A Phase 3, Open-Label, Randomized Study of Amivantamab and Lazertinib in Combination With Platinum-Based Chemotherapy Compared With Platinum-Based Chemotherapy in Patients With EGFR-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer After Osimertinib Failure
Phase: PHASE3
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Janssen Research & Development, LLC

CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 05 April 2024
Janssen Research & Development *
Clinical Protocol
Protocol Title
A Phase 3, Open-Label, Randomized Study of Amivantamab and Lazertinib in 
Combination with Platinum-Based Chemotherapy Compared with Platinum-Based 
Chemotherapy in Patients with EGFR-Mutated Locally Advanced or Metastatic Non-
Small Cell Lung Cancer After Osimertinib Failure
MARIPOSA-2
Protocol 61186372NSC3002 Amendment 7; Phase 3
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.
Studies conducted at sites in the United States (US) will be conducted under US Food & Drug 
Administration Investigational New Drug (IND) regulations (21 CFR Part 312). Studies conducted at 
sites in the European Economic Area (EEA) will be conducted under Regulation European Union [EU] 
No 536/2014.
Regulatory Agency Identifier Number(s):
IND:  146319
EU Trial NUMBER: 2023-506518-33
Status:
       Approved
Date:
       05 April 2024
Prepared by:
       Janssen Research & Development, LLC 
EDMS number:
EDMS-RIM-311424, 10.0
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.
NCT04988295

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 61186372NSC3002 Amendment 7
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 05 April 2024
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 7
05 April 2024
Amendment 6
22 December 2022
Amendment 5
25 November 2022
Amendment 4
23 August 2022
Amendment 3
27 June 2022
Amendment 2
24 March 2022
Amendment 1
06 August 2021
Original Protocol
09 July 2021
Amendment 7 (05 April 2024)
Overall Rationale for the Amendment:
The MARIPOSA-2 study has completed its primary analysis for progression-free survival (PFS). To 
continue collecting data of clinical relevance/importance while reducing the burden on participants after 
completion of the second interim analysis for overall survival (OS) an option is being added for the study 
to transition to an Open-label extension (OLE) phase or Long-term extension (LTE) phase with reduced 
protocol-required visits and assessments. All efficacy and key safety assessments continue during the OLE 
Phase of the study. Protocol-required assessments will be further reduced in the LTE phase, while 
continuing to provide access to study treatment. 
Clarifications related to the management of pneumonitis/interstitial lung disease (ILD) have also been 
added to the protocol.
Additionally, 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 61186372NSC3002 as part of Protocol Amendment 7 are listed 
below, including the rationale of each change and a list of all applicable sections. Changes made in previous 
protocol amendments are listed in Section 10.16 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, 
Figure 2 (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: Table 1
Added text to the title to indicate that the 
Schedule of Activities for the OLE and LTE 
Phases are provided in Table 20 and Table 21, 
respectively.
Added the following note:
Guidance on study conduct during natural 
disaster, major disruption, or pandemic (eg, 
To highlight the distinct Schedules of 
Activities in the OLE and LTE 
phases.
To clarify the guidance to study 
conduct during natural disaster, major
disruption, or pandemic.

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Clinical Protocol 61186372NSC3002 Amendment 7
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Status: Approved,  Date: 05 April 2024
Section Number
and Name
Description of Change
Brief Rationale
COVID 19), is provided in a standalone 
appendix that will be provided to the site with 
the protocol.
1.3. Schedule of 
Activities: 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.
6.8. Continued Access 
to Study Treatment
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.
10.4 Appendix 4: 
Anticipated Events
The text shown below was added under the 
subheading for Safety Assessment Committee 
(SAC).
The review of anticipated events was stopped 
after the database lock associated with the 
primary endpoint of the study.
To transition anticipated events 
review from SAC to ongoing medical 
review.
10.14 Appendix 14: 
Open-Label Extension 
Phase
This appendix was added.
To specify content related to the 
addition of this study phase.
10.15 Appendix 15: 
Long-Term Extension 
Phase
This appendix was added.
To specify content related to the 
addition of this study phase.
Changes related to the management of pneumonitis/ILD
6.5.3.6. 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 requirements, and other template-specific changes
Cover page
The EU Trial number was added.
To comply with the EU CTR 
requirements.
Cover page
Added text on EU regulation, per EU CTR 
requirement.
Revised text for US regulation.
To align with the current protocol 
template.
1.1. Synopsis
The IND number and EU Trial number were 
added.
To comply with the EU CTR 
requirements.
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 
requirements.
5.1 Inclusion Criteria
Criterion 10
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 (in alignment with the 
current protocol template). 
5.1 Inclusion Criteria
Criterion 11.1
Text has been updated as shown below.
A woman participant must be either of the 
following (as defined in Appendix 5: 
Contraceptive Guidance):
To make language more inclusive and 
gender-neutral (in alignment with the 
current protocol template). 

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 61186372NSC3002 Amendment 7
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved,  Date: 05 April 2024
Section Number
and Name
Description of Change
Brief Rationale
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 7 months 
after receiving the last dose of study treatment.
To make language more inclusive and 
gender-neutral (in alignment with the 
current protocol template). 
5.1 Inclusion Criteria
Criterion 13.1
Text has been updated as shown below.
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 and his the partner must also be 
practicing a highly effective method of 
contraception (see Appendix 5: Contraceptive 
Guidance).
A male participant who is vasectomized must 
still use a condom for prevention of passage of 
exposure through ejaculation, but the 
participant’s female partner is not required to 
use contraception.
To make language more inclusive and 
gender-neutral (in alignment with the 
current protocol template). 
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 (in alignment with the 
current protocol template). 
5.4. Screen Failures
Added the text shown below under Participant 
Identification, Enrollment, and Screening Logs
This study will use an interactive web response 
system (IWRS). The investigator will generate 
screening and enrollment logs directly from 
IWRS.
To align 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).
To align with the current protocol 
template and comply 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 4: Anticipated Events.
To align 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 
To align with the current protocol 
template and to include additional
requirements in the pregnancy 
reports. 

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 61186372NSC3002 Amendment 7
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Status: Approved,  Date: 05 April 2024
Section Number
and Name
Description of Change
Brief Rationale
the event using the appropriate pregnancy 
notification form.
10.2.4. Recruitment 
Strategy (new 
subheading)
Section added.
To comply with EU CTR guidance.
10.2.5. Data Protection
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 
requirements.
10.2.8. Use of 
Information and 
Publication
Revised text regarding publication by 
Investigator. Added optional text on disclosure 
of the study results per EU CTR requirement.
To align with the current protocol 
template and to comply with the EU 
CTR requirement.
10.2.14. Record 
Retention
Additional text added on record retention under 
EU regulation.
To comply with EU CTR 
requirement.
10.3.4. Special 
Reporting Situations
Text was revised as shown below.
Participant-specific special reporting situations 
should be recorded in the eCRF.
To align with the current protocol 
template.
10.5. Appendix 5
Contraceptive Guidance 
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, and 
bilateral oophorectomy.
To align with the current protocol 
template.
10.5. Appendix 5
Contraceptive Guidance 
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 (in alignment with the 
current protocol template). 
10.5. Appendix 5
Contraceptive Guidance 
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 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.)
To make language more inclusive and 
gender-neutral (in alignment with the 
current protocol template).
Other miscellaneous changes
4.3.1 Study-Specific 
Ethical Design 
Consideration
Additional text added related to LAR and 
information on sources to obtain written consent 
To align with the current protocol 
template.

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 61186372NSC3002 Amendment 7
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 05 April 2024
Section Number
and Name
Description of Change
Brief Rationale
7.2.1 Withdrawal From 
the Use of Study 
Samples
Header and text were revised 
To align with the current protocol 
template.
7.3 Lost to Follow-up
Additional bullet has been added
•
Should the participant continue to be 
unreachable, they will be considered to have
withdrawn from the study.
To align with the current protocol 
template.
8.3.6
Disease-related 
Events and Disease-
related Outcomes Not 
Qualifying as Adverse 
Events or Serious 
Adverse Events.
Updated the criteria for disease related events 
and outcomes not qualifying as adverse events or 
serious adverse events
To align with the current protocol 
template.
9.4.3 Secondary 
Endpoints
Death was included in the definition of Time to 
Symptomatic Progression (TTSP) endpoint.
Death was inadvertently omitted from 
the definition of TTSP in the 
protocol. Additional clarification 
regarding the definition of TTSP to 
include both symptomatic progression 
and death as events was provided in 
Statistical Analysis Plan (SAP) 
Amendment 3 (dated 19 May 2023, 
prior to the primary analysis for PFS).
9.4.3 Secondary 
Endpoints
3. Objective and 
Endpoints; 
Intracranial endpoints (ORR, DoR, time to 
intracranial disease progression) have been 
included.
To align with the intracranial 
endpoints included in SAP 
Amendment 3 (dated 19 May 2023, 
prior to the primary analysis for PFS). 
Throughout the 
protocol
The words “female” and “male” were removed 
and replaced by participant.
To make the protocol more inclusive 
and gender-neutral (in alignment with 
the current protocol template).
Changes were made to text. ‘legally acceptable 
representative’ replaced by ‘legally designated 
representative’.
To align with the current protocol 
template.
10.3.2 Attribution 
Definitions
Listed factors to be considered in causality 
assessment and specified that a causal 
relationship to study intervention should be 
documented in the participant’s medical records. 
Removed “reasonable causal relationship”.
To align with the current protocol 
template.
10.2.6 Storage, Use, 
Transfer, and Retention 
of Data and Samples
Heading and text has been revised. 
To align with the current protocol 
template.
Throughout the 
protocol
Minor editorial and formatting changes were 
made.
Minor errors, discrepancies, or 
omissions were noted.

JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 61186372NSC3002 Amendment 7
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 05 April 2024
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 7
LIST OF IN-TEXT TABLES AND FIGURES.............................................................................................. 11
1.
PROTOCOL SUMMARY ................................................................................................................... 12
1.1.
Synopsis......................................................................................................................................... 12
1.2.
Schema .......................................................................................................................................... 17
1.3.
Schedule of Activities..................................................................................................................... 19
2.
INTRODUCTION................................................................................................................................ 26
2.1.
Background .................................................................................................................................... 27
2.2.
Study Rationale.............................................................................................................................. 28
2.2.1.
Amivantamab.............................................................................................................................. 28
2.2.2.
Lazertinib .................................................................................................................................... 29
2.2.3.
Amivantamab and Lazertinib Combination................................................................................. 29
2.2.4.
Rationale for Adding EGFR-Targeted Therapy to Chemotherapy ............................................. 31
2.2.5.
Rationale for Amivantamab and Platinum Doublet Chemotherapy............................................ 31
2.2.6.
Rationale for Adding Lazertinib and Amivantamab to Platinum-Doublet Chemotherapy........... 32
2.2.7.
Rationale for Chemotherapy Comparator................................................................................... 33
2.3.
Benefit-Risk Assessment ............................................................................................................... 34
2.3.1.
Risks for Study Participation....................................................................................................... 34
2.3.2.
Benefits for Study Participation .................................................................................................. 35
2.3.3.
Benefit-Risk Assessment for Study Participation ....................................................................... 35
3.
OBJECTIVES AND ENDPOINTS ..................................................................................................... 36
4.
STUDY DESIGN ................................................................................................................................ 38
4.1.
Overall Design................................................................................................................................ 38
4.1.1.
Screening.................................................................................................................................... 39
4.1.2.
Treatment Phase ........................................................................................................................ 39
4.1.3.
Follow-up Phase......................................................................................................................... 41
4.1.4.
Open-label Extension Phase and Long-Term Extension Phase ................................................ 42
4.2.
End of Study Definition................................................................................................................... 42
4.3.
Scientific Rationale for Study Design............................................................................................. 43
4.3.1.
Study-Specific Ethical Design Considerations ........................................................................... 43
4.4.
Justification for Dose...................................................................................................................... 44
5.
STUDY POPULATION ...................................................................................................................... 45
5.1.
Inclusion Criteria ............................................................................................................................ 46
5.2.
Exclusion Criteria ........................................................................................................................... 48
5.3.
Lifestyle Considerations................................................................................................................. 53
5.4.
Screen Failures .............................................................................................................................. 53
5.5.
Criteria for Temporarily Delaying Randomization .......................................................................... 53
6.
STUDY TREATMENT AND CONCOMITANT THERAPY ................................................................ 54
6.1.
Study Treatments Administered..................................................................................................... 54
6.1.1.
Scheduled Dosage and Timing .................................................................................................. 54
6.1.2.
Lazertinib .................................................................................................................................... 56
6.1.3.
Chemotherapy ............................................................................................................................ 56
6.1.4.
Amivantamab.............................................................................................................................. 56
6.2.
Preparation/Handling/Storage/Accountability ................................................................................ 57
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................................. 58
6.4.
Study Treatment Compliance ........................................................................................................ 59
6.5.
Dose Modification........................................................................................................................... 59
6.5.1.
Dose Delay Guidance................................................................................................................. 60

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6.5.2.
Dose Modification of Amivantamab and Lazertinib .................................................................... 61
6.5.3.
Dose Modification and Management of Specific Adverse Events (Arms A/A2 and Arms 
C/C2)........................................................................................................................................... 63
6.5.3.1.
Infusion-Related Reactions ..................................................................................................... 63
6.5.3.2.
Rash-Related Adverse Events ................................................................................................ 66
6.5.3.3.
Pruritus .................................................................................................................................... 69
6.5.3.4.
Paronychia............................................................................................................................... 70
6.5.3.5.
Oral Mucositis.......................................................................................................................... 70
6.5.3.6.
Pulmonary Toxicity .................................................................................................................. 71
6.5.3.7.
Cardiac Adverse Events .......................................................................................................... 72
6.5.3.8.
Liver Chemistry Abnormalities................................................................................................. 73
6.5.3.9.
Ocular Toxicity......................................................................................................................... 73
6.5.3.10.
Diarrhea................................................................................................................................... 74
6.5.3.11.
Paresthesia.............................................................................................................................. 75
6.5.3.12.
Venous Thromboembolic Events............................................................................................. 76
6.5.4.
Chemotherapy Dose Modification .............................................................................................. 77
6.5.4.1.
Management of Chemotherapy Toxicities............................................................................... 77
6.6.
Treatment of Overdose .................................................................................................................. 78
6.7.
Concomitant Therapy..................................................................................................................... 78
6.7.1.
Recording Prestudy and Concomitant Therapies....................................................................... 78
6.7.2.
Permitted and Required Medications and Therapies ................................................................. 79
6.7.2.1.
Pre- and Post-Infusion Medications for Chemotherapy .......................................................... 79
6.7.2.2.
Pre- and Post-Infusion Medications for Amivantamab (Arms A/A2 and Arms C/C2).............. 80
6.7.2.3.
Supportive Care....................................................................................................................... 81
6.7.2.4.
Radiotherapy ........................................................................................................................... 81
6.7.2.5.
Hormonal Contraception.......................................................................................................... 81
6.7.3.
Prohibited or Restricted Medications and Therapies.................................................................. 82
6.8.
Continued Access to Study Treatment .......................................................................................... 83
7.
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................... 83
7.1.
Discontinuation of Study Treatment............................................................................................... 83
7.2.
Participant Discontinuation/Withdrawal From the Study................................................................ 83
7.2.1.
Withdrawal From the Use of Study Samples.............................................................................. 84
7.3.
Lost to Follow-up............................................................................................................................ 84
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 84
8.1.
Efficacy Assessments .................................................................................................................... 86
8.1.1.
Symptomatic Progression........................................................................................................... 87
8.1.2.
Patient-Reported Outcomes ....................................................................................................... 87
8.2.
Safety Assessments....................................................................................................................... 88
8.2.1.
Physical Examinations................................................................................................................ 88
8.2.2.
Vital Signs................................................................................................................................... 89
8.2.3.
Electrocardiograms..................................................................................................................... 89
8.2.4.
Left Ventricular Ejection Fraction................................................................................................ 90
8.2.5.
Pregnancy Testing...................................................................................................................... 90
8.2.6.
Ophthalmologic Assessment ...................................................................................................... 90
8.2.7.
ECOG Performance Status ........................................................................................................ 90
8.2.8.
Clinical Safety Laboratory Assessments .................................................................................... 90
8.3.
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 90
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information.................................................................................................................................. 91
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 91
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 92
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 92
8.3.5.
Pregnancy................................................................................................................................... 92
8.3.6.
Disease-Related Events and Disease-Related Outcomes Not Qualifying as Adverse 
Events or Serious Adverse Events ............................................................................................. 92

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Status: Approved,  Date: 05 April 2024
8.3.7.
Adverse Events of Special Interest............................................................................................. 93
8.4.
Pharmacokinetics........................................................................................................................... 93
8.4.1.
Evaluations ................................................................................................................................. 93
8.4.2.
Analytical Procedures................................................................................................................. 94
8.4.3.
Pharmacokinetic Parameters and Evaluations........................................................................... 94
8.5.
Biomarkers ..................................................................................................................................... 94
8.6.
Immunogenicity Assessments ....................................................................................................... 95
8.7.
Medical Resource Utilization and Health Economics .................................................................... 96
9.
STATISTICAL CONSIDERATIONS.................................................................................................. 96
9.1.
Statistical Hypotheses.................................................................................................................... 96
9.1.1.
Multiplicity ................................................................................................................................... 96
9.2.
Sample Size Determination ........................................................................................................... 98
9.3.
Populations for Analysis Sets ........................................................................................................ 99
9.4.
Statistical Analyses ........................................................................................................................ 99
9.4.1.
General Considerations.............................................................................................................. 99
9.4.2.
Primary Endpoint ........................................................................................................................ 99
9.4.3.
Secondary Endpoints................................................................................................................ 100
9.4.4.
Exploratory Endpoints............................................................................................................... 103
9.4.5.
Safety Analyses ........................................................................................................................ 104
9.4.6.
Other Analyses ......................................................................................................................... 105
9.5.
Interim Analysis............................................................................................................................ 106
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......................... 107
10.1.
Appendix 1: Abbreviations ........................................................................................................... 107
10.2.
Appendix 2: Regulatory, Ethical, and Study Oversight Considerations....................................... 109
10.2.1.
Regulatory and Ethical Considerations .................................................................................... 109
10.2.2.
Financial Disclosure.................................................................................................................. 112
10.2.3.
Informed Consent Process ....................................................................................................... 112
10.2.4.
Recruitment Strategy................................................................................................................ 113
10.2.5.
Data Protection ......................................................................................................................... 114
10.2.6.
Storage, Use, Transfer, and Retention of Data and Samples.................................................. 114
10.2.7.
Committees Structure............................................................................................................... 115
10.2.8.
Use of Information and Publication........................................................................................... 115
10.2.9.
Data Quality Assurance............................................................................................................ 116
10.2.10.
Case Report Form Completion................................................................................................. 116
10.2.11.
Source Documents ................................................................................................................... 117
10.2.12.
Monitoring ................................................................................................................................. 118
10.2.13.
On-Site Audits........................................................................................................................... 118
10.2.14.
Record Retention...................................................................................................................... 119
10.2.15.
Study and Site Start and Closure ............................................................................................. 119
10.3.
Appendix 3: Adverse Events, Serious Adverse Events, Product Quality Complaints, and 
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting............................................................................................................................... 121
10.3.1.
Adverse Event Definitions and Classifications ......................................................................... 121
10.3.2.
Attribution Definitions................................................................................................................ 122
10.3.3.
Severity Criteria ........................................................................................................................ 123
10.3.4.
Special Reporting Situations .................................................................................................... 123
10.3.5.
Procedures ............................................................................................................................... 124
10.3.6.
Product Quality Complaint Handling......................................................................................... 125
10.3.7.
Contacting Sponsor Regarding Safety, Including Product Quality........................................... 125
10.4.
Appendix 4: Anticipated Events ................................................................................................... 126
10.5.
Appendix 5: Contraceptive Guidance .......................................................................................... 128
10.6.
Appendix 6: Liver Event Follow-Up Requirements ...................................................................... 131
10.7.
Appendix 7: Eastern Cooperative Oncology Group (ECOG) Performance Status...................... 132
10.8.
Appendix 8: New York Heart Association Criteria ....................................................................... 133
10.9.
Appendix 9: Clinical Laboratory Tests ......................................................................................... 134
10.10.
Appendix 10: Cockcroft-Gault Formula for Estimated Creatinine Clearance .............................. 135

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10.11.
Appendix 11: Medications With Potential for QT Interval Prolongation....................................... 136
10.12.
Appendix 12: Dosing Synchronization for Arms A/A2 and C/C2 ................................................. 138
10.13.
Appendix 13: Open-label Randomized Extension Cohort ........................................................... 139
10.13.1.
Synopsis ................................................................................................................................... 139
10.13.2.
Background and Rationale ....................................................................................................... 139
10.13.3.
Objectives and Endpoints......................................................................................................... 140
10.13.4.
Study Design ............................................................................................................................ 140
10.13.5.
Study Population: See Section 5 of the Protocol...................................................................... 140
10.13.6.
Study Treatment and Concomitant Therapy: See Section 6 of the Protocol............................ 141
10.13.7.
Discontinuation of Study Treatment and Participant ................................................................ 141
10.13.8.
Study Assessments and Procedures: See Section 8 of the Protocol....................................... 142
10.13.9.
Statistical Considerations and Analyses................................................................................... 142
10.14.
Appendix 14: Open-Label Extension Phase ................................................................................ 143
10.14.1.
Eligibility Criteria ....................................................................................................................... 143
10.14.2.
Study Treatment Administration................................................................................................ 143
10.14.3.
Study Procedures ..................................................................................................................... 143
10.15.
Appendix 15: Long-term Extension Phase................................................................................... 150
10.15.1.
Eligibility Criteria ....................................................................................................................... 150
10.15.2.
Study Treatment Administration ............................................................................................... 150
10.15.3.
Study Procedures ..................................................................................................................... 150
10.16.
Appendix 16: Protocol Amendment History ................................................................................. 152
11.
REFERENCES................................................................................................................................. 166
INVESTIGATOR AGREEMENT ............................................................................................................... 169

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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Schedule of Activities (All Treatment Arms, Unless Otherwise Indicated) ............................... 19
Table 2:
Collection Times for Pharmacokinetics and Immunogenicity Samplesa (Arms A/A2 and 
C/C2)......................................................................................................................................... 24
Table 3:
Collection Times for Pharmacokinetics Samplesa for Lazertinib (Arms receiving ACP-L 
– Arm A Dosing Schedule 2 and Arm A2) ................................................................................ 25
Table 4:
Study Treatment Dosing ........................................................................................................... 55
Table 5:
Arms A/A2: General Guidance for Withholding Doses for Toxicities Considered 
Related to Lazertinib or Amivantamab, Based on Gradea........................................................ 61
Table 6:
Guidance for Lazertinib Stepwise Dose Reduction (Arms A/A2) ............................................. 62
Table 7:
Guidance for Amivantamab Stepwise Dose Reduction (Arms A/A2 and Arms C/C2) ............. 62
Table 8:
Arms C/C2: General Guidance for Withholding Doses for Toxicities Considered 
Related to Amivantamab, Based on Gradea............................................................................. 63
Table 9:
Management of Infusion-Related Reactions ............................................................................ 65
Table 10:
Suggested Algorithm for Management of Rash (Arms A/A2)................................................... 67
Table 11:
Suggested Algorithm for Management of Rash (Arms C/C2) .................................................. 68
Table 12: Suggested Algorithm for Management of Diarrhea for Arms A/A2........................................... 74
Table 13: Suggested Algorithm for Management of Diarrhea for Arms C/C2 .......................................... 75
Table 14:
Guidance for Dose Modifications for Hematologic Chemotherapy Toxicity ............................. 78
Table 15:
Guidance for Dose Modifications for Non-Hematologic Chemotherapy Toxicity...................... 78
Table 16:
Concomitant Medications for Pemetrexed................................................................................ 79
Table 17: Preinfusion Medications for Amivantamab ............................................................................... 80
Table 18: Postinfusion Medications for Amivantamab.............................................................................. 81
Table 19:
Anticipated Events .................................................................................................................. 126
Table 20
Schedule of Activities in the Open Label Extension Phase (All Arms, Unless 
Otherwise Indicated)............................................................................................................... 145
Table 21:
Schedule of Activities in the Long-term Extension Phase (All Arms, Unless Otherwise 
Indicated) ................................................................................................................................ 151
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 17
Figure 2:
Schematic Overview of the Extension cohort ........................................................................... 18
Figure 3:
Waterfall Plot of Investigator-Assessed Best Percentage Change from Baseline in 
Sum of Diameters (SoD) of Target Lesions by Combination Therapy (Amivantamab + 
Lazertinib) Expansion Cohorts; Response Evaluable at RP2CD Analysis Set in 
Combination Therapy (JNJ-61186372 + Lazertinib) (Study 61186372EDI1001)..................... 30
Figure 4: 
Graphical Testing Strategy Controlling an Overall Family-wise Type I Error Rate .................. 98
Figure 5:
Schematic Overview of the extension cohort ......................................................................... 140

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1.
PROTOCOL SUMMARY
1.1.
Synopsis
A Phase 3, Open-Label, Randomized Study of Amivantamab and Lazertinib in Combination with 
Platinum-Based Chemotherapy Compared with Platinum-Based Chemotherapy in Patients with 
EGFR-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer After Osimertinib 
Failure
IND:
146319
EU Trial NUMBER:
2023-506518-33
Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are becoming 
standard of care as first-line therapy for non-small cell lung cancer (NSCLC) harboring EGFR Exon 19del 
or L858R mutations. While the third-generation EGFR TKI osimertinib represents a significant advance 
over earlier EGFR TKIs, almost all patients eventually relapse. Platinum-based chemotherapy is the current 
standard of care for NSCLC that progresses during or after osimertinib treatment, despite the fact that 
osimertinib-resistant disease may remain dependent upon EGFR and/or MET signaling. This remains an 
unmet need for the treatment of EGFR-mutated NSCLC after osimertinib. 
Amivantamab (JNJ-61186372) is a low fucose, fully human IgG1-based bispecific antibody directed 
against EGFR and MET tyrosine kinase receptors. It shows clinical activity against tumors with primary 
activating EGFR mutations Exon 19del and Exon 21 L858R substitution, EGFR Exon 20ins mutations, 
EGFR resistance mutations T790M and C797S, or activation of the MET pathway.
Lazertinib (JNJ-73841937; YH-25448) 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, with less inhibition of wild-type EGFR. 
The combination of lazertinib and amivantamab results in more robust and durable antitumor activity, with 
a higher confirmed objective response rate (ORR), greater median duration of response, and improved
clinical benefit rate compared with amivantamab monotherapy. Lazertinib also provides antitumor activity 
within the central nervous system. These findings support adding amivantamab and lazertinib to standard
of care platinum-based chemotherapy after osimertinib failure. This study will compare the efficacy and 
safety of lazertinib, amivantamab, carboplatin, and pemetrexed (“LACP”; Arm A) versus carboplatin and 
pemetrexed (“CP”; Arm B) in participants with EGFR-mutated locally advanced or metastatic NSCLC 
following progression on or after osimertinib treatment. On 07 November 2022, an Urgent Safety Measure 
was implemented to modify the dosing schedule of lazertinib on Arm A whereby it is only started after 
carboplatin therapy is completed. This dosing schedule is termed ACP-L. The primary efficacy analysis of 
LACP/ACP-L (Arm A) versus CP remains unchanged, and will include all participants randomized to Arm 
A. The contribution of lazertinib to the activity of LACP/ACP-L will be assessed descriptively by 
comparing the efficacy of LACP/ACP-L with that of amivantamab, carboplatin, and pemetrexed (“ACP”; 
Arm C).
An open-label randomized extension cohort will be used to further describe the safety and efficacy of the 
ACP-L dosing schedule versus ACP with additional data.
BENEFIT-RISK ASSESSMENT
The safety profiles of amivantamab and lazertinib are largely distinct from those associated with 
chemotherapeutic agents, and amivantamab has demonstrated safety and tolerability in addition to either 
lazertinib or chemotherapy in Phase 1 studies. 
Platinum-based chemotherapy is the current standard of care treatment for patients with locally advanced 
or metastatic NSCLC with EGFR Exon 19 deletion or Exon 21 L858R mutations whose disease has 

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progressed on or after treatment with osimertinib. All participants in the study will accordingly be treated 
with platinum-based chemotherapy (carboplatin and pemetrexed). Combining amivantamab with 
chemotherapy or with chemotherapy plus lazertinib is hypothesized to provide improved clinical benefit 
for this patient population through targeted anti-EGFR and anti-MET action, antitumor activity within the 
central nervous system (CNS), and recruitment of immune cells with antitumor activity. The distinct 
mechanisms of action of amivantamab and lazertinib have the potential to inhibit the EGFR pathway more 
potently than either agent alone.
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) reviewed safety and tolerability data periodically. Dose modification guidance is also 
provided to manage toxicities that occur during the study. Taking into account these measures to minimize 
risk to participants in the study, the potential risks associated with amivantamab and lazertinib are justified 
by the anticipated benefits that may be afforded to participants in the study.
OBJECTIVES AND ENDPOINTS
The dual primary objectives of the study are to assess the efficacy of LACP/ACP-L versus CP, and ACP 
versus CP in participants with locally advanced or metastatic EGFR Exon 19del or Exon 21 L858R 
substitution NSCLC. Key secondary objectives are further measures of clinical benefit and safety. All
secondary and exploratory objectives and endpoints are described in the protocol.
For the extension cohort, the primary objectives are to further describe the safety and efficacy of the ACP-L 
dosing schedule versus ACP using additional data.
Hypothesis
The study has dual primary hypotheses:

LACP/ACP-L will demonstrate superior progression-free survival (PFS) compared with CP.

ACP will demonstrate superior progression-free survival (PFS) compared with CP.
There is no separate hypothesis for extension cohort.
OVERALL DESIGN
This study is a randomized, open-label, active-controlled, parallel, multicenter, Phase 3 study to compare 
the efficacy and safety of LACP/ACP-L (Arm A) versus CP (Arm B) and ACP (Arm C) versus CP (Arm 
B) in participants with EGFR-mutated locally advanced or metastatic nonsquamous NSCLC who have 
progressed on or after treatment with osimertinib. The study consists of a Screening Phase (up to 28 days), 
a Treatment Phase (from randomization until the End of Treatment visit) and a Follow-up Phase (from End 
of Treatment Visit until the end of study, death, lost to follow-up, or withdrawal of consent, whichever 
comes first).
To further describe the safety and efficacy of the ACP-L dosing schedule versus ACP, a separate open-
label randomized extension cohort has been added to the study. Enrollment of participants into the extension 
cohort may begin after enrollment into the main study is complete and when the Sponsor opens the 
extension cohort for enrollment. The extension cohort will have the same eligibility criteria, study 
procedures and operate within the same investigational sites as the main study.
This study may transition to an open-label extension (OLE) phase or long-term extension (LTE) phase 
following the second interim analysis for OS.
If an OLE Phase is implemented, participants will be provided the option to reduce certain 
protocol-specified procedures and assessments while continuing their current study treatment until 
protocol specified discontinuation criteria are met. (see details provided in Section 10.14 [Appendix 14]).

