A Phase 3, Open-label, Randomized Study of Lazertinib With Subcutaneous Amivantamab Compared With Intravenous Amivantamab in Patients With EGFR-mutated Advanced or Metastatic Non-small Cell Lung Cancer After Progression on Osimertinib and Chemotherapy
Phase: PHASE3
Conditions: Advanced or Metastatic Non-small Cell Lung Cancer
Sponsor: Janssen Research & Development, LLC

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Status: Approved,  Date:  31 May 2024
Janssen Research & Development *
Clinical Protocol
A Phase 3, Open-label, Randomized Study of Lazertinib with Subcutaneous Amivantamab 
Compared with Intravenous Amivantamab in Patients with EGFR-mutated Advanced or 
Metastatic Non-small Cell Lung Cancer After Progression on Osimertinib and 
Chemotherapy
PALOMA-3
Protocol 61186372NSC3004; Phase 3
Version: Amendment 5
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 [EU] No 536/2014.
Regulatory Agency Identifier Number(s):
IND: 146319
EudraCT NUMBER: 2022-000525-25
EU TRIAL NUMBER: 2024-512045-16
Status:
Approved
Date:
31 May 2024
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-RIM-594424, 7.0
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.
NCT05388669

JNJ-61186372  (amivantamab) and JNJ-73841937 (lazertinib) Clinical Protocol 61186372NSC3004 Amendment 5
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Status: Approved,  Date:  31 May 2024
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 5
31 May 2024
Amendment 4
21-Nov-2023
Amendment 3
11-Aug-2023
Amendment 2
27-Oct-2022
Amendment 1
25-Aug-2022
Original Protocol
12-Apr-2022
Amendment 5 (31 May 2024)
Overall Rationale for the Amendment:
To continue providing participants access to study treatment and collect data of clinical 
relevance/importance while reducing the burden on participants after the primary analysis by adding an 
long-term extension (LTE) phase to the study.
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 61186372NSC3004 as part of Protocol Amendment 5 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.
Section Number
and Name
Description of Change
Brief Rationale
Title Page
Added text on EU regulation and EU Trial 
number.
To comply with the EU CTR 
requirements.
1.1. Synopsis
The Investigational New Drug Application
(IND) number, European Union Drug 
Regulating Authorities Clinical Trials 
Database (EudraCT) 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.
1.2. Schema
Updated the study schematic to include the 
LTE Phase.
To add the LTE Phase to the 
overall study design.
1.1. Synopsis (Study 
Design)
A description of the LTE Phase was added, 
with cross-references to the newly added 
appendix.
To add the LTE Phase to the 
overall study design.
4.1.4. Long-term Extension 
Phase
1.3.1. Schedule of 
Activities (SoA): Table 1
Added text to the title to indicate that the 
Schedule of Activities for the LTE Phase is
provided in Table 13.
To distinguish the Schedules of 
Activities in the main study from 
that in the LTE Phase.
1.3.3. Schedule of 
Activities for the Long-term 
Extension Phase
New section added for the study procedures 
for the LTE Phase.
To add the LTE Phase to the 
overall study design.
5.4. Screen Failures
Added text related to Interactive Web 
Response System (IWRS) to align with the 
sponsor template.
To clarify the use of IWRS.
6.1. Study Treatments
Administered
Added a new table categorizing the study 
treatments as Investigational Medicinal 
Products (IMPs) or Non-Investigational 
To comply with the EU CTR 
requirements.

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Medicinal Products (NIMPs)/Auxiliary 
Medicinal Products (AxMPs).
6.6. Continued Access to 
Study Treatment After the 
End of the Study
Text referring to the LTE Phase was added.
For guidance on details related 
to continued access to study 
treatment for participants who 
are still benefiting from study 
treatment.
10.2.4. Recruitment 
Strategy
New section added to describe the recruitment 
strategy.
To comply with the EU CTR 
requirements.
10.2.14. Record Retention
Added text regarding record retention under 
EU regulation.
To comply with the EU CTR 
requirements.
10.15. Appendix 15: Long-
term Extension Phase (new 
appendix)
The study design was modified to include a 
new study phase (an LTE Phase), whose 
purpose is to continue providing participants 
access to study treatment while further 
reducing the burden on participants. 
To provide detailed information 
on study conduct during the LTE 
Phase.
Throughout the protocol
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted.

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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 8
1.
PROTOCOL SUMMARY ..................................................................................................................... 9
1.1.
Synopsis........................................................................................................................................... 9
1.2.
Schema .......................................................................................................................................... 12
1.3.
Schedule of Activities (SoA)........................................................................................................... 13
1.3.1.
Schedule of Activities.................................................................................................................. 14
1.3.2.
Collection Times for PK and Immunogenicity Samples.............................................................. 17
1.3.3.
Schedule of Activities for the Long-term Extension Phase......................................................... 19
2.
INTRODUCTION................................................................................................................................ 20
2.1.
Study Rationale.............................................................................................................................. 20
2.2.
Background .................................................................................................................................... 21
2.2.1.
Non-small Cell Lung Cancer....................................................................................................... 21
2.2.2.
Amivantamab (JNJ-61186372)................................................................................................... 22
2.2.2.1.
Amivantamab IV ...................................................................................................................... 22
2.2.2.2.
Amivantamab SC-CF............................................................................................................... 23
2.2.3.
Lazertinib (JNJ-73841937) ......................................................................................................... 23
2.2.4.
Amivantamab IV and Lazertinib Combination Therapy.............................................................. 24
2.3.
Benefit-Risk Assessment ............................................................................................................... 25
2.3.1.
Risks for Study Participation....................................................................................................... 25
2.3.2.
Benefits for Study Participation .................................................................................................. 26
2.3.3.
Benefit-Risk Assessment for Study Participation ....................................................................... 26
3.
OBJECTIVES AND ENDPOINTS ..................................................................................................... 28
4.
STUDY DESIGN ................................................................................................................................ 29
4.1.
Overall Design................................................................................................................................ 29
4.1.1.
Screening.................................................................................................................................... 30
4.1.2.
Treatment Phase ........................................................................................................................ 30
4.1.3.
Follow-up Phase......................................................................................................................... 31
4.1.4.
Long-term Extension Phase ....................................................................................................... 31
4.2.
Scientific Rationale for Study Design............................................................................................. 32
4.2.1.
Study-Specific Ethical Design Considerations ........................................................................... 32
4.3.
Justification for Dose...................................................................................................................... 33
4.3.1.
Amivantamab IV Dose................................................................................................................ 33
4.3.2.
Amivantamab SC-CF Dose ........................................................................................................ 33
4.3.3.
Lazertinib Dose........................................................................................................................... 34
4.4.
End of Study Definition................................................................................................................... 34
5.
STUDY POPULATION ...................................................................................................................... 34
5.1.
Inclusion Criteria ............................................................................................................................ 35
5.2.
Exclusion Criteria ........................................................................................................................... 37
5.3.
Lifestyle Considerations................................................................................................................. 40
5.4.
Screen Failures .............................................................................................................................. 41
5.5.
Criteria for Temporarily Delaying Randomization .......................................................................... 41
6.
STUDY TREATMENT AND CONCOMITANT THERAPY ................................................................ 42
6.1.
Study Treatments Administered..................................................................................................... 42
6.1.1.
Scheduled Dosage and Timing .................................................................................................. 45
6.1.2.
Amivantamab SC-CF by Manual Injection (Arm A) .................................................................... 45
6.1.3.
Amivantamab IV (Arm B)............................................................................................................ 45
6.1.4.
Lazertinib .................................................................................................................................... 46

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6.2.
Preparation/Handling/Storage/Accountability ................................................................................ 46
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................................. 47
6.4.
Study Treatment Compliance ........................................................................................................ 48
6.5.
Dose Modification........................................................................................................................... 48
6.5.1.
Dose Delay Guidance................................................................................................................. 48
6.5.2.
Dose Modification of Amivantamab and Lazertinib .................................................................... 49
6.5.3.
Dose Modification and Management of Specific Adverse Events.............................................. 51
6.5.3.1.
Infusion-Related Reactions and Local Administration-Related Reactions.............................. 51
6.5.3.2.
Rash-related Adverse Events.................................................................................................. 56
6.5.3.3.
Suspected Pulmonary Toxicity ................................................................................................ 59
6.5.3.4.
Cardiac Adverse Events .......................................................................................................... 59
6.5.3.5.
Liver Chemistry Abnormalities................................................................................................. 60
6.5.3.6.
Pruritus .................................................................................................................................... 61
6.5.3.7.
Paronychia............................................................................................................................... 62
6.5.3.8.
Oral Mucositis.......................................................................................................................... 62
6.5.3.9.
Diarrhea................................................................................................................................... 63
6.5.3.10.
Venous Thromboembolic Events............................................................................................. 64
6.6.
Continued Access to Study Treatment After the End of the Study................................................ 65
6.7.
Treatment of Overdose .................................................................................................................. 65
6.8.
Concomitant Therapy..................................................................................................................... 65
6.8.1.
Recording Prestudy and Concomitant Therapies....................................................................... 65
6.8.2.
Permitted and Required Medications and Therapies ................................................................. 66
6.8.2.1.
Pre- and Post-dose Medications for Amivantamab................................................................. 66
6.8.2.2.
Supportive Care....................................................................................................................... 66
6.8.2.3.
Radiotherapy ........................................................................................................................... 66
6.8.3.
Prohibited or Restricted Medications and Therapies.................................................................. 66
7.
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................... 68
7.1.
Discontinuation of Study Treatment............................................................................................... 68
7.2.
Participant Discontinuation/Withdrawal From the Study................................................................ 68
7.2.1.
Withdrawal From the Use of Research Samples ....................................................................... 69
7.3.
Lost to Follow-up............................................................................................................................ 69
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 69
8.1.
Efficacy Assessments .................................................................................................................... 71
8.1.1.
Patient-Reported Outcomes ....................................................................................................... 71
8.2.
Safety Assessments....................................................................................................................... 72
8.2.1.
Physical Examinations................................................................................................................ 72
8.2.2.
ECOG Performance Status ........................................................................................................ 72
8.2.3.
Vital Signs................................................................................................................................... 73
8.2.4.
Electrocardiograms..................................................................................................................... 73
8.2.5.
LVEF measurements by echocardiography (ECHO) or Multigated Acquisition (MUGA) 
scan ............................................................................................................................................ 73
8.2.6.
Ophthalmologic Assessment ...................................................................................................... 73
8.2.7.
Pregnancy Testing...................................................................................................................... 74
8.2.8.
Clinical Safety Laboratory Assessments .................................................................................... 74
8.3.
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 74
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information.................................................................................................................................. 75
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 75
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 75
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 76
8.3.5.
Pregnancy................................................................................................................................... 76
8.3.6.
Disease-Related Events and Disease-Related Outcomes Not Qualifying as Adverse 
Events or Serious Adverse Events ............................................................................................. 76
8.3.7.
Adverse Events of Special Interest............................................................................................. 77
8.4.
Pharmacokinetic and Immunogenicity Assessments..................................................................... 77

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8.4.1.
Evaluations ................................................................................................................................. 77
8.4.2.
Analytical Procedures................................................................................................................. 77
8.4.3.
Pharmacokinetic Parameters and Evaluations........................................................................... 78
8.5.
Pharmacogenomics ....................................................................................................................... 78
8.6.
Biomarkers ..................................................................................................................................... 78
8.7.
Medical Resource Utilization and Health Economics .................................................................... 79
9.
STATISTICAL CONSIDERATIONS.................................................................................................. 79
9.1.
Statistical Hypotheses.................................................................................................................... 79
9.2.
Sample Size Determination ........................................................................................................... 80
9.3.
Populations for Analysis Sets ........................................................................................................ 82
9.4.
Statistical Analyses ........................................................................................................................ 82
9.4.1.
General Considerations.............................................................................................................. 82
9.4.2.
Primary Endpoints ...................................................................................................................... 83
9.4.3.
Secondary Endpoints.................................................................................................................. 83
9.4.4.
Exploratory Endpoint(s) .............................................................................................................. 86
9.4.5.
Safety Analyses .......................................................................................................................... 86
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 88
10.1.
Appendix 1: Abbreviations ............................................................................................................. 88
10.2.
Appendix 2: Regulatory, Ethical, and Study Oversight Considerations......................................... 90
10.2.1.
Regulatory and Ethical Considerations ...................................................................................... 90
10.2.2.
Financial Disclosure.................................................................................................................... 93
10.2.3.
Informed Consent Process ......................................................................................................... 93
10.2.4.
Recruitment Strategy.................................................................................................................. 95
10.2.5.
Data Protection ........................................................................................................................... 95
10.2.6.
Long-term Retention of Samples for Additional Future Research.............................................. 95
10.2.7.
Committees Structure................................................................................................................. 96
10.2.8.
Publication Policy/Dissemination of Clinical Study Data ............................................................ 96
10.2.9.
Data Quality Assurance.............................................................................................................. 97
10.2.10.
Case Report Form Completion................................................................................................... 98
10.2.11.
Source Documents ..................................................................................................................... 98
10.2.12.
Monitoring ................................................................................................................................... 99
10.2.13.
On-Site Audits........................................................................................................................... 100
10.2.14.
Record Retention...................................................................................................................... 100
10.2.15.
Study and Site Start and Closure ............................................................................................. 101
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............................................................................................................................... 102
10.3.1.
Adverse Event Definitions and Classifications ......................................................................... 102
10.3.2.
Attribution Definitions................................................................................................................ 103
10.3.3.
Severity Criteria ........................................................................................................................ 104
10.3.4.
Special Reporting Situations .................................................................................................... 104
10.3.5.
Procedures ............................................................................................................................... 105
10.3.6.
Product Quality Complaint Handling......................................................................................... 106
10.3.7.
Contacting Sponsor Regarding Safety, Including Product Quality........................................... 107
10.4.
Appendix 4: Anticipated Events ................................................................................................... 108
10.5.
Appendix 5: Contraceptive and Barrier Guidance ....................................................................... 110
10.6.
Appendix 6: Clinical Laboratory Tests ......................................................................................... 113
10.7.
Appendix 7: Liver Safety: Follow-up Assessments and Study Treatment Rechallenge 
Guidelines .................................................................................................................................... 114
10.8.
Appendix 8: Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference ........... 115
10.9.
Appendix 9: New York Heart Association Criteria ....................................................................... 117
10.10.
Appendix 10: Eastern Cooperative Oncology Group (ECOG) Performance Status Score ......... 118
10.11.
Appendix 11: Health Care Provider (HCP) - Ease of Use and Satisfaction Questionnaires ....... 119
10.12.
Appendix 12: Formulas for Estimating Glomerular Filtration Rate Using Modified Diet in 
Renal Disease Formula (in mL/min) ............................................................................................ 120
10.13.
Appendix 13: Allowed Recent Second or Prior Malignancies...................................................... 121

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10.14.
Appendix 14: Modified Therapy Administration Satisfaction Questionnaires for IV infusion 
(TASQ-IV) or SC injections (TASQ-SC)....................................................................................... 122
10.15.
Appendix 15: Long-term Extension Phase................................................................................... 127
10.15.1.
Eligibility Criteria ....................................................................................................................... 127
10.15.2.
Study Treatment Administration ............................................................................................... 127
10.15.3.
Study Procedures ..................................................................................................................... 127
10.16.
Appendix 16: Protocol Amendment History ................................................................................. 129
11.
REFERENCES................................................................................................................................. 142
INVESTIGATOR AGREEMENT ............................................................................................................... 144

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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Schedule of Activities................................................................................................................ 14
Table 2:
Collection Times for PK and Immunogenicity Samples a ......................................................... 17
Table 3:
Mitigation Strategies for Possible Risks Associated with amivantamab and lazertinib ............ 25
Table 4:
Guidance for Withholding Doses for Toxicities Based on Grade ............................................. 50
Table 5:
Guidance for Lazertinib Stepwise Dose Reduction .................................................................. 51
Table 6:
Guidance for Amivantamab Stepwise Dose Reduction............................................................ 51
Table 7:
Predose Medications for Amivantamab (all arms).................................................................... 53
Table 8:
Postdose Medications for Amivantamab (all arms) .................................................................. 54
Table 9:
Management of Infusion-related Reactions.............................................................................. 55
Table 10:
Suggested Algorithm for Management of Rash........................................................................ 58
Table 11:
Suggested Algorithm for Management of Diarrhea .................................................................. 64
Table 12:
Anticipated Events .................................................................................................................. 108
Table 13:
Schedule of Activities in the Long-term Extension Phase (All Arms, Unless Otherwise 
Indicated) ................................................................................................................................ 128
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 12
Figure 2: 
Primary and Key Secondary Endpoints Testing Strategy......................................................... 80

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1.
PROTOCOL SUMMARY
1.1.
Synopsis
IND: 146319
EudraCT NUMBER: 2022-000525-25
EU TRIAL NUMBER: 2024-512045-16
A Phase 3, Open-label, Randomized Study of Lazertinib with Subcutaneous Amivantamab Compared with 
Intravenous Amivantamab in Patients with EGFR-mutated Advanced or Metastatic Non-small Cell Lung 
Cancer After Progression on Osimertinib and Chemotherapy.
Amivantamab (JNJ-61186372) is a low fucose, fully human IgG1-based bispecific antibody directed 
against epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (cMET)
tyrosine kinase receptor that is being developed for the treatment of solid tumors, including EGFR-mutated 
non-small cell lung cancer (NSCLC). Amivantamab administered intravenously is conditionally approved 
by the FDA for patients with EGFR Exon 20ins mutations after treatment with chemotherapy. 
In this study subcutaneous amivantamab will be administered as a co-formulation with recombinant human 
hyaluronidase (rHuPH20). This combination will be designated as amivantamab subcutaneous and
co-formulated with recombinant human hyaluronidase (SC-CF) throughout the protocol.
This is a Phase 3, open-label, randomized study to demonstrate the pharmacokinetic noninferiority of 
amivantamab SC-CF administered via manual injection compared with amivantamab IV, both in 
combination with lazertinib.
Lazertinib (JNJ-73841937) is an oral, highly potent, third-generation, irreversible EGFR tyrosine kinase 
inhibitor (TKI) with no demonstrated pharmacokinetic (PK) interaction with amivantamab. It selectively 
inhibits both activating EGFR mutations (Exon 19del, L858R) and the EGFR T790M resistance mutation 
while showing mutant-selective activity for EGFR. 
BENEFIT-RISK ASSESSMENT
The safety and tolerability of amivantamab and lazertinib in combination has been investigated in several 
studies.
This study protocol includes elements to mitigate unforeseen safety risks for study participants. In addition 
to monitoring participants closely for safety throughout the study, an Independent Data Monitoring 
Committee (IDMC) will be commissioned to review efficacy, safety and tolerability data periodically. Dose 
modification guidance is also provided to manage toxicities that occur during the study.
Amivantamab, lazertinib, and the combination have each demonstrated activity in patients with locally 
advanced or metastatic NSCLC with EGFR mutations. Amivantamab, as a monotherapy or in combination 
with lazertinib, has demonstrated activity in the osimertinib-relapsed setting. It is anticipated that lazertinib 
will have similar benefits to osimertinib, and that combining the targeted therapies, amivantamab and 
lazertinib, will be more effective than either targeted monotherapy for the treatment of NSCLC with EGFR 
Exon 19del or L858R mutations, by delaying or preventing the emergence of resistance to third generation 
TKI therapy mediated by either the EGFR or cMET pathways.
Taking into account the measures taken to minimize risk to participants of this study, the possible risks 
identified in association with amivantamab and lazertinib are justified by the anticipated benefits that may 
be afforded to participants, locally advanced or metastatic NSCLC with EGFR Exon 19del or Exon21 
L858R mutations.

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OBJECTIVES AND ENDPOINTS
The primary objective is to assess the pharmacokinetic noninferiority of amivantamab SC-CF via manual 
injection versus amivantamab IV. Key secondary objectives are to assess efficacy (objective response rate 
[ORR] and progression-free survival [PFS]) and safety of the different administrations.
Exploratory objectives are described in Section 3.
Hypotheses
The primary hypothesis of the study is that amivantamab SC-CF, administered via manual injection at the 
SC recommended Phase 2 dose (RP2D), exhibits a PK profile that is noninferior to amivantamab 
administered at the IV recommended dose in participants with locally advanced or metastatic NSCLC with 
EGFR Exon 19del or Exon 21 L858R mutations whose disease has progressed on or after treatment with 
osimertinib (or another approved 3rd generation EGFR TKI) and platinum-based chemotherapy.
OVERALL DESIGN
Study 61186372NSC3004 (PALOMA-3) is a randomized, open-label, parallel, multicenter, Phase 3 study, 
which will optimize the administration of amivantamab in participants with EGFR mutated locally 
advanced or metastatic NSCLC who have progressed on or after treatment with osimertinib (or another 
approved 3rd generation EGFR TKI) and platinum-based chemotherapy. The study will compare the PK, 
efficacy, and safety of combining lazertinib with amivantamab SC-CF administered via manual injection 
(Arm A) versus amivantamab IV (Arm B).
The study will include Screening (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).
Participants who continue to benefit from study treatment(s), as determined by their investigator, after 
completion of the primary analysis may continue to receive access to study treatment(s) within the study 
by transferring to the long-term extension (LTE) Phase, where only serious adverse event data and the study 
treatment compliance will be collected. The LTE Phase will continue to provide participants access to study 
treatment and further reduce protocol-required visit procedures and assessments, after the primary analysis 
is complete.
The LTE Phase will begin after the primary analysis, and will continue until the discontinuation criteria are 
met, or until 3 years after local marketing authorization is obtained, whichever occurs first. For transition 
to the LTE Phase (after the primary analysis), notification from the sponsor will be provided.
NUMBER OF PARTICIPANTS
A target of 400 participants will be enrolled in this study and will be randomized 1:1 between Arms A and 
B. Randomization will be stratified by brain metastases at baseline (yes vs no), EGFR mutation (L858R vs 
Exon19del), race (Asian vs non-Asian), and last therapy (osimertinib [or another approved 3rd generation 
EGFR TKI] vs chemotherapy).
TREATMENT
All participants will receive lazertinib 240 mg orally once daily.
In Cycle 1:

Amivantamab SC-CF by manual injection, doses at 1,600 mg (2,240 mg if body weight (BW) ≥80 kg)
will occur on Days 1, 8, 15, and 22, or

Amivantamab IV infusion doses at 1,050 mg (1,400 mg if BW ≥80 kg) will occur on Days 1--2 (split 
dose), 8, 15, and 22. 

