies
To assess health related quality of life and disease related 
symptoms in participants treated with the amivantamab and 
lazertinib combination compared with osimertinib
NSCLC SAQ
EORTC QLQ C30
To assess the efficacy of the amivantamab and lazertinib 
combination, compared with lazertinib monotherapy, in 
participants with EGFR mutation positive, locally advanced
or metastatic NSCLC
PFS
Overall survival
Exploratory
To further assess the clinical benefit achieved using the 
amivantamab and lazertinib combination compared with 
osimertinib in participants with EGFR mutation positive, 
locally advanced or metastatic NSCLC
Disease control rate
Time to treatment discontinuation
Time to subsequent therapy
To assess the intracranial activity of the amivantamab and 
lazertinib combination compared with osimertinib. 
Intracranial objective response rate
Intracranial duration of response
Time to intracranial disease progression
To further assess health related quality of life in participants 
treated with the amivantamab and lazertinib combination
compared with osimertinib
EQ 5D 5L
To explore genetic biomarkers predictive of improved 
outcome in participants treated with amivantamab in 
combination with lazertinib, compared with lazertinib and 
osimertinib monotherapies. 
Characterization of tumor genetics by NGS of ctDNA
and genetic analysis oftumor biopsy material at baseline,
and at progression
Characterization of circulating EGFR mutation levels by
ddPCR of ctDNA at baseline, on therapy, and at
progression
To explore mechanisms of resistance to amivantamab and 
lazertinib and amivantamab/lazertinib combination therapy  
Characterization of tumor protein markers by
immunohistochemistry (eg, EGFR, MET) at baseline and
at progression
Characterization of changes in tumor genetics, relative to
baseline, by NGS of ctDNA and genetic analysis of
tumor biopsy material at progression
ctDNA circulating tumor deoxyribonucleic acid; ddPCR digital droplet polymerase chain reaction; EGFR epidermal growth
factor receptor; EORTC QLQ C30 European Organization for the Research and Treatment of Cancer Quality of Life
Questionnaire Core 30; EQ 5D 5L EuroQol five dimensional descriptive system (5 level version); MET mesenchymal
epithelial transition; NGS next generation sequencing; NSCLC non small cell lung cancer; NSCLC SAQ Non Small Cell
Lung Cancer Symptom Assessment Questionnaire; PFS progression free survival; RECIST Response Evaluation Criteria in
Solid Tumors.
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
HYPOTHESIS
The hypothesis is that the amivantamab and lazertinib combination (Arm A) will demonstrate
superior PFS compared with single-agent osimertinib (Arm B).
4. 
STUDY DESIGN
4.1. 
Overall Design
This is a randomized, multicenter, Phase 3 study to compare the efficacy and safety of combined
amivantamab and lazertinib therapy (Arm A) versus single-agent, standard of care, osimertinib
(Arm B) as first-line treatment in participants with EGFR-mutated locally advanced or metastatic
NSCLC. The contribution of amivantamab to the activity of the combination will be assessed by
comparing the efficacy observed in the amivantamab and lazertinib combination arm (Arm A)
with that in the lazertinib monotherapy arm (Arm C). The study will include a Screening Phase, a
Treatment Phase, and a Follow-up Phase.
An IDMC will be commissioned for this study. Refer to Committees Structure in Appendix 2:
Regulatory, Ethical, and Study Oversight Considerations for details.
A diagram of the study design is provided in Section 1.2.
4.1.1. 
Screening Phase
The informed consent form (ICF) must be signed before the first study-related activity  is
conducted. If a fresh tumor biopsy is required to meet eligibility, the biopsy can be obtained at any
time before randomization, provided informed consent has been given. All other screening
procedures must be completed within 28 days before randomization.
To be eligible for participation, all participants must have been previously diagnosed with Exon
19del or Exon 21 L858R substitution EGFR mutations, as determined by local testing with an
FDA-approved or other validated test in a Clinical Laboratory Improvement Amendments
(CLIA)-certified laboratory (sites in the US) or accredited local laboratory (sites outside of the
US). Tumor tissue must be collected at or after the diagnosis of locally advanced or metastatic
NSCLC and must be submitted to the sponsor (Section 8.7). A copy of the test report documenting
the EGFR mutation must be included in the participant records and a de-identified copy must also
be submitted to the sponsor.
4.1.2. 
Treatment Phase
The Treatment Phase for a participant will begin on Cycle 1 Day 1 and continue as 28-day cycles
until the End of Treatment visit, approximately 30 days after discontinuation of study treatment.
Approximately 1000 eligible participants will be randomly assigned to study treatment in a
2:2:1 ratio (Arm A, B, and C respectively). Randomization will be stratified by mutation type
(Exon 19del vs Exon 21 L858R), race (Asian vs non-Asian), and history of brain metastasis
(present vs absent).
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
Arm A: Approximately 400 participants will be assigned to open-label treatment with the
combination of amivantamab (1050 mg for body weight <80 kg and 1400 mg for body weight
≥80 kg IV, once weekly for the first 4 weeks and then once every 2 weeks) and lazertinib
(240 mg orally, once daily).
Arm B: Approximately 400 participants will receive double-blind treatment with single-agent
osimertinib (80 mg orally, once daily).
Arm C: Approximately 200 participants will receive double-blind treatment with single-agent
lazertinib (240 mg orally, once daily).
Study treatment should continue until documented disease progression using Response Evaluation
Criteria in Solid Tumors (RECIST) v1.1 confirmed by BICR or another reason for discontinuation
of study treatment (Section 7.1). Continuation of study treatment after disease progression is
allowed in accordance with local practice, after consultation with the Medical Monitor, if the
investigator believes the participant is deriving clinical benefit. Participants continuing treatment
after progression will continue within the Treatment phase of the study and comply with associated
visits and procedures, including scheduled disease assessments, until the termination of study
treatment.
4.1.3. 
Follow-up Phase
Participants who discontinue study treatment for any reason will be followed for survival and
symptomatic progression in the Follow-up Phase.
Survival, subsequent anticancer treatment, and disease status will be assessed every 12 weeks
(±14 days) after the last dose of study treatment or disease progression (whichever occurs first),
until the end of study, death, lost to follow-up, or withdrawal of consent, whichever comes first. If
the information is obtained via telephone contact, written documentation of the communication
must be available for review in the source documents. If the participant has died, the date and cause
of death will be collected and documented on the electronic case report form (eCRF). Investigators
may recontact the participant to obtain long-term follow-up information regarding the participant's
safety or survival status as noted in the ICF (refer to Informed Consent in Appendix 2: Regulatory,
Ethical, and Study Oversight Considerations).
Note: For participants who discontinue study treatment prior to disease progression confirmed by
BICR, tumor imaging should continue per schedule of activities, until PD is confirmed by BICR
review.
4.1.4. 
Open-label Extension Phase and Long-term Extension Phase
Following the primary PFS analysis for efficacy, the study will transition to an open-label
extension (OLE) Phase (see details provided in Section 10.14 [Appendix 14]). The purpose of the
OLE Phase is to collect data of clinical relevance/importance while reducing protocol-required
visit procedures and assessments and the burden on participants after the primary PFS analysis and
unblinding. Unblinding will occur for blinded Arms B and C. Only active treatment will be
provided, without placebo.
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JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
39
Status: Approved, Date: 14 November 2023
Participants will be provided the option to continue their current study treatment in the OLE Phase
until the final analysis for overall survival, after which the study will transition to a long-term
extension (LTE) Phase. Unblinding will occur for blinded Arms B and C. Only active treatment
will be provided, without placebo.
Participants who continue to benefit from study treatment(s), as determined by their investigator,
at the time of completion of the OLE Phase may continue to receive access to study treatment(s)
within the study by transferring to the LTE Phase, where only serious adverse event data and study
treatment compliance will be collected. The LTE Phase will continue to provide participants access
to study treatment and further reduce protocol-required visit procedures and assessments, after the
final analysis for overall survival is complete.
The LTE Phase (see details provided in Section 10.15 [Appendix 15]) will begin after the final
analysis for overall survival, and will continue until the discontinuation criteria described in
Section 7.1 are met, or until 4 years after local marketing authorization is obtained for the studied
indication, whichever occurs first.
The OLE phase will begin after approval of Amendment 4 by health authorities of
countries/territories in which this study is being conducted at the time of transition, and by study
site Independent Ethics Committees/Institutional Review Boards (IECs/IRBs). In addition, for
transition to the LTE Phase (after final analysis for overall survival), notification from the sponsor
will be provided.
4.2. 
Scientific Rationale for Study Design
Blinding, Control, Study Phase/Periods, Treatment Groups
Active controls will be used to establish the frequency and magnitude of changes in clinical
endpoints that occur with the combination of amivantamab and lazertinib (Arm A), as compared
to single-agent osimertinib (Arm B) or single-agent lazertinib (Arm C). Randomization will be
used to minimize bias in the assignment of participants to treatment groups, to increase the
likelihood that known and unknown participant attributes (eg, demographic and baseline
characteristics) are evenly balanced across treatment groups, and to enhance the validity of
statistical comparisons across treatment groups. Blinded treatment will be used in the control arms
(Arms B and C) to reduce potential bias during data collection and evaluation of clinical endpoints.
Open-label treatment will be used in Arm A; only the participants in this treatment arm will receive
infusions.
Clinical Pharmacology Assessments
Blood samples will be analyzed for amivantamab serum and lazertinib plasma concentrations.
Immunogenicity (antibodies to amivantamab) will be evaluated for impact on PK, safety, and
efficacy. A population PK model will be developed for exposure response analysis to support
regulatory submission.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
DNA and Biomarker Collection
Tumor tissue and ctDNA will be collected to centrally confirm the pretreatment mutational status
of EGFR (Exon 19del or L858R). In addition, these samples may be evaluated to identify co-
occurring EGFR mutations, MET alterations, and mutations in other key oncogenes to characterize
the tumor to explain interindividual variability in clinical outcomes, or to identify population
subgroups that respond differently to a treatment. Circulating tumor deoxyribonucleic acid
(ctDNA) and biomarker samples may be used to explore their potential to predict clinical benefit,
relapse, and/or identify mechanisms of resistance to assigned therapy.
The pharmacogenomic samples will be collected to test for null or non-null glutathione
S- -transferase Mu-1 (GSTM-1) genotype for participants in Arm A on Cycle 1 Day 1. The goal
of the pharmacogenomic sample is to collect deoxyribonucleic acid (DNA) to allow the
identification of GSTM-1 polymorphism that may influence the PK, safety/tolerability or efficacy
of lazertinib.
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 adverse events of the study, and provide their consent voluntarily will be
enrolled.
Thorough scientific evaluation of any treatment before market authorization is an ethical
requirement. As the benefits and risks of the combination of amivantamab and lazertinib in this
study population are not fully known, this study will evaluate the safety and clinical activity of
these agents in  combination, and of lazertinib as a monotherapy. Participants will be closely
monitored throughout the study, as discussed throughout this protocol, for both safety and clinical
benefit. The IDMC will review evolving safety data from this study, as well as efficacy data as
appropriate. Based on the mechanism of action of both  amivantamab and lazertinib there is
adequate justification, for evaluating these drugs in combination for the treatment of NSCLC in
participants who are eligible for this study.
All participants will undergo regular disease assessments to monitor the underlying disease.
Participants will also have pre- and post-treatment tumor biopsies. In general, these procedures are
routinely performed during a participant’s diagnostic workup and follow-up care. Archival tumor
material collected at or after the time of locally advanced or metastatic diagnosis may be submitted
in lieu of pre-treatment biopsies. Prior EGFR testing in accordance with site standard of care,
obtained at or after the diagnosis of locally advanced or metastatic NSCLC  and before signing
informed consent will be used to document EGFR mutation status to minimize delay to treatment
initiation. Archival or fresh  tissue from the corresponding biopsy is required for central
confirmation of mutation status. If insufficient, a new biopsy will be required. Although biopsy
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
collection is associated with risk, the complication rate for these procedures is low. The data
obtained from this procedure is required to confirm eligibility and will generate valuable scientific
data on the pharmacodynamic effect of the combination of these study treatments in this study
population. As with all clinical studies, there are risks associated with venipuncture and multiple
blood sample collection. The blood sample collection scheme was designed to collect the
minimum number of blood samples that accurately and completely describe the pharmacology of
the study treatment. This minimizes the number of venipunctures and the total volume of blood
collected from each participant during the study. 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 American Red Cross.2
4.3. 
Justification for Dose
The doses selected for this study are supported by the following safety and activity results from
clinical studies of participants with advanced NSCLC and EGFR mutations:
Lazertinib: Lazertinib was generally well tolerated in a Phase 1/2 study, with no DLTs
reported during dose escalation and no MTD identified.3,13 Partial responses were observed
across all assessed doses from 20 to 320 mg. The RP2D was determined to be 240 mg orally
once daily, based on the totality of exposure, safety, and efficacy data.
Amivantamab: Amivantamab was generally well tolerated in a Phase 1 study up to the dose
of 1750 mg, with no DLTs reported during dose escalation and no MTD identified.10,12 Based
on the totality of exposure, safety, and efficacy data, the RP2D was determined to be 1050 mg
for body weight <80 kg and 1400 mg for body weight ≥80 kg, administered by IV infusion in
28day- cycles: once weeklyin Cycle 1 (with a split dose on Days 1-2), and then every 2 weeks
in subsequent cycles.
Amivantamab and lazertinib in combination: Based on the totality of exposure, safety, and
efficacy data, the RP2D for the combination in a Phase 1 study was determined to be
amivantamab 1050/1400 mg and lazertinib 240 mg (ie, each component of the combination
at its respective RP2D).12 No DLTs were observed with the proposed doses and regimens for
both amivantamab and lazertinib and PK data analysis was consistent with no drug-drug
interaction between amivantamab and lazertinib.
Osimertinib: The dose of osimertinib selected for a control arm in this study (80 mg,
administered orally once daily) was shown to be safe and effective in Phase 3 studies of
participants with advanced NSCLC and EGFR mutations and is the recommended dose. Refer
to the local prescribing information for additional details.37
4.4. 
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.
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JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
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 or has not prematurely discontinued the study for another reason (Section 7.1) by the
end of the study.
5. 
STUDY POPULATION
Screening for eligible participants will be performed within 28 days before randomization. Refer
to Section 5.4 for conditions under which the repeat of any screening procedures is 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.
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. 
Participant must be ≥18 years of age (or the legal age of consent in the jurisdiction in
which the study is taking place).
2. 
Criterion modified per Amendment 1.
   2.1 
Participant must have newly diagnosed, histologically or cytologically confirmed, locally
advanced or metastatic NSCLC  that is treatment naïve and not amenable to curative
therapy including surgical resection or chemoradiation.
3. 
Criterion modified per Amendment 1.
    3.1 
The tumor (meeting criteria described in Inclusion Criterion no. 2) harbors Exon 19del or
Exon 21 L858R substitution, as detected by an FDA-approved or other validated test in a
CLIA certified laboratory (sites in the US) or an accredited local laboratory (sites outside
of the US) in accordance with site standard of care. (Note: A copy of the test report
documenting the EGFR mutation must be included in the participant records and must
also be submitted to the sponsor.)
4. 
Criterion modified per Amendment 1.
    4.1 Mandatory submission  of unstained tissue from tumor meeting criteria described in
Inclusion Criterion no. 2 (in a quantity sufficient to allow for central analysis of EGFR
mutation status) and blood (for ctDNA, digital droplet polymerase chain reaction
[ddPCR], and pharmacogenomic analysis). See Section 8.7.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
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Status: Approved, Date: 14 November 2023
5. 
Any toxicities from prior anticancer therapy must have resolved to Common Terminology
Criteria for Adverse Events (CTCAE)Grade 1 or baseline level.
6. 
Participant must have at least 1 measurable lesion, according to RECIST v1.1 that has not
been previously  irradiated. Measurable lesions should not have been biopsied during
screening, but if only 1 non-irradiated measurable lesion exists, it may undergo a
diagnostic biopsy and be acceptable as a target lesion, provided the baseline tumor
assessment scans are performed at least 14 days after the biopsy.
7. 
Criterion modified per Amendment 1.
    7.1 
Participant must have adequate organ and bone marrow function as follows, without
history of red blood cell transfusion, platelet transfusion, or granulocyte
colony-stimulating factor (G-CSF)within 7 days prior to the date of the test.
Hemoglobin ≥10 g/dL
Absolute neutrophil count ≥1.5 109/L, without any prior use of G-CSF
Platelets ≥75 109/L
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 upper
limit of normal (ULN)
Total bilirubin ≤1.5 
ULN (participants with Gilbert’s syndrome can enroll if
conjugated bilirubin is within normal limits)
Serum creatinine <1.5 ULN and creatinine clearance >45 mL/min as measured or
calculated; refer to Appendix 11: Cockcroft-Gault Formula for Estimated Creatinine
Clearance
If urinalysis reveals bacteria and leukocytes, a urine culture must be done to rule out
a urinary tract infection prior to randomization.
8. 
Participant must have Eastern Cooperative Oncology Group (ECOG) status of 0 or 1
(refer to Appendix 5: Eastern Cooperative Oncology Group (ECOG) Performance
Status).
9. 
Participant must sign an ICF (or their legally acceptable representative must sign)
indicating that he or she understands the purpose of, and procedures required for, the study
and is willing to participate in the study.
10. 
Criterion modified per Amendment 1.
  10.1. Criterion modified per Amendment 4.
   10.2 A participant of childbearing potential must have a negative serum pregnancy test at
screening and within 72 hours of the first dose of study treatment and must agree to further
serum or urine pregnancy tests during the study.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
11. 
Criterion modified per Amendment 1.
   11.1 Criterion modified per Amendment 2.
   11.2 Criterion modified per Amendment 4.
   11.3 A participant must be (as defined in Appendix 4: Contraceptive Guidance and Collection
of Pregnancy Information) either of the following:
a. Not of childbearing potential
b. Of child-bearing potential and practicing true abstinence during the entire period of
the study, including up to 6 months after the last dose of study treatment is given
c. Of childbearing potential and practicing 2 methods of contraception, including 1
highly effective user independent method and a second method (examples of highly
effective methods of contraception are located in Appendix 4: Contraceptive
Guidance and Collection of Pregnancy Information).
Participant must agree to continue contraception throughout the study and through
6 months after the last dose of study treatment.
Note: If the childbearing potential changes after start of the study (eg, participant
who is not sexually active becomes active, premenarchal woman experiences
menarche) the participant must begin birth control, as described above.
12. 
Criterion modified per Amendment 4
12.1 
A participant must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study and for 6 months after receiving the last dose of study
treatment.
13. 
Criterion modified per Amendment 4
13.1 
A participant must wear a condom when engaging in any activity that allows for passage
of ejaculate to another person during the study and for 6 months after receiving the last
dose of study treatment. A participant who is sexually active with a person of childbearing
potential must agree to use a condom with spermicidal foam/gel/film/cream/suppository
and the partner must also be practicing a highly effective method of contraception (ie,
established use of oral, injected, or implanted hormonal methods of contraception;
placement of an intrauterine device [IUD] or intrauterine hormone-releasing system
[IUS]).
A vasectomized participant must still use a condom (with or without spermicide) for
prevention of passage of exposure through ejaculation, but the participant’s partner is not
required to use contraception.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
14. 
Criterion modified per Amendment 4
14.1 
A participant must agree not to donate sperm for the purpose of reproduction during the
study and for a minimum of 6 months after receiving the last dose of study treatment.
15. 
Participant must be willing and able to adhere to the lifestyle restrictions specified in this
protocol.
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
1. 
Criterion modified per Amendment 1
    1.1 
Criterion modified per Amendment 2.
    1.2 Participant has received any prior systemic treatment at any time for locally advanced
Stage III or metastatic Stage IV disease (adjuvant or neoadjuvant therapy for Stage I or
II disease is allowed, if administered more than 12 months prior to the development of
locally advanced or metastatic disease).
2. 
Criterion modified per Amendment 1.
    2.1 Participant has symptomatic brain metastases. A participant with asymptomatic or
previously treated and stable brain metastases may participate in this study. Participants
who have received definitive radiation or surgical treatment for symptomatic or
unstable brain metastases and have been clinically stable and asymptomatic for at least
2 weeks before randomization are eligible, provided they have been either off
corticosteroid treatment or are receiving low-dose corticosteroid treatment (≤10 mg/day
prednisone or equivalent) for at least 2 weeks prior to randomization.
3. 
Participant has an active or past medical history of leptomeningeal disease.
4. 
Criterion modified per Amendment 1.
    4.1 Participant with untreated spinal cord compression. A participant that has been
definitively treated with surgery or radiation and has a stable neurological status for at
least 2 weeks prior to randomization is eligible provided they are off corticosteroid
treatment or receiving low-dose corticosteroid treatment ≤10 mg/day prednisone or
equivalent.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
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Status: Approved, Date: 14 November 2023
5. 
Participant has uncontrolled tumor-related pain (symptomatic lesions amenable to
palliative radiotherapy [eg, bone metastases or metastases causing nerve impingement]
should be treated prior to Screening).
6. 
Participant has an active or past medical history of ILD/pneumonitis, including
drug-induced or radiation ILD/pneumonitis.
7. 
Criterion modified per Amendment 1.
    7.1 Participant has an uncontrolled illness, including but not limited to:
Uncontrolled diabetes
Ongoing or active infection (includes infection requiring treatment with
antimicrobial therapy [participants will be required to complete antibiotics 1 week
prior to starting study treatment] or diagnosed or suspected viral infection.
Active bleeding diathesis
Impaired oxygenation requiring continuous oxygen supplementation
Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
swallow the formulated product, or previous significant bowel resection that would
preclude adequate absorption of study treatment
Psychiatric illness, social situation, or any other circumstances that would limit
compliance with study requirements
Any ophthalmologic condition that is clinically unstable
8. 
Criterion modified by Amendment 1.
   8.1 
Participant has concurrent or prior malignancy other than the disease under study. The
following exceptions require consultation with the Medical Monitor:
d. Non-muscle invasive bladder cancer (NMIBC) treated within the last
24 months that is considered completely cured.
e. Skin cancer (non-melanoma or melanoma) treated within the last 24 months
that is considered completely cured.
f. Non-invasive cervical cancer treated within the last 24 months that is
considered completely cured.
g. Localized prostate cancer (N0M0):
with a Gleason score of 6, treated within the last 24 months or untreated
and under surveillance,
with a Gleason score of 3+4 that has been treated more than 6 months prior
to full study screening and considered to have a very low risk of recurrence,
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
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Status: Approved, Date: 14 November 2023
or history of localized prostate cancer and receiving androgen deprivation
therapy and considered to have a very low risk of recurrence.
h. Breast cancer:
lobular carcinoma in situ or ductal carcinoma in situ  that is considered
completely cured.
f. 
Participant has undergone curative therapy and is considered cured after
5 years with no evidence of disease recurrence since initiation of that therapy.
9. 
Criterion modified per Amendment 1.