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If an LTE Phase is implemented, participants will be provided continued access to study treatment with 
further reduction in protocol-specified procedures and assessments. During the LTE phase, only serious 
adverse event data and study treatment compliance will be collected (see details provided in 
Section 10.15 [Appendix 15]).
NUMBER OF PARTICIPANTS
Approximately 600 eligible participants will be randomly assigned to study treatment in a 2:2:1 ratio 
(Arms A:B:C). Randomization will be stratified by osimertinib line of therapy (first-line vs second-line), 
history of brain metastases (yes vs no), and Asian race (yes vs no).
In the extension cohort, approximately 90 eligible participants will be randomly assigned to receive ACP-L 
or ACP in a 2:1 ratio (Arms A2:C2) – the same ratio as in the main study. Randomization will be stratified 
by osimertinib line of therapy (first-line vs second-line), history of brain metastases (yes vs no), and Asian 
race (yes vs no), also as in the main study.
STUDY TREATMENT GROUPS AND DURATION
Main Study Arms
Arm A Dosing Schedule 1 (LACP, from study start until 6 November 2022) :

Lazertinib 240 mg orally, once daily

Amivantamab by intravenous (IV) infusion in 21-day cycles:

1,400 mg (1,750 mg if body weight ≥80 kg) on Cycle 1 Days 1/2, 8, and 15, and Cycle 2 Day 1

1,750 mg (2,100 mg if body weight ≥80 kg) on Day 1 of each 21-day cycle, starting with Cycle 3

Carboplatin and pemetrexed as in Arm B.
Arm A Dosing Schedule 2 (started on 07 November, 2022, ACP-L):

Lazertinib 240 mg orally, once daily starting Cycle 5 Day 1 or sooner if carboplatin is discontinued
earlier

Amivantamab by IV infusion in 21-day cycles:

1,400 mg (1,750 mg if body weight ≥80 kg) on Cycle 1 Days 1/2, 8, and 15, and Cycle 2 Day 1

1,750 mg (2,100 mg if body weight ≥80 kg) on Day 1 of each 21-day cycle, starting with Cycle 3

Carboplatin and pemetrexed as in Arm B.
Arm B (CP):

Carboplatin AUC 5 on Day 1 of each 21-day cycle, for up to 4 cycles

Pemetrexed 500 mg/m2 on Day 1 of each 21--day cycle, with carboplatin for up to 4 cycles, and then 
as maintenance until disease progression
Arms C (ACP):

Amivantamab as in Arm A

Carboplatin and pemetrexed as in Arm B
Extension Cohort Arms
Arm A2 (ACP-L):

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
Lazertinib 240 mg orally, once daily starting Cycle 5 Day 1 or sooner if carboplatin is discontinued 
earlier

Amivantamab by IV infusion in 21-day cycles:

1,400 mg (1,750 mg if body weight ≥80 kg) on Cycle 1 Days 1/2, 8, and 15, and Cycle 2 Day 1

1,750 mg (2,100 mg if body weight ≥80 kg) on Day 1 of each 21-day cycle, starting with Cycle 3

Carboplatin AUC 5 on Day 1 of each 21-day cycle, for up to 4 cycles

Pemetrexed 500 mg/m2 on Day 1 of each 21-day cycle, with carboplatin for up to 4 cycles, and then 
as maintenance until disease progression
Arm C2 (ACP):

Amivantamab by IV infusion in 21-day cycles:

1,400 mg (1,750 mg if body weight ≥80 kg) on Cycle 1 Days 1/2, 8, and 15, and Cycle 2 Day 1

1,750 mg (2,100 mg if body weight ≥80 kg) on Day 1 of each 21-day cycle, starting with Cycle 3

Carboplatin AUC 5 on Day 1 of each 21-day cycle, for up to 4 cycles

Pemetrexed 500 mg/m2 on Day 1 of each 21-day cycle, with carboplatin for up to 4 cycles, and then 
as maintenance until disease progression
Study treatment may be withheld, and dosages may be modified, as needed to manage adverse events (AEs). 
If toxicity results in withholding or discontinuing 1 study treatment, then it may be possible to continue the 
other study treatment(s). Refer to Section 6.5 of the protocol for specific guidance.
Study treatment should continue until the following occurs: BICR confirmed 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, AE) it is in the best interest of the participant to 
discontinue study treatment, 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 is confirmed by BICR.
PHARMACOKINETIC EVALUATIONS
Blood samples will be collected from participants in Arms A/A2 for the measurement of serum 
amivantamab and plasma lazertinib concentrations and in Arms C/C2 for measurement of serum 
amivantamab concentrations. Sample collection and testing will comply with local regulations.
IMMUNOGENICITY EVALUATIONS
Blood samples will be collected from participants receiving amivantamab and will be analyzed for 
antibodies to amivantamab using a validated immunoassay in Arms A/A2 and Arms C/C2. Serum samples 
will be screened for antibodies binding to amivantamab, and other immunogenicity analyses may be 
performed to further characterize any immune responses generated. Sample collection and testing will 
comply with local regulations.

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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. Sample collection and testing will 
comply with local regulations.
SAFETY EVALUATIONS
Safety will be assessed by physical examinations, laboratory tests, vital signs, electrocardiograms, Eastern 
Cooperative Oncology Group (ECOG) performance status, monitoring of AEs, and concomitant medication 
usage.
STATISTICAL METHODS
Two dual hypotheses will be independently investigated: LACP/ACP-L and ACP will reduce the risk of 
either disease progression or death by 35%, as individually compared with CP (median PFS of 8.5 and 5.5 
months, respectively). The primary efficacy analysis of LACP/ACP-L versus CP will include all 
participants randomized to Arm A. The median PFS for CP is estimated to be 5.5 months (Mok 2017; Soria 
2015). Assuming a median PFS of 8.5 months for both LACP/ACP-L and ACP, with an approximate 16-
month accrual period and an additional 3-month follow-up, a total of 350 PFS events across all 3 arms 
combined will provide approximately 93% power for LACP/ACP-L over CP, and 83% power for ACP over 
CP to detect a 35% reduction in the risk of either progression or death, (HR of 0.65 for LACP/ACP-L vs 
CP and ACP vs CP, respectively) with a log-rank test, assuming an overall family-wise Type I error rate at 
two-sided significance level of 5%. Taking account of the accrual period, follow-up, and an annual dropout 
rate of 5%, the total sample size is approximately 600 eligible participants will be randomized in a 2:2:1 
ratio (Arm A: Arm B: Arm C) in the study. Comparison of LACP/ACP-L (Arm A) with ACP (Arm C) will 
be performed to describe the contribution of lazertinib based on intracranial PFS, ORR, DoR, and PFS, 
using summary statistics and nominal p-values; there will be no formal hypothesis testing for this 
comparison.
To control the overall Type I error rate at 5% for the hypotheses testing of primary endpoint (PFS) and key 
secondary endpoints (ORR and overall survival [OS]), a graphical approach in a group sequential design 
setting as described by Maurer (2013) will be applied.
The primary efficacy endpoint of PFS by BICR will be analyzed using a log-rank test stratified by 
osimertinib line of therapy (first-line vs second-line), Asian race (yes vs no), and history of brain metastasis 
(yes vs no) for each of the dual primary analyses. The hazard ratio (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 primary objectives of the extension cohort are to further describe the safety and efficacy of the ACP-L 
dosing schedule (Arm A2) versus ACP (Arm C2) with additional data. Arms A2 and C2 are only a part of 
the extension cohort – not the main study. No hypothesis testing will be performed. The statistical analysis 
plan will provide details on descriptive statistics of combining data from the main study and the extension 
cohort to provide additional data on safety and tolerability of ACP-L dosing schedule.

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1.2.
Schema
Figure 1:
Schematic Overview of the Study
ACP-L=amivantamab, carboplatin, pemetrexed, and lazertinib (lazertinib started after carboplatin treatment is completed);
AUC=area under the concentration-time curve; C#D#=Cycle # Day #; IV=intravenously; LACP=lazertinib, amivantamab,
carboplatin, and pemetrexed (all drugs started C1D1); LTE=long-term extension; OLE=open-label extension; OS=overall
survival; QD=once daily; QW=once weekly.
Arm A Dosing schedule 2 (ACP-L) started on 7 November 2022.
*
Stratification factors: osimertinib line of therapy (first-line vs second-line), history of brain metastases (yes vs no), Asian race 
(yes vs no)
†
Doses shown by body weight (<80 kg/≥80 kg)
‡
Cycle 1: Days 1/2 (split dose), 8, and 15; Cycle 2: Day 1
#
Lazertinib for participants receiving dosing schedule 2 in Arm A may start sooner if carboplatin discontinued earlier than 
Cycle 4.

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Figure 2:
Schematic Overview of the Extension cohort
ACP-L=amivantamab, carboplatin, pemetrexed, and lazertinib (lazertinib started after carboplatin treatment is completed);
AUC=area under the concentration-time curve; C#D#=Cycle # Day #; IV=intravenously; LTE=long-term extension;
OLE=open-label extension; OS=overall survival; QD=once daily; QW=once weekly.
*
Stratification factors: osimertinib line of therapy (first-line vs second-line), history of brain metastases (yes vs no), Asian race 
(yes vs no)
†
Doses shown by body weight (<80 kg/≥80 kg)
‡
Cycle 1: Days 1/2 (split dose), 8, and 15; Cycle 2: Day 1
#
Lazertinib for participants in Arm A2 may start sooner if carboplatin is discontinued earlier than Cycle 4

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2.
INTRODUCTION
This study will compare the efficacy and safety of adding lazertinib and amivantamab to
carboplatin and pemetrexed (LACP and ACP-L dosing schedules) versus standard-of-care 
chemotherapy (carboplatin and pemetrexed; CP) alone in participants with epidermal growth 
factor receptor (EGFR)-mutated locally advanced or metastatic non-small cell lung cancer 
(NSCLC) who have progressed on or after treatment with osimertinib.
Amivantamab (JNJ-61186372) is a low fucose, fully human IgG1-based bispecific antibody 
directed against EGFR and mesenchymal-epithelial transition (MET) tyrosine kinase receptors that 
is being developed for the treatment of solid tumors, including EGFR-mutated NSCLC. Lazertinib 
(JNJ-73841937; YH-25448) is an oral, highly potent, third-generation, EGFR tyrosine kinase 
inhibitor (TKI). Lazertinib 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. After progression on or after osimertinib treatment, 
adding lazertinib to amivantamab results in more robust and durable antitumor activity, with a 
higher confirmed objective response rate (ORR), greater median duration of response, and 
improved clinical benefit rate compared with amivantamab monotherapy (see Section 2.2.3). 
Lazertinib also provides antitumor activity within the central nervous system (CNS; see 
Section 2.2.2).
Treatment guidelines for locally advanced or metastatic NSCLC recommend platinum-based 
combination chemotherapy regimens, including carboplatin-pemetrexed, in patients with 
EGFR -mutated NSCLC who experience disease progression on or after EGFR TKI treatment 
(ESMO 2020, NCCN 2021, Planchard 2018). Carboplatin is a platinum coordination compound 
that exerts its cytotoxic effects via formation of deoxyribonucleic acid (DNA) cross-links
(Carboplatin USPI 2018). Pemetrexed inhibits enzymes involved in folate -dependent metabolism, 
thereby disrupting cellular replication (Alimta USPI 2019).
For the most comprehensive nonclinical and clinical information regarding amivantamab and
lazertinib refer to the latest version of the Investigator’s Brochure (IB) and Addenda for
amivantamab and lazertinib. For further information regarding carboplatin and pemetrexed, refer 
to the local prescribing information for each product.
The term “study treatment” throughout the protocol refers to study drug (lazertinib, amivantamab, 
carboplatin, or pemetrexed) as defined in Section 6.1, Study Treatments Administered.
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
The term "participant" throughout the protocol refers to the common term "patient".

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2.1.
Background
Lung cancer is one of the most common types of cancer and is the most common cause of death 
from cancer. Lung cancer is a major global health concern, with more than 235,000 new diagnoses 
annually in the United States, 490,000 in the European Union, and over 1 million in Asia, with the 
highest reported incidence rates in Korea and China (Bray 2018; Pakzad 2015; SEER 2021). 
NSCLC accounts for approximately 85% of lung cancers (Globocan 2012). Advanced NSCLC is 
a serious terminal illness that accounts for approximately 20% of all cancer mortality, and until 
recently had a median overall survival (OS) of approximately 1 year. Patients with locally 
advanced or metastatic NSCLC and EGFR mutations also have poor health-related quality of life 
(Leighl 2020).
Over the past decade, there has been significant advancement in the understanding of the 
underlying biology of NSCLC, including the identification of multiple “driver” mutations that can 
result in a constitutive activation of pro-growth signaling pathways, typically occurring in NSCLC 
of adenocarcinoma histology. In patients with metastatic disease, driver mutations are observed in 
approximately 60% of adenocarcinomas (Herbst 2018). Among patients with NSCLC 
adenocarcinoma, the most prevalent of these driver mutations are those that result in the activation 
of EGFR, which are identified in approximately 15% of Western patients (Pao 2011) and in up to 
40% to 50% of Asian patients (Jänne 2006). The most frequently identified EGFR mutations, 
Exon 19del and L858R, are identified in approximately 85% of subjects with activating EGFR 
mutations (Harrison 2020).
The third-generation EGFR TKI osimertinib is indicated for the first- and second-line treatment of 
adult patients with locally advanced or metastatic NSCLC with activating EGFR mutations. 
Compared with first- and second-generation EGFR TKIs, third-generation EGFR TKIs provide 
better efficacy benefits in general and may penetrate the blood-brain barrier better and more 
effectively treat brain metastasis, which occurs in approximately 10% to 20% of patients with
treatment-naïve EGFR-mutated NSCLC (Reungwetwattana 2018). With its demonstrated activity 
against the EGFR T790M+ resistance mutation, as well as brain metastases, it was hypothesized 
that osimertinib as a first-line treatment would delay emergence of T790M-mediated resistance, 
as well as relapse within the central nervous system, resulting in improved disease control. 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 (Soria 2018) and demonstrated a statistically significant improvement in 
progression-free survival (PFS) and OS for participants randomized to osimertinib treatment. In 
patients receiving osimertinib versus a first-generation EGFR TKI, median PFS was 18.9 versus 
10.2 months, respectively, with a HR of 0.46; and median OS was 38.6 versus 31.8 months, 
respectively, with a HR of 0.80 (Ramalingam 2020; Soria 2018). This significant improvement in
median PFS with osimertinib treatment was not associated with an improved ORR, suggesting the 
majority of benefit may have been derived from activity of osimertinib against the T790M+ 
resistance mutation and improved activity within the central nervous system. 

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Despite improved initial disease control with osimertinib front-line therapy, all patients treated 
with osimertinib will relapse. Once emergence of resistance renders treatment with osimertinib 
ineffective, there are no targeted therapies approved in osimertinib-relapsed disease, despite
evidence that many patients have disease that continues to be dependent on signaling through 
either EGFR and/or MET pathways (Leonetti 2019). Standard of care, therefore, remains
platinum- based doublet chemotherapy, such as carboplatin and pemetrexed (ESMO 2020; NCCN 
2021; Planchard 2018). The ORR associated with this therapy, as determined in Phase 3 studies of 
similar populations, have been approximately 30%, with a median PFS of 4-5 months (Mok 2017;
Soria 2015). Therefore, treatment options for patients with EGFR-mutated NSCLC are limited 
after front-line or second-line osimertinib, and there is a high unmet need for additional 
therapeutics that further control tumor growth before non-targeted therapies are used.
2.2.
Study Rationale
2.2.1.
Amivantamab
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). 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).
On 21 May 2021, the US Food and Drug Administration (FDA) granted accelerated approval to 
amivantamab for adult patients with locally advanced or metastatic NSCLC with EGFR Exon 
20ins mutations, as detected by an FDA-approved test, whose disease has progressed on or after 
platinum-based chemotherapy. Evidence of clinical activity has also 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) (Haura 2019; Park 2020). As of 28 December 2020, 108 evaluable participants had 
received amivantamab in the post-osimertinib setting, including 85 participants with documented 
EGFR-based or MET-based resistance. Among the 108 evaluable participants, amivantamab 
demonstrated antitumor activity as a monotherapy, with a majority of participants demonstrating 
evidence of tumor shrinkage and approximately 30% achieving a best response of partial response 
(PR), per investigator assessment. Not all responses were durable, however, as the confirmed ORR 
was 20% (95% confidence interval [CI]: 13%, 29%) and clinical benefit rate (complete response 
[CR], PR, or stable disease) was 46% (95% CI: 37%, 56%). Median duration of response was 5.9 
months (95% CI: 4.1, 13.4) and median PFS was 4.3 months (95% CI: 2.8, 5.4).

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As of 08 October 2020, among 302 participants treated with amivantamab monotherapy at the 
recommended Phase 2 dose (RP2D), the most common treatment-emergent adverse events 
(TEAEs) (ie, frequency 20%) were infusion-related reactions (IRRs; 66%), paronychia (40%), 
dermatitis acneiform (36%) and rash (34%), hypoalbuminemia (26%), nausea (23%), constipation 
(22%), dyspnea (21%), and peripheral edema (20%). Nearly all IRRs occurred during the first 
infusion (Cycle 1 Day 1) and generally did not recur with subsequent infusions. Grade 3 or higher 
treatment-related TEAEs were reported in 49 (16%) participants, the most common (≥2%) of 
which were IRRs (2%) and paronychia (2%). Treatment-related serious TEAEs were reported in 
18 (6%) participants. There were no treatment-related deaths. TEAEs leading to dose reduction or 
drug discontinuation, considered related to amivantamab, were observed in 11% and 3% of 
participants, respectively. For additional information, refer to the IB.
2.2.2.
Lazertinib
The activity and tolerability of lazertinib, a novel third-generation EGFR TKI, as a single agent 
has been demonstrated in EGFR-mutated NSCLC after prior treatment with an EGFR TKI in the 
ongoing Phase 1/2 Study 73841937NSC2001. This study has enrolled 181 participants with 
EGFR-mutated advanced NSCLC that progressed following prior therapy with an EGFR TKI. In 
participants with T790M+ disease, the ORR was 57% and the median PFS was 9.7 months 
(95% CI: 8.1, 15.0) across all dose levels of lazertinib. Among participants in the Phase 1/2 study 
with measurable brain metastasis at baseline (n=22), the intracranial ORR of lazertinib at any dose 
was 55%, indicating effective blood-brain barrier penetration, with intracranial responses observed 
in participants beginning at lazertinib 40 mg (Cho 2020). The available safety and efficacy profile 
of lazertinib in this study appeared consistent with that of osimertinib as a second-line therapy 
(Mok 2017). The most common TEAEs (any grade) were rash, pruritus, diarrhea, paresthesia, 
constipation, upper respiratory tract infection, and decreased appetite. Treatment related events of 
≥Grade 3 were observed in 10% of patients and treatment related serious TEAEs in 3%. Overall, 
the incidence and severity of AEs seen in this study were similar to those of osimertinib in the 
Phase 1 AURA study (Jänne 2015). However, cardiac safety assessment in these participants has 
shown that lazertinib has no clinically relevant effect on QT interval and left ventricular ejection 
fraction (LVEF) at doses of 20 mg to 320 mg (Ahn 2019; Jang 2021). For additional information, 
refer to the IB.
2.2.3.
Amivantamab and Lazertinib Combination
The combination of amivantamab and lazertinib is being investigated in ongoing clinical studies 
including the Phase 1 Study 61186372EDI1001, the Phase 1 Study 73841937NSC1001, and the 
Phase 3 Study 73841937NSC3003. As a third-generation EGFR-TKI targeting activating EGFR 
mutations, lazertinib has a distinct mechanism of action from amivantamab, which targets the 
extracellular domains of both the EGFR and cMET proteins. The distinct mechanisms of action of 
amivantamab and lazertinib targeting the extracellular ligand binding domain and the intracellular 
active site, respectively, have the potential to inhibit the EGFR pathway more potently than either 
agent alone.
 
 In 
addition, the potential of the combined antibody and TKI/small molecule approach has been 
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≥20% of participants) were IRR (60%), paronychia (47%), dermatitis acneiform (45%), 
hypoalbuminemia (37%), stomatitis (35%), rash (30%), alanine aminotransferase (ALT) increased 
(25%), nausea (23%), pruritis (22%), and peripheral edema and aspartate aminotransferase (AST)
increased (22% each). TEAEs of Grade 3 or Grade 4 severity were reported in 48 participants
(32%) and 3 participants (2%), respectively, with 32 participants (22%) experiencing treatment 
(amivantamab or lazertinib)-related TEAEs of ≥Grade 3 severity. There was no consistent pattern 
of TEAEs with Grade ≥3 severity; those events seen in >2% of participants were dermatitis 
acneiform (5%); dyspnea, pneumonia, and hypoalbuminemia (4% each); paronychia and ALT 
increased (3% each); and hyponatremia and AST increased (3%). A single Grade 5 TEAE,
pneumonitis, was reported as being related to study treatment. This was originally reported as a 
Grade 3 event but was upgraded to Grade 5 when the participants died as a result of rapidly 
progressing disease.
2.2.4.
Rationale for Adding EGFR-Targeted Therapy to Chemotherapy
With the approval of EGFR TKIs for the treatment of NSCLC, several studies have investigated 
the optimal application of these agents, including potentially adding EGFR TKIs to chemotherapy. 
While early studies evaluating the potential of EGFR TKI plus chemotherapy failed to demonstrate 
clinical benefit, the failure to use molecular markers to select for populations with EGFR-driven 
disease may have confounded the interpretation of these results. With the significant improvement 
in efficacy observed with second- and third-generation EGFR TKIs relative to chemotherapy, 
platinum-based chemotherapies were reserved for salvage therapy after TKI failure, after tumors 
had developed mutations that made them resistant to targeted approaches.
More recent studies have suggested a possible benefit with EGFR TKI plus chemotherapy in the 
subset of patients with EGFR-mutated NSCLC. A meta-analysis of nine trials of adding TKI 
therapy to chemotherapy reported that erlotinib and chemotherapy resulted in significant 
improvement of PFS and OS, compared to chemotherapy alone (Xu 2015), in the subset of patients 
with EGFR-mutated NSCLC. Subsequently, two recent prospective studies that added gefitinib (a 
first-generation EGFR TKI) to carboplatin and pemetrexed demonstrated improved outcomes, as 
compared to gefitinib alone, in terms of ORR, PFS, and OS (Hosomi 2020; Noronha 2020). In 
addition to the suggested benefit of adding targeted inhibition of the EGFR pathway to 
chemotherapy, amivantamab antitumor activity is hypothesized to include ADCC -dependent 
mechanisms that are not associated with EGFR TKIs. Thus, there may be additional benefit with 
amivantamab plus chemotherapy arising from disruption of an inhibitory tumor microenvironment 
(Galluzzi 2015) and targeting of Fc receptor-bearing immune cells to tumor cells.
2.2.5.
Rationale for Amivantamab and Platinum Doublet Chemotherapy
Participants in Arms C/C2 will receive amivantamab, carboplatin, and pemetrexed (ACP), which
was first explored in the Phase 1 Study 61186372EDI1001. In this regimen, amivantamab is dosed 
weekly for first 4 doses on Cycle 1 Day 1/Day 2, Day 8, Day 15 and Cycle 2 Day 1 (at 1,400 mg 
for <80kg, 1,750 mg for ≥80 kg), followed by Q3 week dosing starting with Cycle 3 Day 1 (at 
1,750 mg for <80kg, 2,100 mg for ≥ 80 kg), and added to standard-of-care carboplatin (AUC 5) 
and pemetrexed (500 mg/m2) on Day 1 of each cycle in a 21-day cycle for up to 4 cycles, followed 
by maintenance with pemetrexed and amivantamab in 21-day cycles. The first dose of 

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amivantamab is split over 2 days, with 350 mg administered on Cycle 1 Day 1, and the remainder 
administered on Day 2. On 26 August 2020, the Safety Evaluation Team (SET) reviewed data 
(with a cutoff of 20 August 2020) from 5 participants enrolled in the initial dose-finding cohort 
and recommended expansion to the full cohort (N=20).
Data collected through 20 October 2020 from 16 participants in Study 61186372EDI1001 who 
had received at least 1 dose of amivantamab with carboplatin and pemetrexed (500 mg/m2 [or per 
local guidance]) in 21-day cycles and found neither evidence of additive toxicity nor evidence that 
the anticipated hematologic toxicity with chemotherapy was worsened or prolonged by adding 
amivantamab. The most frequently reported (>20% of participants) TEAEs were IRR (69%), 
constipation (44%), thrombocytopenia (38%), rash (31%) and dermatitis acneiform (44%), fatigue 
(31%), and neutropenia (25%). The EGFR and MET-associated toxicities of rash, stomatitis, 
peripheral edema, and diarrhea were reported at an incidence and severity consistent with the 
monotherapy experience of amivantamab. TEAEs of ≥Grade 3 severity occurred in 7 of 16 (44%) 
participants, with the most frequently reported ≥Grade 3 TEAEs collectively reflecting anticipated 
chemotherapy-related cytopenia (neutropenia [19%], anemia [6%], and thrombocytopenia [6%]). 
Importantly, Cycle 1 declines in absolute neutrophil count (ANC) and platelet count that were 
observed in all participants recovered in time to allow each participant to receive the Cycle 2 Day 
1 dose of chemotherapy and amivantamab, as scheduled. Consistent with the protocol, no 
participants received prophylactic granulocyte colony stimulating factor (G-CSF) during Cycle 1; 
however, 1 participant with Grade 3 neutropenia and 2 participants with Grade 4 neutropenia 
required treatment with G-CSF for chemotherapy-related neutropenia. All events of ≥Grade 3 
severity were unrelated to amivantamab, with the exception of Grade 3 nausea in a participant with 
baseline Grade 1 nausea who was reported to have experienced worsening Grade 3 nausea, which 
was attributed to all 3 study agents. There were no Grade 5 events. The addition of amivantamab 
to chemotherapy is currently being investigated as a frontline regimen for the treatment of EGFR 
Exon 20ins NSCLC in Study 61186372NSC3001 (NCT04538664).
2.2.6.
Rationale for Adding Lazertinib and Amivantamab to 
Platinum-Doublet Chemotherapy
Participants in Arms A/A2 will receive LACP or ACP-L. Recent studies have demonstrated the 
improved outcomes that can be achieved by adding targeted therapy to chemotherapy in patients 
with EGFR- mutated NSCLC (Hosomi 2020; Noronha 2020). The combination of amivantamab 
and lazertinib has demonstrated significant antitumor activity in patients with EGFR-mutated 
NSCLC who have progressed on or after osimertinib (Section 2.2.3). The level of activity with 
this combination exceeds that observed with amivantamab monotherapy and is consistent with the 
activity of the current standard of care for osimertinib-relapsed disease, platinum-based 
chemotherapy, while additionally providing CNS protection with lazertinib. The addition of 
amivantamab and lazertinib to platinum-based chemotherapy, therefore, has the potential to 
provide superior clinical efficacy as compared to standard-of-care chemotherapy alone.
Amivantamab, which has been demonstrated to exhibit ADCC-dependent mechanisms in 
preclinical models, may provide additional benefit arising from disruption of an inhibitory tumor 
microenvironment (Galluzzi 2015) and targeting of Fc receptor-bearing immune cells to tumor 

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cells. The safety profiles for amivantamab and lazertinib are largely distinct from those associated 
with chemotherapeutic agents, and amivantamab has been demonstrated to be safe and tolerable 
in addition to either lazertinib or chemotherapy.
The Phase 1 Study 73841937NSC1001 will include a cohort of 20 participants with locally 
advanced or metastatic EGFR-mutated NSCLC who have received a maximum of 3 lines of prior 
therapy in the metastatic setting and progressed on or after an EGFR TKI as the most recent line 
of therapy. These participants will be treated with LACP. A SET for the Phase 1 study will review 
safety and tolerability results for this cohort before enrollment begins in 61186372NSC3002.
In summary, the addition of amivantamab and lazertinib to standard-of-care platinum-based 
chemotherapy is hypothesized to provide improved clinical benefit for patients with locally 
advanced or metastatic NSCLC with EGFR Exon 19 deletions or Exon 21 L858R mutations whose 
disease has progressed on or after treatment with osimertinib, through targeted anti-EGFR and 
anti-MET action, antitumor activity within the CNS, and recruitment of immune cells with 
antitumor activity.
2.2.7.
Rationale for Chemotherapy Comparator
Participants in the comparator arm of this study (Arm B) will receive CP, without EGFR--targeted 
therapy. There are no approved targeted therapies for patients with EGFR-mutated NSCLC who 
have progressed on or after osimertinib therapy. Treatment guidelines for locally advanced or 
metastatic NSCLC recommend platinum-based combination chemotherapy regimens, including 
carboplatin pemetrexed or cisplatin-pemetrexed, in patients with EGFR-mutated NSCLC who 
experience disease progression on or after EGFR TKI treatment (ESMO 2020; NCCN 2021;
Planchard 2018). The median PFS associated with platinum-based chemotherapy after failure of 
an EGFR TKI, as determined in Phase 3 studies of similar populations, is 4.4 to 5.4 months 
(Mok 2017; Soria 2015). The activity of carboplatin and cisplatin in NSCLC are largely similar, 
with no associated difference in OS (Griesinger 2019).
Pemetrexed, which is approved for use in patients with non-squamous NSCLC, has become the 
recommended agent for use in combination with platinum-based chemotherapy in the treatment of 
NSCLC, both as a result of improved safety profile and the ability to continue pemetrexed 
monotherapy as a maintenance therapy. The addition of pemetrexed to carboplatin or cisplatin 
treatment regimens with additional pemetrexed maintenance following 4 cycles of carboplatin or 
cisplatin treatment has been demonstrated to improve outcomes (PFS and OS) for patients 
compared to docetaxel or gemcitabine combinations (Ciuleanu 2009; Li 2012; Treat 2012).
Platinum-based chemotherapy with cisplatin is typically reserved for therapies with curative intent, 
where a potential slight benefit in ORR may outweigh greater toxicity and patient burden in 
patients who can tolerate it. Carboplatin-based regimens, with their improved safety profile, are 
used more often in the metastatic NSCLC setting, within clinical regimens with palliative intent, 
especially in frailer patients. This study will enroll patients with locally advanced or metastatic 
disease after progressing on or after osimertinib, which is the best available standard of care for 

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EGFR-mutated NSCLC. Thus, carboplatin and pemetrexed is a more appropriate combination than 
cisplatin and pemetrexed for this patient population.
The importance of an improved toxicity profile and reduced infusion times associated with 
carboplatin administration, as well as the decreased need for preinfusion and postinfusion 
hydration for these patients, is reflected in reviews of real-world usage patterns, which demonstrate 
that carboplatin-pemetrexed is the most frequently used platinum-based doublet regimen in the US 
for the first-line treatment of metastatic, nonsquamous NSCLC, and cisplatin-based regimens are 
used infrequently in this setting (<5%) (Abernethy 2017). Thus, carboplatin-pemetrexed has 
become the standard of care in the US for the intended study population.
Given the above, the use of carboplatin-pemetrexed combination chemotherapy in this study 
ensures every enrolled participant will receive treatment with standard-of-care treatment for EGFR 
mutated NSCLC that progresses on or after osimertinib, which will enable the most robust 
assessment of amivantamab and lazertinib efficacy and safety when administered in combination 
with carboplatin and pemetrexed.
2.3.
Benefit-Risk Assessment
More detailed information about the known and expected benefits and risks of amivantamab and 
lazertinib may be found in the IB for each product. Information about the benefits and risks of 
carboplatin and pemetrexed may be found in the local prescribing information.
2.3.1.
Risks for Study Participation
As clinical data for the addition of amivantamab to chemotherapy are limited, unforeseen safety 
risks associated with the study treatments are possible. Previous studies adding EGFR TKIs or 
anti-EGFR mAbs to chemotherapy have shown they were generally well tolerated (Hosomi 2020;
Noronha 2020; Park 2020; Peeters 2010). Amivantamab with chemotherapy is expected to have a 
similar safety profile to adding an EGFR TKI or mAb to chemotherapy.
The safety profiles of amivantamab and lazertinib are largely distinct from those associated with 
chemotherapeutic agents. However, pemetrexed has been reported to be associated with bullous 
and exfoliative skin toxicity as well as interstitial pneumonitis, which should be considered when 
evaluating and managing potential skin and pulmonary toxicities.
The safety and tolerability of amivantamab monotherapy was shown in the Phase 1 
Study 61186372EDI1001 (Section 2.2.1). The safety and tolerability of single-agent lazertinib was 
shown in the Phase 1/2 Study 73841937NSC2001 (Section 2.2.3). The safety and tolerability of 
amivantamab 
and 
lazertinib 
in 
combination 
was 
also 
shown 
in 
the 
Phase
1 
Study 61186372EDI1001 (Section 2.2.3) and is being further explored in 73841937NSC1001. The 
safety and tolerability of carboplatin and pemetrexed were shown in clinical trials (refer to local 
prescribing information).
Unforeseen safety risks associated with the study treatments are possible. This study protocol 
includes the following elements to mitigate risks for study participants:

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
An Independent Data Monitoring Committee (IDMC) will review safety results for LACP in 
the ongoing Phase 1 Study 73841937NSC1001 prior to randomization of participants in this 
Phase 3 study. Participants will be monitored closely for safety throughout the study 
(Section 8.2) and the IDMC will review safety and tolerability data periodically.