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Starting in Cycle 2, doses will occur on Day 1 and 15 of each 28-day cycle, as one of the following:

amivantamab SC-CF by manual injection at 1,600 mg (2,240 mg if BW ≥80 kg), or

amivantamab by IV infusion at 1,050 mg (1,400 mg if BW ≥80 kg)
EFFICACY EVALUATIONS
Disease assessment will be performed using CT, MRI, and other imaging/examination, as applicable, of the 
chest, abdomen, pelvis, brain, and any other known disease location at Screening, 6 (+1) weeks from 
randomization, every 6 (±1) weeks for the first 18 months, then every 12 (±1) weeks thereafter until 
progressive disease (PD). Tumor response will be assessed by the investigator according to Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 
PHARMACOKINETIC EVALUATIONS
Blood samples will be collected from participants to assess the serum concentration of amivantamab and 
the plasma concentration of lazertinib. Samples will be analyzed using a validated method by or under the 
supervision of the sponsor. Serum and plasma PK samples may be stored for future analysis.
IMMUNOGENICITY EVALUATIONS
Blood samples will be collected to assess the generation of antibodies to amivantamab and to rHuPH20.
EASE OF USE AND SATISFACTION QUESTIONNAIRE
For all participants, health care professionals (HCPs) will evaluate the administration of the therapy with 
an Ease of Use and Satisfaction Questionnaire.
PATIENT-REPORTED OUTCOMES
Cancer therapy satisfaction in participants will be assessed using the modified Therapy Administration 
Satisfaction Questionnaire (TASQ).
MEDICAL RESOURCE UTILIZATION
Time and motion studies will evaluate participant chair time, treatment room time, duration of treatment 
administration, and active HCP time for drug preparation, treatment administration, and post-treatment 
monitoring.
SAFETY EVALUATIONS
Safety will be assessed by physical examinations, vital signs, electrocardiograms, echocardiograms, 
ophthalmologic assessments, laboratory tests, AE frequency and severity (by Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0) monitoring, and concomitant medication use.
BIOMARKER EVALUATIONS
Blood samples collected from participants will undergo circulating tumor deoxyribonucleic acid (ctDNA)
analysis by the sponsor to evaluate pretreatment mutational status of EGFR, cMET, and other key 
oncogenes to characterize the tumor. Blood samples will also be collected for potential analysis of 
circulating biomarkers (eg, cytokines, growth factors) in samples taken before and after exposure to study 
treatment(s). Additional biomarkers (eg, DNA, RNA, and protein) relevant to cancer and/or metabolism of 
study treatments may also be assessed.

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STATISTICAL METHODS
The study is designed to establish noninferiority based on the co-primary pharmacokinetic endpoints, Ctrough
of amivantamab (at steady state [Cycle 4 Day 1] for all regions other than EU and others accepting Cycle 
2 Day 1 and pre-dose on Cycle 2 Day 1 for EU and any applicable region) and AUCD1-D15 in Cycle 2, 
between amivantamab SC-CF and amivantamab IV. Amivantamab SC-CF will be considered noninferior 
to IV if the lower bound of the 90% CI for the ratio of the geometric means of Ctrough (at steady state [Cycle 
4 Day 1] for all regions other than EU and others accepting Cycle 2 Day 1 and pre-dose on Cycle 2 Day 1 
for EU and any applicable region) and AUCD1-D15 in Cycle 2 is at least 80% (noninferiority margin of 20%). 
The planned 400 participants (200 from Arm A and 200 from Arm B) will provide a power >95% for a 
one-sided alpha of 0.05 for each of the endpoints. This assumes a true geometric mean ratio of Ctrough to be 
1 and a true geometric mean ratio of the AUCD1-D15 to be 1 between the 2 treatment groups, and a coefficient 
of variation (CV) of 56% for both endpoints. 
1.2.
Schema
Figure 1:
Schematic Overview of the Study
C#=Cycle #; CF=co-formulation; IV=intravenous; LTE= long-term extension; QD=once daily; QW=once weekly; 
Q2W=every 2 weeks; SC=subcutaneous.
NOTE: Stratification factors for randomization: brain metastases at baseline (yes vs no), EGFR mutation (L858R vs 
Exon19del), race (Asian vs non-Asian), last therapy (osimertinib [or another approved 3rd generation EGFR 
TKI] vs chemotherapy).
‡
Cycle 1 for IV: Days 1-2 (Day 2 applies to IV split dose only), 8, 15, and 22; Cycle 1 for SC: Days 1, 8, 15, and 
22; Cycle 2 for all: Days 1, 15
*
The 400 participants will be randomized between Arms A and B. 

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1.3.
Schedule of Activities (SoA)
Tables reflecting the Schedule of Activities are presented in this section, including sample 
collection schedules for PK and immunogenicity. 
Dose schedules and pretreatment medications are presented in Section 6.1.

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b.
The C1D2 Visit and all of the activities shown for that day only apply to participants randomized to Arm B, ie, those who will receive IV amivantamab split dose over Cycle 1 Day 1 
and 2.
c.
Minimum criteria for the availability of documentation supporting the eligibility criteria are described in Source Documentation in Appendix 2: Regulatory, Ethical, and Study 
Oversight Considerations. A copy of the initial test report documenting the EGFR mutation must be included in the participant records and a deidentified copy must also be 
submitted to the sponsor.
d.
HIV, HBV and HCV (all participants). HIV viral load and CD4 count for known HIV-positive participants only.
e.
Serum test required at Screening; urine test may be used at all other times. Test within 72 hrs before Day 1 of each cycle or monthly, whichever is more frequent.
f.
Including slit lamp examination, fundoscopic examination, and visual acuity test. See Section 8.2.6.
g.
Symptom-directed PE as clinically indicated of involved organs and other body systems, with clinically significant abnormalities reported as AEs. Record weight on D1 of each 
cycle. See Section 8.2.1. Evaluate for early signs and symptoms of VTE. Focused physical examination of extremities and evaluation of respiratory status (including pulse oximetry) 
should be performed.
h.
Heart rate, blood pressure, temperature, and O2 saturation. See Section 8.2.3. For participants receiving IV amivantamab, collect vital sign measurements ≤30 minutes before 
amivantamab infusion, at 30-minute intervals (±5 minutes) during each amivantamab infusion, and at the end of the infusion (±5 minutes). 
i.
Single ECG at Screening. In case of abnormal results, confirm with triplicate ECG. See Section 8.2.4.
j.
Continue until PD. For participants who discontinue treatment prior to PD, tumor imaging should continue until PD is documented. If participant begins a new anticancer therapy 
before PD, obtain tumor imaging before the new therapy. If a participant receives study treatment beyond confirmed documented PD, continue disease assessments as scheduled.
k.
Collect information on type of therapy, start date, and stop date.
l.
Start study treatment within 3 days of randomization.
m.
Complete the PGIS before any tests or procedures. Complete the modified TASQ after study drug administration, and then complete the PGIC.
n.
At EoT, blood sample within 30 days of PD; obtain before next anti-cancer therapy. If participant receives study treatment(s) beyond PD, collect additional samples at each post-
progression disease assessment. If unable to collect during the disease evaluation visit, the sample may be collected at the next visit prior to subsequent study treatment 
administration.
o.
Record all prescription and over-the-counter treatments administered up to 28 days before randomization through 30 days after the last dose of study treatment (or the start of a 
subsequent systemic anticancer therapy, if earlier); >30 days after the last dose of study treatment in conjunction with SAEs considered related to study treatment, until resolution of 
event or start of subsequent anticancer therapy. For participants with Grade 3 or 4 AEs considered related to study drug, record concomitant medications through the end of follow-
up of that AE.
p.
Continuous from the time ICF is signed through 30 days after last dose of study treatment (or >30 days for an SAE, if considered related to study treatment).
q.
Time and motion studies will evaluate participant chair time, treatment room time, duration of treatment administration, and active HCP time for drug preparation, treatment 
administration, and post-treatment monitoring.
r.
The questionnaire is to be filled out once per participant. 
s.
See Section 6 and the IPPI for study treatment administration instructions. A missed dose is defined as failure to administer study treatment within 1 day of the scheduled dosing date 
in Cycles 1 and 2, or failure to administer study treatment within 7 days of the scheduled dosing date in Cycle 3 and beyond. If a dose is missed, as defined above, it will not be made 
up. Administration may resume at the next planned dosing date. 
t.
Prophylactic-dose anticoagulation is recommended during the first 4 months of treatment. Refer to Section 6.5.3.10 for additional information. Refer to NCCN guidelines Version 
1.2022 Cancer-Associated Venous Thromboembolic Disease, Section VTE-B for examples of prophylactic-dose anticoagulants in ambulatory cancer patients.
u.
The exploratory biomarker sample is collected only on Day 1 of Cycles 1 to 4. No collection required for subsequent cycles.
v.
PK samples are collected on Day 1 of Cycles 5, 7, 9, and 11 (see Table 2).

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e.
If Cycle 4 Day 1 dose is delayed or withheld, the amivantamab serum PK sample should be collected on the planned day per protocol. This collection will be considered an 
unscheduled serum PK sample.

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1.3.3.
Schedule of Activities for the Long-term Extension Phase
Refer to Table 13 for the study procedures for the LTE Phase.

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2.
INTRODUCTION
This is a Phase 3, open-label, randomized study to demonstrate the pharmacokinetic noninferiority 
of amivantamab SC-CF administered via manual injection compared with amivantamab IV. In this 
study, amivantamab will be administered in combination with orally administered lazertinib. This 
study will compare amivantamab IV versus amivantamab SC-CF via manual injection.
Amivantamab (JNJ-61186372) is a fully human, low-fucose, IgG1-based bispecific Ab directed 
against the EGFR and cMET receptor. Amivantamab shows activity against tumors with primary 
activating EGFR mutations (Exon 19 deletion [Exon 19del], Exon 21 leucine 858 to arginine 
substitution ([L858R], and Exon 20ins mutations), EGFR resistance mutations (tyrosine 790 to 
methionine [T790M] or cysteine 797 to serine [C797S] mutations), overexpressed wild type 
EGFR, and activation of the cMET pathway. Lazertinib is an oral, highly potent, mutant-selective, 
and irreversible third-generation EGFR TKI that targets both the Exon 19del and the Exon 21 
L858R EGFR activating mutations, as well as the T790M resistance mutation. Lazertinib has 
demonstrated efficacy in participants with EGFR-mutated NSCLC, with activity observed in both 
systemic and central nervous system lesions, demonstrating its ability to cross the blood-brain 
barrier. Combining lazertinib, which targets the intracellular EGFR tyrosine kinase site, with 
amivantamab, which targets the extracellular EGFR ligand-binding domains, has the potential to 
more potently inhibit the EGFR signaling pathway, attenuate frequent EGFR dependent and 
independent resistance mechanisms to EGFR TKIs, and induce deeper responses than either agent 
alone.
For the most comprehensive nonclinical and clinical information regarding the combination of 
lazertinib with either amivantamab as monotherapy or in combination with chemotherapy, refer to 
the latest version of the IBs for amivantamab and lazertinib.
The term “study treatment” throughout the protocol, refers to amivantamab (JNJ-61186372) and/or 
lazertinib (JNJ-73841937) 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.
2.1.
Study Rationale
One of the most common side effects associated with amivantamab are IRRs, which were 
experienced by 64% of participants receiving amivantamab IV. The vast majority (97%) of IRRs 
occurred during the first infusion, with a median time to onset of 56 minutes. To mitigate the risk 
of IRRs, the initial dose of amivantamab is preceded by glucocorticoid premedication and is 
administered at reduced infusion rates, which requires splitting of the first dose over 2 days. 
Subsequent infusions within Cycle 1 occur at an increased rate, with maintenance doses (starting 
Cycle 2) administered over 2-hour infusions. These mitigations, which increase the time a patient 
spends in clinic, present a significant opportunity to improve both patient and health care provider 
experience with amivantamab.

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To simplify amivantamab administration and reduce dose times, a new formulation of 
amivantamab, amivantamab SC-CF, is being developed in the ongoing Phase 1 PALOMA study 
for subcutaneous administration. This formulation has the potential to enhance both the patient 
and physician experience with amivantamab by providing easier and accelerated administration 
via manual injection. 
This study is focused on participants with NSCLC with Exon 19 deletions and Exon 21 L858R 
mutations in EGFR who have progressed on or after both a third generation TKI and platinum 
based chemotherapy. Amivantamab in combination with lazertinib has demonstrated clinical 
activity in this patient population (Shu 2021). The rationale for conducting this study in this setting 
is based on 2 factors. First, previously-treated NSCLCs harboring an EGFR Exon 19del or Exon 
21 L858R mutation represents a large patient population with profound unmet medical needs. 
Second, in order to identify the impact of changing amivantamab from an IV administration to a 
SC route of administration, the ideal clinical setting is one where amivantamab is anticipated to be 
the major contributor to the observed anti-tumor activity. Among patients who have already 
experienced disease progression on the third generation EGFR TKI osimertinib (or another 
approved 3rd generation EGFR TKI), it is unlikely that the third-generation EGFR TKI lazertinib 
alone would have significant activity. Therefore, the ORR in this setting more closely reflects the 
clinical activity of amivantamab and is therefore the most appropriate clinical setting to 
demonstrate the non-inferiority of amivantamab SC versus amivantamab IV combinations. The 
pharmacokinetic results of this study are not expected to be affected by the line of therapy or 
combinations with agents that do not affect the pharmacokinetic profile of amivantamab. As a 
result, the results from this trial can potentially provide supportive data supporting future 
administration of amivantamab subcutaneous regimens.
2.2.
Background
2.2.1.
Non-small Cell Lung Cancer
Lung cancer is one of the most common types of cancer and is the most common cause of death 
from cancer. 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. The most prevalent of 
these driver mutations considered actionable 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, the Exon 19del and Exon 21 L858R point 
mutation, are identified in 80% to 85% of participants with activating EGFR mutations. The 
FLAURA study established the EGFR TKI osimertinib as the preferred front-line therapy for 
patients with metastatic NSCLC and Exon 19del or L858R mutations (Soria 2018).
Despite improved initial disease control, almost all patients treated with osimertinib will relapse, 
and there are no approved targeted therapies for the treatment of these patients. Notably, the most 
common mechanisms of resistance to osimertinib are based in the EGFR (EGFR amplification, 

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C797S mutation, and others) and cMET (cMET amplification, cMET Exon 14 skipping mutations, 
and others) genes. A targeted therapy with activity against both EGFR and cMET might be 
particularly relevant in this setting. Once emergence of resistance renders treatment with 
osimertinib ineffective, National Comprehensive Cancer Network (NCCN) treatment guidelines 
for advanced or metastatic NSCLC recommend platinum-based chemotherapy, such as carboplatin 
and pemetrexed, as the next line of therapy (NCCN 2021). The overall response rate (ORR) 
associated with this therapy, as determined in Phase 3 studies of similar populations, has been 
approximately 30%, with the median PFS of 4.4 months to 5.4 months (Mok 2017, Soria 2015).
After disease progression on platinum-based chemotherapy, treatment options are quite limited. 
The standard of care is single agent chemotherapy with an ORR of 14% (Garon, 2014). Therefore, 
treatment options for patients with EGFR-mutated NSCLC are limited after first-line or second-
line osimertinib, and there is a high unmet need for additional targeted therapies that further control 
the growth of tumors reliant on aberrant EGFR and/or cMET.
2.2.2.
Amivantamab (JNJ-61186372)
2.2.2.1.
Amivantamab IV
Amivantamab IV has been granted conditional approval by the FDA, EMA, and other health 
authorities for patients with EGFR Exon 20ins mutations whose disease has progressed on or after 
platinum-based chemotherapy. Unlike EGFR TKIs, which bind to the intracellular portion of the 
EGFR, amivantamab is a bispecific antibody that targets the extracellular domain of both EGFR 
and cMET, the 2 pathways most frequently involved in tumor resistance to EGFR TKIs. 
Amivantamab has a manageable safety profile, consistent with inhibition of EGFR and cMET 
pathways. In Study 61186372EDI1001, as of 17 Jan 2022, the most common TEAEs (ie, frequency 
≥20%) in participants (N=518) treated at the recommended dose were IRRs (67%), paronychia 
(43%), rash (36%) dermatitis acneiform (35%) hypoalbuminemia (30%), constipation (23%), 
nausea (23%) peripheral oedema (21%), stomatitis (20%), and dyspnea (20%). Nearly all IRRs 
occurred during the first infusion (Cycle 1 Day 1) and did not recur with subsequent infusions. 
TEAEs of Grade ≥3 severity were reported in 240 (46.3%) participants, with 98 (18.9%) of these 
participants experiencing TEAEs of Grade ≥3 severity reported as related to amivantamab by the 
investigator. The most common treatment-related TEAEs with Grade ≥3 severity (occurring in 
≥1% of participants) were IRR (2.5%), paronychia (1.9%), dermatitis acneiform, (1.7%), rash 
(1.5%), hypoalbuminemia (1.2%), and oedema peripheral (1.0%). There was no consistent pattern 
of treatment-related TEAEs of Grade ≥3 severity; only IRRs were reported in 2.5% of participants. 
(See Section 2.2.4 for additional details regarding Study 61186372EDI1001.)
Background information on the combination of amivantamab IV and lazertinib that is relevant to 
this study is provided in Section 2.2.4. For clinical information regarding the combination of 
lazertinib with either amivantamab IV as monotherapy or in combination with chemotherapy, refer 
to the latest version of the IB for amivantamab and for lazertinib.. 

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2.2.2.2.
Amivantamab SC-CF
The 61186372NSC1003 (PALOMA) study was initiated to evaluate the safety and effectiveness 
of amivantamab SC in participants with advanced solid malignancies. In this dose escalation study, 
amivantamab SC was administered to participants with a solid malignancy who were deemed by 
the investigators to possibly benefit from treatment with an EGFR- or cMET-directed therapy, 
with and without co-formulation with recombinant human hyaluronidase (rHuPH20), the active 
ingredient of the commercial product Hylenex® recombinant (hyaluronidase human injection). 
Hylenex®, which was approved for use in the United States in December 2005, is also approved 
in combination with multiple protein therapeutics for SC administration in the United States and 
European Union, such as HyQvia (Immune globulin infusion 10% [human] with recombinant 
human hyaluronidase), as well as anticancer medications such as Herceptin® SC (trastuzumab), 
MabThera® SC (rituximab), Rituxan Hycela® SC (rituximab), and subcutaneous Darzalex 
(Darzalex Faspro® in the US [daratumumab]).
Study 61186372NSC1003 is an open-label, non-randomized, multicenter, Phase 1b, 3-part study 
evaluating the PK, safety, and antitumor activity of amivantamab SC in participants with advanced 
solid malignancies using different formulations (low concentration and high concentration 
formulations of amivantamab SC, with and without rHuPH20). Part 1 consists of 2 cohorts 
(approximately 8 participants per cohort), with participants receiving amivantamab SC at the same 
concentration and dose used for amivantamab IV (50 mg/mL, 1,050 mg/1,400 mg), with 
(Cohort 1a) or without (Cohort 1b) rHuPH20. In Part 2, participants receive the same doses of 
amivantamab utilizing a high concentration formulation (160 mg/mL) with (Cohort 2a) or without 
(Cohort 2b) rHuPH20. Additional dose levels in Part 2 are being evaluated to confirm the proposed 
SC recommended Phase 2 dose (RP2D). Part 3 will evaluate the safety and PK of high 
concentration amivantamab SC at the RP2D from Part 2 in combination with lazertinib.
In Study 61186372NSC1003, the co-formulation of high concentration amivantamab with 
rHuPH20 (ie, amivantamab SC-CF) shortened the needed injection time to approximately 
5 minutes, with a bioavailability (BA) estimated to be 65% and was selected for further 
development. The RP2D for NSC3004 will be 1,600 mg for participants with a BW <80 kg and 
2,240 mg for participants with a BW ≥80 kg. This dose is currently undergoing confirmation in 
Study 61186372NSC1003. At the 9 February 2022 SET meeting, the safety of the modeled RP2D 
of 1600/2240 mg was confirmed in 4 participants, and expansion of the cohort was initiated. In 
total, 37 participants have been treated with amivantamab -SC at any dose. At the 1600/2240 mg 
dose in Study 61186372NSC1003, no DLTs and no new safety signals were identified and 
subsequent evaluation of safety, PK and PD among 25 subjects in this cohort at the 25 July 2022 
SET meeting confirmed 1600/2240 mg as the SC Q2W RP2D. Refer to Section 4.3.2 for additional 
details regarding the justification for the amivantamab SC-CF dose used in this study.
2.2.3.
Lazertinib (JNJ-73841937)
Lazertinib (JNJ-73841937) is an oral, highly potent, third-generation, irreversible EGFR TKI with 
no demonstrated PK interaction with amivantamab. Like osimertinib, it selectively inhibits both 
activating EGFR mutations (Exon 19del, L858R) and the EGFR T790M resistance mutation while 
showing mutant-selective activity for EGFR. Lazertinib has demonstrated efficacy in patients with 

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EGFR-mutated NSCLC, with activity observed in both systemic and central nervous system 
lesions, demonstrating its ability to cross the blood-brain barrier. Lazertinib received approval 
from the Ministry of Food and Drug Safety in South Korea for use in patients with advanced EGFR 
T790M+ NSCLC. Lazertinib monotherapy is being further evaluated as front-line treatment for 
patients with NSCLC, EGFR-activating mutations Exon 19del and Exon 21 L858R 
(YH25448-301).
Lazertinib was tested in a Phase 1/2 study (73841937NSC2001; YH25448-201) in which 
181 participants were enrolled with EGFR-mutated advanced NSCLC that progressed following 
prior therapy with an EGFR TKI. In dose escalation, clinical activity was observed in each dose 
cohort, from 20 mg through the highest dose cohort of 320 mg, with no dose-limiting toxicities, 
and no maximum tolerated dose was identified. The RP2D of lazertinib was determined to be 
240 mg PO once daily. At the recommended dose of 240 mg, the response rate of lazertinib in the 
T790M+ TKI-relapsed population was 58%, with a median PFS of 11.0 months (refer to the 
lazertinib IB). In participants 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 the 40 mg dose level (Kim 2020).
Lazertinib was well tolerated across all doses (dose range 20 to 320 mg) in 228 participants who 
were evaluable for safety (Ahn 2019; refer to lazertinib IB). The most commonly reported TEAEs 
(any grade) were rash (32%), pruritus (30%), diarrhea (24%), paresthesia (23%), constipation 
(22%), and decreased appetite (21%). Grade 3 or 4 events were observed in 29% of participants. 
Drug-related serious TEAEs were reported in 8 participants (4%). TEAEs leading to dose 
reduction or drug discontinuation were observed in 10% and 7% of participants, respectively. 
Overall, the incidence and severity of adverse events seen in this study were similar to those of 
osimertinib in the Phase 1 AURA study (Jänne 2015). Importantly, cardiac safety assessment in 
these participants has shown that lazertinib has no clinically relevant effect on QT interval or left 
ventricular ejection fraction (LVEF) (Ahn 2019). In summary, the currently available safety and 
efficacy profile of lazertinib appears similar to that of osimertinib as a second-line therapy. A 
Phase 3 trial evaluating lazertinib as a first-line monotherapy for participants with metastatic 
disease bearing Exon 19del or Exon 21 L858R substitution EGFR mutations is underway 
(NCT04487080).
2.2.4.
Amivantamab IV and Lazertinib Combination Therapy 
As a third-generation EGFR-TKI targeting activating EGFR mutations, lazertinib has a mechanism 
of action complementary to amivantamab. The mechanisms of action of amivantamab and 
lazertinib suggest potential improvement in clinical outcomes through the combination of these 
2 agents. By expanding coverage against additional EGFR TKI resistance mutations (eg, C797S 
and cMET amplification), the combination of amivantamab with lazertinib is hypothesized to 
delay the development of disease resistance, thereby prolonging disease control beyond that 
observed with a third-generation TKI alone. In addition, the complementary mechanisms of action 
of amivantamab combined with anti-EGFR TKI therapy, which targets both the extracellular 
ligand binding domain and the intracellular active site, respectively, has the potential to more 
potently inhibit the EGFR pathway than either agent alone.

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the time of IDMC review, no Grade 5 VTEs were identified, and only 1 participant discontinued 
study treatment due to VTE events.
VTE -related changes implemented during protocol Amendment 1 for this study are intended to 
1) provide guidance to increase awareness of the potential increased incidence of VTE events 
during the first 4 months of treatment with the amivantamab and lazertinib combination, 
2) describe measures to increase monitoring for these VTE events, 3) increase data collection 
related to all VTE events to better understand these events and their potential relatedness to study 
drugs, and 4) recommend prophylactic anticoagulation during the first 4 months of combination 
therapy. These measures are being implemented in each study of amivantamab and lazertinib 
combination therapy to further optimize the benefit-risk balance for participants.