    9.1 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 randomization or any of the following within 6 months prior to
randomization: myocardial infarction, unstable angina, stroke, transient ischemic
attack, coronary/peripheral artery bypass graft, or any acute coronary syndrome.
Clinically non-significant thrombosis, such as non-obstructive catheter-associated
thrombus, incidental or asymptomatic pulmonary embolism, are not exclusionary.
Prolonged corrected QT interval by Fridericia’s (QTcF >470 msec), clinically
significant cardiac arrhythmia (eg, atrial fibrillation with uncontrolled rate) or
abnormalities in conduction or morphology of electrocardiogram (ECG) (eg,
complete left bundle branch block, third- or second-degree heart block, PR interval
>250 msec), or electrophysiologic disease (eg, placement of implantable
cardioverter defibrillator).
Any factors that increase the risk of corrected QT interval (QTc) prolongation or
risk of arrhythmic events such as, hypokalemia, congenital long QT syndrome,
family history of long QT syndrome, or unexplained sudden death under 40 years
of age in first degree relatives or any concomitant medications known to prolong
QT interval or induce Torsades de Pointes.
Uncontrolled (persistent) hypertension: systolic blood pressure >160 mm Hg;
diastolic blood pressure >100 mm Hg.
Congestive heart failure (CHF), defined as New York Heart Association (NYHA)
class III-IV or hospitalization for CHF (any NYHA class; refer to Appendix 6: New
York Heart Association Criteria) within 6 months of randomization.
An active or past medical history of pericarditis, pericardial effusion that is
clinically unstable, or myocarditis. Pericardial effusion considered due to the
disease under study is permitted if clinically stable at Screening.
Baseline LVEF  either <50% or below the lower limit of normal (LLN) per
institutional guidelines, as assessed by screening echocardiogram (ECHO) or
multigated acquisition (MUGA) scan.
10. 
Participant has known allergy, hypersensitivity, or intolerance to the excipients used in
formulation of amivantamab, lazertinib, or osimertinib, or any contraindication to the
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use of osimertinib (refer to amivantamab and lazertinib IBs and local prescribing
information for osimertinib).12,13,37
11. 
Criterion modified per Amendment 1.
   11.1 Participant is currently receiving medications or herbal supplements known to be potent
CYP3A4/5 inducers and is unable to stop use for an appropriate washout period prior
to randomization (see Appendix 8: Prohibited and Restricted Medications and
Therapies That Induce, Inhibit, or Are Substrates of CYP3A4/5).
12. 
Participant has received any prior treatment with an EGFR TKI.
13. 
Participant has received an investigational medication within 12 months before
randomization or is currently enrolled in an investigational study.
14. 
Participant is pregnant, breast-feeding, or planning to become pregnant while enrolled
in this study or within 6 months after the last dose of study treatment.
15. 
Participant plans to father a child while enrolled in this study or within 6 months after
the last dose of study treatment.
16. 
Participant has any condition for which, in the opinion of the investigator, participation
would not be in the best interest ofthe participant (eg, compromise the well-being) or
that could prevent, limit, or confound the protocol-specified assessments
17. 
Participant has at Screening:
Positive hepatitis B (hepatitis B virus [HBV]) surface antigen (HBsAg)
Note: Participants 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)
an 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.
Positive hepatitis C (hepatitis C virus [HCV]) 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
18. 
Participant is positive for human immunodeficiency virus (HIV), with 1 or more of the
following:
Not receiving highly active antiretroviral therapy (ART)
Had a change in ART within 6 months of the start of screening
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Status: Approved, Date: 14 November 2023
Receiving ART that may interfere with study treatment (consult sponsorfor review
of medication prior to enrollment)
CD4 count <350 at screening
AIDS-defining opportunistic infection within 6 months of start of screening
Not agreeing to start ART and be on ART>4 weeks plus having HIV viral load
<400 copies/mL at end of 4-week period (to ensure ART is tolerated and HIV
controlled).
19. 
Criterion modified per Amendment 1.
   19.1 Participant had major surgery excluding placement of vascular access or tumor biopsy,
or had significant traumatic injury within 4 weeks before randomization, or will not
have fully recovered from surgery, or has surgery planned during the time the
participant is expected to participate in the study.
Note: Participants with planned surgical procedures to be conducted under local
anesthesia may participate.
NOTE: Investigators must ensure that all study enrollment procedures have been completed
during the screening period and eligibility confirmed on the date of, and prior to, randomization.
If a participant’s clinical status changes/declines during the screening period, eligibility must be
re-confirmed prior to randomization. The required source documentation to support meeting the
enrollment criteria are noted in Appendix 2: 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 course of the study to be eligible for participation:
1. 
Refer to Section 6.5.4 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).
5.3.1. 
Activity
1. 
Agree to use sun protective measures (such as a hat, sunglasses, and protective clothing),
limit prolonged exposure to natural sunlight, and avoid artificial sunlight (tanning beds or
phototherapy) from baseline until the last dose of study treatment. Avoid unnecessary
exposure to sunlight. Use broad-spectrum sunscreen (containing titanium dioxide or zinc
oxide) with a skin protection factor (SPF)≥30 (refer to Section 6.6.3.2).
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
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Status: Approved, Date: 14 November 2023
5.4. 
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification 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. This study will use interactive web response
system (IWRS). The investigator will generate screening and enrollment logs directly from IWRS.
The participant identification and enrollment log will be treated as confidential and will be filed
by the investigator in the study file. To ensure participant confidentiality, no copy 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 randomized
into the study, the date seen and age at initial informed consent will be used.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened. Participants who are determined to be eligible for the study after their condition
changes must sign a new ICF.
6. 
STUDY MEDICATION AND CONCOMITANT THERAPY
Study treatment administration must be captured in the source documents and the eCRF. Study-site
personnel will instruct participants on how to store study treatment for at-home use as indicated
for this protocol.
Refer to the Investigational Product Preparation Instructions (IPPI) or the study Site
Investigational Product and Procedures Manual (SIPPM) for detailed guidance on study treatment
dosage and administration.
6.1. 
Study Treatments Administered
For this study, “study treatment” refers to amivantamab, lazertinib, and osimertinib.
Amivantamab, lazertinib, and osimertinib are considered investigational medicinal products
(IMPs).
All other study-specified medications (see Section 6.5) are considered concomitant medications.
Designation 
Product
Investigational Medicinal Products 
(IMPs)
amivantamab, lazertinib, osimertinib
Authorization Status in the EU:
Used in accordance with Marketing Authorization: osimertinib
Used not in accordance with Marketing Authorization: amivantamab
Authorized 
amivantamab, osimertinib
Unauthorized 
lazertinib
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JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
Designation 
Product
Non-investigational Medicinal Products 
(NIMPs)/Auxiliary Medicinal Products
(AxMPs)
Not applicable
Eligible participants will be randomly assigned to 1 of 3 treatment arms: open-label treatment with
amivantamab and lazertinib (Arm A), double-blind treatment with single-agent osimertinib
(Arm B), or single-agent treatment with lazertinib (Arm C). Initial dosages for study treatment, by
treatment arm, are shown in Table 4. To maintain the blind between active osimertinib and placebo
osimertinib, both active and placebo osimertinib tablets will be over-encapsulatedto look identical.
Active and placebo lazertinib tablets look identical without over-encapsulation. Participants in
Arm B and Arm C will take an initial dosage of 4 pills, once daily: 1 osimertinib capsule (or 1
matching placebo) and 3 lazertinib tablets (or 3 matching placebos). All cycles are 28 days and
each study visit must be scheduled based on date of Cycle 1 Day 1. The site should not re-adjust
visit schedule based on treatment interruptions or delays.
Table 4: 
Initial Dosages for Study Treatment, by Treatment Arm
Arm A 
(Open-Label) 
Arm B  
(Double-Blind) 
Arm C
(Double-Blind)
Amivantamab 
(350 mg/vial) 
1050 mg (1400 mg if ≥80 kg) 
IV infusion in 28-day cycles
Cycle 1: Days 1/2a, 8, 15, and 22
Cycles 2+: Day 1 and Day 15
- 
-
Osimertinib 
(80 mg capsule) 
- 
1 osimertinib capsuleb 
once daily  
1 placebo capsule
once daily
Lazertinib 
(80 mg tabletc) 
3 lazertinib tablets 
once daily  
3 placebo tablets 
once daily  
3 lazertinib tablets
once daily
IV=intravenous.
a. 
The first dose of amivantamab will be split over 2 days as follows: Cycle 1 Day 1, 350 mg (regardless of body
weight); Cycle 1 Day 2, 700 mg (1050 mg if ≥80 kg).
b. 
Osimertinib will be provided as 80-mg tablet (initial dose) and 40-mg tablet (as needed for dose reduction) and
over-encapsulated to maintain the blind.
c. 
Lazertinib will be provided as 80 mg tablets (initial dose is three tablets [240 mg]).
6.1.1. 
Amivantamab
Amivantamab is supplied for this study in a glass vial containing 350 mg/vial with concentration
50 mg/mL in a 7 mL vial. Amivantamab will be manufactured and provided under the
responsibility of the sponsor. Refer to the IB for a list of excipients. The IV infusion will be
prepared at the site in 250 mL of diluent (Refer to IPPI).
The dosage of amivantamab will be based on the participant’s body weight at Screening: 1050 mg
(if body weight is <80 kg) or 1400 mg (if body weight is ≥80 kg). The dose remains based on body
weight at Screening regardless of subsequent changes in body weight during the course of
treatment. Qualified site personnel will administer amivantamab as an IV infusion in 28-day cycles
as follows:
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
Cycle 1: once weekly (with the first dose split over Day 1 [350 mg] and Day 2 [700 mg if
body weight is <80 kg or 1050 mg if body weight is ≥80 kg])
Cycles 2+: Days 1 and 15 of each cycle
Amivantamab will be administered intravenously using the escalating infusion rate regimen as
specified in the IPPI. At the discretion of the investigator, the infusion rate can be slower, but not
faster than specified in the IPPI. The product must be infused via a peripheral vein for all Cycle 1
doses; infusion via central line is allowed for subsequent dosing starting with the Cycle 2 Day 1
dose.
Infusion durations that exceed the planned length of time due to IV bag overfill, minor equipment
calibration factors, and/or participant factors not under the control of administering personnel will
not be considered protocol deviations. The actual infusion time should be accurately recorded.
Refer to IPPI for information describing the stability and administration of amivantamab.
Amivantamab must be administered according to the procedures described in the IPPI and clinical
protocol, under the supervision of qualified staff. Additional guidance is provided below:
On Day 1 of each cycle, review results of hematology and chemistry laboratory assessments
before administering study treatment.
Amivantamab must be diluted and administered as described in the IPPI
Do not mix or dilute amivantamab with other drugs.
Amivantamab must not be administered as an IV push or bolus.
The administration set IV line will be primed with diluent prior to the initiation of each IV
bag of diluted amivantamab as described in the IPPI.
After 12 cycles of amivantamab (1 year), participants receiving the full dosage of amivantamab
can skip up to 3 doses in a year and participants on a reduced dose of amivantamab (refer to
Section 6.6.2) can skip up to 2 doses in a year, as needed for life events. The skipped doses should
be at least 3 months apart and should be avoided when feasible.
6.1.2. 
Lazertinib
Lazertinib 80 mg for oral administration is an oblong, yellow, and film-coated tablet. Refer to the
IB for a list of excipients. The matching placebo tablet (for Arm B) is an oblong, yellow, and
film-coated tablet, matched in appearance to the lazertinib 80 mg tablet.
Participants will self-administer lazertinib (or matching placebo tablets in Arm B) as an oral
therapy, with an initial dosage of 240 mg (3 tablets) once daily. Lazertinib tablets can be
administered with or without food. In Arm A, 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. If a participant misses taking a
scheduled dose, it is acceptable to take the dose within a window of 12 hours. If it is more than
12 hours after the scheduled dose time, the missed dose should not be taken, and the participant
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
53
Status: Approved, Date: 14 November 2023
should be instructed to take the next dose at the next scheduled time. If a participant vomits after
taking his/her study treatment, he/she should not make up for this dose, but should take the next
scheduled dose. The time of vomiting should be captured in the source document.
6.1.3. 
Osimertinib
Osimertinib 80 mg for oral administration is provided as over-encapsulated tablets in red capsules
to maintain the blind for this study. Osimertinib 40 mg (also over-encapsulated tablets in red
capsules) is provided for dose reduction, as needed. Refer to the local prescribing information for
a list of excipients.37 Inactive placebo capsules (for Arm C) are matched in appearance to the
over-encapsulated osimertinib tablets.
Participants will self-administer osimertinib capsule (or an inactive capsule in Arm C) as an oral
therapy, with an initial dosage of 80 mg (1 capsule) once daily. Osimertinib can be administered
with or without food. Osimertinib should be taken at approximately the same time each day,
approximately 24 hours apart, if possible. If a participant misses taking a scheduled dose, it is
acceptable to take the dose within a window of 12 hours. If it is more than 12 hours after the
scheduled dose time, the missed dose should not be taken, and the participant should be instructed
to take the next dose at the next scheduled time. If a participant vomits after taking his/her study
treatment, he/she should not make up for this dose, but should take the next scheduled dose. The
time of vomiting should be captured in the source document.
6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study treatment must be stored at controlled temperatures according to the requirements on the
label. Amivantamab must be protected from light prior to use. Refer to the pharmacy manual/study
SIPPM for additional guidance on study treatment preparation, handling, and storage.
Accountability
The investigator is responsible for ensuring that all study treatment received at the site is
inventoried and accounted for throughout the study.
For amivantamab, the study treatment administered to the participant must be documented on the
treatment accountability form. All study treatment will be stored and disposed of according to the
sponsor's instructions. Study-site personnel must not combine contents of the study treatment
containers.
For lazertinib (or inactive) and osimertinib (or inactive), the dispensing of study treatment to the
participant, and the return of study treatment from the participant (if applicable), must be
documented on the treatment accountability form. Participants, or their legally acceptable
representatives where applicable, must be instructed to return all original containers, whether
empty or containing study treatment.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
Study treatment must be handled in strict accordance with the protocol and the container label, and
study treatment must be stored at the study site in a limited-access area or in a locked cabinet under
appropriate environmental conditions. Unused study treatment, and study treatment returned by
the participant, must be available for verification by the sponsor's study site monitor during on-
site monitoring visits. The return to the sponsor of unused study treatment, or used returned study
treatment for destruction, will be documented on the treatment return form. When the study site is
an authorized destruction unit and study treatment supplies are destroyed on-site, this must also be
documented on the treatment return form.
Potentially hazardous materials containing hazardous liquids, such as used ampules, needles,
syringes and vials, should be disposed of immediately in a safe manner and therefore will not be
retained for treatment accountability purposes.
Study treatment should be dispensed under the supervision of the investigator or a qualified
member of the study-site personnel, or by a hospital/clinic pharmacist. Study treatment will be
supplied only to participants participating in  the study. Returned study treatment must not be
dispensed again, even  to the same participant. Whenever a participant brings his or her study
treatment to the study site for pill count, this is not seen as a return of supplies. Study treatment
may not be relabeled or reassigned for use by other participants. The investigator agrees neither to
dispense the study treatment 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 study
treatments are provided in the SIPPM.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Treatment Allocation
Procedures for Randomization and Stratification
Participants will be randomly assigned to 1 of 3 treatment groups based on a computer-generated
randomization schedule prepared before the study by or under the supervision of the sponsor. The
randomization will be balanced by using randomly permuted blocks and will be stratified by
mutation type (Exon 19del vs Exon 21 L858R), race (Asian vs non-Asian), and history of brain
metastasis (present vs absent). Participants who have undergone treatment for metastatic brain
lesions, including a complete resection must be stratified as brain metastasis present. For
randomization and statistical analyses, a participant will be stratified as Asian if they report their
race is either Asian or mixed, with any Asian component.
The interactive web response system (IWRS) will assign a unique treatment code, which will
dictate the treatmentassignment and matching study treatmentkit for the participant. The requestor
must use his or her own user identification and personal identification number when contacting
the IWRS and will then give the relevant participant details to uniquely identify the participant.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
Blinding
To maintain the study blind in Arm B and Arm C, the study treatment container will have a label
containing the study name, study treatment number, and reference number. The label will not
identify the study treatment in the container. However, if it is necessary for a participant's safety,
the study blind may be broken and the identity of the study treatment ascertained. The study
treatment number will be entered in the eCRF when the study treatment is dispensed. The study
treatments will be identical in appearance and will be packaged in identical containers.
Data that may potentially unblind the treatment assignment (ie, study treatment
preparation/accountability data, treatment allocation, and biomarker or other specific laboratory
data) will be handled with special care to ensure that the integrity of the blind is maintained and
the potential for bias is minimized. This can include making special provisions, such as segregating
the data in question from view by the investigators, clinical team, or others as appropriate until the
time of database lock and unblinding.
Under normal circumstances, the blind should not be broken until the database is finalized, and
given the similarity of the blinded treatments (each is a third-generation EGFR TKI), it is
anticipated that need for unblinding will be infrequent. The investigator may in an emergency
determine the identity of the treatment by contacting the IWRS. Telephone contact with the
sponsor or its designee will be available 24 hours per day, 7 days per week. In the event the blind
is broken, the sponsor must be informed as soon as possible. The date and reason for the unblinding
must be documented in the source document.
Participants who have had their treatment assignment unblinded should continue to return for
scheduled evaluations.
In general, randomization codes will be disclosed fully only if the study is completed and the
clinical database is closed. However, if an interim analysis is specified, the randomization codes
and, if required, the translation of randomization codes into treatment and control groups will be
disclosed to those authorized and only for those participants included in the interim analysis. The
study may be unblinded after the primary analysis for PFS; see details for the OLE Phase
(Section 10.14 [Appendix 14])and the LTE Phase (Section 10.15 [Appendix 15]).
6.4. 
Study Treatment Compliance
Study treatments should be prescribed only by the principal investigator or a qualified physician
listed as a sub-investigator on required forms. Study treatments may not be used for any purpose
other than that outlined in this protocol, including other human studies, animal investigations, or
in vitro testing. The study personnel at the study site will account for all treatments dispensed and
for appropriate return. The certificates of delivery and return should be signed.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
6.5. 
Concomitant Therapy
6.5.1. 
Recording Prestudy and Concomitant Therapies
Prestudy therapies administered up to 28 days before randomization must be recorded.
Concomitant therapies must be recorded throughout the study beginning with randomization to
30 days after the last dose of study treatment or start of subsequent anticancer therapy, whichever
is first. Concomitant therapies should also be recorded beyond 30 days only in conjunction with
serious adverse events considered related to study treatment, until resolution of event or start of
subsequent therapy.
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 eCRF. 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.
6.5.2. 
Amivantamab Pre-infusion and Post-infusion Medications
Amivantamab Pre-Infusion Medications
Required and optional amivantamab pre-infusion medications for IRRs are summarized in Table 5.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
Table 5: 
Pre-Infusion Medications
Medication 
Dose 
Route of 
Administration  
Recommended Dosing
Window Before
Infusion 
Cycle/Day
Required Pre-Infusion Medicationsa, b, d, e
Glucocorticoid
Dexamethasone (10 mg) or
Methylprednisolone (40 mg) 
IV or Oral 
45 to 60 minutes
Cycle 1 Day 1
Cycle 1 Day 2
Antihistamine
Diphenhydramine (25 to 50 mg) 
or equivalent
IV or 
15 to 30 minutes
All
Oral 
30 to 60 minutes
Antipyretic
Paracetamol (acetaminophen 650 to 
1,000 mg) or equivalent 
IV or 
15 to 30 minutes
All
Oral 
30 to 60 minutes
Optional Additional Pre-Infusion Medicationsa, f
Glucocorticoidc
Dexamethasone (10 mg)
Methylprednisolone (40 mg) 
IV or 
45 to 60 minutes 
Cycle 1 Day 8
and beyond
Oral 
60 to 90 minutes 
H2 antagonist 
Ranitidine (50 mg) or equivalent 
IV  
15 to 30 minutes 
Any
Antiemetic 
Ondansetron (16 mg) or equivalent 
IV  
15 to 30 minutes
Any
Ondansetron (8 mg) or equivalent 
Oral 
15 to 30 minutes
IV intravenous.
a. If a medication noted in this table is not locally available, a similar medication and dose may be substituted and administered
per local guidelines.
b. Participants for whom required medications are contraindicated should explore alternative medications with their study
physician. If alternative medications are not suitable for the intent above, participants are not required to take the
corresponding medication.
c. Beginning with Cycle 1 Day 8, optional predose steroids may be administered if clinically indicated for participants who
experienced an infusion related reaction on Cycle 1 Day 1 or Cycle 1 Day 2.
d. The recommended dose of dexamethasone to be administered is 10 mg and should not be lower than 9. 8 mg.
e. Required Pre Infusion glucocorticoid, antihistamine, and antipyretic may be administered IV or oral route.
f. Optional Pre Infusion glucocorticoid may be administered by IV push or oral route.
Amivantamab Post-Infusion Medications
Optional amivantamab post-infusion medications may be prescribed and continued for up to
48 hours after the infusion if clinically indicated, at the discretion of the investigator (Table 6).
Table 6: 
Post-Infusion Medications
Medication 
Dose
Route of 
Administration  
Administration 
Instructions 
Cycle/
Day
Optional Post-Infusion Medicationsa
Glucocorticoid Dexamethasone (10 mg) or comparable corticosteroid 
IV or Oral 
As clinically indicated 
Any
Antihistamine 
Diphenhydramine (25 to 50 mg) or equivalent 
IV or Oral 
As clinically indicated 
Any
Antipyretic 
Paracetamol (acetaminophen) (650 to 1,000 mg)or
equivalent
IV or Oral 
As clinically indicated 
Any
Opiates 
Meperidine (25 to 100 mg) 
IV or Oral 
As clinically indicated 
Any
Antiemetic 
Ondansetron (8 to 16 mg) or equivalent;
long or short acting agents
IV
As clinically indicated 
Any
Ondansetron (8 mg) or equivalent;
long or short acting agents
Oral
IV intravenous.
a. Optional medications can be used prophylactically as clinically indicated. If a medication noted in this table is not locally
available, a similar medication and dose may be substituted and administered per local guidelines.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
6.5.3. 
Permitted Medications and Therapies
6.5.3.1. 
Supportive Care
Supportive care (eg, antibiotics, analgesics, transfusions, diet, osteoclast inhibitors) and
concomitant medications may be administered according to the standard of care at the site, and at
the treating physician’s discretion, as clinically indicated.
6.5.3.2. 
Radiotherapy
Localized, limited radiotherapy of short duration (eg, 5 days) for palliative purposes may be
permitted, but only after consultation with the Medical Monitor. Study treatment interruption is
not required but is allowed as per investigator discretion. Radiotherapy should be scheduled for
the week between scheduled biweekly doses of amivantamab.
6.5.3.3. 