Dose modification guidance is provided to manage toxicities that occur during the study 
(Section 6.5.3), including specific guidance for IRRs, rash, pruritus, interstitial lung disease 
(ILD), cardiac adverse events (AEs), liver chemistry abnormalities, oral mucositis, 
paronychia, ocular toxicity, paresthesia, and venous thromboembolic (VTE) events.
2.3.2.
Benefits for Study Participation
Given the heterogeneity of mechanisms that lead to osimertinib resistance, there is an unmet need 
for therapies that can be widely used in this setting without the need for biomarker selection. 
Platinum-based chemotherapy is the standard of care in this patient population. All participants in 
the study will accordingly be treated with platinum-based chemotherapy.
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. 
Antitumor activity for addition of amivantamab to platinum-based chemotherapy has been 
observed in the Phase 1 Study 61186372EDI1001. It is anticipated that efficacy offered by the 
unique mechanisms of action of amivantamab and lazertinib, the CNS protection demonstrated by 
lazertinib, and the addition of platinum-based chemotherapy to target TKI resistant tumor cells 
will be more effective than platinum-based chemotherapy alone for the treatment of patients with 
TKI-sensitive, EGFR-mutated NSCLC who have relapsed on osimertinib.
2.3.3.
Benefit-Risk Assessment for Study Participation
Considering the measures taken to minimize risk to participants in this study, the potential risks 
identified for addition of lazertinib and amivantamab to standard-of-care carboplatin and 
pemetrexed are justified by the anticipated benefits that may be afforded to participants with 
locally advanced or metastatic NSCLC and EGFR Exon 19del or L858R mutations who have 
progressed on or after osimertinib.
 
 
 
 
 
 
 
VTE event related changes implemented during protocol amendment 4 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 
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(all drugs started C1D1); NGS=Next-Generation Sequencing; NSCLC=non-small cell lung cancer; NSCLC-SAQ=Non-Small 
Cell Lung Cancer - Symptom Assessment Questionnaire; ORR= Objective response rate ; PFS=progression-free survival; PRO 
CTCAE=Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events; PROMIS-PF=Patient-
Reported Outcomes Measurement Information System Physical Function; RECIST=Response Evaluation Criteria in Solid 
Tumors.
a Secondary endpoints of intracranial ORR, duration of response (DoR), and time to intracranial disease progression were 
included in statistical analysis plan (SAP) Amendment 3 (dated 19 May 2023), which was prior to the primary analysis for 
PFS. 
The primary objectives of the extension cohort are to further describe the safety and efficacy of
the ACP-L dosing schedule versus ACP; see Appendix 13: Open-label Randomized Extension 
Cohort for details.
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESIS
This study has dual primary hypotheses that:

LACP/ACP-L will demonstrate superior progression-free survival (PFS) compared with CP

ACP will demonstrate superior progression-free survival (PFS) compared with CP
The secondary hypotheses are that LACP/ACP-L and ACP, compared with CP independently in 
the aforementioned population, will demonstrate superior ORR and overall survival.
There is no separate hypothesis for extension cohort. 
4.
STUDY DESIGN
4.1.
Overall Design
This study is a randomized, open-label, active-controlled, parallel, multicenter, Phase 3 study to 
compare the efficacy and safety of LACP/ACP-L (Arm A) versus CP (Arm B) and ACP (Arm C) 
versus CP (Arm B) in participants with EGFR-mutated locally advanced or metastatic NSCLC 
who have progressed on or after treatment with osimertinib. Participants in a third treatment arm 
will receive ACP, in order to be independently compared to CP, and to describe the contribution 
of lazertinib to the activity of LACP/ACP-L in this setting. Approximately 600 eligible participants 
will be randomly assigned in this study. The study will include a Screening Phase (Section 4.1.1), 
a Treatment Phase (Section 4.1.2), and a Follow-up Phase (Section 4.1.3).
An Independent Data Monitoring Committee will be commissioned for this study. Refer to
Committee Structure in Appendix 2: Regulatory, Ethical, and Study Oversight Considerations for 
details. A diagram of the study design is provided in Section 1.2.
Under Protocol Amendment 6, after enrollment for the main study is completed, a separate open-
label randomized extension cohort will enroll approximately an additional 90 participants to 
further describe the safety and efficacy of the ACP-L dosing schedule versus ACP with additional 
data, but no formal hypothesis testing is planned within the extension cohort. The primary and 
secondary analyses for the hypothesis testing described above will be based on the data from the 
main study only, and the data from the extension cohort will not be included.

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4.1.1.
Screening
The informed consent form (ICF) must be signed before the first study-related activity is conducted
but can be signed >28 days prior to randomization. All other screening procedures must be 
completed within 28 days before randomization.
To be eligible for participation, all participants must have locally advanced or metastatic non-
squamous NSCLC 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). 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 for review during the Screening Phase. If provision of this report is not permitted by the 
site or local policies, then sponsor-approved equivalent documentation must be provided. If tumor 
tissue collected at or after the diagnosis of locally advanced or metastatic NSCLC is available, it 
should be submitted to the central laboratory (as permitted by local regulations). Participants may 
also undergo an optional biopsy during screening.
All participants must have progressed on or after osimertinib monotherapy as the most recent line 
of treatment. To ensure the study population is balanced for participants who failed first-line versus 
second-line treatment with osimertinib, this study will limit enrollment of those who failed 
treatment with osimertinib in the second line to approximately 40% (~240 participants).
All information required for randomization purposes must be available at the time of 
randomization, including all screening assessments per the Schedule of Activities (Table 1),
documentation to support mutation status. In addition, results of the Cycle 1 Day 1 assessments 
such as ECOG performance status, ECG, laboratory values, pregnancy test (as applicable), and 
symptom-directed physical exam should be available and reviewed by the Investigator prior to 
randomization. See the Schedule of Activities for details on completion of assessments within
72 hours prior to the first dose of study treatment.
4.1.2.
Treatment Phase
The Treatment Phase will begin at randomization, with first treatment on Cycle 1 Day 1 to occur 
within 72 hours, and continue in 21-day cycles until the End of Treatment visit, approximately 
30 days after the last dose of study treatment. Study treatment will continue until documented 
disease progression (using Response Evaluation Criteria in Solid Tumors [RECIST] v1.1) 
confirmed by BICR, or until the participant meets another criterion for discontinuation of study 
treatment (Section 7.1). Participants will be stratified based on osimertinib line of therapy 
(first- line vs second-line), history of brain metastases (yes or no), and Asian race (yes vs no), and 
assigned randomly in a 2:2:1 ratio into 1 of 3 treatment arms as follows:
Main Study Arms
Arm A Dosing Schedule 1 (LACP, from study start until 06 November 2022):

Lazertinib 240 mg orally once daily

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
Amivantamab by intravenous (IV) infusion in 21-day cycles:
-
1,400 mg (1,750 mg if body weight ≥80 kg) on Cycle 1 Days 1/2, 8, and 15, and Cycle 2 
Day 1
-
1,750 mg (2,100 mg if body weight ≥80 kg) on Day 1 of each 21-day cycle, starting with 
Cycle 3

Carboplatin and pemetrexed as in Arm B.
Arm A Dosing Schedule 2 (started on 07 November, 2022) (ACP-L):

Lazertinib 240 mg orally, once daily starting Cycle 5 Day 1 or sooner if carboplatin 
discontinued earlier than Cycle 4

Amivantamab by IV infusion in 21-day cycles:
-
1,400 mg (1,750 mg if body weight ≥80 kg) on Cycle 1 Days 1/2, 8, and 15, and Cycle 2 
Day 1
-
1,750 mg (2,100 mg if body weight ≥80 kg) on Day 1 of each 21-day cycle, starting with 
Cycle 3

Carboplatin and pemetrexed as in Arm B.
Arm B (CP):

Carboplatin AUC 5, up to 750 mg, on Day 1 of each 21-day cycle, for up to 4 cycles

Pemetrexed 500 mg/m2 (with folic acid and vitamin B12 supplementation) on Day 1 of each 
21-day cycle, in combination with carboplatin for up to 4 cycles, and then as maintenance 
until disease progression
Arms C (ACP):

Amivantamab as in Arm A

Carboplatin and pemetrexed as in Arm B

Extension cohort Arms
Arm A2 (ACP-L):

Lazertinib 240 mg orally, once daily starting Cycle 5 Day 1 or sooner if carboplatin is discontinued 
earlier

Amivantamab by IV infusion in 21-day cycles:

1,400 mg (1,750 mg if body weight ≥80 kg) on Cycle 1 Days 1/2, 8, and 15, and Cycle 2 Day 1

1,750 mg (2,100 mg if body weight ≥80 kg) on Day 1 of each 21-day cycle, starting with Cycle 3

Carboplatin AUC 5 on Day 1 of each 21-day cycle, for up to 4 cycles

Pemetrexed 500 mg/m2 on Day 1 of each 21-day cycle, with carboplatin for up to 4 cycles, and then 
as maintenance until disease progression

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Arm C2 (ACP):

Amivantamab by IV infusion in 21-day cycles:

1,400 mg (1,750 mg if body weight ≥80 kg) on Cycle 1 Days 1/2, 8, and 15, and Cycle 2 Day 1

1,750 mg (2,100 mg if body weight ≥80 kg) on Day 1 of each 21-day cycle, starting with Cycle 3

Carboplatin AUC 5 on Day 1 of each 21-day cycle, for up to 4 cycles

Pemetrexed 500 mg/m2 on Day 1 of each 21-day cycle, with carboplatin for up to 4 cycles, and then 
as maintenance until disease progression
Disease assessments will occur as close as possible to the start of treatment (baseline screening 
scans), 6 weeks (+1 week) after randomization (the first on study assessment should be no earlier 
than 42 days after randomization), then every 6 weeks (±1 week) for the first 12 months and every 
12 weeks (±1 week) thereafter, until objective radiographic disease progression is confirmed by 
BICR. Timing of disease assessments is relative to randomization, regardless of when study 
treatment is administered. 
At each study visit during the Treatment Phase, participants will undergo safety evaluations, 
including physical examinations and assessment of TEAEs, vital signs, concomitant medication 
usage, and clinical laboratory parameters. Participants will complete questionnaires for 
patient- reported outcomes (PROs) at selected visits. Participants will also have blood samples 
drawn for assessment of pharmacokinetics (PK) and immunogenicity parameters, and for 
biomarker evaluations, at selected visits. If a participant provides a baseline biopsy, an optional 
post-progression biopsy may be obtained if the participant consents and the procedure is clinically 
feasible within 30 days of disease progression but before subsequent anticancer therapy.
Continuation of study treatment after BICR-confirmed disease progression by RECIST v1.1 may 
be allowed after approval from the Medical Monitor, if the investigator believes the participant is 
deriving clinical benefit, as described in Section 7.1, Discontinuation of Study Treatment. 
Participants continuing treatment after documented progression will continue within the Treatment 
phase of the study and comply with all associated visits and procedures, including scheduled 
disease assessments, until the termination of study treatment.
4.1.3.
Follow-up Phase
For participants who discontinue treatment prior to disease progression, tumor imaging should 
continue as scheduled (see Table 1) until disease progression is documented, if clinically feasible.
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 

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noted in the ICF (refer to Informed Consent in Appendix 2: Regulatory, Ethical, and Study 
Oversight Considerations).
4.1.4.
Open-label Extension Phase and Long-Term Extension Phase
Following the second interim analysis for OS, the study may transition to an OLE Phase or LTE 
phase. If the study transitions to an OLE phase, then upon completion of the final analysis for OS 
the study can subsequently transition to an LTE phase. There is also a possibility for the study to 
directly transition to an LTE phase if statistical significance for OS as outlined in the SAP is met
at the time of the second interim analysis for OS. 
A determination as to whether and how the study transitions to an OLE or LTE phase will be made 
by the Sponsor after completion of the second interim analysis and after approval of Amendment 
7 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). The timing of the initiation of OLE or LTE phase will be made by the Sponsor based 
on regulatory interactions and the Sponsor will communicate at the time the decision is made to 
initiate either the OLE or LTE phase.
In the OLE phase, the purpose is to continue to collect clinically relevant data, while reducing 
protocol-required visit procedures and assessments and the burden on participants (see details 
provided in Section 10.14 [Appendix 14]). Participants will be provided the option to continue 
their current study treatment in the OLE phase until the study transitions to an LTE phase. In the 
LTE phase, (see details provided in Section 10.15.1 [Appendix 15]), participants will be provided 
continued access to study treatments with further reduction in protocol-required visit procedures 
and assessments. In the LTE phase, only serious adverse event data and study treatment 
compliance will be collected. The LTE phase will continue until the last participant meets the 
discontinuation criteria described in Section 7.1, or until 4 years after local marketing authorization 
is obtained for the studied indication, whichever occurs first. Consent will be obtained from 
participants prior to inclusion into any of these phases.
4.2.
End of Study Definition
End of Study Definition
The end of study is considered as the last scheduled study assessment shown in the Schedule of 
Activities for the last participant in the study. The final data from the study site will be sent to the 
sponsor (or designee) after completion of the final participant assessment at that study site, in the 
time frame specified in the Clinical Trial Agreement.
Study Completion Definition
A participant will be considered to have completed the study if the participant has died before the 
end of the study or has not prematurely discontinued the study for another reason.

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4.3.
Scientific Rationale for Study Design
Blinding, Control, Study Phase/Periods, Treatment Groups
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. Due to differences in safety profile, safety 
monitoring, premedication requirements, and administration, blinded study treatment and a 
placebo control will not be used.
Clinical Pharmacology Assessments
Blood samples will be analyzed for serum amivantamab and plasma lazertinib concentrations. 
Immunogenicity (antibodies to amivantamab) will be evaluated for impact on PK, safety and 
efficacy. A population PK model will be developed as a means to derive the individual 
participant’s exposure, for determination of participant covariates that influence the PK of 
amivantamab and lazertinib, and for exposure-response analysis to support regulatory submission.
Sample collection and testing will comply with local regulations.
ctDNA and Biomarker Collection
Circulating tumor deoxyribonucleic acid (ctDNA) will be collected 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. The ctDNA and biomarker samples may be used to explore the 
potential to predict clinical benefit, relapse, and/or identify mechanisms of resistance to assigned 
therapy, and to enable the development of safer, more effective, and ultimately individualized 
therapies. Sample collection and testing will comply with local regulations.
4.3.1.
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during 
the study, participants will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only participants who are fully able to understand the risks, benefits, 
and potential AEs of the study, and provide their consent voluntarily will be enrolled. If the 
participant requires a legally designated representative the legally designated representative must 
confirm with their signature on the ICF that the participant understands the purpose of and 
procedures required for the study and the participant is willing to participate. Written consent may 
be obtained through various sources (eg, paper or electronic such as eConsent, eSignature, or digital 
signature) as determined by regulations as well as study and patient preferences.
Thorough scientific evaluation of any treatment before marketing authorization is an ethical and 
regulatory requirement. As the benefits and risks of adding amivantamab, lazertinib, carboplatin, 
and pemetrexed in this study population are not fully known, this study will evaluate safety and 
clinical activity. Participants will be closely monitored throughout the study, as discussed 

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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 observed activity 
of both amivantamab and lazertinib in this setting, there is adequate justification for evaluating the 
addition of these drugs to chemotherapy 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. 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. Pre- or post-treatment tumor biopsies are optional in this study. Archival 
tumor material collected at or after the time of locally advanced or metastatic diagnosis will be 
submitted if available, or a participant may undergo an optional pre-treatment biopsy. A participant
for whom a pre-treatment biopsy was collected may elect to also undergo a post-treatment biopsy. 
Although biopsy collection is associated with risk, the complication rate for these procedures is 
low. The data obtained from this procedure will generate valuable scientific data on the effect 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 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 blood donation standards of the American Red Cross (2020) and the World Health Organisation 
(WHO 2012).
4.4.
Justification for Dose
The combinations of amivantamab and lazertinib, as well as amivantamab and platinum-based
chemotherapy, have been explored in the ongoing Phase 1 Study 61186372EDI1001. The safety 
and tolerability of the lazertinib and amivantamab combination was demonstrated when 
administered at the respective RP2Ds of lazertinib 240 mg once daily and amivantamab 1,050 mg 
(1,400 mg for body weight ≥80 kg). No dose-limiting toxicities (DLTs) were identified and no 
new safety signals were observed. The safety profile of the combination, as assessed in 91 total 
participants with a 6-month median follow-up, suggested a tolerable profile. The majority of 
toxicities were Grade 1 or 2 in severity (a treatment-related TEAE of ≥Grade 3 severity was 
reported for 11% of participants), and TEAEs leading to discontinuation of either or both drugs
occurred in 6% of participants. The lack of any PK interaction was confirmed when lazertinib and 
amivantamab were administered in combination, resulting in predictable exposures of both agents
consistent with their respective monotherapy PK profiles.
In the Part 1 “Chemotherapy Combination” cohort of Study 61186372EDI1001, amivantamab was 
dosed in 21-day cycles at 1,400 mg (1,750 mg if body weight was ≥80 kg) on Cycle 1 Day 1/Day 2, 
Day 8, and Day 15, and then on Cycle 2 Day 1. Beginning on Cycle 3 Day 1, the dose of 
amivantamab was increased to 1,750 mg (2,100 mg if body weight was ≥80 kg) administered on 

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Day 1 of each 21-day cycle. Carboplatin (AUC 5 through Cycle 4 Day 1) and pemetrexed 
(500 mg/m2) were administered on Day 1 of each 21-day cycle. Adding amivantamab to 
chemotherapy was safe and tolerable, and no new safety signal was detected. 
 
 
 
 
 
 
 
 
 
The dosages for LACP in this study will also be supported by data from the ongoing Phase 1 study 
73841937NSC1001. That study will include a cohort (“the Phase 1b LACP Combination Cohort”) 
of 20 participants. Results for LACP will be assessed by an IDMC prior to the initiation of 
enrollment into the current Study 61186372NSC3002 and will support the chosen dosage.
The ACP-L dosing schedule for Arms A and A2, which starts lazertinib on Cycle 5 Day 1 (or 
sooner if carboplatin is discontinued earlier than Cycle 4) is recommended by the IDMC based on 
the review of the unblinded safety data and is also supported by the emerging data that concurrent 
chemotherapy with third generation EGFR TKIs is associated with a higher than expected rate of 
toxicities traditionally in association with chemotherapy (Tanaka 2021). In an open-label, 
randomized phase 2 study where osimertinib combined with carboplatin and pemetrexed, Tanaka, 
et al presented that the incidence of AEs of ≥ Grade 3 was significantly higher in the osimertinib 
combination group (83.8%) compared to the osimertinib monotherapy group (45.2%), and the 
majority were hematologic AEs (leukopenia 38.7% vs 3.2%, neutropenia 51.6 vs 9.7%, anemia 
25.8% vs 0%, and thrombocytopenia 29.0% vs 0%, respectively). The grade 3 or 4 non-
hematologic adverse events occurred only in the combination group (stomatitis, nausea, diarrhea, 
and paronychia, each at 3.2%), The reported AEs were also significantly higher than those in
AURA3 study with similar population treated with platinum and pemetrexed, where the reported 
≥ Grade 3 AEs were leukopenia 4%, neutropenia 12%, anemia 12%, and thrombocytopenia 7%
(Mok 2017). These data, 
, indicate that there may be 
a class effect for the combination of 3rd generation EGFR TKIs with chemotherapy. The ACP-L 
dosing schedule is designed to minimize such toxicities while still evaluating the efficacy benefit 
of continuing a 3rd generation EGFR TKI among patients with EGFR mutated NSCLC.
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 
CCI
CCI

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representative and resolve any issues before enrolling a participant in the study. Waivers are not 
allowed.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2.
5.1.
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1.
At least 18 years of age (or the legal age of consent in the jurisdiction in which the study 
is taking place).
2.
Participant must have histologically or cytologically confirmed, locally advanced or 
metastatic, non-squamous NSCLC, characterized at or after the time of locally advanced 
or metastatic disease diagnosis by either EGFR Exon 19del or Exon 21 L858R mutation,
by an FDA-approved or other validated test of either ctDNA or tumor tissue in a CLIA 
certified laboratory (sites in the US) or an accredited local laboratory (sites outside of the 
US). A de-identified copy of the initial test report documenting the EGFR mutation must 
be included in the participant records and must be submitted to the sponsor during the 
Screening Phase. If provision of this report is not permitted by the site or local policies, 
then sponsor-approved equivalent documentation must be provided.
3.
Criterion modified per Amendment 2
3.1 Participant must have progressed on or after osimertinib monotherapy as the most 
recent line of treatment. Osimertinib must have been administered as either the first-line 
treatment for locally advanced or metastatic disease or in the second-line setting after 
prior treatment with first- or second-generation EGFR TKI as a monotherapy. 
Participants who received either neoadjuvant and/or adjuvant treatment of any type are 
eligible if progression to locally advanced or metastatic disease occurred at least 
12 months after the last dose of such therapy and then the participant progressed on or 
after osimertinib in the locally advanced or metastatic setting.
Treatment with osimertinib must be discontinued at least 8 days (4 half-lives) prior to 
randomization (ie, last dose no later than Day -8).
4.
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 the 
optional diagnostic biopsy and be acceptable as a target lesion, provided the baseline 
tumor assessment scans are performed at least 14 days after the biopsy.
5.
Criterion modified per Amendment 2
5.1 Participants with a history of brain metastases must have had all lesions treated as 
clinically indicated (ie, no current indication for further definitive local therapy). Any 

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definitive local therapy to brain metastases must have been completed at least 14 days 
prior to randomization and the participant can be receiving no greater than 10 mg 
prednisone or equivalent daily for the treatment of intracranial disease.
6.
Participant must have Eastern Cooperative Oncology Group (ECOG) status of 0 or 1.
Refer to Appendix 7: Eastern Cooperative Oncology Group (ECOG) Performance Status.
7.
Criterion modified per Amendment 2
7.1 Participant must have adequate organ and bone marrow function as follows, without 
history of red blood cell transfusion, platelet transfusion, erythropoietin stimulating 
agents, or platelet-boosting treatments within 7 days prior to the date of the laboratory 
test:

Hemoglobin ≥10 g/dL

Absolute neutrophil count ≥1.5109/L, without use of G-CSF within 10 days prior 
to the date of the test

Platelets ≥100109/L

ALT and AST ≤3×upper limit of normal (ULN)

Total bilirubin ≤1.5ULN if no liver metastasis, or ≤3×ULN in the presence of 
liver metastasis (participants with Gilbert’s syndrome can enroll if conjugated 
bilirubin is within normal limits)
Creatinine clearance >50 mL/min as measured or calculated by Cockcroft-Gault 
formula (see Appendix 10: Cockcroft-Gault Formula for Estimated Creatinine 
Clearance)
8.
Any toxicities from prior systemic anticancer therapy must have resolved to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
Version 5.0 Grade 1 or baseline level (except for alopecia [any grade], Grade ≤2 
peripheral neuropathy, or Grade ≤2 hypothyroidism stable on hormone replacement).
9.
Participant must sign an ICF indicating that the participant understands the purpose of, 
and procedures required for, the study and is willing to participate in the study.
10.
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.
11.
Criterion modified per Amendment 2
11.1 A participant must be either of the following (as defined in Appendix 5: 
Contraceptive Guidance):
a.
Not of childbearing potential; or

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b. Of childbearing potential and

practicing true abstinence during the entire period of the study, including up to 
7 months after the last dose of study treatment is given; or

have a sole partner who is vasectomized; or

practicing at least 1 highly effective user independent method of contraception 
(examples are located in Appendix 5: Contraceptive Guidance).
Participant must agree to continue contraception throughout the study and through 
7 months after the last dose of study treatment.
Note: If a participant becomes of childbearing potential after start of the study, the 
participant must comply with point (b.).
12.
Criterion modified per Amendment 2
12.1 A participant must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the study and for 7 months after receiving the last dose of study 
treatment.
13.
Criterion modified per Amendment 2
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 participant of 
childbearing potential must agree to use a condom and the partner must also be practicing 
a highly effective method of contraception (see Appendix 5: Contraceptive Guidance).
A participant who is vasectomized must still use a condom for prevention of passage of 
exposure through ejaculation, but the participant’s partner is not required to use 
contraception.
14.
Criterion modified per Amendment 2
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. 
Participants should be advised to consider preservation of sperm prior to treatment with 
pemetrexed or carboplatin, as these agents may impair fertility.
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:

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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 at least 
1 week prior to starting study treatment] or diagnosed or suspected viral infection), 
except as allowed by Exclusion Criterion 17 for HIV

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 or any other circumstances (including social circumstances) that 
would limit compliance with study requirements

Any ophthalmologic condition that is clinically unstable 
2.
Participant received prior systemic anticancer therapy in the locally advanced or 
metastatic setting, or in the adjuvant setting, for the same nonsquamous NSCLC intended 
for treatment now, except as allowed by Inclusion Criterion 3.
3.
Participant received radiotherapy for palliative treatment of NSCLC less than 14 days 
prior to randomization.
4.
Criterion modified per Amendment 2
4.1 Participants with symptomatic or progressive brain metastases.
5.
Participant previously enrolled in 
the Sponsor’s 
study 
73841937NSC3003
(NCT04487080).
6.
Criterion modified per Amendment 2
6.1 Participant has history of or current evidence of leptomeningeal disease, or participant 
has spinal cord compression not definitively treated with surgery or radiation.
7.
Participant has known small cell transformation.
8.
Participant has uncontrolled tumor-related pain. Symptomatic lesions amenable to 
palliative radiotherapy (eg, bone metastases, or metastases causing nerve impingement) 
should be treated at least 14 days prior to randomization.
9.
Participant has a medical history of ILD, including drug-induced ILD or radiation 
pneumonitis.

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10.
Participant has a history of hypersensitivity to carboplatin or pemetrexed, or to any 
excipient of carboplatin, pemetrexed, amivantamab, or lazertinib.
11.
Participant has an active malignancy (ie, progressing or requiring treatment change in the 
last 24 months) other than the disease being treated under study. Exceptions include 
participants who have undergone curative therapy and have no evidence of disease 
recurrence since completion of that therapy, and those with local cancers that have been 
apparently cured such as:
a.
Non-muscle invasive bladder cancer (NMIBC) treated within the last 24 months that 
is considered completely cured.
b. Skin cancer (non-melanoma or melanoma) treated within the last 24 months that is 
considered completely cured.
c.
Non-invasive cervical cancer treated within the last 24 months that is considered 
completely cured.
d. 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,

or history of localized prostate cancer and receiving androgen deprivation 
therapy and considered to have a very low risk of recurrence. 
e.
Breast cancer:

lobular carcinoma in situ or ductal carcinoma in situ that is considered 
completely cured, or history of localized breast cancer and receiving 
antihormonal agents and considered to have a very low risk of recurrence.
f.
Other malignancy that is considered cured with minimal risk of recurrence.
12.
Participant has any contraindication to treatment with pemetrexed or carboplatin or 
participant has a history of hypersensitivity to, or cannot take, vitamin B12 or folic acid.
13.
Criterion modified per Amendment 2
Criterion 13.1 modified per Amendment 5
13.2 Participant has a history of clinically significant cardiovascular disease including, 
but not limited to the following:

Diagnosis of deep vein thrombosis or pulmonary embolism within 4 weeks prior to 
randomization, or any of the following within 24 weeks prior to randomization: 
myocardial infarction, unstable angina, stroke, transient ischemic attack, 
coronary/peripheral artery bypass graft, or acute coronary syndrome. (Note: 

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clinically non-significant thrombosis, such as non-obstructive catheter-associated 
thrombus, or incidental or asymptomatic pulmonary embolism, is not exclusionary.)

Participant has a significant genetic predisposition to venous thromboembolic events 
(VTE; such as Factor V Leiden).

Participant has a prior history of VTE and is not on appropriate therapeutic
anticoagulation as per NCCN or local guidelines.

Prolonged corrected QT (QTcF) interval >480 msec, uncontrolled hypokalemia or 
clinically significant cardiac arrhythmia or electrophysiologic disease (eg, placement 
of implantable cardioverter defibrillator or atrial fibrillation with uncontrolled rate).

Uncontrolled (persistent) hypertension despite optimal treatment: systolic blood 
pressure >160 mmHg or diastolic blood pressure >100 mmHg.

Congestive heart failure (CHF) defined as New York Heart Association (NYHA) 
class III-IV (see Appendix 8: New York Heart Association Criteria) or 
hospitalization for CHF (any NYHA class) within 6 months of randomization.

Pericarditis, pericardial effusion, or myocarditis that is clinically unstable. 
Pericardial effusion considered due to the disease under study is permitted if 
clinically stable at screening.

Baseline LVEF below the institution’s lower limit of normal (LLN) at screening, as
assessed by echocardiogram or multigated acquisition (MUGA) scan.
14.
Participant had major surgery or had significant traumatic injury within 4 weeks before 
randomization, or will not have fully recovered from surgery, or has surgery planned 
during study participation that will require general anesthesia.

Note: Placement of vascular access or tumor biopsy within 4 weeks before 
randomization is permitted.