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Severity; PK=pharmacokinetic(s); rHuPH20=recombinant human hyaluronidase; SC=subcutaneous(ly); 
TASQ=Therapy Administration Satisfaction Questionnaire; TTR=time to response.
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESIS
The primary hypothesis of the study is that amivantamab SC-CF, administered via manual 
injection at the RP2D, is noninferior to amivantamab IV in participants with locally advanced or 
metastatic NSCLC with EGFR Exon 19del or Exon 21 L858R mutations whose disease has 
progressed on or after treatment with osimertinib (or another approved 3rd generation EGFR TKI) 
and platinum-based chemotherapy.
4.
STUDY DESIGN
4.1.
Overall Design
Study 61186372NSC3004 (PALOMA-3) is a randomized, open-label, parallel, multicenter, Phase 
3 study, which will optimize the administration of amivantamab in participants with EGFR 
mutated locally advanced or metastatic NSCLC who have progressed on or after treatment with 
osimertinib (or another approved 3rd generation EGFR TKI) and platinum-based chemotherapy. 
The study will compare the PK, efficacy, and safety of combining lazertinib with amivantamab 
SC-CF administered via manual injection (Arm A) versus amivantamab IV (Arm B).
Approximately 400 participants will be enrolled in this study. Participants will be stratified by 
brain metastases at baseline (yes versus no), EGFR mutation (L858R versus Exon 19del), race 
(Asian versus non-Asian), and last therapy (osimertinib [or another approved 3rd generation EGFR 
TKI] versus chemotherapy).
The Schema is shown above (Figure 1). The study will include Screening (Section 4.1.1), a 
Treatment Phase (Section 4.1.2), and a Follow-up Phase (Section 4.1.3).
The study will aim to enroll a participant population that is geographically reflective of the overall 
incidence/prevalence of this disease. Enrollment of study participants in a given country may 
continue beyond the global enrollment period defined to reach the overall planned sample size, to 
ensure adequate representation in the study.
A target of 400 participants will be enrolled in this study and will be randomized 1:1 between 
Arms A and B. An IDMC will be commissioned for this study. Refer to Committees Structure in 
Appendix 2: Regulatory, Ethical, and Study Oversight Considerations for details.
A diagram of the study design is provided in Section 1.2, Schema.
Note: For clarity this protocol uses arm names ‘A’ and ‘B’, however in other documents and 
systems these may be referred to as ‘A1’ and ‘B1’ as these were already in place at the time of this
Global Amendment 2 to remove Part 2 of the study

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4.1.1.
Screening
The informed consent form (ICF) must be signed before the first study-related activity is 
conducted. Screening procedures must be completed within 28 days before randomization. 
All information required for randomization purposes must be available at the time of 
randomization, including all screening assessments per the applicable Schedule of Activities 
(Table 1) and 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 28-day cycles until the End of Treatment visit, approximately 
30 days after the last dose of study treatment. Study treatment will continue until documented 
clinical or radiographic (Response Evaluation Criteria in Solid Tumors [RECIST] v1.1
[Appendix 8]) disease progression or until the participant meets another criterion for 
discontinuation of study treatment (Section 7.1). Participants will be stratified based on the 
presence or history of brain metastases at baseline (yes vs no), EGFR mutation (L858R vs 
Exon19del), race (Asian vs non-Asian), and last therapy (osimertinib [or another approved 3rd 
generation EGFR TKI] vs chemotherapy) and assigned randomly in a 1:1 ratio into 1 of 2 treatment 
arms as follows:
Arm A:

Lazertinib 240 mg orally once daily

Amivantamab SC-CF by manual injection into the abdomen in 28-day cycles:

1,600 mg (2,240 mg if BW ≥80 kg) on Cycle 1 Days 1, 8, 15, and 22

1,600 mg (2,240 mg if BW ≥80 kg) on Day 1 and 15 of each subsequent 28-day cycle, 
starting on Cycle 2
Arm B:

Lazertinib 240 mg orally once daily

Amivantamab by IV infusion in 28-day cycles:

1,050 mg (1,400 mg if BW ≥80 kg) on Cycle 1 Days 1-2 (split dose), 8, 15, and 22

1,050 mg (1,400 mg if BW ≥80 kg) on Days 1 and 15 of each subsequent 28-day cycle, 
starting on Cycle 2
Disease assessments will occur within 28 days before randomization to the start of treatment 
(baseline screening scans), 6 weeks (+1 week) after randomization, every 6 weeks (±1 week) for 
the first 18 months and every 12 weeks (±1 week) thereafter, until radiographic disease progression 

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is confirmed. Timing of disease assessments is relative to randomization, regardless of when study 
treatment is administered. 
At study visits 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 PROs at selected 
visits. Participants will also have blood samples drawn for assessment of PK parameters, 
immunogenicity, and biomarker evaluations at selected visits. Medical resource utilization data 
associated with medical encounters will be collected by HCPs for all participants throughout the 
study. 
Continuation of study treatment after 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. 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 Schedule of Activities) until disease progression is documented, if 
clinically feasible. Participants who discontinue study treatment for any reason will be followed 
in the Follow-up Phase after last study treatment until disease progression or death, whichever 
comes first. If the information is obtained via telephone contact, written documentation of the 
communication must be available for review in the source documents. If the participant has died, 
the date and cause of death will be collected and documented on the electronic case report form 
(eCRF). Investigators may recontact the participant to obtain long-term follow-up information 
regarding the participant's safety or survival status as noted in the ICF (refer to Informed Consent 
in Appendix 2: Regulatory, Ethical, and Study Oversight Considerations).
4.1.4.
Long-term Extension Phase
Participants who continue to benefit from study treatment(s), as determined by their investigator, 
after completion of the primary analysis may continue to receive access to study treatment(s) 
within the study by transferring to the LTE Phase, where only serious adverse event data and the 
study treatment compliance data will be collected. The LTE Phase will continue to provide 
participants access to study treatment and further reduce protocol-required visit procedures and 
assessments, and burden on participants after the primary analysis is complete.
The LTE Phase (see details provided in Section 10.15 [Appendix 15]) will begin after the primary 
analysis, and will continue until the discontinuation criteria described in Section 7.1 are met, or 
until 3 years after local marketing authorization is obtained, whichever occurs first. For transition 
to the LTE Phase (after primary analysis), notification from the sponsor will be provided.

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4.2.
Scientific Rationale for Study Design
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 and 
estimation of PK parameters. PK noninferiority of amivantamab SC-CF administrated via manual 
injection versus amivantamab IV will be assessed using Ctrough (at steady state [Cycle 4 Day 1] for 
all regions other than EU and others accepting Cycle 2 Day 1 and pre-dose on Cycle 2 Day 1 for 
EU and any applicable region) and AUCD1-D15 in Cycle 2. 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. Exposure-response analysis may be 
conducted. Sample collection and testing will comply with local regulations.
ctDNA Collection
Circulating tumor deoxyribonucleic acid (ctDNA) will be collected to identify co-occurring EGFR 
mutations, cMET 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 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.
4.2.1.
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during 
the study, participants will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may 
be withdrawn at any time with no reason given and without penalty or loss of benefits to which 
they would otherwise be entitled. Only participants who are fully able to understand the risks, 
benefits, and potential AEs of the study, and provide their consent voluntarily will be enrolled. 
Thorough scientific evaluation of any treatment before marketing authorization is an ethical and 
regulatory requirement. As the benefits and risks of combining lazertinib with amivantamab IV or
amivantamab SC-CF via manual injection 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 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 

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for evaluating these drugs in combination for the treatment of NSCLC in participants who are 
eligible for this study.
All participants will undergo regular disease assessments to monitor their 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.
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 (American Red Cross 2022) and the 
World Health Organisation (WHO 2012).
4.3.
Justification for Dose
4.3.1.
Amivantamab IV Dose
The recommended dose of 1050 mg for BW <80 kg and 1400 mg for BW ≥80 kg, once weekly for 
the first 4 weeks and every 2 weeks thereafter on a 28-day cycle for amivantamab was established 
based on the totality of PK, PD, safety, and efficacy data obtained in the ongoing Phase 1 Study 
61186372EDI1001. Amivantamab was generally well tolerated in a Phase 1 study up to the dose
of 1750 mg, with no DLTs reported during dose escalation and no MTD identified. This dose of 
1050/1400 mg every 2 weeks was subsequently approved for patients with NSCLC characterized 
by EGFR Exon20ins mutation after progression on chemotherapy by the FDA, EMA and other 
health authorities. The safety and tolerability of amivantamab IV at this same dose combined with 
lazertinib was demonstrated in the Study 61186372EDI1001 and is being further explored in 
Study 73841937NSC1001 (Section 2.2.2.1 and Section 2.2.4) and 73841937NSC3003. 
4.3.2.
Amivantamab SC-CF Dose
The SC Q2W RP2D for amivantamab SC-CF (160 mg/mL co-formulated with rHuPH20) in the 
current Study 61186372NSC3004 was determined to be 1,600 mg for participants with a BW 
<80 kg and 2,240 mg for participants with a BW ≥80 kg (Section 2.2.2.2).
The proposed recommended dosing regimens for SC amivantamab are selected to ensure that the 
resulting exposures are similar to those observed with the IV recommended dose regimens.
Bioavailability was estimated by comparing the observed AUC following SC dosing (cohorts with 
and without rHuPH20 formulations) to the corresponding observed AUC following IV dosing. The 
SC cohorts were dosed at the IV recommended dose (1050 mg for participants with a BW <80 kg 
and 1400 mg for participants with a BW ≥80 kg). At this dose, saturation of soluble free EGFR 
and cMET was achieved after the first SC dose. Following the first dose in Cycle 2 (after the 
weekly induction dosing in Cycle 1), the mean (CV%, n) area under the concentration time curves 

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(AUC)C2D1-C2D15 were 95,416 µg×h/mL (45.4%, 7) and 75,378 µg×h/mL (27.0%, 5) for cohorts 
from 160mg/ml with and without rHuPH20, respectively. Based on these results and supported by 
preliminary compartmental PK modeling, the estimated bioavailability was 65% with rHuPH20.
Emerging data from Study 61186372NSC1003 indicates a lower incidence of IRRs (18.7% overall 
and 0 Grade ≥3) than previously reported with amivantamab IV (65.9% overall and 2.3% 
Grade ≥3). As a result of the reduced incidence and severity of IRRs, the study demonstrated the 
feasibility of a single-day infusion of amivantamab SC for the first dose.
4.3.3.
Lazertinib Dose
Lazertinib 240 mg QD is the approved dose for lazertinib monotherapy in Korea based on previous 
single agent studies in participants with NSCLC. Lazertinib 240 mg QD is designated as the RP2D 
in this combination study. Preliminary PK data in Study 61186372EDI1001 demonstrated a lack 
of drug-drug interaction between amivantamab IV and lazertinib, as the PK profile of both 
amivantamab IV and lazertinib was consistent when administered as monotherapies and in 
combination. To date, lazertinib 240 mg has been combined with amivantamab at the
recommended dose in 890 participants.
4.4.
End of Study Definition
End of Study Definition
The end of study is considered as 12 months after the last participant has been randomized. 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.
The sponsor will make every effort to ensure that participants benefiting from treatment with 
amivantamab will be able to continue receiving treatment after the end of the study. For 
participants ongoing at the time of completion of the study and who are eligible for a continued 
access program (post study access or other open-label extension study under a different/separate 
protocol), the end of study for that participant is defined as the end of treatment visit.
Participant Study Completion Definition
A participant will be considered to have completed the study if the participant (1) died while on 
study, or (2) was on study at the time of end-of-study. Participants who prematurely discontinue 
study treatment for any reason other than death before completion of the randomized treatment 
phase will not be considered to have completed the study..
5.
STUDY POPULATION
Screening for eligible participants will be performed within 28 days before randomization. Refer 
to Section 5.4 for conditions under which the repeat of any screening procedures is allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If 
there is a question about these criteria, the investigator must consult with the appropriate sponsor 

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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.
Be ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is 
taking place) at the time of informed consent.
2.
Have histologically or cytologically confirmed, advanced or metastatic NSCLC, 
characterized 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 
copy of the initial test report documenting the EGFR mutation must be included in the 
participant records and a deidentified copy must also be submitted to the sponsor.
3.
Criterion modified per Amendment 1
3.1 Have progressed on or after osimertinib (or another approved 3rd generation EGFR 
TKI) and platinum-based chemotherapy (irrespective of order).

The 3rd generation EGFR TKI must have been administered as the first EGFR TKI 
for metastatic disease or as the second TKI after prior treatment with first- or 
second-generation EGFR TKI in participants with metastatic EGFR T790M 
mutation positive NSCLC.

Participants who decline or are otherwise ineligible for chemotherapy may be 
enrolled after discussion with the medical monitor.

Any adjuvant or neoadjuvant treatment, whether with a 3rd generation EGFR TKI 
or platinum-based chemotherapy, would count towards the prior treatment 
requirement if the participant experienced disease progression within 6 months of 
the last dose.
4.
Have at least 1 measurable lesion, according to RECIST v1.1. If the only target lesion has 
been previously irradiated, it must show signs of disease progression since radiation was 
completed.
5.
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
(Section 10.10).
6.
Have adequate organ and bone marrow function as follows, without history of red blood 
cell transfusion or platelet transfusion within 7 days prior to the date of the laboratory 
test:

Hemoglobin ≥9 g/dL

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
Absolute neutrophil count ≥1.5×109/L, without use of granulocyte colony stimulating 
factor within 10 days prior to the date of the test

Platelets ≥75×109/L

ALT and AST ≤3×ULN if no demonstrable liver metastases or ≤5xULN in the 
presence of liver metastases. 

Total bilirubin:

≤1.5×ULN if no demonstrated liver metastasis 

≤3×ULN in the presence of liver metastasis 

≤3×ULN for those participants with known Gilbert’s syndrome with conjugated 
[direct] bilirubin <1.5xULN 

Creatinine clearance >50 mL/min as measured or calculated by MDRD
(Appendix 12: Formulas for Estimating Glomerular Filtration Rate Using Modified 
Diet in Renal Disease Formula (in mL/min))
7.
Human immunodeficiency virus-positive participants are eligible if they meet all of the 
following:
a.
No detectable viral load (ie, <50 copies/mL) at screening
b.
CD4+ count >300 cells/mm3 at screening
c.
No acquired immunodeficiency syndrome-defining opportunistic infection within 
6 months of screening
d.
Receiving HAART. Any changes in HAART due to resistance/progression should 
occur at least 3 months prior to screening. A change in HAART due to toxicity is allowed 
up to 4 weeks prior to screening.
Note: HAART that could interfere with study treatment is excluded (consult the sponsor 
for a review of medications prior to enrollment).
8.
Any toxicities from prior anticancer therapy must have resolved to CTCAE Version 5.0 
Grade 1 or baseline level (except for alopecia [any grade], Grade ≤2 peripheral 
neuropathy, and Grade ≤2 hypothyroidism stable on hormone replacement).
9.
A female participant of childbearing potential must have a negative serum pregnancy test 
at screening and must agree to further serum or urine pregnancy tests within 72 hours of 
the first dose, during the study, and for 7 months after the last dose of study treatment.
10.
A female participant must be either of the following (as defined in Appendix 5: 
Contraceptive and Barrier Guidance):
a.
Not of childbearing potential, or

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b.
Of childbearing potential and practicing at least 1 highly effective method of 
contraception (details in Appendix 5: Contraceptive and Barrier Guidance) 
throughout the study and through 7 months after the last dose of study treatment. 
Note: If a female participant becomes of childbearing potential after the start of the study, 
the female participant must comply with (b.).
11.
A female participant must agree not to donate eggs (ova, oocytes) or freeze for future use 
for the purposes of assisted reproduction during the study and for a period of 7 months 
after receiving the last dose of study treatment. Female participants should consider 
preservation of eggs prior to study treatment as anti-cancer treatments may impair 
fertility.
12.
A male participant must wear a condom when engaging in any activity that allows for 
passage of ejaculate to another person during the study and for 7 months after receiving 
the last dose of study treatment.
If partner is a female of childbearing potential, the male participant must use condom and 
the partner must also be practicing a highly effective method of contraception (see
Appendix 5: Contraceptive and Barrier Guidance). A male participant who is 
vasectomized must still use a condom, but the partner is not required to use contraception. 
13.
A male participant must agree not to donate sperm for the purposes of reproduction during 
the study and for 7 months after receiving the last dose of study treatment. Male 
participants should consider preservation of sperm prior to study treatment as anti-cancer 
treatments may impair fertility.
14.
Must sign an ICF (or their legally acceptable representative must sign if allowed per local 
regulation) indicating that the participant understands the purpose of, and procedures 
required for, the study and is willing to participate in the study.
15.
Be willing and able to adhere to the lifestyle restrictions specified in this protocol.
16.
Criterion moved from Exclusion Criteria to Inclusion Criteria per Amendment 2
A female participant must agree not to be pregnant, breast-feeding, or planning to become 
pregnant while enrolled in this study or within 7 months after the last dose of study 
treatment.
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 received cytotoxic, investigational, or targeted therapies beyond one 
regimen of platinum-based chemotherapy and EGFR inhibitors, as allowed in Inclusion 
criterion 3.
2.
Participant has a history of uncontrolled illness, including but not limited to the following:

Uncontrolled diabetes

Ongoing or active infection (includes infection requiring treatment with 
antimicrobial therapy [participants will be required to complete antibiotics 1 week 
prior to starting study treatment] or diagnosed or suspected viral infection).

Active bleeding diathesis

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
3.
Participant has received radiotherapy for palliative purposes less than 7 days prior to 
randomization.
4.
Participant has symptomatic or progressive brain metastases. Participants with treated 
metastases that are clinically stable and asymptomatic for at least 2 weeks and who are 
off or receiving low-dose corticosteroid treatment (≤10 mg prednisone or equivalent) for 
at least 2 weeks prior to randomization are eligible.
5.
Participant has leptomeningeal disease, or participant has spinal cord compression not 
definitively treated with surgery or radiation.
6.
Participant has uncontrolled tumor-related pain. Symptomatic lesions amenable to 
palliative radiotherapy (eg, bone metastases, or metastases causing nerve impingement) 
should be treated more than 7 days prior to the randomization.
7.
Participant has a medical history of ILD, including drug-induced ILD or radiation 
pneumonitis.
8.
Have a prior or concurrent second malignancy (other than the disease under study) which
natural history or treatment is likely to interfere with any study endpoints of safety or the 
efficacy of the study treatment(s) (see Appendix 13: Allowed Recent Second or Prior 
Malignancies for details).
9.
Participant has a history of hypersensitivity to any of the excipients of amivantamab, 
lazertinib, or to rHuPH20.

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10.
Criterion modified per Amendment 3
10.1 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 1 month prior to 
the first dose of study treatment, or any of the following within 6 months prior to the 
first dose of study treatment: myocardial infarction, unstable angina, stroke, transient 
ischemic attack, coronary/peripheral artery bypass graft, or any acute coronary 
syndrome. Clinically non-significant thrombosis, such as non-obstructive catheter-
associated clots, are not exclusionary.

Participant has a significant genetic predisposition to venous thromboembolic (VTE) 
events 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 QTcF interval >480 msec or clinically significant cardiac arrhythmia or 
electrophysiologic disease (eg, placement of implantable cardioverter defibrillator or 
atrial fibrillation with uncontrolled rate).

Uncontrolled (persistent) hypertension: systolic blood pressure >160 mmHg; 
diastolic blood pressure >100 mmHg

Congestive heart failure (CHF) defined as New York Heart Association (NYHA) 
class III-IV (see Appendix 9: New York Heart Association Criteria) or 
Hospitalization for CHF (any NYHA class) within 6 months of randomization

Pericarditis/clinically significant pericardial effusion

Myocarditis
11.
Participant had major surgery (eg, requiring general anesthesia), excluding placement of 
vascular access or tumor biopsy, or had significant traumatic injury within 4 weeks before 
signing the ICF, or will not have fully recovered from surgery, or has surgery planned 
during the time the participant is expected to participate in the study.
Note: Participants with planned surgical procedures to be conducted under local 
anesthesia may participate.
12.
Participant has at Screening any of the following:

Seropositive for hepatitis B: defined by a positive test for hepatitis B surface antigen 
[HBsAg]. Participants with resolved infection (ie, participants who are HBsAg 
negative with antibodies to total hepatitis B core antigen [anti-HBc] with or without 
the presence of hepatitis B surface antibody [anti-HBs]) must be screened using real-
time polymerase chain reaction (RT-PCR) measurement of hepatitis B virus (HBV) 
DNA levels. Those who are RT-PCR positive will be excluded. Participants with 
serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only 
serologic marker) AND a known history of prior HBV vaccination, do not need to 
be tested for HBV DNA by RT-PCR.

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
Positive hepatitis C antibody test result at screening or within 3 months prior to 
starting study treatment. 
NOTE: Participants with positive hepatitis C antibody due to prior resolved disease 
can be enrolled only if a confirmatory negative hepatitis C RNA test is obtained.

Positive hepatitis C RNA test result at screening or within 3 months prior to first dose 
of study treatment. 
NOTE: Test is optional and participants with negative hepatitis C antibody test are 
not required to also undergo hepatitis C RNA testing.