Hormonal Contraception
Participants using hormonal contraceptives as a means of birth control must continue to use the
same hormonal contraceptives throughout the study and through 6 months after the last dose of
study treatment.
6.5.3.4. 
Prophylactic Medications
Prophylactic medications are described in Section 6.6.3.
6.5.4. 
Prohibited or Restricted Medications and Therapies
Prohibited Medications and Therapies
The following concomitant medications and therapies are prohibited during the study. The sponsor
must be notified as soon as possible of any instances in which prohibited therapies were
administered.
Any chemotherapy, systemic anticancer therapy, or experimental therapy (other than study
treatments).
Radiotherapy to tumor lesions being assessed for tumor response prior to radiographic
progression.
Medications, herbal supplements and/or ingestions of foods with known potent (strong)
inducer effects on CYP3A4/A5 activity. Use of medications known to be strong inhibitors of
CYP3A4 is restricted and should be avoided, when possible, or used with caution. Guidance
on drugs that require close monitoring and washout periods is given in Appendix 8: Prohibited
and Restricted Medications and Therapies That Induce, Inhibit, or Are Substrates of
CYP3A4/5.
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.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
Avoid co-administration of medicines that prolong QT interval (Appendix 12: Medications
With Potential for QT Interval Prolongation). If there are no other alternative medications that
can be used, limit treatment duration when possible.
Medications that are substrates of P-glycoprotein (P-gp), multi-drug resistance protein 4
(MRP4) Breast Cancer Resistance Protein (BCRP), and Organic Cation Transporter 1 (OCT1)
should be used with caution. A list of substrates is provided in Appendix 9: Substrates of P-
glycoprotein (P-gp), multi-drug resistance protein 4 (MRP4), and Breast Cancer Resistance
Protein (BCRP): Exercise Caution.
Avoid concomitant use of CYP1A2 or CYP3A4/5 substrate drugs. If no other alternatives
exist monitor participants more closely  for adverse reactions. Guidance on CYP1A2 or
CYP3A4/5 substrates that require close monitoring (Appendix 8: Prohibited and Restricted
Medications and Therapies That Induce, Inhibit, or Are Substrates of CYP3A4/5).
Due to the potential for hypomagnesemia associated with EGFR inhibitors, concomitant
medications that may decrease serum magnesium should be avoided if possible.
6.6. 
Dose Modification Guidance
Any dose/dosage adjustment should be overseen by medically  qualified study-site personnel
(principal or sub-investigator unless an immediate safety risk appears to be present).
6.6.1. 
Withholding Treatment
If a participant experiences a clinically significant CTCAE grade 3 or higher and/or unacceptable
toxicity (any grade)not attributable to the disease or disease-related processes under investigation,
and the investigator considers the adverse event of concern to be specifically associated with the
study treatment, then dosing should be interrupted and supportive therapy administered as required
in accordance with local practice/guidelines. For the majority of clinically significant toxicities
withholding doses and dose modifications should occur as per the guidelines described in Table 7
(for Arm A) and in Table 8 (for Arm B or Arm C), with the following additional considerations
for all treatment arms:
In instances of intolerable toxicity, study treatment should be withheld and may be restarted
upon resolution of the intolerable toxicity to ≤Grade 1 or baseline status (except for rash, oral
mucositis, or paronychia which should recover to ≤Grade 2 or baseline).
If study treatment is withheld for more than 28 days, consider a dose reduction per Table 9or
Table 10 when restarting study treatment.
The following additional considerations apply to combination treatment in Arm A (amivantamab
and lazertinib combination):
If withholding one treatment is felt to be clinically indicated (eg, moderate toxicity), dosing
with amivantamab should be preferentially withheld, unless the experienced toxicity is
strongly suspected to be related to lazertinib alone (refer to respective IBs).
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
If both agents are withheld, one or both agents can be restarted upon resolution of toxicity. In
general, ifboth are to be continued, lazertinib should be restarted at least 7-14 days prior to
the next infusion of amivantamab to ensure stability on monotherapy.
Starting with Cycle 2, amivantamab infusions delayed >7 days cannot be made up. The
delayed dose should be skipped and the participant dosed at the next scheduled visit.
If amivantamab is withheld for 2 or more consecutive doses for any reason, consult with the
Medical Monitor before restarting amivantamab to discuss plans for infusion.
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 study
treatment can be resumed at the discretion of the investigator.
While recommendations in Table 7 and Table 8 are provided as guidelines to toxicity management
with the combination, investigators should exercise their clinical judgement, taking into account
the nature of the toxicity, each agents’ potential contribution to the toxicity, as well as each agent’s
potential contribution to any observed clinical benefit. For specific guidance regarding the
management of IRRs in Arm A and rash, refer to Section 6.6.3.1 and Section 6.6.3.2, respectively.
Table 7: 
Guidance for Withholding Doses for Toxicities Based on Grade (Arm A)
Gradea 
Actionb 
Dose Modification After Resolution of Toxicityc, d
1 
None 
Continue both agents at current dose level; consider
supportive care according to local standards as
appropriate
2
None, or consider either withholding dose or
dose reduce amivantamab (or lazertinib if
the experienced toxicity is strongly
suspected to be related to lazertinib alone)
If withheld <28 days, restart study treatment at current
dose level or consider dose reduction.
3 or 4 
Withhold amivantamab and lazertinib 
After consultation with the Medical Monitor, may
restart study treatment at current dose level or consider
dose reduction of study treatment
a. 
Per National Cancer Institute-Common Terminology Criteria for Adverse Events Version 5.0.
b. 
For all toxicities, consider supportive care according to protocol as appropriate.
c. 
Resolution defined as: ≤Grade 1 or back to baseline status for the participant (except for rash, oral
mucositis, or paronychia which should recover to ≤Grade 2 or baseline).
d. 
No dose reduction required for VTE events. Study treatment initially held for stable, treated pulmonary
embolism and deep vein thrombosis ≤Grade 3 can be resumed at the discretion of the investigator. For VTE
events associated with clinical instability (eg, respiratory failure or cardiac dysfunction) in participants being
treated with the combination of amivantamab and lazertinib, study treatment should be held until the
participant recovers from the event. Thereafter, the study treatment can be resumed at the discretion of the
investigator.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
Table 8: 
Guidance for Withholding Doses for Toxicities Based on Grade (Arm B or Arm C)
Gradea 
Actionb 
Dose Modification After Resolution of Toxicityc, d
1 
None
Continue at current dose level: consider supportive care according
to local standards as appropriate
2 
None, or consider either 
withholding or dose reduce 
study treatment 
If withheld up to 28 days, restart at current dose level or consider
dose reduction.
If withheld ≥28 days, consult the Medical Monitor before restarting
3 or 4 
Withhold study treatment
After consultation with the Medical Monitor, restart study treatment
at current dose level or consider dose reduction
a. 
Per National Cancer Institute - Common Terminology Criteria for Adverse Events Version 5.0.
b. 
For all toxicities, consider supportive care according to protocol as appropriate.
c. 
Resolution defined as: ≤Grade 1 or back to baseline status for the participant (except for rash, oral
mucositis, or paronychia which should recover to ≤Grade 2 or baseline.
d. 
No dose reduction required for VTE events. Study treatment initially held for stable, treated pulmonary
embolism and deep vein thrombosis ≤Grade 3 can be resumed at the discretion of the investigator.
A participant for whom treatment was withheld should be assessed at least weekly to ensure
adequate supportive care is being administered and to assess for improvement of toxicity. In
instances of prolonged treatment interruptions, subsequent dose reductions may be indicated and
should occur in accordance with Section 6.6.2. Dose adjustment should be overseen by medically
qualified study-site personnel (preferably the principal or sub-investigator) unless an immediate
safety risk appears to be present. Guidelines for management of specific toxicities are provided in
the following sections.
Dose modifications should be recorded in the eCRF  as close to the scheduled dosing day  as
possible, in accordance with the eCRF guidelines. A change to study treatment dosing (ie,
withholding doses, change in dose, change in infusion rate), and the reason for the change, must
be recorded in the eCRF. For withheld doses, the duration of withholding study treatment is to be
recorded. Infusion rate must also be noted for each dose of amivantamab.
6.6.2. 
Dose Reduction
If a participant in Arm A experiences a toxicity requiring dose reduction after withholding study
treatment and resolution, then the dose of amivantamab should be preferentially reduced, as
outlined in Table 9, unless the experienced toxicity is strongly suspected to be related to lazertinib
alone (refer to respective IBs), in which case lazertinib can be reduced.
Given the potential for increased anti-EGFR activity in the combination Arm A, accelerated (ie,
proactive) dose reductions are allowed if toxicity is encountered. Upon resolution of the toxicity,
or with improved control with supportive measures, reescalation of the reduced therapy dose may
be subsequently increased to the previous dose.
In Arm A, if the decision is made to withhold amivantamab, lazertinib may be escalated to its
240 mg dose (ie, Dosage Level 5) with subsequent dose reduction to 160 mg if needed, consistent
with dosing in Arm C. Amivantamab may be restarted, if the symptoms have improved and
treatment with the combination is thought to be in the participant’s best interest. If 2 consecutive
doses of amivantamab are withheld, please consult the medical monitor.
NCT04487080

NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
63
Status: Approved, Date: 14 November 2023
6.6.3.1. 
Infusion-Related Reactions (Arm A only)
General Guidelines for Infusion-Related Reactions
Infusion-related reactions have been commonly observed during treatment with amivantamab,
predominantly with the first exposure on Cycle 1 Day 1, and typically within the first 90 minutes
of the infusion. The majority of IRRs are Grade 1 or 2 (Section 2.2). Refer to Summary of Data
and Guidance for Investigators in the current version of the IB for amivantamab. The guidelines
described here relate to the safe administration of amivantamab during initial dosing.
During the amivantamab infusions, participants should be clinically monitored at regular intervals
as specified in the Schedule of Activities (including an assessment prior to the start of infusion).
The monitoring should include heart rate, blood pressure, temperature, respiratory rate, and oxygen
saturation measurements.
Particularly with the initial dose (Cycle 1, Days 1 and 2), participants should be educated on 1) the
likelihood of experiencing an IRR with the initial dose, 2) the symptoms to anticipate (which
include chills, dyspnea, chest discomfort, fever, flushing, among others), 3) that they should alert
nursing staff if they experience these symptoms, and 4) that the experience of an IRR will not
preclude further therapy with amivantamab. Participants must be monitored closely for early signs
and symptoms indicative of an acute IRR. Even with mild symptoms, the study treatment infusion
should be interrupted immediately, as described in the tables below, to prevent more serious grade
IRRs from occurring. Trained clinical personnel should be prepared to intervene in the event of
IRRs. 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) must be readily available.
Prevention of Infusion-Related Reactions
Required prophylaxis for IRRs is described in Section 6.5.2.
Treatment of Infusion-Related Reactions
Participants who experience early symptoms of IRRs, manifesting as fever, chills, rigors,
bronchospasm, headache, rash, pruritus, arthralgia, hypo- orhypertension or other symptoms, must
have their amivantamab infusion interrupted, if indicated, and the symptoms managed according
to the recommendations provided in Table 11. With the initial dose of amivantamab (Cycle 1, Days
1 and 2), interrupting the infusion should be considered even with mild symptoms to prevent more
severe manifestations of IRR. All Grade 3 or 4 IRRs should be reported within 24 hours to the
Medical Monitor.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
64
Status: Approved, Date: 14 November 2023
Table 11: 
Management of Infusion-Related Reactions
Toxicity Grade* 
Treatment 
Premedication at
Subsequent Dosing or
Other Action to be Taken
Grade 1 
Mild reaction  
Monitor participant as medically indicated until recovery from 
symptoms. If occurring with initial dose (ie, Cycle 1 Day 1 or 
Day 2), consider early infusion interruption to prevent more 
severe symptoms. If infusion is interrupted, please follow the
guidance for Grade 2 interruptions.
Antihistamine, antipyretic,
and glucocorticoid, as per
Table 5.
Grade 2 
Mild to moderate reaction; 
therapy or infusion 
interrupted 
but responds promptly to 
symptomatic treatment 
Interrupt infusion 
If clinically indicated, start IV fluids; give diphenhydramine 50 
mg (or equivalent) IV and/or paracetamol (acetaminophen) 650 
to 1000 mg; consider corticosteroids and bronchodilator
therapy; H1 and H2 antagonist, antiemetic and; supplemental 
oxygen; monitor participant closely until recovery from 
symptoms 
First interruption for IRR: Restart infusion at 50% of the
rate at the time of interruption: if no further evidence of IRR
after 30 minutes, the rate may be increased to 100% of the
infusion rate at the time of interruption; monitor participant
closely. Infusion rate escalation may resume per the IPPI
schedule, after the infusion has been administered for at least
30 minutes at 100% of the infusion rate used at the time of
dose interruption.
Second interruption for IRR: Stop and consider
discontinuation of further study treatment at that visit;
administer diphenhydramine 50 mg IV or equivalent and
monitor participant until resolution of symptoms. The amount
of study treatment infused must be recorded in the eCRF. If
continuing administration after the second interruption, restart
infusion at 50% of the rate at the time of the second
interruption. If no further evidence of IRR after 30 minutes, the
rate may be increased to 100% of the infusion rate at the time
of interruption; monitor participant closely. Infusion rate
escalation may resume per the IPPI schedule, after the infusion
has been administered for at least 30 minutes at 100% of the
infusion rate used at the time of dose interruption.
Antihistamine, antipyretic,
and glucocorticoid, as per
Table 5.
Consider meperidine if
participant experiences chills
and rigors.
Grade 3 or 4 
Severe reaction  
Grade 3: prolonged (ie, not 
rapidly responsive to 
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) 
Grade 4: life threatening; 
pressor or ventilator
support indicated
Stop infusion 
Start IV saline infusion; recommend bronchodilators, 
supplemental oxygen; epinephrine 0.2 to 1 mg of a 1:1000 
solution for subcutaneous administration or 0.1 to 0.25 mg of a 
1:10000 solution injected slowly for IV administration, and/or 
diphenhydramine 50 mg IV with methylprednisolone 100 mg 
IV (or equivalent), as needed (other drugs as appropriate). 
Participant should be monitored until the investigator is 
comfortable that the symptoms will not recur. Investigators
should follow their institutional guidelines for the treatment of
anaphylaxis. In the case of late occurring hypersensitivity
symptoms (eg, appearance of a localized or generalized
pruritus within 1 week after treatment), symptomatic treatment
may be given (eg, oral antihistamine, or corticosteroids), as
appropriate.
Based on severity of
symptoms, consider
permanent discontinuation of
study treatment. Consultation
with Medical Monitor
required before continuing
with subsequent dosing.
Grade 4: Do not re challenge
eCRF electronic case report form; IPPI Investigational Product Preparation Instructions; IRR infusion related reaction;
IV intravenous.
*Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
65
Status: Approved, Date: 14 November 2023
6.6.3.2. 
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 combination amivantamab and lazertinib, 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.).
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 participants randomized to Arm A, 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: both a topical antibiotic (clindamycin, mupirocin, or fusidic
acid) on sun-exposed skin, and 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.
Strongly 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).
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
66
Status: Approved, Date: 14 November 2023
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, see Section 6.6.3.3.
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 de-escalating broad spectrum antibiotic and continuing
or resuming prophylactic antibiotics.
A suggested algorithm for stepwise management of rash is provided in Table 12. Refer to Table 7
and Table 9for recommended dose adjustment.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
67
Status: Approved, Date: 14 November 2023
Table 12: 
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
study treatment
2 
Initiate reactive management as above 
Reassess after 2 weeks
Continue current dose(s) of
study treatment or consider 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 (2030 mg/day)
Reassess weekly
Consider dermatology consultation and
manage rash per recommendation
Temporarily withhold study treatment
until rash improves to ≤Grade 2
For guidance on withholding study
treatment and dose reduction, refer to
Table 7 and Table 9for Arm A, and
Table 8 and Table 10 for Arms B and C
4 
Initiate reactive management 
Start moderate strength topical
corticosteroidsc 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
Temporarily withhold lazertinib until
rash improves to ≤Grade 2
Please refer to the dose modification
guidance Section 6.6.3 for further
instructions
Permanently discontinue amivantamab
Severe 
bullous, 
blistering, or 
exfoliating 
skin
conditions
including
toxic
epidermal
necrolysis
(TEN)
Consult dermatologist and manage rash per 
recommendation. 
Permanently discontinue amivantamab
and hold lazertinib. Consider restarting
lazertinib per investigator assessment of
causality, once resolved.
a. Grading per National Cancer Institute - Common Terminology Criteria for Adverse Events (Version 5.0).
b. Ifamivantamab must be withheld due to toxicity for 2 consecutive doses, consult 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.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
68
Status: Approved, Date: 14 November 2023
Scalp Rash
Atypical 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 antidandruff 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.
Topical Acetic acid 0.25% solution irrigation
Application of a steroid lotion may also be effective (eg, betamethasone valerate 0.1% lotion,
mometasone furoate 0.1% lotion, fluocinonide 0.05% lotion, or betamethasone dipropionate
0.05% lotion).
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.
6.6.3.3. 
Pruritus
Reactive Management Recommendations6
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).
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
69
Status: Approved, Date: 14 November 2023
6.6.3.4. 
Paronychia
Paronychia is a well-recognized toxicity associated with anti-EGFR therapeutics. As a result, there
are recommendations that should be followed to prevent or minimize patient discomfort associated
with this toxicity.
Prophylaxis Recommendations
Avoid skin irritants.
Cushion affected areas.
Wear gloves and comfortable shoes.
Apply moisturizer to nails.
Reactive Management Recommendations
Grade 1 paronychia:
Use antimicrobial soaks once or twice daily: warm bowl of water + 5 mL of bleach (sodium
hypochlorite) or vinegar (DO NOT USE BOTH TOGETHER); soak for 5 minutes, rinse, pat
dry, and then apply either emollient or topical treatments below.
Apply topical antiseptic (povidone-iodine 10% solution) twice daily.
Apply a topical steroid ointment (eg, betamethasone valerate 0.1% or clobetasol) or topical
calcineurin inhibitor (eg, tacrolimus 0.1%) twice daily. If using topical steroid, once resolved,
switch to topical calcineurin inhibitor daily or decrease to twice per week to maintain.
Grade 2 or 3 paronychia:
In addition to the guidance for Grade 1 paronychia above:
Apply topical antibiotic/antifungal agent (eg, mupirocin, fusidic acid, clotrimazole, or
miconazole) twice daily.
Initiate oral antibiotic for at least 14 days (eg, doxycycline 100 mg twice daily,
minocycline 100 mg twice daily, or cephalexin 500 mg twice daily).
Consult a dermatologist or podiatrist.
6.6.3.5. 
Oral Mucositis
Mucositis is a well-recognized toxicity associated with anti-EGFR therapeutics, and may be
mild/moderate and localized (Grades 1-2) or severe and widespread (≥Grade 3). As a result, there
are recommendations that should be followed to prevent or minimize patient discomfort associated
with this toxicity. Prophylaxis should occur accordingto local institutional practice and guidelines,
and should include the following:
Prophylaxis Recommendations
Use good oral hygiene, dentition review and referral to an oral hygienist if necessary.
Use a soft toothbrush.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
70
Status: Approved, Date: 14 November 2023
Use mild-flavored toothpastes.
Use saline-peroxide or salt and soda mouthwashes 3 or 4 times per day.
Use water soluble lubrication agents like artificial saliva (for xerostomia or dry mouth).
Avoid spicy, acidic, hard, and hot food and beverages.
Reactive Management Guidelines
Asymptomatic or mild symptoms: topical steroid (dexamethasone 0.5/mL elixir) and
lidocaine 2%-5% jelly or solution (swish and spit) 4 times per day.
Co-trimoxazole lozenges can be used to prevent secondary candida infection.
In cases of moderate to severe pain:
Compounded mouthwash (eg, “magic mouthwash”) including an antifungal, steroid,
antihistamine, anesthetic, and/or antacid/mucosal coating agent as per local practice and
guidelines.
Dexamethasone solution 3.3 mg/5 mL swish and spit 4 times per day, and lidocaine jelly
2%-5% or solution 4 times per day.
6.6.3.6. 
Pulmonary Toxicity
Patients with NSCLC are at risk of multiple adverse events affecting pulmonary function,
including disease progression, pulmonary embolus, infectious pneumonias, and more rarely,
drug-related ILD/pneumonitis. Patient respiratory status should be assessed at every visit; any
clinically significant change in respiratory status 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, study treatments should be withheld, and appropriate treatment management
should be promptly initiated.
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 exam including full assessment of vital signs (with pulse oximetry).
Unscheduled radiological assessment, including chest x-ray or computerized tomography
(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,
and cultures as feasible
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
71
Status: Approved, Date: 14 November 2023
Evaluation of cardiac function, if indicated
Where other causes of respiratory symptoms have been excluded, a diagnosis of ILD/pneumonitis
should be considered, and study treatment permanently discontinued. Study treatment should not
be restarted until pneumonitis/ILD is ruled out. For symptomatic patients with pneumonitis
(Grade 2 and above), treatment with steroids should be initiated per local guidelines, in addition
to withholding of study treatment. Confirmation of ILD/pneumonitis of any grade should prompt
discontinuation of all study treatment and should be reported as a serious adverse event (see
Section 8.3.1). In the absence of a diagnosis of ILD/pneumonitis, study treatment may be restarted.
6.6.3.7. 
Cardiac Adverse Events
Newly diagnosed or suspected changes in cardiac status, including QTcF prolongation or change
in LVEF, should prompt additional investigations, including referral to cardiologists as per local
practice or guidelines.
QTcF Prolongation
Check the quality ofECG recording and check for electrolyte abnormalities (eg, potassium,
calcium, magnesium); correct as needed.
QTc prolongation of >60 msec from baseline, or absolute value of >500 msec
For QTcF prolongation >60 msec from baseline, or absolute value >500 msec (from a
manual ECG read), medications should be reviewed to rule out new or existing
concomitant medications with potential for QT prolongation (Appendix 12: Medications
With Potential for QT Interval Prolongation), and these should be discontinued, if
possible, with action reported in eCRF.
Check for electrolyte abnormalities and correct as needed (eg, potassium, calcium,
magnesium).
If QTcF prolongation is confirmed and potentially attributable to study treatments, then
study treatment should be withheld.
Retreatment, at a reduced dose, should only occur once QTc interval is less than
481 msec, as measured by repeat triplicate ECG, or recovery to baseline is documented.
If retreatment is indicated, Arms B and C should be dose reduced to Dose Level 2 (see
Table 10) and lazertinib in Arm A should be dose reduced to Dose Level 3 (see Table 9).
Treat as per local standard of care in consultation with a cardiologist.
QTc interval prolongation with signs/symptoms of life-threatening arrhythmia, including but
not limited to the following: documented episode of ventricular tachycardia, ventricular
fibrillation, complete heart block (Grade III atrioventricular block) or second-degree
atrioventricular block Mobitz type II, QTc >500 msec at repeated ECG measurements, after
dose adjustment was performed
Permanently discontinue study treatment.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
Change in LVEF
Absolute LVEF decline of >10% and absolute LVEF value below LLN:
For participants experiencing absolute decline of LVEF of >10% from baseline and
absolute LVEF percentage below LLN, the decline should first be confirmed by having
the 2 assessments read, and measurements confirmed, by the same cardiologist.