Note: Participants with planned surgical procedures to be conducted under local 
anesthesia may participate.
15
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 positive for HCV antibody are eligible only if polymerase chain 
reaction is negative for HCV ribonucleic acid (RNA).

Other clinically active infectious liver disease.

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16.
Participant has received a live or live attenuated vaccine within 4 weeks before 
randomization.
17.
Participant is known to be 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

Receiving ART that may interfere with study treatment (consult Sponsor for review 
of medication prior to enrollment)

CD4 count <350 at screening

AIDS-defining opportunistic infection within 6 months of start of screening

Does not agree 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).
18.
Criterion modified per Amendment 3
18.1 Participant is currently receiving a medication or herbal supplement known to be a 
strong cytochrome P450 (CYP) 3A4/5 inducer and is not able to stop use for an 
appropriate washout period prior to randomization (For a list of such medications refer
US FDA 2022).
19.
Participant has received an investigational agent within 12 months before randomization 
or is currently enrolled in an investigational study. (An investigational COVID-19 
vaccine within 12 months before randomization is permitted.)
20.
Criterion modified per Amendment 2
20.1 Participant is pregnant, breast-feeding, or planning to become pregnant while 
enrolled in this study or within 7 months after the last dose of study treatment.
21.
Participant plans to father a child while enrolled in this study or within 6 months after the 
last dose of study treatment.
22.
Participant has any condition for which, in the opinion of the investigator, participation 
would not be in the best interest of the participant (eg, compromise the well-being) or 
that could prevent, limit, or confound the protocol-specified assessments
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 
reconfirmed prior to randomization. The required source documentation to support meeting the 
enrollment criteria is noted in Appendix 2: Regulatory, Ethical, and Study Oversight 
Considerations.

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5.3.
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions 
during the study to be eligible for participation:
1.
Refer to Section 6.7, Concomitant Therapy for details regarding prohibited and 
restricted therapy during the study.
2.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
3.
Criterion modified per Amendment 2
3.1 Criterion modified per Amendment 6
3.2 Participants in Arms A/A2 and C/C2 must agree to use sun protective measures,
such as a hat, sunglasses, protective clothing, and broad-spectrum sunscreen (containing 
titanium dioxide or zinc oxide) with a skin protection factor (SPF) ≥30, avoid 
unnecessary exposure to natural sunlight, and avoid artificial sunlight (tanning beds or 
phototherapy) from baseline until 2 months after the last dose of study treatment.
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 prior to re-screening.
5.5.
Criteria for Temporarily Delaying Randomization
Not applicable.

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The infusion times for carboplatin and pemetrexed should be according to the local guidelines and 
regulatory labeling (eg, pemetrexed can be given over approximately 10 to 15 minutes and 
carboplatin can be given over approximately 30 to 60 minutes). Refer to IPPI for detailed 
information on amivantamab administration. Due to the multiple infusions in Arms A/A2 and 
C/C2, dosing should be scheduled to begin with sufficient time to accommodate all infusions on 
Cycle 1 Day 1. If, however, delays in initiation of therapy leave insufficient time on Cycle 1 Day 
1 for full amivantamab dosing, the initial split dose of amivantamab (Cycle 1 Day 1 and Day 2) 
may be delayed (until Cycle 1 Day 2 and Day 3), with corresponding changes to scheduled 
activities (PK and vital signs) and pre-medications and should be reported in the eCRF as a dose 
delay. If amivantamab treatment is delayed from Cycle 1 Day 1 to Day 2 and Cycle 1 Day 2 to 
Day 3, appropriate premedications should be administered before amivantamab infusion. 
Please refer to Table 17 in Section 6.7.2.2 for premedications required with amivantamab. The 
sequence of administration and dosage of study treatments in each arm are outlined in Table 4. For 
carboplatin and pemetrexed dosages, local prescribing information/guidelines may be followed.
Table 4:
Study Treatment Dosing
Cycle
Days
Study Treatment
Treatment Arm
Study Treatment Dosage
A/A2
B
C/C2
Cycle 1
Days 1-21
Lazertinib (Dosing 
Schedule 1 (LACP) only*)
X
240 mg 
Day 1
Pemetrexed 
X
X
X
500 mg/m2
Carboplatin 
X
X
X
AUC 5 (up to 750 mg)
Amivantamab
X
X
350 mg
Day 2
Amivantamab
X
X
1,050 mg (<80 kg) / 1,400 mg (≥80 kg)
Day 8 and Day 15
Amivantamab
X
X
1,400 mg (<80 kg) / 1,750 mg (≥80 kg)
Cycle 2
Days 1-21
Lazertinib (Dosing 
Schedule 1 (LACP) only*)
X
240 mg 
Day 1
Pemetrexed 
X
X
X
500 mg/m2
Carboplatin
X
X
X
AUC 5 (up to 750 mg)
Amivantamab
X
X
1,400 mg (<80 kg) / 1,750 mg (≥80 kg)
Cycles 3-4
Days 1-21
Lazertinib (Dosing 
Schedule 1 (LACP) only*)
X
240 mg 
Day 1
Pemetrexed 
X
X
X
500 mg/m2
Carboplatin
X
X
X
AUC 5 (up to 750 mg)
Amivantamab
X
X
1,750 mg (<80 kg) / 2,100 mg (≥80 kg)
Cycles 5+
Days 1-21
Lazertinib
X
240 mg 
Day 1
Pemetrexed 
X
X
X
500 mg/m2
Amivantamab
X
X
1,750 mg (<80 kg) / 2,100 mg (≥80 kg)
*
For Arms A dose schedule 2/A2 (ACP-L), Lazertinib may be administered from Cycle 5 Day 1 or sooner if 
carboplatin is discontinued earlier than Cycle 4.

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6.1.2.
Lazertinib
Lazertinib 80 mg for oral administration is an oval, yellow, and film-coated tablet. Refer to the IB 
for a list of excipients. Participants in Arms A/A2 will self-administer lazertinib as an oral therapy, 
with an initial dosage of 240 mg (3 tablets) once daily. Lazertinib tablets can be administered with 
or without food. Lazertinib should be dosed at the study site on Cycle 5 Day 1 or sooner if 
carboplatin discontinued earlier than Cycle 4. Lazertinib should only start once all hematologic 
toxicities, nausea, and stomatitis from the combination of amivantamab, carboplatin, and 
pemetrexed have resolved. Resolution is defined as ≤Grade 1 or back to baseline status for the 
participant (except for oral mucositis which should recover to ≤Grade 2 or baseline). 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 should be instructed to take the next dose at the next 
scheduled time. If a participant vomits after taking lazertinib, the participant 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.
Chemotherapy
Depending on regional requirements, chemotherapy may be sourced centrally or locally. When 
provided by the sponsor, chemotherapy will be supplied as carboplatin (600 mg/vial, with 
concentration 10 mg/mL in a 60 mL vial) and pemetrexed (500 mg/vial powder concentrate for 
solution for infusion). For locally sourced carboplatin and pemetrexed, refer to local prescribing 
information for each agent for a list of excipients.
6.1.4.
Amivantamab
Amivantamab is supplied for this study in a glass vial containing 350 mg/vial with concentration 
50 mg/mL, 7 mL per vial. Amivantamab will be manufactured and provided under the 
responsibility of the sponsor. Refer to the amivantamab IB for a list of excipients.
The dosage of amivantamab will be based on the participant's body weight at screening. 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 21-day cycles as follows:

1,400 mg (1,750 mg if body weight ≥80 kg) on Cycle 1 Days 1/2, 8, and 15, and Cycle 2 
Day 1

1,750 mg (2,100 mg if body weight ≥80 kg) on Day 1 of each 21-day cycle, starting with 
Cycle 3.
Amivantamab will be administered by IV using the escalating infusion rate regimen as specified 
in the IPPI. The product must be infused via a peripheral vein for all Cycle 1 doses; Infusion via 
central line is allowed only at Cycle 1 Day 15 and onwards if the participant’s most recent dose 
(eg, Cycle 1 Day 8) was successfully administered without an infusion related reaction.

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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 start and end times of each infusion and infusion 
rate(s) 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:

Do not mix or dilute amivantamab with other drugs.

IV tubing should be primed with diluent, rather than amivantamab solution.

Amivantamab must not be administered as an IV push or bolus.

Due to the risk of infusion-related reactions, equipment and agents for treating anaphylaxis 
(eg, epinephrine, corticosteroids, IV antihistamines, bronchodilators, oxygen, resuscitation 
equipment) must be available during amivantamab administration. Trained personnel (eg,
resuscitation team) must also be available.
6.2.
Preparation/Handling/Storage/Accountability
The instructions below on study treatment preparation, handling, and storage apply only to 
lazertinib, amivantamab and/or centrally sourced chemotherapy. For locally sourced 
chemotherapy, please follow the instructions on the local package insert.
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. For additional guidance on study 
treatment preparation, handling, and storage, refer to the IPPI/SIPPM for amivantamab, the SIPPM 
for lazertinib, and local prescribing information for carboplatin and pemetrexed.
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, 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 designated representatives where applicable, must be instructed to 
return all original containers, whether empty or containing study treatment. 
Study treatment must be handled in strict accordance with the protocol and the container label and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study treatment, and study treatment returned by the participant, 

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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
Study Treatment Allocation
Procedures for Randomization 
Central randomization will be implemented in this study. In the main study, participants will be 
randomly assigned to 1 of 3 study treatment groups based on a computer-generated randomization 
schedule prepared before the study by or under the supervision of the sponsor. In the extension 
cohort, participants will be randomly assigned to 1 of 2 study treatment groups based on a 
computer-generated randomization schedule prepared before the extension cohort by or under the 
supervision of the sponsor. In both the main study and the extension cohort, the randomization 
will be balanced by using randomly permuted blocks and will be stratified by osimertinib line of 
therapy (first-line vs second-line), history of brain metastases (yes vs no), and Asian race (yes vs 
no). Participants who have adequate treatment for metastatic brain lesions, including a complete 
response or resection, must be identified as having a history of brain metastases. The interactive 
web response system (IWRS) will assign a unique treatment code, which will dictate the treatment
assignment and matching study treatment kit 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.
Blinding
As this is an open-label study, blinding procedures are not applicable.

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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. The study personnel at the study site will account 
for all study treatments dispensed and for appropriate return. The certificates of delivery and return 
should be signed. Study drugs provided by the sponsor may not be used for any purpose other than 
that outlined in this protocol, including other human studies, animal investigations, or in vitro 
testing.
Preinfusion Medications
Administration of preinfusion medications and chemotherapy prophylaxis will be documented in 
the source documents and eCRF. 
Lazertinib
The dispensing of lazertinib to the participant and the return of lazertinib from the participant must 
be documented on the treatment accountability form. Participants, or their legally designated
representatives where applicable, must be instructed to return all original containers, whether 
empty or containing lazertinib. Study-site personnel must not combine contents of the lazertinib
containers.
Chemotherapy (Carboplatin and Pemetrexed)
Carboplatin and pemetrexed will be administered as IV infusions by qualified study-site personnel 
according to local guidelines and/or product labeling, and the details of each administration will 
be recorded in the eCRF (including date, start, and stop times of the IV infusion, and volume 
infused). Dispensing of all study drug must also be recorded in the participant’s source documents.
Amivantamab 
Amivantamab will be administered as an IV infusion by qualified study-site personnel and the 
details of each administration will be recorded in the eCRF (including date, start, and stop times 
of the IV infusion, and volume infused). Dispensing of all study treatment must also be recorded 
in the participant’s source documents. 
6.5.
Dose Modification
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). Based on 
clinical experience with the study treatments, the anticipated toxicities of amivantamab (Arms 
A/A2 and C/C2) and lazertinib (Arms A/A2) are expected to be distinct from those associated with 
chemotherapy. Hematologic toxicities are expected to be most likely associated with 
chemotherapy, whereas anti-EGFR toxicities are likely to be associated with both amivantamab
(Arms A/A2 and C/C2) and lazertinib (Arms A/A2), and anti-MET toxicities associated with 
amivantamab alone.
If a participant experiences a clinically significant CTCAE Grade 3 (except for VTE; see 
Section 6.5.3.12) or higher and/or unacceptable toxicity (any grade) then dosing of the causative 

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treatment(s) should be interrupted and supportive therapy administered in accordance with local 
practice/guidelines. The sections below provide further guidance on managing dose delays 
(Section 6.5.1) and dose modifications for amivantamab and lazertinib (Sections 6.5.2 and 6.5.3) 
and chemotherapy (Section 6.5.4).
6.5.1.
Dose Delay Guidance
In instances where treatment delay is indicated, treatment with chemotherapy and/or amivantamab
(Arms A/A2 and C/C2) may be delayed until recovery of toxicity to a level allowing continuation 
of therapy. A participant for whom treatment was delayed should be assessed at least weekly to 
ensure adequate supportive care is being administered and to assess for improvement of toxicity.
Participants must meet retreatment criteria for chemotherapy (as per Section 6.5.4.1 based on 
product labeling and as per local regulations and guidelines) and/or amivantamab (as per 
Section 6.5.2), in accordance with protocol, prior to redosing with the respective agents. 

All Arms:
Chemotherapy: If retreatment criteria are not met for carboplatin and/or pemetrexed, then 
treatment should be delayed by 1 week at a time. If chemotherapy administration is delayed beyond 
42 days (±3 days) from the last treatment, chemotherapy will be discontinued unless continued 
treatment is approved by the sponsor. Carboplatin administration cannot exceed a total of 4 cycles.
For Arms A/A2
For VTE events associated with clinical instability (eg, respiratory failure or cardiac dysfunction)
in participants receiving the combination of amivantamab and lazertinib, study treatment should 
be held until the patient recovers from the event. Thereafter, the treatment can be resumed at the 
discretion of the investigator.

Arms A/A2 and Arms C/C2: 
Chemotherapy: If chemotherapy cannot be administered on the scheduled day, dosing with 
amivantamab should proceed as planned, if amivantamab retreatment criteria are met. If 
chemotherapy is delayed by a week (eg, administered on Day 8 of the cycle) subsequent cycle 
dosing of amivantamab may be delayed by 1 week to align with the chemotherapy dosing schedule. 
Alternatively, if chemotherapy is delayed by 2 weeks (eg, administered on Day 15 of the cycle), 
then the subsequent cycle dosing of amivantamab can be accelerated by 1 week to align with 
chemotherapy (see Appendix 12: Dosing Synchronization for Arms A/A2 and C/C2). While some 
flexibility in the amivantamab dosing schedule is allowed as described above, combination 
chemotherapy must be dosed at a minimum interval of 21 days (-1 day for Cycle 2 or -3 days 
beginning with Cycle 3).
Amivantamab: In the event amivantamab dosing on Day 1 of the cycle is delayed, but retreatment 
criteria for chemotherapy are met, dosing with chemotherapy should continue as planned and 
participants should be evaluated weekly for retreatment with amivantamab.
If both chemotherapy and amivantamab must be delayed, participants should be re-evaluated 
weekly for retreatment. Dosing with amivantamab may proceed once retreatment criteria are met, 
whether on Day 8 or Day 15 of the cycle. The dosing of both chemotherapy and amivantamab may 
resume on the subsequent cycle once retreatment criteria for pemetrexed ± carboplatin are met, as 

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described above. The Medical Monitor may be consulted if there are questions regarding restarting 
of protocol treatment after dose delays.
6.5.2.
Dose Modification of Amivantamab and Lazertinib
Decisions regarding dose modification of the individual study treatments should be guided by the 
observed toxicity, the safety profile of each drug, the likelihood of causality to each agent, as well 
as each agent’s potential contribution to any observed clinical benefit. 
Arms A/A2: For toxicities associated with EGFR inhibition that require treatment modification, 
and which can be attributed to either drug, modification should be instituted for lazertinib prior to 
modification of amivantamab dosing. Refer to Table 5 for guidance on dose modification based 
on the toxicity grade of AEs other than those specified in Section 6.5.3, with dose reductions of 
lazertinib and amivantamab conducted according to Table 6 and Table 7, respectively. In the case 
of a second occurrence of the same Grade 4 toxicity, permanently discontinue lazertinib or 
amivantamab or both lazertinib and amivantamab, if investigator considers the event related to 
either or both study drugs, respectively.
Arms C/C2: In the case of a second occurrence of the same Grade 4 toxicity, permanently 
discontinue amivantamab, if investigator considers the event related to this study drug.
Table 5:
Arms A/A2: General Guidance for Withholding Doses for Toxicities Considered Related to 
Lazertinib or Amivantamab, Based on Gradea
Gradeb
Actionc
Dose Modification After Resolution of Toxicityd,e
1
None
Continue both agents at current dose level; consider 
supportive care according to local standards as 
appropriate
2
None, or consider withholding lazertinib 
(unless the experienced toxicity is strongly 
suspected to be related to amivantamab
alone, in which case amivantamab should be 
withheld).
If lazertinib is withheld, restart on Day 1 of next cycle 
at either the same or a reduced dose (see Table 6 for 
lazertinib dose reduction guidance). 
If amivantamab is withheld, restart study treatment at 
current dose level at either Day 8 or Day 15 of the 
current cycle or Day 1 of the following cycle. 
3
Withhold lazertinib and amivantamab
If Grade 3 adverse reaction improves to Grade 0-2 after 
withholding study drugs for up to 3 weeks, then upon 
resolution:

Restart amivantamab at the same dose or a reduced
dose on Day 8 or Day 15 of the current cycle or Day 
1 of the next cycle.

Restart lazertinib at a reduced dose on Day 1 of next 
cycle.
If Grade 3 adverse reaction does not improve to Grade 
0-2 after withholding study drugs for up to 3 weeks, 
permanently discontinue lazertinib, amivantamab, or 
both.

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Table 5:
Arms A/A2: General Guidance for Withholding Doses for Toxicities Considered Related to 
Lazertinib or Amivantamab, Based on Gradea
Gradeb
Actionc
Dose Modification After Resolution of Toxicityd,e
4
Withhold lazertinib and amivantamab
If Grade 4 adverse reaction improves to Grade 0-2 after 
withholding study drugs for up to 3 weeks, then upon 
resolution: 

Restart amivantamab at a reduced dose on Day 8 or 
Day 15 of the current cycle or Day 1 of the next 
cycle.

Restart lazertinib at a reduced dose on Day 1 of next 
cycle.
If Grade 4 adverse reaction does not improve to Grade 
0-2 after withholding study drugs for up to 3 weeks, 
permanently discontinue lazertinib, amivantamab, or 
both.
If a Grade 4 adverse reaction reoccurs, permanently 
discontinue lazertinib or amivantamab, or both, if 
investigator considers the event related to either or both 
study drugs, respectively.
a.
For rash related events in Arms A/A2, see Table 10
b.
Per National Cancer Institute-Common Terminology Criteria for Adverse Events Version 5.0.
c.
For all toxicities, consider supportive care according to protocol as appropriate.
d.
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).
e.
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 patient recovers 
from the event. Thereafter, the treatment can be resumed at the discretion of the investigator.
Table 6:
Guidance for Lazertinib Stepwise Dose Reduction (Arms A/A2)
Dose Level
Lazertinib (any cycle)
0 (starting dose)
240 mg
-1
160 mg
-2
80 mg
-3
Discontinue
Table 7:
Guidance for Amivantamab Stepwise Dose Reduction (Arms A/A2 and Arms C/C2)
Dose Level
Amivantamab (up to Cycle 2 Day 1)
Amivantamab (Cycle 3+)
0 (starting dose)
1,400 mg (1,750 mg if body weight ≥80 kg)
1,750 mg (2,100 mg if body weight ≥80 kg)
-1
1,050 mg (1,400 mg if body weight ≥80 kg)
1,400 mg (1,750 mg if body weight ≥80 kg)
-2
700 mg (1,050 mg if body weight ≥80 kg)
1,050 mg (1,400 mg if body weight ≥80 kg)
-3
Discontinue
Discontinue
Arms C/C2: Refer to Table 8 for guidance on dose modification based on the toxicity grade of 
AEs other than those specified in Section 6.5.3. Dose reductions for amivantamab should occur as 
specified in Table 7.

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Table 8:
Arms C/C2: General Guidance for Withholding Doses for Toxicities Considered Related to 
Amivantamab, Based on Gradea
Gradeb
Actionc
Dose Modification After Resolution of Toxicityd
1
None
Continue amivantamab at current dose level.
2
None, or consider withholding amivantamab 
Restart study treatment at current dose level. 
3
Withhold amivantamab
If Grade 3 adverse reaction improves to Grade 0-2 after 
withholding study drug for up to 3 weeks, study drug 
may be restarted at the same dose or a reduced dose on 
Day 8 or Day 15 of the current cycle or Day 1 of the 
next cycle.
If Grade 3 adverse reaction does not improve to Grade 
0-2 after withholding study drugs for up to 3 weeks, 
permanently discontinue amivantamab. 
4
Withhold amivantamab
If Grade 4 adverse reaction improves to Grade 0-2 after 
withholding study drug for up to 3 weeks, study drug 
may be restarted at a reduced dose on Day 8 or Day 15 
of the current cycle or Day 1 of the next cycle.
If Grade 4 adverse reaction does not improve to Grade 
0-2 after withholding study drugs for up to 3 weeks, 
permanently discontinue amivantamab.
If Grade 4 adverse reaction reoccurs, permanently 
discontinue amivantamab, if investigator considers the 
event related to the study drug.
a.
For rash related events in Arms C/C2, see Table 11.
b.
Per National Cancer Institute-Common Terminology Criteria for Adverse Events Version 5.0.
c.
For all toxicities, consider supportive care according to protocol as appropriate.
d.
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).
Note: This table discusses Arms C/C2. For details pertaining to Arms A/A2, see Table 5.
Re-escalation of amivantamab and/or lazertinib after a prior dose reduction is allowed if 
determined to be in the best interest of the participant.
6.5.3.
Dose Modification and Management of Specific Adverse Events
(Arms A/A2 and Arms C/C2)
6.5.3.1.
Infusion-Related Reactions
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 2.2.1). 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). 

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The monitoring should include heart rate, blood pressure, temperature, respiratory rate, and oxygen 
saturation measurements. 
Particularly with the initial dose (Cycle 1, Day 1 and Day 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 6.7.2.2.
Treatment of Infusion-Related Reactions 
Participants who experience early symptoms of IRRs, manifesting, but not limited to, as fever, 
chills, rigors, bronchospasm, headache, rash, pruritus, arthralgia, hypo- or hypertension or other 
symptoms, must have their amivantamab infusion interrupted, if indicated, and the symptoms 
managed according to the recommendations provided in Table 9. 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. The start and end time and grade of each IRR 
symptom as well as the overall IRR should be reported in the eCRF.

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Table 9:
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, follow the 
guidance for Grade 2 interruptions.
Antihistamine, antipyretic, 
and glucocorticoid, as per
Table 17 (Section 6.7.2.2)
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 1,000 mg; consider corticosteroids and bronchodilator 
therapy; 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 17 (Section 6.7.2.2)
Consider meperidine if 
participant experiences chills 
and rigors.
Grade 3 
Severe reaction that is 
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)
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 
amivantamab. Consultation 
with Medical Monitor
required before continuing 
with subsequent dosing.
Grade 4
Life-threatening; pressor 
or ventilator support 
indicated
Same as for Grade 3
Amivantamab treatment must 
be permanently discontinued.
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

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6.5.3.2.
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 amivantamab and lazertinib (Arms A/A2), 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, it 
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.

A 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: a topical antibiotic (clindamycin, mupirocin, or fusidic acid) on sun-exposed 
skin, or an oral antibiotic (such as doxycycline 100 mg once daily, minocycline 100 mg once daily, 
or cephalexin 500 mg once daily), or both.
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 AE.

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).

Consultation with a dermatologist is required if the rash is Grade 4.

Initiate a topical corticosteroid (cream or ointment) twice daily.

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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 6.5.3.3.

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 gradually tapering the antibiotic.
A suggested algorithm for stepwise management of rash is provided in Table 10 for Arms A/A2
and Table 11 for Arms C/C2.
Table 10:
Suggested Algorithm for Management of Rash (Arms A/A2)
Gradea
Management
Dose Adjustment
1

Initiate reactive 
management as above

Reassess weekly
Continue current dose(s) of study treatment
2

Initiate reactive 
management as above

Reassess weekly
Continue current dose(s) of study treatment;
or
If intolerable, consider withholding lazertinib. Upon 
satisfactory resolution, restart on Day 1 of next cycle 
at either the same or a reduced dose. See Table 6 for 
lazertinib dose reduction and Table 7 for 
amivantamab dose reduction guidance.
3

Initiate reactive 
management as above

Start moderate strength 
topical corticosteroidsb 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 weekly

Consider dermatology 
consultation and manage 
rash per recommendation
Withhold lazertinib and amivantamab until rash 
improves to ≤Grade 2.
If Grade 3 adverse reaction improves to Grade 0-2 
after withholding study drugs for up to 3 weeks, then 
upon resolutionc: 

Restart amivantamab at the same dose or a 
reduced dose on Day 8 or Day 15 of the current 
cycle or Day 1 of the next cycle.

Restart lazertinib at a reduced dose on Day 1 of 
next cycle.
If Grade 3 adverse reaction does not improve to 
Grade 0- 2 after withholding study drugs for up to 3 
weeks, permanently discontinue either lazertinib or 
amivantamab or both.

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a.
Grading per National Cancer Institute - Common Terminology Criteria for Adverse Events (Version 5.0).
b.
For example, hydrocortisone 2.5% cream or fluticasone propionate 0.5% cream.
c. Resolution defined as: ≤Grade 2 or back to baseline status for the participant.
Table 11:
Suggested Algorithm for Management of Rash (Arms C/C2)
Gradea
Management
Dose Adjustment
1

Initiate reactive management as 
above

Reassess weekly
Continue current dose(s) of study treatment
2

Initiate reactive management as 
above

Reassess weekly
Continue current dose(s) of study treatment;
or
If intolerable, consider withholding amivantamab. 
Upon satisfactory resolution, restart on Day 8 or 
Day 15 of the current cycle or Day 1 of next cycle at 
either the same or a reduced dose (see Table 7 for 
amivantamab dose reduction guidance).
3

Initiate reactive management as 
above

Start moderate strength topical 
corticosteroidsb 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 weekly

Consider dermatology 
consultation and manage rash per 
recommendation
Withhold amivantamab until rash improves to 
≤Grade 2.
If Grade 3 adverse reaction improves to Grade 0-2 
after withholding amivantamab for up to 3 weeks, 
restart amivantamab at the same dose or a reduced
dose on Day 8 or Day 15 of the current cycle or Day 
1 of the next cycle.
If Grade 3 adverse reaction does not improve to 
Grade 0-2 after withholding amivantamab for up to 
3 weeks, permanently discontinued amivantamab.
4

Initiate reactive management as 
above

Start moderate strength topical 
corticosteroidsb and systemic 
antibiotics as above, plus systemic 
Permanently discontinue all study drugs 
(amivantamab, pemetrexed, and carboplatin).
4

Initiate reactive 
management as above

Start moderate strength 
topical corticosteroidsb 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 weekly

Consult dermatologist and 
manage rash per 
recommendation
Permanently discontinue all study drugs 
(amivantamab, lazertinib, pemetrexed, and 
carboplatin).
Severe bullous, 
blistering, or 
exfoliating skin 
conditions 
including toxic 
epidermal 
necrolysis (TEN)

Consult dermatologist and 
manage rash per 
recommendation
Permanently discontinue all study drugs 
(amivantamab, lazertinib, pemetrexed, and 
carboplatin).

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Table 11:
Suggested Algorithm for Management of Rash (Arms C/C2)
prednisone (0.5 mg/kg) for 7 days

Consider low doses of acitretin or 
isotretinoin (20-30 mg/day)

Reassess weekly

Consult dermatologist and manage 
rash per recommendation
Severe bullous, 
blistering, or 
exfoliating skin 
conditions 
including toxic 
epidermal 
necrolysis (TEN)

Consult dermatologist and manage 
rash per recommendation
Permanently discontinue all study drugs 
(amivantamab, pemetrexed, and carboplatin).
a.
Grading per National Cancer Institute - Common Terminology Criteria for Adverse Events (Version 5.0).
b.
For example, hydrocortisone 2.5% cream or fluticasone propionate 0.5% cream.
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 anti-dandruff shampoo with 
anti- inflammatory, antibacterial, and antifungal properties (eg, ketoconazole, selenium 
sulfide [Selsun®], zinc pyrithione [Head and Shoulders®], or Ciclopirox). These shampoos 
should be used twice/week, massaging into scalp, leaving on for 2-5 minutes, and then rinsing. 

Application of a steroid lotion may also be effective (eg, betamethasone valerate 0.1% lotion, 
mometasone furoate 0.1% lotion, or betamethasone dipropionate 0.05% lotion). 

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.
6.5.3.3.
Pruritus
Reactive Management Recommendations (Fischer 2013)
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.

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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).
6.5.3.4.
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.
6.5.3.5.
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 according to local institutional practice and guidelines, 
and should include the following: 

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Prophylaxis Recommendations

Use good oral hygiene, dentition review and referral to an oral hygienist if necessary.

Use a soft toothbrush.

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% to 
5% or solution 4 times per day. 
6.5.3.6.
Pulmonary Toxicity
Patients with NSCLC are at risk of multiple AEs affecting pulmonary function, including disease 
progression, pulmonary embolus, infectious pneumonias, and more rarely, drug-related 
ILD/pneumonitis. Participant 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 AE is observed, including ILD/pneumonitis, all study 
treatments, including carboplatin and pemetrexed, 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.

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
Hematology and other laboratory tests, including serum albumin levels.

Referral to pulmonologist for evaluation, including bronchoscopy with biopsy, cell counts, 
and cultures as feasible.

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 participants with symptomatic pneumonitis 
(Grade 2 or 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 
treatments and should be reported as a serious adverse event (SAE). In the absence of a diagnosis 
of ILD/pneumonitis, study treatment may be restarted after discussion with Medical Monitor.
6.5.3.7.
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 of electrocardiogram (ECG) 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 11: 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 all study 
treatments, including carboplatin and pemetrexed, should be withheld.
o
Retreatment, at a reduced dose, should only occur once QTc interval is ≤480 msec, 
as measured by repeat triplicate ECG, or recovery to baseline is documented. If 
retreatment is indicated, lazertinib and amivantamab should be reduced by 1 dose 
level each (see Table 6 and Table 7).
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.

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Change in LVEF

Absolute LVEF decline of >10% and absolute LVEF value below the 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 all study treatments, including carboplatin and pemetrexed.
6.5.3.8.
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 6.5.2). In addition, if the following 
criteria are observed, then study treatment should be withheld, and the event should be reported as 
an SAE to the sponsor within 24 hours:
a) ALT or AST ≥3×ULN (if baseline was normal; ≥3×baseline if baseline was abnormal) and 
bilirubin ≥2×ULN (if baseline was normal; ≥2×baseline if baseline was abnormal) (>35% 
direct bilirubin).

