A Phase II, Two-arm Study to Investigate Tepotinib Combined With Osimertinib in MET Amplified, Advanced or Metastatic NSCLC Harboring Activating EGFR Mutations and Having Acquired Resistance to Prior Osimertinib Therapy (INSIGHT 2)
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer
Sponsor: EMD Serono Research & Development Institute, Inc.

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Clinical Study Protocol
Title Page
Clinical Study Protocol Title:
A Phase II, two-arm study to investigate tepotinib 
combined with osimertinib in MET amplified, 
advanced or metastatic non-small cell lung cancer 
(NSCLC) harboring activating EGFR mutations 
and having acquired resistance to prior osimertinib 
therapy (INSIGHT 2 Study)
Study Number:
MS200095-0031
Amendment Number
2
Merck Compound Number:
MSC2156119J/EMD1214063
Merck Registered Compound Name in 
Japan:
TEPMETKO
Short Title:
Tepotinib plus osimertinib in osimertinib-relapsed 
MET amplified NSCLC
Coordinating Investigator:
Sponsor Name and Legal Registered 
Address:
For all countries, except the US, Canada, and 
Japan:
Merck Healthcare KGaA
an affiliate of Merck KGaA, Darmstadt, Germany
Frankfurter Str. 250
Darmstadt, Germany
In the US and Canada:
EMD Serono Research & Development Institute, 
Inc.
an affiliate of Merck KGaA, Darmstadt, Germany
45A Middlesex Turnpike
Billerica, MA, 01821, USA
In Japan:
Merck Biopharma Co., Ltd.
an affiliate of Merck KGaA, Darmstadt, Germany
Arco Tower. 1-8-1 Shimomeguro Meguro-ku.
Tokyo 153-8926, Japan
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Medical Responsible:
Name:
Address: Merck Healthcare KGaA, Frankfurter 
Str. 250, Darmstadt, Germany 
Phone: + 49 6151 720
Fax: Not applicable
Regulatory Agency Identifying 
Numbers:
IND Number: 128073
ClinicalTrials.gov: NCT03940703
European Clinical Trials Database: 
2019-001538-33
Protocol Version:
Version 3.0
Replaces Version:
09 April 2020 /Version 2.0
Approval Date:
04 May 2021
Medical Monitor Name and Contact 
Information:
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Protocol Amendment Summary of Changes
Protocol History
Version Number
Type
Version Date
1.0
Original protocol
20 Mar 2019
1.1 DEU
Local Amendment 1
04 Oct 2019
1.2 DEU
Local Amendment 2
06 Mar 2020
2.0
Global Amendment 1
09 Apr 2020
2.1 KOR
Local Amendment 1 for Republic of 
Korea only
03 Sep 2020
2.2 CHN
Local Amendment 2 for China only
21 Sep 2020
2.3 ITA
Local Amendment 3 for Italy only
17 Dec 2020
3.0
Global Amendment 2
04 May 2021
Protocol Version 3.0 (04 May 2021)
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The purpose of this amendment is to provide a global protocol incorporating country-specific 
protocol amendments (local Amendment 2.1 KOR (03 September 2020), local Amendment 2.2 
CHN (21 September 2020) and local Amendment 2.3 ITA (17 December 2020), in addition to 
administrative updates. Apart from these changes, safety part (e.g., new identified risks or similar, 
dose modification table) was updated in alignment with the most current Investigator’s Brochure 
(IB).
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Section # and 
Name
Description of Change
Brief Rationale
Title page
Clinical study protocol version updated and details of
Coordinating Investigator Signature address.
Administrative update.
1.1 Synopsis
1.2 Schema, text, 
and Figure 1 
4.1 Overall Design 
Text and Figure 3 
6.3 Measures to 
Minimize Bias: 
Study Intervention 
Assignment and 
Blinding
A statement was added to clarify that participants in 
the Republic of Korea will not undergo randomization 
but will be assigned exclusively to the combination of 
tepotinib plus osimertinib, and therefore will not be 
treated with tepotinib monotherapy.
The exclusion of participants from 
the monotherapy arm was 
requested by the Republic of 
Korea Ministry of Food and Drug 
Safety (MFDS).
1.1 Synopsis
4.1 Overall Design 
4.2 Scientific 
Rationale for Study 
Design
7.1 Discontinuation 
of Study 
Intervention
8.1 Efficacy 
Assessments and 
Procedures
A statement was added to clarify that during the
randomized part of the study, verification of disease 
progression by Independent Review Committee (IRC)
is required. 
Updated to reflect the need for the 
verification of disease progression 
by IRC in the randomized part of 
the study. 
1.1 Synopsis
4.1 Overall Design 
A statement was added to clarify that End of 
Treatment (EoT) Visit will be conducted within 
14 days since documented decision by the 
Investigator to permanently discontinue study 
intervention.
In case EoT Visit and Safety Follow-up Visit end up 
falling within the same 7 days, only EoT Visit should 
be performed.
Updated to make clear the time 
window for EoT visit and Safety 
Follow-up Visit.
1.1 Synopsis
4.1 Overall Design
4.2 Scientific 
Rationale for Study 
Design
7.1 Discontinuation 
of Study 
Intervention
A statement was added to clarify that when 
progression by the IRC is verified, tepotinib 
monotherapy can be continued, if judged appropriate 
by the Investigator, until the switch over to the 
combination of tepotinib plus osimertinib.
Updated to clarify study treatment 
during tepotinib monotherapy.
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Section # and 
Name
Description of Change
Brief Rationale
1.3 Schedule of 
Activities
It is clarified that the EoT Visit should be ≤ 14 days
since decision to interrupt IMP.
Clarification on the study 
procedures.
1.3 Schedule of 
Activities
The footnote “Time window from enrollment to 
administration of first dose: 72 hours” was moved to 
the notes.
Administrative update.
1.3 Schedule of 
Activities 
8.8 Biomarkers 
A statement has been added to clarify that circulating 
tumor DNA (ctDNA) blood sampling and exploratory 
biomarker blood sampling during treatment (including 
Cycle 1 Day 1 for exploratory biomarkers) and at the 
End of Treatment Visit is optional for participants in 
China.
Clarification that for sites in China, collection of 
participant samples for biomarker research is either a 
mandatory or optional part of this study.
The leading Ethics Committee in 
China requested to move the “on 
treatment ctDNA testing” to the 
optional informed consent form 
(ICF) referring back to the Office of 
Human Genetic Resource 
Administration (OHGRA) 
application where the testing of 
ctDNA and blood exploratory 
biomarkers are part of the 
exploratory application form.
2.3 Benefit/Risk 
Assessment
Updated information on identified risks of tepotinib, 
including edema (mainly peripheral edema), 
creatinine increased, hypoalbuminemia, amylase and 
lipase increased, aspartate aminotransferase (AST) 
and alanine aminotransferase (ALT) increased, 
diarrhea, and nausea and vomiting.
Updated to provide current 
guidance on tepotinib.
3 Objectives and 
Endpoints
9.4.1 Efficacy 
Analyses
The tertiary/exploratory endpoint on intracranial 
response has been updated to clarify that intracranial 
response (confirmed CR or PR) will be assessed by 
IRC.
Updated to clarify the requirement 
of IRC (and not by Investigator) 
assessment of intracranial 
response.
4.3 Justification for
dose
The results of the safety run-in treatment part of the
study until 11 August 2020, when the SMC meeting
took place, are presented.
The Italian Medicines Agency
(Agenzia italiana del farmaco,
AIFA) requested that the results
from the safety run-in part of the
MS200095-0031 (INSIGHT-2)
study, supporting the SMC
recommendation to continue the
enrollment in the expansion part of 
the study with tepotinib 500 mg
daily combined regimen, to be
included and discussed in the
study protocol.
6.6 Dose Selection 
and Modification, 
Table 3 
Adverse reaction on target organs including Body and 
Pancreas, with dose modification recommendations, 
have been added.
The Other Adverse event has been changed to any 
other adverse reaction of Grade ≥3 and has been 
split into Grade 3 and Grade 4. Dose modification 
recommendations have been updated. 
Updated to provide current 
guidance on tepotinib.
6.6 Dose Selection 
and Modification
The following have been added:
Updated with the approval of 
tepotinib in the US. Clarification on
the amount of tepotinib free base 
administered.
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Section # and 
Name
Description of Change
Brief Rationale

The dose of 500 mg tepotinib once daily is the 
labeled dose of tepotinib in US and Japan for 
patients with NSCLC with METex14 skipping 
alterations.