Confirmed drops in LVEF assessments should prompt withholding study treatment,
referral to a cardiologist for further evaluation, and consultation with the Medical
Monitor; repeat LVEF assessment within at least 2 weeks to monitor status.
Symptomatic CHF:
Permanently discontinue study treatment.
6.6.3.8. 
Liver Chemistry Abnormalities
Liver chemistry threshold stopping criteria have been established to provide safety to the
participants and to better assess the etiology of a liver event. Liver chemistry should be monitored
according to the Schedule of Activities and study treatment should be withheld for any liver
chemistry abnormality of ≥Grade 3 severity (refer to Section 6.6.1). In addition, if the following
criteria are observed, the event should be reported as a serious adverse event to the sponsor within
24 hours:
a) ALT or AST ≥3x ULN and bilirubin ≥2x ULN (>35% direct bilirubin) (or ALT ≥3x ULN and
INR >1.5, if INR measured).
Exception to the bilirubin elevation is made if the participant has Gilbert’s disease and
the elevated bilirubin is predominantly unconjugated.
b) ALT or AST ≥3x ULN (if baseline was normal) withthe concomitant appearance ofworsening
symptoms suggestive ofdrug induced liver injury, such as the appearance of fatigue, nausea,
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or new onset eosinophilia
(>5%).
In the event abnormalities of liver function tests require withholding study treatment, liver
chemistry should be repeated within 1-3 days and until abnormal values resolve/return to baseline.
Etiology of the liver chemistry abnormality should be investigated, as described in Appendix 10:
Liver Event Follow-Up and Rechallenge Criteria. If no alternative etiology of liver toxicity is
identified, study treatment should be permanently discontinued.
6.6.3.9. 
Diarrhea
If participants experience diarrhea, they should be encouraged to drink 8 to 10 large glasses (2 L)
of clear liquids per day while on study to maintain adequate hydration. Maintenance of electrolyte
balance using electrolyte containing drinks, broth, and clear juices should be considered. If an
infectious cause of the diarrhea is suspected, perform stool testing and administer antibiotic
therapy (avoiding strong CYP3A4 inhibitors, when possible) as appropriate.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
73
Status: Approved, Date: 14 November 2023
General dietary measures to limit impact of diarrhea include the following:
Stop all lactose-containing products in participants with evidence of lactose intolerance
Eat frequent small meals if experiencing increased frequency of stools
Consider low-fat regimen enriched with bananas, rice, applesauce, and toast
Diarrhea management guidelines are shown in Table 13.
Table 13: 
Suggested Algorithm for Management of Diarrhea
Grade Management 
Study Treatment
1 
Loperamide (4 mg at first onset, then 2 mg 
every 2-4 hours until symptom free for
12 hours).
Fluid intake of at least 2 L as described above.
Continue study treatment(s).
2 
Loperamide (4 mg at first onset, then 2 mg 
every 2-4 hours until symptom free for 
12 hours), or consider diphenoxylate and 
atropine formulations. 
Fluid intake of at least 2 L as described above. 
Monitor participant closely and consider 
intravenous hydration.
If not improved to ≤Grade 1 within 24
hours despite use of loperamide, hold
treatment until ≤Grade 1.
If diarrhea of >Grade 1 recurs after initial
improvement, consider reduction by one
dose level
3 
Oral therapy with diphenoxylate and atropine 
formulations, or tincture of opium. 
Fluid intake of at least 2 L should be maintained 
as described above, intravenously if necessary. 
Consider use of octreotide 100-150 µg
subcutaneously twice daily with escalation to
500 μg 3 times daily.
Consider hospitalization if does not improve to
≤Grade 2 within 24 hours, or in presence of
fever, abdominal pain, etc.
Withhold study treatment(s). Upon
resolution to ≤Grade 1, resume study
treatment(s) with consideration of reduction
by 1 dose level.
4 
Maximal inpatient fluid and nutritional support, 
antibiotics as indicated in judgment of 
investigator for fever, leukocytosis, marked
dehydration, etc.
Hold study treatment until ≤Grade 1.
Mandatory dose reduction by 1 dose level.
6.6.3.10. 
Ocular Toxicity
Ophthalmologic complications are infrequently observed with anti-EGFR therapeutics. In the case
of signs or symptoms associated with ophthalmologic toxicity, including change in vision
(including change in acuity or visual distortion), eye inflammation, lacrimation, light sensitivity,
or eye pain, among others, the participant should be referred for ophthalmologic assessment
(Section 8.2.5). Participants should be advised of the increased risk for eye toxicity associated with
anti-EGFR therapeutics with the use of contact lenses.
6.6.3.11. 
Paresthesia
If a participant experiences paresthesia, contributing medical conditions should first be considered
and optimally managed. For example:
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Vitamin or mineral deficiency (eg, Vitamin B1 (thiamine), B6 (pyridoxine), B12 (cobalamin),
B9 (folate), Vit E, Copper) should be corrected
Diabetes should be optimally managed
General safety measures are recommended to protect against injury, infection etc.
The following symptomatic management guidance is provided in the event the paresthesia is
considered related to study drug:
Grade 1: Nutraceutical/non-pharmacologic interventions may be considered (ie, vitamin
supplementation  including vitamins B1, B6, B9, B12, E, glutamine, alpha-lipoic acid,
glutathione, calcium/magnesium, copper). Topical therapy (eg, capsaicin) may be considered.
Grade 2: Duloxetine, pregabalin, or gabapentin are recommended. Titrate dose for efficacy
and tolerability. Adding tricyclic or selective serotonin reuptake inhibitor antidepressant may
be considered. Opioids (tramadol or strong opioids) may be considered. Neurologic
consultation if symptoms persist on medication.
Grade 3: Neurologic consultation. Duloxetine, pregabalin, or gabapentin are recommended.
Titrate dose for efficacy and tolerability. Adding tricyclic or selective serotonin reuptake
inhibitor antidepressant may be considered. Opioids (tramadol or strong opioids) may be
considered.
If treatment modification is indicated, consider preferential interruption or dose reduction of
lazertinib for participants in Arm A or lazertinib/osimertinib in Arms B/C.
6.6.3.12. 
Venous Thromboembolic Events
Patients with NSCLC are at risk of developing complications, including VTE events. Investigators
should closely monitor all participants 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. For participants who 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 treating physician’s discretion.
All study participants receiving the combination of amivantamab and lazertinib (Arm A) 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. 4, 33
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
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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 study
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 study treatment with either amivantamab or lazertinib (but not both) at the discretion of
the treating physician.
Refer to Table 7, Table 8, Table 9, and Table 10 for recommended dose adjustment for any adverse
events.
6.7. 
Continued Access to Study Treatment
Participants who are still benefiting from study treatment, as determined by the investigator, will
be able to receive continued access to investigational drug; see details for the OLE Phase
(Section 10.14 [Appendix 14])and the LTE Phase (Section 10.15 [Appendix 15]).
7. 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Treatment
A participant's study treatment must be discontinued ifany of the following apply:
The participant withdraws consent to receive study treatment
The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it
is in the best interest of the participant to discontinue study treatment
The participant becomes pregnant. Refer to Appendix 4: Contraceptive Guidance and
Collection of Pregnancy Information.
Noncompliance with study treatment or procedure requirements as judged by investigator
Radiographic disease progression (RECIST, Version 1.1) (Exception: Continuation of study
treatment after disease progression is allowed in accordance with local practice, after
consultation with the Medical Monitor, if the investigator believes the participant is deriving
clinical benefit)
Disease progression that, at the discretion of the treating investigator, requires the initiation
of a new systemic anti-cancer treatment.
Participants who discontinue study treatment for any reason should have the End of Treatment
assessments, document any subsequent therapy in the eDC  and continue to be followed up in
accordance with the -Follow up phase (Section 4.1.3).
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Study treatment assigned to the participant who discontinued study treatment may not be assigned
to another participant. Further guidance on study drug discontinuation can be found in
Section 8.1.1.
7.2. 
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
When a participant withdraws before study  completion, the reason for withdrawal is to be
documented in the eCRF and in the source document. If the reason for withdrawal from the study
is withdrawal ofconsent, 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.
7.2.1. 
Withdrawal From the Use of Research Samples
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for research (refer to Long-Term
Retention of Samples for Additional Future Research  in Appendix 2: Regulatory, Ethical, and
Study Oversight Considerations). In such a case, samples will be destroyed after they are no longer
needed for the clinical study. Details of the sample retention for research are presented in the ICF.
7.3. 
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, prior to randomization
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 he or she 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:
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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, e-
mails, 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.
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 measurements applicable to
this study.
When possible, all PRO assessments should be conducted/completed before tests, procedures, or
other consultations to prevent influencing participant perceptions.
Additional serum or urine pregnancy tests may be performed, 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.
The total blood volume to be collected from each participant depends upon the duration of
participation, but the approximate volume for participants in Arm A is 540 mL, including
screening, 26 dosing cycles, and the End of Treatment Visit.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory
requisition form.
Refer to the Schedule of Activities for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the
laboratory manual that will be provided.
Study-Specific Materials
The investigator will be provided with the following supplies:
Clinical Protocol
IB for amivantamab
IB for lazertinib
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Local prescribing information for osimertinib
IPPI and SIPPM
Laboratory Manual and kits
Electronic data capture (eDC) Manual
IWRS Manual
Imaging Manual
ECG Manual
ECHO/MUGA Manual
NCI CTCAE Version 5.0
RECIST guidelines, Version 1.1
Sample ICF
Wallet cards
Study treatment
Ancillary supplies (as needed)
Tablet (for PRO collection)
8.1. 
Efficacy Assessments
8.1.1. 
Disease Assessments
RECIST v1.1 criteria will be used to assess participant response to treatment: complete response,
PR, stable disease, progressive disease, or unevaluable. Disease assessments will include imaging
of the chest, abdomen, and pelvis, and any other disease location(s). Baseline disease assessments
should be performed no more than 28 days prior to randomization. Post-randomization disease
assessments will occur every 8 weeks (±1 week) for the first 30 months, and then every 12 weeks
(±1 week) relative to randomization until disease progression is confirmed by BICR, even if a
participant discontinues treatment prior to progression or receives another systemic anti-cancer
therapy. If an imaging assessment is performed outside of the scheduled visit and the participant
has not progressed, every attempt should be made to perform the subsequent assessment at their
scheduled visit timepoint. Refer to the latest Imaging Site manual.
CT scan of the chest, abdomen, pelvis, and any other disease location(s) should be performed with
an IV contrast agent and oral contrast. 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 contrast
enhanced magnetic resonance imaging (MRI) of the abdomen and pelvis. Participants with
contraindications to IV CT and MRI contrast may be able to undergo non-IV contrast CT exams
of the chest abdomen and pelvis with proper documentation of medical contraindication. Oral
contrast should be used for CT exams of the abdomen and pelvis. Contraindications to the CT scan
with IV contrast that develop postbaseline require investigator discretion. MRI can also be used to
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evaluate sites of disease that cannot be adequately imaged using CT. If possible, the same imaging
modality 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. Any site at which
new disease is suspected should also be imaged. Techniques other than CT or MRI may be used
based upon investigator’s 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. Further details are provided in the Imaging Manual.
Brain MRI (or brain CT scan  if MRI is contraindicated) will also be performed at Screening.
Participants with a history of brain metastasis at Screening will undergo postbaseline brain MRI
every 8 weeks (±1 week) for the first 30 months and then every 12 weeks (±1 week) until disease
progression. Participants with no history of brain metastasis at Screening will undergo postbaseline
surveillance brain MRI every 24 weeks (±1 week). Postbaseline brain MRI will be scheduled
relative to randomization and will continue until disease progression  is confirmed by BICR.
Unscheduled brain MRI may also occur if new disease or progressive disease in the brain is
suspected at any time. Further details are provided in the Imaging Manual.
The primary endpoint for this study is PFS as assessed by BICR. Sites will be required to obtain
digital copies of radiologic images (eg, CT, MRI) used for all scheduled and unscheduled disease
assessments and submit them to a Janssen-appointed Clinical Research Organization (CRO) for
BICR.
During the independent radiology review, radiographic exams will be evaluated using RECIST
1.1. A clinical oncology review will be performed for participants with relevant clinical data in
addition to the radiographic review. The BICR will determine an overall (integrated radiographic
and clinical) assessment at the primary analysis of PFS. The BICR will also conduct a separate
review of intracranial disease assessed using modified RECIST 1.1 criteria. Investigator assessed
PFS will be based on data collected in the imaging assessment eDC forms.
In the event the Investigator suspects radiographic disease progression in a participant, a set of
imaging scans will be submitted to the BICR CRO together with the appropriate documentation.
These scans may be from a regularly scheduled time point or an unscheduled time point. The BICR
CRO will initially perform an expedited review to confirm radiographic progression. Investigators
should use BICR of imaging data to guide decisions regarding treatment discontinuation for
radiographic progression.
The Investigator should not discontinue study treatment until confirmation of progression has been
received from the BICR CRO. If radiographic progression is not confirmed by BICR the
participant should continue to receive study treatment and undergo imaging in accordance with the
protocol, although a set of imaging scans to re-assess suspected progression can be repeated prior
to the scheduled disease assessment (eg, at 4 weeks).
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If the Investigator suspects clinical progression, full details (procedures, biopsy data, cytology
data, AEs) must be documented in eDC forms. In addition, a set of imaging scans should be
performed at the time of suspected progression and submitted to the BICR CRO together with the
appropriate documentation. All participants suspected of clinical progression but without disease
progression confirmed by BICR should continue study treatment, and undergo imaging
assessments according to the protocol until progression is confirmed.
After progression has been confirmed by BICR, participants who remain on study treatment should
undergo disease assessments according to the protocol. Participants who switch to a new systemic
anti-cancer therapy after BICR confirmed progression should have disease assessments as per local
standard of care and provide documentation of best response, progression information (PFS2) and
other data in the eDC Subsequent Systemic Therapy forms.
If the participant is suspected of having disease progression and the Investigator considers that it
is in the best interest of the participant not to wait for confirmation of progression by BICR, the
Sponsor should be consulted before discontinuing study drug or beginning a new systemic
anti-cancer therapy. A set of imaging scans should be performed before starting a new systemic
anti-cancer treatment. Every effort should be made to continue tumor imaging in accordance with
the protocol until progressive disease has been confirmed by BICR, even if a participant receives
another systemic anti-cancer therapy.
For all participants who discontinue study treatment prior to BICR confirmed progressive disease,
every effort should be made to continue tumor imaging in accordance with the protocol until
progressive disease has been confirmed by BICR. This includes participants who discontinue study
treatment due to toxicity, withdraw consent for study treatment, or switch to another anti-cancer
therapy.
All participants who discontinue study treatment for any reason should have the End of Treatment
assessments, document any subsequent therapy in the eDC, and continue to be followed up in
accordance with the Follow-up phase (Section 4.1.3). Additional follow-up calls may be made in
the 2 weeks before a data cutoff date to assess participant survival before the next scheduled
assessment.
If the investigator is in doubt as to whether progression has occurred, particularly with response to
nontarget lesions or the appearance of a new lesion, treatment should be continued until the next
scheduled assessment (or sooner if clinically indicated) and reassess the participant’s status. If the
repeated scans confirm progression, then the date of the initial scan should be declared as the date
of progression. To achieve “unequivocal progression” on the basis ofnontarget lesions, there must
be an overall substantial worsening in nontarget lesions such that, even in the presence of stable
disease or PR in target disease, the overall tumor burden has increased sufficiently to merit
discontinuation of therapy. A modest “increase” in size of 1 or more nontarget lesions is usually
not sufficient to qualify for unequivocal progression status.
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If symptomatic deterioration (on the basis of global deterioration of health status) is recorded as
the basis for discontinuation of study treatment, then the clinical findings used to make the
determination must be specified in the eCRF 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.
8.1.2. 
Symptomatic Progression
Symptoms, attribution, and related treatments will be recorded on the eCRF at the times specified
in the Schedule of Activities. If symptomatic progression is not reported prior to treatment
discontinuation, continued assessment is required during the follow up period, even after
subsequent therapy is initiated.
8.1.3. 
Patient-Reported Outcomes
Patient-reported outcomes measures will be collected at the times specified in the Schedule of
Activities. All PROs should be administered prior to other assessments. The PRO instrument will
be provided in the local language in accordance with local guidelines. The PRO instrument must
be available for regulators and for IRB/IRC submissions, therefore the PRO instrument or screen
shots need to be attached to the protocol or provided in a companion manual with the instruments
that will be submitted with the protocol. The PRO and adverse event data will not be reconciled
with one another.
The Non-Small Cell Lung Cancer - Symptom Assessment Questionnaire (NSCLC-SAQ) was
developed in accordance with US FDA PRO Guidance and scientific best practices for use in
clinical trials of NSCLC.17 It contains 7 items that assess cough, pain, dyspnea, fatigue, and poor
appetite over a 7-day recall period.
Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change (PGIC)
are single-item questionnaires that provide an anchor-based comparison for the NSCLC-SAQ. The
PGIS and PGIC should be administered prior to other PRO assessments. The PGIC will not be
administered at the first visit because it captures change.
The EQ-5D-5L is a validated tool to measure health status and health utility, including mobility,
self-care, usual activities, pain, discomfort, and anxiety/depression.11
The European Organization of Research and Treatment of Cancer Quality of Life Questionnaire
Core 30 (EORTC-QLQ-C30) assesses functioning domains and common cancer symptoms with
recall in the past week.18
8.2. 
Safety Assessments
Details regarding the IDMC are provided in Committees Structure in Appendix 2: 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 and
Appendix 3: Adverse Events: 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 eCRF. 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.
To align frequency of safety assessments across treatment arms, participants in Arm A are not
required to be evaluated by a physician on Day 15 of Cycles 3 and beyond, unless clinically
indicated.
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.
Participants should be questioned for skin and eye symptoms at all visits with directed physical
examinations conducted as appropriate and specialty referral as indicated. In addition, participants
should similarly be questioned for 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.
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.
8.2.2. 
Vital Signs
Vital sign measurements will include the following assessments and be obtained as indicated in
the Schedule of Activities.
Temperature
Heart rate
Respiratory rate
Oxygen saturation
Blood pressure
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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
available.
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. 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.
Triplicate ECGs are required at Screening, Cycle 1 Day 1 (within 72 hours before study treatment),
Cycle 2 Day 1 (Arm A: within 30 minutes postinfusion; Arms B/C: 2-4 hours after oral
administration), and then to confirm any clinically significant finding during the study. At each
time point at which triplicate ECGs are required, 3 individual ECG tracings should be obtained as
closely as possible in succession, approximately 2 minutes apart. Refer to the ECG Manual for
additional details.
The clinical investigator will review the ECG, including ECG morphology, for immediate
management. The results will be entered into the eCRF. Abnormalities noted at Screening should
be included in the medical history. Triplicate ECGs will be submitted to a Janssen-appointed CRO
on an ongoing basis.
8.2.4. 
Left Ventricular Ejection Fraction
During the Screening Phase each participant will undergo a baseline LVEF assessment performed
locally by cardiac ECHO or MUGA scan in order to demonstrate eligibility (ie, a LVEF within the
normal range [refer to Appendix 6: New York Heart Association Criteria]). Participants will
undergo postbaseline LVEF assessments according to the Schedule of Activities. ECHO or MUGA
scans will be submitted to a Janssen-appointed CRO on an ongoing basis.
8.2.5. 
Ophthalmologic Assessment
An ophthalmologic assessment, including slit lamp examination, fundoscopic examination, and
visual acuity test will be performed at screening and should be repeated if a participant experiences
any visual symptoms (including blurring of vision), with additional tests if clinically indicated.
Any clinically significant findings, including those confirmed by the ophthalmologist must be
reported as an adverse event. Photographs, especially of anterior eye, should be performed to
record any clinically significant findings. These photographs should be available for review by the
Medical Monitor if necessary. Ophthalmology examination results should be recorded on the
procedures page in the database.
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8.2.6. 
ECOG Performance Status
ECOG performance status score (refer to Appendix 5: Eastern Cooperative Oncology Group
(ECOG) Performance Status) will be determined during the Screening Phase and at time points
listed in the Schedule of Activities. Any decline in ECOG performance status score should be
reported as an adverse event.
8.2.7. 
Clinical Safety Laboratory Assessments
Clinical laboratory assessments will be performed locally. Blood samples for serum chemistry,
hematology, coagulation, and a urine sample for urinalysis as noted in Appendix 7: Clinical
Laboratory Tests will be collected at the times listed in the Schedule of Activities. The investigator
must review the laboratory results, document this review, and record any clinically relevant
changes occurring during the study in the adverse event section of the eCRF. The laboratory reports
must be filed with the source documents. At the start of each new cycle, the investigator must
confirm that participants meet treatment criteria.
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information from clinical studies
including adverse events, serious adverse events, and product quality complaints (PQC)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.
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 adverse events, serious adverse events, and PQC can be found in Appendix 3:
Adverse Events: 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 adverse events and special reporting situations, whether serious or non-serious, will be reported
from the time a signed and dated ICF is obtained until completion of the participant's last study-
related procedure, which may include contact for follow-up of safety.
Serious Adverse Events
All serious adverse events as well as PQC 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.
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Serious adverse events, including those spontaneously reported to the investigator within 30 days
after the last dose of study treatment, must be reported using a serious adverse event form. A
serious adverse event spontaneously reported to the investigator more than 30 days after the last
dose of study treatment must also be reported using a serious adverse event form, if the investigator
considers the event to be related to study treatment. The sponsor will evaluate any safety
information that is spontaneously reported by an investigator beyond the time frame specified in
the protocol.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious
Adverse Event Form and Safety Report Form of the eCRF, which must be completed and reviewed
by a physician from the study site and transmitted to the sponsor within 24 hours. The initial and
follow-up reports of a serious adverse event 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 adverse events or serious adverse events.
Open-ended and nonleading verbal questioning of the participant is the preferred method to inquire
about adverse event occurrence.
Solicited Adverse Events
Solicited adverse events are predefined local and systemic events for which the participant is
specifically questioned.
Unsolicited Adverse Events
Unsolicited adverse events are all adverse events 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 adverse event,
serious adverse event, or 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 3: Adverse Events: 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 adverse events to the regulatory
authorities. The sponsor will also report to the investigator (and the head of the investigational
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institute where required) all suspected unexpected serious adverse reactions (SUSARs). The
investigator (or sponsor where required) must report SUSARs to the appropriate IEC/IRB that
approved the protocol unless otherwise required and documented by the IEC/IRB. A SUSAR will
be reported to regulatory authorities unblinded. Participating investigators and IEC/IRB will
receive a blinded SUSAR summary, unless otherwise specified.