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 ≥3×ULN (if baseline was normal; ≥3×baseline if baseline was abnormal) and 
international normalized ratio (INR) >1.5 if INR is measured.
c) ALT or AST ≥3×ULN (if baseline was normal; ≥3×baseline if baseline was abnormal) with 
the concomitant appearance of worsening symptoms attributable to drug 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 6: 
Liver Event Follow-Up Requirements. If no alternative etiology of liver toxicity is identified, all 
study treatments, including carboplatin and pemetrexed, should be permanently discontinued. 
6.5.3.9.
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 

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(Section 8.2.6). Participants should be advised of the increased risk for eye toxicity associated with 
anti-EGFR therapeutics with the use of contact lenses.
6.5.3.10.
Diarrhea
If participants experience diarrhea, they should be encouraged to drink 8 to 10 large glasses (total 
volume of 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. 
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 12 for Arms A/A2 and Table 13 for Arms
C/C2.
Table 12: 
Suggested Algorithm for Management of Diarrhea for Arms A/A2
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 lazertinib 
treatment until ≤Grade 1.

Upon satisfactory resolution, restart on Day 1 of 
next cycle at either the same or a reduced dose. 
See Table 6 for lazertinib dose reduction and 
Table 7 for amivantamab dose reduction 
guidance.
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.

Hold lazertinib. Upon resolution to ≤Grade 1, 
resume lazertinib with consideration of reduction 
by 1 dose level. Restart lazertinib at a reduced 
dose on Day 1 of next cycle.
4

Maximal inpatient fluid and nutritional 
support, antibiotics as indicated in 
judgment of investigator for fever, 
leukocytosis, marked dehydration, etc.
Hold lazertinib and amivantamab. Upon resolution to 
≤Grade 1:

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
Restart amivantamab at a reduced dose on Day 8 or 
Day 15 of the current cycle or Day 1 of the next 
cycle.

Restart lazertinib at a reduced dose on Day 1 of 
next cycle.
Table 13: 
Suggested Algorithm for Management of Diarrhea for Arms C/C2
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 amivantamab 
treatment until ≤Grade 1. 

If diarrhea of >Grade 1 recurs after initial 
improvement, consider reduction of 
amivantamab dose 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.

Hold amivantamab. Upon resolution to 
≤Grade 1, resume amivantamab on Day 8 or 
Day 15 of the current cycle or Day 1 of the next 
cycle.

Consider reducing dose by 1 level.
4

Maximal inpatient fluid and nutritional 
support, antibiotics as indicated in judgment 
of investigator for fever, leukocytosis, 
marked dehydration, etc.

Hold amivantamab until ≤Grade 1. Upon 
resolution to ≤Grade 1, resume amivantamab at 
a reduced dose on Day 8 or Day 15 of the 
current cycle or Day 1 of the next cycle.
6.5.3.11.
Paresthesia
If a participant experiences paresthesia, contributing medical conditions should first be considered 
and optimally managed. For example:

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:

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
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 Arms A/A2.
Refer to Table 5 and Table 8 for recommended dose adjustment.
6.5.3.12.
Venous Thromboembolic Events 
Participants 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 that have 
experienced VTE, if symptoms persist or in case of worsening VTE, further imaging studies 
(which may include doppler studies) should be performed to assess the resolution of the event with 
corrective measures, as per the treating physician’s discretion.
All study participants receiving the combination of amivantamab and lazertinib (Arms A/A2) are 
recommended to receive prophylactic-dose anticoagulation as per local guidelines during the first 
4 months of combination therapy (For patients receiving the LACP dosing schedule this would 
start Cycle 1 Day 1, for those receiving the ACP-L dosing schedule this would start when lazertinib 
is initiated - on Cycle 5 Day 1 or sooner if carboplatin discontinued earlier than Cycle 4). Vitamin 
K antagonists are not recommended due to numerous drug interactions. The benefit-risk 
assessment for participants to tolerate prophylactic-dose anticoagulation is at the discretion of the 
treating investigator. Notably, prophylactic-dose anticoagulation has been found to be safe and 
effective in multiple prior studies (Carrier 2019; Rutjes 2020).
If a VTE event is diagnosed, the participant should be treated with treatment-dose anticoagulation 
as per local guidelines. Vitamin K antagonists are not recommended because of numerous drug 
interactions. For VTE events associated with clinical instability (eg respiratory failure or cardiac 
dysfunction) in participants receiving the combination of amivantamab and lazertinib, study 
treatment should be held until the patient recovers from the event. Thereafter, the treatment can be 
resumed at the discretion of the investigator.

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In the case of a recurrent VTE whilst on therapeutic anticoagulation therapy, the combination of 
amivantamab and lazertinib should be permanently discontinued. Participants may continue to 
receive treatment with either amivantamab or lazertinib (but not both) at the discretion of the 
treating physician.
Refer to Table 5, Table 6, Table 7, and Table 8 for recommended dose adjustment for any adverse 
events.
6.5.4.
Chemotherapy Dose Modification
Dose modifications of chemotherapy should be based on the maximum toxicity experienced during 
a cycle. Treatment should be delayed until the toxicity resolves to ≤Grade 1 or the baseline status 
of the participant. Final treatment decisions should depend on clinical judgment, based on local 
regulations and labeling. Decisions on study treatment dose modification should be guided by the 
safety profile of each drug and the likelihood of causality. 
Dose modifications will be based on the maximum toxicity experienced during a cycle. 
Participants may have a maximum of 2 dose modifications to each treatment throughout the study 
for toxicities before the agent should be discontinued. Dose reduction should be based upon the 
most severe toxicity if multiple toxicities are experienced concurrently. Do not re-escalate 
chemotherapy dosing after a prior dose reduction.
6.5.4.1.
Management of Chemotherapy Toxicities
Given the prevalent use of platinum-based doublet chemotherapy in the treatment of NSCLC, the 
safety profiles of both carboplatin and pemetrexed are well described. Safety monitoring and dose 
modifications should therefore follow local regulations and labeling. 
In general, participants should be monitored for chemotherapy-related toxicities and should 
undergo laboratory assessments including a complete blood count with platelet counts, as well as 
an evaluation of liver and kidney function, per the respective approved prescribing information 
(for example, Alimta USPI 2019, Carboplatin USPI 2018). Chemotherapy should be delayed if 
absolute neutrophil count is <1,500/µL, platelet count is <100,000/µL, or the participant is 
experiencing non-hematologic toxicity of > Grade 2 severity. All participants who experience 
hematologic toxicities while on treatment are recommended to receive colony stimulating factors 
as per international guidelines (eg, MGF-3 and TGF-1 from the NCCN Guidelines for 
Hematopoietic Growth Factors as an example). Table 14 and Table 15 provide additional guidance 
for dose modification to manage hematologic and non-hematologic toxicities related to 
chemotherapy based on product labeling. Refer to local labeling for complete information 
regarding dose adjustment for carboplatin and pemetrexed. 

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Table 14:
Guidance for Dose Modifications for Hematologic Chemotherapy Toxicity
Platelets (Nadir)
Absolute Neutrophil 
Count (Nadir)
Pemetrexed Dosage
Carboplatin Dosage
≥50,000/µL
≥500/µL
100% of previous dose
100% of previous dose
≥50,000/µL
<500/µL
75% of previous dose
75% of previous dose
<50,000/µL
without bleeding
Any
75% of previous dose
75% of previous dose
<50,000/µL
with ≥Grade 2 bleeding
Any
50% of previous dose
50% of previous dose
≥50,000/µL
<1,000/µL +
fever ≥38.5°C (101°F)
75% of previous dose
75% of previous dose
Table 15:
Guidance for Dose Modifications for Non-Hematologic Chemotherapy Toxicity
Pemetrexed Dosage
Carboplatin Dosage
Any Grade 3 or 4 toxicities except mucositis
75% of previous dose
75% of previous dose
Grade 3 or 4 mucositis
50% of previous dose
100% of previous dose
Pemetrexed therapy should be discontinued if the participant experiences any hematologic or 
nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 
neurotoxicity is observed. Refer to local labeling for complete information.
6.6.
Treatment of Overdose
There are no data on overdose from studies of amivantamab or lazertinib (refer to IB for each 
agent). In the event of an overdose, the investigator or treating physician should:

Contact the Medical Monitor immediately.

Evaluate the participant to determine, in consultation with the Medical Monitor, whether study 
treatment should be interrupted or whether the dose should be reduced.

Closely monitor the participant for AE/SAE and laboratory abnormalities.

Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF.
6.7.
Concomitant Therapy
6.7.1.
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 
SAEs and Grade 3 or Grade 4 AEs considered related to study treatment, until resolution of event 
or start of subsequent therapy.

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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.
6.7.2.
Permitted and Required Medications and Therapies 
6.7.2.1.
Pre- and Post-Infusion Medications for Chemotherapy
Corticosteroids, folic acid, and vitamin B12 will be administered concomitantly with pemetrexed 
(Table 16), according to local prescribing information or per standard local practice. 
Table 16:
Concomitant Medications for Pemetrexed
Medication
Dose
Timing
Corticosteroid
Dexamethasone 4 mg 
orally twice daily or 
equivalent
1 day before, the day of, and 1 day after each dose of pemetrexeda
Folic Acidb
350-1,000 µg orally
Daily beginning 7 days prior to first infusion and continuing until 
21 days after the last dose of pemetrexed
Vitamin B12
1,000 µg 
intramuscularly
1 dose within 7 days prior to and including Cycle 1 Day 1, then every 
3 cycles afterwards. Vitamin B12 may be administered on the same 
day as pemetrexed
a. For participants in Arms A/A2 and C/C2, dexamethasone 4 mg orally twice daily dose can be skipped on Cycle
1 Day 1 and Day 2, at the discretion of the investigator since IV dexamethasone is administered as a pre-infusion 
medication for amivantamab on those days per Table 17. 
b. Folic acid may be given either as a separate preparation or as a component of a multivitamin.
Participants may receive other pre-treatment or concomitant treatment for pemetrexed or 
carboplatin as recommended by local prescribing information, local practice guidelines, or as 
clinically indicated. Permitted prophylactic medications include the following: 

Appropriate prophylactic antiemetic regimens for high risk of emesis associated with 
carboplatin (eg, ondansetron, aprepitant, dexamethasone), in accordance with institutional 
practice or current NCCN and/or ESMO guidelines.

Leukocyte-depleted blood transfusions are allowed at any time after Cycle 1 Day 1.

G-CSFs should not be used prophylactically during screening. Use of prophylactic colony 
stimulating factors may be considered after first dose as per local guidelines or prescribing 
information.
Concomitant medications for the symptomatic treatment of related toxicities (Grade 1-4) may be 
administered according to the standard of care at the site and at the treating physician’s discretion, 
as clinically indicated. Supportive care and other medications that are considered necessary for the 
participant’s well-being may be given at the discretion of the investigator.

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6.7.2.2.
Pre- and Post-Infusion Medications for Amivantamab (Arms A/A2 and 
Arms C/C2)
Preinfusion Medications
Required preinfusion medications and optional preinfusion medications for amivantamab are 
summarized in Table 17.
Table 17: 
Preinfusion Medications for Amivantamab
Cycle/Day
Medication
Dose
Route of
Administration
Recommended
Dosing
Window Before
Amivantamab 
Infusion
Required Preinfusion Medicationsa,b,c
Cycle 1 Day 1
Glucocorticoid
Dexamethasone 20 mgd
IV
60 to 120 minutes
Cycle 1 Day 2
Glucocorticoid
Dexamethasone 10 mg or 
Methylprednisolone 40 mg
IV
45 to 60 minutes
All
Antipyretic
Paracetamol (acetaminophen)
650 to 1,000 mg (or 
equivalent)
IV 
15 to 120 minutes
Oral
30 to 150 minutes
All
Antihistamine
Diphenhydramine 25 to 50 mg
(or equivalent)
IV
15 to 120 minutes
Oral
30 to 150 minutes
Optional Preinfusion Medicationsa
Cycle 1 Day 8
and beyond
Glucocorticoide
Dexamethasone 10 mg or
methylprednisolone 40 mg
IV
45 to 60 minutes
Oral
60 to 90 minutes
Any
Histamine
H2-antagonist
Ranitidine 50 mg (or 
equivalent)
IV
15 to 30 minutes
Any
Antiemetic
Ondansetron 8-16 mg
(or equivalent)
Oral or IV
15 to 120 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 
doctor. If alternative medications are not suitable for the intent above, participants are not required to take the corresponding 
medication.
c.
If the dose of amivantamab is delayed until Cycle 1 Day 2 and Cycle 1 Day 3, then the dosing days of preinfusion 
medications should be adjusted accordingly.
d.
This dose and recommended dosing window allow a single dose of dexamethasone to serve as the pre-infusion glucocorticoid 
for both chemotherapy and amivantamab. If chemotherapy is dosed on Cycle 1 Day 1 and amivantamab is dosed on Cycle 1 
Day 2 and Cycle 1 Day 3, then the amivantamab preinfusion glucocorticoid dose should be dexamethasone 10 mg (or 
methylprednisolone 40 mg) on Cycle 1 Day 2 and Cycle 1 Day 3.
e.
Beginning with Cycle 1 Day 8, optional predose steroids may be administered prior to amivantamab if clinically indicated for 
participants who experienced an infusion-related reaction during either day of the first dose of amivantamab.
On days when multiple study drugs are dosed together, the order of medications should be as 
follows:
a.
Lazertinib (Arms A/A2 only)
b. Preinfusion medications for chemotherapy (eg, antiemetic, antihistamine, glucocorticoid) 
per local guidelines or site practice
c.
Pemetrexed per label/site practice

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d. Carboplatin (up to a maximum of 4 cycles) per label/site practice
e.
Premedications for amivantamab (per Table 17), to commence after completion 
carboplatin infusion (Arms A/A2 and C/C2). Note: Participants in Arms A/A2 and C/C2
should receive the required pre-medications, but if the medications are already
administered prior to chemotherapy, administration does not need to be repeated prior to 
initiation of the amivantamab infusion if dose was administered within the recommended 
window.
f.
Amivantamab (Arms A/A2 and C/C2)
Postinfusion Medications
Optional postinfusion medications may be prescribed and continued for up to 48 hours after any 
infusion if clinically indicated, at the discretion of the investigator (Table 18).
Table 18: 
Postinfusion Medications for Amivantamab 
Medication
Dose
Route of
Administration
Administration 
Instructions
Cycle/
Day
Optional Postinfusion 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
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
IV
As clinically indicated
Any
Ondansetron 8 mg or equivalent
Oral 
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. 
6.7.2.3.
Supportive Care
Supportive care (eg, antibiotics, analgesics, transfusions, diet) 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.
6.7.2.4.
Radiotherapy
Localized, limited radiotherapy of short duration (eg, 5 days or less) for palliative purposes of 
nontarget lesions 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 weeks between scheduled doses of amivantamab.
6.7.2.5.
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 7 months after the last dose of 
study treatment.

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6.7.3.
Prohibited or Restricted Medications and Therapies
Prohibited Medications and Therapies
The following concomitant medications and therapies are prohibited until the End of Treatment 
visit. The sponsor must be notified as soon as possible of any instances in which prohibited 
therapies were administered.

Any chemotherapy, anticancer therapy, or experimental therapy (other than study treatments) 
for the treatment of NSCLC is prohibited.

Radiotherapy to a target lesion is prohibited.

Use of live or live attenuated vaccines is prohibited until at least 90 days after the last dose of 
study treatment.

Use of phenytoin or fosphenytoin with carboplatin is prohibited.

Prescription and over the counter medications, herbal supplements or ingestion of foods with 
known potent inducer effects on CYP3A4/5 activity (For a list of such medications, refer 
US FDA 2022). Strong inducers of CYP3A4/5 are prohibited and should be discontinued for 
an appropriate period (at least 4 elimination half-lives) before starting study treatment 
regimens that include lazertinib. Appropriate medical judgment is required, if any of the 
strong CYP3A4/5 inducer medications should be utilized, if clinically indicated, for the 
treatment of AEs. Please contact the local pharmacist or Medical Monitor with any questions.
Restricted Medications and Therapies
The following concomitant medications and therapies are restricted until the End of Treatment 
visit and should be avoided, when possible, or used with caution.

Use caution with co-administration of medicines that prolong QT interval (Appendix 11: 
Medications With Potential for QT Interval Prolongation). If there are no other alternative 
medications that can be used, limit treatment duration when possible. Please contact the local 
pharmacist or Medical Monitor with any questions.

Avoid concomitant use of CYP3A4/5 substrate drugs and medications known to be strong 
inhibitors of CYP3A4/5 (For a list of such medications, refer US FDA 2022). If no other 
alternatives exist monitor participants more closely for adverse reactions. Please contact the 
local pharmacist or Medical Monitor with any questions.

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. (For a list of such medications, refer US FDA 2022).
Please contact the local pharmacist or Medical Monitor with any questions. 

Due to the potential for hypomagnesemia associated with EGFR inhibitors, concomitant 
medications that may decrease serum magnesium should be avoided if possible.

Nephrotoxic or ototoxic agents should be used cautiously with carboplatin. Nephrotoxic drugs 
should also be used cautiously with pemetrexed. Concomitant administration of 
aminoglycosides should be avoided with carboplatin. 

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
Caution should be exercised when administering pemetrexed concurrently with a nonsteroidal 
anti-inflammatory drug to a participant whose creatinine clearance is <80 mL/min (exception: 
low-dose aspirin once daily is permitted during the study). Ibuprofen should be avoided from
2 days before until 2 days after administration of pemetrexed.
6.8.
Continued Access to Study Treatment
At the end of the study, participants who are benefiting from the study treatment, as determined 
by their investigator, will be able to receive continued access via post-study independent requests 
from their investigators, as permitted by local regulations and guidelines. 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 if any of the following apply:

The participant experiences a Grade 4 rash, severe bullous, blistering, or exfoliating skin 
conditions including toxic epidermal necrolysis (TEN).

The participant withdraws consent to receive study treatment

The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the best 
interest of the participant to discontinue study treatment

The participant becomes pregnant

Noncompliance with study drug administration or procedure requirements as judged by the 
investigator

Radiographic disease progression by BICR using RECIST (Version 1.1) (Exception: 
Continuation of study treatment after disease progression may be allowed in accordance with 
local practice, after consultation with the Medical Monitor, if the investigator believes the 
participant is deriving clinical benefit. In general, this implies the absence of significant 
worsening of clinical symptoms or signs of disease progression, including clinically 
significant worsening of laboratory abnormalities, deterioration in ECOG performance status, 
or rapid progression at critical anatomical sites which may require urgent alternative medical 
intervention.)
If a participant discontinues study treatment for any reason before the end of the treatment period,
then the End of Treatment assessments should be obtained and scheduled assessments off study 
treatment should be continued. Study treatment assigned to the participant who discontinued study 
treatment may not be assigned to another participant. Additional participants will not be entered.
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

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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 of consent, 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 Study Samples
Withdrawal From the Use of Study Samples
The participant may withdraw consent for use of study samples, including optional study samples, 
for research not required by the protocol. In such a case, samples will be destroyed after they are 
no longer needed for the clinical study. Details of sample retention 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 the participant repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed 
lost to follow-up until all reasonable efforts made by the study site personnel to contact the 
participant are deemed futile. The following actions must be taken if a participant fails to return to 
the study site for a required study visit:

The study site personnel must attempt to contact the participant to reschedule the missed visit 
as soon as possible, to counsel the participant on the importance of maintaining the assigned 
visit schedule, to ascertain whether the participant wishes to or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must make every 
reasonable effort to regain contact with the participant (where possible, 3 telephone calls, 
emails, fax, and, if necessary, a certified letter to the participant’s last known mailing address, 
or local equivalent methods. These contact attempts should be documented in the participant’s 
medical records.
8.
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities summarizes the frequency and timing of measurements applicable to 
this study.

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When possible, all PRO assessments should be conducted/completed before any tests, procedures, 
or other consultations to prevent influencing participant responses.
The total blood volume to be collected from each participant depends upon the duration of 
participation and the required blood volume for local laboratory assessments, but through 17 cycles 
of treatment and the End of Treatment visit, the total amount of blood drawn from each participant 
in this study is anticipated to be approximately 390 mL in Arms A/A2, 210 mL in Arm B, and 
370 mL in Arms C/C2. Depending on country-specific regulations, volume requirements at local 
laboratories, and availability of blood collection tubes the total blood volume may vary.
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. Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Sample collection and testing should comply with local 
regulations.
Study-Specific Materials
The investigator will be provided with the following supplies:

IB for amivantamab

IB for lazertinib

Local prescribing information for carboplatin (if carboplatin is centrally sourced)

Local prescribing information for pemetrexed (if pemetrexed is centrally sourced)

IPPI and SIPPM

Laboratory manual and kits

eCRF completion guidelines

IWRS Manual

Imaging Manual

NCI CTCAE Version 5.0

RECIST guidelines, Version 1.1

Sample ICF

Wallet cards

Study treatment (lazertinib and amivantamab will be supplied centrally; depending on 
regional requirements, chemotherapy may be sourced centrally or locally)

Ancillary supplies (as needed)

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
Tablet (for PRO collection)
8.1.
Efficacy Assessments
Blinded independent central review (BICR) will use RECIST v1.1 criteria to assess participant 
response to treatment: CR, PR, stable disease, progressive disease, or unevaluable. Disease 
assessments will include 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 at 6 weeks (+1 week) after randomization (ie, 
no earlier than 42 days after randomization), then every 6 weeks (±1 week) for the first 12 months
and every 12 weeks (±1 week) afterward until disease progression is confirmed by BICR. Timing 
is relative to randomization; if an assessment is delayed, subsequent assessments should occur 
according to the original schedule. For participants who discontinue treatment prior to disease 
progression, tumor imaging should continue until disease progression is confirmed by BICR, if 
clinically feasible.
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. MRI can also be used to 
evaluate sites of disease that cannot be adequately imaged using CT. Identical methodology (CT 
scan with contrast agent or MRI) should be used for disease assessment at baseline and throughout 
the study. 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. Further details are provided in the Imaging Manual.
Brain MRI (or brain CT scan if MRI is medically prohibited) will be performed at screening, at 
6 weeks (+1 week) and 12 weeks (±1 week), and then every 12 weeks (±1 week). Postbaseline 
brain MRI will be scheduled relative to randomization and will continue until intracranial disease 
progression is confirmed by BICR. Unscheduled brain MRI may also be conducted if clinically 
indicated. For those who have confirmed extracranial progression per RECIST v1.1, brain MRI 
should be continued, if feasible, until intracranial progression is confirmed by BICR. Further 
details are provided in the Imaging Manual.
Timing for each disease assessment is relative to randomization, regardless of dose modifications, 
and will continue until disease progression. If an 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. Any other area at which new disease is 
suspected should also be imaged. 
Sites will be required to obtain digital copies of radiologic images (eg, CT, MRI) used for all 
scheduled and unscheduled disease assessments and submit to a Janssen-appointed Clinical 
Research Organization for central review by BICR.

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For participants who discontinue study treatment due to toxicity or a reason other than objective 
progressive disease, tumor assessments should be continued per schedule until radiographic 
progressive disease is confirmed by BICR. Following disease progression, these participants 
should continue to be followed up for survival every 12 weeks (±14 days). 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 a participant begins a new cancer therapy before disease progression, obtain tumor imaging 
before the new therapy and continue imaging per schedule until BICR confirms progression.
If a participant is treated beyond BICR-confirmed disease progression, disease assessments will 
continue according to the Schedule of Activities.
If the investigator is in doubt as to whether progression has occurred, particularly with respect 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 the participant’s status should then be 
reassessed. If the repeated scans confirm progression, then the date of the initial scan should be 
declared as the date of progression. To achieve “unequivocal progression” on the basis of nontarget 
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.
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.
8.1.1.
Symptomatic Progression
Symptoms, attribution, and related treatments will be recorded on the eCRF at the times specified 
in the Schedule of Activities.
8.1.2.
Patient-Reported Outcomes
Patient-reported outcomes measures will be collected at the times specified in the Schedule of 
Activities. When feasible, 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 AE 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 

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clinical trials of NSCLC (McCarrier 2016). 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 EuroQol 5-dimensional descriptive system (5-level version) (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 (Herdman 2011).
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 (Montazeri 1998).
The PROMIS-PF short-form v2.0 (8c 7-day version) will be used to characterize and better 
understand the level of physical ability and conduct of activities of daily living (Kluetz 2016). This 
version of PROMIS-PF contains 6 items to capture physical ability, including walking and 
climbing stairs, with a 7-day recall period.
The National Cancer Institute (NCI) Patient-Reported Outcomes version of the Common 
Terminology Criteria for Adverse Events (PRO-CTCAE) is a validated tool to assess the 
symptomatic toxicities self-reported by participants in clinical trials (NIH 2021). 
8.2.
Safety Assessments
Details regarding the IDMC are provided in Committees Structure in Appendix 2: Regulatory, 
Ethical, and Study Oversight Considerations. The frequency of IDMC meetings will be described 
in the IDMC charter. AEs will be reported and followed by the investigator as specified in 
Section 8.3 and Appendix 3: Adverse Events, Serious Adverse Events, Product Quality 
Complaints, and Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event 
section of the 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.
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. 

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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 signs and symptoms of VTE events, and a focused physical 
examination of extremities and evaluation of respiratory status (including pulse oximetry) should 
be performed, particularly during the first 4 months of assigned therapy. Any changes from 
baseline should prompt consideration for further diagnostic evaluation, including unscheduled CT 
exam or lower-extremity Doppler evaluation.
On Day 1 of each cycle, and at the end of treatment visit, 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 (Table 1). 

Temperature

Heart rate

Respiratory rate

Oxygen saturation

Blood pressure
Blood pressure and pulse/heart rate measurements should be assessed in a seated or supine 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, and procedures are less 
than 1 hour apart, the procedures should be performed in the following order: ECG(s), vital signs, 
blood draw.
Collection of ECGs will be obtained as indicated in the Schedule of Activities (Table 1). For 
triplicate ECGs at Screening and other times if clinically indicated, 3 individual ECG tracings 
should be obtained as closely as possible in succession, approximately 2 minutes apart. 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.

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8.2.4.
Left Ventricular Ejection Fraction
During the Screening Phase each participant will undergo a baseline LVEF assessment performed 
locally by cardiac echocardiogram or MUGA scan to demonstrate eligibility (ie, an LVEF within 
the normal range). 
8.2.5.
Pregnancy Testing
For participants of childbearing potential, a negative serum pregnancy test is required at screening
and within 72 hours before the first dose of study treatment. A serum or urine pregnancy test is 
required within 72 hours before the first dose of each subsequent treatment cycle, at the End of 
Treatment Visit, and monthly for 6 months after the last dose for participants in Arms A/A2 and 
Arms C/C2. Additional serum or urine pregnancy tests may be performed as determined necessary 
by the investigator, or as required by local regulation, to establish the absence of pregnancy at any 
time during participation in the study.
8.2.6.
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 AE. 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 in the eCRF.
8.2.7.
ECOG Performance Status
ECOG performance status (refer to Appendix 7: Eastern Cooperative Oncology Group (ECOG) 
Performance Status) will be assessed at timepoints described in the Schedule of Activities (Table
1).
8.2.8.
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 9: 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 AEs, SAEs, 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 

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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.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally designated representative). Further details on AEs, SAEs, and PQC can be 
found in Appendix 3: Adverse Events, Serious Adverse Events, Product Quality Complaints, and 
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting.
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from the 
time a signed and dated ICF is obtained until through 30 days after the last dose of study treatment 
or before starting subsequent anticancer treatment, whichever occurs first (or >30 days for an SAE, 
if considered related to study treatment).
Serious Adverse Events
All SAEs 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.
SAEs, including those spontaneously reported to the investigator within 30 days after the last dose 
of study treatment, must be reported. The sponsor will evaluate any safety information that is 
spontaneously reported by an investigator beyond the time frame specified in the protocol.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event 
Form and Safety Report Form of the 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 an SAE should be transmitted electronically or by facsimile (fax). Telephone reporting should 
be the exception and the reporter should be asked to complete the appropriate form(s) first.
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading 
verbal questioning of the participant is the preferred method to inquire about AE occurrence.
Solicited Adverse Events
Solicited AEs are predefined local and systemic events for which the participant is specifically 
questioned.
Unsolicited Adverse Events
Unsolicited AEs are all AEs for which the participant is not specifically questioned.

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8.3.3.
Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and evaluations as medically indicated to elucidate the nature and causality of the AE, SAE, or 
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, Serious Adverse Events, Product Quality Complaints, and Other 
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting.
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute where 
required) all suspected unexpected serious adverse reactions (SUSARs). The investigator (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.
An anticipated event is an AE 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 4: Anticipated Events.
8.3.5.
Pregnancy
All initial reports of pregnancy in participants or their partners (through sperm of participant/from 
sexual intercourse) must be reported to the sponsor by the study-site personnel within 24 hours of 
their knowledge of the event using the appropriate pregnancy notification form. Abnormal 
pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, 
ectopic pregnancy) are considered SAEs and must be reported using 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 an SAE will be reported as SAEs, regardless of whether they 
are protocol-specific assessments.
Expected progression of disease, which is part of the natural course of the disease under study,
should not be considered or reported as an AE (or SAE). However, if determined by the 
investigator to be more likely related to the study treatment than being expected from the 
underlying disease, the treatment-invoked progression (ie, the -treatment invoked signs/symptoms 

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of such progression) should be reported per the usual reporting requirements (refer to Adverse 
Event Definitions and Classifications in Appendix 3: Adverse Events, Serious Adverse Events, 
Product Quality Complaints, and Other Safety Reporting: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting).
Death or hospitalization that is attributed by the Investigator to progression of disease should not 
be considered nor reported as an AE (or SAE). Of note, worsening of disease (and associated 
hospitalization or death) determined by the investigator to be caused by the study treatment should 
be reported per the usual reporting requirements (refer to Adverse Event Definitions and
Classifications in Appendix 3).
However, if determined by the investigator to be more likely related to the study treatment than 
being expected from the underlying disease, the treatment-invoked death due to progression should 
be reported per the usual reporting requirements (refer to Adverse Event Definitions and 
Classifications in Appendix 3: Adverse Events, Serious Adverse Events, Product Quality 
Complaints, and Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting).
Progression of disease and death due to disease progression should be documented on the 
appropriate eCRF forms (eg, the Disease Progression form and the Death form). Signs or 
symptoms of disease progression that are of clinical significance, such as spinal cord compression, 
vena cava superior syndrome, major vessel rupture, efflux obstruction or organ failure should be 
documented on the appropriate eCRF forms (eg, the Symptomatic Progression form).
8.3.7.
Adverse Events of Special Interest
AEs of special interest are pneumonitis/ILD, rash, IRR and VTE events. Additional information 
will be collected for these events. Refer to the monitoring and management guidelines for these 
events in Section 6.5.3. Confirmed cases of pneumonitis/ILD (regardless of grade) should be 
reported as SAEs (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.
8.4.
Pharmacokinetics 
Serum samples will be used to evaluate the PK of amivantamab, 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.
8.4.1.
Evaluations
Serum samples will be collected from participants in Arms A/A2 and Arms C/C2 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 LACP for the evaluation of PK of lazertinib 
at the time points outlined in Table 2 (For participants receiving the LACP dosing schedule this 
would start on Cycle 1 Day 1) and for participants receiving the ACP-L dosing schedule ( those in 

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Arms A/A2) evaluation of PK of lazertinib will be collected at the time points outlined in Table 3
(For those receiving the ACP-L dosing schedule this would start when lazertinib is initiated on 
Cycle 5 Day 1 or sooner if carboplatin discontinued earlier than Cycle 4). 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 collected for PK may additionally 
be used to identify circulating metabolites and/or evaluate safety or efficacy aspects that address 
concerns arising during or after the study period.
8.4.2.
Analytical Procedures 
Serum samples will be analyzed to determine concentrations of amivantamab using a validated, 
specific, and sensitive electrochemiluminescence-based immunoassay (ECLIA) 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 
samples may be stored for future analysis of other co-administered treatments, protein binding, 
and the metabolite profile.
8.4.3.
Pharmacokinetic Parameters and Evaluations
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. The concentration-time data from this study 
may be analyzed using a population PK approach. PK parameters derived using population PK 
analysis may be used to assess the relationship between PK or immunogenicity and selected safety 
and efficacy endpoints.
8.5.
Biomarkers
Blood Samples
Mandatory screening blood samples collected from all participants will undergo ctDNA 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.