Other clinically active infectious liver disease.
13.
Participant has received a live or live attenuated vaccine within 3 months before 
randomization. The seasonal influenza vaccine and non-live vaccines against COVID-19 
are not exclusionary.
14.
Criterion modified per Amendment 1
14.1 Participant is currently receiving medications or herbal supplements known to be 
potent CYP3A4/5 inducers and is unable to stop use for an appropriate washout period 
prior to randomization.
15.
Participant previously enrolled in the Sponsor’s studies
73841937NSC3003 
(NCT04487080) or 61186372NSC3002 (NCT04988295). 
16.
Criterion added per Amendment 1
16.1 Criterion moved to Inclusion Criterion 16 per Amendment 2
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.
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 6.8, Concomitant Therapy for details regarding prohibited and 
restricted therapy during the study.
2.
If the participant’s last treatment was osimertinib (or another approved 3rd generation 
EGFR TKI), this must be discontinued at least 8 days prior to first dose of study drug

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(ie, last dose no later than Study Day -8). If the participant’s last treatment contained 
chemotherapy, the last dose of treatment must be no later than 2 weeks or 4 half-lives 
prior to study treatment, whichever is longer. For agents such as immunotherapy with 
a long half-life, the maximum required time since last dose is 6 weeks.
3.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
4.
Participants must agree to use sun protective measures (such as a hat, sunglasses, and 
protective clothing), limit prolonged exposure to natural sunlight, and avoid artificial 
sunlight (tanning beds or phototherapy) from baseline until the last dose of study 
treatment. Participants must agree to avoid unnecessary exposure to sunlight and use 
broad-spectrum sunscreen (containing titanium dioxide or zinc oxide) with a skin 
protection factor (SPF) ≥30.
5.
Carry a “wallet study card” with pertinent information about the study for the duration 
of study participation.
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 does use interactive web response system (IWRS). During the screening and 
enrollment, the investigator did not 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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6.
STUDY TREATMENT AND CONCOMITANT THERAPY
6.1.
Study Treatments Administered
Study treatment administration must be captured in the source documents and the eCRF. Study site 
personnel will instruct participants on how to store study treatment for at-home (lazertinib only)
use as indicated for this protocol.
Amivantamab and lazertinib will be manufactured and provided under the responsibility of the 
sponsor. Refer to the IB for amivantamab and the IB for lazertinib for lists of excipients.
Refer to the Investigational Product Preparation Instructions (IPPI) or Site Investigational Product 
Procedures Manual (SIPPM) for additional guidance on preparation, handling, and storage of study 
treatments.
For a definition of study treatment overdose, refer to Section 6.7, Treatment of Overdose.
Designation
Product
Investigational Medicinal Products 
(IMPs)
amivantamab, lazertinib
Authorization Status in the EU:
Used not in accordance with Marketing Authorization: amivantamab
Authorized
Amivantamab IV
Unauthorized
Amivantamab SC, lazertinib
Non-investigational Medicinal Products 
(NIMPs)/Auxiliary Medicinal Products 
(AxMPs)
Not applicable

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Description of Treatments
Arm Name
All Arms
Arms A 
Arm B
Treatment Name
Lazertinib
Amivantamab SC-CF 
Amivantamab IV
Type
Drug
Drug
Drug
Dose Formulation
Oval, yellow, film-coated 
tablet
25R vial
7 mL vial
Unit Dose Strength(s)
80 mg
1600 or 2240 mg/vial with 
concentration of 
160 mg/mL co-formulated 
with rHuPH20 
350 mg/vial with 
concentration of 
50 mg/mL; IV infusion 
will be prepared at the site 
in ~250 mL diluent
Dosage Level(s)
240 mg once daily
Up to Cycle 2 Day 1: once 
weekly 1600 mg (2240 mg 
if BW is ≥80 kg)
Cycles 2+: 1600 mg 
(2240 mg if BW is ≥80 kg) 
on Day 1 and 15 of each 
28-day cycle
Up to Cycle 2 Day 1: once 
weekly (with the first dose 
split over Days 1-2): 1050 
mg (1400 mg if BW is ≥80 
kg)
Cycles 2+: 1050 mg 
(1400 mg if BW is ≥80 kg) 
on Day 1 and 15 of each 
28-day cycle
Route of Administration
oral
other: subcutaneous by 
manual injection
IV infusion
Use
Experimental
Experimental
Experimental
Investigational Medicinal Product (IMP)
Yes
Yes
Yes
Non-Investigational Medicinal 
Product/Auxiliary Medicinal Product 
(NIMP/AxMP)
No
No
No
Sourcing
Provided centrally by the 
Sponsor
Provided centrally by the 
Sponsor
Provided centrally by the 
Sponsor
Packaging and Labeling
(Labels will contain information to meet the 
applicable regulatory requirements.)
Will be provided in a 
93-count bottle
pre-filled vials of either 
1600 mg or 2240 mg 
amivantamab at 160 
mg/mL co-formulated with 
rHuPH20
pre-filled vials of 350 mg 
at 50 mg/mL
Child resistant packaging
Not in child resistant 
packaging
Not in child resistant 
packaging

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Arm Name
All Arms
Arms A 
Arm B
Delivery Instructions
Self-administered with or 
without food; first 2 doses 
(cycle 1, Day 1 and 2), 
should be taken in the 
clinic (on visit days), more 
than 15 minutes prior to 
initiation of premedication 
for amivantamab. The 
tablets should be 
swallowed intact with
water ad libitum and taken 
around the same time each 
day, approximately 24 
hours apart, if possible. 
Per Investigational Product 
Preparation and 
Administration 
Instructions.
Per Investigational Product
Preparation and 
Administration 
Instructions.
Current/Former Name(s) or Alias(es)
JNJ-73841937; YH25448
JNJ-61186372
JNJ-61186372

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6.1.1.
Scheduled Dosage and Timing
Administration of study treatment should begin within 3 days of randomization. On days when 
multiple study drugs are dosed together, the order of medications should be as follows: 
1) lazertinib, 2) predose medications required with amivantamab; 3) amivantamab. Refer to 
Table 7 for predose medications required with amivantamab.
6.1.2.
Amivantamab SC-CF by Manual Injection (Arm A)
Amivantamab SC-CF will be manufactured and provided for this study under the responsibility of 
the sponsor. Refer to the amivantamab IB for a list of excipients.
In Arm A, amivantamab SC-CF will be delivered by means of a manual injection into the abdomen. 
Doses will be administered at alternating locations on the abdomen in the periumbilical area. Refer 
to the IPPI for details regarding the needle gauge, angle, and depth. The dosage of amivantamab 
SC-CF will be based on the participant's BW at screening. The dose remains based on BW at 
screening regardless of subsequent changes in BW during the course of treatment. Qualified site 
personnel will administer amivantamab as a manual injection in 28-day cycles as follows:

1,600 mg (2,240 mg if BW ≥80 kg) on Cycle 1 Days 1, 8, 15, and 22

1,600 mg (2,240 mg if BW ≥80 kg) on Day 1 and 15 of each 28-day cycle, starting on Cycle 2
The actual start and end times of each injection should be accurately recorded. 
6.1.3.
Amivantamab IV (Arm B)
Amivantamab IV will be manufactured and provided for this study under the responsibility of the 
sponsor. Refer to the amivantamab IB for a list of excipients. 
The dosage of amivantamab IV will be based on the participant's BW at screening. The dose 
remains based on BW at screening regardless of subsequent changes in BW during the course of 
treatment. Qualified site personnel will administer amivantamab as an IV infusion in 28-day cycles 
as follows:

1,050 mg (1,400 mg if BW ≥80 kg) on Cycle 1 Days 1-2 (split dose), 8, 15, and 22

1,050 mg (1,400 mg if BW ≥80 kg) on Days 1 and 15 of each 28-day cycle, starting on Cycle 2
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 for subsequent dosing starting with the Cycle 2 Day 1 dose. In cases where 
peripheral access may be limiting to treatment administration, use of a central line for 
amivantamab infusion in Cycle 1 starting after Cycle 1 Day 8 may be considered, only after prior 
approval by the Medical Monitor.
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. 

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Amivantamab IV 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.
6.1.4.
Lazertinib
Lazertinib for oral administration is an 80 mg oval, yellow, film-coated tablet. Refer to the IB for 
a list of excipients. Participants 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 Day 1 of each cycle. Lazertinib should be 
taken at approximately the same time each day, approximately 24 hours apart, if possible. If a 
participant misses 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.
6.2.
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study treatment must be stored at controlled temperatures according to the requirements on the 
label. Amivantamab must be protected from light prior to use. For additional guidance on study 
treatment preparation, handling, and storage, refer to the IPPI/SIPPM.
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 acceptable representatives where applicable, must be instructed to 
return all original containers, whether empty or containing study treatment.

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Amivantamab treatment must be handled in strict accordance with the protocol and as indicated 
on 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, 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, must be disposed of immediately in a safe manner and therefore will not be 
retained for treatment accountability purposes. 
Study treatment must 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 and Stratification
Central randomization will be implemented in this study. Participants will be randomly assigned 
to 1 of 2 treatment groups based on a computer-generated randomization schedule prepared before 
the study by or under the supervision of the sponsor. The randomization will be balanced by using 
randomly permuted blocks and will be stratified by brain metastases at baseline (yes vs no), EGFR 
mutation (L858R vs Exon19del), race (Asian vs non-Asian), and last therapy (osimertinib [or 
another approved 3rd generation EGFR TKI] vs chemotherapy). The 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 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.
Predose Medications
Administration of predose medications 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 acceptable 
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.
Amivantamab
Amivantamab will be administered as an IV infusion or SC manual injection by qualified study 
site personnel, and the details of each administration will be recorded in the eCRF. Dispensing of 
all study treatment must also be recorded in the participant’s source documents.
6.5.
Dose Modification
Any dose/dosage adjustment must be overseen by medically qualified study site personnel 
(principal or subinvestigator unless an immediate safety risk appears to be present).
Guidance on dose modification is provided in Sections 6.5.2 and 6.5.3. Refer to Table 4, Table 5, 
and Table 6 for guidance on delay and modification of the amivantamab dose or lazertinib dose 
based on the toxicity grade of AEs other than those specified in Section 6.5.3. When possible, the 
medical monitor should be notified prior to dose modifications.
Changes to amivantamab and/or lazertinib dosing (including dose interruptions, change in dose, 
or change in infusion rate) and the reason for the change, must be recorded in the CRF. For a dose 
interruption, the duration of the interruption is to be recorded. 
6.5.1.
Dose Delay Guidance
In instances where study treatment delay is indicated, treatment with amivantamab and/or 
lazertinib 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 amivantamab and/or lazertinib (as per Section 6.5.2), in accordance 
with protocol, prior to redosing.

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For VTE events associated with clinical instability (eg, respiratory failure or cardiac dysfunction) 
in participants receiving the combination of amivantamab and lazertinib, study treatment should 
be held until the participant recovers from the event. Thereafter, the treatment can be resumed at 
the discretion of the investigator.
6.5.2.
Dose Modification of Amivantamab and Lazertinib
Decisions regarding dose modification of amivantamab and lazertinib 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. 
For toxicities associated with EGFR inhibition that require treatment modification, and which can 
therefore be attributed to either drug, modification should be instituted for lazertinib prior to 
modification of amivantamab dosing. 
If a participant experiences a CTCAE Grade 3 or higher and/or unacceptable toxicity (any grade) 
that the investigator considers to be specifically associated with EGFR inhibition, then dosing with 
lazertinib should be interrupted immediately and supportive therapy administered as required in 
accordance with local practice/guidelines. The participant should be reassessed at next scheduled 
amivantamab dose (Day 1 of the next cycle), for resolution of symptoms and need for amivantamab 
dosing modifications (delay or dose modification). For the majority of clinically significant 
toxicities withholding doses and dose modifications should occur per the guidelines described in 
Table 4 below, with the following additional considerations:

In instances of intolerable toxicity, study treatment should be withheld and may be restarted 
upon resolution of the intolerable toxicity to ≤Grade 1 or baseline status (except for rash, oral 
mucositis, or paronychia, which should recover to ≤Grade 2 or baseline).

If amivantamab is withheld for 2 consecutive doses for any reason, consult with the Medical 
Monitor before restarting amivantamab to discuss plans for dose. 

While recommendations in Table 4 are provided as guidelines to toxicity management with 
the combination, investigators should exercise their clinical judgement, taking into account 
the nature of the toxicity, each agent’s potential contribution to the toxicity, as well as each 
agent’s potential contribution to any observed clinical benefit. For guidance around specific 
adverse events, see Section 6.5.3.

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Table 4:
Guidance for Withholding Doses for Toxicities Based on Grade
Gradea
Actionb,c
Dose Modification After Resolution of Toxicityd
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 amivantamab is withheld <21 days, restart study 
treatment at current dose level. If lazertinib is withheld, 
restart on Day 1 of next cycle at a reduced dose.
3 or 4
Withhold lazertinib and if not resolved by 
next scheduled dose, hold amivantamab.
Grade 3: If Grade 3 adverse event improves to 
Grade 0-2 after withholding study drugs for up to 
3 weeks, then upon resolution:
- Restart lazertinib at a reduced dose on Day 1 of next 
cycle. Restart amivantamab at current dose level or 
consider dose reduction on Day 8, Day 15, or Day 22 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 lazertinib, 
amivantamab, or both
Grade 4: If Grade 4 adverse reaction improves to 
Grade 0-2 after withholding study drugs for up to 
3 weeks, then upon resolution:
Restart lazertinib at a reduced dose on Day 1 of next 
cycle. Restart amivantamab at a reduced dose on Day 8, 
Day 15, or Day 22 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 lazertinib, 
amivantamab, or both.
a.
Per National Cancer Institute-Common Terminology Criteria for Adverse Events Version 5.0.
b.
For all toxicities, consider supportive care according to protocol as appropriate.
c.
For toxicities related to EGFR inhibition, lazertinib should be held first.
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).
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.
Amivantamab and Lazertinib Dose Reduction
If a participant experiences an EGFR TKI-related toxicity requiring dose reduction after 
withholding study treatment and resolution, then the dose of lazertinib should be preferentially 
reduced, as outlined in Table 5 below, unless the experienced toxicity is strongly suspected to be 
related to amivantamab alone (refer to respective IBs), in which case the dose of amivantamab 
should be reduced according to Table 6. 
Given the potential for increased anti-EGFR activity on this study, accelerated (ie, proactive) dose 
reductions are allowed if toxicity is encountered. Upon resolution of the toxicity, or with improved 
control with supportive measures, the dose of the reduced therapy dose may be increased on Day 1 
of the next cycle.

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Table 5:
Guidance for Lazertinib Stepwise Dose Reduction 
Dose Level
Lazertinib (any cycle)
0 (starting dose)
240 mg
-1
160 mg
-2
80 mg
-3
Discontinue
Table 6:
Guidance for Amivantamab Stepwise Dose Reduction
Dose 
Level
Amivantamab IV
Amivantamab SC-CF
0 
(starting 
dose)
1,050 mg (1,400 mg if BW
≥80 kg)
1600 mg (2240 mg if BW ≥80 kg)
-1
700 mg (1,050 mg if BW
≥80 kg)
1050 mg (1600 mg if BW ≥80 kg)
-2
350 mg (700 mg if BW
≥80 kg)
700 mg (1050 mg if BW ≥80 kg)
-3
Discontinue
Discontinue
6.5.3.
Dose Modification and Management of Specific Adverse Events
6.5.3.1.
Infusion-Related Reactions and Local Administration-Related 
Reactions
General Guidelines for Infusion-Related Reactions
Infusion-related reactions have been commonly observed during treatment with amivantamab IV, 
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 2.2.2.1). 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 (IV and SC-CF) during initial 
dosing. 
During the amivantamab infusions, participants should be clinically monitored at regular intervals 
as specified in the Schedule of Activities (including an assessment prior to the start of infusion). 
The monitoring should include heart rate, blood pressure, temperature, and oxygen saturation 
measurements. For Cycle 1 Day 1 only, participants in Arm A will remain at the site for at least 
4 hours after the amivantamab injection for observation. For participants in Arm B, the 4-hour 
infusion time is considered adequate for observation; no additional observation time is needed.
Particularly with the initial dose (Cycle 1, Day 1 and Day 2 in case of split dose), 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 generally preclude further therapy with amivantamab. Participants 
must be monitored closely for early signs and symptoms indicative of an acute IRR. Even with 

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mild symptoms, any ongoing 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: Predose Medications
Required predose medications and optional predose medications for amivantamab are summarized 
in Table 7. Required predose medications are 1 each of an antihistamine and antipyretic on all dose
days, as well as a glucocorticoid on Cycle 1 Day 1 and, for amivantamab IV only, on Cycle 1 
Day 2.

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Prevention of Infusion-Related Reactions: Postdose Medications
Optional postdose medications may be prescribed and continued for up to 48 hours after any 
dose if clinically indicated, at the discretion of the investigator (Table 8).
Table 8:
Postdose Medications for Amivantamab (all arms)
Medication
Dose
Route of
Administration
Administration 
Instructions
Cycle/
Day
Optional Postdose 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. 
Treatment of Infusion-Related Reactions 
Participants who experience early symptoms of IRRs, manifesting 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, Day 
1 for Arm A and Cycle 1, Days 1 and 2 for Arm B), 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.
Management of Local Administration Related Reactions
Local administration related reactions are considered a potential risk of subcutaneous 
administration. Subcutaneous administration of amivantamab in abdominal subcutaneous tissue 
was associated with LARRs, such as induration and erythema, in some participants. Local 
administration related reactions should be managed per institutional standards. The prophylactic 
and reactive management recommendations for LARRs are the same as those of infusion-related 
reactions (as described above).

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Table 9:
Management of Infusion-related Reactions
Toxicity Gradea
Treatment
Premedication at 
Subsequent Dosing
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.
Antihistamine, antipyretic, 
and glucocorticoid.
Grade 2 
Moderate reaction; 
therapy or infusion 
interrupted
but responds promptly 
to symptomatic 
treatment
Interrupt infusion, if ongoing
If clinically indicated, start IV fluids; give 
diphenhydramine 50 mg (or equivalent) IV and/or 
paracetamol (acetaminophen) 650 to 1000 mg; consider 
corticosteroids and bronchodilator therapy; 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.
Consider meperidine if 
participant experiences chills 
and rigors.

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Table 9:
Management of Infusion-related Reactions
Toxicity Gradea
Treatment
Premedication at 
Subsequent Dosing
Grade 3 or 4
Grade 3: severe 
reaction, prolonged (ie, 
not rapidly responsive 
to symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates)
Grade 4: life-
threatening; pressor or 
ventilator support 
indicated
Stop infusion, if ongoing
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 1:10,000 solution injected slowly for IV 
administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as 
needed (other drugs as appropriate). 
Participant should be monitored until the investigator is 
comfortable that the symptoms will not recur. 
Investigators should follow their institutional guidelines 
for the treatment of anaphylaxis. In the case of late-
occurring hypersensitivity symptoms (eg, appearance of 
a localized or generalized pruritus within 1 week after 
treatment), symptomatic treatment may be given (eg, 
oral antihistamine, or corticosteroids), as appropriate. 
Based on severity of 
symptoms, consider 
permanent discontinuation of 
study treatment. Consultation
with Medical Monitor
required before continuing 
with subsequent dosing.
eCRF=electronic case report form; IPPI=Investigational Product Preparation Instructions; IRR=infusion-related reaction; 
IV=intravenous.
a.
Per National Cancer Institute - Common Terminology Criteria for Adverse Events Version 5.0
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. 
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.

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
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: either a topical antibiotic (clindamycin, mupirocin, or fusidic 
acid) on sun-exposed skin, or an oral antibiotic (such as doxycycline 100 mg once daily, 
minocycline 100 mg once daily, or cephalexin 500 mg once daily).

A topical corticosteroid of medium to low potency twice daily on the face and chest (such 
as alclometasone 0.05% or desonide 0.05% cream) may also be considered. 
Reactive Management Recommendations
It is strongly recommended that participants who develop rash/skin toxicities receive evaluations 
for management on the specific 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).

Initiate a topical corticosteroid (cream or ointment) twice daily

Examples to use for face: betamethasone valerate 0.05%, hydrocortisone valerate 0.2% 
or desonide 0.05% 

Examples to use for body: betamethasone valerate 0.1%, triamcinolone acetonide 0.1%

If not already initiated for prophylaxis, initiate systemic antibiotic (such as doxycycline 
100 mg twice daily, minocycline 100 mg twice daily, or cephalexin 500 mg twice daily), or 
increase the dosing if already administered.

If an associated skin infection is suspected, obtain bacterial and fungal cultures followed by 
adjustment of antibiotic or antifungal therapy, based upon culture and susceptibility 
determination. 

For skin fissures, use of Monsel’s solution (ferric subsulfate solution), silver nitrate, zinc oxide 
cream, or cyanoacrylate sealant 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.

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Table 10:
Suggested Algorithm for Management of Rash
Gradea
Management
Dose Adjustment
1

Initiate reactive management as 
above

Reassess after 2 weeks
Continue current dose(s) of amivantamab and 
lazertinib
2

Initiate reactive management as 
above

Reassess after 2 weeks
Continue current dose(s) of amivantamab and 
lazertinib.
Refer to the dose modification guidance for 
further instructions.
3 

Initiate reactive management as 
above

Start moderate strength topical 
corticosteroidsc and systemic 
antibiotics as above, plus 
systemic prednisone (0.5 mg/kg) 
for 7 days

Consider low doses of acitretin 
or isotretinoin (20-30 mg/day)

Reassess after 2 weeks

Consider dermatology 
consultation and manage rash per 
recommendation
Temporarily withhold lazertinib until rash 
improves to Grade ≤2 (If rash does not 
improve by the next scheduled amivantamab 
dose, then amivantamab administration 
should be held as well until the rash improves 
to Grade ≤2)b.
Refer to the dose modification guidance for 
further instructions
4

Initiate reactive management as 
above

Start moderate strength topical 
corticosteroidsc and systemic 
antibiotics as above, plus 
systemic prednisone (0.5 mg/kg) 
for 7 days

Consider low doses of acitretin 
or isotretinoin (20-30 mg/day)

Reassess after 2 weeks

Consider dermatology 
consultation and manage rash per 
recommendation
Permanently discontinue amivantamab and 
hold lazertinib. Consider restarting lazertinib 
per investigator assessment of causality, once 
resolved.
Severe bullous, 
blistering, or 
exfoliating skin 
conditions including 
toxic epidermal 
necrolysis (TEN)

Consult dermatologist and 
manage rash per 
recommendation
Permanently discontinue amivantamab and 
hold lazertinib. Consider restarting lazertinib 
per investigator assessment of causality, once 
resolved.
a. Grading per National Cancer Institute - Common Terminology Criteria for Adverse Events (Version 5.0).
b. If amivantamab must be withheld due to toxicity for ≥21 days, the study treatment cannot be restarted without 
consultation from the medical monitor. Participants considered by the investigator and sponsor to be benefiting 
from treatment may be continued, potentially at a lower dose upon satisfactory resolution of the toxicity.
c. For example, hydrocortisone 2.5% cream or fluticasone propionate 0.5% cream.

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6.5.3.3.
Suspected Pulmonary Toxicity
Participants 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, including a change in radiographic lung images, should
prompt immediate investigation into the etiology in accordance with local practice/guidelines to 
institute appropriate treatments and to rule out early ILD/pneumonitis. If new or worsening 
pulmonary symptoms (eg, dyspnea) or radiological abnormality suggestive of pulmonary adverse 
event is observed, including ILD/pneumonitis, study treatments should be withheld, and 
appropriate treatment management should be promptly initiated.
The following evaluations are recommended in order to exclude alternative etiologies such as 
lymphangitic carcinomatosis, pulmonary embolism, infection, allergy, and cardiogenic edema:

Detailed focused history reviewing respiratory status and exercise tolerance

Focused physical exam, including full assessment of vital signs (with pulse oximetry)

Unscheduled radiological assessment, including chest X-ray or CT scan (high-resolution CT 
is preferred)

Infectious evaluation, including blood and sputum cultures, atypical pneumonia panels, 
SARS-CoV-2 testing, and broader viral panels if indicated

Hematology and other laboratory tests, including serum albumin levels

Referral to pulmonologist for evaluation, including bronchoscopy with biopsy, cell counts, 
and cultures as feasible

Evaluation of cardiac function, if indicated
Documentation of ILD/pneumonitis of any grade should prompt withholding study treatment and 
contacting the Medical Monitor. Pertinent radiological images and reports should be submitted to 
the Sponsor. For symptomatic participants with pneumonitis (Grade 2 and above), treatment with 
steroids should be initiated per local guidelines, in addition to withholding of study treatment. 
Study treatment/s should be discontinued upon confirmation of ILD/pneumonitis. In the absence 
of a diagnosis of ILD/pneumonitis, study treatment may be restarted.
6.5.3.4.
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 per local 
practice or guidelines. 
QTcF Prolongation

Check the quality of ECG recording and check for electrolyte abnormalities (eg, potassium, 
calcium, magnesium); correct as needed.

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
QTcF 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, 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 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 5). 

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.
Change in LVEF

Drug-related absolute LVEF decline of >10% from baseline 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 at least 2 weeks after initial assessment to monitor 
status. 

Symptomatic CHF:

Permanently discontinue all study treatments.
6.5.3.5.
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 

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criteria are observed, then study treatment should be withheld, and the event should be reported as 
an serious adverse events (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 
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 to 3 days and until abnormal values resolve/return to 
baseline. Etiology of the liver chemistry abnormality should be investigated, as described in 
Appendix 7. If no alternative etiology of liver toxicity is identified, all study treatments should be 
permanently discontinued. 
6.5.3.6.
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.
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).