An anticipated event is an adverse event that commonly occurs in the study population independent
of exposure to the drug under investigation. For the purposes of this study, anticipated events will
be periodically analyzed as specified in Appendix 13: Anticipated Events.
8.3.5. 
Pregnancy
All initial reports of pregnancy in participants or their partners of participants (through sperm of
participant/from sexual intercourse and if appropriate consent is given) 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 serious
adverse events and must be reported using the Serious Adverse Event Form. Any participant who
becomes pregnant during the study must discontinue further study treatment.
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 a serious adverse event will be reported as serious adverse
events, regardless of whether they are protocol-specific assessments.
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 3: Adverse Events: 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. Additional
information will be collected for these events. Refer to the monitoring and management guidelines
for these events in Section 6.6.3. Confirmed cases of pneumonitis/ILD (regardless of grade) should
be reported as serious adverse events (see 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.
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8.4. 
Treatment of Overdose
There are no data on overdose from studies of amivantamab or lazertinib (refer to IB for each
agent) or from studies of osimertinib (refer to local prescribing information37).
In the event of an overdose, the investigator or treating physician should:
Contact the Medical Monitor immediately.
Closely monitor the participant for adverse events/serious adverse events, and laboratory
abnormalities.
Document the quantity of the excess dose as well as the duration of the overdosing in the study
drug administration eCRF.
8.5. 
Pharmacokinetics
Serum samples will be used to evaluate the PK ofamivantamab and plasma samples will be used
to evaluate the PK of lazertinib. Serum or plasma collected for PK may additionally be used to
evaluate safety or efficacy aspects that address concerns arising during or after the study period.
Genetic analyses will not be performed on these serum samples. Participant confidentiality will be
maintained.
8.5.1. 
Evaluations
Serum samples will be collected from participants in Arm A for PK and immunogenicity
assessments of amivantamab at the time points outlined in Table 2. Plasma samples will be
collected from participants in Arm A for the evaluation of PK of lazertinib at the time points
outlined in Table 2. The exact dates and times of blood sampling must be recorded on the
laboratory requisition form. Refer to the Laboratory Manual for sample collection requirements.
Blood samples should not be collected from the same extremity in which the amivantamab infusion
was administered.
Blood collected for PKmay additionally be used to identify circulating metabolites and/or evaluate
safety or efficacy aspects that address concerns arising during or after the study period.
8.5.2. 
Analytical Procedures
Pharmacokinetics
Serum samples will be analyzed to determine concentrations of amivantamab using a validated,
specific, and sensitive enzyme-linked immunosorbent assay (ELISA) method by or under the
supervision of the sponsor.
Plasma samples will be analyzed to determine concentrations of lazertinib using a validated liquid
chromatography-tandem mass spectrometry method.
If required, some plasma and serum samples may be analyzed to document the presence of
circulating metabolites using a qualified research method. In addition, plasma and serum PK
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samples may be stored for future analysis of other co-administered treatments, protein binding,
and the metabolite profile.
8.5.3. 
Pharmacokinetic Parameters and Evaluations
Pharmacokinetic analysis ofserum/plasma concentration data for amivantamab and lazertinib will
be performed. Serum (amivantamab) and plasma (lazertinib) concentrations and PK parameters
will be listed and summarized by sampling interval.
Pharmacokinetic serum/plasma concentration-time data from this study will be analyzed using a
population PK approach. The data collected from this study may also be combined with similar
data from other studies to perform population PK and assess the relationship between PK or
immunogenicity and selected safety and efficacy endpoints. Details will be provided in a
population PK and exposure-response analysis plan and results of the analysis will be presented in
a separate report.
8.6. 
Pharmacogenomics
A pharmacogenomic blood sample will be collected from participants in Arm A to allow for
assessment of GSTM-1 to understand correlation of genetic variants with PK, safety, tolerability
and efficacy.
8.7. 
Biomarkers
Mandatory Tumor Biopsy Sample for Central Mutation Analysis
It is mandatory to provide an unstained tumor tissue sample obtained from the newly diagnosed,
locally advanced, or metastatic NSCLC meeting criteria described in Inclusion Criterion no. 2 for
each participant. This biopsy sample must be obtained before randomization. It will undergo
central genetic analysis and other testing for biomarker analysis and to confirm EGFR status. If
possible, the tumor tissue provided for central analysis should be from the same biopsy utilized for
local testing and identification of Exon 19del or L858R. Biopsy samples taken from bone
metastasis, fine needle aspiration (FNA), and cytology samples are unsuitable for testing and
should not be provided. Samples may be collected from primary or metastatic tumor deposits but
must not be taken from a previously irradiated lesion.
The tumor tissue sample must be unstained, formalin-fixed and paraffin-embedded (FFPE) and in
a sufficient quantity to allow for central analysis of EGFR mutation status. Unstained FFPE tumor
tissue blocks must be provided whenever possible. Alternatively, a minimum of10 (up to 15 when
available) re-cut unstained sections from FFPE tumor tissue block, presented on slides must be
provided. Each section is to be 5 µm. Sites should ship the FFPE tumor sample to the
sponsor-designated testing laboratory as soon as it is available. Please refer to the laboratory
manual.
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Blood Samples
Mandatory screening blood samples collected from all participants may  undergo ctDNA and
ddPCR analysis by the sponsor to evaluate pre-treatment mutational status of EGFR, MET, and
other key oncogenes to characterize the tumor. Additional blood samples will be collected during
the study and may be evaluated for ctDNA to assess changes in the levels or types of genetic
alterations observed over time, and to monitor for the emergence of potential markers of resistance
to the study therapy.
Blood samples will also be collected at time points specified in the Schedule of Activities for
potential analysis of circulating biomarkers (eg, cytokines, growth factors) in samples taken prior
to and after exposure to study treatment(s). Changes in circulating markers may be assessed in pre-
and post-treatment samples and levels correlated with response to study treatments.
Additional biomarkers (eg, DNA, RNA, and protein) relevant to cancer and/or metabolism of study
treatments may also be assessed in blood and tissue samples collected during the study to better
understand the disease and mechanisms of response or resistance to study therapy.
Stopping Analysis
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and
clinical response rates. Biomarker analysis may be deferred or not performed, if during or at the
end of the study, it becomes clear that the analysis will not have sufficient scientific value for
biomarker evaluation, or if there are not enough samples or responders to allow for adequate
biomarker evaluation. In the event the study is terminated early or shows poor clinical efficacy,
completion of biomarker assessments is based on justification and intended utility of the data.
Additional Collections
If it is determined at any time before study completion that additional material is needed from a
formalin-fixed, paraffin-embedded tumor sample for the successful completion of the protocol-
specified analyses, the sponsor may request that additional material be retrieved from existing
samples. Also, based on emerging scientific evidence, the sponsor may request additional material
from previously collected tumor samples during or after study completion for a retrospective
analysis. In this case, such analyses would be specific to research related to the study treatment(s)
or diseases being investigated.
8.8. 
Immunogenicity Assessments
Serum samples will be collected for immunogenicity assessments of amivantamab (anti-drug
antibodies to amivantamab) from participants in Arm A at the time points outlined in Table 2. The
detection and characterization of antibodies to amivantamab will be performed using a validated
assay method by or under the supervision ofthe sponsor. All serum samples collected for detection
of antibodies to amivantamab will also be evaluated for amivantamab serum concentration to
enable interpretation of the immunogenicity data. Other analyses may be performed to characterize
immunogenicity.
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Antibodies to amivantamab will be evaluated in serum samples collected from all participants
according to the Schedule of Activities. Additionally, serum samples should also be collected at
the final visit from participants who discontinued study treatment or were withdrawn from the
study. These samples will be tested by the sponsor or sponsor's designee.
Serum samples will be screened for antibodies binding to amivantamab and the titer of confirmed
positive samples will be reported. Other analyses may be performed to verify the stability of
antibodies to amivantamab and/or further characterize the immunogenicity of amivantamab.
Serum samples will be used to evaluate the immunogenicity of anti-amivantamab antibodies.
Samples collected for immunogenicity analyses may additionally be used to evaluate safety or
efficacy aspects that address concerns arising during or after the study period. Genetic analyses
will not be performed on these serum samples. Participant confidentiality will be maintained.
Analytical Procedures
The detection and characterization of antibodies to amivantamab will be performed using a
validated assay method by or under the supervision of the sponsor. All samples collected for
detection of antibodies to amivantamab will also be evaluated for amivantamab serum
concentration to enable interpretation of the antibody data. Antibodies may be further
characterized and/or evaluated for their ability to neutralize the activity of the study treatment(s).
Samples may be stored up to 15 years (or according to local regulations) following the last
participant’s last visit for the study at a facility selected by the sponsor to enable further analysis
of immune responses to amivantamab.
8.9. 
Medical Resource Utilization and Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are not
evaluated in this study.
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 null hypothesis is that there is no difference of treatment effect in PFS between amivantamab
and lazertinib combination and single agent osimertinib in participants with EGFR mutation (Exon
19del or Exon 21 L858R) positive, locally advanced or metastatic NSCLC. The alternative
hypothesis is that, compared with single agent osimertinib, the amivantamab and lazertinib
combination will prolong PFS.
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9.2. 
Sample Size Determination
The primary objective of the study is to assess the efficacy of the combination of amivantamab
and lazertinib, compared with single-agent osimertinib, as measured by PFS by BICR, in
accordance with RECIST v1.1 guidelines. The sample size calculation was based on the
assumption that the combination therapy will result in a 27% reduction in the risk of either
progression or death over the single agent osimertinib therapy (an HR of 0.73, prolongs the median
PFS from 19 months35 to 26 months). A total of 450 PFS events in Arm A and Arm B will provide
approximately 90% power to achieve a statistically significant difference between the 2 treatment
arms with the stratified log-rank test (2-sided alpha 0.05).
Approximately 1000 eligible participants will be randomized in a 2:2:1 ratio to the three arms
(Arm A: Arm B: Arm C). Assuming a 25-month recruitment period and an annual dropout rate of
approximately 5%, 560 PFS events (approximately 450 events in Arm A and Arm B combined)
are expected to occur approximately 42 months after the first participant is enrolled.
9.3. 
Populations for Analyses Sets
For purposes of analysis, the study populations are defined in Table 14.
Table 14: 
Populations for Analyses
Population 
Description
Full Analysis Set 
All randomized participants, classified according to their assigned treatment arm regardless
of the actual treatment received.
Safety  
Randomized participants who receive at least 1 dose of study treatment.
Pharmacokinetics Randomized participants who receive at least 1 dose of study treatment and have at least
1 evaluable postbaseline concentration measurement.a
Biomarkers 
Randomized participants who receive at least 1 dose of study treatment and have at least
1 biomarker measurement.
a. Participants may be removed from the estimation of certain pharmacokinetic parameters on an individual basis
due to, for example, missing pharmacokinetic samples such that the pharmacokinetic parameters cannot be
appropriately derived. These participants will be identified at the time of the analyses along with their reason for
removal.
9.4. 
Statistical Analyses
The statistical analysis plan, which will be finalized prior to the interim analysis (Section 9.5), will
include a more technical and detailed description of the statistical analyses described in this
section. This section is a summary of the planned statistical analyses of the primary and key
secondary endpoints.
9.4.1. 
General Considerations
Continuous variables will be summarized using number of participants (n), mean, standard
deviation (SD), median, minimum, and maximum. Discrete variables will be summarized with
number and percent. The Kaplan-Meier product limit method and a stratified Cox model will be
used to estimate time-to-event variables and to obtain the HR and confidence interval. Unless
otherwise specified, stratified log-rank tests will be used to test the treatment effect for
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time-to-event variables; response rate variables will be evaluated using the chi square statistic or
the exact test if the cell counts are small.
The hypothesis testing of primary efficacy endpoint and key secondary efficacy endpoint will be
performed for the comparison between the combination of amivantamab and lazertinib therapy
(Arm A) and single agent osimertinib (Arm B). The comparison of the combination of
amivantamab and lazertinib therapy (Arm A) with the lazertinib monotherapy arm (Arm C) will
also be performed to demonstrate the contribution of amivantamab to the activity of the
combination using summary statistics of primary endpoint and secondary endpoints (PFS and OS)
along with nominal p-values; there will be no hypothesis testing for this comparison.
9.4.2. 
Primary Endpoint
The primary efficacy endpoint of PFS is defined as the time from randomization until the date of
objective disease progression or death, whichever comes first, based on BICR using RECIST v1.1.
Participants who have not progressed or have not died at the time of analysis will be censored at
the time of the latest date of assessment from their last evaluable RECIST v1.1 assessment. If the
participant progresses or dies after 2 or more missed disease assessments, the participant will be
censored at the time of the last evaluable RECIST v1.1 assessment. If the participant has no
evaluable visits or does not have baseline data, the participant will be censored at Day 1 unless the
participant dies within 2 visits of baseline.
The treatment effect of the combination, compared with osimertinib, on PFS will be analyzed in
the Full Analysis Set using the log-rank test stratified by mutation type (Exon 19del vs Exon 21
L858R), race (Asian vs non-Asian), and history of brain metastasis (present vs absent). The HR
for PFS will be calculated, along with its 95% confidence interval, from a stratified Cox model
using the same stratification factors as for the log-rank test. The effect of the combination
compared to lazertinib on PFS will be assessed using the same analysis methods.
9.4.3. 
Secondary Endpoints
Secondary endpoints will be analyzed using the Full Analysis Set.
Overall Survival
The secondary endpoint of OS is defined as the time from the date of randomization until the date
of death due to any cause. Any participant not known to have died at the time of analysis will be
censored based on the last recorded date on which the participant was known to be alive. OS will
be analyzed using the same methodology and model as for the analysis of PFS. To strongly control
Type I error rate at 0.05 for the study, a hierarchical testing approach for the primary endpoint and
key secondary endpoint will be used. The comparison between the combination and osimertinib
for OS will be conducted only if PFS shows statistical significance. The analysis of OS will be
conducted at 2 timepoints, based on the group sequential design with the O’Brian Fleming alpha
spending approach:
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At the time of the final analysis of primary endpoint of PFS, when approximately 340 deaths
overall (all treatment arms combined) are anticipated. With approximately  270 deaths in
Arm A and Arm B combined, based on the O’Brian Fleming alpha spending approach, a
2-sided alpha of 0.0140 will be allocated to the interim analysis.
Approximately 60 months after the first participant is enrolled, when 490 deaths overall (all
treatment arms combined) are anticipated, with approximately 390 deaths from Arm A and
Arm B combined.
Objective Response Rate
The ORR is defined as the proportion of participants who achieve either a complete response or
PR, as defined by BICR using RECIST v1.1. ORR will be analyzed using a logistic regression
stratified by mutation type (Exon 19del vs Exon 21 L858R) and race (Asian vs non-Asian) and
history of brain metastasis (present vs absent). The results of the analysis will be presented in terms
of an odds ratio together with its associated 95% confidence intervals.
Duration of Response
Duration of response is defined as the time from the date of first documented response (CR or PR)
until the date of documented progression or death, whichever comes first. The end of response
should coincide with the date of progression or death from any cause used for the PFS endpoint.
If a participant does not progress following a response, then his/her duration of response will use
the PFS censoring time. A Kaplan-Meier plot and median duration of response with 95%
confidence interval (calculated from the Kaplan-Meier estimate) will be presented by treatment
group.
Progression-free Survival After the First Subsequent Therapy
The PFS2 is defined as the time from randomization until the date of second objective disease
progression, after initiation of subsequent anticancer therapy, based on investigator assessment
(after that used for PFS) or death, whichever comes first. Participants alive and for whom a second
disease progression has not been observed should be censored at the last time known to be alive
and without a second disease progression. PFS2 will be analyzed using the same method as PFS.
Time to Symptomatic Progression
Time to symptomatic progression (TTSP) is defined as the time from randomization to
documentation in the eCRF of any of the following (whichever occurs earlier): onset of new
symptoms or symptom worsening that is considered by the investigator to be related to lung cancer
and requires either a change in anticancer treatment and/or clinical intervention to manage
symptoms or death, whichever comes first. The symptomatic progression can be reported before,
after, or at the time radiographic disease progression is identified and should continue to be
assessed after subsequent therapy has been initiated. The TTSP for a participant who does not
experience any of these events will be censored on the date on which the participant was last known
to be event free. The TTSP will be analyzed using similar methods as the analysis of PFS.
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Intracranial Progression-Free Survival
Intracranial PFS is defined as the time from randomization until the date of objective intracranial
disease progression or death, whichever comes first, based on BICR using RECIST v1.1  in
participants who had a history of brain metastasis at screening in the full analysis set. Participants
who have not progressed intracranially or died at the time of analysis will be censored at the time
of the latest date of assessment from their last evaluable RECIST v1.1 assessment. It will be
analyzed using a similar method as the analysis of PFS.
Patient Reported Outcomes Analyses
Results for EORTC-QLQ-C30 and NSCLC-SAQ will be summarized for the full analysis set.
Time to worsening in EORTC-QLQ-C30 total score and individual scales will be analyzed using
a Kaplan-Meier method and stratified Cox proportional-hazard model. Additional analysis may be
done, if appropriate. Analysis details will be included in the Statistical Analysis Plan.
The NSCLC-SAQ data will be summarized descriptively by treatment group and study visit. Each
multi-item scale and individual item will be summarized using count and percent.
9.4.4. 
Exploratory Endpoints
Analyses of exploratory endpoints will be described in the Statistical Analysis Plan.
9.4.5. 
Safety Analyses
All safety analyses will use the Safety Population.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded
using the Medical Dictionary for Regulatory Activities (MedDRA). Any adverse event occurring
at or after the initial administration of study treatment through the day of last dose plus 30 days,
or until the start of subsequent anticancer therapy (if earlier), is considered to be
treatment-emergent. All reported TEAEs will be included in the analysis. For each adverse event,
the percentage of participants who experience at least 1 occurrence of the given event will be
summarized by study treatment group.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue study treatment due to an adverse event, or who experience
a severe or serious adverse event.
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. Changes from
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baseline results will be presented in pre- versus post-treatment cross-tabulations (with classes for
below, within, and above normal ranges). 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.
Parameters with predefined NCI CTCAE toxicity grades will be summarized. Change from
baseline to the worst adverse event grade experienced by the participant during the study will be
provided as shift tables.
Electrocardiogram
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and
frequency tabulations. These tables will include observed values and changes from baseline values
(the predose ECG will be used as baseline).
Electrocardiogram data will be summarized by ECG parameter. The ECG variables that will be
analyzed are heart rate, PR interval, QRS interval, QT interval, and QT corrected according to
Fridericia's formula (QTcF).
Vital Signs
Vital signs including weight, temperature, pulse/heart rate, respiratory rate, and blood pressure
(systolic and diastolic) will be summarized over time, using descriptive statistics and/or
graphically. The percentage of participants with values beyond clinically important limits will be
summarized.
LVEF Assessments
LVEF will be determined using either ECHO or MUGA scan. Descriptive statistics for LVEF and
changes from baseline will be summarized at each scheduled time point. The percentage of
participants with values beyond clinically important limits will be summarized.
9.4.6. 
Other Analyses
An Independent Data Monitoring Committee (IDMC) will be established as noted in Committees
Structure in Appendix 2: Regulatory, Ethical, and Study Oversight Considerations.
Pharmacokinetic Analyses
The PK analyses will use the PK Population (Table 14). For participants randomized to the
combination of amivantamab and lazertinib, all plasma/serum concentrations below the lowest
quantifiable concentration or missing data will be labeled as such in the concentration data
presentations or Statistical Analysis Software (SAS) dataset. Concentrations below the lower
quantifiable concentration will be treated as zero in the summary statistics. All participants and
samples excluded from the analysis will be clearly documented in the CSR.
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Biomarkers Analyses
Biomarkers analyses will use the Biomarkers Population (Table 14). Each baseline tumor status
will be evaluated by both tumor genetic analysis and ctDNA NGS analysis in order to characterize
potential mechanisms of resistance to amivantamab in combination with lazertinib.
The association of biomarker-positivity (eg, EGFR mutation status, circulating biomarkers) with
clinical response or time-to-event endpoints will be assessed using statistical methods appropriate
for each endpoint (eg, analysis of variance, categorical, or survival models). Correlation of baseline
biomarker expression levels with clinical response or relevant time-to-event endpoints will be
performed to identify responsive (or resistant) subgroups.
Assessment of additional genes or biomarkers (DNA, RNA, or protein) relevant to lung or other
cancers and assessment of the mechanism of action or metabolism of study treatments may also
be performed in blood and tissue samples collected on study to better understand mechanisms of
response or resistance to study treatments. Alterations in blood characteristics may be evaluated
for correlation with response to study treatments, tumor burden, and disease progression as data
warrant.
Immunogenicity Analyses
The incidence of anti-amivantamab antibodies will be summarized for all participants in the PK
Population (Table 14). A listing of participants who are positive for antibodies to amivantamab
will be provided. The maximum titers of antibodies to amivantamab will be summarized for
participants who are positive for antibodies to amivantamab. Other immunogenicity analyses may
be performed to further characterize the immune responses that are generated.
Pharmacokinetic/Pharmacodynamic Analyses
The exposure-response relationship between amivantamab and lazertinib measures of exposure
(eg, derived AUC or trough concentrations) and key efficacy (eg, PFS and OS) and safety
parameters (eg, skin rash), will be explored graphically, as data allow. In addition, the relationship
may be characterized using an exposure-response or logistic regression model. Details will be
provided in an analysis plan and detailed results may be reported separately from the CSR.
9.5. 
Interim Analysis
A futility analysis based on PFS will be conducted when approximately 150 PFS events have
occurred overall (all treatment arms combined). Futility will be assessed at this analysis and a
nominal alpha of 0.00001 will be allocated to this analysis. The analysis method for primary
efficacy endpoint described in Section 9.4.2 Primary Endpoints, will be used for the interim
analysis. If the HR for combination versus osimertinib is ≥1.0, the study will be stopped for futility.
An interim analysis of PFS will be performed when approximately 350 PFS events have occurred
overall (all treatment arms combined). With approximately 280 PFS events in Arm A and Arm B
combined, based on the group sequential design with the O’Brian Fleming alpha spending
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approach as implemented by the Lan-DeMets method, a 2-sided alpha of 0.0090 will be spent at
the interim analysis. If there are 450 PFS events at the final analysis, the 2-sided alpha for the
comparison between the combination and osimertinib will be 0.0472.
An interim analysis of OS will be conducted at the time of the final analysis for PFS, when
approximately 340 deaths overall (all treatment arms combined) are anticipated. The key
secondary endpoint of OS will be tested with a total 2-sided alpha of 0.05 only if statistical
significance for PFS is achieved. With 270 deaths in Arm A and Arm B combined, based on the
O’Brian Fleming alpha spending approach, a 2-sided alpha of 0.0140 will be allocated to the
interim analysis. If there are 390 deaths at the OS final analysis, the 2-sided alpha for the
comparison between the combination and osimertinib will be 0.0457.