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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.
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.
8.6.
Immunogenicity Assessments
Serum samples will be collected for immunogenicity assessments of amivantamab (anti-drug 
antibodies to amivantamab) from participants in Arms A/A2 and Arms C/C2 at the time points 
outlined in Table 2. Additionally, serum samples should also be collected at the final visit from 
participants who discontinued study treatment or were withdrawn from the study. The detection 
and characterization of antibodies to amivantamab will be performed using a validated 
immunoassay by or under the supervision of the 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. Immunogenicity assessment may also be 
performed on any PK sample. 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.
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 immunoassay assay method by or under the supervision of the sponsor. Antibodies may 

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be further characterized and/or evaluated for their ability to neutralize the activity of the study 
treatment(s).
8.7.
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 the main study, unless otherwise specified. A general description of analysis of data from
the extension cohort will be in Appendix 13: Open-label Randomized Extension Cohort. Specific 
details will be provided in the Statistical Analysis Plan for both the main study and the extension 
cohort.
9.1.
Statistical Hypotheses
This study has dual primary hypotheses to be tested in participants with osimertinib-relapsed 
EGFR-mutated locally advanced or metastatic NSCLC:

LACP/ACP-L will demonstrate superior progression-free survival (PFS) compared with CP

ACP will demonstrate superior progression-free survival (PFS) compared with CP
The secondary hypotheses are that LACP/ACP-L and ACP, compared with CP independently in 
the aforementioned population, will demonstrate superior ORR and overall survival.
There is no separate hypothesis for the extension cohort. 
9.1.1.
Multiplicity
Multiplicity due to multiple hypotheses of interest and multiple analyses will be addressed using 
a graphical approach applied in a group sequential design setting as described by Maurer (2013). 
A primary analysis for PFS and key secondary endpoints (ie, ORR and OS) is planned in the study. 
In addition, OS will be analyzed at 2 additional timepoints, at 75% information fraction of OS and
final OS analysis. Additional sensitivity analyses of PFS by dosing schedule will be performed.
The proposed graphical testing strategy controlling an overall family-wise Type I error rate at the 
two-sided significance level of 0.05 is presented by Figure 4. The 6 elementary hypotheses are 
grouped into the 2 families of F1 = {H1: PFS, H2: ORR, H3: OS} and F2 = {H4: PFS, H5: ORR, 
H6: OS} for the comparison of LACP/ACP-L vs CP and ACP vs CP, respectively. A sequential 
(hierarchical) testing approach is utilized within each family starting with PFS, followed by ORR, 
and OS.
Figure 4 schematically shows the distribution of initial amount of alpha (local significance level) 
allocated to the 6 hypotheses; the local significance levels are represented as numerical values 
within the circular nodes corresponding to each hypothesis of interest. Particularly H1 and H4 have 

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the initial assigned local alpha of

  and 

 , respectively. The local significance levels are 
re-allocated after each hypothesis is rejected per the algorithm described (Maurer 2013) according 
to the directed edges with the associated weights, and the weights are represented as numerical 
values within the squares. For example, after the primary endpoint (H1:PFS) rejection, the local 
significance level associated with H1:PFS is split between the corresponding 2 hypotheses, the 
half of

  is passed to test the next hypothesis of interest in the same family (H2:ORR) and the 
half of 

  is allocated to test the primary endpoint in the other family (H4:PFS).
The O’Brien Fleming alpha spending function as implemented by the Lan-DeMets method will be 
used to determine the statistical boundary for each of the interim analyses of OS.

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Figure 4: Graphical Testing Strategy Controlling an Overall Family-wise Type I Error 
Rate
ACP-L=amivantamab, carboplatin, pemetrexed, and lazertinib (lazertinib started after carboplatin is completed); ACP= 
amivantamab, carboplatin, and pemetrexed combination therapy; CP=carboplatin and pemetrexed; LACP=lazertinib, 
amivantamab, carboplatin, and pemetrexed (all drugs started C1D1); PFS=progression-free survival; OS=overall survival; 
ORR=objective response rate.
9.2.
Sample Size Determination
A total of approximately 600 eligible participants will be randomized in a 2:2:1 ratio (Arm A: Arm 
B: Arm C) in the study. The median PFS for CP is estimated to be 5.5 months (Mok 2017;
Soria 2015). Assuming a median PFS of 8.5 months for LACP/ACP-L and ACP, respectively, 
with an approximate 16-month accrual period and an additional 3-month follow-up, a total of 350

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PFS events in all 3 arms combined will provide approximately 93% power for LACP/ACP-L over 
CP, and 83% power for ACP over CP to detect a 35% reduction in the risk of either progression 
or death, (HR of 0.65 for LACP/ACP-L vs CP and ACP vs CP, respectively) with a log-rank test, 
assuming an overall family-wise Type I error rate at two-sided significance level of 5%. 
9.3.
Populations for Analysis Sets
For purposes of analysis, the following populations are defined for the main study:
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 measurementa
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.
Participants enrolled in the extension cohort (Arms A2 and C2) are not considered part of the Full 
Analysis Set or Safety population in the main study.
9.4.
Statistical Analyses
The Statistical Analysis Plan will be finalized prior to database lock for the primary analysis and
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 most important 
endpoints including 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 
frequency counts and percentages. For time-to-event variables, the Kaplan-Meier method will be 
used for descriptive summaries.
Hypothesis testing of the primary efficacy endpoints and key secondary efficacy endpoints will be 
performed for LACP/ACP-L (Arm A) versus CP (Arm B) and ACP (Arm C) versus CP (Arm B), 
respectively. Comparison of LACP/ACP-L (Arm A) with ACP (Arm C) will be performed to 
describe the contribution of lazertinib based on intracranial PFS, ORR, DoR, and PFS, using 
summary statistics and nominal p-values; there will be no formal 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. 

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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.
The primary estimand for PFS, the main clinical quantity of interest to be estimated, is defined 
by the following components:

Study treatment:
Experimental: LACP/ACP-L and ACP
Control: CP

Population: participants with osimertinib-relapsed EGFR-mutated locally advanced or 
metastatic NSCLC

Variable: time to event, PFS

Population-level summary: hazard ratio for LACP/ACP-L vs CP and ACP vs CP

Intercurrent events and their corresponding strategies
Intercurrent Events
Name of Strategy for Addressing Intercurrent Events and Its Description
Study treatment discontinuation 
due to any reason
Treatment Policy strategy: use time to disease progression or death, regardless 
of whether or not study treatment discontinuation had occurred
Study treatment switching to other 
anticancer therapy
Treatment Policy strategy: use time to disease progression or death, regardless 
of whether or not started subsequent anticancer therapies
Death
Composite Variable strategy: death being a component of the variable
Primary analysis of PFS will be conducted when 350 PFS events in all 3 arms combined have been 
observed. PFS will be analyzed in the Full Analysis Set using the log-rank test stratified by 
osimertinib line of therapy (first-line vs second-line), history of brain metastases (yes vs no), and 
Asian race (yes vs no). The HR for PFS will be calculated, along with its 95% CI, from a stratified 
Cox model using the same stratification factors as for the log-rank test. The Kaplan--Meier method 
will be used to estimate the distribution of PFS by treatment group. Additional sensitivity analyses 
of PFS by dosing schedule will be performed, details will be described in the Statistical Analysis 
Plan.
9.4.3.
Secondary Endpoints 
Secondary endpoints will be analyzed using the Full Analysis Set. Additional analyses by dosing 
schedule on the secondary endpoints listed below will be performed, details will be described in 
the Statistical Analysis Plan.
Objective Response Rate (ORR)
The key secondary endpoint of overall response is defined as those participants who achieve either 
a PR or CR as their best response, as defined by BICR using RECIST v1.1. Data obtained up until 
progression or last evaluable disease assessment in the absence of progression will be included in 
the assessment of ORR. Participants who do not have a tumor response assessment for any reason 
will be considered non-responders and will be included in the denominator when calculating the 
response rate.

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The primary estimand for ORR, the main clinical quantity of interest to be estimated, is defined 
by the following components:

Study treatment:
Experimental: LACP/ACP-L and ACP
Control: CP

Population: participants with osimertinib-relapsed EGFR-mutated locally advanced or 
metastatic NSCLC

Variable: overall response

Population-level summary: odds ratio for LACP/ACP-L vs CP and ACP vs CP

Intercurrent events and their corresponding strategies
Intercurrent Events
Name of Strategy for Addressing Intercurrent Events and Its Description
Study treatment switching to 
other anticancer therapy
Hypothetical strategy: use best overall response until subsequent anti-cancer 
therapy
ORR will be analyzed using a logistic regression stratified by osimertinib line of therapy (first-line 
vs second-line), history of brain metastases (yes vs no), and Asian race (yes vs no). The results of 
the analysis will be presented in terms of an odds ratio together with its associated 95% CI and 
corresponding p-value.
Overall Survival (OS)
The key 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.
The primary estimand for OS, the main clinical quantity of interest to be estimated, is defined by 
the following components:

Study treatment:
Experimental: LACP/ACP-L and ACP
Control: CP

Population: participants with osimertinib-relapsed EGFR-mutated locally advanced or 
metastatic NSCLC

Variable: OS

Population-level summary: hazard ratio for LACP/ACP-L vs CP and ACP vs CP

Intercurrent events and their corresponding strategies
Intercurrent Events
Name of Strategy for Addressing Intercurrent Events and Its Description
Study treatment switching to 
other anticancer therapy
Treatment Policy strategy: use time to death, regardless of whether or not started 
subsequent anticancer therapies

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OS will be analyzed using the same methodology and model as for the analysis of PFS.
Two interim analyses of OS will be performed (see Section 9.5). The final analysis of OS will be 
conducted at the end of study. The O’Brien Fleming alpha spending function as implemented by 
the Lan-DeMets method will be used to determine the statistical boundary for each of the interim 
analyses of OS. 
Duration of Response (DoR)
The DoR is defined as the time from the date of first documented response (PR or CR) until the 
date of documented progression or death, whichever comes first, for participants who have PR or 
CR. 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 duration 
of response will be until the PFS censoring time. Participants who started a subsequent anticancer 
therapy in the absence of progression will be censored at the last disease assessment before the 
start of subsequent therapy. A Kaplan–Meier plot for duration of response and median duration of 
response with 95% CI (calculated from the Kaplan–Meier estimate) will be presented by treatment 
group.
Time to Subsequent Therapy (TTST)
The TTST is defined as the time from the date of randomization to the start date of the subsequent 
anticancer therapy following study treatment discontinuation or death, whichever comes first. 
Participants alive and not starting subsequent therapy will be censored on the date on which the 
participant was last known to be alive. The TTST will be analyzed using the similar method as the 
primary analysis of PFS.
Progression-free Survival After the First Subsequent Therapy (PFS2)
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 (ie, last disease assessment). PFS2 will be analyzed using 
the similar method as the primary analysis of PFS.
Time to Symptomatic Progression (TTSP)
The 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. 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 the similar method as the 
primary 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. 
Specifically, intracranial disease progression is defined as having progression of brain metastasis 
or occurrence of new brain lesion. Participants who have not progressed intracranially or died will 
be censored at their last evaluable intracranial disease assessment date. Intracranial PFS will be 
analyzed using the similar method as the primary analysis of PFS in Full Analysis Set.
Intracranial Objective Response Rate (ORR)
Intracranial ORR is defined as the proportion of participants who achieve either an intracranial 
complete response (CR) or partial response (PR), as defined by BICR using RECIST v1.1. Data 
obtained up until intracranial progression or last intracranial evaluable disease assessment in the 
absence of progression will be included in the assessment of intracranial ORR. However, any 
intracranial CR or PR, which occurred after a subsequent anticancer therapy was received, will not 
be included in the numerator for the ORR calculation. Participants who do not have a tumor 
response assessment for any reason will be considered non-responders and will be included in the 
denominator when calculating the response rate. Intracranial ORR will be analyzed using the 
similar method as the primary analysis of ORR for subjects with baseline intracranial disease by 
BICR.
Intracranial Duration of Response (DoR)
Intracranial DoR is defined as the time from the date of first documented intracranial response (PR 
or CR) until the date of documented intracranial progression or death, whichever comes first, for 
participants who have intracranial CR or PR. The end of response should coincide with the date of 
intracranial progression or death from any cause used for the intracranial PFS endpoint. If a 
participant does not progress following an intracranial response, then his/her duration of response 
will be until the intracranial PFS censoring time. Participants who started a subsequent anticancer 
therapy in the absence of intracranial progression will be censored at the last intracranial disease 
assessment before the start of subsequent therapy. Intracranial DoR will be analyzed using the 
similar method as the primary analysis of DoR.
Time to Intracranial Disease Progression
Time to intracranial disease progression is defined as the time from randomization until the date 
of objective intracranial disease progression, based on BICR using RECIST v1.1. Specifically, 
intracranial disease progression is defined as having progression of brain metastasis or occurrence 
of new brain lesion. Participants who have not progressed intracranially will be censored at their 
last evaluable intracranial disease assessment date. Time to intracranial disease progression will 
be analyzed using the similar method as the primary analysis of PFS.
9.4.4.
Exploratory Endpoints 
Analyses of exploratory endpoints will be described in the Statistical Analysis Plan.

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9.4.5.
Safety Analyses
All safety analyses will use the Safety Population. Additional safety analyses by dosing schedule 
will be performed, details will be described in the Statistical Analysis Plan.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the initial 
administration of study 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 
treatment-emergent AEs will be included in the analysis. For each AE, the percentage of 
participants who experience at least 1 occurrence of the given event will be summarized by 
treatment group.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those 
participants who die, who discontinue treatment due to an AE, or who experience a ≥Grade 3 AE 
or an SAE.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline and 
for observed values and changes from baseline at each scheduled time point. Frequency tabulations 
of the laboratory abnormalities will be made. A listing of participants with any laboratory results 
outside the reference ranges will be provided. A listing of participants with any markedly abnormal 
laboratory results will also be provided. 
Parameters with predefined NCI CTCAE toxicity grades will be summarized. Change from 
baseline to the worst AE 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, oxygen saturation, and 
blood pressure (systolic and diastolic) will be summarized over time, using descriptive statistics 

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and/or graphically. The percentage of participants with values beyond clinically important limits 
will be summarized.
9.4.6.
Other Analyses
Pharmacokinetic Analyses
The PK analyses will use the PK Population (Section 9.3). For participants randomized to Arms
A/A2 and Arms C/C2, all plasma/serum concentrations (when applicable) 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.
Individual PK parameters will be estimated by inspection of the concentration-time profiles. Based 
on the individual plasma or serum concentration-time data, using the actual sampling times, the 
following PK parameters of amivantamab will be determined.

Cmax: maximum plasma/end of infusion (EOI) serum concentration

Cmax,ss: maximum plasma/EOI serum concentration at steady state

tmax: time to reach the maximum plasma concentration 

tmax,ss: time to reach the maximum plasma concentration at steady state

Ctrough: plasma/serum concentration immediately prior the next study treatment administration

Ctrough,ss: plasma/serum concentration immediately prior the next study treatment 
administration at steady state
The PK data collected from this study may also be combined with similar data from other studies 
to perform population PK. 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.
Biomarkers Analyses
Biomarkers analyses will use the Biomarkers Population (Section 9.3). Each baseline tumor status 
will be evaluated by ctDNA NGS analysis, for exploratory purposes, to characterize potential 
mechanisms of resistance to LACP/ACP-L, as permitted by local regulations.
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.

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Immunogenicity Analyses
The incidence of anti-amivantamab antibodies will be summarized for all participants in the PK 
Population (Section 9.3). 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. Exposure-response 
analysis with relevant PROs may also be explored as data permit. Details will be provided in an 
analysis plan and detailed results may be reported separately from the CSR.
Patient-Reported Outcomes Analyses
NSCLC-SAQ and PROMIS-PF will be summarized descriptively by treatment group and study 
visit. It is hypothesized that mean change from baseline will demonstrate proximal symptom and 
physical functioning stability compared to the effect of the active comparator. PGIS is an numeric 
rating anchor in the NSCLC-SAQ for clinical meaningful change. Time to worsening in 
EORTC‑QLQ‑C30 total score and individual scales will be analyzed using a Kaplan–Meier 
method and stratified Cox proportional‑hazards model. Additional analysis may be done, if 
appropriate. Analysis details will be provided in the Statistical Analysis Plan.
9.5.
Interim Analysis
There is no interim analysis planned for PFS.
For both LACP/ACP-L vs CP and ACP vs CP, two interim analyses are planned for OS. The first 
interim analysis for OS will be performed at the time of the analysis for PFS, when approximately 
170 deaths (all 3 Arms combined, approximately 43% of the total planned OS events) are 
anticipated. The second interim analysis for OS will be performed approximately 32 months after 
the first participant is randomized, when approximately 300 deaths (all 3 arms combined, 
approximately 75% of the total planned OS events) are anticipated. Final analysis for OS will be 
conducted at approximately 48 months after the first participant is randomized, when 
approximately 400 deaths (all 3 arms combined) are anticipated.
Following the testing algorithm for multiple hypotheses using the graphical procedure as described 
in Section 9.1.1, OS will be tested in the FAS population at the two-sided alpha re-allocated from 
previous rejected hypotheses to the respective comparisons of LACP/ACP-L vs CP and ACP vs 
CP. The significance level at the interim analyses for OS will be determined based on the O’Brien 
Fleming alpha spending approach as implemented by the Lan-DeMets method.
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
ACP-L
Amivantamab, carboplatin, pemetrexed, and lazertinib (lazertinib started after carboplatin is 
completed)
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
CI
confidence interval
CLIA
Clinical Laboratory Improvement Amendments
Cmax
maximum plasma/serum concentration
Cmax,ss
maximum plasma/serum concentration at steady state
CNS
central nervous system
CR
complete response
CT
computerized tomography
ctDNA
circulating tumor deoxyribonucleic acid
CYP
cytochrome P450
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
eDC
electronic data capture
ECLIA
electrochemiluminescence-based immunoassay
EGFR
epidermal growth factor receptor
EQ-5D-5L
EuroQol five-dimensional descriptive system (5-level version)
FDA
Food and Drug Administration
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
IRR
infusion-related reaction
IV
intravenous
IWRS
interactive web response system

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LACP
lazertinib, amivantamab, carboplatin, and pemetrexed (all drugs started C1D1)
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
NCCN
National Comprehensive Cancer Network
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
RP2D
recommended Phase 2 dose
SAC
Safety Assessment Committee
SAP
statistical analysis plan 
SAE
serious adverse event
SET
Safety Evaluation Team
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 ICH guidelines on GCP, and applicable regulatory and country-or territories 
specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human participants. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study participants are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
Protocol Clarification Communications
If text within a final approved protocol requires clarification (eg, current wording is unclear or 
ambiguous) that does not change any aspect of the current study conduct, a PCC may be prepared. 
The PCC Document will be communicated to the Investigational Site, Site Monitors, LTMs, 
CTMs, and/or CROs who will ensure that the PCC explanations are followed by the investigators.
The PCC Document may be shared by the sites with IECs/IRBs per local regulations.
The PCC Documents must NOT be used in place of protocol amendments, but the content of the 
PCC Document must be included in any future protocol amendments.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by 
the sponsor. All protocol amendments must be issued by the sponsor and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or 
when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the participants, in which case the amendment must 
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the 
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where 
required) only needs to be notified.
In situations where a departure from the protocol is unavoidable during the study, the investigator 
or other physician in attendance will contact the appropriate sponsor representative listed in the 
Contact Information page(s), which will be provided as a separate document. Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
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.

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

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Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB 
with current and complete copies of the following documents (as required by local regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the participants)

IB (or equivalent information) and amendments/addenda

Sponsor-approved participant recruiting materials

Information on compensation for study-related injuries or payment to participants for 
participation in the study, if applicable

Investigator’s curriculum vitae or equivalent information (unless not required, as documented 
by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for participants

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
participants, data or study conduct, unless required locally), the ICF, applicable recruiting 
materials, and participant compensation programs, and the sponsor has received a copy of this 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to participants

If applicable, new or revised participant recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to participants for 
participation in the study, if applicable

New edition(s) of the IB and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of AEs that are serious, unlisted/unexpected, and associated with the study treatment

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

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
Report of deaths of participants under the investigator’s care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about 
the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
Country/Territory Selection
This study will only be conducted in those countries/territories where the intent is to launch or 
otherwise help ensure access to the developed product if the need for the product persists, unless 
explicitly addressed as a specific ethical consideration in Section 4.3.1, Study-Specific Ethical 
Design Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.3.1.
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 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 designated representative, (unless prohibited by local regulations) 
must give written consent according to local requirements after the nature of the study has been 
fully explained. The ICF(s) must be signed before performance of any study-related activity. The 
ICF(s) that is/are used must be approved by both the sponsor and by the reviewing IEC/IRB and 
be in a language that the participant can read and understand. The informed consent should be in 
accordance with principles that originated in the Declaration of Helsinki, current ICH and GCP 
guidelines, applicable regulatory requirements, and sponsor policy.

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Informed consent may be obtained remotely by telephone or video conferencing where local 
policies and regulations permit. 
Before enrollment in the study, the investigator or an authorized member of the study site personnel 
must explain to potential participants or their legally designated 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 
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 designated
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 designated 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 
designated 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 designated 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 designated representative is obtained.
When prior consent of the participant is not possible and the participant’s legally designated
representative is not available, enrollment procedures should be described in the protocol with 
documented approval/favorable opinion by the IEC/IRB to protect the rights, safety, and 
well- being of the participant and to ensure compliance with applicable regulatory requirements. 
The participant or legally designated representative must be informed about the study as soon as 
possible and give consent to continue.
10.2.4.
Recruitment Strategy
Enrollment is now complete; the last participant was randomized in the Extension cohort on 05
September 2023.
Refer to Recruitment and Informed Consent Procedure Template for details.

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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 designated representative, 
as permitted by local regulations) 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. The informed consent also 
provides 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.
Storage, Use, Transfer, and Retention of Data and Samples
Study samples will be coded or anonymized at all times in accordance with the informed consent 
and will not be labeled with personal identifiers.

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Investigator and study site will only store, use, transfer and retain data and study samples, including 
optional study samples, in accordance with the informed consent and applicable law, and in 
accordance with any separate written agreement with sponsor. Other than what is specified in a 
separate written agreement with sponsor, study site and investigator shall not conduct or facilitate 
any research by a third party not required by the protocol (i) on participants if such research 
interferes with the conduct of the study or (ii) on samples collected from study participants during 
the study, including optional samples, if the research relates to amivantamab or lazertinib (iii) on 
data collected from study participants during the study if the research relates to amivantamab or 
lazertinib.
Sponsor may store, use, transfer or retain the data and study samples, including optional study 
samples, for uses not specified by the protocol, including compatible research, in compliance with 
the informed consent and applicable law.
10.2.7.
Committees Structure
Independent Data Monitoring Committee
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 first IDMC meeting will occur after the first 50 participants have been randomized and treated 
for at least 2 cycles. Thereafter, the committee will meet periodically to review interim data. After 
the review, the IDMC will make recommendations regarding the continuation of the study.
10.2.8.
Use of Information and Publication 
All information, including but not limited to information regarding amivantamab or lazertinib, 
supplied by the sponsor to study site or investigator and not previously published, and any data 
analysis generated as a result of this study, are considered confidential and remain the sole property 
of the sponsor. Study site and investigator shall not use this information except in the performance 
of this study and shall not disclose this information to anyone except to persons involved in the 
study that need such information to assist in conducting the study, and then only on like terms of 
confidentiality and non-use.
Study site and investigator shall not publish study results except as required by law or as specified 
in a separate, written agreement between the sponsor and the study site or the investigator.
The Sponsor will register the study and publish the study results in compliance with applicable 
law and may register the study or publish study results when not required. 
Authorship of any peer-reviewed publications will be determined by mutual agreement in line with 
International Committee of Medical Journal Editors authorship guidelines. 

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In accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In this case, 
a coordinating investigator will be designated by mutual agreement.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the interim results of clinical studies as required by law. 
For studies conducted in the EU under Regulation EU 536/2014 appropriate provisions for interim 
analyses should always be described in the protocol. Use one of the options below as appropriate. 
Other options might be considered in specific situations.
The summary of the results from the interim analysis 2 [second interim analysis for OS] as
described in Section 9.5, may be submitted to the EU database within one year of the intermediate 
data analysis date.
The disclosure of the study results will be performed after the end of study.
10.2.9.
Data Quality Assurance
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study site personnel before the study, and periodic monitoring visits by the sponsor. 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 may review the 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 the 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.
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.

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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 electronic data capture (eDC) tool. If corrections to 
a 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 AEs and follow-up of AEs; 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. Given that patient-reported 
outcomes (PROs) are reports of a patient’s health condition that come directly from the patient, 
without interpretation by a clinician or anyone else, the responses to PRO measures entered by 
trial participants into source records cannot be overridden by site staff or investigators.
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 another 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.
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 

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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 may 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. 
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 

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regulatory submission. The investigator should immediately notify the sponsor if the participant
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. For trials performed under Regulation [EU] No. 536/2014, the sponsor 
and the investigator shall archive the content of the clinical trial master file for at least 25 years 
after the end of the clinical trial.
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/Site Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been collected 
and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.

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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, Serious Adverse Events, Product Quality 
Complaints, and Other Safety Reporting: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a 
pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have 
a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that medicinal 
(investigational or non-investigational) product. (Definition per International Council on 
Harmonisation [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to All Adverse Events
under Section 8.3.1, for time of last AE recording).
Serious Adverse Event
A SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for Human 
Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or hospitalization but may jeopardize the participant or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
should usually be considered serious. This also includes the situation when treatment-invoked 
signs and symptoms of disease progression are determined by the investigator to be more likely 
related to the study treatment than being expected from the underlying disease.

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Note: Events that do not qualify as AEs cannot be reported as SAEs, even if seriousness conditions 
are met. This in particular is the case for events due to disease progression.
Expected signs or symptoms of disease progression should not be considered an AE (or SAE). 
However, if determined by the investigator to be more likely related to the study treatment than 
the underlying disease, the clinical signs or symptoms of progression and the possibility that the 
study treatment is enhancing disease progression, should be reported per the usual reporting 
requirements.
If a serious and unexpected AE 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 Suspected Unexpected Serious Adverse Reaction even if it is a component of the study 
endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product 
reference safety information. For amivantamab or lazertinib, the expectedness of an AE will be 
determined by whether or not it is listed in the IB. For carboplatin or pemetrexed, the expectedness 
of an AE will be determined by whether or not it is listed in the local prescribing information.
10.3.2.
Attribution Definitions
Assessment of Causality
The causal relationship to study treatment is determined by the Investigator and documented in the 
Medical Records.
The assessment of causality must consider the following factors:

Temporal relationship

Clinical characteristics of event

Pharmacological plausibility

Confounding risk factors:
Concomitant medication
Underlying/concurrent disease
Family/social history

Challenge:
De-challenge: Did the reaction improve when the investigational product was withdrawn, in 
the absence of any other treatment?
Re-challenge: What happens if participant is re-challenged with investigational product?

Other considerations: Participant characteristics and past medical history, and quality of 
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The following selection must be used to assess all AEs.
Related
There is a reasonable causal relationship between study treatment administration and the AE.
Related events include those that are probably and possibly related events.
Not Related
There is not a reasonable causal relationship between study treatment administration and the AE.
Not related events include those that are doubtfully related events.
10.3.3.
Severity Criteria 
Adverse event severity is a clinical determination of the intensity of an AE. The severity 
assessment for an AE or serious AE should be completed using the NCI-CTCAE, Version 5.0. 
Any AE or SAE not listed in the NCI-CTCAE, Version 5.0 will be graded according to the 
investigator clinical judgment by using the standard grades as follows:

Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated

Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age- appropriate instrumental activities of daily livinga

Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
livingb

Grade 4: Life-threatening consequences; urgent intervention indicated

Grade 5: Death related to AE
a
Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.
b
Self-care ADL refers to bathing; dressing and undressing; feeding self; using the toilet; taking medications; and 
not bedridden.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the participant (eg, laboratory abnormalities).
10.3.4.
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

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
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 an SAE should be recorded on the SAE page of the 
eCRF.
10.3.5.
Procedures
All Adverse Events
All AEs, 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 
AE to study therapy. All measures required for AE management must be recorded in the source 
document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be 
provided with a “wallet (study) card” and instructed to carry this card with them for the duration 
of the study indicating the following: 

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
Serious Adverse Events
All SAEs that have not resolved by the end of SAE reporting period, or that have not resolved 
upon the participant’s discontinuation from the study, must be followed until any of the following 
occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study treatment or to factors unrelated to 
study conduct

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
It becomes unlikely that any additional information can be obtained (participant or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts)
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during 
participation in the study must be reported as an SAE, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending 
placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the 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 SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.

For convenience the investigator may choose to hospitalize the participant for the duration of 
the treatment period.
10.3.6.
Product Quality Complaint Handling
Definition
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, reliability, or performance of a distributed product, including its labeling, drug delivery 
system, or package integrity. A PQC may have an impact on the safety and efficacy of the product.
In addition, it includes any technical complaints, defined as any complaint that indicates a potential 
quality issue during manufacturing, packaging, release testing, stability monitoring, dose 
preparation, storage or distribution of the product or the drug delivery system.
Procedures
All initial PQCs must be reported to the sponsor by the study site personnel within 24 hours after 
being made aware of the event.
A sample of the suspected product should be maintained under the correct storage conditions until 
a shipment request is received from the sponsor.
10.3.7.
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues, PQC, or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.

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10.4.
Appendix 4: Anticipated Events
An anticipated event is an 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 19 will be considered anticipated events. 
Table 19:
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
Spinal cord compression
Reporting of Anticipated Events
All AEs will be recorded in the 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.
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.

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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 analysis 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.

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10.5.
Appendix 5: Contraceptive Guidance
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, Serious 
Adverse Events, Product Quality Complaints, and Other Safety Reporting: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting.
Definitions
Participants of Childbearing Potential (POCBP)
A participant is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Participants Not of Childbearing Potential

Premenarchal: state in which menarche has not yet occurred.

Postmenopausal: 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 participants 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 a highly effective method of contraception, 
as described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by participants should be consistent with local regulations 
regarding the acceptable methods of contraception for those participating in clinical studies.
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
1.
HIGHLY EFFECTIVE METHODS (Failure rate of <1% per year when used 
consistently and correctly.)
1.1.
USER INDEPENDENT – Highly Effective Methods.