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6.5.3.7.
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 participant 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.
6.5.3.8.
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 participant discomfort 
associated with this toxicity. Prophylaxis should occur according to local institutional practice and 
guidelines, and should include the following: 
Prophylaxis Recommendations

Use good oral hygiene, dentition review and referral to an oral hygienist if necessary.

Use a soft toothbrush.

Use mild-flavored toothpastes.

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
Use saline-peroxide or salt and soda mouthwashes 3 or 4 times per day.

Use water soluble lubrication agents like artificial saliva (for xerostomia or dry mouth).

Avoid spicy, acidic, hard, and hot food and beverages.
Reactive Management Guidelines

Asymptomatic or mild symptoms: topical steroid (dexamethasone 0.5/mL elixir) and 
lidocaine 2%-5% jelly or solution (swish and spit) 4 times per day. 

Co-trimoxazole lozenges can be used to prevent secondary candida infection.

In cases of moderate to severe pain: 

Compounded mouthwash (eg, “magic mouthwash”) including an antifungal, steroid, 
antihistamine, anesthetic, and/or antacid/mucosal coating agent as per local practice and 
guidelines.

Dexamethasone solution 3.3 mg/5 mL swish and spit 4 times per day, and lidocaine jelly 
2%-5% or solution 4 times per day. 
6.5.3.9.
Diarrhea
Reactive Management Recommendations
If participants experience diarrhea, they should be encouraged to drink 8 to 10 large glasses (2 L) 
of clear liquids per day while on study to maintain adequate hydration. Maintenance of electrolyte 
balance using electrolyte containing drinks, broth, and clear juices should be considered. If an 
infectious cause of the diarrhea is suspected, perform stool testing and administer antibiotic 
therapy (avoiding strong CYP3A4/5 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 11.

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Table 11:
Suggested Algorithm for Management of Diarrhea
Grade
Management
Study Treatment
1
Loperamide (4 mg at first onset, then 2 mg 
every 2-4 hours until symptom free for 
12 hours). 
Fluid intake of at least 2 L as described 
above.
Continue study treatment(s).
2
Loperamide (4 mg at first onset, then 2 mg 
every 2-4 hours until symptom free for 
12 hours) or consider diphenoxylate and 
atropine formulations. 
Fluid intake of at least 2 L as described 
above. Monitor participant closely and 
consider intravenous hydration.
If not improved to ≤Grade 1 within 24 
hours despite use of loperamide, hold 
treatment until ≤Grade 1. 
If diarrhea of >Grade 1 recurs after initial 
improvement, consider reduction by one 
dose level (see Table 5 and Table 6).
3
Oral therapy with diphenoxylate and 
atropine formulations, or tincture of 
opium. 
Fluid intake of at least 2 L should be 
maintained as described above, 
intravenously if necessary.
Consider use of octreotide 100-150 µg 
subcutaneously twice daily with 
escalation to 500 μg 3 times daily.
Consider hospitalization if does not 
improve to ≤Grade 2 within 24 hours, or 
in presence of fever, abdominal pain, etc.
Withhold study treatment(s). Upon 
resolution to ≤Grade 1, resume study 
treatment(s) with consideration of 
reduction by 1 dose level see Table 5 and 
Table 6).
4
Maximal inpatient fluid and nutritional 
support, antibiotics as indicated in 
judgment of investigator for fever, 
leukocytosis, marked dehydration, etc.
Hold study treatment until ≤Grade 1. 
Mandatory dose reduction by 1 dose level 
(see Table 5 and Table 6).
6.5.3.10.
Venous Thromboembolic Events
Patients with NSCLC are at risk of developing complications, including VTE events. Investigators 
should closely monitor 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 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 are recommended to receive prophylactic-dose anticoagulation as per local 
guidelines during the first 4 months of combination therapy. Vitamin K antagonists are not 
recommended due to numerous drug interactions. The benefit-risk assessment for participants to 
tolerate prophylactic-dose anticoagulation is at the discretion of the treating investigator. Notably, 

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prophylactic-dose anticoagulation has been found to be safe and effective in multiple prior studies 
(Carrier 2019, Rutjes 2020, NCCN Guidelines Version 1.2022).
If a VTE event is diagnosed, the participant should be treated with treatment-dose anticoagulation 
as per local guidelines. Vitamin K antagonists are not recommended because of numerous drug 
interactions. For VTE events associated with clinical instability (eg, respiratory failure or cardiac 
dysfunction) in participants receiving the combination of amivantamab and lazertinib, study 
treatment should be held until the patient recovers from the event. Thereafter, the treatment can be 
resumed at the discretion of the investigator.
In the case of a recurrent VTE whilst on therapeutic anticoagulation therapy, the combination of 
amivantamab and lazertinib should be permanently discontinued. Participants may continue to 
receive treatment with either amivantamab or lazertinib (but not both) at the discretion of the 
treating physician.
6.6.
Continued Access to Study Treatment After the End of the Study
The sponsor will make every effort to ensure that participants benefiting from treatment with 
amivantamab will be able to continue receiving treatment after the end of the study; see details for 
the LTE Phase (Section 10.15 [Appendix 15]) and Section 4.1.4.
6.7.
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.
6.8.
Concomitant Therapy
6.8.1.
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.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, exercise 
regimens, or other specific categories of interest) different from the study treatment must be 

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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.
6.8.2.
Permitted and Required Medications and Therapies
6.8.2.1.
Pre- and Post-dose Medications for Amivantamab
See Section 6.5.3.1.
6.8.2.2.
Supportive Care
Concomitant medications for the symptomatic treatment of related toxicities (Grades 1 through 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. 
6.8.2.3.
Radiotherapy
Localized, limited radiotherapy of short duration for palliative purposes of nontarget lesions may 
be permitted, but only after consultation with the Medical Monitor.
6.8.3.
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 or systemic anticancer therapy, approved or experimental, other than study 
treatments, except as allowed by Exclusion criterion #8.

Radiotherapy to target lesions prior to disease progression.

Use of live or live attenuated vaccines. (Except for live or live attenuated vaccines, vaccination 
is allowed per local guidelines including annual influenza and inactivated SARS-CoV-2 
vaccines; see also stand-alone appendix.) 

Due to the potential for hypomagnesemia associated with EGFR inhibitors, concomitant 
medications that may decrease serum magnesium should be avoided if possible.

Prescription and over the counter medications, herbal supplements and/or ingestion of foods 
with known potent inducer effects on CYP3A4/5 activity (For some examples see: US FDA. 
Drug development and drug interactions: Table of Substrates, Inhibitors and Inducers 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. 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.

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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:

Avoid concomitant use of CYP3A4/5 substrate drugs and medications known to be strong 
inhibitors of CYP3A4/5 (For some examples see: US FDA. Drug development and drug 
interactions: Table of Substrates, Inhibitors and Inducers 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-gp, MRP4, BCRP, and OCT1 should be used with caution 
(For some examples see: US FDA. Drug development and drug interactions: Table of 
Substrates, Inhibitors and Inducers 2022). Please contact the local pharmacist or Medical 
Monitor with any questions.

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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 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 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 must 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
When a participant withdraws before study completion, the reason for withdrawal is to be 
documented in the CRF and in the source document. If the reason for withdrawal from the study 
is withdrawal 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.

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7.2.1.
Withdrawal From the Use of Research Samples
The participant may withdraw consent for the use of samples for research (refer to Long-term 
Retention of Samples for Additional Future Research in Appendix 2: Regulatory, Ethical, and 
Study Oversight Considerations). In such a case, samples will be destroyed after they are no longer 
needed for the clinical study. Details of the sample retention for research are presented in the main 
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.

Should the participant continue to be unreachable, they will be considered to have withdrawn 
from the study.
8.
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedules of Activities summarize the frequency and timing of measurements applicable to 
this study.
The modified TASQ should be completed after study drug administration. PGIS should be 
conducted/completed before any tests, procedures, or other consultations to prevent influencing 
participant responses, when possible.
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. Through the first 
5 cycles of treatment and the End of Treatment visit, the total amount of blood drawn from each 

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participant in this study is anticipated to be approximately 376 mL. Depending on 
country/territory-specific regulations, 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. If Cycle 4 Day 1 dose is delayed or withheld, the amivantamab serum PK sample 
should be collected on the planned day per protocol. This collection will be considered an 
unscheduled serum PK sample. Refer to the Schedules 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 will comply with local 
regulations.
Study-Specific Materials
The investigator will be provided with the following supplies:

Study protocol (and any amendments)

IB for amivantamab

IB for lazertinib

IPPI and SIPPM; amivantamab SC-CF IPPI 

PQC reporting form

Laboratory manual and kits

eCRF completion guidelines

IWRS Manual

eDC Manual

Imaging Manual

NCI CTCAE Version 5.0

RECIST guidelines, Version 1.1

PRO questionnaires and PRO completion guidelines

Tablet (for PRO collection)

Sample ICF

Wallet cards

Study treatment

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8.1.
Efficacy Assessments
Disease assessment will be performed using CT, MRI, and other imaging/examination, as 
applicable, of the chest, abdomen, pelvis, brain, and any other disease location at Screening, 
6 (+1) weeks from randomization, every 6 (±1) weeks for the first 18 months, then every 
12 (±1) weeks thereafter until PD. Repeat brain imaging will be performed every 6 weeks if brain 
mets are present at baseline and being followed as non-target lesions and if there are no brain mets 
at baseline then perform as clinically indicated. For participants who discontinue treatment prior 
to PD, tumor imaging should continue until PD is documented. If participant begins a new 
anticancer therapy before PD, tumor imaging should be obtained before the new therapy. If a 
participant receives study treatment beyond confirmed documented PD, continue disease 
assessments as scheduled. Tumor response evaluation will be assessed by the investigator 
according to RECIST v1.1. Further details are provided in the Imaging Manual.
8.1.1.
Patient-Reported Outcomes
Patient-reported outcomes measures will be collected at the times specified in the Schedule of 
Activities. 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 modified TASQ (Appendix 14) is an 11-item questionnaire measuring the impact of each 
mode of treatment administration on five domains: Physical Impact, Psychological Impact, Impact 
on Activities of Daily Living, Convenience, and Satisfaction. Example questions include, “How 
satisfied or dissatisfied were you with the SC injection/IV infusion?”, “How much pain did you 
experience at the site of the SC injection/IV site?”, and “How convenient is it for you to get your 
SC injection/IV infusion?” The modified TASQ-IV will be completed by participants in Arm B
and the modified TASQ-SC by participants in Arm A. The modified TASQ should be completed 
after the study drug administration. 
The TASQ was derived from the Rituxan Administration Satisfaction Questionnaire (RASQ). 
Modification addresses the administration site of amivantamab. TASQ is designed for an adult 
population to measure the impact of the mode of treatment administration on 5 domains, including 
9 items: Physical Impact (3 items), Psychological Impact (1 item), Impact on Activities of Daily 
Living (1 item), Convenience (2 items), and Satisfaction (2 items). Recall/Observation period is 
based on participants most recent SC injection/IV infusion (Theodore-Oklota, 2016).
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 TASQ. The PGIC 
will not be administered at the first visit because it captures change.
The PGIS should be conducted/completed before any tests, procedures, or other consultations to
prevent influencing participant responses, when possible.

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8.2.
Safety Assessments
Independent Data Monitoring Committee
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. A first IDMC meeting will be held after the first 20 participants complete 
2 cycles of treatment. 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.
Medical history, including but not limited to, all ongoing relevant and clinically significant 
comorbidities according to NCI-CTCAE Version 5.0, including severity grade will be recorded 
during screening.
8.2.1.
Physical Examinations
A complete physical examination will be conducted at screening. Symptom-directed physical 
examinations will be conducted thereafter. Clinically significant postbaseline abnormalities should 
be reported as AEs.
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, directed physical examinations of involved organs and other body 
systems, as indicated, will be performed and participant BW will be obtained. 
8.2.2.
ECOG Performance Status
Assessment of ECOG status should be part of regular ongoing clinical monitoring of patients.
Decline in ECOG performance status score (refer to Appendix 10: Eastern Cooperative Oncology 
Group (ECOG) Performance Status) should be reported as an AE.

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8.2.3.
Vital Signs
Vital sign measurements will include the following assessments:

Temperature

Heart 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).
For participants receiving IV amivantamab, collect vital sign measurements ≤30 minutes before 
amivantamab infusion, at 30-minute intervals (±5 minutes) during each amivantamab infusion, 
and at the end of the infusion (±5 minutes).
8.2.4.
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 single ECG recording, the 
procedures should be performed in the following order: single ECG(s), vital signs, blood draw.
Clinically significant abnormal results should be confirmed by triplicate ECG assessments.
At each time point at which triplicate ECGs are required, 3 individual ECG tracings should be 
obtained as closely as possible in succession, approximately 2 minutes apart. 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.
8.2.5.
LVEF measurements by echocardiography (ECHO) or Multigated 
Acquisition (MUGA) scan
During the Screening Phase each participant will undergo a baseline LVEF assessment performed 
locally by cardiac echocardiogram or MUGA scan to demonstrate eligibility (ie, a LVEF within 
the normal range). 
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. 

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Clinically significant findings noted at screening should be included in the medical history, and 
not as an AE. After screening, 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.
Pregnancy Testing
For women of childbearing potential, a negative serum pregnancy test is required at screening. A 
negative serum or urine pregnancy test is required within 72 hours before Day 1 of each cycle, at 
the EOT Visit, monthly during treatment and through 7 months after the last dose of study 
treatment. At other times, a serum or urine pregnancy test should be performed as clinically 
indicated, according to local regulation requirements, or following the local practice of the study 
site. 
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 6: Clinical 
Laboratory Tests will be collected at the times listed in the Schedules 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, including AEs, SAEs, 
and product quality complaints (PQC), from clinical studies are crucial for the protection of 
participants, investigators, and the sponsor, and are mandated by regulatory agencies worldwide. 
The sponsor has established Standard Operating Procedures in conformity with regulatory 
requirements worldwide to ensure appropriate reporting of safety information; all clinical studies 
conducted by the sponsor or its affiliates will be conducted in accordance with those procedures.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally acceptable representative) for the duration of the study. Further details 
on AEs, SAEs, and PQCs can be found in Appendix 3: Adverse Events, Serious Adverse Events, 
Product Quality Complaints, and Other Safety Reporting: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.

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8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from the 
time a signed and dated ICF is obtained until 30 days after last dose of study treatment (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 immediately, but no later than 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.
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 and the special reporting situation of 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.

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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 Independent Ethics 
Committee/Institutional Review Board (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 are 
discussed in Appendix 4: Anticipated Events.
8.3.5.
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants (if appropriate 
consent is given) must be reported to the sponsor by the study site personnel within 24 hours of their 
knowledge of the event using the appropriate pregnancy notification form. Abnormal pregnancy 
outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) 
are considered SAEs and must be reported using an SAE reporting form. Any participant who 
becomes pregnant during the study must discontinue further study treatment. 
Follow-up information regarding the outcome of the pregnancy for female participants who become 
pregnant, or where the pregnancy was the result of male participant and his partner, and any postnatal 
sequelae in the infant will be required.
8.3.6.
Disease-Related Events and Disease-Related Outcomes Not 
Qualifying as Adverse Events or Serious Adverse Events
All events that meet the definition of a serious adverse event will be reported as 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 adverse event (or serious adverse event).
However, if determined by the investigator to be more likely related to the study treatment,
protocol design, or protocol procedures than being expected from the underlying disease, the 
treatment-invoked progression (ie the treatment-invoked signs/symptoms of such progression) 
should be reported per the usual reporting requirements (refer to Adverse Event Definitions and 
Classifications in Appendix 3: Adverse Events, Serious Adverse Events, Product Quality 
Complaints, and Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting).
Death that is attributed by the Investigator explicitly to progression of disease should not be 
considered nor reported as an AE (or SAE). However, if determined by the investigator to be more 
likely related to the study treatment, protocol design, or protocol procedures than being expected 
from the underlying disease, the treatment-invoked death due to progression should be reported 

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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, but not limited to, spinal 
cord compression, vena cava superior syndrome, major vessel rupture, efflux obstruction or organ 
failure should be documented on the appropriate eCRF forms (eg, the Clinical Progression form).
8.3.7.
Adverse Events of Special Interest
AEs of special interest are pneumonitis/ILD, rash, IRR, LARR and VTE. 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 (ie, via email). Events of rash and VTE should follow standard reporting 
guidelines.
8.4.
Pharmacokinetic and Immunogenicity Assessments
8.4.1.
Evaluations
Blood samples to assess the serum concentration (PK) of amivantamab, the plasma concentration 
of lazertinib (PK), and the generation of antibodies to amivantamab (immunogenicity) will be 
obtained from all participants according to Section 1.3.2.
Plasma samples will also be collected to evaluate the immunogenicity of rHuPH20 according to 
Section 1.3.2. 
The exact dates and times of blood sampling must be recorded. Refer to the Laboratory Manual or 
equivalent document for sample collection requirements. Collected samples must be stored under
the specified and controlled conditions for the temperatures indicated in the laboratory manual. 
Samples collected for determining serum concentrations/immunogenicity of amivantamab or 
immunogenicity of rHuPH20 in this study may be retained to address questions about drug 
characteristics that may arise at a later time point.
Participant confidentiality will be maintained. Additional information about the collection, 
handling, and shipment of biological samples can be found in the Laboratory Manual.
8.4.2.
Analytical Procedures
Serum and plasma samples will be analyzed to determine concentrations of amivantamab and 
lazertinib, respectively, using a validated method by or under the supervision of the sponsor. In 
addition, serum and plasma PK samples may be stored for future analysis.

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The detection and characterization of antibodies to amivantamab and rHuPH20 will be performed 
using a validated assay method by or under the supervision of the sponsor. All samples collected 
for detection of antibodies to amivantamab will also be evaluated for amivantamab serum 
concentration to enable interpretation of the antibody data. Antibodies may be further 
characterized and/or evaluated for their ability to neutralize the activity of the study drug(s). 
Samples may be stored up to 15 years (or according to local regulations) following the last 
participant’s last visit for the study at a facility selected by the sponsor to enable further analysis 
of immune responses to amivantamab and rHuPH20.
8.4.3.
Pharmacokinetic Parameters and Evaluations
The PK assessments are defined as follows:

Ctrough
Observed concentration immediately prior to the next drug administration

AUC(D1-D15)
Area under the concentration time curve from Day 1 to Day 15
The primary PK endpoints are Ctrough (at steady state in Cycle 4 Day 1 for all regions other than 
EU and others accepting Cycle 2 Day 1 and pre-dose on Cycle 2 Day 1 for EU and any applicable 
region) prior to administration of Cycle 2 Day 1 dose and AUCD1-D15 at Cycle 2. The secondary 
endpoint, model-predicted AUC D1-D15 at Cycle 4, will be estimated based on the Population PK 
modeling. The details and the results of the Population PK modeling and simulation will be 
presented in a separate report.
The incidence of anti-amivantamab antibodies will be summarized for all participants who receive 
a dose of amivantamab and have appropriate samples for detection of antibodies to amivantamab. 
The prevalence and incidence of anti-rHuPH20 antibodies will be summarized for all participants 
who receive a dose of amivantamab co-formulated with rHuPH20 and have appropriate samples 
for detection of anti-rHuPH20 antibodies.
Samples collected for immunogenicity analyses may additionally be used to evaluate safety or 
efficacy aspects that address concerns arising during or after the study period. Genetic analyses 
will not be performed on these serum samples. Participant confidentiality will be maintained.
8.5.
Pharmacogenomics
Pharmacogenomics are not evaluated in this study. 
8.6.
Biomarkers
Blood Samples
Baseline blood samples collected from all participants may undergo ctDNA analysis by the 
sponsor to evaluate pretreatment mutational status of EGFR, cMET, 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 the time points specified in the Schedule of Activities and 

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may be analyzed to investigate circulating factors, eg cytokines, associated with response to 
treatment.
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.
8.7.
Medical Resource Utilization and Health Economics
Time and motion studies will evaluate participant chair time, treatment room time, duration of 
treatment administration, and active HCP time for drug preparation, treatment administration, and 
post-treatment monitoring.
9.
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan.
9.1.
Statistical Hypotheses
The primary statistical hypothesis of the study is that amivantamab SC-CF, administered via 
manual injection at the RP2D, is noninferior to amivantamab IV based on the co-primary 
pharmacokinetics endpoints, Ctrough (at steady state [Cycle 4 Day 1] for all regions other than EU 
and others accepting Cycle 2 Day 1 and pre-dose on Cycle 2 Day 1 for EU and any applicable 
region) and AUCD1-D15 in Cycle 2. The hypotheses are the lower bounds of the 90% CI for the ratio 
of the geometric means of amivantamab SC-CF vs amivantamab IV are at least 80% (non-
inferiority margin of 20%) for both Ctrough (at steady state of amivantamab in Cycle 4 Day 1 for all 
regions other than EU and others accepting Cycle 2 Day 1 and pre-dose on Cycle 2 Day 1 for EU 
and any applicable region) and AUCD1-D15 in Cycle 2.
A key secondary hypothesis is that amivantamab SC-CF, administered via manual injection at the 
RP2D, is noninferior to amivantamab IV based on ORR in the aforementioned population. The

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hypothesis is that the lower bounds of the 95% CI for the relative risk of amivantamab SC-CF vs 
amivantamab IV for ORR is 60%. Another key secondary hypothesis is that amivantamab SC-
CF will reduce the risk of either disease progression or death compared with amivantamab IV.
To control familywise Type I error rate at a two-sided significance level of 0.05, a hierarchical 
procedure for hypothesis testing between primary PK endpoints and key secondary efficacy 
endpoints will be implemented. Once the null hypothesis of inferiority is rejected for both the 
Ctrough (at steady state for all regions other than EU and others accepting Cycle 2 Day 1 and 
pre-dose on Cycle 2 Day 1 for EU and any applicable region) and AUCD1-D15 in Cycle 2, a testing 
for ORR and PFS at a two-sided significance level of 0.05 will be tested in a sequential order 
(Figure 2).
Figure 2: 
Primary and Key Secondary Endpoints Testing Strategy
9.2.
Sample Size Determination
200 participants will be randomized to Arm A and 200 participants will be randomized to Arm B. 
(Figure 1).
The study is designed to establish noninferiority based on the co-primary pharmacokinetics 
endpoints, Ctrough (at steady state of amivantamab in Cycle 4 Day 1 for all regions other than EU 
and others accepting Cycle 2 Day 1 and pre-dose on Cycle 2 Day 1 for EU and any applicable 
region) and AUCD1-D15 in Cycle 2, between amivantamab SC-CF and amivantamab IV. 
Amivantamab SC-CF will be considered noninferior to IV if the lower bound of the 90% CI for 
the ratio of the geometric means of Ctrough (at steady state [Cycle 4 Day 1] for all regions other than 

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EU and others accepting Cycle 2 Day 1 and pre-dose on Cycle 2 Day 1 for EU and any applicable 
region) and AUCD1D15 in Cycle 2 is at least 80% (noninferiority margin of 20%). The planned 400
participants (200 from Arm A and 200 from Arm B) will provide a power >95% for a one-sided 
alpha of 0.05 for each of the endpoints. This assumes a true geometric mean ratio of Ctrough to be 1 
and a true geometric mean ratio of the AUCD1D15 to be 1 between the 2 treatment groups, and a 
coefficient of variation (CV) of 56% for both endpoints.
One of the key secondary objectives is to assess efficacy of SC-CF (Arm A) compared to IV (Arm 
B) in terms of ORR. In a previous clinical study (73841937NSC1001), of 50 participants with 
locally advanced or metastatic NSCLC with EGFR Exon 19del or Exon 21 L858R mutations 
whose disease had progressed on or after treatment with osimertinib and platinum-based 
chemotherapy and who were treated with the combination of amivantamab IV and lazertinib, an 
ORR of 32.1% (95% CI:23.3%, 41.8%) was observed. Non-inferiority of amivantamab SC-CF to 
amivantamab IV in the current study is defined using a 60% retention of the lower bound (23.3%) 
of the 95% CI from Study 73841937NSC1001. With a planned 1:1 randomization, the sample size 
of 400 participants will provide 80% power to demonstrate the non-inferiority of Arm A compared 
with Arm B, with a one-sided alpha of 0.025, assuming the true ORR is the same for both treatment 
arms.