The proposed administered dose of 500 mg 
tepotinib corresponds to 500 mg tepotinib 
hydrochloride hydrate and is equivalent to 
450 mg tepotinib (free base form). The 250 mg 
tepotinib corresponds to 250 mg tepotinib 
hydrochloride hydrate and is equivalent to 
225 mg tepotinib (free base form).
6.9 Management of 
Specific Adverse 
Events, Adverse 
Events of Special 
Interest or Adverse 
Drug Reactions
When referring to edema as a specific adverse event 
of tepotinib, cross-reference to Section 6.6 has been 
added for dose modification recommendations.
Updated to provide current 
guidance on tepotinib.
7.1 Discontinuation 
of Study 
Intervention
A statement was added to clarify that participants 
must be discontinued from study intervention if there 
is objective disease progression as per RECIST 
Version 1.1 as per Investigator.
Clarification on the study 
procedures.
8 Study 
Assessments and 
Procedures
A statement was added to clarify that submission of 
tumor tissue and blood sample obtained after 
progression on first-line osimertinib, is mandatory for 
all patients for MET amplification testing during 
Prescreening.
Added to make emphasis (as 
already in other sections) on the 
mandatory submission of tumor 
tissue and blood sample.
8 Study 
Assessments and 
Procedures
The word “previous” was added before local FISH 
testing for MET amplification.
Administrative update.
8.1 Efficacy 
Assessments and 
Procedures
A statement was added to clarify that tumor 
assessment according to RECIST Version 1.1 at EoT
Visit is requested only if last tumor assessment was 
performed ≥ 6 weeks within the first 9 months, or ≥ 12 
weeks after 9 months prior to EoT Visit.
Clarification on the study 
procedures.
8.2.4 Clinical safety 
Laboratory 
Assessments
Appendix 5 Clinical 
Laboratory Tests
A statement has been made to clarify that in sites in 
China, laboratory assessments (e.g., lipase) can be 
performed in a local or a central laboratory, 
depending on the availability of the test in the local 
laboratory.
The reason of this change is the 
fact that some sites in China 
cannot perform some laboratory 
assessments locally (e.g., lipase).
8.8 Biomarkers
A statement was added to clarify that for a local FISH 
assay to be acceptable must evaluate both MET gene 
copy number and MET/CEP7 ratio.
Clarification on the requirements of 
a local FISH assay.
10 References
Added full title of reference stated in Appendix 7.
Administrative update.
Appendix 1
Abbreviations have been updated.
Administrative update.
Appendix 5 Clinical 
Laboratory Tests
It is clarified that for Calcium the following values 
must be reported: Total Calcium and Calculated [or 
Adjusted] and/or Ionized [or free] Calcium.
Updated to provide clarification on 
the Calcium measurement. 
Appendix 5 Clinical 
Laboratory Tests
It is clarified that aPTT may be expressed directly in 
seconds or in ratio.
Updated to provide clarification on 
aPTT measurement.
Appendix 7 
Response
Reference abbreviated to internal presentation
convention.
Administrative update.
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Section # and 
Name
Description of Change
Brief Rationale
Evaluation Criteria 
in Solid Tumors
(RECIST) Version 
1.1
Appendix 9
Reference to changes described in this table.
Administrative update.
Appendix 10 
Sponsor Signature 
Page
Clinical study protocol version updated.
ClinicalTrials.gov and European Clinical Trials 
Database numbers added for consistency.
Administrative update.
Appendix 11
Coordinating 
Investigator 
Signature Page
Clinical study protocol version updated and details of 
Coordinating Investigator address.
ClinicalTrials.gov and European Clinical Trials 
Database numbers added for consistency.
Administrative update.
Appendix 12
Principal 
Investigator 
Signature Page
Clinical study protocol version updated.
ClinicalTrials.gov and European Clinical Trials 
Database numbers added for consistency.
Administrative update.
– Confidential –
This document is the property of Merck Healthcare KGaA, Darmstadt, Germany, or one of its subsidiaries. It is 
intended for restricted use only and may not – in full or part – be passed on, reproduced, published or used without 
express permission of Merck KGaA, Darmstadt, Germany, or its subsidiary. Copyright © 2021 by Merck KGaA, 
Darmstadt, Germany, or its subsidiary. All rights reserved.
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Table of Contents
Title Page
..............................................................................................................1
Table of Contents
..............................................................................................................8
Table of In-Text Tables .....................................................................................................11
Table of In-Text Figures....................................................................................................11
1
Protocol Summary ..............................................................................12
1.1
Synopsis..............................................................................................12
1.2
Schema................................................................................................16
1.3
Schedule of Activities.........................................................................17
2
Introduction.........................................................................................25
2.1
Study Rationale...................................................................................25
2.2
Background.........................................................................................25
2.3
Benefit/Risk Assessment ....................................................................26
3
Objectives and Endpoints ...................................................................29
4
Study Design.......................................................................................32
4.1
Overall Design....................................................................................32
4.2
Scientific Rationale for Study Design ................................................37
4.3
Justification for Dose..........................................................................40
4.4
End of Study Definition......................................................................41
5
Study Population.................................................................................41
5.1
Inclusion Criteria ................................................................................41
5.2
Exclusion Criteria...............................................................................44
5.3
Lifestyle Considerations .....................................................................46
5.4
Screen Failures....................................................................................46
6
Study Intervention(s) ..........................................................................47
6.1
Study Intervention(s) Administration.................................................47
6.2
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability.....................................................................................48
6.3
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................49
6.4
Study Intervention Compliance..........................................................50
6.5
Concomitant Therapy .........................................................................50
6.5.1
Rescue Medicine.................................................................................50
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6.5.2
Permitted Medicines...........................................................................50
6.5.3
Prohibited Medicines..........................................................................51
6.5.4
Other Interventions.............................................................................51
6.6
Dose Selection and Modification........................................................52
6.7
Study Intervention after the End of the Study ....................................54
6.8
Special Precautions.............................................................................54
6.9
Management of Specific Adverse Events, Adverse Events of 
Special Interest or Adverse Drug Reactions.......................................54
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal...............................................................55
7.1
Discontinuation of Study Intervention................................................55
7.2
Participant Discontinuation/Withdrawal from the Study ...................56
7.3
Lost to Follow-Up...............................................................................56
8
Study Assessments and Procedures....................................................57
8.1
Efficacy Assessments and Procedures................................................59
8.2
Safety Assessments and Procedures ...................................................60
8.2.1
Physical Examinations........................................................................60
8.2.2
Vital Signs ..........................................................................................61
8.2.3
Electrocardiograms.............................................................................61
8.2.4
Clinical Safety Laboratory Assessments ............................................61
8.3
Adverse Events and Serious Adverse Events.....................................62
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information....................................................62
8.3.2
Method of Detecting Adverse Events and Serious Adverse Events...62
8.3.3
Follow-up of Adverse Events and Serious Adverse Events ...............63
8.3.4
Regulatory Reporting Requirements for Serious Adverse Events .....63
8.3.5
Pregnancy ...........................................................................................64
8.4
Treatment of Overdose .......................................................................64
8.5
Pharmacokinetics................................................................................65
8.6
Pharmacodynamics.............................................................................66
8.7
Pharmacogenetics ...............................................................................66
8.8
Biomarkers..........................................................................................66
8.9
Immunogenicity Assessments ............................................................67
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9
Statistical Considerations....................................................................68
9.1
Statistical Hypotheses.........................................................................68
9.2
Sample Size Determination ................................................................68
9.3
Populations for Analyses ....................................................................70
9.4
Statistical Analyses.............................................................................71
9.4.1
Efficacy Analyses ...............................................................................71
9.4.2
Safety Analyses ..................................................................................74
9.4.3
Other Analyses....................................................................................75
9.4.4
Sequence of Analyses.........................................................................75
10
References...........................................................................................77
11
Appendices .........................................................................................80
Appendix 1
Abbreviations......................................................................................80
Appendix 2
Study Governance...............................................................................82
Appendix 3
Contraception......................................................................................88
Appendix 4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting................................................90
Appendix 5
Clinical Laboratory Tests ...................................................................94
Appendix 6
Pharmacogenetics ...............................................................................95
Appendix 7
Response Evaluation Criteria in Solid Tumors (RECIST) Version
1.1 .......................................................................................................96
Appendix 8
Examples of Drugs that Prolong QT Interval and Have a  Known 
Risk of Causing Torsade de Pointe...................................................105
Appendix 9
Protocol Amendment History...........................................................106
Appendix 10 
Sponsor Signature Page....................................................................107
Appendix 11
Coordinating Investigator Signature Page........................................108
Appendix 12
Principal Investigator Signature Page...............................................109
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Table of In-Text Tables
Table 1
Schedule of Activities.........................................................................18
Table 2
Bayesian Optimal Interval Design Decision Criteria for Tepotinib 
Dose Changes .....................................................................................34
Table 3
Recommended Dose Modifications for Tepotinib and Osimertinib...53
Table 4
Confidence limits for the objective response rates in the 
monotherapy arm................................................................................69
Table 5
Protocol-Required Clinical Laboratory Assessments.........................94
Table 6
Examples of drugs with a known risk for Torsade de Pointe due to 
QTc prolongation..............................................................................105
Table of In-Text Figures
Figure 1
Study Schema .....................................................................................17
Figure 2
Safety Run-In......................................................................................33
Figure 3
Main Treatment ..................................................................................35
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Objectives
Endpoints (Outcome Measures)
To assess the efficacy of tepotinib 
monotherapy in participants with 
advanced or metastatic EGFRm+ 
NSCLC and MET amplification
determined centrally by FISH.
Objective response (CR or PR) determined according to RECIST 
Version 1.1 as per IRC.
To assess tolerability and safety in 
participants with advanced or 
metastatic EGFRm+ NSCLC and 
MET amplification treated with the 
combination of tepotinib plus 
osimertinib.
Occurrence of Adverse Events (AEs) and treatment related AEs.
Occurrence of abnormalities (Grade ≥3) in laboratory test values 
(hematology and coagulation, biochemistry) and urinalysis.
Occurrence of markedly abnormal vital sign measurements change in 
body weight, and Eastern Cooperative Oncology Group (ECOG) 
performance status. 
Occurrence of clinically significantly abnormal electrocardiograms 
(ECGs).
To assess tolerability and safety in 
participants with advanced or 
metastatic EGFRm+ NSCLC and 
MET amplification treated with 
tepotinib monotherapy.
Occurrence of AEs and treatment related AEs. 
Occurrence of abnormalities (Grade ≥3) in laboratory test values 
(hematology and coagulation, biochemistry) and urinalysis.
Occurrence of markedly abnormal vital sign measurements change in 
body weight, and ECOG performance status. 
Occurrence of clinically significantly abnormal ECGs.
To further assess efficacy of tepotinib 
combined with osimertinib in 
participants with advanced or 
metastatic EGFRm+ NSCLC and 
MET amplification, determined 
centrally by FISH.
Objective response according to RECIST Version 1.1 assessed by 
Investigator.
Confirmed CR assessed by IRC and by Investigator.
Duration of response assessed from CR or PR until progressive disease 
(PD), death, or last tumor assessment assessed by IRC and by 
Investigator.
Disease control (confirmed CR + PR or stable disease [SD] lasting at 
least 12 weeks) as assessed by IRC and by Investigator.
Progression free survival according to RECIST Version 1.1 by IRC and by 
Investigator.
Overall survival.
To further assess efficacy of tepotinib 
combined with osimertinib in 
participants with advanced or 
metastatic EGFRm+ NSCLC and 
MET amplification, determined 
centrally by blood-based next 
generation sequencing.
Objective response according to RECIST Version 1.1 assessed by 
Investigator.
Confirmed CR assessed by IRC and by Investigator.
Duration of response assessed from CR or PR until PD, death, or last 
tumor assessment assessed by IRC and by Investigator.
Disease control (confirmed CR + PR or stable disease [SD] lasting at 
least 12 weeks) as assessed by IRC and by Investigator.
Progression free survival according to RECIST Version 1.1 by IRC and by 
Investigator.
Overall survival.
To further assess efficacy of tepotinib 
monotherapy in participants with 
advanced or metastatic EGFRm+ 
NSCLC and MET amplification, 
determined centrally by FISH.
Objective response according to RECIST Version 1.1 assessed by 
Investigator.
Confirmed CR assessed by IRC and by Investigator.
Duration of response assessed from CR or PR until PD, death, or last 
tumor assessment assessed by IRC and by Investigator.
Disease control (confirmed CR + PR or stable disease [SD] lasting at 
least 12 weeks) as assessed by IRC and by Investigator.
Progression free survival according to RECIST Version 1.1 by IRC and by 
Investigator.
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Objectives
Endpoints (Outcome Measures)
To assess health-related quality of life
in participants with advanced or 
metastatic EGFRm+ NSCLC and 
MET amplification treated with the 
combination of tepotinib plus 
osimertinib.
Patient-reported outcomes/health-related quality of life as reported using 
the following:
EuroQol Five Dimension Five Level Scale. 
European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire C30. 
NSCLC Symptom Assessment Questionnaire.
To assess the pharmacokinetics (PK)
of tepotinib and osimertinib and their 
metabolites.
Single- and multiple-dose PK profile of osimertinib, tepotinib, and their 
metabolites including but not limited to AUC0-t, Cmax, and tmax after first 
dose (Day 1) and after multiple study intervention dose administrations 
(Day 15) (safety run-in).
Population PK profile of osimertinib, tepotinib, and their metabolites, 
including, but not limited to, CL/f and VZ/f based on sparse PK sampling on 
Day 1, Cycle 1 and 2 (all study participants).
To assess resistance marker related 
to EGFR and other molecular 
pathways 
Mutation status in EGFR and other pathways assessed in circulating 
tumor deoxyribonucleic acid (ctDNA) at Baseline and progression (all 
study participants).
Overall Design: Phase II, two-arm, open-label study. This study will assess the antitumor activity, 
safety, tolerability, and pharmacokinetics of tepotinib combined with osimertinib and tepotinib 
monotherapy in participants with advanced or metastatic NSCLC harboring activating EGFR 
mutations and having relapsed on previous first-line osimertinib treatment due to MET 
amplification.
An initial subset of at least 6 participants will be enrolled in a safety run-in to confirm if the 
combination of 500 mg once daily tepotinib dose (as currently used in the Phase II single agent 
VISION study) together with osimertinib 80 mg once daily (approved dose for NSCLC) is 
appropriate or needs adjustment. A Safety Monitoring Committee (SMC) will monitor these 
participants and, based on the safety, tolerability, and available pharmacokinetic information, 
decide on the final tepotinib dose and regimen. 
Number of Participants: It is anticipated that approximately 120 participants will be enrolled.
Study Intervention Groups and Duration: Study participation is composed of the following 
stages:
1. Prescreening (performed after progression on first-line osimertinib): After providing 
written Prescreening consent, MET amplification status will be assessed centrally by FISH 
or by reviewing pre-existing local FISH results using tumor tissue (TBx), and centrally by
blood-based next generation sequencing (LBx).
2. Screening: After providing written consent at Screening, study eligibility will be assessed 
within -28 to -1 days prior to Day 1 of study intervention. 
3. Treatment Period: 
a.
For the safety run-in, an initial subset of at least 6 participants, who are detected to 
be MET amplified with any of the methods (central/local TBx or central LBx)
described at Prescreening, will be enrolled to confirm the combination dose of 
tepotinib 500 mg once daily and osimertinib 80 mg once daily; the decision will be 
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made by the SMC based on predefined dose-limiting toxicity criteria and supported 
by a Bayesian Optimal Interval Design (BOIN). 
b. For the main treatment, eligible participants who are detected to be MET 
amplification positive by central or local FISH (TBx) will be randomly assigned in 
a ratio of 2:1 to either the combination of tepotinib at a dose defined by the SMC 
and osimertinib at the recommended daily dose of 80 mg or tepotinib alone at the 
daily dose of 500 mg (as currently used in the Phase II single agent VISION study) 
in cycles of 21-day duration until disease progression (according to RECIST 
Version 1.1), death, adverse event (AE) leading to discontinuation, study 
withdrawal or consent withdrawal. The randomization to the two arms of the study 
will continue until 12 participants who are MET amplification positive by centrally 
confirmed FISH (TBx), are enrolled in the monotherapy arm. After this, all 
participants will be assigned to the combination of tepotinib plus osimertinib. For 
participants in the randomized part of the study, verification of disease progression 
by IRC is required. Participants who are randomized to the tepotinib monotherapy 
will have the opportunity to switch over to receive the combination of tepotinib plus 
osimertinib if they experience disease progression according to RECIST 
Version 1.1 reported by Investigator and verified by IRC. Until progression is 
verified by IRC and the switch over to the combination of tepotinib plus osimertinib 
takes place, tepotinib monotherapy can be continued, if judged appropriate by the 
Investigator. However, if disease progression is not verified by IRC, the participant 
must discontinue study intervention. Participants who permanently discontinue 
tepotinib monotherapy due to an AE, withdraw consent, or for any reason other 
than progressive disease, will not be eligible to switch over to receive the 
combination of tepotinib plus osimertinib. Participants in the Republic of Korea 
will not undergo randomization but will be assigned exclusively to the combination 
of tepotinib plus osimertinib, and therefore will not be treated with tepotinib 
monotherapy.
Eligible participants who are detected to be MET amplified only by central 
blood-based next generation sequencing (LBx) will be assigned to the combination 
of tepotinib at a dose defined by the SMC and osimertinib at the recommended 
daily dose of 80 mg in cycles of 21-day duration until disease progression 
(according to RECIST Version 1.1), death, AE leading to discontinuation, study 
withdrawal or consent withdrawal. There will be no monotherapy arm for 
participants who are detected to be MET amplified only by central blood-based 
next generation sequencing (LBx).
4. Treatment follow-ups (for all participants): End of Treatment (EoT) Visit will be conducted 
within 14 days since documented decision by the Investigator to permanently discontinue 
study intervention.
5. Safety Follow-up Visit (for all participants): 30 ± 3 days after the last dose of study 
intervention for those who discontinue study intervention permanently. In case EoT Visit 
and Safety Follow-up Visit end up falling within the same 7 days, only EoT Visit should 
be performed.
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6. Participants who discontinue study intervention for reasons other than PD or death will 
have additional visits for tumor assessments every 6 weeks until 9 months after first 
administration of study intervention and every 12 weeks thereafter until disease 
progression. Survival follow-up is to be performed every 3 months (± 2 weeks) at clinic 
visits or by telephone contact.
The primary analysis will be conducted once all participants with advanced or metastatic EGFRm+ 
NSCLC and MET amplification, determined centrally by FISH (TBx), have either been treated 
with the recommended Phase II dose of tepotinib and osimertinib for at least 9 months, died or 
have prematurely discontinued study intervention for any reason, whichever comes first.