The Statistical Analysis Plan will describe the planned interim analyses in greater detail.
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations
ADCC  
antibody-dependent cellular cytotoxicity
ALT  
alanine aminotransferase
Anti-HCV  
hepatitis C virus antibody
ART  
antiretroviral therapy
AST  
aspartate aminotransferase
AxMP  
auxiliary medicinal product
BCRP  
breast cancer resistance protein
BICR  
blinded independent central review
CHF  
congestive heart failure
CLIA  
Clinical Laboratory Improvement Amendments
Cmin  
minimum plasma/serum concentration
CNS  
central nervous system
CRO  
Clinical Research Organization
CT  
computerized tomography
CTCAE 
Common Terminology Criteria for Adverse Events
ctDNA  
circulating tumor deoxyribonucleic acid
CYP  
cytochrome P450
ddPCR  
digital droplet polymerase chain reaction
DLT  
dose-limiting toxicity
DNA  
deoxyribonucleic acid
ECG  
electrocardiogram
ECHO  
echocardiogram
ECOG  
Eastern Cooperative Oncology Group
eCRF  
electronic case report form
eDC  
electronic data capture
EGFR  
epidermal growth factor receptor
ELISA  
enzyme-linked immunosorbent assay
EQ-5D-5L 
EuroQol five-dimensional descriptive system (5-level version)
FDA  
Food and Drug Administration
FFPE 
formalin-fixed and paraffin-embedded
FSH  
follicle stimulating hormone
G-CSF  
granulocyte colony-stimulating factor
GCP  
Good Clinical Practice
HBsAg 
hepatitis B surface antigen
HBV  
hepatitis B virus
HCV  
hepatitis C virus
HGF  
hepatocyte growth factor
HIV  
human immunodeficiency virus
HR  
hazard ratio
HRT  
hormonal replacement therapy
IB  
investigator’s brochure
ICF  
informed consent form
ICH  
International Council for Harmonization
ICMJE  
International Committee of Medical Journal Editors
IDMC  
Independent Data Monitoring Committee
IEC  
Independent Ethics Committee
ILD  
interstitial lung disease
IMP  
investigational medicinal product
INR  
international normalized ratio
IPPI 
Investigational Product Preparation Instructions
IRB  
Institutional Review Board
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IRR  
infusion-related reaction
IV  
intravenous
IWRS  
interactive web response system
LLN  
lower limit of normal
LTE 
long-term extension
LVEF  
left ventricular ejection fraction
MET  
mesenchymal-epithelial transition
MRI 
magnetic resonance imaging
MRP4 
multi-drug resistance protein 4
MTD  
maximum tolerated dose
MUGA  
multigated acquisition
NCI CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse Events
NGS  
next-generation sequencing
NIMP  
non-investigational medicinal product
NSCLC  
non-small cell lung cancer
NSCLC-SAQ  
Non-Small Cell Lung Cancer - Symptom Assessment Questionnaire
NYHA  
New York Heart Association
OLE 
open-label extension
ORR  
objective response rate
OS  
overall survival
PFS  
progression-free survival
PGIC  
Patient Global Impression of Change
PGIS  
Patient Global Impression of Severity
PK 
pharmacokinetic(s)
PQC  
product quality complaint
PR 
partial response
PRO  
patient-reported outcomes
QT 
uncorrected QT interval
QTc 
corrected QT
QTcF  
corrected QT interval by Fridericia
RECIST  
Response Evaluation Criteria in Solid Tumors
RNA  
ribonucleic acid
RP2CD  
recommended Phase 2 combination dose
RP2D  
recommended Phase 2 dose
SAC  
Safety Assessment Committee
SAE 
serious adverse event
SAP  
statistical analysis plan
SIPPM  
Site Investigational Product and Procedures Manual
SPF  
skin protection factor
SUSAR  
suspected unexpected serious adverse reaction
TEAE  
treatment-emergent adverse event
TKI 
tyrosine kinase inhibitor
TTSP  
time to symptomatic progression
ULN  
upper limit of normal
US  
United States
VTE 
venous thromboembolic
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10.2. Appendix 2: Regulatory, Ethical, and Study Oversight Considerations
10.2.1. 
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current International Council for Harmonization (ICH) guidelines on Good Clinical
Practice (GCP), and applicable regulatory and country-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 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.
During the course of the study, in situations where a departure from the protocol is unavoidable,
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 agree on an appropriate course of action. The data recorded in the eCRF 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, 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:
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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
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
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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 adverse events that are serious, unlisted/unexpected, and associated with the study
treatment
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
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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 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.
10.2.2. 
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 course of
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above)for details on financial disclosure.
10.2.3. 
Informed Consent Process
Each participant (or a legally acceptable representative) 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 the first 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 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 or their legally acceptable representatives 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
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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 or legally acceptable representative 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 either the participant's or his or her legally
acceptable representative'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 or legally acceptable representative 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 or legally acceptable representative is obtained.
10.2.4. 
Recruitment Strategy
Enrollment is now complete; the last participant started study treatment on 19 May 2022.
10.2.5. 
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
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 (or his or her legally acceptable representative)
includes information about, and where required per applicable regulations, explicit consent for the
processing of personal data and for the investigator/institution to 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 The informed consent also addresses the provides
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information to address the lawful 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, or make requests
concerning his or her personal data in accordance with applicable data protection law. 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.
10.2.6. 
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations)
for additional research. Samples will only be used to understand amivantamab and lazertinib, to
understand the disease under investigation, to understand differential treatment responders, and to
develop tests/assays related to amivantamab, lazertinib, and NSCLC. The research may begin at
any time during the study or the post-study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be
labeled with personal identifiers. Participants may withdraw their consent for their samples to be
stored for research (refer to Section 7.2.1).
10.2.7. 
Committees Structure
Independent Data Monitoring Committee (IDMC)
An IDMC will be established to monitor data on an ongoing basis. 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 IDMC will make
recommendations regarding the continuation of the study.
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10.2.8. 
Publication Policy/Dissemination of Clinical Study Data
All information, including but not limited to information regarding amivantamab, 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 biomarker 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 accomplish the
goals of 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 of amivantamab and 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 biomarker
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 the 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
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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
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 interim 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.
10.2.9. 
Data Quality Assurance
Data Quality Assurance/Quality Control
Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues that can impact
participant safety and/or reliability of study results. These pre-defined parameters will be
monitored during the study and important deviations from the QTLs and remedial actions taken
will be summarized in the clinical study report.
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. Written
instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before
the start of the study. The sponsor will review eCRF 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.
10.2.10. 
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 eCRF. All eCRF 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 eCRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an
eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the sponsor.
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Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any
such worksheets will become part of the participant's source documents. Data must be entered into
eCRF in English. The eCRF 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 an eCRF are needed after
the initial entry into the eCRF, this can be done in either of the following ways:
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.
10.2.11. 
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 adverse events and follow-up of adverse events; concomitant medication;
treatment receipt/dispensing/return records; study treatment administration information; and date
of study completion and reason for early discontinuation of study treatment 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 and Section 5.2 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.
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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 eCRF in the protocol include the
eSource system but information collected through eSource may not be limited to that found in the
eCRF.
10.2.12. 
Monitoring
The sponsor will use a combination of monitoring techniques (central, remote, or on-site
monitoring) to monitor this study.
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 will compare the data entered into the eCRF 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
eCRF 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.
Central monitoring will take place for data identified by the sponsor as requiring central review.
10.2.13. 
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.
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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.
10.2.14. 
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF
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.
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.
10.2.15. 
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 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.
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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 study treatment development
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
10.3.1. 
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study participant administered
a medicinal (investigational or non-investigational) product. An adverse event does not necessarily
have a causal relationship with the treatment. An adverse event 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 for 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 adverse events 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 adverse event recording).
Serious Adverse Event
A serious adverse event 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 intervention 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 adverse event occurs for which there is evidence suggesting a causal
relationship between the study treatment 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 adverse event is considered unlisted if the nature or severity is not consistent with the applicable
product reference safety information. For amivantamab or lazertinib, the expectedness of an
adverse event will be determined by whether or not it is listed in the IB. For osimertinib, the
expectedness of an adverse event will be determined by whether or not it is listed in the local
prescribing information.37
10.3.2. 
Attribution Definitions
Assessment of Causality
The causal relationship to study treatment is determined by the investigator. The following
selection should be used to assess all adverse events (AE).
Related
There is a reasonable causal relationship between study treatment administration and the AE.
Not Related
There is not a reasonable causal relationship between study treatment administration and the AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
10.3.3. 
Severity Criteria
An assessment of severity grade will be made by the investigator according to the National Cancer
Institute-Common Terminology Criteria for Adverse Events, Version 5.0 using the following
categorical descriptors:
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only;
intervention not indicated.
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting
age-appropriate instrumental activities of daily living.
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization
or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily
living.
Grade 4: Life-threatening consequences; urgent intervention indicated.
Grade 5: Death related to adverse event.
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10.3.4. 
Special Reporting Situations
Safety events of interest on a sponsor study treatment in an interventional study that may require
expedited reporting or safety evaluation include, but are not limited to:
Overdose of a sponsor study treatment
Suspected abuse/misuse of a sponsor study treatment
Accidental or occupational exposure to a sponsor study treatment
Medication error, intercepted medication error, or potential medication error involving a
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson &
Johnson medicinal product, eg, product name confusion, product label confusion, intercepted
prescribing or dispensing errors)
Exposure to a sponsor study treatment from breastfeeding
Participant-specific special reporting situations should be recorded in the eCRF. Any special
reporting situation that meets the criteria of a serious adverse event should be recorded on the
serious adverse event page of the eCRF.
10.3.5. 
Procedures
All Adverse Events
All adverse events, regardless of seriousness, severity, or presumed relationship to study treatment,
must be recorded using medical terminology in the source document and the eCRF. 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 eCRF  their opinion concerning the
relationship of the adverse event to study therapy. All measures required for adverse event
management must be recorded in the source document and reported according to sponsor
instructions.
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:
Study number
Statement, in the local language(s), that the participant is participating in a clinical study
Investigator's name and 24-hour 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
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Serious Adverse Events
All serious adverse events that have not resolved by the end of the study, or that have not resolved
upon discontinuation of the participant's participation in 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 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)
Suspected transmission of an infectious agent by a medicinal product will be reported as a serious
adverse event. Any event requiring hospitalization (or prolongation of hospitalization) that occurs
during the course of a participant's participation in a study must be reported as a serious adverse
event, except hospitalizations for the following:
Hospitalizations not intended to treat an acute illness or adverse event (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 eCRF).
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 serious adverse events. Any adverse event that results in a prolongation of the
originally planned hospitalization is to be reported as a new serious adverse event.
For convenience the investigator may choose to hospitalize the participant for the duration of
the treatment period.
Progression of disease should not be recorded 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.
10.3.6. 
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.
10.3.7. 
Product Quality Complaint Handling
A 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, or reliability of a
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product, including its labeling or package integrity. A PQC may have an impact on the safety and
efficacy of the product. Timely, accurate, and complete reporting and analysis of PQC information
from studies are crucial for the protection of participants, investigators, and the sponsor, and are
mandated by regulatory agencies worldwide. The sponsor has established procedures in
conformity with regulatory requirements worldwide to ensure appropriate reporting of PQC
information; all studies conducted by the sponsor or its affiliates will be conducted in accordance
with those procedures.
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.
If the defect is combined with a serious adverse event, the study-site personnel must report the
PQC to the sponsor according to the serious adverse event reporting timelines (refer to
Section 8.3.1, Time Period and Frequency for Collecting Adverse Event and Serious Adverse
Event Information). A sample of the suspected product should be maintained for further
investigation if requested by the sponsor.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding product quality issues are listed in the Contact Information page(s), which will be
provided as a separate document.
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10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy
Information
Participants must follow contraceptive measures as outlined in Section 5.1. Pregnancy information
will be collected and reported as noted in Section  8.3.5 and Appendix 3: Adverse Events:
Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting.
Definitions
Participants of Childbearing Potential (WOCBP)
A participant is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Participants Not of Childbearing 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 participants 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 participants on HRT, the participant will be
required to use one of the non-estrogen-containing hormonal highly effective contraceptive
methods if they wish to continue HRT during the study.
permanent absence of reproductive potential (for the purpose of this study)
Has undergone a procedure that precludes reproductive potential.
Has a congenital abnormality that precludes reproductive potential.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal participant
experiences menarche) or the risk of pregnancy changes (eg, a participant becomes sexually active
where pregnancy can occur), a participant must begin 2  methods of contraception, including 1
highly effective method, as described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by participants 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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Pregnancy During the Study
Participants who become pregnant during the study will be withdrawn from the study treatment
and followed for safety.
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Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
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)
Vasectomized partner
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual
partner of the participant 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
74 days.)
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 from intercourse where pregnancy could occur
(Sexual abstinence is considered a highly effective method only if defined as refraining from sexual
intercourse where the possibility of pregnancy exists during the entire period of risk associated with
exposure to 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.
Condom with or without spermicidec
Cap, diaphragm, or sponge with spermicide
A combination of 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)
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) Multiple types of condoms should not be used together (due to risk of failure with friction).
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10.5. Appendix 5: Eastern Cooperative Oncology Group (ECOG) Performance
Status
Grade Eastern Cooperative Oncology Group Performance Status
0 
Fully active, able to carry on all predisease 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 housework, 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).23
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10.6. Appendix 6: New York Heart Association Criteria
The following table presents the NYHA 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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CYP1A2. Appropriate medical judgment is required, and any of these medications should be
utilized, if clinically indicated, for the treatment of adverse events. The Medical Monitor can be
contacted with any questions.
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10.9. Appendix 9: Substrates of P-glycoprotein (P-gp), multi-drug resistance
protein 4 (MRP4), and Breast Cancer Resistance Protein (BCRP): Exercise
Caution
Transporter 
Substrates
P-gp 
Dabigatran etexilate
Digoxin
Fexofenadine
Loperamide
Quinidine
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
Source: References20,38
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10.10. Appendix 10: Liver Event Follow-Up and Rechallenge Criteria
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, alkaline phosphatase, bilirubin [including bilirubin
fractions], and INR), creatinine phosphokinase, and lactate dehydrogenase, 1 to 2 times per
week until resolution, stabilization, or return to participant’s baseline values
Monitor clinical condition closely
Draw blood samples for unscheduled PK analysis at timepoints when liver chemistry is
assessed for Arm A participants
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 IgM antibody
Hepatitis B surface antigen and Hepatitis B core antibody (IgM)
Hepatitis C RNA
Hepatitis E IgM antibody
Cytomegalovirus IgM antibody
Epstein-Barr viral capsid antigen IgM antibody (or equivalent test)
Assess anti-nuclear antibody, anti-smooth muscle antibody, and type 1 anti-liver kidney
microsomal antibodies
Conduct liver imaging (ultrasound, MRI, or CT) to evaluate liver disease
Refer to a specialist as appropriate
Rechallenge Criteria
Resumption of study treatment(s) may be considered if all the following criteria are met:
Hy’s Law has been excluded
A reversible underlying cause not associated with study treatment(s) (eg, alcohol use or
concomitant medication) is clearly identified and agreed upon in consultation with the
Medical Monitor.
Liver chemistry abnormalities have resolved or values have returned to baseline.
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10.11. Appendix 11: Cockcroft-Gault Formula for Estimated Creatinine Clearance
Cockcroft-Gault Formula for Estimated Creatinine Clearance for Adults
eCrCl  (140-Age) x Mass (Kilograms) x [0.85 if female]
                      72 x Serum Creatinine (in mg/dL)
OR
eCrCl  (140-Age) x Mass (Kilograms) x Constant
                     Serum Creatinine (in µmol/L)
Where Constant  1.23 for men and 1.04 for women
Reference: http://www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation/
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10.12. Appendix 12: Medications With Potential for QT Interval Prolongation
The following drugs are known to or may possibly prolong QT interval or induce Torsades de
Pointes should not be used for any participant in this study. This list is not meant to be
exhaustive, and similar restrictions should be applied to other drugs known to prolong QT
interval or induce Torsades de Pointes. Appropriate medical judgment is required.
Medications known to prolong QT interval or induce Torsades de Pointes
Restricted drugs 
Washout period
prior to study
treatment
anagrelide, ciprofloxacin, clarithromycin, cocaine (only medical
use), domperidone, droperidol, erythromycin, ibutilide, levofloxacin,
ondansetron, papaverine HCl (intra-coronary), procainamide,
quinidine, sulpiride, sultopride, terlipressin, thioridazine
2 days
chlorpromazine, cilostazol, disopyramide, dofetilide, dronedarone,
ibogaine, levosulpiride, moxifloxacin, sotalol
4 days
citalopram, escitalopram, flecainide, fluconazole, levomepromazine
(ethotrimeprazine), roxithromycin, sevoflurane
1 week
methadone, pimozide, terodiline 
2 weeks
azithromycin, donepezil, propofol 
15 days
halofantrine, pentamidine 
2 months
haloperidol 
4 months
amiodarone, chloroquine 
10 months
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Medications that may prolong QT interval or induce Torsades de pointes
Restricted drugs 
Washout period
prior to study
treatment
apomorphine, benperidol, clotiapine, dexmedetomidine, dolasetron, 
eliglustat, encorafenib, gemifloxacin, granisetron, hydrocodone-ER,
isradipine, melperone, nicardipine, ofloxacin, oxytocin, perflutren
lipid microspheres, pilsicainide, primaquine phosphate, prothipendyl,
risperidone, saquinavir, telavancin, tetrabenazine, tiapride,
tolterodine, tramadol, tropisetron, vardenafil
2 days
alfuzosin, clozapine, cyamemazine (cyamepromazine), 
deutetrabenazine, dextromethorphan/quinidine, ezogabine
(retigabine), lacidipine, lopinavir/ritonavir, mifepristone,
moexipril/HCTZ, pasireotide, perphenazine, promethazine,
telithromycin, venlafaxine
4 days
asenapine, atomoxetine, betrixaban, felbamate, imipramine 
(melipramine), ketanserin, nortriptyline, paliperidone, pipamperone,
trimipramine, valbenazine, zotepine, zuclopenthixol (zuclopentixol,
oral)
1 week
buprenorphine, delamanid, desipramine, iloperidone, lithium, 
maprotiline, mirabegron, mirtazapine, palonosetron, rilpivirine,
tacrolimus, tizanidine
2 weeks
aripiprazole, clomipramine, efavirenz, memantine 
3 weeks
artemether/lumefantrine, sertindole 
1 month
fingolimod, flupentixol, pimavanserin  
1.5 months
zuclopenthixol (zuclopentixol, IM injection) 
3.5 months
artenimol/piperaquine 
6 months
clofazimine 
12 months
nusinersen  
15 months
bedaquiline 
28 months
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Clinical Protocol 73841937NSC3003 Amendment 4
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Status: Approved, Date: 14 November 2023
10.13. Appendix 13: Anticipated Events
An anticipated event is an adverse event (AE; serious or nonserious) that commonly occurs as a
consequence of the underlying disease or condition under investigation (disease-related) or
background regimen. For the purposes of this study, the events in Table 15 will be considered
anticipated events: The review of anticipated events was stopped after the database lock associated
with the primary endpoint of the study.
Table 15: 
Anticipated Events
Constitutional
Dehydration
Sepsis
Weakness/asthenia
Fatigue
Fever/pyrexia
Weight loss
Failure to thrive
Decreased appetite/anorexia
General physical health deterioration
Cardiovascular
Superior vena cava syndrome
Pericardial effusion
Cardiac tamponade (associated with pericardial metastasis)
Myocardial infarction
Stroke
Gastrointestinal
Dysphagia
Esophageal obstruction
Intestinal obstruction
Bleeding ulcers
Diverticulitis
Respiratory
Pneumonia
Upper respiratory infection
Lower lung infection
Hypoxia
Dyspnea
Bronchitis
Emphysema
Chronic obstructive pulmonary
disease exacerbation
Malignant pleural effusion
Cough
Empyema
Pulmonary emboli
Respiratory failure
Pneumothorax
Hemoptysis
Radiation pneumonitis
Musculoskeletal (associated with metastatic or advanced disease)
Pain
Fracture (pathologic fracture)
Hematologic
Thromboembolic events –deep vein thromboses, pulmonary emboli
Anemia
Neurologic (associated with metastatic or advanced disease)
Cranial nerve palsies
Weakness of upper, lower extremities
Confusion
Mental status changes
Seizures
Unstable gait
Reporting of Anticipated Events
All AEs will be recorded in the electronic case report form (eCRF), regardless of whether
considered to be anticipated events and will be reported to the sponsor as described in Section 8.3.
Any anticipated event that meets serious criteria will be reported to the sponsor as described in
Section 8.3. Each anticipated event will be assessed by the investigator at the individual case level
and if considered to be drug-related will undergo expedited reporting (if appropriate) per
applicable clinical trial legislation to Health Authorities and IRB/IECs (Note: Japan will not
identify anticipated events for the Health Authorities). If an anticipated event is considered disease-
related or not related to study drug the event will be exempt from expedited reporting.
NCT04487080

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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
To meet US regulatory clinical trial legislation, the sponsor will perform aggregate review of
anticipated events as outlined below, and if determined to be drug-related will implement
expedited reporting of these events to Health Authorities and IRBs/IECs. If an interim analysis of
trial results leads to an unblinded, aggregate review of safety data by the study team, the sponsor
may terminate the review of pre-specified anticipated events outlined above.
Safety Assessment Committee (SAC)
A Safety Assessment Committee (SAC) will be established to perform reviews of pre-specified
anticipated events at an aggregate level. The SAC is a safety committee within the sponsor’s
organization that is independent of the sponsor’s study team. The SAC will meet to aid in the
recommendation to the sponsor’s study team as to whether there is a reasonable possibility that an
anticipated event is related to the study treatment based on a review of the aggregate data by arm.
The review of anticipated events was stopped after the database lock associated with the primary
endpoint of the study..
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold
to trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated
Events Safety Monitoring Plan.
NCT04487080

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Status: Approved, Date: 14 November 2023
10.14. Appendix 14: Open-Label Extension Phase
The purpose of the OLE Phase is to collect data of clinical relevance/importance while reducing
protocol-required visit procedures and assessments andthe burden on participants after the primary
PFS analysis and unblinding. Data collected during this phase will be limited to those procedures
and assessments specified in Table 16.
The OLE Phase will begin after approval of Amendment 4 by health authorities of
countries/territories in which this study is being conducted at the time of transition, and by study
site ECs/IRBs.
During the OLE Phase:
Participants in Arm A (amivantamab + lazertinib) will continue to receive the open-label
study treatment they are currently receiving at the time of transition to the OLE Phase and
until the discontinuation criteria described in Section 7.1 are met, or until the end of the OLE
Phase and/or transition to the LTE Phase.