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9.3.
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
Population
Description
Full analysis set
All participants who were randomized in the study
PK primary 
endpoint 
evaluable
For applicable regions per health authority recommendation:
All randomized participants who receive all doses in Cycle 1, without dose
modifications and provide Cycle 2 Day 1 Ctrough
All randomized participants who receive all doses in Cycle 1-3, without dose 
modifications and provide Cycle 4 Day 1 Ctrough, OR
All randomized participants who receive all doses up to Cycle 2 Day 1, without dose 
modifications and provide all necessary PK samples to derive Cycle 2 AUCD1-D15
based on which Cycle 4 Day 1 Ctrough would be predicted using per protocol dosing 
and population PK modeling and simulation.
For all regions:
All randomized participants who receive all doses up to Cycle 2 Day 1, without dose 
modifications and provide all necessary PK samples to derive primary PK endpoint 
Cycle 2 AUCD1-D15. 
Other PK -
evaluable
All randomized participants who receive at least 1 dose of study treatment and have at least 
1 evaluable postbaseline concentration measurement. Participants will be excluded from the 
PK analysis if their data do not allow for accurate assessment of the PK.
Safety
All randomized participants who receive at least 1 dose of study drug. 
Immunogenicity
All participants who receive at least 1 dose of study drug and provide at least 1 postdose 
immunogenicity sample.
Biomarker
All participants who receive at least 1 dose of study drug and provide at least 1 postdose 
biomarker sample.
a  Participants may be removed from the estimation of certain pharmacokinetic parameters on an individual basis due 
to, for example, missing pharmacokinetic samples such that the pharmacokinetic parameters cannot be appropriately
derived. These participants will be identified at the time of the analyses along with their reason for removal.
9.4.
Statistical Analyses
The Statistical Analysis Plan will be finalized prior to database lock for the primary analysis and 
it 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. The Kaplan-Meier product limit method and a stratified Cox 
model will be used to estimate time-to-event variables and to obtain the HR and confidence 
interval. Unless otherwise specified, stratified log-rank tests will be used to test the treatment effect 
for time-to-event variables; response rate variables will be evaluated using the chi square statistic 
or the exact test if the cell counts are small.

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9.4.2.
Primary Endpoints
The co-primary PK noninferiority endpoints are defined as follows:
All regions other than EU and others accepting 
Cycle 2 Day 1
EU and any applicable region
Ctrough on Cycle 4 Day 1
Ctrough pre-dose on Cycle 2 Day 1
All regions
AUCD1-D15 in Cycle 2
The primary estimand for the co-primary PK endpoints, the main clinical quantity of interest to 
be estimated, is defined by the following components:

Study treatment:

Experimental: Amivantamab SC-CF administered via manual injection

Control: Amivantamab IV

Population: participants with EGFR-mutated locally advanced or metastatic NSCLC who 
have progressed on or after treatment with osimertinib (or another approved 3rd generation 
EGFR TKI) and platinum-based chemotherapy

Variable: PK endpoint, Ctrough (at steady state [Cycle 4 Day 1] for all regions other than EU 
and others accepting Cycle 2 Day 1 and pre-dose on Cycle 2 Day 1 for EU and any applicable 
region) and AUCD1-D15 in Cycle 2

Population-level summary: Ratio of geometric means (Ctrough [at steady state Cycle 4 Day 1
for all regions other than EU and others accepting Cycle 2 Day 1 and pre-dose on Cycle 2 Day 
1 for EU and any applicable region] and AUCD1-D15 in Cycle 2) between SC-CF and IV
administrations

Intercurrent events and their corresponding strategies: no additional intercurrent events
The ratio of the geometric means and the corresponding 90% CI between Arm A and Arm B for
each primary endpoint will be provided based on the PK Analysis Set. Summary statistics such as 
the geometric mean, coefficient of variation, median, and range will be provided by treatment 
group.
9.4.3.
Secondary Endpoints
Ctrough
In regions other than EU and others accepting Cycle 2 Day 1, a Ctrough of amivantamab pre-dose 
on Cycle 2 Day 1 will be a secondary endpoint. Similar analysis method used for the primary 
endpoint will be used.

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In EU and any applicable region, a Ctrough of amivantamab at steady state (Cycle 4 Day 1) will be 
a secondary endpoint. Similar analysis method used for the primary endpoint will be used.
ORR
The key secondary endpoint of ORR is defined as the proportion of participants who achieve either 
a complete response or PR as best response, based on 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.
The primary estimand for ORR, the main clinical quantity of interest to be estimated, is defined 
by the following components:

Study treatment:

Experimental: Amivantamab SC-CF administered via manual injection

Control: Amivantamab IV

Population: participants with EGFR-mutated locally advanced or metastatic NSCLC who 
have progressed on or after treatment with osimertinib (or another approved 3rd generation 
EGFR TKI) and platinum-based chemotherapy

Variable: overall response

Population-level summary: odds ratio of amivantamab SC-CF vs amivantamab IV

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 randomization strata. The results of 
the analysis will be presented in terms of a risk ratio together with its associated 95% confidence 
intervals. If the lower bound of the 95% CI is ≥60%, the non-inferiority of amivantamab SC-CF 
relative to amivantamab IV will be concluded. If non-inferiority in ORR is established and the 
lower limit of the 95% CI of the relative risk is >100%, the superiority of amivantamab SC-CF 
relative to amivantamab IV will be concluded.
PFS
The key secondary endpoint of PFS is defined as the time from randomization until the date of 
objective disease progression or death, whichever comes first, based on RECIST v1.1.
The primary estimand for PFS, the main clinical quantity of interest to be estimated, is defined by the 
following components:

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
Study treatment:

Experimental: Amivantamab SC-CF administered via manual injection

Control: Amivantamab IV

Population: participants with EGFR-mutated locally advanced or metastatic NSCLC who 
have progressed on or after treatment with osimertinib (or another approved 3rd generation 
EGFR TKI) and platinum-based chemotherapy

Variable: time to event, PFS

Population-level summary: odds ratio for amivantamab SC-CF vs amivantamab IV

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
The median PFS and 95% CI in each treatment group will be estimated using the Kaplan-Meier 
method. The PFS distributions between the 2 treatment groups will be compared using the 
stratified log-rank test. The treatment effect (hazard ratio) and its 2-sided 95% CI will be estimated 
using a stratified Cox regression model with treatment as the sole explanatory variable.
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. A Kaplan-Meier plot and median duration of response with 95% confidence interval 
(calculated from the Kaplan-Meier estimate) will be presented by treatment group.
Time to Response (TTR)
Time to response (i.e. time to first response) is defined as the time from the date of randomization
to the date of first documentation of a response (PR or CR) prior to any disease progression and
subsequent anticancer therapy, as defined by RECIST v1.1., for participants who have PR or CR 
as their best response. A descriptive summary for TTR will be provided.
Modified Therapy Administration Satisfaction Questionnaire
This validated PRO instrument is designed to assess patient satisfaction with cancer therapy. 
Descriptive statistics will be reported for the individual items and domain scores at baseline and 
at each visit for absolute value and for change from baseline.
Time and motion analysis
The time and motion analysis is a healthcare burden impact study investigating differences in 
participant chair time, treatment room time, duration of treatment administration, and active HCP 

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time for drug preparation, treatment administration, and post-treatment monitoring. Descriptive 
statistics will be provided for the analysis by country/territory and pooled.
Immunogenicity
The incidence of anti-amivantamab antibodies will be summarized for all participants who receive 
a dose of amivantamab and have appropriate samples for detection of antibodies to amivantamab. 
The incidence of anti-rHuPH20 antibodies will be summarized for all participants who receive a 
dose of amivantamab SC-CF and have appropriate samples for detection of anti-rHuPH20 
antibodies.
Model predicted AUCss
Model-predicted AUC at steady state will estimate exposures for Cycle 4 Day 1- Day 15 using 
Population PK approach. Population PK analysis of serum concentration-time data of 
amivantamab will be performed using nonlinear mixed-effects modeling (NONMEM) and may be 
combined with similar data from other studies, with the aim of providing estimates of AUCss. 
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.
9.4.4.
Exploratory Endpoint(s)
Additional details about the exploratory endpoints analyses will be described in the Statistical 
Analysis Plan or a separate analysis plan.
Biomarkers
Biomarkers analyses will use the Biomarkers Population. Each baseline tumor status may be 
evaluated by ctDNA NGS analysis, for exploratory purposes, to characterize potential mechanisms 
of resistance to amivantamab and lazertinib, and to evaluate the presence of mutations across 
treatment arms, 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 samples collected on study to better understand mechanisms of response or 
resistance to study treatment. Alterations in blood characteristics may be evaluated for correlation 
with response to study treatment, tumor burden, and disease progression as data warrant.
Efficacy
Overall Survival (OS): The OS is defined as the time from the first dose of study treatment until 
the date of death due to any cause. The median OS and 95% CI will be estimated using the Kaplan-
Meier method for each arm.
9.4.5.
Safety Analyses
All safety analyses will be made on the Safety Population.

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Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using
MedDRA. Any AE occurring at or after the initial administration of study treatment through 
30 days after the last dose of study treatment but prior to the start of subsequent anticancer therapy, 
is considered to be treatment emergent. Any SAE that occurs beyond the 30 days after the last dose 
of study treatment and is considered related to study treatment will be considered as 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.

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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1.
Appendix 1: Abbreviations
Ab
antibody
AE
Adverse events
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AxMP
Auxiliary Medicinal Product (also known as NIMP)
BCRP
breast cancer resistance protein
BW
body weight
CD4
cluster of differentiation 4
CF
co-formulation
CHF
congestive heart failure
CLIA
Clinical Laboratory Improvement Amendments
Cmax
maximum plasma/serum concentration
cMET
mesenchymal-epithelial transition factor
CTCAE
Common Terminology Criteria for Adverse Events
CTR
Clinical Trial Regulations
ctDNA
circulating tumor deoxyribonucleic acid
Ctrough
plasma/serum concentration immediately prior the next study treatment administration
CV
coefficient of variation
CYP
cytochrome P450
DoR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form 
EEA
European Economic Area
eDC
electronic data capture
EGFR
epidermal growth factor receptor
EU
European Union
FDA
US Food & Drug Administration
FOCBP
female participant(s) of childbearing potential 
FOIA
Freedom of Information Act
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
HAART
highly active antiretroviral therapy
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HCP
health care professional
HIV
human immunodeficiency virus
HR
hazard ratio
IB
investigator’s brochure
ICF
informed consent form
ICH
International Council on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IFU
instructions for use
Ig
immunoglobulin
ILD
interstitial lung disease
IMP
Investigational Medicinal Product
INR
internationalized normalized ratio
IPPI
Investigational Product Preparation Instructions
IRB
Institutional Review Board
IV
intravenous(ly)

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IWRS
interactive web response system
LARR
local administration related reaction
LLN
lower limit of normal
LTE
long-term extension
LVEF
left ventricular ejection fraction
MDRD
Modified Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MRP4
multidrug resistance protein 4
NIMP
Non-Investigational Medicinal Product
NSCLC
non-small cell lung cancer
NYHA
New York Heart Association
OCT1
Organic Cation Transporter 1
ORR
objective response rate
OS
overall survival
PD
progressive disease
PFS
progression-free survival
PO
per os, ie by mouth
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PQC
Product Quality Complaint
PRO
patient-reported outcome(s) (paper or electronic as appropriate for this study)
Q2W
every 2 weeks
QTcF
corrected QT interval by Fridericia
RECIST
Response Evaluation Criteria in Solid Tumors
rHuPH20
recombinant human hyaluronidase
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
SAE
Serious adverse events
SC
subcutaneous(ly)
SC-CF
subcutaneous and co-formulated with recombinant human hyaluronidase
SIPPM
Site Investigational Product Procedures Manual
SoA
Schedule of Activities
SUSAR
suspected unexpected serious adverse reaction
TASQ
Therapy Administration Satisfaction Questionnaire
TKI
tyrosine kinase inhibitor
TTR
time to response
ULN
upper limit of normal
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 Good Clinical Practice (GCP), and applicable regulatory and 
country/territory-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human participants. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study participants are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
Protocol Clarification Communications
If text within a final approved protocol requires clarification (eg, current wording is unclear or 
ambiguous) that does not change any aspect of the current study conduct, a protocol clarification 
communication (PCC) may be prepared. The PCC Document will be communicated to the 
Investigational Site, Site Monitors, Local Trial Managers (LTMs), Clinical Trial Managers 
(CTMs), and/or Contract Research Organizations (CROs) who will ensure that the PCC 
explanations are followed by the investigators.
The PCC Document may be shared by the sites with Independent Ethics Committees/Institutional 
Review Boards (IECs/IRBs) per local regulations.
The PCC Documents must NOT be used in place of protocol amendments, but the content of the 
PCC Document must be included in any future protocol amendments.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by 
the sponsor. All protocol amendments must be issued by the sponsor and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or 
when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the participants, in which case the amendment must 
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the 
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where 
required) only needs to be notified.
In situations where a departure from the protocol is unavoidable during the study, the investigator 
or other physician in attendance will contact the appropriate sponsor representative listed in the 
Contact Information page(s), which will be provided as a separate document. Except in emergency 
situations, this contact must 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 

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

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
Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB 
with current and complete copies of the following documents (as required by local regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the participants)

IB (or equivalent information) and amendments/addenda

Sponsor-approved participant recruiting materials

Information on compensation for study-related injuries or payment to participants for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as documented 
by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for participants

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
participants, data or study conduct, unless required locally), the ICF, applicable recruiting 
materials, and participant compensation programs, and the sponsor has received a copy of this 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
Approval for the collection of optional samples for research and for the corresponding ICF must 
be obtained from the IEC/IRB. Approval for the protocol can be obtained independent of this 
optional research component.
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

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
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

Report of deaths of participants under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about 
the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
Country/Territory Selection
This study will only be conducted in those countries/territories where the intent is to launch or 
otherwise help ensure access to the developed product if the need for the product persists, unless 
explicitly addressed as a specific ethical consideration in Section 4.2.1, Study-Specific Ethical 
Design Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
10.2.2.
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 acceptable representative, as permitted by local regulations) must 
give written consent according to local requirements after the nature of the study has been fully 

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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.
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 acceptable representatives the aims, methods, 
reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Participants will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time. They will be informed 
that choosing not to participate will not affect the care the participant will receive for the treatment 
of his or her disease. Participants will be told that alternative treatments are available if they refuse 
to take part and that such refusal will not prejudice future treatment. Finally, they will be told that 
the investigator will maintain a participant identification register for the purposes of long-term 
follow up if needed and that their records may be accessed by health authorities and authorized 
sponsor personnel without violating the confidentiality of the participant, to the extent permitted 
by the applicable law(s) or regulations. By signing the ICF the participant or legally acceptable 
representative is authorizing such access, which includes permission to obtain information about 
his or her survival status. It also denotes that the participant agrees to allow his or her study 
physician to recontact the participant for the purpose of obtaining consent for additional safety 
evaluations, and subsequent disease-related treatments, if needed.
The participant or legally acceptable representative will be given sufficient time to read the ICF 
and the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of either the participant's or his or her legally 
acceptable representative's personally dated signature. After having obtained the consent, a copy 
of the ICF must be given to the participant.
If the participant or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the ICF after the oral consent of the 
participant or legally acceptable representative is obtained.
Participants who are rescreened are required to sign a new ICF.
When prior consent of the participant is not possible and the participant's legally acceptable 
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 acceptable representative must be informed about the study as soon as 
possible and give consent to continue.

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10.2.4.
Recruitment Strategy
Recruitment is closed, as of Amendment 4.
10.2.5.
Data Protection
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of participants confidential.
The informed consent obtained from the participant (or his or her legally acceptable representative) 
includes information about, and where required per applicable regulations, explicit consent for the 
processing of personal data and for the investigator/institution to allow direct access to his or her 
original medical records (source data/documents) for study-related monitoring, audit, IEC/IRB 
review, and regulatory inspection. 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.
Long-term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations) 
for additional research. Samples will only be used to understand amivantamab or lazertinib, to 

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understand differential treatment responders, and to develop tests/assays related to amivantamab, 
lazertinib, or NSCLC. The research may begin at any time during the study or the post-study 
storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Participants may withdraw their consent for their samples to be 
stored for research (refer to Section 7.2.1, Withdrawal From the Use of Research Samples).
10.2.7.
Committees Structure
Independent Data Monitoring Committee
An IDMC will be established. This committee will consist of at least one medical expert in the 
relevant therapeutic area and at least one statistician; committee membership responsibilities, 
authorities, and procedures will be documented in its charter. The committee will meet periodically 
to review interim data. A first IDMC meeting will be held after the first 20 participants complete 
2 cycles of treatment. After the review, the IDMC will make recommendations regarding the 
continuation of the study.
10.2.8.
Publication Policy/Dissemination of Clinical Study Data
All information, including but not limited to information regarding the combination of lazertinib 
with either amivantamab or the sponsor's operations (eg, patent application, formulas, 
manufacturing processes, basic scientific data, prior clinical data, formulation information) 
supplied by the sponsor to the investigator and not previously published, and any data, including 
pharmacogenomic or exploratory biomarker research data, generated as a result of this study, are 
considered confidential and remain the sole property of the sponsor. The investigator agrees to 
maintain this information in confidence and use this information only to accomplish this study and 
will not use it for other purposes without the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of the combination of lazertinib with either 
amivantamab, and thus may be disclosed as required to other clinical investigators or regulatory 
agencies. To permit the information derived from the clinical studies to be used, the investigator 
is obligated to provide the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of 
pharmacogenomic or exploratory biomarker analyses performed after the Clinical Study Report 
has been issued will be reported in a separate report and will not require a revision of the Clinical 
Study Report.
Study participant identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from copyright 

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protection (except any publication by the investigator as provided for below) shall be the property 
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter) 
data and information without approval from the investigator. The investigator has the right to 
publish study site-specific data after the primary data are published. If an investigator wishes to 
publish information from the study, a copy of the manuscript must be provided to the sponsor for 
review at least 60 days before submission for publication or presentation. Expedited reviews will 
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow for 
filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will 
not mandate modifications to scientific content and does not have the right to suppress information. 
For multicenter study designs and sub-study approaches, secondary results generally should not 
be published before the primary endpoints of a study have been published. Similarly, investigators 
will recognize the integrity of a multicenter study by not submitting for publication data derived 
from the individual study site until the combined results from the completed study have been 
submitted for publication, within 18 months after the study end date, or the sponsor confirms there 
will be no multicenter study publication. Authorship of publications resulting from this study will 
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations 
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which 
state that the named authors must have made a significant contribution to the conception or design 
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the 
work or revised it critically for important intellectual content; and given final approval of the 
version to be published; and agreed to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the interim results of clinical studies as required by law. The 
disclosure of the study results will be performed after the end of study in order to ensure the 
statistical analyses are relevant.
10.2.9.
Data Quality Assurance
Data Quality Assurance/Quality Control
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 

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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.
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 must 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 
study participants into source records cannot be overridden by site staff or investigators.

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Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring guidelines 
(or other equivalent document).
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and 
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by participant interview or other protocol required assessment (eg, physical 
examination, laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or 
clinic record to document medical care (eg, electronic source documents) as well as the clinical 
study-specific data fields as determined by the protocol. This data is electronically extracted for 
use by the sponsor. If eSource is utilized, references made to the CRF in the protocol include the 
eSource system but information collected through eSource may not be limited to that found in the 
CRF.
10.2.12.
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.

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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 
regulatory submission. The investigator must immediately notify the sponsor if he or she has been 
contacted by a regulatory agency concerning an upcoming inspection.
10.2.14.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF and 
all source documents that support the data collected from each participant, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents as specified by the applicable regulatory requirement(s). The 
investigator/institution will take measures to prevent accidental or premature destruction of these 
documents.
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.

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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 participant screened is considered the first act of recruitment and it becomes the study 
start date.
Study/Site Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been collected 
and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further 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 adverse event is any untoward medical occurrence in a clinical study participant administered 
a pharmaceutical (investigational or non-investigational) product. An adverse event does not 
necessarily have a causal relationship with the treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational or non-investigational) product, whether or 
not related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference 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 adverse events starting with the signing of the ICF (refer 
to All Adverse Events under Section 8.3.1, Time Period and Frequency for Collecting Adverse 
Events and Serious Adverse Events Information, for time of last adverse event recording).
All adverse events, regardless of seriousness, severity, or presumed relationship to study treatment, 
must be recorded using medical terminology in the source document and the CRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as “upper 
respiratory infection”). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event
management must be recorded in the source document and reported according to sponsor 
instructions.
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (The participant was at risk of death at the time of the event. It does not 
refer to an event that hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*

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Note: Events that do not qualify as an AE cannot be reported as a SAE, even if the conditions for 
seriousness are met. In particular, this is the case for events due to disease progression leading to 
death, hospitalization, etc.
* 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 may not 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.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study treatment and the event (eg, death from anaphylaxis), the event 
must be reported as a serious and unexpected suspected adverse reaction even if it is a component 
of the study endpoint (eg, all-cause mortality).
For combination products with a device constituent, SAEs include adverse device effects that 
resulted in any of the consequences characteristic of an SAE. An unanticipated serious adverse 
device effect is a serious adverse device effect which by its nature, incidence, severity or outcome 
has not been identified in the current version of the risk analysis report (see Section 2.3. 
Benefit-Risk Assessment).
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 the combination of lazertinib with either amivantamab and 
lazertinib, the expectedness of an AE will be determined by whether or not it is listed in the IB. 
10.3.2.
Attribution Definitions
Assessment of Causality
The causal relationship to study treatment is determined by the Investigator. The following 
selection should be used to assess all 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.
The term “reasonable causal relationship” means there is evidence to support a causal relationship.

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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

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

Reporting of participant pregnancy or participant partner(s) pregnancy
Special reporting situations must be recorded in the CRF. Any special reporting situation that 
meets the criteria of an SAE must be recorded on the SAE page of the CRF.

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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 CRF. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough, 
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory 
infection"). Investigators must record in the CRF their opinion concerning the relationship of the 
AE to study therapy. All measures required for AE management must be recorded in the source 
document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following:

Study number

Statement, in the local language(s), that the participant is participating in a clinical study

Investigator's name and 24hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical personnel only)

Site number

Participant number
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon the 
participant's discontinuation from the study, must be followed until any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study treatment or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (participant or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts)
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during 
participation in the study must be reported as an SAE, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending 
placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 

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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. 
Expected progression of disease should not be considered an AE (or SAE). However, if determined 
by the investigator to be more likely related to the study treatment, protocol design, or protocol 
procedures 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.
Information regarding SAEs will be transmitted to the sponsor using an SAE reporting form, which 
must be completed and signed by a physician from the study site, and transmitted in a secure 
manner to the sponsor within 24 hours. The initial and follow-up reports of an SAE should be 
made by facsimile (fax). Telephone reporting should be the exception and the reporter should be 
asked to complete the appropriate form(s) first. 
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.
This definition includes any PQC related to a device constituent in a combination product, 
including those used in the administration of the study treatment. A device deficiency is an 
inadequacy of a device with respect to its identity, quality, durability, reliability, safety, or 
performance. Device deficiencies include malfunctions, use errors, and inadequate labeling.
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.
Any device identified as having a product-defect related PQC will be returned to the sponsor or 
sponsor delegate for analysis in the original packaging.