Participants assigned to tepotinib monotherapy and who are MET amplification positive by 
centrally confirmed FISH (TBx) will be evaluated for a secondary efficacy objective of the study. 
The efficacy outcomes of the participants in each of the two arms who are MET amplification 
positive only by local but not centrally confirmed FISH (TBx) will only be listed. Participants who 
are MET amplification positive by central blood-based next generation sequencing (LBx) will be 
evaluated for a secondary efficacy objective of the study.
The final analysis will be done 3 years after the last participant’s first dose or when all participants 
have discontinued study intervention and two thirds of the participants have died, whichever comes
first.
Involvement of Special Committee(s): Yes
1.2
Schema
This two-arm, open-label, Phase II study will assess the antitumor activity, safety, tolerability, and 
pharmacokinetics of the mesenchymal-epithelial transition factor (MET) inhibitor tepotinib alone 
and combined with the 3rd generation epidermal growth factor receptor (EGFR) inhibitor 
osimertinib (Tagrisso®), in participants with advanced or metastatic non-small cell lung cancer 
(NSCLC) harboring activating EGFR mutations and having relapsed on prior first-line osimertinib 
due to MET amplification. 
The study design is presented in Figure 1 below. 
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Figure 1
Study Schema
DLT: dose-limiting toxicity; RP2D: recommended Phase II dose.
*
After the safety run-in part, there will be an initial assignment of participants with MET amplification based on 
FISH (TBx) into the combination and the monotherapy arm according to a 2:1 randomization. As soon as 12 
participants (MET amplification centrally confirmed by FISH) are enrolled in the monotherapy arm, all further 
participants will receive combination treatment. Participants who are MET amplification positive only by central 
blood-based next generation sequencing (LBx) will be assigned directly to the combination arm. Participants in 
the Republic of Korea will not undergo randomization but will be assigned exclusively to the combination of 
tepotinib plus osimertinib, and therefore will not be treated with tepotinib monotherapy.
a:
Approximately 120 participants in total are expected to achieve 80 in the primary analysis combination set and 
12 for the secondary analysis of the monotherapy arm.
1.3
Schedule of Activities
The Schedule of Activities including all study assessments is provided in Table 1.
The eligibility of participants is checked at Screening by review of inclusion/exclusion criteria,
considering the available information (including information gathered at Prescreening). The last 
measurement of an assessment prior to the first administration of the study intervention will serve 
as baseline value.
Prescreening must happen prior to Screening, and after participants have relapsed on previous 
first-line osimertinib treatment. Tumor and blood samples for MET amplification testing must be 
collected after progression on first-line osimertinib. Screening should only occur once results from 
Prescreening assessments have been received. 
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2
Introduction
Tepotinib is a novel, highly selective, reversible adenosine triphosphate (ATP)-competitive, small 
molecule inhibitor of mesenchymal-epithelial transition factor (MET). Oncogenic activation of 
this tyrosine kinase receptor via mechanisms such as MET mutations or MET amplification has 
been identified not only to drive primary tumorigenesis but also to mediate resistance to cancer 
treatments including epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs). In 
both settings, tepotinib has shown activity in preclinical models and in clinical studies in patients 
with non-small cell lung cancer (NSCLC). 
Complete information on the chemistry, pharmacology, efficacy, and safety of tepotinib is in the
Investigator’s Brochure (IB).
2.1
Study Rationale
MET amplification has been identified as a common resistance mechanism to all, ie, 1st to 
3rd generation, EGFR TKIs in NSCLC (Shi. 2016). Tepotinib is a highly selective MET inhibitor, 
which has already shown signals of clinical efficacy in the previous INSIGHT study 
(NCT01982955) in patients with MET amplified, EGFR TKI-relapsed, T790M negative NSCLC 
in combination with the 1st generation EGFR TKI gefitinib (Wu. 2018). The 3rd generation EGFR 
TKI osimertinib has been propelled into first-line therapy for patients with advanced or metastatic 
NSCLC with activating EGFR mutations, regardless of their T790M status, based on the results of 
the FLAURA Phase III trial (Soria 2018). However, there is currently no personalized treatment 
option available for patients who have relapsed on previous osimertinib treatment when used as 
first-line EGFR TKI. This study seeks to fill this current knowledge gap in a NSCLC population 
with high unmet medical need.
2.2
Background
Lung cancer remains the leading cause of cancer death worldwide. Approximately 85% of patients 
have NSCLC and most present with advanced stage disease (not amenable to curative intent). 
Novel targeted therapies that interfere with specific molecular signaling pathways have emerged 
as a new standard option for selected patients with EGFR mutation, including the oral EGFR TKIs. 
EGFR TKIs inhibit the intracellular tyrosine kinase domain of the EGFR and therefore block the
signal transduction pathways implicated in the proliferation and survival of cancer cells.
A secondary mutation in the EGFR gene (T790M mutation) has been identified as the main reason 
for resistance to 1st and 2nd generation EGFR TKIs in NSCLC. Osimertinib is a 3rd generation, 
T790M directed, EGFR TKI. This product showed benefit in patients with EGFR mutant 
(EGFRm+) NSCLC who relapsed on previous 1st and 2nd generation EGFR TKIs and received 
approval in this indication based on the results of the AURA 3 study (Mok 2017). Osimertinib was 
also recently approved as first-line treatment in NSCLC in patients whose tumors harbor activating 
EGFR mutations irrespective of the T790M status based on the results from the FLAURA study 
(Soria 2018). In addition to the United States (US) and European Union, osimertinib is also 
approved in Japan and in China. Osimertinib is the first EGFR TKI monotherapy to show a 
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statistically significant overall survival benefit versus another EGFR TKI. The final overall 
survival analysis of FLAURA study reinforces osimertinib as the standard of care for first-line 
treatment in patients with EGFRm+ advanced or metastatic NSCLC (Ramalingam 2020).
While most patients with EGFRm+ NSCLC suffer from resistance caused by mutations and 
genetic alterations within the EGFR pathway, a subset of patients also relapses on previous 
EGFR TKI treatment via activation of other oncogenic pathways, such as MET. Indeed, the 
combination of tepotinib and EGFR inhibitors has been shown to result in enhanced antitumor 
activity compared with either agent alone in NSCLC tumor models expressing EGFR wild-type or 
EGFR with activating kinase domain mutations, when these tumor cell lines also harbored MET 
activating alterations (Friese-Hamim 2017). 
MET amplification was identified as a relevant resistance mechanism to 1st and 2nd generation 
EGFR TKIs, and several clinical studies have already shown the benefit of a combined 
administration of MET inhibitors with a 1st generation EGFR TKI after previous EGFR TKI 
resistance (Salgia 2017). Among these studies, the combination of tepotinib with gefitinib was 
investigated in the INSIGHT study (NCT01982955, Cheng 2018). The overall intention-to-treat 
population in the INSIGHT study, which consisted of patients with NSCLC with moderate to high 
MET overexpression or MET amplification, had similar progression-free survival (PFS) to the 
platinum doublet chemotherapy control arm. However, the predefined subset of MET amplified 
patients showed highly significant differences in PFS with a hazard ratio of 0.17 (90% confidence 
interval [CI]; 0.05, 0.57) with median PFS in the tepotinib/gefitinib arm of 16.6 months (90% CI 
8.3, not estimable) compared with median PFS in the control arm of 4.2 months (90% CI 1.4, 7.0). 
Furthermore, an objective response rate (ORR) of 67% was observed in MET amplified patients. 
Safety and tolerability results from this study also showed that the combination of tepotinib with 
gefitinib was well tolerated. 
However, MET amplification was not only identified to trigger resistance to 1st and 2nd generation 
EGFR TKIs but was also shown to cause resistance to osimertinib. Approximately 15% and 19% 
of patients with EGFRm+ NSCLC enrolled in first-line (FLAURA) and second-line (AURA 3) 
NSCLC studies were shown to harbor MET amplification by use of a liquid biopsy (LBx), next 
generation sequencing, testing methodology, respectively (Papadimitrakopoulou
2018; 
Ramalingam 2018). A first study (TATTON) indicated that the combination of the MET inhibitor 
savolitinib with osimertinib could overcome MET related osimertinib resistance (Sequist 2020). 
Based on the available preclinical and clinical experience with tepotinib in combination with 
EGFR TKIs, the INSIGHT 2 study (MS200095-0031) will investigate the combination of 
osimertinib and tepotinib in patients who relapsed on previous first-line osimertinib due to MET 
amplification. The study introduces a single agent tepotinib arm to additionally assess the 
contribution of tepotinib to the osimertinib and tepotinib combination therapy. There is currently 
no personalized treatment option available for these selected NSCLC patients and therefore 
constitutes a clinical condition with high unmet medical need.
2.3
Benefit/Risk Assessment
Clinical efficacy and safety information for the use of MET inhibitors in combination with EGFR 
inhibitors is available from several studies. This includes information for tepotinib with the 
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1st generation EGFR TKI gefitinib, osimertinib with a selective MET inhibitor, savolitinib, and a 
head-to-head comparison between osimertinib and the 1st generation EGFR TKIs, gefitinib and 
erlotinib, which have been approved for decades (approved in the US in May 2003) and have been
shown to be safe in patients with NSCLC. 
The use of tepotinib in combination with gefitinib has already been investigated in patients with 
advanced NSCLC after failure of previous EGFR TKI treatment (NCT01982955, Cheng 2018). In 
particular, the subgroup of participants with MET amplified, T790M negative tumors, 
demonstrated positive efficacy signals including an ORR of 67% and a median PFS of 16.6 months 
were seen. Furthermore, 60 participants were exposed to tepotinib with the EGFR inhibitor. While 
all participants receiving this treatment experienced treatment-emergent adverse events (TEAEs), 
the majority of these TEAEs were mild or moderate. A comparison of tepotinib plus gefitinib 
versus chemotherapy showed 9.7% versus 4.3% having TEAEs leading to permanent 
discontinuation, 3.2% versus 0% of TEAEs leading to death (none of the TEAEs was related), 
16.1% versus 30.4% had serious related TEAEs, 51.6% versus 52.2% had Grade ≥3 related 
TEAEs, and 12.9% versus 8.7% had lipase/amylase increase Grade ≥3 not accompanied by 
pancreatitis or respective symptoms. Overall, tepotinib in combination with gefitinib was 
considered safe and well tolerated (Cheng 2018).
Moreover, the 3rd generation EGFR TKI osimertinib was investigated in a clinical study in 
combination with the selective MET inhibitor savolitinib (TATTON, NCT02143466). The study 
results showed efficacy with ORRs of 30% in patients previously treated with a 3rd generation 
EGFR TKI, 67% in patients who had received no prior 3rd generation EGFR TKI (T790M positive) 
and 64% to 65% in patients who had received no prior 3rd generation EGFR TKI (T790M negative; 
Sequist 2020). Patients who received study treatment (n=138) were included in the safety analysis 
set, with 98% reporting an AE. Nausea (n=67 [49%]), fatigue (n=48 [35%]) and decreased appetite 
(n=47 [34%]) were the most commonly reported AEs. The incidence of Grade 3 or higher AEs 
was 57%. Serious adverse events (SAEs) were reported in 62 patients (45%) consisting mainly of 
pneumonia (4%), anaphylactic reactions (4%), pyrexia (4%) and dyspnea (4%). In the 
confirmatory expansion (Part D) part of the TATTON study 42 patients were included in the safety 
analysis set, with 93% experiencing any AE. The most common AEs were nausea (n=13 [31%]) 
and diarrhea, edema peripheral and rash (all n=8 [19%]). There were 16 patients with Grade 3 or 
greater AEs in this group. SAEs were reported in 11 (26%) patients consisting mainly of 
pneumonia (10%) and anaphylactic reactions (2%) (Sequist 2020).
In addition, osimertinib was investigated head-to-head in a randomized Phase III study in first-line 
NSCLC versus 1st generation EGFR TKIs, ie, gefitinib and erlotinib (FLAURA, Soria 2018). 
Osimertinib not only showed superior efficacy but also had a comparable safety profile to the two 
1st generation EGFR TKIs, with a smaller number of severe TEAEs, but a slightly higher frequency 
of cardiovascular events and interstitial lung disease (ILD). As summarized by Mezquita 2018, 
279 participants received osimertinib and 55 participants crossed over to osimertinib from the 
standard EGFR TKI arm. Fewer Grade ≥3 AEs (34%) were reported with osimertinib compared 
with the 1st generation EGFR TKIs (45%), with a similar overall toxicity profile and a lower SAE 
rate. The most common AEs were diarrhea (58%), rash (58%), and dry skin (36%). QTc 
prolongation was reported in 10% of participants (n = 29, one Grade ≥ 3) and ILD in 4% (n = 11, 
six Grade ≥3), with no fatal events. In the osimertinib group, 7 of 11 participants recovered from 
ILD, and the other 4 were recovering. The rate of permanent discontinuation was lower in the 
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osimertinib group than with the 1st generation EGFR TKIs (13% versus 18%); however, the rate 
of dose interruption (24% to 25%) and dose reduction (4% to 5%) due to AEs was similar in both 
groups.
ILD is considered an important identified risk for tepotinib in patients with advanced NSCLC due 
to the possible severity and mortality that can be associated with these events. This condition is 
known to occur in association with treatment with other TKIs or other MET inhibitors in the 
NSCLC setting. In the MS200095-0022 (VISION) study, 1 fatal case of acute respiratory failure 
secondary to an ILD-like event has been reported that was considered related to tepotinib by the 
Investigator. The causal relationship between ILD and tepotinib is confounded by the presence of 
other factors, such as the underlying NSCLC disease, smoking, prior anticancer treatments, the 
heterogeneity of manifestations, or the partly unconfirmed ILD diagnosis in some reported cases. 
However, due to the severity and mortality that can be often associated with this type of events, 
mitigation measures include careful monitoring in case of symptoms, withdrawal of treatment 
when ILD is suspected, treatment discontinuation and appropriate treatment for the event (eg, with 
steroids) upon ILD diagnosis. In summary, considering the severe implications of the condition, 
the risk can be well managed by the prompt diagnosis and permanent discontinuation of tepotinib 
treatment. For further details refer to the tepotinib IB.
Edema (mainly peripheral edema), creatinine increased, hypoalbuminemia, amylase and lipase 
increased, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) increased, 
diarrhea, and nausea and vomiting are the risks that are considered adverse reactions to tepotinib. 
More detailed safety information on classification of risks is provided in the tepotinib IB.
Based on current knowledge, the risk for mutual drug interactions between osimertinib and 
tepotinib is considered low. Osimertinib is mainly metabolized via cytochrome P450 3A4 
(CYP3A4), while tepotinib had no relevant effect on the exposure of the sensitive CYP3A4 
substrate midazolam based on results from a clinical study (MS200095-0030), ie, is lacking a 
relevant influence on this drug metabolizing enzymes. However, both tepotinib and osimertinib 
have the potential to inhibit P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). 
Tepotinib is a P-gp substrate and may therefore be susceptible to a drug transporter-mediated 
interaction with osimertinib. However, in the human mass balance study (EMR200095-007), 
77.9% of the total radioactivity was recovered in feces including a high fraction (45%) of the 
administered tepotinib dose as parent compound. Since its absorption is high, resulting in an oral 
bioavailability of 72%, the fecal parent recovery is assumed to partly stem from systemic clearance 
via biliary secretion that may be in part dependent on active, P-gp-mediated efflux. Worst-case 
estimation suggests that full inhibition of this mechanism may increase tepotinib exposure by 43%. 
In addition, there could be enhanced absorption when intestinal P-gp is inhibited, leading to a 40% 
increase in exposure at most. However, given the favorable safety profile of tepotinib at doses up 
to 1400 mg, this is not considered clinically relevant. Similarly, osimertinib may not be prone to 
clinically relevant drug-drug interactions inhibiting its elimination because dose escalations up to 
240 mg were performed in monotherapy without defining a maximum tolerated dose and a 
dedicated study with the CYP3A inhibitor itraconazole did not show a relevant effect on 
osimertinib (osimertinib Summary of Product Characteristics [SmPC]). 
Nevertheless, to monitor any potential influence on the pharmacokinetics (PK) of each drug in the 
present study, rich PK sampling after the first and after multiple doses is planned for the safety 
run-in to evaluate tepotinib exposure under osimertinib co-administration and vice versa. In 
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4
Study Design
4.1
Overall Design
This Phase II, two-arm, open-label study will assess the antitumor activity, safety, tolerability, and 
PK of the MET inhibitor tepotinib alone and combined with the 3rd generation EGFR inhibitor 
osimertinib in participants with advanced or metastatic NSCLC harboring activating EGFR 
mutations and having relapsed on prior first-line osimertinib due to MET amplification.
Prescreening 
After written informed consent for Prescreening procedures has been obtained, MET amplification 
status will be centrally assessed by fluorescence in situ hybridization (FISH) or by reviewing 
pre-existing local FISH results using tumor tissue (TBx), and centrally by blood-based next 
generation sequencing (LBx). Biospecimens for TBx (central and local) and LBx prescreening 
must be collected after documented relapse of participants with EGFRm+ NSCLC on previous 
first-line osimertinib treatment. 
Participants with MET amplification detected locally by FISH are required to sign the Prescreening 
informed consent form (ICF) and provide the information on the results and the local FISH assay 
used. Those participants must also provide blood for the central LBx testing after signing 
prescreening ICF (Section 8.8).
In case of administrative, operational
or logistical errors, insufficient TBx material 
available/provided from previous local FISH testing or if the provided TBx or LBx sample could 
not be evaluated at the testing laboratory, repeat collections of TBx and/or LBx may be performed 
without the need to obtain a new written informed consent for Prescreening. 
Participants who were identified MET amplification positive and who had progressed on previous 
first-line osimertinib are recommended to continue treatment with osimertinib beyond progression,
at the discretion of the Investigators, also in line with current clinical guidelines (NCCN Version 3, 
2019) and criteria as defined by Jackman 2010, until they either receive the experimental treatment 
as defined in this study, or in the case of ineligibility, a follow-up treatment as discussed with their 
physician. 
Screening Period
After MET amplification positive participants (by central or local TBx, or by central LBx) have
given written informed consent for screening procedures, study eligibility will be assessed within 
-28 to -1 days prior to Day 1 of study intervention. If, at Screening, the participant meets all the 
protocol-defined inclusion criteria and none of the exclusion criteria, the participant will be 
considered eligible and will be enrolled into the study. The screening period will include a baseline 
tumor RECIST Version 1.1 assessment and the confirmation of measurable tumor disease by two 
independent radiologists. Participants with MET amplification detected locally by FISH must 
provide tumor tissue at Screening (or at Prescreening) for central confirmation of the result. Central 
confirmation is not mandated prior to the start of study treatment. Participants who fail to meet the 
protocol-specified criteria or who discontinue the study before enrollment will be considered 
screening failures.
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Treatment Period
During the treatment period of the INSIGHT 2 study, an initial subset of at least 6 participants will 
be enrolled in a safety run-in treatment part for their first treatment cycle and the rest of the 
participants will be enrolled directly in the main treatment part as shown in Figure 2 and 
Figure 3.
a.
SAFETY RUN-IN 
An initial subset of at least 6 participants, who are detected to be MET amplified with any of the 
methods (central/local TBx or central LBx) described at Prescreening, will be enrolled in a safety 
run-in to confirm the safety of the combination dose of 500 mg once daily of tepotinib as currently 
used in the Phase II single agent VISION study together with osimertinib 80 mg once daily
(Figure 2). 
Figure 2
Safety Run-In 
EGFR: Epidermal Growth Factor Receptor; NSCLC: Non-Small Cell Lung Cancer; TKI: Tyrosine Kinase Inh bitor; MET: Mesenchymal-
epithelial Transition Factor; amp: amplification; FISH: fluorescence in situ hybridization; NGS: Next Generation Sequencing; TBx: 
Tissue Biopsy; LBx: Liquid Biopsy.
a
Enrollment will be allowed based on positive local FISH testing; tumor tissue must be provided for central confirmation of result 
by FISH during Prescreening or Screening but central confirmation is not mandated prior to the start of study treatment; if 
available and allowed locally: additional tissue material to be provided for central TBx NGS.
For this part of the study, there will be a dedicated Safety Monitoring Committee (SMC) consisting 
of Sponsor representatives (including, but not limited to the Patient Safety Strategy Lead (chair), 
the Medical Responsible, and the Biostatistician), the coordinating and enrolling Investigators, or 
their deputies. The SMC will review safety, tolerability, and available PK data. The SMC will 
meet after 3 participants have completed Cycle 1 for an interim assessment, and again after at least 
6 participants of the respective cohort have completed Cycle 1, to decide on the final tepotinib 
dose and regimen to be used in the study.
The first participant of the initial dose cohort will be observed for at least 2 days by the enrolling 
Investigator before the second participant can be treated. The observation does not require 
hospitalization and includes vital signs, labs, and ECG, on Cycle 1 Day 2. Thereafter, enrollment 
will not be interrupted until a final decision for the combination is made. However, interruption of 
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enrollment and a related SMC meeting may be requested at any time by SMC member(s) if a safety 
or tolerability signal requires expedited discussions.
The SMC will recommend the Phase II dose (RP2D) of tepotinib to be used in the whole study in 
combination with osimertinib. The SMC may also recommend reducing the tepotinib dose to 
250 mg in combination with osimertinib as part of the safety run-in and/or for the whole study.
The SMC will be guided by the results of Bayesian Optimal Interval design (BOIN). The 
recommendation of the BOIN design is not binding (ie, the SMC may choose a different dose level 
other than suggested by the BOIN design; re-escalation is allowed). The RP2D for the whole study 
will be based on SMC recommendation and Sponsor decision (Medical Safety and Ethics Board 
[MSEB] decision).
Dose-limiting toxicities
Dose-limiting toxicities (DLT) will be evaluated using the NCI-CTCAE v5.0. Limits for dose 
escalations will be considered in accordance to Bayesian Optimal Interval design (BOIN) based 
on a maximum target toxicity rate of 30% and a maximum number of 12 participants (Yuan 2016).
Tepotinib dose changes based on the number of DLTs observed in the total number of participants
treated with the respective dose will be considered by the SMC according to Table 2.