Participants in Arm B (osimertinib) and Arm C (lazertinib) will continue to receive (in an
unblinded manner) the study treatment they are currently receiving at the time of transition to
the OLE Phase and until the discontinuation criteria described in Section 7.1 are met, or until
the end of the OLE Phase and/or transition to the LTE Phase. Only active treatment will be
provided. Placebo will not be provided.
Participants who have already discontinued study treatment and are in the Follow-up Phase in
the main study will continue Follow-up as specified in the Schedule of Activities for the OLE
Phase (Table 16).
10.14.1. 
Eligibility Criteria
All participants who remain in the study are eligible to transfer to the OLE Phase. Informed consent
must be obtained.
10.14.2. 
Study Treatment Administration
Study treatment should continue as specified in Section 6.1. In the OLE Phase, there will be no
placebo. Osimertinib can be provided as either over-encapsulated or non-over-encapsulated active
medication. Study Procedures
All participants in the OLE Phase should follow the Schedule of Activities for the OLE Phase
(Table 16).
Laboratory tests should be conducted by a local laboratory as specified in the Schedule of
Activities for the OLE Phase (Table 16). The investigator should review the laboratory report,
document this review, record only clinically significant abnormalities or changes in the adverse
event eCRF along with documentation of the corresponding laboratory value in the eCRF.
Additional follow-up monitoring as specified in the Schedule of Activities in Table 16 should be
performed. Pregnancy reporting should continue as described in Section 8.3.5. A positive
pregnancy test should be reported via the adverse event/serious adverse event process (see
NCT04487080

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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
Section 8.3.5 and Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting).
After notification from the sponsor to the site that final analysis for overall survival is complete,
participants on study treatment in the OLE Phase will be provided the option to transfer to the LTE
Phase (see Section 10.15 [Appendix 15]).
During the OLE Phase, data for the following study assessments will be collected.
• 
Dosing, including pre-infusion and post-infusion medications
• 
Investigator-assessed disease assessment by RECIST v1.1
• 
Tumor response by blinded independent central review (BICR) according to RECIST v1.1.
• 
Survival data
• 
Symptomatic progression (until final OS analysis)
• 
Subsequent anticancer therapy
• 
PROs (treatment phase: predose every 2 cycles continuing with the next odd-numbered
cycle): EQ-5D-5L, EORT-QLQ-C30, NSCLC-SAQ, PGIS, and PGIC (continue for 1 year
after end of treatment, reducing the data collection frequency from every 3 months to every
6 months after end of treatment
• 
All adverse events (including serious adverse events and adverse events of special interest)
• 
Laboratory test results related to adverse events
• 
Vital sign values related to adverse events and for Arm A, vitals related to amivantamab
administration.
• 
Concomitant medications
• 
Biomarkers
NCT04487080

NCT04487080

NCT04487080

NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
10.15. Appendix 15: Long-Term Extension Phase
The purpose of the LTE Phase is to continue providing participants access to study treatment while
further reducing protocol-required visit procedures and assessments, and burden on participants
after the final analysis for overall survival is complete. Investigators should monitor and assess
each participant’s disease status (response, progression, survival) and safety according to routine
standard practice and local label requirements. The LTE Phase will begin after the final analysis
for overall survival and will continue until the discontinuation criteria described in Section 7.1 are
met, or until 4 years after local marketing authorization is obtained for the studied indication,
whichever occurs first. After notification from the sponsor, participants that remain in the study at
the conclusion of the OLE Phase will be provided with the option to transfer to the LTE Phase.
Data collection will be limited during this phase. Study treatment compliance will be recorded.
Serious adverse events, will be reported on the appropriate serious adverse event form and
recorded by the sponsor in the Global Medical Safety database. Pregnancy reporting should
continue as described in Section 8.3.5. Other safety and efficacy data will not be collected during
the LTE Phase. No analyses other than routine periodic safety reviews consisting of reported
serious adverse events are planned for the LTE Phase.
Participants who had discontinued study treatment and are in the Follow-up Phase, or participants
who elect not to enter the LTE Phase will be discontinued from the study upon the start of the
LTE Phase.
Participants entering the LTE Phase will continue to receive the study treatment they were
receiving at the end of the OLE Phase. The sponsor will continue to provide study drugs until the
discontinuation criteria described in Section 7.1 are met, or until 4 years after local marketing
authorization is obtained for the studied indication, whichever occurs first. Study treatment
dispensation and accountability will be performed via IWRS.
10.15.1. 
Eligibility Criteria
All participants still in the OLE Phase of the study are eligible to transfer into the LTE Phase.
10.15.2. 
Study Treatment Administration
Study treatment should continue as specified in Section 6. In the LTE Phase, osimertinib can be
provided as either over-encapsulated or non-over-encapsulated active medication. There will be
no placebo.
10.15.3. 
Study Procedures
All participants in the LTE Phase should follow the Schedule of Activities for the LTE Phase
(Table 17).
Participants in the LTE Phase should be followed up for disease assessment and safety per local
practice and follow the local label(s). No efficacy data will be collected. Only serious adverse
events will be collected via the serious adverse event form per the serious adverse event reporting
process. Pregnancy reporting should continue as described in Section 8.3.5. A positive pregnancy
test should be documented in the subject file/source notes. Other procedures and safety
NCT04487080

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Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
assessments may be performed per local practice.
No data will be collected in the eCRF during the LTE Phase. However, assessments performed
should continue to be documented in the subject file/source notes.
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
10.16. Appendix 16: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents.
Amendment 3 (22 August 2022)
Overall Rationale for the Amendment: To implement the adverse event of special interest of venous
thromboembolic (VTE) events, as well as associated measures for monitoring and prophylaxis of these
events, and to align the protocol with the information provided in Investigator’s Brochure for the safety of
the participants. This amendment also serves to provide clarity on the schedule of assessments and visits,
timing of pharmacokinetic (PK) sampling, the reporting of symptomatic progression during the follow up
period, and the documentation of ophthalmology examination results and how to report overdose in the
electronic case report form (eCRF).
Section Number 
and Name
Description of Change 
Brief Rationale
1.3. Schedule of 
Activities (Table 1) 
Added notes in computerized tomography (CT) or 
magnetic resonance imaging (MRI) tumor imaging 
and brain MRI to indicate that images should be 
submitted to central vendor per Imaging Manual 
until blinded independent central review (BICR)
confirmed disease progression. Text was added to
clarify that if the participant begins a new cancer
therapy before BICR disease progression, tumor
imaging should be obtained before the new therapy
and if a participant receives study treatment beyond
disease progression, disease assessments should be
continued as scheduled.
To clarify the information
about timing of imaging and
submission to central
vendor.
4.1.3. Follow-up Phase 
Added a note that tumor imaging should continue per
schedule of activities until PD is confirmed by BICR
review for participants who discontinue study
treatment prior to BICR confirmed disease
progression.
1.3. Schedule of 
Activities (Table 1) 
Cells were merged to remove the text that the follow- 
up visit or call for CT or MRI tumor imaging and 
brain MRI at Q12W applies only to participants who 
discontinue study treatment and have not had 
radiographic progression confirmed by BICR.
Corresponding footnote c was deleted.
To clarify the information
about the follow-up visits
for CT or MRI tumor
imaging and brain MRI.
In study treatment Arm A: oral lazertinib, a new 
footnote e was added to indicate that study 
participants who permanently discontinue 
amivantamab and continue open label lazertinib can 
follow the visit schedule for Arms B/C if the 
discontinuation occurs after Cycle 1. 
To provide clarification on
visit schedule for the
participants who
permanently discontinue
amivantamab and continue
lazertinib.
1.3. Schedule of 
Activities (Table 2) 
Footnote d was edited as ‘If an amivantamab dose is 
skipped on a visit where PK collection was required, 
the pre-dose sample should be collected. When 
amivantamab is restarted, the pre and 
postdose/postinfusion sampling should occur at the
next dose administration. Subsequent PK sampling
should occur per Schedule of Activities (SoA)’.
To provide clarification on
collection of sample for PK
when an amivantamab dose
is skipped.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
Section Number 
and Name
Description of Change 
Brief Rationale
A new footnote e was added stating with the 
exception of the end-of-treatment pregnancy test for 
women of childbearing potential, which must occur 
at least 30 days after the last dose of study treatment,
end of treatment procedures may be conducted
before 30 days after last dose of study treatment if
new anti-cancer therapy is to be initiated.
To provide more clarity and
for consistency about the
end of treatment procedures.
1.3. Schedule of 
Activities (Table 1) 
Row and a footnote d added for prophylactic-dose 
anticoagulation during the first 4 months of 
treatment. 
To implement the adverse
event of special interest of
VTE events, as well as
associated measures for
monitoring and prophylaxis
of these events.
2.6.1. Risks for Study
Participation; 8.3.7. 
Adverse Events of Special 
Interest 
Text was updated to include VTE events, a new
adverse event of special interest and other adverse
events which require specific management
guidelines.
2.6.3. Benefit-Risk 
Assessment for Study 
Participation  
Text was updated to include information about
Independent Data Monitoring Committee (IDMC),
who have reviewed both the unblinded safety and
efficacy data of 1038 randomized participants on the
study and confirmed a favorable risk-benefit
assessments, therefore recommended continuation of
the study conduct. In addition, the text was also
added to mitigate an observed increase in VTE
events in Arm A.
6.6.1. Withholding 
Treatment 
In Table 7 and Table 8, a new footnote d was added
to provide dosing guidance for VTE events.
6.6.3.12. Venous 
Thromboembolic Events 
A new section was added to provide guidance on
management of VTE events.
8.2.1. Physical 
Examinations; 1.3. 
Schedule of Activities 
(Table 1) 
A new footnote c to Table 1 was added to include VTE
related text and text related to additional guidance was
added for detection of VTE through physical
examination.
11. References 
References added for VTE text.
4.1.2. Treatment Phase 
Text in bold was added and strikethrough was deleted 
Continuation of study treatment after disease
progression is may be allowed in accordance with
local practice, after consultation with the Medical
Monitor, if the investigator believes the participant is
deriving clinical benefit.
To provide clarification on
study treatment
administration and
associated visits and
procedures.
4.1.2. Treatment Phase 
Text was added to indicate that the participants
continuing treatment after progression will continue
within the Treatment phase of the study and comply
with associated visits and procedures, including
scheduled disease assessments, until the termination
of study treatment.
4.2. Scientific Rationale 
for Study Design  
Text was updated to indicate that the 
pharmacogenomic samples will be collected to test 
for null or non-null glutathione S-transferase Mu-1
(GSTM-1) genotype for participants in Arm A on
Cycle 1 Day 1.
To align the text with
Schedule of Activities.
NCT04487080

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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
Section Number 
and Name
Description of Change 
Brief Rationale
6.1.1. Amivantamab 
Text was added to indicate that skipped doses should 
be avoided when feasible. 
To provide insight into the
approach for amivantamab
dose skipping.
6.6.1. Withholding 
Treatment 
Text in bold was added and strikethrough was deleted  
If study treatment is withheld for more than 28 days,
consider a dose reduction per Table 9 or 10 when
consult with the Medical Monitor before restarting
study treatment.
In general, if both are to be continued, lazertinib
should be restarted at least 7-14 days prior to the next
infusion of amivantamab to ensure stability on
monotherapy, or consult with the Medical Monitor.
To provide clarity on how
doses should be held or
modified in the case of
adverse events.
In Table 7, ‘If 2 consecutive doses of amivantamab
are withheld, consult the Medical Monitor before
restarting’ was deleted for Grade 2 events.
In Table 7 and Table 8, a new footnote d added also
included text to specify that study treatment initially
held for stable, treated pulmonary embolism and deep
vein thrombosis ≤Grade 3 can be resumed at the
discretion of the investigator.
6.6.2 Dose Reduction  
Text in strikethrough was deleted.
Amivantamab may be restarted, after consultation
with the Medical Monitor, if the symptoms have
improved and treatment with the combination is
thought to be in the participant’s best interest. If 2
consecutive doses of amivantamab are withheld,
please consult the medical monitor.
Re-escalation of study treatment after a prior dose
reduction is allowed if determined to be in the best
interest of the participant after consultation with the
Medical Monitor.
6.6.3.2. Rash-Related 
Adverse Events 
Dose adjustment and management of severe bullous, 
blistering, or exfoliating skin conditions including 
toxic epidermal necrolysis was added to Table 12.
Grade 3 and Grade 4 rash events were segregated
and discontinuation of amivantamab for Grade 4 rash
was added.
Footnote b was updated to indicate that
ifamivantamab must be withheld due to toxicity for
2 consecutive doses, the Medical Monitor should be
consulted before restarting for infusion guidance.
To clarify for safety of the
participants.
7.1. Discontinuation of 
Study Treatment; 8.1.1. 
Disease Assessments 
Text in bold was added and strikethrough was 
deleted.
Participants who discontinue study treatment for any
reason should have the End of Treatment
assessments, document any subsequent therapy in the
electronic data capture (eDC) and continue to be
To avoid redundant text
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
Section Number 
and Name
Description of Change 
Brief Rationale
followed up for survival every 12 weeks (±14 days)
and symptomatic progression in accordance with the
Follow-up phase.
Text was added to indicate that the participant’s 
study treatment should be discontinued in case of 
disease progression that requires a new systemic 
anti-cancer treatment at the discretion of the treating
investigator.
To clarify for the safety of
participants and align with
clinical practice.
8.1.1. Disease 
Assessments 
Text in bold was added and strikethrough was 
deleted. 
Participants with contraindications to intravenous 
(IV) CT and MRI contrast may be able to undergo 
non-IV contrast CT exams of the chest abdomen and 
pelvis with proper documentation of medical
contraindication after consultation with the Medical
Monitor. Contraindications to the CT scan with IV
contrast that develop postbaseline require
investigator discretion consultation with the
Medical Monitor.
To provide guidance on the
management of participants
who develop a
contraindication to IV
contrast while on study.
8.1.2. Symptomatic 
Progression 
Text was updated to indicate that if symptomatic 
progression is not reported prior to treatment 
discontinuation, continued assessment is required 
during the follow up period even after subsequent 
therapy is initiated. 
To clarify about
assessments required in
participants with no
symptomatic progression
prior to treatment
discontinuation.
8.2.5. Ophthalmologic 
Assessment 
Text was updated to indicate that ophthalmology 
examination results should be recorded on the 
procedures page in the database.
To provide clarification on
data entry practices.
8.4 Treatment of 
Overdose 
Text was updated to indicate that the quantity of the
excess dose as well as the duration of the overdosing
should be documented in the study drug
administration eCRF.
Section 10.10 
Appendix 10: Liver Event 
Follow-up and 
Rechallenge Criteria 
Text was updated indicate that blood samples for 
unscheduled PK analysis at timepoints when liver 
chemistry is assessed should be drawn for Arm A
participants.
To limit blood sampling to
Arm A participants.
Throughout the protocol 
Minor formatting changes were made. 
Minor errors were noted.
Amendment 2 (23 September 2021)
Overall Rationale for the Amendment: To provide clarity on tumor imaging and brain imaging
assessments, provide additional information on amivantamab infusion, provide additional information on
infusion-related reactions, add information for paresthesia management, provide revised guidance on
initiation and course of corticosteroid therapy for Grades 2 to 4 pneumonitis, provide clarity on computed
tomography (CT) and magnetic resonance imaging (MRI) assessments required at end of treatment, and
align with the latest protocol template.
The new text is captured in bold text, and deleted text as strike-through, wherever applicable.
NCT04487080

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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
Section Number
and Name
Description of Change 
Brief Rationale
1.1. Synopsis (Study
Treatment Groups and
Duration);
4.1.2. Treatment Phase
The term ‘radiographic’ was deleted with respect to 
disease progression. 
To provide clarity that
progression is not limited to
imaging.
1.3. Schedule of
Activities (Table 1)
Deleted the following statement from CT or MRI 
tumor imaging assessment: If participant begins 
a new cancer therapy before disease progression, 
obtain tumor imaging before the new therapy.
Clarified that disease assessment should be
performed until disease progression is confirmed
by blinded independent central review (BICR).
Indicated that CT or MRI imaging assessment
and brain MRI assessment should be performed
in follow-up phase.
The following footnote c was added in Table 1:
Only applies to participants who discontinue
study treatment and have not had radiographic
disease progression confirmed by BICR.
To provide clarity on tumor
imaging and brain imaging
assessments.
Added full term of BICR in Table 1 footnote. 
To define the full term of
abbreviation mentioned in
Table 1.
Added reference to Section 8.1.1. to CT or MRI 
tumor imaging and brain MRI assessment. 
To provide additional
information.
The phrase ‘collect continuously from randomization 
(including during the Follow-up Phase)’ was 
replaced with ‘X’ under the treatment column of 
Table 1 and the phrase was mentioned along with the
assessment (of symptomatic progression events).
To provide clarity, phrase
moved to different column
in Table 1.
The following statement was modified for prestudy 
and concomitant medications as: Collect 
continuously from ICF through 30 days after the last 
dose of study treatment (or start of subsequent
anticancer therapy)., if earlier Concomitant
medications administered >30 days after the last
dose of study treatment in conjunction with serious
adverse events considered related to study treatment,
must continue to be collected until resolution of
event or start of subsequent therapy).
To provide clarity on
collection of concomitant
medications.
The following text was modified from ‘X (x4 
visits/calls)’ to ‘X (Up to 1 year after EOT)’ for 
EuroQol five-dimensional descriptive system 
(5-level version), European Organization for the 
Research and Treatment of Cancer Quality of Life
Questionnaire Core 30, Non-Small Cell Lung Cancer
- Symptom Assessment Questionnaire outcomes at
follow-up visit.
To indicate that patient
reported outcomes should
be collected up to 1 year
after EOT.
1.3. Schedule of
Activities (Table 2 -
Footnote d)
The following footnote was added: 
Contact the Medical Monitor for pharmacokinetic 
guidance if treatment is held. 
To clarify the timing for
pharmacokinetic (PK)
sample collection.
2.4. Amivantamab and
Lazertinib Combination
The following text was modified as : After 7 18 
months of follow-up, the median duration of 
response was not estimable with 16 of 20 subjects 
remaining on therapy without progression. 
To clarify the duration and
subject count with which
the median duration of
response was not estimable.
NCT04487080

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Status: Approved, Date: 14 November 2023
Section Number 
and Name
Description of Change 
Brief Rationale
4.1.2. Treatment Phase 
Specified that study treatment should be continued 
until documented disease progression is confirmed 
by BICR. 
To provide clarity on
continuation of study
treatment in case of disease
progression.
5.1. Inclusion Criteria 
(#11) 
The criterion was modified to include ‘Of 
child-bearing potential and practicing true abstinence 
during the entire period of the study, including up to
6 months after the last dose of study treatment is
given’.T
To align with the study
requirement.
5.2. Exclusion Criteria 
(#1) 
The following criteria was modified as: Participant 
has received any prior systemic treatment at any 
time for locally advanced Stage III or metastatic 
Stage IV disease (adjuvant or neoadjuvant therapy
for early stage Stage I or II disease is allowed, if
administered more than 12 months prior to the
development of locally advanced or metastatic
disease.
To specify the exact disease
stage for participant
selection.
6.1. Study Treatments 
Administered 
The following text was added: All cycles are 28 days 
and each study visit must be scheduled based on date 
of Cycle 1 Day 1. The site should not re-adjust visit 
schedule based on treatment interruptions or delays.
To provide guidance on
study cycle duration and
visit scheduling.
6.1.1. Amivantamab 
Added that the infusion rate of amivantamab can 
be slower but not faster than specified in the 
investigational product preparation instructions 
(IPPI) at the discretion of the investigator.
Specified that amivantamab must be administered
as described in the IPPI; deleted the term ‘prior
to infusion’.
Added the following text: The administration set
IV line will be primed with diluent prior to the
initiation of each IV bag of diluted amivantamab
as described in the IPPI.
To provide additional
information on
amivantamab infusion.
6.2. Preparation/ 
Handling/Storage/ 
Accountability  
Added the term ‘study treatment’ in the following 
statement as follows: Study treatment must be 
handled in strict accordance with the protocol and 
the container label, and study treatment must be
stored at the study site in a limited-access area or in a
locked cabinet under appropriate environmental
conditions.
To provide clarity as the
statement seemed
incomplete.
6.3. Measures to 
Minimize Bias: 
Randomization and 
Blinding 
The following statement was added: Participants 
who have undergone treatment for metastatic brain 
lesions, including a complete resection must be 
stratified as brain metastasis present.
To define the participants
with presence of brain
metastasis.
6.5.2. Amivantamab Pre- 
infusion and Post-infusion 
Medications (Table 5) 
Replaced ‘Optional Pre-Infusion Medications’ with 
‘Optional Additional Pre-Infusion Medications’. 
To indicate the optional
pre-infusion medications as
supplementary to required
medications.
Separated and indicated intravenous (IV) and oral
route of administration against corresponding dosing
windows.
To provide better clarity.
6.5.2. Amivantamab Pre-
infusion and Post-infusion
The footnote f was modified as follows: Optional
Pre-Infusion glucocorticoid may be administered by
IV push or oral route.
To clarify that method of
administration should not be
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
146
Status: Approved, Date: 14 November 2023
Section Number 
and Name
Description of Change 
Brief Rationale
Medications (Table 5- 
footnote f) 
an IV infusion but an IV
push.
6.5.2. Amivantamab Pre- 
infusion and Post-infusion 
Medications (Table 6) 
Added ‘or equivalent’ alongside paracetamol. 
To expand the optional
post-infusion medication
dose of antipyretic.
6.6.1. Withholding 
Treatment 
Added the term ‘clinically significant’ for Grade 3 or 
higher toxicity. 
To indicate an exception for
hematologic Grade 3
toxicities.
6.6.1. Withholding 
Treatment 
Included ‘rash’ and reference to ‘Section 6.6.3.2’ in 
addition to reference for guidance of IRR 
management. 
To indicate section
reference for rash
management.
6.6.1. Withholding 
Treatment (Table 7 and 
Table 8) 
Specified considering dose reduction in case of 
Grade 2 toxicities witnessed in Arms A, B, and C. 
To allow participants to
start treatment at a reduced
dose.
6.6.2. Dose Reduction  
Specified that lazertinib can be preferentially 
reduced if toxicity is considered related to 
lazertinib alone. A footnote ‘a’ explaining the 
same was added in Table 9.
Specified that escalation of lazertinib dose is
applicable for Arm A.
Added the term ‘Recommended’ in Table 9 title.
To allow flexibility in
dosing if toxicity is
experienced.
6.6.3. Dose Modifications 
and Management of 
Specific Adverse Events 
Added reference to Tables 7, 8, 9, and 10 for dose 
modifications in case of toxicities defined in 
Section 6.6.3. 
To cross refer to tables for
dose modifications for
toxicities.
6.6.3.1. Infusion-Related 
Reactions (Arm A only) – 
Table 11 
Added that guidance for Grade 2 interruptions should 
be followed if infusion is interrupted for Grade 1 
infusion-related reactions.
To provide guidance in case
of infusion interruption.