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Product quality complaints (PQC) will be reported for use error or product defects. Investigational 
product with product defect complaints will be sent back to sponsor for root cause analysis per the 
PQC process. Note that while all devices will be returned to the sponsor, devices with a PQC 
should be returned via the PQC process and returned in a special container provided by the sponsor. 
10.3.7.
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who must 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 12 will be considered anticipated events:
Table 12:
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.
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 and Barrier Guidance
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria. 
Pregnancy information will be collected and reported as noted in Section 8.3.5, Pregnancy and 
Appendix 3: Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other 
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting.
Definitions
Females of Childbearing Potential (FOCBP)
A female is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Females Not of Childbearing Potential

premenarchal
A premenarchal state is one in which menarche has not yet occurred.

postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the 
postmenopausal range may be used to confirm a postmenopausal state in female 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 a female participant on HRT, the female participant will 
be required to use one of the non-estrogen-containing hormonal highly effective contraceptive 
methods if she wishes to continue HRT during the study.

permanently sterile

Permanent sterilization methods include hysterectomy, or bilateral salpingectomy, or 
bilateral oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal female 
participant experiences menarche) or the risk of pregnancy changes (eg, a female participant who 
is not heterosexually active becomes active), a female 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 male or female participants must be consistent with local 
regulations regarding the acceptable methods of contraception for those participating in clinical 
studies.
Typical use failure rates may differ from those when used consistently and correctly. Use must be 
consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies.

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

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a) Typical use failure rates may differ from those when used consistently and correctly. Use must be 
consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies.
b) Hormonal contraception may be susceptible to interaction with the study treatment, which may 
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception 
may interact with the study treatment.
c) Male condom and female condom must not be used together (due to risk of failure with friction).

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10.7.
Appendix 7: Liver Safety: Follow-up Assessments and Study Treatment 
Rechallenge Guidelines
Liver Event Follow-Up Requirements
The following follow-up assessments should be conducted for any participant meeting liver 
chemistry stopping criteria:

Monitor liver chemistries (ALT, AST, ALP, bilirubin [including bilirubin fractions], and 
INR), creatinine phosphokinase, and lactate dehydrogenase, 1 to 2 times per week until 
resolution, stabilization, or return to participant’s baseline values

Monitor clinical condition closely

Draw blood samples for unscheduled PK analysis at timepoints when liver chemistry is 
assessed

Record use of concomitant medications, acetaminophen, herbal remedies, other 
over-the-counter medications, or known hepatotoxins

Record alcohol use in the CRF

Check the viral hepatitis serology as appropriate and include:

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, magnetic resonance imaging [MRI], or computerized 
tomography [CT]) to evaluate liver disease

Refer to a specialist as appropriate
Rechallenge Criteria
Resumption of study drug administration may be considered if the following criteria are met:

Hy's Law has been excluded

A reversible underlying cause not associated with study treatments (eg, alcohol use or 
concomitant medication) is clearly identified and agreed upon in consultation with sponsor’s 
medical monitor

Liver chemistry abnormalities have resolved or values have returned to baseline

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10.8.
Appendix 8: Response Evaluation Criteria in Solid Tumors (RECIST) Quick 
Reference
RECIST 1.1
Measurable
Tumor 
Burden
A maximum of 5 target lesions in total (and up to 2 per organ) can be identified
at baseline and measured through the course of therapy.
Minimum Size 
of Measurable
Lesions
≥10 mm in longest diameter (LD) and 2X the slice thickness for extranodal 
lesions.
≥15 mm in short axis diameter (SAD) for nodal lesions.
≥10 mm in LD for clinical lesions (must be measured using electronic calipers).
≥20 mm in LD for chest X-ray (if clearly defined and surrounded by aerated 
lung); CT is preferable.
Ultrasound (US) cannot be used to measure lesions.
Lymph Nodes
Lymph nodes are considered pathologically enlarged if >10 mm in SAD. 
To be measurable, nodal lesions must be ≥15 mm in SAD. 
Nodal lesions with SAD >10 mm and <15 mm are non- measurable.
The sum of the diameters (LD for extranodal target lesions, SAD for nodal
lesions) is followed through the course of therapy.
Bone Lesions
A lytic or mixed lytic-blastic bone lesion with a soft tissue component assessed
on CT/MRI can be measurable if the minimum size criteria are met.
Blastic bone lesions and bone lesions assessed on bone scan, positron emission
therapy (PET) or plain films are non-measurable.
Cystic Lesions
Lesions that meet the criteria for radiographically defined simple cysts are
not malignant.
Cystic lesions thought to be metastases can be measurable if they meet the
minimum size criteria. Non-cystic lesions are preferable.
Lesions with 
Prior Local 
Treatment
Lesions in previously irradiated areas (or areas treated with local therapy) are 
not measurable unless the lesion has progressed since therapy.
Too Small To 
Measure
If a target lesion becomes too small to measure, a default value of 5 mm is
assigned. If the lesion disappears, the measurement is recorded as 0 mm.
Lesions That
Split or 
Coalesce
If extranodal target lesions fragment, the LDs of the fragmented portions are 
added to calculate the sum.
If target lesions coalesce and cannot be distinguished, the LD of the coalesced
lesion is added to the sum.
Definition of 
Complete 
Response (CR)
CR requires the disappearance of all extranodal lesions, the regression of all 
nodal lesions to <10 mm SAD and the normalization of tumor marker level.
Definition of 
Progressive 
Disease (PD)
PD is assessed if the sum of the diameters has increased by ≥20% and ≥5 mm 
from nadir (including baseline if it is the smallest sum).
Patients with measurable disease: for "unequivocal progression" based on non-
target disease, there must be an overall level of substantial worsening that 
merits discontinuation of therapy (if target disease is SD/PR).
Patients without measurable disease: for "unequivocal progression" of non-
target disease, the increase in overall tumor burden must be comparable to the 
increase required for PD of measurable disease.
Assessment of 
New Lesions
New lesions should be unequivocal and not attributable to differences in 
scanning technique or findings which may not be tumor (ie, 'new' bone lesions 
may be healing or flare of pre- existing lesions). If on is equivocal, repeat scans 
are needed to confirm. If confirmed, PD is assessed at the date of the initial 
scan. Lesions identified in anatomic locations not scanned at baseline are 
considered new. New lesions on US should be confirmed on CT/MRI.
FDG-PET
New lesions can be assessed using FDG-PET:(-) PET at baseline and (+) PET 
at follow-up is PD based on a new lesion. No PET at baseline and (+) PET at 
follow-up is PD if the new lesion is confirmed on CT. If a subsequent CT 
confirms the new lesion, the date of the PD is the date of the initial PET scan. 

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No PET at baseline and (+) PET at follow-up corresponding to pre-existing 
lesion on CT that is not progressing; not PD.
Recurrence of 
Lesions
For a patient with SD/PR, a lesion which disappears and then reappears will 
continue to be measured and added to the sum. Response will depend upon the 
status of the other lesions. For a patient with CR, reappearance of a lesion 
would be considered PD.
Overall 
Response
One overall response table integrates target, non-target and new lesions and 
another table integrates non-target and new lesions for the assessment of 
participants without measurable disease.
Confirmation 
of Response
Confirmation of PR/CR is ONLY required for non-randomized trials where 
response is the primary endpoint. In these trials, subsequent confirmation of PR 
with one interim timepoint of SD is acceptable.
Source: Eisenhauer 2009.
Reference: Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.

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10.9.
Appendix 9: 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: Eastern Cooperative Oncology Group (ECOG) Performance 
Status Score
Grade 
Eastern Cooperative Oncology Group (ECOG) Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light 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
Reference: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655

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10.11. Appendix 11: Health Care Provider (HCP) - Ease of Use and Satisfaction 
Questionnaires
To be completed by HCPs that cared for all participants:
1) How was this participant administered amivantamab?
IV infusion                                                SC manual injection                                        
2) How satisfied or dissatisfied were you with the therapy administration?
Very satisfied             Satisfied                     Neutral                Dissatisfied             Very Dissatisfied
3) How convenient is it for you to administer the therapy? 
Very Convenient      Convenient                  Neutral                Inconvenient          Very Inconvenient
4) How bothered were you by the amount of time it takes to administer the therapy?
Not at all bothered      A little bothered   Moderately bothered     Quite bothered      Very bothered

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10.12. Appendix 12: Formulas for Estimating Glomerular Filtration Rate Using 
Modified Diet in Renal Disease Formula (in mL/min)
For standardized serum creatinine (SCr) in mg/dL, the estimated glomerular filtration rate (eGFR) 
is:
eGFR (mL/min) = 175 x [standardized SCr (mg⁄dL)]-1.154 x age-0.203 x 1.212if black x 0.742if female
x BSA* / 1.73
Creatinine levels conversion from µmol/L to mg/dL:
creatinine (mg⁄dL) =
creatinine (µmol)⁄L
88.4
* BSA to be calculated using the Mosteller formula (weight in kg and length in cm):
BSA (m²) = square root of (length * weight/3600)
Standardized SCr: Creatinine assay calibration traceable to an isotope dilution mass spectrometry (IDMS) 
reference measurement procedure (this is the case for most assays).
Sources: Levey (2006, 2007) and Mosteller (1987)

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10.13. Appendix 13: Allowed Recent Second or Prior Malignancies
i.
Any malignancy that was not progressing nor requiring treatment change in the last 
12 months.
ii.
Malignancies treated within the last 12 months and considered at very low risk for 
recurrence:
a) Non-muscle invasive bladder cancer (solitary Ta-PUNLMP or low grade, <3 cm, no CIS).
b) Skin cancer (non-melanoma or melanoma).
c) Non-invasive cervical cancer.
d) Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, 
localized breast cancer and receiving antihormonal agents.
e) Localized prostate cancer (M0, N0) with a Gleason Score ≤7a, treated locally only 
(RP/RT/focal treatment).
iii.
Other malignancy that is considered at minimal risk of recurrence.
In the event of any questions, consult with the sponsor’s medical monitor prior to enrolling a 
participant.

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10.14. Appendix 14: Modified Therapy Administration Satisfaction 
Questionnaires for IV infusion (TASQ-IV) or SC injections (TASQ-SC)
The wording of question 11 in these questionnaires differs from the original. The original wording 
specified that the SC injection would take place in the “thigh,” but these modified questionnaires 
specify that the injection will take place in the “skin”.

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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(s)
within the study while further reducing protocol-required visit procedures and assessments, and 
burden on participants, after the primary analysis is complete. The LTE Phase will begin after the 
primary analysis and will continue until the discontinuation criteria described in Section 7.1 are 
met, or until 3 years after local marketing authorization is obtained, whichever occurs first. After 
notification from the sponsor, participants that are on treatment and who remain in the study after 
completion of the primary analysis will be provided with the option to enter the LTE Phase.
Data collection will be limited during this phase. Study treatment compliance will be recorded. 
Serious adverse events will be reported on the appropriate SAE form and recorded by the sponsor 
in the Global Medical Safety database. Pregnancy reporting should continue as described in 
Section 8.3.5. Other safety and efficacy data will not be collected during the LTE Phase. No 
analyses other than routine periodic safety reviews consisting of reported SAEs are planned for 
the LTE Phase.
Participants who had discontinued study treatment, or participants who elect not to enter the LTE 
Phase will be discontinued from the study upon the start of the LTE Phase.
Participants entering the LTE Phase will continue to receive the study treatment(s) they were 
receiving at the completion of the primary analysis. The sponsor will continue to provide study 
drugs until the discontinuation criteria described in Section 7.1 are met, or until 3 years after local 
marketing authorization is obtained, whichever occurs first. Study treatment dispensation and 
accountability will be performed via IWRS.
10.15.1.
Eligibility Criteria
All participants on study treatment(s) still in the study, and who are willing and able to provide 
informed consent to participate, are eligible to enter the LTE Phase.
10.15.2.
Study Treatment Administration
Study treatment(s) should continue as specified in Section 6.
10.15.3.
Study Procedures
All participants in the LTE Phase should follow the Schedule of Activities for the LTE Phase 
(Table 13).
Participants in the LTE Phase should be followed up for safety per local practice and local label 
requirements. No efficacy data will be collected. Only SAEs will be collected via the SAE form 
per the SAE 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. 
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 (TOC).
Amendment 4 (21 November 2023)
Overall Rationale for the Amendment:
The overall purpose of this amendment is to clarify the PK evaluable analysis set for each of the primary 
PK endpoints following Health Authority interactions and to implement minor updates from various study 
documents. 
The changes made to the clinical protocol 61186372NSC3004 as part of Protocol Amendment 4 are listed 
below, including the rationale of each change and a list of all applicable sections. Changes made in previous 
protocol amendments are listed in Section 10.16.
Section Number
and Name
Description of Change
Brief Rationale
9.3 Populations for 
Analysis Sets
A description of the hybrid approach to 
evaluate the study PK co-primary endpoint 
(Cycle 4 Day 1 Ctrough) was added.
To clarify the PK evaluable 
analysis set for the study PK co-
primary endpoint (Cycle 4 Day 1 
Ctrough) following FDA feedback.
1.1 Synopsis, Statistical 
Methods;
3. Objectives and 
Endpoints;
4.2 Scientific Rationale for 
Study Design;
8.4.3 Pharmacokinetic 
Parameters and 
Evaluations;
9.1 Statistical Hypotheses;
9.2 Sample Size 
Determination;
9.3 Populations for 
Analysis Sets;
9.4.2 Primary Endpoints;
9.4.3 Secondary Endpoints

Throughout the protocol, the following text 
in bold has been added: ‘Ctrough (at steady 
state [Cycle 4 Day 1] for all regions other 
than EU and others accepting Cycle 2 
Day 1 and pre-dose on Cycle 2 Day 1 for 
EU and any applicable region)’.

Section 9.3 – updates were made to clarify 
the PK evaluable analysis set for each of 
the primary PK endpoints.
Updates made following Health 
Authority interactions.
1.3.1 Schedule of Activities

Study Procedure note was revised as 
shown below:
During Cycle 2, if a dose interruption or 
missed dose leads to a cycle delay or a dose 
delay, the sampling schedule (except disease 
assessments) should be delayed accordingly to 
ensure sampling relative to amivantamab dose 
administration, which would trigger the start 
of the next cycle.

The following text was added to footnote 
‘n’:
If unable to collect during the disease 
evaluation visit, the sample may be collected 
at the next visit prior to subsequent study 
treatment administration.

Added the following footnote (‘v’) to Day 
1 Cycle 4+: 
Minor clarification from existing 
information in various study 
documents.

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PK samples are collected on Day 1 of Cycles 
5, 7, 9, and 11 (see Table 2).
1.3.1 Schedule of Activities
6.1 Study Treatments 
Administered (Description 
of Treatments Table) 
Text was updated to provide clarification that 
lazertimib dose is to be administered prior to 
premedication for amivantamab. 
Minor clarification from existing 
information in the training 
manual and site dosing 
instructions.
1.3.1 Schedule of Activities
8.1 Efficacy Assessments
Brain imaging frequency was clarified: 
every 6 weeks if brain mets are present at 
baseline and being followed as non-target 
lesions and if no brain mets at baseline, only as 
clinically indicated.
Clarification as outlined in the 
existing imaging manual.
1.3.2 Collection Times for 
PK and Immunogenicity 
Samples

Updated the window for the EOI ±168 hrs
visit from ±4 hrs to ±1 day. 

Deleted foontotes ‘c’ and ‘d’ and updated 
the order of subsequent footnotes.

Pharmacokinetic window is 
updated to match study visit 
window.

Inadvertently not removed 
during Amendment 2.
1.3.2 Collection Times for 
PK and Immunogenicity 
Samples
8 Study Assessments and 
Procedures
Sample Collection and 
Handling
The following text was added to Section 8 and 
Cycle 4 Day 1 for amivantamab serum PK 
sample (as footnote ‘e’):
If Cycle 4 Day 1 dose is delayed or withheld, 
the amivantamab serum PK sample should 
be collected on the planned day per 
protocol. This collection will be considered 
an unscheduled serum PK sample.
To provide flexibility on sample 
collection for the co-primary 
endpoint.
5.3 Lifestyle Considerations
Updated Criterion 2 that osimertinib must be 
discontinued at least 8 days prior to first dose 
of study drug rather than randomization.
To clarify the washout period is 
required prior to the first dose 
(C1D1).
8.3.1 Time Period and 
Frequency for Collecting 
Adverse Event and Serious 
Adverse Event Information.
9.4.5 Safety Analysis 
Adverse Events
Clarified that AEs are reported through 30 
days after the last study treatment dose.
To align the protocol language 
with the schedule of activities.
8.3.7 Adverse Events of 
Special Interest
Added ‘(ie, via email)’ to provide example of 
reporting method.
To clarify the reporting method 
for severe IRR.
9.4.3 Secondary Endpoints 
Time to Response (TTR)
Modified Therapy 
Administration Satisfaction 
Questionnaire

Deleted ‘BICR using’

Text was reviewed as shown below:
This validated PRO instrument is 
designed to assess patient satisfaction with 
cancer therapy. Descriptive statistics will 
be reported for the individual scores items
and total domain scores at baseline and at 
each visit for absolute value and for 
change from baseline.

Typographical error.

Clarification that the TASQ 
has no total score. The 
measure has scores for 
individual items and for 
each of five domains.
10.6. Appendix 6: Clinical 
Laboratory Tests
Added Urea
and added footnote ‘b’ to the table:
For sites that cannot calculate BUN.
To allow for urea collection for 
sites that cannot test for BUN. 
1.1 Synopsis
Text was added to clearly describe the study.
Updated for clarification.
Throughout the protocol
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted.

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Amendment 3 (11 August 2023)
Overall reason for the Amendment:
The overall purpose of this protocol amendment is to clarify risk mitigation strategies for VTE 
among patients treated with combination of amivantamab and lazertinib.
The changes made to the clinical protocol 61186372NSC3004 as part of Protocol Amendment 3
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
5.2 Exclusion Criteria
Criterion 10 has been updated to add
participants who have a significant genetic 
predisposition to venous thromboembolic 
events such as Factor V Leiden or have a 
prior history of VTE and is not on appropriate 
therapeutic anticoagulation as per NCCN or 
local guidelines.
To clarify and align with the VTE 
risk mitigation and management.
6.5.1 Dose Delay 
Guidance
Resolutions in case of VTE events associated 
with clinical instability text was added.
6.5.2 Dose Modification of 
Amivantamab and 
Lazertinib
Table 4; Footnote ‘d’ updated for VTE in 
participants being treated with the 
combination of amivantamab and lazertinib.
6.5.3.10 Venous 
Thromboembolic Events
Recommendations in case of recurrent VTEs 
have been included.
10.15 Country-specific 
Requirements
Appendix 15 (Country-specific 
Requirements) was deleted.
No longer applicable.
Amendment 2 (27 October 2022)
Overall reason for the Amendment: Due to the impact of the On Body Delivery System (OBDS) 
availability globally, the sponsor decided to only conduct Part 1 of the study. Part 2 of this study, 
which used the OBDS, has been removed.
The rationale for and description of the changes made during this protocol amendment and the 
affected section numbers are provided below. The revisions noted below are representative of the 
changes. When changes are provided verbatim, deleted text is shown as strikethrough, and added 
text is shown as bold font.
The changes made to the clinical protocol 61186372NSC3004 as part of Protocol Amendment 2 
are listed below, including the rationale of each change and a list of all applicable sections. 
Changes made in previous protocol amendments are listed in Section 10.16 Appendix 16: Protocol 
Amendment History.

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Section number
and Name
Description of Change
Brief Rationale
1.1 Synopsis
Removal of text relating to Part 2 of the 
study. Also, deletion of any text that refers to 
Part 1 as an identifier.
Part 2 of the study has been 
deleted. The study now only has 
one part, therefore headings and 
text identifying parts is not 
required. 
1.2 Schema
Adapting diagram after removal of Part 2 of 
the study.
Part 2 of the study has been 
deleted.
1.3 Schedule of Activities
Table 1, Table 2 (previous Table 3) titles 
have ‘for Part 1’ removed. Table 2 and 
Table 4 for Part 2 are now deleted.
Part 2 of the study has been 
deleted. The study now only has 
one part, therefore headings and 
text identifying parts is not 
required. 
1.3 Schedule of Activities
Table 1 has predose timings added for cDNA 
and exploratory biomarker bloodsamples. 
And a footer (u) for exploratory biomarker 
samples was also added to clarify that the 
samples are not required to be collected 
beyond Cycle 4.
The CT/MRI imaging row has the following 
text added: Imaging obtained as part of 
standard care before signing the ICF, but 
within 28 days of randomization, may be 
used for the screening assessment if 
parameters meet the imaging manual 
requirements.
Table 2 (previous Table 3) has had cDNA 
and exploratory biomarker bloodsamples 
rows removed.
Timings were added to instruct the 
site when to collect the samples. 
Alignment with previous 
amivantamab studies to provide 
more flexibility.
This information is now provided 
in Table 1.
2 Introduction
Removal of text related to Part 2 of the study.
Also, deletion of any text that refers to Part 1 
as an identifier.
Part 2 of the study has been 
deleted.
2.1 Study Rationale
Removed text related to OBDS.
Part 2 of the study has been 
deleted.
2.2.2.1 Amivantamab IV
Adding the lazertinib IB as a reference, in 
addition to the amivantamab IB.
For clarity. 
2.2.2.2 Amivantamab SC-
CF
Removed text related to OBDS.
Part 2 of the study has been 
deleted.
2.2.5 On Body Delivery 
System Combination 
Product
This section was removed.
Part 2 of the study has been 
deleted.
2.3.1 Risks for Study 
Participation
Removed text relating to the risks for OBDS.
Part 2 of the study has been 
deleted.
2.3.3. Benefit-Risk 
Assessment for Study 
Participation
Removed text relating to OBDS.
Part 2 of the study has been 
deleted.