Table 2
Bayesian Optimal Interval Design Decision Criteria for Tepotinib Dose 
Changes
Action
Number of participants treated at the current dose
1
2
3
4
5
6
7
8
9
10
11
12
De-escalate from 500 mg to 250 mg 
in case the number of DLTs is ≥
1
1
2
2
2
3
3
3
4
4
4
5
Escalate back from 250 mg to 500 mg
in case the number of DLTs is ≤
0
0
0
0
1
1
1
1
2
2
2
2
DLT: Dose limiting toxicity
At least 6 participants on a dose level are regarded as necessary to select a dose for the Phase II
part of the study. In the safety run-in part of the study, DLTs are defined as any of the following 
toxicities and judged by the Investigator and/or the Sponsor to be not attributable to the disease or 
disease-related processes under investigation:
Grade 4 neutropenia for more than 7 days
Grade ≥3 febrile neutropenia
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with non-traumatic bleeding
Grade ≥3 nausea/vomiting and/or diarrhea that has not improved within 72 hours despite 
adequate and optimal treatment
Any other Grade ≥3 non-hematological AE, except alopecia or Grade 3 nauseas/vomiting 
and/or diarrhea that has improved within 72 hours with optimal treatment. 
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A DLT is also defined specifically in case of: 
Occurrence of Hy’s law cases (defined as aminotransferases > 3 × upper limit of normal (ULN), 
total bilirubin ≥2 × ULN, and alkaline phosphatase (ALP) < 2 × ULN, with no other reason to 
account for these abnormalities)
Grade ≥3 lipase and/or amylase elevation with signs and symptoms suggestive of pancreatitis 
or if confirmation of pancreatitis, either based on clinical or radiological signs. An isolated 
lipase and/or amylase elevation of Grade ≥3 without clinical or radiological evidence of 
pancreatitis will not be defined as DLT
Any QTcF increase associated with signs and symptoms of serious arrhythmia (Grade 4)
Interstitial lung disease/pneumonitis
All participants enrolled in safety run-in who miss > 25% of the planned doses within Cycle 1 will 
be replaced if the dose reduction/interruption was not caused by any safety reasons/DLTs.
b. MAIN TREATMENT 
The main treatment part overview is provided in 
Figure 3.
Figure 3
Main Treatment 
* The randomization (2:1 ratio) in the main treatment part will continue until 12 MET amplification positive by centrally confirmed FISH 
(TBx) participants are enrolled in the monotherapy arm. After this all participants will be assigned to the combination of tepotinib plus 
osimertin b. Participants in the Republic of Korea will not undergo randomization but will be assigned exclusively to the combination 
of tepotinib plus osimertin b, and therefore will not be treated with tepotin b monotherapy.
EGFR: Epidermal Growth Factor Receptor; NSCLC: Non-Small Cell Lung Cancer; TKI: Tyrosine Kinase Inhibitor; MET: Mesenchymal-
epithelial Transition Factor; amp: amplification; FISH: fluorescence in situ hybridization; NGS: Next Generation Sequencing; TBx: 
Tissue Biopsy; LBx: Liquid Biopsy; RP2D: recommended Phase II dose.
a Submission of tumor tissue and blood sample obtained after progression on first-line osimertinib, is mandatory for all patients for 
MET amplification testing at Prescreening. 
b Enrollment will be allowed based on positive local FISH testing; tumor tissue must be provided for central confirmation of result by 
FISH during Prescreening or Screening but central confirmation is not mandated prior to the start of study treatment; if available and 
allowed locally: additional tissue material to be provided for central TBx NGS.
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During the main treatment part, participants with EGFRm+ NSCLC who have relapsed on 
previous first-line osimertinib due to MET amplification will be treated as follows (Figure 3):
-
Eligible participants with MET amplification identified by FISH (TBx) (central or local) 
and independent of the MET status by LBx, will be randomly assigned in a ratio of 2:1 to 
either the combination of tepotinib at a dose defined by the SMC and osimertinib at the 
recommended daily dose of 80 mg or tepotinib alone at the daily dose of 500 mg (as 
currently used in the Phase II single agent study) in cycles of 21-day duration (two-arm 
study). Participants will continue to receive study treatment until disease progression 
(according to RECIST Version 1.1), death, AE leading to discontinuation, study 
withdrawal, or consent withdrawal. The randomization to the two arms of the study will 
continue until 12 participants who are MET amplification positive by centrally confirmed 
FISH (TBx) are enrolled in the monotherapy arm. After this, all participants will be 
assigned to the combination of tepotinib plus osimertinib. For participants in the 
randomized part of the study, verification of disease progression by IRC is required.
Participants who are randomized to the tepotinib monotherapy will have the opportunity to 
switch over to the combination of tepotinib plus osimertinib if they experience disease 
progression according to RECIST Version 1.1 reported by investigator and verified by 
IRC. Until progression is verified by IRC and the switch over to the combination of 
tepotinib plus osimertinib takes place, tepotinib monotherapy can be continued, if judged 
appropriate by the Investigator. However, if disease progression is not verified by IRC, the 
participant must discontinue study intervention. Participants who permanently discontinue 
tepotinib monotherapy due to an AE, withdraw consent, or for any reason other than 
progressive disease, will not be eligible to switch over to the combination of tepotinib plus 
osimertinib.
Note that only participants assigned to the combination of tepotinib plus osimertinib and who are 
MET amplification positive by centrally confirmed FISH (TBx) will be evaluated for the primary 
objective of the study. Participants assigned to tepotinib monotherapy and who are MET 
amplification positive by centrally confirmed FISH (TBx) will be evaluated for a secondary 
efficacy objective of the study. Participants in the Republic of Korea will not undergo 
randomization but will be assigned exclusively to the combination of tepotinib plus osimertinib, 
and therefore will not be treated with tepotinib monotherapy. The efficacy outcomes of participants 
in each of the two arms who are MET amplification positive only by local but not centrally 
confirmed FISH (TBx) will only be listed (See Section 9.4.1).
-
Eligible participants with MET amplification identified centrally by blood-based next 
generation sequencing (LBx) only, will receive the combination of tepotinib at a dose 
defined by the SMC and osimertinib at the recommended daily dose of 80 mg in cycles of 
21-day duration. There will be no monotherapy arm for participants who are detected to be 
MET amplified by central blood-based next generation sequencing (LBx) only. 
Participants will continue to receive study treatment until disease progression (according 
to RECIST Version 1.1), death, AE leading to discontinuation, study withdrawal, or 
consent withdrawal. Approximately 20 participants with MET amplification identified by 
central blood-based next generation sequencing (LBx) only are expected to be assigned to 
the combination of tepotinib plus osimertinib.
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Note that participants who are MET amplification positive by central blood-based next generation 
sequencing (LBx) will be evaluated for a secondary efficacy objective of the study and will not be 
part of the primary analysis set.
In addition to the SMC, which will monitor and guide the safety run-in, an Independent Data 
Monitoring Committee (IDMC) will be formed from a group of experts including one statistician 
and at least one oncologist who will not be participants in this conduct of this study. An IDMC 
charter and the integrated statistical analysis plan (IAP) will provide the details about the conduct 
of the IDMC meeting and frequency. The IDMC will be responsible for periodic (as defined by 
the IDMC charter) evaluations of the clinical study to ensure continued participant safety as well 
as the validity and scientific merit of the study.
Safety and efficacy data outputs for any interim analyses (Refer to Section 9) will be provided to 
the IDMC. The IDMC will give a recommendation regarding further conduct of the study. The 
Sponsor management will take the final decision if the IDMC recommends stopping the study. 
After the enrolment halt the requirements for an IDMC do no longer exist and no further IDMC 
meetings will be conducted.
Follow-up Period
All participants are to be followed up after stop of study intervention, including an EoT visit within 
14 days since documented decision by the Investigator to permanently discontinue study 
intervention. A Safety Follow-up Visit will occur 30 ± 3 days after the last dose of study treatment
for all participants who discontinue study intervention permanently. In case EoT Visit and Safety 
Follow-up Visit end up falling within the same 7 days, only EoT Visit should be performed. 
Participants who withdraw from the treatment for reasons other than progressive disease (PD) or 
death have additional visits for tumor assessments every 6 weeks until 9 months after first 
administration of study intervention and every 12 weeks thereafter until disease progression. 
Survival follow-up is to be performed every 3 months (± 2 weeks) at clinic visit or by telephone 
contact. Participants’ survival information will be collected. Any subsequent anticancer therapy 
given to the participant until death should be recorded.
4.2
Scientific Rationale for Study Design
The Phase II, two-arm, open-label, INSIGHT 2 study has been designed to assess the efficacy and 
safety of tepotinib in combination with osimertinib in patients with EGFRm+ and MET amplified, 
locally advanced or metastatic NSCLC who have progressed on first-line osimertinib. It will also 
assess the contribution of tepotinib to the osimertinib and tepotinib combination therapy by 
assessing tepotinib monotherapy in the same population. No formal statistical comparison between 
the combination arm and the monotherapy arm is planned.
Somatic activating mutations in the tyrosine kinase domain of EGFR are present in 
approximately 10% of Caucasian (Europe and US) and nearly 30% of Asian patients with 
advanced or metastatic NSCLC. Almost 90% of these mutations consist of deletions in exon 19 or 
L858R point mutations within exon 21 (Carbonnaux 2016).
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Several large-scale Phase III clinical trials have consistently demonstrated the superior efficacy of 
1st and 2nd generation EGFR TKIs in comparison with standard first-line platinum-based 
chemotherapy for the treatment of patients with advanced EGFRm+ NSCLC (Sullivan 2017, 
NCCN version 3, 2019). Unfortunately, most patients ultimately progress on EGFR TKI treatment 
via a resistance mechanism most commonly related to EGFR such as the T790M mutation 
(Sullivan 2017). This limitation has been overcome by the introduction of 3rd generation TKIs, 
particularly osimertinib. Currently, osimertinib is the only 3rd generation EGFR TKI approved for 
the treatment of T790M positive patients who have progressed on 1st or 2nd generation EGFR TKIs. 
Osimertinib is also approved as first-line therapy for advanced EGFRm+ NSCLC, regardless of 
T790M mutation status. However, despite the robust clinical activity exerted by osimertinib, 
patients inevitably develop secondary resistance to this treatment, which poses a significant 
challenge due to the paucity of post-osimertinib pharmacological options available to date
(Leonetti 2019).
Next to EGFR-related resistance, MET gene amplification constitutes the most frequent cause of 
bypass pathway activation as an acquired resistance mechanism to EGFR TKIs (Wu 2017; 
Papadimitrakopoulou 2018; Ramalingam 2018). When osimertinib was given as a first-line 
therapy, MET amplification was the most common resistance mechanism, encountered in 15% of 
patients by next generation sequence circulating tumor DNA (ctDNA) analysis. Moreover, this 
percentage is expected to be higher in tissue, due to the underestimation of gene amplification in 
plasma (Leonetti 2019; Ramalingam 2018).
Activated MET thereby acts as a secondary oncogenic driver in EGFRm+ NSCLC, requiring the 
concurrent inhibition of both MET and EGFR (Engelman 2007; Turke 2010). Therefore, INSIGHT 
2 investigates concomitant inhibition of both targets with the combination of the highly selective 
MET inhibitor tepotinib and osimertinib, in patients with EGFRm+ and MET amplified, locally 
advanced or metastatic NSCLC who have progressed on first-line osimertinib. It will also assess 
the contribution of tepotinib to the osimertinib and tepotinib combination therapy in the same 
population but no formal statistical comparison between the combination arm and the monotherapy 
arm is planned.
The strong addiction on the EGFR pathway is also demonstrated by 2 clinical phenomena observed 
in subsets of EGFRm+ NSCLC patients. A disease flare was seen in patients having discontinued 
their EGFR inhibitor treatment after relapse (Chaft 2011). Moreover, single responses were noted 
in patients following wash-out and re-start of EGFR TKI treatment after previous relapse on EGFR 
TKIs (Cappuzzo 2016). Therefore, patients who are identified as MET amplification positive and 
who had documented progression on previous EGFR TKI treatment are recommended to continue 
treatment with the EGFR TKI beyond progression in line with current clinical guidelines (NCCN 
version 3, 2019) and criteria as defined by Jackman 2010 until they either receive the experimental 
treatment as defined in this study, or in the case of non-eligibility, a follow-up treatment as 
discussed with their physician. 
While there is a strong scientific rationale for the combined MET and EGFR inhibition in EGFR 
TKI resistant MET amplified NSCLC as supported by available results from several clinical 
studies (Yang 2017; Ahn 2017; Wu 2018; Cheng 2018), the final population eligible for this 
personalized targeted treatment is obviously small. It is estimated that only 2% to 5% of the overall
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NSCLC population is positive for MET amplification after osimertinib relapse and therefore 
suitable to receive the study intervention. For this reason, the current design has been chosen to 
cope not only with the feasibility issues regarding recruitment of participants into this study but 
also with expectations of the participants having gone through the stringent entry criteria for this 
study. The decision for not including a standard of care control arm also considers the experience 
from the previous INSIGHT (NCT01982955) study, which the Sponsor performed in a comparable 
study population and which had to be prematurely halted due to difficulties recruiting participants 
into the randomized controlled study. The tepotinib monotherapy arm in the study is required in 
order to assess the contribution of tepotinib to the osimertinib and tepotinib combination in 
participants with EGFRm+ NSCLC who have relapsed on previous first-line osimertinib due to 
MET amplification. Only 12 MET amplification positive by centrally confirmed FISH (TBx)
participants are required for the monotherapy arm. A formal statistical comparison between the 
combination and the monotherapy arm will not be performed. For participants in the randomized 
part of the study, verification of disease progression by IRC is required. Participants who are 
randomized to the tepotinib monotherapy will have the opportunity to switch over to the 
combination of tepotinib plus osimertinib if they experience disease progression according to 
RECIST Version 1.1 reported by investigator and verified by IRC. Until progression is verified by 
IRC and the switch over to the combination of tepotinib plus osimertinib takes place, tepotinib 
monotherapy can be continued, if judged appropriate by the Investigator. However, if disease 
progression is not verified by IRC, the participant must discontinue study intervention.
Previous clinical data clearly point to a much higher predictivity of MET amplification as a marker 
for patient stratification compared with MET overexpression in the EGFR TKI resistance setting. 
Tepotinib has already been investigated in a combination with the 1st generation EGFR TKI 
gefitinib in advanced EGFRm+ NSCLC patients. In this previous study participants were selected 
based on Met protein overexpression or gene copy number gain/MET amplification. While the 
respective overall intention-to-treat population had PFS similar to that of the platinum doublet 
chemotherapy control arm, the predefined subset of MET amplified patients showed highly 
significant differences in PFS with a hazard ratio of 0.13 (90% CI 0.04, 0.43) with median PFS in 
the tepotinib/gefitinib arm of 16.6 months (90% CI 8.3, not estimable) compared with a median 
PFS in the control arm of 4.2 months (90% CI 1.4, 7.0). This observation is also in line with 
previous failure in development programs by competitors such as onartuzumab, which only relied 
on Met or HGF protein overexpression for patient stratification and could not show benefit in a 
Phase III lung cancer study (Garber 2014).
In the INSIGHT 2 study, MET amplification status after progression on first-line osimertinib must 
be confirmed centrally by FISH (TBx) or centrally by blood-based next generation sequencing 
(LBx). In the case of local TBx FISH MET amplification testing, sites must provide the minimum 
required tumor tissue samples for central confirmation of MET status by FISH at Screening (or at 
Prescreening) but central confirmation is not mandated prior to the start of study treatment. A MET 
gene copy number ≥ 5 and/or a MET/CEP7 ratio ≥ 2 will be regarded as MET FISH positive. 
In parallel with the clinical development activities, a companion diagnostic strategy for LBx based 
testing is in place including a methodology being monitored closely.
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4.3
Justification for Dose
The dose selected for osimertinib is 80 mg once daily, which is the dose approved for the treatment 
of patients with EGFRm+ NSCLC and in agreement with the SmPC and osimertinib label. A dose 
reduction to 40 mg once daily is allowed but only if required based on individual safety and 
tolerability in line with the osimertinib label. 
The primary dose to be evaluated for tepotinib is 500 mg once daily, which is the dose and regimen 
used in monotherapy as well as in the combination with gefitinib in 4 Phase II studies so far. 
Tepotinib doses up to 1400 mg once daily were administered in the tepotinib first in human (FIH) 
study without defining a maximum tolerated dose. Selection of the 500 mg once daily dose is based 
on a translational modelling approach using preclinical PK, pharmacodynamic, and tumor growth 
data combined with clinical PK and pharmacodynamic data from patients enrolled in the FIH study 
(Xiong 2015). Thereby, a tepotinib concentration could be defined that results in a 95% inhibition 
of the MET receptor which is achieved by > 90% of patients with the 500 mg once daily dosing
(Xiong 2015).
Both drugs, osimertinib and tepotinib, have shown safety and tolerability in monotherapy in their 
FIH studies, which allowed dosing beyond the selected treatment doses, ie, 80 versus 240 mg 
osimertinib and 500 versus 1400 mg tepotinib. In addition, for both drugs there are clinical results 
available showing that a combination of an EGFR and MET inhibitor is safe to be used without 
change in the predefined treatment doses. In addition, the safety profile, especially between the 
1st generation EGFR TKI (including gefitinib) and the 3rd generation EGFR TKI (including 
osimertinib) is also considered comparable (Soria 2018; Mezquita 2018), which may also allow to 
draw the conclusion that the combination of tepotinib and osimertinib may have a manageable risk 
for unexpected toxicity.
Therefore, based on the available clinical information of both drugs, a once daily dose of 500 mg 
tepotinib and 80 mg osimertinib will be assessed in the study. If this dose and regimen can be 
confirmed in the safety run-in by the SMC, the study will continue with the dose and regimen of 
500 mg tepotinib and 80 mg osimertinib once daily. Based on safety, tolerability, and PK results 
in the safety run-in, the SMC may also decide to reduce the tepotinib dose to 250 mg, which is the 
lower dose that is still defined to be pharmacologically active. 
Exposure to neither osimertinib nor tepotinib is subject to ethnic differences. Food has been shown 
to increase osimertinib exposure to a clinically insignificant degree (Planchard 2016). The drug 
combination or tepotinib monotherapy will therefore be administered after food intake, eg, a 
normal breakfast, as done in previous studies with tepotinib.
Results of the safety run-in treatment part
During the safety run-in treatment period of the MS200095-0031 study, two SMC meetings took 
place, the first on 05 May 2020 and the second on the 11 August 2020. 
In the first SMC meeting, 3 participants who had completed Cycle 1 of treatment with the 
combination of tepotinib at the dose of 500 mg once daily together with osimertinib 80 mg once 
daily, were evaluated. No DLTs were noted and the SMC members unanimously confirmed to 
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continue the safety run-in treatment part without modification, until at least 3 more participants 
are enrolled in the study. The Investigators agreed with the decision of the SMC members.
In the second and final SMC meeting, 6 participants who had completed Cycle 1 of treatment with 
the combination of tepotinib at the dose of 500 mg once daily together with osimertinib 80 mg 
once daily, were evaluated (3 of those 6 participants had newly completed Cycle 1 of treatment 
since the first SMC meeting). No DLTs were noted with the data evaluated until 11 August 2020. 
The SMC members unanimously confirmed to continue enrollment in the expansion part of the 
study with a RP2D of 500 mg tepotinib and 80 mg osimertinib. The Investigators agreed with the 
decision of the SMC members and no further patients were included into the safety run-in 
treatment part of the MS200095-0031 study.
4.4
End of Study Definition
A participant has completed the study if he/she has completed all study parts, including all 
scheduled procedures (including survival follow-up).
The end of the study is defined as the date of study intervention discontinuation by all participants 
(due to either disease progression, undue toxicity, or withdrawal, and, therefore, are not likely to 
benefit from the study intervention any longer) and two thirds of the participants have died or were 
followed up for at least 3 years, whatever occurs first. After the end of the study a final analysis, 
including an analysis of efficacy and safety, will be conducted in all participants.
5
Study Population
The criteria in Sections 5.1 (Inclusion Criteria) and 5.2 (Exclusion Criteria) are designed to enroll 
only participants, who are appropriate for the study; thereby, ensuring the study fulfills its 
objectives. All relevant medical and nonmedical conditions should be taken into consideration 
when deciding whether a participant is suitable for this study.
Prospective approval of protocol deviations to inclusion and exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted.
Before performing any study assessments that are not part of the participant’s routine medical care, 
the Investigator will confirm that the participant has provided written informed consent, as 
indicated in Appendix 2 (Study Governance).
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Age
1. Are ≥18 years of age (or having reached the age of majority according to local laws and 
regulations, if the age of majority is > 18 years of age [ie, ≥20 years of age in Japan]), at 
the time of signing the informed consent.
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Type of Participant and Disease Characteristics
2. Are participants with the following:
a) Locally advanced or metastatic NSCLC histology (confirmed by either histology or 
cytology) with documented activating EGFR mutation.
b) Presence of at least 1 independently verified measurable lesion in accordance with 
RECIST Version 1.1, that can be accurately assessed at Baseline with ≥10 mm in the longest 
diameter (except lymph nodes which must have short axis ≥15 mm) with computed 
tomography (CT) or magnetic resonance imaging (MRI), which is suitable for accurate 
repeated measurements and that preferably was not previously irradiated or biopsied.
c) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and a 
minimum life expectancy of 12 weeks.
d) Acquired resistance on previous first-line osimertinib. Participants must meet both of the 
following 2 criteria:

Radiological documentation of disease progression on first-line osimertinib.

Objective clinical benefit documented during previous osimertinib therapy, defined 
by either partial or complete radiological response, or durable stable disease (SD) 
(SD should last > 6 months) after initiation of osimertinib.
e) Have received only first-line osimertinib as a prior line of therapy in the noncurative 
advanced or metastatic NSCLC setting.
f) MET amplification as determined by either FISH testing (central or local) on tumor tissue
(TBx) or central blood-based next generation sequencing (LBx). Tumor and blood samples 
must be collected following progression on prior first-line osimertinib at Prescreening.

Submission of tumor tissue and blood sample obtained after progression on 
first-line osimertinib, is mandatory for all patients for MET amplification testing. 

Submission of tumor tissue during Prescreening or Screening is mandatory for 
patients with tumor tissue tested by local FISH, to confirm MET amplification 
status. Central confirmation is not mandated prior to the start of study treatment.
Weight
Not applicable.
Sex
3. Are male or female
a) Female participants:
Are not pregnant or breastfeeding, and at least 1 of the following conditions applies:
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
Not a woman of childbearing potential (WOCBP)
OR

If a WOCBP, use a highly effective contraceptive method (ie, with a failure rate 
of <1% per year), preferably with low user dependency, as described in Appendix 
3 for the following time periods:
o
Before the first dose of the study intervention(s), if using hormonal 
contraception: 
1. has completed at least one 4-week cycle of an oral contraception pill 
and either had or has begun her menses
OR
2. Has used a depot contraceptive or extended-cycle oral contraceptive 
for least 28 days and has a documented negative pregnancy test 
using a highly sensitive assay.
AND
o
A barrier method, as described in Appendix 3.

During the intervention period

After the study intervention period (ie, after the last dose of study intervention is 
administered) for at least 2 months after the last dose of study intervention and 
agree not to donate eggs (ova, oocytes) for reproduction during this period.
The Investigator evaluates the effectiveness of the contraceptive method in 
relationship to the first dose of study intervention.
Have a negative serum pregnancy test, as required by local regulations, within 
28 days before the first dose of study intervention. 