Added ‘H1 and H2 antagonist and antiemetic’ to the 
list of medications for Grade 2 infusion-related 
reactions.
To provide additional
medications.
Specified that participant with Grade 4 infusion- 
related reaction should not be re-challenged. 
To exclude the participant
with Grade 4
infusion-related reaction.
6.6.3.2. Rash-Related 
Adverse Events 
The following modifications were made: …either 
both a topical antibiotic (clindamycin, mupirocin, or 
fusidic acid) on sun exposed skin, or and an oral 
antibiotic…
To indicate that oral
antibiotic should be strongly
considered as prophylaxis.
Added the term ‘strongly’. 
To indicate that consultation
with dermatologist should
be a must in case of Grade 3
rash or Grade 2 rash which
does not improve within 2
weeks.
The following text was modified as: After the rash is 
controlled, consider gradually tapering the antibiotic 
de-escalating broad spectrum antibiotic and 
continuing or resuming prophylactic antibiotics.
To clearly indicate the steps
to be performed after the
rash is controlled.
Added reference to Table 7 and Table 9. 
To provide clarity to the
sites.
Added ‘or consider dose reduction’ for Grade 2 rash. 
To clarify that study
treatment dose can be
reduced in case of Grade 2
rash.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
147
Status: Approved, Date: 14 November 2023
Section Number 
and Name
Description of Change 
Brief Rationale
Changed the duration of rash reassessment in 
Table 12 from ‘after 2 weeks’ to ‘weekly’ for Grade 
3 or 4 rash. 
To increase the frequency of
rash assessment for Grade 3
or 4 rash.
Added the following treatment options for atypical 
scalp rash and associated infection, 
Topical Acetic acid 0.25% solution irrigation  
Fluocinonide 0.05% lotion. 
To include additional
treatment options for
atypical scalp rash and
associated infection.
6.6.3.6. Pulmonary 
Toxicity  
Information on suspected pulmonary toxicity was 
updated. 
To maintain consistency in
prevention, monitoring, and
management of pulmonary
toxicity guidelines across
program-wide protocols.
The following text was added: For symptomatic 
participants with pneumonitis (Grade 2 and above), 
treatment with steroids should be initiated per local 
guidelines, in addition to withholding of study 
treatment.
To provide revised guidance
on initiation and course of
corticosteroid therapy for
Grades 2 to 4 pneumonitis.
6.6.3.11. Paresthesia 
A section on dose modification and management of 
paresthesia was added. 
To provide guidance on
management of paresthesia.
7.1. Discontinuation of 
Study Treatment 
Deleted the statements pertaining to end of 
treatment assessments in case of treatment 
discontinuation. 
Added reference to section for guidance on study
drug discontinuation.
Added the following statement: Participants who
discontinue study treatment for any reason
should have the End of Treatment assessments
and continue to be followed up for survival
every 12 weeks (±14 days) and symptomatic
progression in accordance with the Follow-up
phase (Section 4.1.3).
To provide clarity on
assessments required at end
of treatment.
8.1.1. Disease 
Assessments 
The following statement was modified as follows: 
Post randomization disease assessments will occur 
every 8 weeks (±1 week) for the first 30 months, and 
then every 12 weeks (±1 week) relative to 
randomization until disease progression is
confirmed by BICR, even if a participant
discontinues treatment prior to progression or
receives another systemic anti-cancer therapy.
To clarify the period and
condition for performing
post-randomization disease
assessments.
Added information related to requirement of CT 
and MRI examinations. 
Section was modified to include requirements 
and period for performing disease assessments.
To provide clarity on
assessments required in the
study  .
8.1.2. Symptomatic 
Progression  
The following text was added: If symptomatic 
progression is not reported prior to treatment 
discontinuation, continued assessment is required 
even after subsequent therapy is initiated. 
To clarify the requirement
of continued assessment
when symptomatic
progression is not reported.
9.4.3. Secondary 
Endpoints 
Added reporting timing for symptomatic 
progression. 
To further clarify that
participants don’t need to
have radiographic
progression in order to
report symptomatic
progression.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
148
Status: Approved, Date: 14 November 2023
Section Number
and Name
Description of Change 
Brief Rationale
10.4. Appendix 4:
Contraceptive Guidance
and Collection of
Pregnancy Information
Bilateral tubal ligation was added to the list of 
permitted contraceptives and the bullet was modified 
as follows: Tubal closure (eg, bilateral tubal 
occlusion, bilateral tubal ligation). 
To align with the
recommendation from the
Women’s Health Group and
updates in the latest
protocol template.
10.7. Appendix 7: 
Clinical Laboratory Tests 
Corrected ‘direct and direct bilirubin’ to ‘direct and 
indirect bilirubin’ in footnote a.
To rectify the error.
Throughout the protocol 
Minor formatting changes were made. 
Minor errors were noted.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
149
Status: Approved, Date: 14 November 2023
Amendment 1 (22 April 2021)
Overall Rationale for the Amendment:  The overall rationale for this amendment is to make clarifications
to study procedures based on investigator and health authority feedback.
Section Number 
and Name
Description of Change 
Brief Rationale
1.3. Schedule of 
Activities –Table 1 
End of Treatment Visit: Footnote b was added. The 
With the exception of pregnancy testing, the End- 
of-Treatment Visit assessments may be performed 
less than 30 days after last dose of study treatment 
if subsequent anticancer therapy is planned before 
then.
To limit the confounding of
treatment effects potentially
introduced by subsequent
anticancer therapy, and to allow
flexibility in study conduct.
Pregnancy test: Serum pregnancy testing is
required at Screening and within 72 hours before
the first dose of Cycle 1. Pregnancy testing (serum
or urine) is required within 72 hours before the first
dose of each subsequent treatment cycle
(previously only required per local regulation).
Text was added to reiterate that a final serum or
urine pregnancy test is required as part of the End
of Treatment Visit at least 30 days after the last
dose of study treatment.
Requirements for pregnancy testing
were clarified to reduce the
possibility that pregnant women
receive study treatment and to
ensure that pregnancy is detected in
women who received treatment.
5.1. Inclusion
Criteria
Criterion 10 was revised to: 1) Remove urine
pregnancy test as an option for the Screening test
and test 72 hours before the first dose of study
treatment; 2) Add that participants must agree to
additional pregnancy testing during the study.
To help ensure only the intended
target population is enrolled.
Tightening pregnancy testing
requirements further limits the
possibility that pregnant women
may be exposed to study treatment.
Criterion 11b was revised to specify that women of
childbearing potential must be practicing 2
methods of contraception, one of which must be a
highly effective user independent method.
Previously, 2 methods of highly effective
contraception were required. Reference to
abstinence and a vasectomized partner were
deleted.
To clarify the requirement for
contraception and reduce the
burden on participants regarding
use of highly effective methods of
contraception. Deleted reference to
abstinence and vasectomized
subjects was redundant with
Appendix 4.
10.4, Appendix 4,
Contraceptive
Guidance
Text was revised for women who gain childbearing
potential during the study to require that they begin
contraception with 2 methods of contraception,
including 1 highly effective method.
To align text with requirements for
contraception described in
Inclusion Criterion 11b.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
150
Status: Approved, Date: 14 November 2023
Section Number 
and Name
Description of Change 
Brief Rationale
1.3. Schedule of 
Activities –Table 1 
ECHO or MUGA: Timeframe for collection (up to 
72 hours prior to study visit) was added. 
To provide flexibility and help
ensure compliance with required
study procedures.
Randomization: start study treatment within 3 days 
or 72 hours of randomization. 
To help ensure compliance with
required study procedures by
quantifying the amount of time that
can elapse between randomization
and C1D1.
ddPCR: Text was added: (After C7, sample can be 
collected on day of disease assessment or with the 
next safety laboratory assessment.) 
To help ensure compliance with
required study procedures by
allowing flexibility in sample
collection, which may increase the
number of participants with
samples for analysis.
1.3. Schedule of 
Activities –Table 1; 
8.6. 
Pharmacogenomics 
Pharmacogenomic testing for GSTM-1: Text was 
added that assessment is only for Arm A and 
specifies that the sample must be collected on 
C1D1. Text stating that samples may be collected 
anytime during the study was deleted.
To reduce blood collection for
participants who are not
subsequently randomized to Arm
A.
1.3. Schedule of 
Activities –Table 1; 
6.6.1. Withholding 
Treatment 
For Arm A: IV amivantamab, text was added that 
starting with C2, infusions delayed >7 days cannot 
be made up. The delayed dose should be skipped, 
and the participant dosed at the next scheduled
visit.
To reduce the possibility that
consecutive doses of amivantamab
are administered <7 days apart.
1.3. Schedule of 
Activities –Table 2  
Text was added for amivantamab serum PK sample 
collection that the end of infusion sample occurs 
within a 0-15 min window.
Specific collection window may
limit error in PK analysis.
Footnote “a” regarding PK sample collection for 
lazertinib at 4h postdose was expanded to state that 
if amivantamab infusion goes beyond 5 hours, then 
the lazertinib 4h postdose sample should still be
collected within the 3-5h window.
Additional guidance on sample
collection requirements may limit
error in PK analysis.
1.3. Schedule of 
Activities –Table 2 
(footnote “c”) 
8.5.1. Evaluations 
Text was added to specify that post-infusion PK 
blood samples should not be collected from the 
same extremity in which the amivantamab infusion 
was administered.
To help ensure that PK blood
samples accurately reflect
circulating amivantamab levels.
6.1.1. Amivantamab Text was added to clarify that amivantamab dose is 
based on the participant’s body weight at Screening 
and will remain the same for the duration of 
treatment. 
Reducing intra-participant
variability in amivantamab
exposure may improve assessment
of treatment effect.
5.1. Inclusion 
Criteria 
Criterion 2 was revised to require that participants 
have newly diagnosed, locally advanced or 
metastatic NSCLC that is treatment naïve and not 
amenable to curative therapy that includes surgical
resection or chemoradiation.
Detail added to help ensure that
only the intended study population
is enrolled.
Criterion 3 was revised to clarify that EGFR 
mutation must be demonstrated in tumor meeting 
the criteria described in Inclusion Criterion no. 2. 
Text made redundant following revision to 
Inclusion Criterion no. 2 was deleted.
To help ensure only the intended
target population is enrolled by
clarifying that assessment reflects
participants’ current disease state.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
151
Status: Approved, Date: 14 November 2023
Section Number
and Name
Description of Change 
Brief Rationale
5.1. Inclusion
Criteria
Criterion 4 was revised to clarify that submission 
of tissue from tumor meeting criteria described in 
Inclusion Criterion no. 2 is mandatory. Text made 
redundant following revision to Inclusion Criterion 
no. 2 was deleted.
To help ensure only the intended
target population is enrolled by
clarifying that assessment reflects
participants’ current disease state.
Criterion 7 was revised to: 1) Require creatinine 
clearance measurement >45 mL/min (units 
corrected) for all participants (bullet 6); 2) Add a 
requirement for urine culture to rule out urinary 
tract infection for participants with urinalysis 
positive for bacteria and leukocytes (bullet 7).
To help ensure only the intended
target population is enrolled by
clarifying requirements for
demonstration of adequate organ
function.
5.2. Exclusion
Criteria
Criterion 1 was revised to clarify that prior 
adjuvant or neoadjuvant therapy must have been 
administered for early stage disease.
To help ensure only the intended
target population is enrolled.
Criterion 2 was revised to clarify that assessment 
of participants with brain metastases will occur at 
the time of randomization, not Screening. 
To help ensure only the intended
target population is enrolled.
Assessment closer to the start of
treatment allows for a more
accurate description of participants’
baseline disease characteristics.
Criterion 4 was revised to specify that participants 
with untreated spinal cord compression are 
excluded and to describe requirements for
participants with prior definitive surgery or
radiation treatment and stable neurologic status.
To help ensure only the intended
target population is enrolled.
Criterion 7 was revised to limit exclusions for 
ophthalmologic conditions to those that are 
clinically unstable (bullet 7).
To help ensure only the intended
target population is enrolled.
Criterion 8 was revised to add that both prior and 
concurrent malignancy is exclusionary. 
Consultation with the Medical Monitor was added
as a requirement before the criterion can be
satisfied by any of the specified exceptions.
Exception “e” pertaining to breast cancer was
revised to clarify that lobular carcinoma in situ or
ductal carcinoma in situ must be considered
completely cured. History of localized breast
cancer and receiving antihormonal agents and
considered to have a very low risk of recurrence
was removed as an exception. Exception “f” was
revised to require that the participant has
undergone curative therapy and is considered cured
after 5 years with no evidence of recurrence since
initiation of that therapy.
To help ensure only the intended
target population is enrolled.
Criterion 9 was revised to: 1) clarify the meaning 
of non-exclusionary thrombosis (bullet 1); 2) 
clarify that pericardial effusion considered due to
the disease under study is not exclusionary if
clinically stable at Screening (bullet 6); 3) set the
lower limit for LVEF at <50% or below the LLN
per institutional guidelines (bullet 7).
To help ensure only the intended
target population is enrolled.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
152
Status: Approved, Date: 14 November 2023
Section Number
and Name
Description of Change 
Brief Rationale
5.2. Exclusion
Criteria
Criterion 11 was revised to delete reference to 
CYP3A4/5 inhibitors for consistency with changes 
to Appendix 8. 
To help protect participant safety
by aligning study conduct with
current understanding of the
interaction between study treatment
and potential concomitant
medication.
Criterion 19 was revised to: 1) remove reference to 
general anesthesia as an example characteristic 
feature of major surgery; 2) move the assessment
of traumatic injury status from the time the ICF is
signed to randomization.
To help ensure only the intended
target population is enrolled.
The NOTE at the end of the section was revised to 
clarify that investigators must ensure that all 
participants continue to meet entry criteria through 
randomization.
To help ensure only the intended
target population is randomized and
receives study treatment.
10.8. Appendix 8:
Prohibited and
Restricted
Medications
Guidance for the use of concomitant medications 
that induce, inhibit, or are substrates of CYP3A4/5 
was revised. The listings of medications that 
induce or inhibit CYP3A4/5 were revised to 
identify prohibited and restricted medications. 
To help protect participant safety
by aligning study conduct with
current understanding of the
interaction between study treatment
and potential concomitant
medication.
6.5.4. Prohibited or
Restricted
Medications and
Therapies
6.6.3.9. Diarrhea
Clarification was added that strong inhibitors of 
CYP3A4 are restricted and should be avoided, 
when possible, or used with caution. 
To help protect participant safety
by aligning study conduct with
current understanding of the
interaction between study treatment
and potential concomitant
medication.
6.6.3.8. Liver
Chemistry
Abnormalities
Item b) was revised. Elevations of ALT or AST 
≥3x (for participants with baseline values in the 
normal range) with other symptoms suggestive of
drug induced liver injury, including new onset
eosinophilia (>5%), should be reported as serious
adverse events.
To improve guidance for reporting
of hepatic serious adverse events.
6.5.2. Amivantamab
Pre-infusion and
Post-infusion
Medications
Table 5, footnotes d, e, and f were added, and the 
Route of Administration column revised for 
required and optional pre-infusion medications. 
Guidance was added to align with
local practice and local availability
of pre-infusion medications.
6.5.3.2.
Radiotherapy
Text was added to provide guidance for study 
treatment interruption and scheduling of 
radiotherapy relative to study treatment. 
Guidance was added to minimize
interruption of study treatment for
participants requiring concomitant
radiotherapy.
6.5.3.1. Supportive
Care
The section heading changed from “Symptomatic 
Treatment” to “Supportive Care”. Osteoclast 
inhibitors were added to the examples of 
supportive care. Reference to concomitant
medications for the symptomatic treatment of
related toxicities was deleted.
Indication for supportive care may
extend beyond management of
treatment-related toxicities.
6.6.1. Withholding
Treatment
6.6.2. Dose
Reduction
Guidance for restarting study treatment at the 
current dose level was changed to be based on 
withheld study treatment up to 28 days for all arms 
(previously 21 days for Arms B and C).
To facilitate study conduct by
aligning dose withholding guidance
for all arms.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
153
Status: Approved, Date: 14 November 2023
Section Number
and Name
Description of Change 
Brief Rationale
6.6.1. Withholding
Treatment
Guidance for restarting both agents in Arm A was 
revised to require consultation with the Medical 
Monitor if both agents are to be restarted and if 
lazertinib is not planned to be restarted before
amivantamab. Requirement for 7 days of lazertinib
dosing before restarting amivantamab was deleted.
Consultation with the Medical Monitor is required
if amivantamab is withheld for 2 or more
consecutive doses.
To ensure participant safety by
clarifying guidance for restarting
study drug in Arm A.
Table 7, Table 8: The option to dose reduce study 
treatment was added for Grade 2 toxicities. 
To provide investigators additional
flexibility to adjust study treatment.
6.3. Measures to
Minimize Bias:
Randomization and
Blinding
Text regarding recommended interaction between 
the investigator and sponsor before breaking the 
treatment code was deleted. 
To facilitate study conduct by
clarifying that the investigator
alone is responsible for breaking
the treatment code.
6.6.3.1. Infusion-
Related Reactions
(Arm A only)
Table 11: The third column heading was revised to 
reflect that the specified information includes
premedication at subsequent dosing as well as
other action to be taken.
Clarification of table content.
6.6.3.7. Cardiac
Adverse Events
Expanded guidance was provided for retreatment at 
a reduced dose for instances of QTcF prolongation. 
Repeat triplicate ECG is required before restarting 
treatment. If retreatment is indicated, Arms B and 
C should be dose reduced to Dose Level 2, and
lazertinib in Arm A should be dose reduced to
Dose Level 3.
To facilitate study conduct by
providing specific guidance for
retreatment and to further protect
participant safety.
7.1. Discontinuation
of Study Treatment
Clarification was added that any of the listed 
reasons is sufficient to require discontinuation of 
study treatment. An additional reason for study 
treatment discontinuation based on investigator
discretion was added (bullet 6).
To facilitate study conduct by
clarifying guidance for treatment
discontinuation.
8.7. Biomarkers
(Mandatory Tumor
Biopsy Sample for
Central Mutation
Analysis)
Text was revised to specify that the tumor tissue 
sample must be collected from the newly 
diagnosed, locally advanced or metastatic NSCLC 
tumor meeting criteria described in Inclusion
Criterion no. 2 before randomization occurs.
Previously, tissue could be obtained before start of
treatment. Fine needle aspiration (FNA) was added
as an unacceptable source of material for mutation
testing.
To facilitate study conduct by
clarifying requirements for
collection of tissue samples.
10.12. Appendix 12:
Medications With
Potential for QT
Interval
Prolongation
Table headings were changed from 
“Contraindicated drugs” to "Restricted drugs” and 
from “Washout period prior to randomization” to 
“Washout period prior to study treatment”. 
To facilitate study conduct by
aligning the washout period for
certain prestudy medications
relative to study treatment.
6.6.1. Withholding
Treatment
Clarification was added that all modifications, not 
only withheld doses, to study treatment should be 
recorded in the eCRF. Extraneous text related to 
withholding or discontinuing study treatment was 
deleted.
To facilitate study conduct by
ensuring that all clinically relevant
data are collected and to improve
readability.
8.1.1. Disease
Assessments
Reference to the latest Imaging Site Manual was 
added. Additional text was added to requirements 
for CT and MRI oral and IV contrast agents. 
To facilitate study conduct by
ensuring that diagnostic imaging
assessments are adequate to
evaluate study endpoints.
NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
154
Status: Approved, Date: 14 November 2023
Section Number
and Name
Description of Change 
Brief Rationale
10.7. Appendix 7:
Clinical Laboratory
Tests
For Protocol-Required Safety Laboratory 
Assessments (Urinalysis) specific assays to be 
performed in case of abnormal dipstick results 
were deleted. Footnotes a-d were added to the
table.
To allow flexibility and align
procedures with local clinical
laboratory practice.
2.3. Lazertinib: A
Third-Generation
EGFR TKI
Lazertinib safety data were updated per the current 
IB. Redundant text regarding drug related serious 
TEAEs was deleted, and reference to the current IB 
was added.
To direct readers to the latest
source of background information
and improve readability.
2.4. Amivantamab
and Lazertinib
Combination
Text was updated to present current information 
consistent with the updated IB and the new 
reference, Cho 2020. 
To provide investigators with
current information related to
combination treatment.
9.3. Populations for
Analyses Sets
The Patient Reported Outcomes population was 
deleted. Description of the Biomarker Population 
was modified so as not to require at least 1 disease 
assessment. 
Patient reported outcomes analyses
will use the Full Analysis Set, as
for other efficacy endpoints. Not all
biomarker analyses will require
disease assessment.
6.7. Continued
Access to Study
Intervention
Section added to describe the sponsor’s 
commitment to provide participants with continued 
access to investigational drug after study closure if 
it is found to be effective treatment. 
To state the conditions for
continued access to investigational
treatment to be provided by the
sponsor.
9.4.3. Secondary
Endpoints;
9.4.6. Other
Analyses (Patient-
Reported Outcomes
Analyses)
The description of Patient Reported Outcomes 
analyses for EORTC-QLQ-C30 and NSCLC-SAQ 
was moved from Section 9.4.6 to Section 9.4.3. 
The analysis population to be used was changed to 
the Full Analysis Population.
To position the description of
patient-reported outcomes analyses
with other secondary endpoints, as
defined in study objectives.
10.2.3. Appendix 
10: Informed 
Consent Process
Text describing a scenario when prior consent of
the participant is not possible has been deleted.
The described situation is
inappropriate for this study with a
28-day screening period.
3. Objectives and 
Endpoints 
PK objectives were clarified to specify that plasma
lazertinib concentrations and serum anti-
amivantamab antibodies will be assessed.
Text aligned with planned PK and
immunogenicity evaluations.
6.6.1. Withholding 
Treatment 
Extraneous text related to withholding or
discontinuing study treatment was deleted.
To improve readability.
11. References 
Reference 4, Cho 2020, was added. In-text
citations were updated accordingly.
To direct investigators to relevant
emerging information.
References to the amivantamab and lazertinib IBs
were updated to the latest editions.
To direct readers to the latest
source of background information.
COVID-19 
Appendix  
The stand-alone COVID-19 appendix was updated
to Version 2. Text was added to specify that
subjects will not be excluded from the study for
having received non-live vaccines that are either
approved or authorized for emergency use (eg,
COVID-19) by local health authorities. The
provision allowing remote consenting for study
screening was deleted.
To provide additional guidance to
investigators regarding COVID-19
vaccine use.
Throughout the 
protocol 
Minor grammatical, formatting, or spelling changes
were made.
Minor errors were noted
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Status: Approved, Date: 14 November 2023
11. 
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Clinical Protocol 73841937NSC3003 Amendment 4
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Status: Approved, Date: 14 November 2023
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Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
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NCT04487080

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 73841937NSC3003 Amendment 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 14 November 2023
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 treatment, 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: 
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
NCT04487080

Signature
User 
Date 
Reason
14-Nov-2023
14:24:10
(GMT)
Document Approval
PPD
NCT04487080