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Section number
and Name
Description of Change
Brief Rationale
3. OBJECTIVES AND 
ENDPOINTS
Deletion of any text that refers to Part 1 as an 
identifier. Removed objectives and endpoints 
related to Part 2 and OBDS. Removed 
hypothesis for Part 2.
Part 2 of the study has been 
deleted. The study now only has 
one part, therefore text identifying 
parts is not required.
4.1 Overall Design
Removal of text relating to Part 2 of the 
study. Also, deletion of any text that refers to 
Part 1 as an identifier.
Part 2 of the study has been 
deleted. The study now only has 
one part, therefore text identifying 
parts is not required.
4.1.1 Screening
Deletion of text that refers to Part 1 as an 
identifier; deletion of reference to Table 2 for 
Part 2.
Part 2 of the study has been 
deleted. The study now only has 
one part, therefore text identifying 
parts is not required.
4.1.2 Treatment Phase
Removal of text relating to Part 2 of the 
study. Also, deletion of any text that refers to 
Part 1 as an identifier.
Part 2 of the study has been 
deleted. The study now only has 
one part, therefore text identifying 
parts is not required.
4.2. Scientific Rationale 
for Study Design
Removal of text relating to Part 2 of the 
study. Also, deletion of any text that refers to 
Part 1 as an identifier.
Part 2 of the study has been 
deleted. The study now only has 
one part, therefore text identifying 
parts is not required.
4.2.1. Study-Specific 
Ethical Design 
Considerations
Removal of text referring to OBDS.
Part 2 of the study has been 
deleted.
4.4 End of Study 
Definition
The participant study completion definition 
has been updated.
Updating study completion 
definition.
5.1 Inclusion Criteria
5.2 Exclusion Criteria
Criterion 16 has been moved from the 
Exclusion Criteria to the Inclusion Criteria.
To align with the Sponsor protocol 
template and to address Health 
Authority request.
6.1 Study Treatments 
Administered 
Removal of header text relating to Part 2 of 
the study. 
Part 2 of the study has been 
deleted.
6.1.2. Amivantamab SC-
CF by Manual Injection 
(Arm A)
Removal of header text relating to Part 2 of 
the study.
Part 2 of the study has been 
deleted.
6.1.3. Amivantamab IV 
(Arm B)
Header updated from B1 to B.
Part 2 of the study has been 
deleted.
6.1.4 Amivantamab SC-CF 
OBDS (Arm B2)
This section has been deleted as it contained 
text related to OBDS. The following 
lazertinib section has now become Section 
6.1.4.
Part 2 of the study has been 
deleted.
6.2. Preparation/Handling/ 
Storage/Accountability
Text relating to amivantamab SC-CF IFU has 
been deleted
Part 2 of the study has been 
deleted
6.4 Study treatment 
compliance 
Text relating to OBDS has been deleted. 
Part 2 of the study has been 
deleted.

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Section number
and Name
Description of Change
Brief Rationale
6.5.2. Dose Modification 
of Amivantamab and 
Lazertinib
Text relating to OBDS has been deleted.
Part 2 of the study has been 
deleted.
6.5.3.1. Infusion-Related 
Reactions and Local 
Administration-Related 
Reactions
Deletion of any text that refers to Part 1 or 
Part 2 as an identifier. Removal of text 
relating to Part 2 of the study.
Part 2 of the study has been 
deleted.
8. STUDY 
ASSESSMENTS AND 
PROCEDURES
Text relating to OBDS has been deleted.
Part 2 of the study has been 
deleted.
8.1.2 Amivantamab SC-CF 
OBDS Performance
8.1.2.1 Amivantamab SC-
CF OBDS Successful 
Completion
8.1.2.2 HCP Questionnaire
Sections relating to OBDS have been deleted.
Part 2 of the study has been 
deleted.
8.4.1. Evaluations
Deletion of any text that refers to Part 1 or 
Part 2 as an identifier.
Part 2 of the study has been 
deleted.
8.4.3. Pharmacokinetic 
Parameters and 
Evaluations
Deletion of any text that refers to Part 1 or 
Part 2 as an identifier. Removal of text 
relating to Part 2 of the study.
Part 2 of the study has been 
deleted.
9.1.Statistical Hypotheses
The primary hypothesis text for Part 2 has 
been deleted.
Part 2 of the study has been 
deleted.
9.2. Sample Size 
Determination
Deletion of any text that refers to Part 1 or 
Part 2 as an identifier. Removal of text 
relating to Part 2 of the study.
Part 2 of the study has been 
deleted.
9.3. Populations for 
Analysis Sets
Deletion of any text that refers to Part 1 or 
Part 2 as an identifier. Removal of text 
relating to Part 2 of the study.
Part 2 of the study has been 
deleted.
9.4.2 Primary Endpoints
Deletion of any text that refers to Part 1 or 
Part 2 as an identifier. Removal of text 
relating to Part 2 of the study.
Part 2 of the study has been 
deleted.
9.4.3. Secondary 
Endpoints
Deletion of any text that refers to Part 1 or 
Part 2 as an identifier. Removal of text 
relating to Part 2 of the study. Text relating to 
OBDS has been deleted.
Part 2 of the study has been 
deleted.
9.5 Interim Analysis
Deleted as is no longer being carried out now 
that Part 2 is removed.
Part 2 of the study has been 
deleted.
10.1. Appendix 1: 
Abbreviations
OBDS and SC-CF OBDS have been deleted.
Part 2 of the study has been 
deleted.
Amendment 1 (25 August 2022)
Overall Rationale for the Amendment: This amendment is being implemented to describe an EU-specific 
approach for the co-primary endpoint of Ctrough based on European Medicines Agency (EMA) recommendation and 

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to address other health authority recommendations; to incorporate guidance related to the Urgent Safety Measure for 
venous thromboembolic events (VTEs); and to apply additional modifications and clarifications.
The rationale for and description of the changes made during this protocol amendment and the affected section 
numbers are provided below. The revisions noted below are representative of the changes. When changes are 
provided verbatim, deleted text is shown as strikethrough, and added text is shown as bold font.
Section Number
and Name
Description of Change
Brief Rationale
Synopsis, Statistical 
Methods;
3. Objectives and 
Endpoints;
4.2 Scientific Rationale 
for Study Design;
8.4.3 Pharmacokinetic 
Parameters and 
Evaluations;
9.1 Statistical 
Hypotheses;
9.2 Sample Size 
Determination;
9.3 Populations for 
Analysis Sets;
9.4.2 Primary Endpoints;
9.5 Interim Analysis
Throughout the protocol, where the co-primary 
endpoint ‘Ctrough at steady state (Cycle 4 Day 1)’ is 
described, the modified text has been added: ‘Ctrough
(at steady state [Cycle 4 Day 1] for all regions other 
than EU and pre-dose on Cycle 2 Day 1 for EU 
only)’.
Changes to the primary 
endpoint (and 
corresponding changes to 
secondary endpoint) 
following EMA advice.
3. Objectives and 
Endpoints;
9.4.3 Secondary 
Endpoints
Secondary endpoint for Ctrough has been revised from:
‘For Part 1, a Ctrough for amivantamab will be 
drawn on Cycle 2 Day 1. Similar analysis method 
used for the primary endpoint will be used.’
To read as follows:
‘In regions other than EU, a Ctrough of 
amivantamab pre-dose on Cycle 2 Day 1 will be 
a secondary endpoint. Similar analysis method 
used for the primary endpoint will be used in 
Part 1.
In EU, a Ctrough of amivantamab at steady state 
(Cycle 4 Day 1) will be a secondary endpoint. 
Similar analysis method used for the primary 
endpoint will be used in Part 1.’
1.2 Schema
The following text (in bold) has been added to the 
note immediately below Figure 1:
NOTE: As OBDS is a combination product, the 
sponsor will ensure provision of regulatory guidance 
throughout the device development process and 
provide further background information through 
a substantial protocol amendment prior to 
initiation of Part 2.
To provide additional clarity 
on this aspect of study 
conduct based on health 
authority input.
1.3.1 Schedule of 
Activities for Part 1
(Table 1);
1.3.2 Schedule of 
Activities for Part 2
(Table 2)
For both tables, row added for prophylactic-dose 
anticoagulation during the first 4 months of 
treatment, and VTE-related footnotes added for 
physical examination and anticoagulation.
For Table 1 only, row added for blood samples for 
exploratory biomarkers.
To implement the adverse 
event of special interest of 
venous thromboembolic 
(VTE) events, as well as 
associated measures for 

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Section Number
and Name
Description of Change
Brief Rationale
2.3.1 Risks for Study 
Participation
VTE has been added to the list of possible risks for 
the amivantamab and lazertinib combination.
monitoring and prophylaxis 
of these events.
2.3.3 Benefit-Risk 
Assessment for Study 
Participation
The rationale for and aims of the VTE-related 
measures have been added.
6.5.2 Dose Modification 
of Amivantamab and 
Lazertinib (Table 6)
The following text has been added to note ‘d’:
No dose reduction required for VTE events. 
Study treatment initially held for stable, treated 
pulmonary embolism and deep vein thrombosis 
≤Grade 3 can be resumed at the discretion of the 
investigator.
6.5.3.10 Venous 
Thromboembolic Events
A new section has been added to provide guidance 
on management of venous thromboembolic events.
8.2.1 Physical 
Examinations
Additional guidance has been added for detection of 
VTE through physical examination.
8.3.7 Adverse Events of 
Special Interest
VTE has been added to the list of AEs of special 
interest. It is noted that events of VTE should follow 
standard reporting guidelines.
8.6 Biomarkers
The following text has been added:
Blood samples will also be collected at the time 
points specified in the Schedule of Activities and 
may be analyzed to investigate circulating factors, 
eg cytokines, associated with response to 
treatment.
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.
1.3.1 Schedule of 
Activities for Part 1
(Table 1)
Vital signs to be collected at Cycle 1 Days 2, 8, 15, 
and 22.
These assessments were 
inadvertently omitted in the 
original protocol.
1.3.1 Schedule of 
Activities for Part 1
(Table 1)
Lazertinib administration row, text changed: 
‘…lazertinib should be taken about 30 minutes more 
than 15 minutes prior to premedication or 
amivantamab initiation…’
This text has been changed 
to align with other sections 
of the protocol.
1.3.2 Schedule of 
Activities for Part 1
(Table 2)
Lazertinib administration row, text changed: 
‘…lazertinib should be taken about 30 minutes more 
than 15 minutes prior to premedication or 
amivantamab initiation…’
This text has been changed 
to align with other sections 
of the protocol.

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Section Number
and Name
Description of Change
Brief Rationale
1.3.3 Collection Times for 
PK and Immunogenicity 
Samples for Part 1
(Table 3)
The footnote below has been added to Table 3 and 
applied to Cycle 2 Days 1 (EOI + 6 hours assessment 
only), 2, 3, 4, 5, and 8.
If on-site visit is not possible, the PK draw could 
be performed outside of the clinic, through a 
Sponsor-designated home health care vendor, if 
approved and allowed by local regulations and 
after requisite consultation with the medical 
monitor.
To allow pharmacokinetic 
(PK) blood draws for 
certain visits to be 
performed at home by a 
vendor.
1.3.3 Collection Times for 
PK and Immunogenicity 
Samples for Part 1
(Table 2)
Text in bold has been added to footnote ‘b’:
Separate blood draws are not required for 
amivantamab PK and immunogenicity when 
collected at the same time point. A separate blood 
draw is required for rHuPH20 plasma 
immunogenicity for Arm A participants only.
Correction.
1.3.4 Collection Times for 
PK and Immunogenicity 
Samples for Part 2
(Table 4)
Text in bold has been added to footnote ‘b’:
Separate blood draws are not required for 
amivantamab PK and immunogenicity when 
collected at the same time point. A separate blood 
draw is required for rHuPH20 plasma 
immunogenicity.
This text was inadvertently 
omitted in original protocol, 
now aligned with guidance 
for collections in Part 1 of 
the study.
2.2.2.2 Amivantamab 
SC-CF;
2.3.1 Risks for Study 
Participation;
4.3.2 Amivantamab 
SC-CF Dose
Wording has been updated to reflect that the SC 
Q2W RP2D for this study has been confirmed via 
Study 61186372NSC1003.
SC Q2W RP2D for this 
study has been confirmed in 
Study 61186372NSC1003.
3. Objectives and 
Endpoints;
9.4.4 Exploratory 
Endpoints
Overall survival has been added as an exploratory 
endpoint.
To explore the direct 
measure of clinical benefit 
in the study population.
4.1 Overall Design
The following text has been incorporated:
Country-specific requirements are described in 
Appendix 15.
To outline countries that 
will require formal approval 
before initiation of Part 2 of 
the study.
Appendix 15, 
Country-specific 
Requirements
A new appendix has been added.
4.1 Overall Design
The following text (in bold) has been added:
The study will aim to enroll a participant population 
that is geographically reflective of the overall 
incidence/prevalence of this disease. Enrollment of 
study participants in a given country may 
continue beyond the global enrollment period 
defined to reach the overall planned sample size, 
to ensure adequate representation in the study.
To include patients from 
underrepresented and/or 
underserved racial and 
ethnic backgrounds within 
each country.
5.1 Inclusion Criteria
In Inclusion Criterion 3, the following modifications 
have been made:
Have progressed on or after osimertinib (or another 
approved 3rd generation EGFR TKI) and 
platinum-based chemotherapy (irrespective of order).
To allow for global 
enrollment to the trial, 
recognizing heterogeneous 
access to osimertinib.

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Section Number
and Name
Description of Change
Brief Rationale
•
Osimertinib The 3rd generation EGFR TKI
must have been administered as the first EGFR TKI 
for metastatic disease or as the second TKI after 
prior treatment with first- or second-generation 
EGFR TKI in participants with metastatic EGFR 
T790M mutation positive NSCLC.
•
Participants who decline or are otherwise 
ineligible for chemotherapy may be enrolled after 
discussion with the medical monitor. 
•
Any adjuvant or neoadjuvant treatment, whether 
with osimertinib a 3rd generation EGFR TKI or 
platinum-based chemotherapy, would count towards 
the prior treatment requirement if the participant 
experienced disease progression within 6 months of 
the last dose.
Throughout protocol
Where ‘osimertinib’ appears in reference to the 
design of this study, the following text has been 
added: ‘(or another approved 3rd generation EGFR 
TKI)’.
5.2 Exclusion Criteria
Exclusion Criterion 14 has been modified to remove 
the reference to Appendix 11.
Interactions text has been 
updated to reflect the latest 
guidance.
6.8.3 Prohibited or 
Restricted Medications 
and Therapies
The wording related to CYP3A4/5 inducers has been 
revised. Reference to Appendix 11 has been removed 
and replaced with US FDA guidance.
The wording related to CYP3A4/5 inhibitors and to 
substrates of P-gp, MRP4, BCRP, and OCT1 has 
been revised. References to Appendix 11 and 
Appendix 12 have been removed and replaced with 
US FDA guidance.
Appendix 11, Prohibited 
and Restricted 
Medications and 
Therapies That Induce, 
Inhibit, or Are Substrates 
of CYP3A4/5
This appendix has been removed.
Appendix 12, Substrates 
of P-glycoprotein (P-gp), 
Breast Cancer Resistance 
Protein (BCRP), and 
multi-drug resistance 
protein 4 (MRP4): 
Exercise Caution
This appendix has been removed.
References
The following citation has been added:
US FDA. Drug development and drug interactions: 
Table of Substrates, Inhibitors and Inducers. 
https://www fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-
table-substrates-inhibitors-and-inducers. Accessed 
2 May 2022.
5.2. Exclusion Criteria
An exclusion criterion (Criterion 16) was added:
A female participant must agree not to be 
pregnant, breast-feeding, or planning to become 
To clarify exclusion of 
pregnant and breast-feeding 
women based on health 
authority feedback.

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Section Number
and Name
Description of Change
Brief Rationale
pregnant while enrolled in this study or within 
7 months after the last dose of study treatment.
5.3 Lifestyle 
Considerations
The following modifications have been made to item 
2:
For agents such as immunotherapy with a long 
half-lifeves, the maximum required time since last 
dose is 6 weeks.
This text has been revised to 
ensure an appropriate 
washout period for 
immunotherapy.
6.1 Study Treatments 
Administered
The following text (in bold) has been added:
Study treatment administration must be captured in 
the source documents and the eCRF. Study site 
personnel will instruct participants on how to store 
study treatment for at-home (lazertinib only) use as 
indicated for this protocol.
To clarify that at-home 
storage of study medication 
is only applicable to 
lazertinib.
6.2 Preparation/Handling/
Storage/Accountability
The following text modifications have been made:
Study Amivantamab treatment must be handled in 
strict accordance with the protocol and as indicated 
on 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.
6.5.2 Dose Modification 
of Amivantamab and 
Lazertinib
(Table 6, Guidance for 
Withholding Doses for 
Toxicities Based on 
Grade)
The following text (in strikethrough) has been 
removed from Table 6:
If amivantamab is withheld <21 days, restart study 
treatment at current dose level. If lazertinib is 
withheld, restart on Day 1 of next cycle at a reduced 
dose.
If 2 consecutive doses of amivantamab are withheld, 
consult the Medical Monitor before restarting
Based on increased 
experience with the 
incidence of recurrent IRR 
with amivantamab IV and 
amivantamab SC-CF.
6.5.3.1 Infusion-Related 
Reactions and Local 
Administration-Related 
Reactions
The following text (in strikethrough) has been 
removed:
The monitoring should include heart rate, blood 
pressure, temperature, respiratory rate, and oxygen 
saturation measurements.
This text has been removed 
to align with other sections 
of the protocol.
6.5.3.1 Infusion-Related 
Reactions and Local 
Administration-Related 
Reactions
The following text has been added:
For Cycle 1 Day 1 only, participants in Arms A1, 
A2, and B2 will remain at the site for at least 
4 hours after the amivantamab injection for 
observation. For participants in Arm B1, the 
4-hour infusion time is considered adequate for 
observation; no additional observation time is 
needed.
This text has been added in 
order to specify observation 
period required after study 
drug administration.
6.5.3.2 Rash-related 
Adverse Events
(Table 12, Suggested 
Algorithm for 
Management of Rash)
The Grade 4 rash row has been separated from the 
Grade 3 rash row, to show different guidance in 
management for these 2 toxicity grades.
A row has been added to provide guidance for 
‘Severe bullous, blistering, or exfoliating skin 
This table has been updated 
based on health authority 
feedback.

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Section Number
and Name
Description of Change
Brief Rationale
conditions including toxic epidermal necrolysis 
(TEN)’.
6.5.3.4 Cardiac Adverse 
Events;
6.8.3 Prohibited or 
Restricted Medications 
and Therapies;
Appendix 10, 
Medications With 
Potential for QT Interval 
Prolongation
Appendix 10 has been removed from the protocol, 
along with any references to this appendix in the 
protocol body. The wording related to 
co-administration of medicines that prolong QT 
interval has been removed.
Emerging data indicate 
study treatments have no 
impact on QT interval.
6.8.3 Prohibited or 
Restricted Medications 
and Therapies
The following text has been removed:
•
Nephrotoxic or ototoxic agents should be used 
cautiously.
This text is not applicable to 
PALOMA-3, as none of the 
study treatments are 
nephrotoxic or ototoxic.
8. Study Assessments and 
Procedures
The following revisions have been applied:
The modified TASQ should be completed after study 
drug administration. Other PRO assessments PGIS
should be conducted/completed before any tests, 
procedures, or other consultations to prevent 
influencing participant responses, when possible.
To align this text with 
guidance in footnote ‘m’ for 
Table 1 andTable 2.
8.1.1 Patient-Reported 
Outcomes
The text in strikethrough has been deleted:
The PGIS and PGIC should be conducted/completed 
before any tests, procedures, or other consultations to 
prevent influencing participant responses, when 
possible.
8.2.2 ECOG Performance 
Status
The text in bold has been added:
Assessment of ECOG status should be part of 
regular ongoing clinical monitoring of patients.
Decline in ECOG performance status score (refer to 
Appendix 10: Eastern Cooperative Oncology Group 
(ECOG) Performance Status) should be reported as 
an AE.
To recommend regular 
monitoring that would 
permit detection of a decline 
in ECOG performance 
status score.
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.

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Section Number
and Name
Description of Change
Brief Rationale
COVID-19 Appendix 
(standalone)
This appendix has been modified to incorporate 
additional detail for the following topics: 
consent/screening, study treatment, treatment and 
follow-up visits, 
telemedicine/teleconferencing/videoconferencing, 
home health care, and monitoring visits.
This appendix has been 
updated for consistency 
across 
amivantamab/lazertinib 
protocols.
Globally
‘Study agent’ has been updated throughout to ‘study 
treatment’.
For consistency across 
amivantamab/lazertinib 
protocols.
Throughout the protocol
Minor formatting changes were made.
Minor errors were noted.

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11.
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Fischer A, Rosen AC, Ensslin CJ, Wu S, Lacouture ME. Pruritus to anticancer agents targeting the EGFR, BRAF, 
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Jänne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J 
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US FDA. Drug development and drug interactions: Table of Substrates, Inhibitors and Inducers. 
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https://www.ncbi.nlm.nih.gov/books/NBK138219/.

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1
Status: Approved,  Date: 01 November 2022
Janssen Research & Development *
Clinical Protocol
COVID-19 Appendix
Protocol Title
A Phase 3, Open-label, Randomized Study of Lazertinib with Subcutaneous Amivantamab 
Compared with Intravenous Amivantamab in Patients with EGFR-mutated Advanced or 
Metastatic Non-small Cell Lung Cancer After Progression on Osimertinib and 
Chemotherapy
PALOMA-3
Protocol 61186372NSC3004; 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.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
Regulatory Agency Identifier Number(s):
IND: 146319
EudraCT NUMBER: 2022-000525-25
Status:
Approved
Date:
01 November 2022
Prepared by:
Janssen Research & Development, LLC  
EDMS number:
EDMS-RIM-704162, 3.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
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.
NCT05388669

Guidance on Study Conduct During the COVID-19 Pandemic
JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 61186372NSC3004
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2
Status: Approved,  Date: 01 November 2022
COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the COVID-19 pandemic may have an impact on the conduct of this clinical 
study due to, for example, isolation or quarantine 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 treatment will be followed.
If, as a result of the COVID-19 pandemic, scheduled visits cannot be conducted in person at the 
study site, they will be performed to the extent possible remotely/virtually or delayed until such 
time that on-site visits can be resumed. At each contact, participants will be interviewed to collect 
safety data. Key efficacy endpoint assessments should be performed if required and as feasible. 
Participants will also be questioned regarding general health status to fulfill any physical 
examination requirement. 
Every effort should be made to adhere to protocol-specified assessments for participants on study 
treatment, including follow-up. Modifications to protocol-required assessments may be permitted 
after consultation with the participant, investigator, and the sponsor. Missed assessments/visits 
will be captured in the clinical trial management system for protocol deviations. Discontinuations 
of study treatments and withdrawal from the study should be documented with the prefix “COVID-
related” in the CRF.
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. 
If the participant has tested positive for COVID-19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for administration of study treatment, performing 
study assessments, and follow-up. Modifications made to the study conduct as a result of the
COVID-19 pandemic should be summarized in the clinical study report.
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.

Guidance on Study Conduct During the COVID-19 Pandemic
JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 61186372NSC3004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved,  Date: 01 November 2022

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 potential COVID-19 
exposure and local travel restrictions. If the situation suggests that this is not possible, the 
participant may be screen failed and re-screened when conditions improve.

COVID-19 screening procedures 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 
COVID-19 related circumstances, these deviations should be noted in the appropriate CRF page, 
as “missed or delayed due to COVID-19”. 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 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.
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 COVID-19 related 
staffing shortages, site policies, or travel restrictions render these infeasible. In such cases, the 
following modifications may be implemented:

Guidance on Study Conduct During the COVID-19 Pandemic
JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 61186372NSC3004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved,  Date: 01 November 2022

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.
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.
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) if applicable. Other 
programs may be implemented with approval from the sponsor, such as Home Health Care Visits 
for study assessments and procedures (eg, physical exam), where feasible and permissible by local 
policy and regulations. Study treatment with amivantamab 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.
For regions significantly impacted by COVID-19 pandemic, the investigator and sponsor may 
explore the possibility of transferring participants to nearby, less impacted, study sites (if 
warranted) on either a temporary or permanent basis. The sponsor should be informed of any 
decisions related to the transfer of participants to other study sites prior to their transfer.

Guidance on Study Conduct During the COVID-19 Pandemic
JNJ-61186372 (amivantamab) and JNJ-73841937 (lazertinib)
Clinical Protocol 61186372NSC3004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved,  Date: 01 November 2022
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 this COVID-19 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.