Additional requirements for pregnancy testing during and after study intervention 
are in Section 8.2.4.
The Investigator reviews the medical history, menstrual history, and recent sexual activity to 
decrease the risk for inclusion of a female with an early undetected pregnancy.
b) Male participants:
Agree to the following during the study intervention period and for at least 4 months after 
the last dose of study intervention:

Refrain from donating sperm
PLUS, either:
o
Abstain from intercourse with a WOCBP
OR
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o
Use a male condom: when having sexual intercourse with a WOCBP, who 
is not currently pregnant, and advise her to use a highly effective 
contraceptive method with a failure rate of < 1% per year, as described in 
Appendix 3, since a condom may break or leak.
Informed Consent
4. Can give signed informed consent, as indicated in Appendix 2 (Study Governance), which 
includes compliance with the requirements and restrictions listed in the informed consent 
form (ICF) and this protocol.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Spinal cord compression or brain metastasis unless asymptomatic, stable or not requiring 
steroids for at least 2 weeks prior to start of study intervention. Prior radiotherapy or surgery 
for brain metastases such as stereotactic radiosurgery/gamma knife must have been 
completed ≥2 weeks, all others ≥4 weeks prior to start of therapy. Participants with 
leptomeningeal disease are ineligible.
2. Any unresolved toxicity Grade 2 or more according to NCI-CTCAE version 5, from previous 
anticancer therapy with the exception of alopecia.
3. Need for transfusion within 14 days prior to the first dose of study intervention.
4. Participants who have brain metastasis as the only measurable lesion
5. Inadequate hematological function:

Hemoglobin < 8.5 g/dL

Neutrophils < 1.5 × 109/L

Platelets < 100 × 109/L.
6. Inadequate liver function:

Total bilirubin > 1.5 × ULN

AST/ALT/ALP > 3 × ULN

For participants with liver metastases:
i. Total bilirubin > 1.5 × ULN
ii. AST/ALT/ALP > 5 × ULN
iii. For participants with bone metastases: ALP > 5 × ULN.
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7. Inadequate renal function:

Renal impairment as evidenced by serum creatinine 1.5 × ULN, or creatinine 
clearance (CrCl) < 30 mL/min calculated by the Cockcroft-Gault formula (24-hour 
CrCl might be requested by the Investigator for confirmation, if calculated CrCl is 
< 50 mL/min. In such case, participants with 24-hour CrCl < 30 mL/min should be 
excluded).
CrCl (mL/min) =
[(140 – age(year)) × weight(kg)]
{× 0.85 for females}
72 × serum creatinine (mg/dL)
8. History of ILD or interstitial pneumonitis including radiation pneumonitis that required 
steroid treatment.
9. Impaired cardiac function:

Left ventricular ejection fraction < 45% defined by echocardiography 

Grade 4 arrhythmia (NCI-CTCAE v5.0)