Implantable progestogen-only hormone contraception associated with inhibition of ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal ligation/occlusion

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(s) of contraception should be used. 
Spermatogenesis cycle is approximately 74 days.)
1.2.
USER DEPENDENT – Highly Effective Methods

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation
oral
intravaginal
transdermal
injectable

Progestogen-only hormone contraception associated with inhibition of ovulation
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.)
2.
NOT HIGHLY EFFECTIVE METHODS (Failure rate of >1% per year)a

USER DEPENDENT and NOT considered to be (highly) effective methods. 
Progestogen- only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action.

Condomb

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
Cap, diaphragm, or sponge with spermicide

A combination of external condom with either cap, diaphragm, or sponge with spermicide 
(double-barrier methods)b

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. Multiple types of condoms should not be used together (due to risk of failure with friction).

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10.6.
Appendix 6: 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

In Arms A and C, draw blood samples for unscheduled PK analysis at timepoints when liver 
chemistry is assessed

Record use of concomitant medications, acetaminophen, herbal remedies, other 
over- the- counter medications, or known hepatotoxins

Record alcohol use in the 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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10.7.
Appendix 7: 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
Source: Oken 1982.

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10.8.
Appendix 8: New York Heart Association Criteria
The following table presents the NYHA classification of cardiac disease:
Functional Capacity 
Objective Assessment 
Class I. Patients with cardiac disease but without resulting limitation of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain.
A. No objective evidence of 
cardiovascular disease.
Class 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.
B. Objective evidence of 
minimal cardiovascular 
disease.
Class 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.
C. Objective evidence of 
moderately severe 
cardiovascular disease.
Class 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.
D. Objective evidence of 
severe cardiovascular disease.
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases 
of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256.

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10.10. Appendix 10: Cockcroft-Gault Formula for Estimated Creatinine Clearance
Cockcroft-Gault Formula for Estimated Creatinine Clearance for Adults
eCrCl = (140-Age) × Mass (Kilograms) × [0.85 if female]
                      72 × Serum Creatinine (in mg/dL)
OR
eCrCl = (140-Age) × Mass (Kilograms) × 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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10.11. Appendix 11: Medications With Potential for QT Interval Prolongation
Although lazertinib and amivantamab have not shown liability for QT prolongation, the 
following drugs are known to or may possibly prolong QT interval or induce Torsades de Pointes 
and should be used with caution 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
anagrelide, ciprofloxacin, clarithromycin, cocaine (only medical use), domperidone, 
droperidol, erythromycin, ibutilide, levofloxacin, ondansetron, papaverine HCl 
(intra- coronary), procainamide, quinidine, sulpiride, sultopride, terlipressin, thioridazine
chlorpromazine, cilostazol, disopyramide, dofetilide, dronedarone, ibogaine, levosulpiride, 
moxifloxacin, sotalol
citalopram, escitalopram, flecainide, fluconazole, levomepromazine (ethotrimeprazine), 
roxithromycin, sevoflurane
methadone, pimozide, terodiline
azithromycin, donepezil, propofol
halofantrine, pentamidine
Haloperidol
amiodarone, chloroquine

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Medications that may prolong QT interval or induce Torsades de pointes
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
alfuzosin, clozapine, cyamemazine (cyamepromazine), deutetrabenazine, 
dextromethorphan/quinidine, ezogabine (retigabine), lacidipine, lopinavir/ritonavir, 
mifepristone, moexipril/HCTZ, pasireotide, perphenazine, promethazine, telithromycin, 
venlafaxine
asenapine, atomoxetine, betrixaban, felbamate, imipramine (melipramine), ketanserin, 
nortriptyline, paliperidone, pipamperone, trimipramine, valbenazine, zotepine, zuclopenthixol 
(oral)
buprenorphine, delamanid, desipramine, iloperidone, lithium, maprotiline, mirabegron, 
mirtazapine, palonosetron, rilpivirine, tacrolimus, tizanidine
aripiprazole, clomipramine, efavirenz, memantine
artemether/lumefantrine, sertindole
fingolimod, flupentixol, pimavanserin
zuclopenthixol (IM injection)
artenimol/piperaquine
Clofazimine
Nusinersen
Bedaquiline

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10.12. Appendix 12: Dosing Synchronization for Arms A/A2 and C/C2
The examples below use Cycles 1-5 for explanatory purposes, but the principles apply to any 
cycles.
*Chemotherapy refers to carboplatin + pemetrexed or pemetrexed alone, depending on cycle.

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10.13. Appendix 13: Open-label Randomized Extension Cohort 
10.13.1.
Synopsis
Following the 04 November 2022 safety data review for MARIPOSA-2, the IDMC recommended 
modification of Arm A to withhold lazertinib during administration of carboplatin due to an 
apparent imbalance in AEs affecting Arm A. The lazertinib dosing schedule for participants 
randomized to Arm A was thus modified in Amendment 5 of the protocol, such that new 
participants randomized to Arm A began treatment with amivantamab, carboplatin, and 
pemetrexed, and only started lazertinib after treatment with carboplatin treatment was complete. 
This dosing schedule is referred to as ACP-L throughout the protocol. 
To further describe the safety and efficacy of the ACP-L dosing schedule versus ACP with 
additional data, the Sponsor is adding a separate open-label randomized extension cohort to the 
study. Enrollment of participants into the extension cohort may begin after enrollment into the 
main study is complete and when the Sponsor opens the extension cohort for enrollment. The 
extension cohort will have the same eligibility criteria, study procedures and operate within the 
same investigational sites as the main study. 
The statistical considerations and the primary analyses for the main study are described in 
Section 9. Participants from the extension cohort (those randomized to Arms A2 and C2) will not 
be included in the primary analysis of the study. The analysis plan for the extension cohort is 
described in Section 10.13.9 and further details are provided in a separate Statistical Analysis Plan. 
10.13.2.
Background and Rationale
At the 04 November 2022 safety data review for MARIPOSA-2, the IDMC observed an imbalance 
in the incidence of SAEs, related SAEs, and Grade 4 AEs for participants receiving the 
combination of lazertinib, amivantamab, carboplatin, and pemetrexed (LACP) in Arm A, where 
the vast majority of these events occurred during the first 4 cycles, when participants are being 
treated with carboplatin in addition to lazertinib, amivantamab, and pemetrexed. The majority of 
these adverse events were toxicities typically associated with the use of chemotherapy: 
hematologic toxicities (eg, neutropenia, thrombocytopenia), opportunistic infections due to 
immunosuppression from chemotherapy, and GI toxicities (eg, nausea and stomatitis). These AE 
incidences led to a higher than expected rate of dose reduction and dose interruption of standard 
of care chemotherapy on Arm A. The reduced exposure to standard of care chemotherapy raised 
concerns to the IDMC that the efficacy could be compromised, but notably, efficacy data was not 
the part of this review for the IDMC. The IDMC recommended modification of Arm A to withhold 
lazertinib during the administration of carboplatin. 
The lazertinib dosing schedule for participants randomized to Arm A was thus modified in 
Amendment 5 of the protocol such that new participants randomized to Arm A began treatment 
with amivantamab, carboplatin, and pemetrexed, and only started lazertinib after treatment with 
carboplatin was complete. This dosing schedule is referred to as ACP-L throughout the protocol. 
The addition of lazertinib on Cycle 5 Day 1 (or sooner if carboplatin is discontinued earlier than 

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Cycle 4) is hypothesized to provide CNS protection while minimizing potential adverse events, 
therefore providing favorable benefit-risk.
The extension cohort of Study 61186372NSC3002 is designed to generate data to further describe
the safety and efficacy of the ACP-L dosing schedule versus ACP with additional data.
10.13.3.
Objectives and Endpoints
The primary objectives of the extension cohort are to further describe the safety and efficacy of 
the ACP-L dosing schedule versus ACP with additional data. See Section 10.13.9 below for a 
general description of planned analyses; full details are in the Statistical Analysis Plan.
10.13.4.
Study Design
Approximately 90 eligible participants will be randomly assigned to receive ACP-L or ACP in a 
2:1 ratio (Arms A2:C2, see Figure 5) in the extension cohort of Study 61186372NSC3002. 
Stratification methods and study procedures for the extension cohort of Study 61186372NSC3002
are largely the same as those for the main study. Procedures specific to the extension cohort are 
outlined below; otherwise, procedures should be followed per Table 1 of the protocol.
Figure 5:
Schematic Overview of the extension cohort
ACP-L=amivantamab, carboplatin, pemetrexed, and lazertinib (lazertinib started after carboplatin treatment is completed); 
AUC=area under the concentration-time curve; C#D#=Cycle # Day #; IV=intravenously; QD=once daily; QW=once weekly.
*
Stratification factors: osimertinib line of therapy (first-line vs second-line), history of brain metastases (yes vs no), Asian race 
(yes vs no)
†
Doses shown by body weight (<80 kg/≥80 kg)
‡
Cycle 1: Days 1/2 (split dose), 8, and 15; Cycle 2: Day 1
#
Lazertinib for participants in Arm A2 may start sooner if carboplatin is discontinued earlier than Cycle 4.
10.13.5.
Study Population: See Section 5 of the Protocol
The prescreening, inclusion, and exclusion criteria for the extension cohort are the same as for the 
main study. 

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10.13.6.
Study Treatment and Concomitant Therapy: See Section 6 of the 
Protocol
Enrollment into the extension cohort will be undertaken only following full approval of Protocol 
Amendment 6 from the Health Authorities and IEC/IRB (as applicable) at a site, completion of 
enrollment into the main study, and when the sponsor opens the extension cohort for enrollment. 
Dosing is as follows:
Arm A2 (ACP-L):

Lazertinib 240 mg orally, once daily starting Cycle 5 Day 1 or sooner if carboplatin is 
discontinued earlier

Amivantamab by IV infusion in 21-day cycles:

1,400 mg (1,750 mg if body weight ≥80 kg) on Cycle 1 Days 1/2, 8, and 15, and Cycle 2 
Day 1

1,750 mg (2,100 mg if body weight ≥80 kg) on Day 1 of each 21-day cycle, starting with 
Cycle 3

Carboplatin AUC 5 on Day 1 of each 21-day cycle, for up to 4 cycles

Pemetrexed 500 mg/m2 on Day 1 of each 21-d-ay cycle, with carboplatin for up to 4 cycles, 
and then as maintenance until disease progression
Arm C2 (ACP):

Amivantamab by IV infusion in 21-day cycles:

1,400 mg (1,750 mg if body weight ≥80 kg) on Cycle 1 Days 1/2, 8, and 15, and Cycle 2 
Day 1

1,750 mg (2,100 mg if body weight ≥80 kg) on Day 1 of each 21-day cycle, starting with 
Cycle 3

Carboplatin AUC 5 on Day 1 of each 21-day cycle, for up to 4 cycles

Pemetrexed 500 mg/m2 on Day 1 of each 21-day cycle, with carboplatin for up to 4 cycles, 
and then as maintenance until disease progression
Dose modification (including dose reduction, dose interruption, and drug discontinuation) 
procedures for the extension cohort are the same as those for participants receiving the relevant 
regimen in the main study (See Section 6.5 of the protocol).
10.13.7.
Discontinuation of Study Treatment and Participant
Discontinuation/Withdrawal: See Section 7 of the Protocol
Procedures 
related 
to 
discontinuation 
of 
study 
treatment 
and 
participant 
discontinuation/withdrawal for the extension cohort are the same as those for the main study.

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10.13.8.
Study Assessments and Procedures: See Section 8 of the Protocol
All study assessments and procedures for the extension cohort are the same as those for the main 
study, except that participants in the extension cohort will be randomized in a 2:1 ratio between 
Arms A2 and C2.
10.13.9.
Statistical Considerations and Analyses
The primary objectives of the extension cohort are to further describe the safety and efficacy for 
the ACP-L dosing schedule versus ACP with additional data. Primary analysis of the extension 
cohort will evaluate the safety data using the same methods specified in Section 9 of the main 
study. Secondary analysis of the extension cohort will assess the contribution of lazertinib to the 
activity of ACP-L descriptively through additional data collection based on intracranial PFS, ORR, 
DoR, and PFS. The same analysis methods as specified in Section 9 of the protocol will be used. 
There is no hypothesis testing for the comparison. Details will be provided in the Statistical 
Analysis Plan including an analysis plan using descriptive statistics to combine data from the main 
study and the extension cohort to provide additional data on safety and tolerability of ACP-L 
dosing schedule.

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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 and burden on participants. Data collected 
during this phase will be limited to those procedures and assessments specified in Table 20.
The OLE Phase may begin at a time determined by the sponsor following completion of the second 
interim analysis for OS and after approval of Amendment 7 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:

All participants 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 or transition to the LTE 
Phase.

Participants who have already discontinued study treatment and are in the Follow-up Phase of
the study will continue Follow-up as specified in the Schedule of Activities for the OLE Phase 
(Table 20).
10.14.1.
Eligibility Criteria
All participants who remain in the study at the time of transition are eligible to transfer to the OLE 
Phase. Informed consent must be obtained.
10.14.2.
Study Treatment Administration
Study treatment administration should continue as specified in Section 6.1.
10.14.3.
Study Procedures
All participants in the OLE Phase should follow the Schedule of Activities for the OLE Phase 
(Table 20).
Laboratory tests should be conducted by a local laboratory as specified in the Schedule of 
Activities for the OLE Phase (Table 20). 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 20 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 Section 
8.3.5 and Appendix 3).
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.

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•
Survival data
•
Symptomatic progression 
•
Subsequent anticancer therapy
•
PROs:EQ-5D-5L, EORTC-QLQ-C30, NSCLC-SAQ, PROMIS-PF and PRO CTCAE, PGIS, 
and PGIC 
•
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/A2 and Arm C/C2 and all vital
signs related to amivantamab administration. 
•
Concomitant medications 
•
Biomarkers
After notification from the sponsor to the site that the OLE Phase 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]).

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NCCN=National Comprehensive Cancer Network;  PE=physical examination; PGIC =Patient Global Impression of Change; PGIS =Patient Global Impression of 
Severity; PRO CTCAE=Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events; PROMIS-PF=Patient-Reported Outcomes 
Measurement Information System – Physical Function; Q12W=every 12 weeks; VTE=venous thromboembolic.
.
a.
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 anticancer therapy is to be initiated.
b.
Evaluate for signs and symptoms of VTE events. A focused physical examination of extremities and evaluation of respiratory status (including pulse oximetry) 
should be performed. 
c.
See Section 6.5.3.12 for additional information. Refer to NCCN Guidelines Version 1.2022 Cancer-Associated Venous Thromboembolic Disease, Section VTEB 
for examples of prophylactic-dose anticoagulants in ambulatory cancer participants.
d.
Continue data collection for 1 year after end of treatment, reducing data collection frequency from every 3 months to every 6 months.

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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. 
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 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 that the LTE phase will be initiated, participants 
remaining in the study be provided with the option to transfer to the LTE Phase. Upon entering the 
LTE Phase, participants will continue to receive the study treatment they were receiving.
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. Study treatment dispensation and 
accountability will be performed via IWRS.
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.
10.15.1.
Eligibility Criteria
All participants who remain on study at the time of transition are eligible to transfer into the LTE 
Phase. Informed consent must be obtained.
10.15.2.
Study Treatment Administration
Study treatment should continue as specified in Section 6.1. 
10.15.3.
Study Procedures
All participants in the LTE Phase should follow the Schedule of Activities for the LTE Phase 
(Table 21).
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 in the eCRF. 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 
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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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 6 (22 December 2022)
Overall Rationale for the Amendment: The overall purpose of this amendment is to add an open-label 
randomized extension cohort to further describe the safety and efficacy of the ACP-L dosing schedule 
versus ACP with additional data.
The changes made to the clinical protocol 61186372NSC3002 as part of Protocol Amendment 6 are listed 
below, including the rationale of each change and a list of all applicable sections. Changes made in previous 
protocol amendments are listed in 10.16 Appendix 16: Protocol Amendment History.
Section number
and Name
Description of Change
Brief Rationale
1.1. Synopsis;
(Objectives and 
Endpoints, Overall 
Design,
Number of 
Participants, Study 
treatment groups 
and duration,
Statistical Methods);
1.3. Schedule of 
Activities;
3. Objectives and 
Endpoints;
4.1. Overall Design;
4.1.2. Treatment 
Phase;
4.4. Justification for 
Dose;
6.3. Measures to 
Minimize Bias: 
Randomization and 
Blinding
9. Statistical 
Considerations;
9.3. Populations for 
Analysis Sets;
Text was added to add an open-label randomized 
extension cohort.
To further describe the safety and 
efficacy of the ACP-L dosing 
schedule versus ACP with 
additional data.
1.2. Schema
Figure 2 was added to represent the schematic 
overview of the extension cohort.
Section 13: 
Appendix 13
Appendix 13 was added to describe the design, 
background, rationale, and statistical 
considerations for the extension cohort.
The subsequent section and appendix were 
renumbered.
Throughout the 
protocol
Mention of Arm A or Arm C was updated to 
“Arms A/A2” or “Arms C/C2”, respectively, to 
align with addition of the extension cohort, as 
appropriate.
1.3. Schedule of 
Activities (Table 1) 
Blood samples for exploratory biomarkers were 
updated to include collection of blood samples on 
Serum collections will undergo 
analysis for circulating factors that 

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Section number
and Name
Description of Change
Brief Rationale
C5D1, C6D1, C7D1, and C8D1 for Arms A/A2 
and C/C2.
may be related to clinical or 
physiological responses to study 
treatments.
8. Study 
Assessments and 
Procedures
Approximate blood volumes to be collected from 
participants were updated.
1.3. Schedule of 
Activities (Table 2)
The term LACP was deleted from the table 
heading and added to column “Plasma Sample for 
Pharmacokinetics (Lazertinib) Arm A LACP only. 
To align with the updates resulting 
from the urgent safety measure on 
07 November 2022.
8.4.1. Evaluations
Text was updated to indicate that samples will be 
collected from participants in Arm A LACP as per 
Table 2 and for participants receiving ACP-L in 
Arms A/A2 as per Table 3 for the evaluation of 
PK of lazertinib.
1.3. Schedule of 
Activities (Table 3)
Added ‘Arm A Dosing Schedule 2 and Arm A2’ in 
the table heading and the plasma sample for 
pharmacokinetics column.
To align with the updated text.
The end of infusion row was deleted.
This table describes lazertinib 
pharmacokinetics – lazertinib is not 
administered as an infusion.
4.3. Scientific 
rationale for Study 
Design
Added the missing word ‘lazertinib’ in Clinical 
Pharmacology Assessments.
To correct an error.
6.1.1. Scheduled 
Dosage and Timing
The abbreviation “LACP” was replaced with the 
word “treatment” for clarity.
Not all participants in Arm A will 
be receiving LACP. 
6.1.2. Lazertinib
Recommendations for resolution of specific 
toxicities prior to initiating lazertinib were added. 
Clarification for safety reasons.
6.1.3. 
Chemotherapy
The description of pemetrexed was updated from 
"powder for concentration” to “powder for 
concentrate.”
To correct an error.
6.5.3.2. Rash-
Related Adverse 
Events (Table 11)
Lazertinib was deleted from dose adjustment 
column. 
To correct an error.
7.3. Lost to Follow-
up
The following language was removed: “Should the 
participant continue to be unreachable, they will be 
considered to have withdrawn from the study.”
Language was inconsistent with 
other instructions allowing 
collection of information using 
alternative follow-up mechanisms.
8.2.7. ECOG 
Performance Status
Language indicating that a decline in ECOG 
performance status should be reported as an 
adverse event was removed.
Language was inconsistent with 
adverse event reporting instructions 
in other sections of the protocol.
11. Reference
One reference was deleted as it was an incorrect
reference.
To correct an error.
Throughout the 
protocol
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted
Amendment 5 (25 November 2022)
Overall Rationale for the Amendment: The overall purpose of this amendment is to formalize the study 
changes required by the Urgent Safety Measure (tolerability risk treated in Arm A with combination of 
amivantamab, lazertinib, carboplatin and pemetrexed) released on 07 November 2022. In addition, this 
amendment will incorporate additional changes that were recommended by health authorities in response 
to the Urgent Safety Measure (VTE risk with combination of amivantamab and lazertinib) released on July 
22 2022. 

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The changes made to the clinical protocol 61186372NSC3002 as part of Protocol Amendment 5 are listed 
below, including the rationale of each change and a list of all applicable sections.
Section Number
and Name
Description of Change
Brief Rationale
1.1 Synopsis (Study 
treatment groups and 
duration); 2 Introduction; 
2.2.6 Rationale for 
Adding Lazertinib and 
Amivantamab to 
Platinum Doublet 
Chemotherapy
2.3.3 Benefit-Risk 
Assessment for Study 
Participation
3. Objectives and 
Endpoints
4.1 Overall Design
4.1.2 Treatment Phase
4.4 Justification of Dose
6.1.1 Scheduled Dosage 
and Timing
6.5.3.12 Venous 
Thromboembolic Events
8.4.1 Evaluations
9.1 Statistical Hypotheses
9.1.1 Multiplicity 
(Figure 3)
9.2 Sample Size 
Determination
9.4.1. General 
Considerations
9.4.2 Primary Endpoint
9.4.3 Secondary 
Endpoints
9.4.6 Other Analyses 
(Biomarker Analyses)
9.5 Interim Analysis
Added text pertaining to a USM whereby the 
dosing schedule of lazertinib on Arm A has 
been modified to only start after 
carboplatin therapy is completed. This 
dosing schedule is termed ‘ACP-L’.
The primary efficacy analyses remains 
unchanged and includes all participants in 
Arm A.
Benefit-Risk Assessment was updated for 
results of the IDMC meeting which 
recommended modification of Arm A to 
withhold lazertinib during administration 
of carboplatin.
The treatment phase was updated to reflect 
Arm A Dosing Schedule 2 (ACP-L, started 
on 7 November 2022)
Dose justification was updated to align with 
the findings of the IDMC meeting based 
on the review of the unblinded safety data 
and is also supported by the emerging data 
that concurrent chemotherapy with third 
generation EGFR TKIs is associated with a 
higher than expected rate of toxicities 
traditionally association with 
chemotherapy.
Overall: Addition of ‘ACP-L’ across the protocol to 
align with this change in dosing schedule. 
Change to lazertinib dosing 
schedule to minimize the 
tolerability risks, as per 
IDMC recommendation.
1.2 Schema
Updated to reflect Arm A Dosing schedule 2 (ACP-
L) started on 7 November 2022.
Change to lazertinib dosing 
schedule to minimize the 
tolerability risks, as per 
IDMC recommendation
1.3 Schedule of 
Activities, Table 1: 
Schedule of Activities 
(All Treatment Arms, 
Unless Otherwise 
Indicated)
In prophylactic anticoagulation row, 2 columns 
were merged to indicate that prophylactic dose 
anticoagulation is recommended during the first 4 
months of treatment for participants receiving the 
combination of amivantamab and lazertinib.
To correct the editorial error 
and align free text and table 
regarding the duration for the 
prophylaxis.
1.3 Schedule of 
Activities, Table 1: 
Schedule of Activities 
(All Treatment Arms, 
Unless Otherwise 
Indicated)
Lazertinib administration and record of compliance 
rows (Arm A only): Updated to reflect dosing 
schedule modification and implementation of 
ACP-L.
To align the lazertinib dose 
schedule.

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Section Number
and Name
Description of Change
Brief Rationale
1.3 Schedule of 
Activities, Table 1: 
Schedule of Activities 
(All Treatment Arms, 
Unless Otherwise 
Indicated)
CT/MRI Tumor imaging and Brain MRI: Notes 
were updated to reflect that study treatment should 
continue until documented disease progression is 
confirmed by BICR. If participant begins a new 
cancer therapy before disease progression, obtain 
tumor imaging before the new therapy, and then
continue imaging per schedule until BICR confirms 
disease progression
To clarify the protocol 
requirement of imaging 
schedule.
1.3 Schedule of Activities
Table 3: Collection times 
for Pharmacokinetics 
(PK) Samples (Arm A 
ACP-L); 8.4.1 
Evaluations
Added a table to describe collection times for 
PK sampling for lazertinib.
Updated evaluations to indicate PK sampling 
timepoints and conditions
Clinic visit for the second 
dose of lazertinib was not 
needed and PK samples are 
not collected on Day 2.
5.2 Exclusion Criteria;
6.5.1 Dose Delay 
Guidance; 6.5.2 Dose 
Modification of 
Amivantamab and 
Lazertinib; 6.5.3.12 
Venous Thromboembolic 
Events;
Criterion 13.1 updated to include participants 
who have a significant genetic 
predisposition to venous thromboembolic 
events (such as Factor V Leiden) or have a 
prior history of VTE and are not on 
appropriate therapeutic anticoagulation as 
per NCCN guidelines or local guidelines.
Subheading Arm A was updated for VTE. 
Table 5; Footnote ‘e’ updated for VTE in 
participants being treated with the 
combination of amivantamab and 
lazertinib.
Table 8; Footnote ‘e’ deleted.
Section for VTE updated with:
o
Further imaging studies to assess 
a resolution in case of worsening 
VTE and/or symptoms
o
Recommendations for participants 
receiving LACP and ACP-L 
schedule.
Resolutions in case of VTE events associated 
with clinical instability.
Recommendations in case of recurrent VTEs 
have been included. 
To clarify and align with the 
VTE risk mitigation and 
management
6.1.4 Amivantamab
Updated the central line infusion criteria to
infusion via central line being allowed only 
at Cycle 1 Day 15 and onwards if the 
participant’s most recent dose (eg, C1D8) 
was successfully administered without an 
infusion related reaction.
To clarify the requirement for 
central line infusion.
6.5.3.2 Rash-Related 
Adverse Events, Table 10 
and Table 11; 7.1 
Discontinuation of Study 
Treatment
Added text to indicate that in case of a Grade 4 rash 
or severe bullous, blistering, or exfoliating skin 
conditions including toxic epidermal necrolysis 
(TEN), all study drugs (amivantamab [Arms A and 
C], lazertinib [Arm A], pemetrexed, and 
carboplatin) should be permanently discontinued.
This change was to optimize 
safety of participants
6.5.4.1 Management of 
Chemotherapy Toxicities
Added: participants who experience hematologic 
toxicities while on treatment are recommended to 
receive colony stimulating factors as per 
international guidelines
To mitigate the risk and 
optimize safety 

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Section Number
and Name
Description of Change
Brief Rationale
9.4.2 Primary Endpoint; 
9.4.3 Secondary 
Endpoints; 9.4.5 Safety 
Analyses
Added analysis by dose schedule.
Updated to indicate that additional sensitivity 
analyses of PFS by dosing schedule 
subgroups will be performed.
Updated to indicate that additional analyses 
by dosing schedule subgroups on the 
secondary endpoints will be performed.
Updated to indicate that additional safety 
analyses by dosing schedule subgroups will 
be performed.
Details will be provided in the SAP.
To add analysis for 
Lazertinib dosing schedule 
change per IDMC 
recommendation.
11. References
Newly added references: Ardizzoni A (2012) and 
Tanaka K (2021).
Throughout the protocol
Minor grammatical, formatting, or spelling 
changes were made.
The term ‘subjects’ was replaced with 
‘participants’.
Minor errors were noted. 
Changes were made for the 
purpose of consistency and 
accuracy of terms used in the 
protocol draft.
Amendment 4 (23 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.
The changes made to the clinical protocol 61186372NSC3002 as part of Protocol Amendment 4 are listed 
below, including the rationale of each change and a list of all applicable sections. 
Section Number
and Name
Description of Change
Brief Rationale
1.3 Schedule of Activities 
(Table 1)
Row added for prophylactic-dose 
anticoagulation during the first 4 months of 
treatment. Venous thromboembolic (VTE) 
events-related footnotes added for physical 
examination and anticoagulation.
To implement the Adverse Event of 
Special Interest of VTE events, as 
well as associated measures for 
monitoring and prophylaxis of 
these events.
1.3 Schedule of Activities 
(Table 1)
8 Study Assessments and 
Procedures; overview
Added blood sample collection timepoints 
for exploratory biomarkers at C2, C3, and 
C4 treatment cycles for Arm A and Arm C.
Also, updated blood withdrawn volume of 
Arm A and Arm C participants to align 
with additional blood sample collection 
timepoints for exploratory biomarkers.
2.3.1 Risks for Study 
Participation
VTE events and paresthesia has been added 
to the list of possible risks for the 
amivantamab and lazertinib combination.
2.3.3 Benefit-Risk 
Assessment for Study 
Participation
The rationale for and aims of the VTE events-
related measures have been added.
6.5.2 Dose Modification of 
Amivantamab and 
Lazertinib
In Table 4 and Table 7, a new footnote e 
has been added to provide dosing guidance 
for VTE events.

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Section Number
and Name
Description of Change
Brief Rationale
6.5.3.12 Venous 
Thromboembolic Events
A new section has been added to provide 
guidance on the management of VTE 
events.
8.2.1 Physical Examinations
Additional guidance has been added for 
detection of VTE events through physical 
examination.
8.3.7 Adverse Events of 
Special Interest
VTE events have been added to the list of 
AEs of special interest. It is noted that 
events of VTE events should follow 
standard reporting guidelines.
11 References
Three new references (Carrier 2019, NCCN 
2022, and Rutjes 2020) have been added to 
the list of references to support VTE-
related information.
6.5 Dose Modification
Updated guidance on the dose modification 
for the participants who experiences 
clinically significant CTCAE Grade 3.
To provide more flexibility in dose 
modification.
8.3.1 Time Period and 
Frequency for Collecting 
Adverse Event and Serious 
Adverse Event Information
Updated guidance on the timeframe for 
reporting adverse events.
To align reporting requirements 
with the Schedule of Activities.
10.3.3 Severity Criteria
The following text has been removed:
Any AE will be graded as per the above. 
Should an AE become fatal or have a fatal 
outcome, the original grade is not changed 
but “fatal” shall be reported as an outcome.
A Grade 5 event is to be reported only in the 
following cases:
•
Death NOS: only for deaths due to 
unknown 
reason 
(pending 
follow up 
information; if further information becomes 
available this should be adapted as 
adequate)
•
Sudden death: a sudden (defined as 
instantaneous or within 1 hour of the onset 
of symptoms) cessation of life that cannot be 
attributed to a CTCAE term
To ensure all Grade 5 events are 
captured.
10.3.5 Procedures: Serious 
Adverse Events
Revised information related to SAE 
reporting period.
To align with revised time period 
and frequency for collecting all 
adverse events information.
Title page,
10.2 Appendix 2: 
Regulatory, Ethical, and 
Study Oversight 
Considerations
Expanded “countries” terminology to
“countries/territories.”
To align with Janssen
template.
Throughout the protocol
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted.