Unstable angina pectoris

Congestive Heart Failure New York Heart Association III and IV 

Myocardial infarction, stroke, or transient ischemic attack within the last 6 months 
prior to study entry.
10. Corrected QT interval by Fredericia (QTcF) > 470 ms for women and > 450 ms for men at 
Screening. Any factors that increase the risk of QTc prolongation or risk of arrhythmic 
events such as hypokalemia, congenital long QT syndrome, family history of long QT 
syndrome or unexplained sudden death under 40 years of age in first degree relatives, or 
any concomitant medication known to prolong the QT interval and cause Torsade de 
Pointes.
11. Hypertension uncontrolled by standard therapies (not stabilized to < 150/90 mmHg).
12. Contraindication to the administration of osimertinib.
13. Medical history of liver fibrosis/cirrhosis.
14. Past or current history of neoplasm other than NSCLC, except for curatively treated 
non-melanoma skin cancer, in situ carcinoma of the cervix,
benign prostate 
neoplasm/hypertropia, or other cancer curatively treated and with no evidence of disease 
for at least 5 years.
15. Medical history of difficulty swallowing, malabsorption, or other chronic gastrointestinal 
disease, or conditions that may hamper compliance and/or absorption of the tested product.
16. Major surgery within 28 days prior to Day 1 of study intervention.
17. Known human immunodeficiency virus positivity.
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18. Known hypersensitivity to any of the study intervention ingredients.
Prior/Concomitant Therapy
19. Prior treatment with other agents targeting the HGF/MET pathway such as crizotinib, 
capmatinib, savolitinib, foretinib, glesatinib, cabozantinib, merestinib, onartuzumab, 
rilotumumab, emibetuzumab, and ficlatuzumab.
20. Participants currently receiving (or unable to stop use at least 1 week prior to receiving the 
first dose of study intervention) medications or herbal supplements known to be potent 
inducers of CYP3A4.
Prior/Concurrent Clinical Study Experience
21. Participation in another interventional clinical study (except those participants who were 
solely involved in other studies where the investigational product was osimertinib in the 
first-line of therapy) within the 30 days prior to randomization/first dose.
Diagnostic Assessments
Not applicable.
Other Exclusions
22. Substance abuse, active infection, or other acute or chronic medical or psychiatric condition 
or laboratory abnormalities that might increase the risk associated with study participation 
at the discretion of Investigators.
23. Legal incapacity or limited legal capacity.
24. Any other reason that, in the opinion of the Principal Investigator, precludes the participant 
from participating in the study.
5.3
Lifestyle Considerations
On days when PK samples are to be drawn, participants should be instructed to attend the study 
visit in a fasted state (minimum 6 hours fasting; plain water consumption is acceptable), with no 
breakfast and prior to taking their dose of tepotinib and osimertinib. After a predose PK blood 
sample is drawn, the assigned dose of tepotinib and osimertinib should be taken after breakfast. 
No further food should be consumed until 2 hours after the dose (water is allowed).
Participants will abstain from strenuous exercise for 48 hours before each blood collection for 
clinical laboratory tests. 
5.4
Screen Failures
Prescreening
Generally, repeat of Prescreening is not permitted. However, in case of administrative errors or the 
provided TBx and/or LBx sample cannot be evaluated at the central testing laboratory, the TBx 
and/or LBx sample may be collected again (but always after progression on first-line osimertinib 
and before initiation of study intervention) from a participant without obtaining new consent for 
Prescreening and using the already assigned participant number. 
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Screening
Generally, individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened. However, the Sponsor may be re-approached by the Investigator for an 
individual participant and may grant an exception to repeat screening procedures. This participant 
must have a confirmed MET amplification as defined in this protocol but may have failed other 
inclusion or exclusion criteria in the initial screening. In this case, the rescreened participants will 
be assigned a new participant number.
6
Study Intervention(s)
Study intervention is any investigational intervention(s), marketed product(s), placebo, or medical 
device(s) intended to be administered to a study participant per the study protocol. In this protocol, 
this refers to tepotinib and osimertinib combination therapy or tepotinib monotherapy.
Note: Osimertinib is an approved drug (Tagrisso). While this protocol describes the use of 
osimertinib in this study, more comprehensive information about osimertinib can be found in the 
prescribing information/SmPC and other reference sources. Investigators are advised to also take 
this information into account.
6.1
Study Intervention(s) Administration
Study Intervention Name:
Tepotinib and osimertinib combination, or tepotinib monotherapy
Dose Formulation:
Tepotinib: 250 mg tablets.
Osimertinib: 80 mg (and 40 mg) tablets.
Unit Dose Strength(s)/Dosage 
Level(s):
Tepotinib 500 mg (2 tablets of 250 mg) per day, orally, in cycles of 
21-day duration.
Osimertinib (Tagrisso): 80 mg once daily. A dose reduction to 40 mg 
once daily is allowed if required based on individual safety and 
tolerability in line with the prescribing information.
Route of Administration:
Oral with food
Dosing Instructions:
Participants will take tepotinib at the assigned dose together with
osimertinib at the approved dose of 80 mg, orally once daily, 
approximately at the same time (± 2 hours), preferentially each morning 
immediately after food intake with a full glass of water (approximately 
200 mL).
Participants assigned to the monotherapy tepotinib treatment will take 
tepotinib at the 500 mg once daily dose (as currently used in the single 
agent Phase II study).
Participants will be instructed to swallow the tablets wholly and to avoid 
biting or breaking the tablets or attempting to dissolve in water before 
taking the dose.
For comprehensive dosing instructions refer to Section 6.6.
Supplier/Manufacturer:
Tepotinib: manufactured by Merck Healthcare KGaA.
Osimertinib: manufactured by AstraZeneca.
Tepotinib and osimertinib are to be supplied by Merck Healthcare 
KGaA.
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Packaging and Labeling
A description of pharmaceutical properties and composition of the 
formulation is provided in the IB for tepotinib and in the SmPC for 
osimertinib. 
Each container will be packaged and labeled per all applicable 
regulatory requirements and Good Manufacturing Practice Guidelines.
Tepotinib and osimertinib kits will be supplied in a ready-to-use format 
for dispensing to the participant. No additional preparation or labeling 
steps will be required.
Additional details of packaging, including quantity per container and 
anticipated length of supply per container, and labeling of the study 
interventions will be defined in a separate Pharmacy Manual.
6.2
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for study intervention accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records).
Upon receipt of the study intervention(s), the Investigator or designee must confirm appropriate 
temperature conditions have been maintained during transit and any discrepancies are reported 
and resolved before use. Also, the responsible person will check for accurate delivery and 
acknowledge receipt by signing or initialing and dating the appropriate document and returning 
it to the location specified. A copy will be archived for the Investigator Site File.
Only participants enrolled in the study may receive study intervention(s) and only authorized 
site staff may supply it. All study intervention(s) must be stored in a secure, environmentally-
controlled, and monitored (manual or automated) area, in accordance with the labeled storage 
conditions, and with access limited to the Investigator and authorized site staff. Any deviations 
from the recommended storage conditions (refer to the Pharmacy Manual for details) should be 
immediately reported to the Sponsor, and the study interventions should not be used until 
authorization has been received from the Sponsor. Tepotinib and osimertinib must not be used 
for any purpose other than the study. For details regarding special handling instructions of the 
study interventions refer to the Pharmacy Manual and the osimertinib prescribing instructions.
Dispensing will be recorded on the appropriate accountability forms so that accurate records 
will be available for verification at each monitoring visit.
Study intervention(s) accountability records at the study site will include the following:
Confirmation of receipt, in good condition and in the defined temperature range.
The inventory provided for the clinical study and prepared at the site.
The dose(s) each participant used during the study.
The disposition (including return, if applicable) of any unused study intervention(s).
Dates, quantities, batch numbers, container numbers, expiry dates, and the participant 
numbers.
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The Investigator site will maintain records, which adequately documents that participants were 
provided the doses specified in this protocol, and all study intervention(s) provided were fully 
reconciled.
Unused study intervention(s) must not be discarded or used for any purpose other than the 
present study. No study intervention that is dispensed to a participant may be re-dispensed to a 
different participant.
A Study Monitor will periodically collect the study intervention(s) accountability forms.
Further guidance and information for the final disposition of unused study intervention(s) are 
provided in the Operations Manual.
The administration of tepotinib or osimertinib to participants who have not been enrolled into 
the study is not covered by the study insurance. 
Disposal of study intervention should be according to local regulations and institutional 
guidelines.
6.3
Measures to Minimize Bias: Study Intervention Assignment 
and Blinding
This study is performed two-arm, open-label. Once the participant meets all the inclusion and none 
of the exclusion criteria, the Investigator or delegate will request the study treatment assignment 
using the Interactive Voice Response System (IVRS). Eligible participants with MET 
amplification identified centrally or locally by FISH (TBx) will be randomized at a 2:1 ratio to 
either combination therapy with tepotinib and osimertinib or tepotinib monotherapy. Participants 
in the Republic of Korea will not undergo randomization but will be assigned exclusively to the 
combination of tepotinib plus osimertinib, and therefore will not be treated with tepotinib 
monotherapy. The randomization is implemented in order to assure an objective assignment to the 
combination and monotherapy to avoid any influence of participant’s characteristics on the 
decision for treatment. The assignment to the two arms will continue until 12 participants with 
centrally confirmed (FISH testing) MET amplification are included in the monotherapy arm. 
Afterwards all enrolled participants will receive the combination treatment.
Approximately 20 participants with MET amplification identified by central blood-based next 
generation sequencing (LBx) only are expected to be assigned to the combination of tepotinib plus 
osimertinib. 
An IRC is implemented to strengthen objectivity and consistency in the evaluation of the primary 
endpoint.
In addition, an Independent Data Monitoring Committee (IDMC) of external experts will perform 
periodic reviews and assess benefit risk of the overall study including all participants. This 
independent review is considered to also improve the overall quality of the data. 
Participant numbers will be assigned in the appropriate format and will reflect study number, site 
number and participant identification. Participant numbers will not be reassigned to other 
participants or reused in this study. If a participant is replaced, the replacement will be enrolled 
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with a unique participant number. If a participant is allowed to be re-screened for the study, a new 
participant number will have to be assigned.
6.4
Study Intervention Compliance
Acceptable compliance for this study will be defined in the Monitoring Plan.
Each participant will record on a diary card the number of tablets and dosage of 
tepotinib/osimertinib taken daily including actual time of intake. This diary card will be returned 
to the Investigator site at each visit.
Participants may be withdrawn from the study intervention in the event of noncompliance that is 
deemed by the Investigator or Sponsor to compromise participant safety or study integrity (refer 
to Section 7.1 and Section 8.4).
Participants should be instructed to bring with them to each visit both opened and unopened 
tepotinib/osimertinib packages, in order to allow the assessment of compliance with study 
intervention. Tepotinib/osimertinib administration must be recorded in the electronic Case Report 
Form (eCRF), as applicable.
6.5
Concomitant Therapy
Record in the eCRF all concomitant therapies (eg, medicines or nondrug interventions) used from 
the time the participant signs the informed consent until completion of the study, including any 
changes. For prescription and over-the-counter medicines, vaccines, vitamins, and herbal 
supplements, record the name, reason for use, dates administered, and dosing information.
Contact the Medical Monitor for any questions on concomitant or prior therapy.
6.5.1
Rescue Medicine
The study will be performed at a clinical research site with personnel trained in basic or immediate 
life support. Equipment and other agents (epinephrine and prednisolone equivalents, etc.) will be 
available at the site in case of allergic reactions.
6.5.2
Permitted Medicines
Any medicines that are considered necessary to protect the participant’s welfare in emergencies 
may be given at the Investigator’s discretion, regardless if it results in a protocol deviation.
The only permitted medications are the following, but restrictions may apply:
Concomitant medications that have a narrow therapeutic window and are known to be 
transported by P-gp (eg, rivaroxaban, apixaban, ranolazine, talinolol, and digoxin), BCRP 
(eg, rosuvastatin), OCT2, MATE1, and MATE2 (eg, dofetilide and metformin), OATP1B1 and 
OCT1 are permitted. However, cautionary use and close monitoring of signs of changed 
tolerability due to potentially increased exposure is advised.
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Refer to Appendix 3 for contraceptive methods for WOCBP and female partners with 
childbearing potential of male study participants. Accordingly, WOCBP enrolled in the study 
are to use effective contraception during study intervention and for 2 months after final dose. 
Males and their female partners are to use effective contraception for 4 months after final dose.
Supportive treatment, eg, bisphosphonates, agents for improving appetite, if initiated prior to 
study entry can continue. Change in dose/schedule on study is discouraged. 
Symptomatic treatment of brain metastasis with anticonvulsants known to have a reduced risk 
for drug interactions such as lamotrigine, levetiracetam, pregabalin, or valproic acid.
The Investigator will record all concomitant medications/procedures taken by the participant 
during the study, from the date of signature of main informed consent, in the appropriate section 
of the eCRF.
6.5.3
Prohibited Medicines
Any additional concomitant therapy or procedure that becomes necessary during the study and any 
change to concomitant drugs must be recorded in the corresponding section of the eCRF, noting 
the name, dose, duration, and indication of each drug.
The following are not permitted during the study:
Any other concomitant cancer drug therapy, including chemotherapy, biological therapy, 
hormonal therapy for anticancer purposes, targeted therapy, or any investigational product other 
than tepotinib and osimertinib as defined in this protocol
Any concomitant medication known to prolong the QT interval and cause Torsade de Pointes
(refer to Appendix 8)
Drug(s), for which the package insert/SmPC includes a contraindication for P-gp (eg,
dabigatran, aliskiren, colchicine), BCRP, OCT1, OCT2, MATE1, MATE2, or OATP1B1 
inhibiting drugs
Drug(s) that are known to be potent inducers of CYP3A or P-gp and thereby may decrease 
efficacy of osimertinib and tepotinib, including carbamazepine, phenytoin, rifampicin, and 
Saint John’s wort.
Use of prohibited medicines for any reason must result in withdrawal of the participant from this
study. For further details with regard to drug-drug interactions, refer to the tepotinib IB.
6.5.4
Other Interventions
Participants may receive palliative radiotherapy, eg, for painful bone metastasis. However, the use 
of any localized radiation therapy during the study should be discussed with the Sponsor (or 
delegate) on a case-by-case basis considering the influence on imaging assessments of 
target/non-target lesions.
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6.6
Dose Selection and Modification
Participants assigned to the combination of tepotinib plus osimertinib will take tepotinib at the 
assigned dose and dose regimen (dose for the overall study confirmed by SMC after the safety-run 
in) together with osimertinib at the approved dose of 80 mg, orally once daily, approximately at 
the same time (± 2 hours), preferentially each morning immediately after food intake with a full 
glass of water (approximately 200 mL). 
Participants assigned to the tepotinib monotherapy treatment will take tepotinib at the 500 mg once 
daily dose (as currently used in the Phase II single agent VISION study), approximately at the 
same time (± 2 hours), preferentially each morning immediately after food intake with a full glass 
of water (approximately 200 mL). 
The dose of 500 mg tepotinib once daily is the labeled dose of tepotinib in US and Japan for 
patients with NSCLC with METex 14 skipping alterations. The proposed administered dose of 500 
mg tepotinib corresponds to 500 mg tepotinib hydrochloride hydrate and is equivalent to 450 mg 
tepotinib (free base form). The 250 mg tepotinib corresponds to 250 mg tepotinib hydrochloride 
hydrate and is equivalent to 225 mg tepotinib (free base form).
Participants will be instructed to swallow the tablets whole and to avoid biting or breaking the 
tablets or attempting to dissolve them in water before taking the dose.
Refer to Section 5.3 for food restrictions prior to PK sampling.
If a participant misses taking a scheduled dose of study drug, within a window of 12 hours, it is 
acceptable to take the dose. If it is more than 12 hours after the scheduled dose time, the missed 
dose should not be taken, and participants should be instructed to take the next dose at the next 
scheduled time. 
If a participant vomits after taking their study drug, they should not make up for this dose, but 
should take the next scheduled dose.
If intolerable toxicities are observed and judged by Investigator to be related to either or both 
components of the study combination intervention, dose reduction of either or both components 
will be permitted, if criteria for participant withdrawal from study intervention have not been met. 
Thereby, the Investigator should notify the Sponsor (or delegate) immediately and each case 
should be discussed including the reason for dose reduction.
In case a dose reduction is necessary, the study intervention will be administered as follows: 
If there is a Grade 3 or higher AE related to either or both components of the combination 
intervention, dose interruption of either or both components will be permitted for up to 3 weeks. 
If this AE is not recovered to Grade ≤2 or baseline values after 3 weeks of interruption, the 
participant may have to permanently discontinue osimertinib, tepotinib, or both drugs. If this AE 
recovered to Grade ≤2 or baseline values in less than 3 weeks, continuation of intervention can be 
restarted at the same dose or at a lower dose of the respective study interventions. In case of 
osimertinib, a lower dose of 40 mg is available. In case of tepotinib, depending on the RP2D, a 
reduction to 250 mg or change in dose regimen is possible. The Investigator is also permitted to 
reduce the dose of osimertinib and tepotinib for AEs that he/she deem related to the intervention
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but is also allowed to escalate back again if the clinical condition allows. Immediate notification 
of the Sponsor (or delegate) is mandatory.
Further guidance on dose modification of osimertinib is given in Table 3, following information 
as provided in the Tagrisso EU SmPC dated 28 August 2018. Since this table only provides a 
snapshot of current available knowledge the Investigator is advised to consider any update of 
osimertinib information given in respective SmPC revisions.
Table 3
Recommended Dose Modifications for Tepotinib and Osimertinib
Target organ 
Adverse reactiona
Dose modification 
Pulmonary 
ILD/Pneumonitis.
Permanently discontinue osimertinib and tepotinib.
Cardiac 
QTc interval greater than 500 ms on at 
least 2 separate ECGs.
Withhold osimertinib until QTc interval is less than 
481 ms or recovery to baseline if baseline QTc is 
greater than or equal to 481 ms, then resume at the 
reduced 40 mg dose. 
QTc interval prolongation with 
signs/symptoms of serious arrhythmia.
Permanently discontinue osimertinibb
Symptomatic congestive heart failure
Permanently discontinue osimertinibb
Body
Edema Grade 1 or 2
Dose level of tepotinib can be maintained
Edema Grade 3 
The dose of tepotinib must be interrupted until edema 
recovers to ≤ Grade 2 or baseline but for no more than 
21 days.
After recovery the patient can restart at the same dose 
or at 250 mg daily. 
If edema Grade 3 reoccurs the tepotinib dose must be 
interrupted again until edema recovers to ≤ Grade 2 or 
baseline but for no more than 21 days. After recovery, 
tepotinib must then be dose reduced to 250 mg daily (if 
the previous dose was 500 mg daily).
If edema Grade 3 reoccurs at 250 mg dose, tepotinib 
must be permanently discontinued.
Generalized edema Grade 4
Permanently discontinue tepotinib
Pancreas
Pancreatic enzyme elevation Grade ≥3
See detailed instruction in Section 6.8.
Other
Any other adverse reaction of Grade ≥3 
The dose of tepotinib must be interrupted until event 
resolves to ≤ Grade 2 or baseline but for no more than 
21 days. After recovery, tepotinib may be restarted at 1 
dose level below: 250 mg daily.
ECG: electrocardiogram; ILD: interstitial lung disease.
a
Adverse reactions graded by NCI CTCAE v5.0
b
In the case of permanent discontinuation of tepotinib or osimertinib due to toxicity, participants must permanently 
discontinue study treatment.
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Any clinical circumstances leading to dose modifications and which are not covered by above 
criteria may be grounds for dose reductions or intervention interruptions and should be discussed 
with the Sponsor on a case-by-case basis.
6.7
Study Intervention after the End of the Study
The Sponsor will not provide any additional care to participants after they leave the study because 
such care would not differ from what is normally expected for patients with NSCLC.
6.8
Special Precautions
The study will be performed at a clinical research site with personnel trained in basic or immediate 
life support. Equipment and other agents (epinephrine and prednisolone equivalents, etc.) will be 
available at the site in case of allergic reactions. In case of localized radiation therapy this should 
be discussed with the Sponsor (or delegate) on a case-by-case basis.
6.9
Management of Specific Adverse Events, Adverse Events of 
Special Interest or Adverse Drug Reactions
Tepotinib
Specific Adverse Events
Interstitial Lung Disease
Interstitial lung disease or ILD-like adverse reactions have been reported in the clinical study 
program with tepotinib in patients with NSCLC.
Participants should be monitored for pulmonary symptoms indicative for ILD or ILD-like 
reactions. Tepotinib should be withheld and participants should be promptly investigated for 
alternative diagnosis or specific etiology of ILD. Tepotinib must be permanently discontinued if 
ILD is confirmed and the participant be treated appropriately.
Edema
Edema has been reported frequently in the study program. It is an identified risk for treatment with 
tepotinib. Other AEs related to fluid retention, such as generalized edema and pleural effusion 
have been observed. To gain further information to the occurrence and resolution of edema, any 
AEs of edema, the current edema status or AE resolution is to be specifically documented at each 
visit.
In the case of edema, please follow the advice provided in Table 3 in Section 6.6. 
Asymptomatic Pancreatic Enzyme Elevation
If an asymptomatic lipase/amylase elevation of Grade ≥ 3 occurs, the participant will undergo 
clinical evaluation for the presence of signs and symptoms typical of acute pancreatitis and for 
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other risk factors for pancreatitis. In addition, a computed tomography (CT) scan and/or magnetic 
resonance imaging (MRI) of the abdomen will be performed to assess the pancreas. The Sponsor 
(or delegate) will be notified of the outcome of the CT/MRI. Dosing with study treatment can 
continue during the evaluation period unless the clinical evaluation indicates pancreatitis. If there 
is no clinical or radiological evidence of pancreatitis, treatment with tepotinib should be continued, 
particularly if there is a potentially positive benefit for the individual participant. However, the 
continuation of study treatment for the participant will be individually discussed with the 
Investigator on a participant by participant basis.
In case of dose reduction (Section 6.6), the Investigator should notify the Sponsor immediately 
and each case should be discussed on a case-by-case basis, providing the reason for dose reduction.
For further information on tepotinib please refer to the tepotinib IB.
Adverse Event of Special Interest (AESI)
Adverse events suggestive of drug-induced liver injury including hepatic/liver failure and hepatitis 
(non-infectious) are considered AEs of special interest (AESIs) and will be reported to the Sponsor 