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Amendment 3 (27 June 2022)
Overall Rationale for the Amendment: To add hypothesis testing for amivantamab, carboplatin, and 
pemetrexed (ACP) versus carboplatin and pemetrexed (CP) as a dual primary and secondary hypotheses 
with an increased study population to provide sufficient power; modify the statistical analysis plan for such 
analyses; remove biomarker defined subgroup analyses.
Section Number
and Name
Description of Change
Brief Rationale
1.1 Synopsis: Objectives 
and Endpoints, 
Hypothesis, overall 
design, and Statistical 
Methods; 
3 Objectives and 
Endpoints and 
Hypothesis; 4.1 Overall 
Design; 9.1 Statistical 
Hypotheses; 9.4.2 
Primary Endpoint; 9.4.3 
Secondary Endpoints; 
9.5 Interim Analysis
Text was updated to add dual primary efficacy 
hypothesis specifying that efficacy will also be 
assessed for ACP versus CP in addition to 
lazertinib, amivantamab, carboplatin, and 
pemetrexed (LACP) versus CP.
Text was updated specifying that objectives of 
efficacy, safety, health-related quality of life and 
disease related symptoms, and biomarkers will 
also be also assessed for ACP versus CP in 
addition to LACP versus CP.
To add hypothesis testing for the 
analysis of ACP vs CP.
1.1 Synopsis: Statistical 
Methods; 9.1 Statistical 
Hypotheses; 9.4.1 
General Considerations
Text describing comparison of LACP versus CP 
was revised to add comparison of ACP versus 
CP.
1.1 Synopsis: Number of 
Participants and 
Statistical Methods; 
1.2 Schema; 4.1 Overall 
Number of participants was increased from 500 
to 600.
Sample size calculation text was updated 
accordingly.
To provide sufficient power for 
hypothesis testing for both 
LACP versus CP and ACP 
versus CP.
CCI

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Section Number
and Name
Description of Change
Brief Rationale
Design; 9.2 Sample Size 
Determination
1.1 Synopsis: Statistical 
Methods; 9.1.1 
Multiplicity
Text was added to specify that a graphical 
approach will be applied in a group sequential 
design setting for testing of primary endpoints 
(PFS) and key secondary endpoints (ORR and 
overall survival [OS]). Earlier text for the 
hypothesis testing for these endpoints was 
removed.
A new subsection for multiplicity was added.
To adjust the statistical 
hypothesis testing strategy to 
control overall family-wise Type 
I error rate after adding ACP 
versus CP comparison.
1.1 Synopsis: Statistical 
Methods
Following text was added to synopsis:
Comparison of LACP (Arm A) with ACP (Arm 
C) will be performed to describe the contribution 
of lazertinib based on intracranial PFS, ORR, 
DoR, and PFS, using summary statistics and 
nominal p-values; there will be no formal 
hypothesis testing for this comparison.
For consistency with protocol 
text.
4.1.1 Screening
Enrollment of number of participants who failed 
treatment with osimertinib in the second line to 
approximately 40% was changed from 200 to 
240.
To increase the size in 
proportion with new sample 
size.
6.5.3.2 Rash-Related 
Adverse Events
In Table 9 it was mentioned to permanently 
discontinue amivantamab and hold lazertinib and 
lazertinib to restart once resolved per investigator 
assessment of causality for Grade 4 event in 
Arm A.
In Table 10 it was mentioned to permanently 
discontinue amivantamab for Grade 4 event in 
Arm C.
Dose adjustment and management of severe 
bullous, blistering, or exfoliating skin conditions 
including toxic epidermal necrolysis was added to 
Table 9 and Table 10. 
To clarify for safety of the 
participants.
6.5.3.10 Diarrhea
Study treatment algorithm is updated for 
lazertinib and added for amivantamab for Arm A 
in Table 11.
A new table, Table 12 was added for algorithm 
for management of diarrhea for Arm C.
Subsequent tables were renumbered. 
To clarify for safety of the 
participants.
5.2 Exclusion Criteria; 
6.7.3 Prohibited or 
Restricted Medications 
and Therapies; 
Appendix 12: Prohibited 
and Restricted 
Medications and 
Therapies That Induce, 
Inhibit, or Are Substrates 
of CYP3A4/5; 
Appendix 13 Substrates 
of P-glycoprotein (P-gp), 
Breast Cancer 
Resistance Protein 
(BCRP), and multi-drug 
resistance protein 4 
Prohibited and restricted medications that induce, 
inhibit, or are substrate of CYP3A4/5, and 
substrates of P-glycoprotein, Breast Cancer 
Resistance Protein, and multi-drug resistance 
protein 4 are added in-text and the appendices 
were deleted and text was added to contact local 
pharmacist or Medical Monitor in case of any 
questions.
The reference for these appendices within the 
protocol text was removed. A new reference of 
US FDA 2022 was added for list of medications.
Subsequent appendices were renumbered.
To remove the duplicate 
information as these information 
are added in-text.

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Section Number
and Name
Description of Change
Brief Rationale
(MRP4): Exercise 
Caution
8 Study Assessments and 
Procedures: Overview
Bold text was added to the statement: 
Depending on country specific regulations, 
volume requirements at local laboratories, and 
availability of blood collection tubes the total 
blood volume may vary.
For further clarification
8.6 Immunogenicity 
Assessments
Text in the section revised to remove redundancy.
For further clarification
9.4.2 Primary Endpoint
Text was updated to show that primary analysis 
of PFS will be conducted when 350 PFS events in 
all 3 arms combined have been observed.
To update the text based on 
updated statistical analysis plan.
9.4.3 Secondary 
Endpoints
Following text was added: Secondary endpoints 
will be analyzed using the Full Analysis Set.
9.4.6 Other Analyses: 
Pharmacokinetic 
Analyses
Arm C was added with Arm A for 
pharmacokinetic analyses.
To update PK analysis for 
Arm C based on updates to 
statistical analysis plan.
9.5 Interim Analysis
The timepoint for interim analysis is updated as 
170 deaths (all 3 Arms combined, approximately 
43% of the total planned overall survival (OS) 
events) for first interim analysis for OS and the 
second interim analysis for OS will be performed 
approximately 32 months after the first 
participant is randomized, when approximately 
300 deaths (all 3 arms combined, approximately 
75% of the total planned OS events).
The timepoint for final analysis was also updated 
to 400 deaths (all 3 arms combined).
Text was updated for the analysis of OS.
To update the timing and 
number of OS events to be 
expected for interim and final 
analysis of OS per increased 
sample size.
10.12 Appendix 12 
Dosing Synchronization 
of Arms A and C
The example figure for administration of study 
treatments is updated. 
To correct the error in previous 
protocol amendment.
11 Reference
The references were updated according to 
changes in the document.
To update the references.
Throughout the protocol
Minor grammatical, formatting, or spelling 
changes were made
Minor errors were noted.
Amendment 2 (24 March 2022)
Overall Rationale for the Amendment: To update the timeframe for conduct of the primary 
progression-free survival (PFS) analysis per the request of the United States Food and Drug Administration 
(US FDA), modify inclusion criteria related to brain metastases, provide additional and clarified guidance 
to investigators for the management of toxicities, modify prohibited and restricted medications based on 
the availability of new information, and to incorporate feedback received from health authorities.
Section 
number
and Name
Description of Changes
Brief Rationale
9.4.2 Primary Endpoint
The timeframe for conduct of the primary analysis 
for PFS was updated at the request of the USFDA.
To update the timing of the final 
analysis 
to 
be 
strictly 
event-driven 
without 
any 
contingency for follow-up for the 
last randomized participant.
1.1 Synopsis: Efficacy 
Text was added for CT/MRI tumor imaging and 
To provide more clarification.

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Section 
number
and Name
Description of Changes
Brief Rationale
Evaluations; 1.3
Schedule of Activities; 
4.1.2 Treatment Phase; 
8.1 Efficacy 
Assessments
brain MRI to indicate that imaging or study 
treatment  should continue until progression is 
confirmed by blinded independent central review.
The term ‘radiographic’ was deleted with respect 
to disease progression.
5.1 Inclusion Criteria
Criterion 5 was updated to allow participants with 
brain metastases who had all lesions treated as 
clinically indicated, local therapy must have been 
completed at least 14 days prior to randomization, 
and participant receiving no greater than 10 mg 
daily prednisone or equivalent.
To align with current clinical 
practice.
5.2 Exclusion Criteria
Text in bold was added to the criterion 4: 
Participant has history of or current evidence of
leptomeningeal disease, or participant has spinal 
cord compression not definitively treated with 
surgery or radiation.
6.5.2 Dose Modification 
of Amivantamab and 
Lazertinib; Table 5;
Table 8
Text was added to discontinue lazertinib
or 
amivantamab or both lazertinib and amivantamab 
(Arm A) and amivantamab (Arm C) permanently 
in case of a second occurrence of the same 
drug-related Grade 4 toxicity.
To incorporate request from 
health authorities.
6.5 Dose Modification
Text was updated to indicate that only the study 
treatment(s) for which the investigator assessed 
causal relatedness will be interrupted in the event 
of a Grade 3 or higher toxicity. Exceptions for 
hematologic toxicities were removed.
To correct the error in prior 
versions of the protocol.
6.5.3.1 Infusion-Related 
Reactions Table 9
Text was added to follow guidance for Grade 2 
interruptions, if infusion is interrupted for Grade 1 
infusion-related reactions (IRR).
Added ‘antiemetic’ to the list of medications for 
Grade 2 infusion-related reactions.
To 
provide 
guidance 
for 
management of IRR in case of 
infusion interruption.
To 
provide 
additional 
medications for Grade 2 IRR.
6.5.3.2 Rash-Related 
Adverse Events
Text was updated to indicate that topical or oral 
antibiotics or both are recommended for rash 
prophylaxis.
To provide more clarification.
6.5.3.10 Diarrhea
New section including Table 12 was added to 
provide guidance for diarrhea management. 
Subsequent tables were renumbered accordingly.
To 
provide 
guidance 
on 
management of diarrhea.
6.5.3.11 Paresthesia
New section was added to provide guidance for 
paresthesia management.
To 
provide 
guidance 
on 
management of paresthesia.
2.2.2 Lazertinib; 
11 References
The outcome of cardiac safety study was added, 
and the corresponding reference was added.
To update the sections based on 
new data available which show 
that lazertinib has no clinically 
relevant effect on QT interval and 
left ventricular ejection fraction 
at doses of 20 mg to 320 mg and 
supports 
the 
removal 
of 
prohibitions on the use of 
medications with the potential to 
prolong the QTc interval.
6.7.3 Prohibited or 
Restricted Medications 
and Therapies; 10.11
Appendix 11: 
Medications With 
Potential for QT Interval 
Prolongation
Text was updated to remove prohibitions and 
wash-out periods for medications affecting QT 
interval or induce Torsades de pointes.
6.7.2.1 Pre- and Post-
Infusion Medications for 
Chemotherapy
Text was modified to indicate that prophylactic use 
of leukocyte-depleted blood transfusions are 
allowed at any time after Cycle 1 Day 1. 
To provide more clarification
Appendix 12 Prohibited 
and Restricted 
Fluconazole, cimetidine, and aprepitant were 
removed from the list of strong inhibitors of 
To update the section with new 
available information.

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Section 
number
and Name
Description of Changes
Brief Rationale
Medications and 
Therapies That Induce, 
Inhibit, or Are 
Substrates of CYP3A4/5
CYP3A4.
Following text was removed: “Appropriate 
medical judgment is required, and any of these 
medications should be utilized, if clinically 
indicated, for the treatment of AEs.”
1.3 Schedule of 
Activities; 4.1.1 
Screening
Added a note that informed consent signature can 
be performed > 28 days prior to randomization, but 
all other screening procedures must be completed 
within 28 days of randomization.
To 
provide 
flexibility 
and 
convenience and define the 
criterion 
for 
repetition 
of 
screening assessments.
1.3 Schedule of 
Activities;
Text was added to clarify when laboratory 
assessments and physical examination need to be 
repeated if chemotherapy and amivantamab are 
administered on different days.
To clarify the criterion for 
repetition 
of 
laboratory 
assessments 
and
physical 
examination. 
The 
original 
language was unclear.
Notes were updated to clarify when predose 
Cycle 1 Day 1 assessments must be conducted 
relative to randomization.
To provide more clarification as 
the 
original 
language 
was 
unclear.
Text indicating that amivantamab doses delayed 
for >7 days could not be made up was deleted.
To correct the error in prior 
versions of the protocol.
Arm C was added for carboplatin to be 
administered 
after 
pemetrexed 
and 
before 
amivantamab.
Footnote ‘b’ was updated to specify that the results 
must be reviewed by the investigator to confirm 
eligibility for the study.
To provide clarification.
Footnote ‘c’ was added to some screening 
activities.
To 
provide 
flexibility 
and 
convenience.
4.1.2 Treatment Phase
A reference of Section 7.1 Discontinuation of 
Study Treatment is provided for continuation of 
study treatment after disease progression.
To provide clarification.
5.1 Inclusion Criteria; 
5.2 Exclusion Criteria; 
6.7.2.5 Hormonal 
Contraception
Inclusion Criteria 11, 12, and Exclusion Criterion 
20 and text in other section was updated to increase 
the duration to follow contraceptive measures for a 
female participant from 6 to 7 months after the last 
dose of study treatment.
To incorporate request from a 
health authority.
5.1 Inclusion Criteria; 
10.5 Appendix 5 
Contraceptive Guidance
Inclusion criteria 13 and text in other section was 
updated to remove the use of spermicidal 
foam/gel/film/cream/suppository 
along 
with 
condom for contraception.
To provide flexibility.
5.1 Inclusion Criteria
Criteria 3, 7, and 14  were updated for clarity; text 
in bold was added to following criteria:
Criterion 
3: 
Osimertinib 
must 
have 
been 
administered as either the first-line treatment for 
locally advanced or metastatic disease or in the 
second-line setting after prior treatment with first-
or 
second-generation 
EGFR 
TKI 
as 
a 
monotherapy. 
Participants who received either neoadjuvant 
and/or adjuvant treatment of any type are eligible 
if progression to locally advanced or metastatic 
disease occurred at least 12 months after the last 
dose of such therapy.
Criterion 7: Participant must have adequate organ 
and bone marrow function as follows, without 
history of red blood cell transfusion, platelet 
To provide more clarification, as 
the 
original 
language 
was 
unclear.

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Section 
number
and Name
Description of Changes
Brief Rationale
transfusion, erythropoietin stimulating agents, or 
platelet-boosting treatments within 7 days prior 
to the date of the laboratory test.
Criterion 14 was updated to add following text: 
“male participants should consider preservation of 
sperm prior to treatment with pemetrexed or 
carboplatin, as these agents may impair fertility.”
5.2 Exclusion Criteria
Criterion 6 was updated to clarify that participants 
with 
history 
of 
or 
current 
evidence 
of 
leptomeningeal disease will be excluded.
To provide more clarification.
Criterion 13 was updated to add the text to exclude 
participants with uncontrolled hypokalemia.
To incorporate request from 
health authorities.
5.3 Lifestyle 
Considerations
Criterion 3 was updated to indicate use of sun 
protective measures for additional 2 months: 
changed from ‘until the last dose’ to ‘until at least 
2 months after the last dose’ of study treatment.
Additionally, Arm C, which also contains 
amivantamab, has been added to this criterion for 
completeness. 
To align criterion language with 
the amivantamab USPI.
To correct the error in prior 
versions of the protocol.
1.3 Schedule of 
Activities; 6.5.1 Dose 
Delay Guidance; 6.7.2.2
Pre-and Post-Infusion 
Medications for 
Amivantamab (Arm A 
and Arm C)
Text was added to indicate that the total number of 
carboplatin administration cycles cannot exceed 4 
cycles.
To align with clinical practice. 
6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding
Following text was added: “participants who have 
adequate treatment for metastatic brain lesions, 
including a complete response or resection, must 
be identified as having a history of brain 
metastases.”
To provide more clarification.
6.5.1 Dose Delay 
Guidance
‘If chemotherapy is delayed twice’ is replaced by 
‘If chemotherapy is delayed by 2 weeks’ for Arm 
A and Arm C.
Window period was added for chemotherapy 
dosing, Cycle 2 onwards.
To provide more clarification.
To align with clinical practice.
6.7.2.1 Pre- and Post-
Infusion Medications for 
Chemotherapy Table 16
Footnote 
‘a’ 
updated 
to 
indicate 
oral 
dexamethasone can be skipped on Cycle 1 Day 1 
and Day 2, at the discretion of the investigator. Of 
note, IV dexamethasone is administered as a pre-
infusion medication for amivantamab on those 
days.
To correct the error in prior 
versions of the protocol.
6.7.2.2
Pre-and Post-
Infusion Medications for 
Amivantamab (Arm A 
and Arm C)
The 
recommended 
dosing 
windows 
before 
amivantamab for pre-infusion medications in 
Table 17 were updated.
Table 17 footnote ‘e’, indicating that the dose of 
paracetamol 
may 
be 
split, 
was 
removed. 
Footnote ‘f’ was re-lettered as footnote ‘e’.
Text was added to indicate that if required 
amivantamab pre-infusion medication is already 
given as chemotherapy prophylaxis, it does not 
To align with clinical practice.
To align with clinical practice.
To provide more clarification.

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Section 
number
and Name
Description of Changes
Brief Rationale
need to be re-administered prior to amivantamab 
infusion if dosed within recommended window.
Arm A and C were mentioned for amivantamab.
6.7.3 Prohibited or 
Restricted Medications 
and Therapies
In the list of prohibited medications and therapies, 
the prohibition of live or live attenuated vaccines 
was extended until at least 90 days after the last 
dose of study treatment.
To eliminate risk associated with 
concomitant administration of 
live or live attenuated vaccines 
with pemetrexed and carboplatin.
The list of restricted medications and therapies was 
updated to indicate that nephrotoxic drugs should 
also be used cautiously with pemetrexed. 
To eliminate risk associated with 
concomitant administration of 
nephrotoxic 
drugs 
and 
pemetrexed.
7.1 Discontinuation of 
Study Treatment
Added guidelines for treatment of participants after 
disease progression.
To incorporate request from 
health authority.
8. Study Assessments 
and Procedures
The total estimated blood volume to be collected 
during the study was updated.
To be consistent with ICF 
language.
1.3 Schedule of 
Activities; 8.2.1
Physical Examinations
Text was added to indicate that a physical 
examination is also required at the end of treatment 
visit.
To correct the error in prior 
versions of the protocol.
8.2.3
Electrocardiograms
8.2.3
Electrocardiograms
Text was added to clarify that the order for blood 
sampling, vital sign measurement, and ECG to 
follow if procedures are less than 1 hour apart.
Text was added to specify ECG can be collected in 
triplicate at other times in addition to screening 
visit if clinically indicated.
To provide more clarification.
For 
consistency 
with 
other 
sections
1.3 Schedule of 
Activities; 8.2.5
Pregnancy Testing
Requirement for monthly pregnancy testing for 
6 months after last dose for participants in Arm A 
and Arm C was added.
For consistency with clinical trial 
facilitation 
group 
(CTFG) 
contraception recommendations.
10.5 Appendix 5: 
Contraceptive Guidance
Footnote b, which stated ‘The study treatment may 
interact with hormonal contraception, which may 
reduce the efficacy of the contraceptive method. In 
addition, consider if the hormonal contraception 
may interact with the study treatment.’ has been 
deleted. 
Footnote c was renumbered to footnote b.
To 
update 
contraceptive 
guidance as no interaction is 
expected 
between 
study 
treatments 
and 
hormonal 
contraception. 
Appendix 14: Dosing 
Synchronization for 
Arms A and C
Figure was updated with cycle numbers, days, and 
visit windows.
New explanatory text was added.
To provide more clarification.
Throughout the protocol
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted.

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Amendment 1 (06 August 2021)
Overall Rationale for the Amendment: The requirement to review each assessment with the Medical 
Monitor when a participant is treated beyond BICR-confirmed disease progression was removed. Text was 
added to clarify timing of the first Independent Data Monitoring Committee (IDMC) meeting. 
Section number
and Name
Description of Change
Brief Rationale
Table 1;
8.1 Efficacy 
Assessments
Removed the requirement to review clinical 
benefit with the Medical Monitor at each 
assessment when a participant is treated 
beyond BICR-confirmed disease progression.
Per Section 4.1.2, continuation of study 
treatment after disease progression 
requires approval from the Medical 
Monitor; reapproval is not required at 
each subsequent assessment.
Table 1; 
8.2.5 Pregnancy 
Testing
Added pregnancy testing (serum or urine) 
within 72 hours before Day 1 of each cycle.
Other studies of amivantamab (with or 
without lazertinib or chemotherapy) 
have similar requirements.
10.2.6 Committees 
Structure
Added timing of the first IDMC meeting as 
occurring after 50 participants are randomized 
and complete at least 2 cycles of treatment.
The original protocol did not specify 
timing of the first IDMC meeting.
Throughout the 
protocol
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted

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11.
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Status: Approved,  Date: 05 April 2024
Janssen Research & Development *
Clinical Protocol
GUIDANCE ON STUDY CONDUCT DURING NATURAL DISASTER /MAJOR 
DISRUPTION/PANDEMIC
Protocol Title
A Phase 3, Open-Label, Randomized Study of Amivantamab and Lazertinib in 
Combination with Platinum-Based Chemotherapy Compared with Platinum-Based 
Chemotherapy in Patients with EGFR-Mutated Locally Advanced or Metastatic Non-
Small Cell Lung Cancer After Osimertinib Failure
MARIPOSA-2
Protocol 61186372NSC3002; Phase 3
JNJ-61186372  (amivantamab) and JNJ-73841937 (lazertinib)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. 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). Studies conducted at sites in the 
European Economic Area (EEA) will be conducted under Regulation [EU] No 536/2014.
Regulatory Agency Identifier Number(s):
IND:  146319
EU Trial NUMBER: 2023-506518-33
Status:
       Approved
Date:
       05 April 2024
Prepared by:
       Janssen Research & Development, LLC  
EDMS number:
EDMS-RIM-1251528, 1.0
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.
NCT04988295

Guidance on Study Conduct During Natural Disaster/Major Disruption/Pandemic
JNJ-61186372 (amivantamab) and JNJ-73841937 lazertinib
Clinical Protocol 61186372NSC3002
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Status: Approved,  Date: 05 April 2024
Study Conduct During a Natural Disaster/Major Disruption/Pandemic
GUIDANCE ON STUDY CONDUCT DURING NATURAL DISASTER/ MAJOR 
DISRUPTION/PANDEMIC
It is recognized that the natural disaster/major disruption/pandemic may have an impact on the 
conduct of this clinical study due to, for example, isolation or quarantine of participants and study 
site personnel; travel restrictions/limited access to public places, including hospitals; study site 
personnel being unavailable, isolated, or reassigned to critical tasks.
The sponsor is providing options for study related participant management in the event of 
disruption to the conduct of the study. This guidance does not supersede any local or government 
requirements or the clinical judgement of the investigator to protect the health and well-being of 
participants and site staff. If, at any time, a participant’s travel to the study site is considered to be 
dangerous, study participation may be interrupted, and study follow-up conducted. If it becomes 
necessary to discontinue participation in the study, the procedures outlined in the protocol for 
discontinuing study intervention will be followed.
If, as a result of the natural disaster/major disruption/pandemic scheduled visits cannot be 
conducted in person at the study site, they will be performed to the extent possible 
remotely/virtually or delayed until such time that on-site visits can be resumed. At each contact, 
participants will be interviewed to collect safety data. Key efficacy endpoint assessments should 
be performed if required and as feasible. Participants will also be questioned regarding general 
health status to fulfill any physical examination requirement. 
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow up. Modifications to protocol-required assessments may be 
permitted after consultation with the participant, investigator, and the sponsor. Missed 
assessments/visits will be captured in the clinical trial management system for protocol deviations. 
Discontinuations of study interventions and withdrawal from the study should be documented with 
the prefix “Natural Disaster-related”/Major Disruption-related/Pandemic-related” (eg, “Regional 
crisis”, "COVID-19-related") in the eCRF
NATURAL DISASTER/MAJOR DISRUPTION (eg, regional crisis): The sponsor will continue 
to monitor the conduct and progress of the clinical study, and any changes will be communicated 
to the sites and to the health authorities according to local guidance. Modifications made to the 
study conduct as a result of the natural disaster/major disruption should be summarized in the 
clinical study report.
PANDEMIC (eg, COVID-19): If the participant has tested positive for the pandemic 
(eg, COVID-19), the investigator should contact the sponsor’s responsible medical officer to 
discuss plans for administration of study intervention, performing. study assessments, and follow-
up. Modifications made to the study conduct as a result of the pandemic (eg, COVID-19) should 
be summarized in the clinical study report.

Guidance on Study Conduct During Natural Disaster/Major Disruption/Pandemic
JNJ-61186372 (amivantamab) and JNJ-73841937 lazertinib
Clinical Protocol 61186372NSC3002
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Status: Approved,  Date: 05 April 2024
Consent/Screening

Consenting of participants for study screening can be performed remotely by telephone or 
video conferencing per local policies and regulations. Re-consenting of active participants due 
to new safety information or updated study design should also be assessed for its feasibility 
to be conducted remotely per local policies and regulations.

All screening procedures and assessments must be conducted per protocol at the investigative 
site. 

During screening of participants, the investigator should evaluate the feasibility of participants 
returning for scheduled dosing visits per protocol based on history of exposure to a pandemic 
and local travel restrictions due to a natural disaster or major disruption. If the situation 
suggests that this is not possible, the participant may be screen failed and re-screened when 
conditions improve.

Screening procedures to a pandemic that may be mandated by local healthcare systems do not 
need to be reported as an amendment to the protocol even if done during clinical study visits.

As SARS-CoV-2 represents a new infectious agent, and COVID-19 a new clinical syndrome, 
it is unclear how infection with this virus will impact the benefit/risk assessment with regards 
to study treatment, particularly given its association with the risk of severe viral pneumonia. 
As per the study exclusion criteria, participants with active infection, including viral illnesses 
such as COVID-19, should be excluded from study participation.
Study Treatment 
Study treatment should continue to be administered at the investigative site in accordance with the 
protocol. Potential interruptions to therapy should be assessed on a case-by-case basis and include 
consideration of potential impact on participant’s safety. If doses are missed or delayed due to 
natural disaster, major disruption or pandemic related circumstances, these deviations should be 
noted in the appropriate eCRF page, as “missed or delayed due to natural disaster/major 
disruption/pandemic”, as applicable. The sponsor’s medical monitor should be alerted to any 
anticipated interruption in study treatment.
Study treatment should be held for all participants with suspected (symptomatic) or documented 
SARS-CoV-2 positive disease, until recovery from all infection-related symptoms. The latest 
official guidance (eg, United States Food and Drug Administration, American Society of Clinical 
Oncology, European Society of Medical Oncology) should be followed and treatment decisions 
should be made in consultation with the medical monitor. Given the unmet medical need of this 
study population, and the unknown impact of prior COVID-19 infection on the risk of study 
treatment, re-initiation of study treatments should be evaluated with the medical monitor on a 
case-by-case basis, taking into account the severity of the COVID-19 related symptoms, and the 
observed clinical benefit from study treatment. Please report the event to the sponsor, following 
usual adverse event (AE) reporting requirements.
Note: Administration of non-live vaccines approved or authorized for emergency use 
(eg, COVID-19) by local health authorities are allowed before or during this study.

Guidance on Study Conduct During Natural Disaster/Major Disruption/Pandemic
JNJ-61186372 (amivantamab) and JNJ-73841937 lazertinib
Clinical Protocol 61186372NSC3002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved,  Date: 05 April 2024
Treatment and Follow-up Visits
All study visits and assessments specified in the Schedule of Activities including key efficacy 
endpoint assessments should be followed in accordance to the protocol, unless natural disaster, 
major disruption, or pandemic related staffing shortages, site policies, or travel restrictions render 
these infeasible. In such cases, the following modifications may be implemented:

If study imaging procedures cannot be performed at the active clinical study site, 
participants will be permitted to use other local imaging facilities (eg, at hospitals that are 
not the active study site). In these cases, digital copies should be made available to the 
investigator for submission to the central imaging vendor. 

Safety evaluations (eg, laboratory assessments) may be conducted at certified testing and 
triage facilities or at other local hospitals. Records for these evaluations must be available 
for the investigator to review prior to dosing and copies of the results should be included 
in the participant’s study chart as a source document.
Audits

During the natural disaster/major disruption/pandemic (eg, COVID-19) at the impacted sites, 
clinical site Good Clinical Practice (GCP) audits with direct impact/engagement with the 
clinical Investigator team will not be conducted to comply with national, local and/or 
organizational restrictions. Additional quality assurance activities such as remote audits or 
focused review of study-related documents may take place with limited impact/engagement, 
if possible.
Telemedicine/Teleconferencing/Videoconferencing:
If the participant is doing well and has no safety concerns, scheduled visits that cannot be 
conducted in person at the study site will be performed to the extent possible remotely/virtually 
(eg, conducted via phone or computer), where feasible, or delayed until such time which access is 
determined to be appropriate by the Investigator and Sponsor. At each telephone or telemedicine 
contact:

Review of new, and follow-up of existing, AEs and concomitant medications between
regularly scheduled on-site visits (eg, weekly assessments of AEs leading to treatment 
delay).

The participant can complete any scheduled patient-reported outcome (PRO) assessments.

Review of body systems and collection of general health status (to be followed up with 
in-person examination if indicated) prior to dosing days, if consistent with site’s typical 
practice.

Study assessments requiring investigator judgement should be conducted by the 
investigator. 

Guidance on Study Conduct During Natural Disaster/Major Disruption/Pandemic
JNJ-61186372 (amivantamab) and JNJ-73841937 lazertinib
Clinical Protocol 61186372NSC3002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved,  Date: 05 April 2024
Home Health Care
Blood sample collection may be done at the participant’s home by mobile study personnel 
(ie, nurse or mobile phlebotomist) or at a commercial laboratory (eg, LabCorp). Other programs 
may be implemented with approval from the sponsor, such as Home Health Care Visits on a 
case-by-case basis for study assessments and procedures (eg, physical exam), where feasible and 
permissible by local policy and regulations. Study treatment with amivantamab and/or 
chemotherapy will only be administered at the study site and will not be administered at Home 
Health Care Visits.
Flexibility for all protocol-required assessments will be provided on a case-by-case basis, and with 
agreement between the sponsor and investigator. However, every effort should be made to adhere 
to protocol-specified assessments, including follow-up, if it is in the best interest of the participant. 
Monitoring Visits
When on-site monitoring by the sponsor is not feasible due to changes in hospital or clinic’s 
visitation policies, the sponsor’s site monitor will contact the study site to schedule remote visits. 
In such cases, on-site monitoring visits will resume when feasible, with increased frequency to 
address the source data verification backlog.
Even with staffing limitations during a natural disaster, major disruption, or pandemic, all routine 
operations related to clinical trials should be well-documented and archived as part of standard 
process. When conditions permit, all parties involved in this clinical trial should communicate 
relevant information in a timely manner so that all relevant parties remain sufficiently informed 
to take any necessary measures in a timely manner.
Transfer of study subjects:
For regions significantly impacted by the major disruption, the investigator and sponsor may
explore the possibility of transferring subjects to nearby, less impacted study sites (if warranted). 
In addition, for subjects relocating to other countries, on either a temporary or permanent basis, 
transfer to existing study sites in these countries may be explored. The sponsor should be informed 
of any decisions related to the transfer of subjects to other study sites prior to their transfer. In case 
there is an urgent need to open new trial site(s) for clinical trial visits, for example outside the 
hospital, this may be implemented by the sponsor per local Health Authority.