(or delegate) in an expedited fashion (refer to Section 8.3).
Osimertinib
For information on osimertinib please refer to the osimertinib prescribing information.
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1
Discontinuation of Study Intervention
Participants must be discontinued from study intervention when they meet one of the following 
criteria: 
Pregnancy (Section 8.3.5)
ILD/pneumonitis 
Objective disease progression as per RECIST Version 1.1 as per Investigator or participant is 
no longer receiving clinical benefit. 
For participants in the randomized part of the study, verification of disease progression by IRC is 
required. Participants who are randomized to the tepotinib monotherapy will have the opportunity 
to switch over to the combination of tepotinib plus osimertinib if they experience disease 
progression according to RECIST Version 1.1 reported by investigator and verified by IRC. Until 
progression is verified by IRC and the switch over to the combination of tepotinib plus osimertinib 
takes place, tepotinib monotherapy can be continued, if judged appropriate by the Investigator. 
However, if disease progression is not verified by IRC, the participant must discontinue study 
intervention. Participants who permanently discontinue tepotinib monotherapy due to an AE, 
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Tepotinib plus osimertinib in osimertinib-relapsed MET 
MS200095-0031
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withdraw consent, or for any reason other than progressive disease, will not be eligible to switch 
over to the combination of tepotinib plus osimertinib.
The Investigator must consider discontinuation of study intervention if he/she believes it is in the 
best interest of the participant or when a participant meets one of the conditions outlined below:
Abnormal liver function as defined by the occurrence of Hy’s law defined as aminotransferases 
> 3 × ULN, ALP < 2 × ULN, total bilirubin ≥ 2 × ULN, with no other reason to account for 
these abnormalities
Grade 4 QTcF increase associated with signs and symptoms of serious arrythmia
Grade ≥ 3 lipase and/or amylase elevation with signs and symptoms suggestive of pancreatitis 
or if pancreatitis is confirmed based on clinical or radiological signs.
The Investigator may consider discontinuation of study intervention when a participant has an 
increase in QTcF interval greater than 500 ms on at least 2 separate ECGs in line with Table 3.
The Schedule of Activities specifies the data to collect at study intervention discontinuation and 
follow-up, and any additional evaluations that need to be completed. The reason for study 
intervention discontinuation should be recorded. If the participant discontinues at a scheduled visit, 
the EoT assessment can be performed on that day.
7.2
Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study at any time, at his/her own request.
If the participant withdraws consent for future involvement in the study, any data collected up 
to that point may still be used, but no future data can be generated, and any biological samples 
collected will be destroyed.
A participant has the right at any time to request destruction of any biological samples taken. 
The Investigator must document this in the site study records.
The participant may be withdrawn by the Investigator due to participation in another clinical 
study.
The participant may be withdrawn at any time at the discretion of the Investigator for safety,
behavioral, compliance, or administrative reasons.
The Schedule of Activities specifies the data to collect at study discontinuation and follow-up, 
and any additional evaluations that need to be completed. The Investigator will secure the safety 
of the study participants and make every attempt to collect data.
7.3
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:
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The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain if the participant wants to or should continue in the study.
Before a participant is deemed “lost to follow-up”, the Investigator or designee must make every 
effort to regain contact with the participant: 1) where possible, make 3 telephone calls; 2) if 
necessary, send a certified letter (or an equivalent local method) to the participant’s last known 
mailing address, and 3) if a participant has given the appropriate consent, contact the 
participant’s general practitioner for information. These contact attempts should be documented 
in the participant’s medical record.
Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study.
8
Study Assessments and Procedures
Study assessments and procedures and their timing are summarized in the Schedule of 
Activities.
No protocol waivers or exemptions are allowed.
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study intervention.
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of 
all participants screened, to confirm eligibility, and if applicable, record reasons for screening 
failure.
Prior to performing any study assessments that are not part of the participant’s routine medical 
care, the Investigator will obtain written informed consent as specified in Appendix 2 (Study 
Governance).
Procedures conducted as part of the participant’s routine medical care (eg, blood count) and 
obtained before signing of the ICF may be used for Screening or Baseline purposes provided 
the procedures met the protocol-specified criteria and were performed within the time frame 
defined in the Schedule of Activities.
On days when PK samples are to be drawn, participants should be instructed to attend the study 
visit in a fasted state, with no breakfast and prior to taking their dose of tepotinib/osimertinib.
The following assessments and information will be obtained at Prescreening after Prescreening 
informed consent (or where applicable optional consents) has been given (to occur prior to 
screening, but not time limited):
Documentation of relapse to first-line osimertinib
Documentation of EGFR alterations
Documentation of NSCLC histology 
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Demographic characteristics, including age, gender, height, weight, race and ethnicity
Smoking status
Collection of tumor biopsy material to determine MET amplification. Only tissue biopsy material 
which was collected after progression on first-line osimertinib is eligible. Submission of tumor 
tissue and blood sample obtained after progression on first-line osimertinib, is mandatory for all 
patients for MET amplification testing during Prescreening. In the case of previous local FISH 
testing for MET amplification, participants who are identified MET amplification positive are 
required to provide tumor tissue during Prescreening or Screening for central confirmation. Central 
confirmation is not mandated prior to the start of study treatment (Section 8.8).
Blood Collection for central blood-based next generation sequencing (LBx) to determine 
MET amplification. 
Note: In case of administrative, operational or logistical errors, insufficient TBx material 
available/provided from previous local FISH testing or if the provided TBx or LBx sample 
could not be evaluated at the testing laboratory, repeat collections of TBx and/or LBx may 
be performed without the need to obtain a new written informed consent for Prescreening. 
In all cases samples for TBx/LBx MET amplification testing must be collected after 
progression on first-line osimertinib relapse until prior to first study intervention is eligible.
Tissue collected after progression on first-line osimertinib is recommended to be provided
(if available and allowed locally) from all participants for central next generation sequencing 
TBx MET amplification testing. 
The following assessments and information will be obtained during the screening period
(Days -28 to -1) after signing the study consent and, where applicable, optional informed 
consents:
Demographic characteristics
Medical and disease history (including prior lines of therapy, and time to progression, best 
overall response (BOR) and duration of response on all line[s] of therapy prior to entry to 
the study) 
ECOG performance status and life expectancy assessment
Independent confirmation of measurable disease by independent radiologists, in accordance 
with the RECIST Version 1.1 criteria (Appendix 7)
Brain imaging
Chest X-ray (not necessary if chest CT is performed as part of the tumor assessment at 
Screening)
Laboratory parameters, ECG, vital signs, and AEs
Serum pregnancy test.
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Collection of tumor tissue for central confirmation (central FISH TBx) of MET 
amplification, in the case of participants who are locally identified MET amplification 
positive by FISH testing 
Full physical examination
Ophthalmology examination
Echocardiogram
Patient reported outcomes (PROs)
8.1
Efficacy Assessments and Procedures
Complete tumor assessment of all lesions by radiographic modality (using RECIST Version 1.1) 
is required. CT or MRI of the chest and abdomen (including imaging of the whole of the liver and 
adrenal glands), must be conducted to evaluate disease in these locations. Additional anatomical 
areas, such as the pelvis or other body areas in question, should be investigated in case of suspicion 
of presence of metastases based on signs, symptoms, biochemical results and/or non-study imaging 
of individual participants. 
In addition, all participants must have brain imaging by MRI with IV contrast enhancement, 
including T2/FLAIR sequences of the brain, at Screening and at Follow-up in participants with 
brain metastases confirmed by IRC  on the baseline brain scan. For participants who are enrolled 
in the study and present with brain metastasis when possible, the MRI assessment shall include 
Coronal 3D Gd-T1WI, Axial TSE/T2WI, Axial FLAIR, Axial T1WI, Axial Gd-T1WI, and 
Coronal 3D Gd-T1WI. MRI may be performed without contrast enhancement, if contrast is 
contraindicated. At Screening and during the Follow-up visits, if brain MRI is not clinically 
feasible, CT of the brain with IV contrast enhancement may be used; CT may be performed without 
contrast enhancement, if contrast is contraindicated.
During the follow-up, tumors will be assessed every 6 weeks (± 7 days) following the Cycle 1 
Day 1 visit until 9 months, and every 12 weeks (± 14 days) thereafter according to RECIST
Version 1.1, until disease progression as per Investigator, death, study withdrawal, or withdrawal 
of consent. Both IRC and Investigator assessments will be conducted. For participants in the 
randomized part of the study, verification of disease progression by IRC is required. The same 
method of assessment and the same technique should be used to characterize each identified and 
reported lesion at Baseline and during the study. Tumor assessment according to RECIST 
Version 1.1 at EoT Visit is requested only if last tumor assessment was performed ≥ 6 weeks 
within the first 9 months, or ≥ 12 weeks after 9 months prior to EoT Visit.
When a pleural effusion occurs as an adverse event and is punctured, cytology should be evaluated 
for malignancy and the results communicated to the IRC for consideration of their assessment, as 
outlined in the IRC charter.
Participants who withdraw from the study intervention for reasons other than PD or death will
have additional visits for tumor assessments every 6 weeks until 9 months, and every 12 weeks 
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thereafter. A ± 7-days time window is permitted for these additional follow-up visits until 
9 months, and ± 14 days thereafter. Reasons for study termination should be recorded if this visit 
is the last visit for the participant. Recording of any new anticancer therapy will be made (a tumor 
assessment is mandatory before initiating the new therapy).
Survival follow-up is to be performed every 3 months ± 2 weeks at clinic visit or by telephone 
contact. Participants’ survival information will be collected. Recording of any new anticancer 
therapy will be made until death. For patient reported outcomes (PROs) (EuroQol Five Dimension 
Five Level Scale [EQ-5D-5L], European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 [EORTC QLQ-C30] and Non-small Cell Lung Cancer 
Symptom Assessment Questionnaire [NSCLC-SAQ]), the questionnaires will be completed at 
Screening (or at Day 1 of Cycle 1 prior to any other intervention or drug intake if it was missed at 
Screening) and every 6 weeks from Cycle 1, Day 1 until 9 months and every 12 weeks thereafter 
until disease progression, death, study withdrawal, or withdrawal of consent. At all visits indicated 
including EoT and Safety Follow-up, every effort should be made to have the questionnaires 
completed by the participant prior to the initiation of any other study activities (including RECIST
Version 1.1 assessments) or active treatment and prior to any contact with the Investigator.
8.2
Safety Assessments and Procedures
The safety profile of the study intervention will be assessed through the recording, reporting and 
analysis of baseline medical conditions, AEs, physical examination findings, vital signs, 
electrocardiograms, echocardiograms, chest X-ray (or CT scan), and laboratory tests.
Comprehensive assessment of any potential toxicity experienced by each participant will be 
conducted starting when the participants give Prescreening informed consent (Prescreening ICF)
and throughout the study. The Investigator will report any AEs, whether observed by the 
Investigator or reported by the participant; the reporting period is specified in Section 8.3.1 (Time 
Period and Frequency for Collecting Adverse Event and Serious Adverse Event Information).
Apart from the Investigator, safety data will also be assessed continuously by the Sponsor 
medical monitoring activities, as well as by the following committees:
Safety Data Committee: for dose definition during the safety run-in (refer to Section 4.1 and 
Appendix 2).
Independent Data Monitoring Committee: periodic reviews on safety and efficacy data; (refer 
to Section 4.1 and Appendix 2).
8.2.1
Physical Examinations
A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. In addition, skin 
examination is to be performed. Height (measured during Prescreening) and weight will also 
be measured and recorded.
A brief physical examination will include, at a minimum, assessments of the cardiovascular, 
neurologicaland respiratory symptoms and the skin.
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Sufficient ophthalmological examination (including visual acuity and fundus) should be 
performed at Screening and end of treatment/withdrawal, or in case of any visual symptom 
(including blurred vision). Any clinically significant examination results, including results 
confirmed by the ophthalmologist, should be reported as AEs. Photographs should be taken to 
record any clinically significant findings. Ophthalmological examination results should be 
collected in the eCRF. Patients with corneal ulcer have to discontinue study treatment
Investigators should pay special attention to clinical signs related to previous serious illnesses, 
including ILD, pancreatitis, and cardiovascular diseases. 
8.2.2
Vital Signs
Temperature, pulse rate, respiratory rate, and blood pressure and weight will be assessed; height 
will be assessed at Pre-Screening only.
Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available.
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (eg, television, cell phones).
Vital signs will be measured preferably in a semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, and pulse and respiratory rates. Three 
readings of blood pressure and pulse will be taken. The first reading should be rejected. The 
second and third readings should be averaged to give the measurement to be recorded in the 
CRF.
8.2.3
Electrocardiograms
Single 12-lead ECG will be obtained as outlined in the Schedule of Activities using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTcF
intervals. Participants will rest for 5 minutes in a semi-supine or supine position before the 
reading is taken. For study discontinuation criteria involving clinically significant QTcF
findings, refer to Section 7.1.
8.2.4
Clinical Safety Laboratory Assessments
Blood and urine samples will be collected for the clinical laboratory tests listed in Appendix 5, 
at the time points listed in the Schedule of Activities. All samples should be clearly identified. 
Additional tests may be performed at any time during the study, as determined necessary by the 
Investigator or required by local regulations.
The tests will be performed by the local laboratory. It is required that these local laboratories 
are certified, perform and document interlaboratory testing at regular time intervals and provide 
a list of normal range laboratory values including units as defined by international system of 
units (SI). A 3-day window for collection of blood and urine samples scheduled to be collected 
on Day 1 of Cycle 1 is permitted.
In sites in China, laboratory assessments (e.g., lipase) can be performed in a local or a central 
laboratory, depending on the availability of the test in the local laboratory.
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The Sponsor must receive a list of the local laboratory normal ranges before shipment of study 
intervention(s). Any changes to the ranges during the study must be forwarded to the Sponsor.
The Investigator must review each laboratory report, document their review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents.
Methods for sample identification during shipping and handling, as well as sampling methods, 
processing and storage of samples are detailed in the local Laboratory Manuals.
Pregnancy testing (serum or highly sensitive urine, as required by local regulations) will be 
conducted at the time points specified in the Schedule of Activities during study intervention 
administration.
Pregnancy testing (serum or highly sensitive urine, as required by local regulations) will be 
conducted at the end of relevant systemic exposure of the study intervention.
8.3
Adverse Events and Serious Adverse Events
The definitions of an AE and a SAE are in Appendix 4.
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information
The AE reporting period for safety surveillance begins when the participant is initially included in 
the study (from time of signature of the Prescreening ICF) and continues until Safety Follow-up 
Visit (30 ± 3 days after the last dose of tepotinib/osimertinib).
Any SAE assessed as related to study intervention must be recorded and reported, as indicated in 
Appendix 4, whenever it occurs, irrespective of the time elapsed since the last administration of 
study intervention.
The method of recording, evaluating, and assessing causality of AEs (including SAEs) and the 
procedures for completing and transmitting SAE reports are in Appendix 4.
8.3.2
Method of Detecting Adverse Events and Serious Adverse 
Events
At each study visit, the participant will be queried on changes in his or her condition. During the 
reporting period, any unfavorable changes in the participant’s condition will be recorded as AEs, 
regardless if reported by the participant or observed by the Investigator.
Complete, accurate, and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the eCRF. 
All SAEs and all nonserious AEs of special interest must be additionally documented and reported 
using the appropriate Report Form as specified in Appendix 4.
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8.3.3
Follow-up of Adverse Events and Serious Adverse Events
Adverse events are recorded and assessed continuously throughout the study, as specified in 
Section 8.3.1 (Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information) and are assessed for their outcome at the Safety Follow-up Visit (30 ± 3 days 
after the last dose of tepotinib/osimertinib). All SAEs ongoing at the Safety Follow-up Visit must 
be monitored and followed up by the Investigator until stabilization or until the outcome is known, 
unless the participant is documented as “lost to follow-up”. Reasonable attempts to obtain this 
information must be made and documented. It is also the responsibility of the Investigator to ensure 
that any necessary additional therapeutic measures and follow-up procedures are performed. 
Further information on follow-up procedures is given in Appendix 4 (Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and Reports).
Details regarding the monitoring and management of AEs and AESI can be found in Section 6.9.
8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
For sites outside Japan:
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving study participants to the independent ethics 
committee (IEC)/institutional review board (IRB) that approved the study.
In accordance with International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP), the Sponsor/designee will inform the Investigator of findings that could adversely affect 
the safety of participants, impact the conduct of the study or alter the IEC’s/IRB’s 
approval/favorable opinion to continue the study. In line with respective regulations, the 
Sponsor/designee will inform the Investigator of AEs that are both serious and unexpected and 
considered to be related to the administered product (“suspected unexpected serious adverse 
reactions” or suspected unexpected serious adverse reactions [SUSARs]). The Investigator 
should place copies of Safety Reports in the Investigator Site File. National regulations
regarding Safety Report notifications to Investigators will be considered.
For sites in Japan:
The Investigator must report SAEs (particularly deaths) in accordance with applicable site-
specific requirements to the IRB that approved the study.
In accordance with ICH GCP and the Japanese ministerial ordinance on GCP, the 
Sponsor/designee will immediately inform all the study Investigators and the Heads of the study 
sites of findings that could adversely affect the safety of participants, impact the conduct of the 
study or alter the IRB’s approval/favorable opinion to continue the study. In line with respective 
applicable regulations, the Sponsor/designee will immediately inform all the study Investigators 
and the Heads of the study sites of AEs that are both serious and unexpected and considered to 
be related to the administered product (“suspected unexpected serious adverse reactions” or 
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SUSARs). In addition, per applicable regulations, the Sponsor/designee will inform the study 
Investigators and the Heads of the study sites of all SAEs which were reported to the health 
authorities. In accordance with the Japanese regulatory requirements concerning safety 
reporting the Investigator should place copies of the Safety Reports in the Investigator Site File. 
The Head of the study site should also maintain copies of safety reports appropriately.
For all sites:
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records of 
these notifications. When direct reporting is not clearly defined by national or site-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned IEC/IRB 
of any Safety Reports provided by the Sponsor/designee and of filing copies of all related 
correspondence in the Investigator Site File.
For studies covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with 
that Directive and with the related Detailed Guidance documents.
8.3.5
Pregnancy
Only pregnancies the Investigator considers to be related to the study intervention (eg, resulting 
from a drug interaction with a contraceptive method) are AEs. However, all pregnancies with an 
estimated conception date during the period defined in Section 8.3.1 (Time Period and Frequency 
for Collecting Adverse Event and Serious Adverse Event Information) must be recorded in the AE 
page/section of the CRF for both pregnancies in female participants and pregnancies in female 
partners of male participants. The Investigator must notify the Sponsor/designee in an expedited 
manner of any pregnancy using the Pregnancy Report Form, which must be transmitted by the 
same process specified for SAE reporting in Appendix 4, section on Reporting Serious Adverse 
Events, Adverse Events of Special Interest and Dose Limiting Toxicities.
Investigators must actively follow up, document, and report on the outcome of all these 
pregnancies, even if the participants are withdrawn from the study.
The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy Report 
Form. If an abnormal outcome occurs, the SAE Report Form will be used if the participant sustains 
an event and the Parent-Child/Fetus Adverse Event Report Form if the child/fetus sustains an 
event. Any abnormal outcome (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) must be reported in an expedited manner, as specified in 
Section 8.3.1, while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a participant occurring during the study, the participant must be 
discontinued from study intervention. The Sponsor/designee must be notified without delay and 
the participant must be followed as indicated above.
8.4
Treatment of Overdose
For this study, any dose of tepotinib or osimertinib which exceeds the daily dose that is defined in 
this clinical study protocol will be considered an overdose.
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The Sponsor does not recommend specific treatment for an overdose.
Even if it not associated with an AE or a SAE, any overdose is recorded in the eCRF and reported 
to drug safety in an expedited manner. Overdoses are reported on a SAE Report Form, following 
the procedure in Appendix 4, section on Reporting Serious Adverse Events, Adverse Events of 
Special Interest and Dose Limiting Toxicities.
8.5
Pharmacokinetics
The following PK parameters will be calculated, when appropriate:
Symbol
Definition
AUC0-t
The area under the concentration-time curve (AUC) from time zero (= dosing time) to the last sampling 
time (tlast) at which the concentration is at or above the lower limit of quantification. Calculated using the 
mixed log-linear trapezoidal rule (linear up, log down).
CL/f
The apparent total body clearance of study intervention following extravascular administration, taking 
into account the fraction of dose absorbed. 
CL/f = Dose p o  /AUC0-∞. Either the observed or predicted AUC0-∞ should be used, depending on the 
study specific requirements.
Cmax
Maximum observed concentration
tmax
The time to reach the maximum observed concentration collected during a dosing interval (unless 
otherwise defined, take the 1st occurrence in case of multiple/identical Cmax values)
Vz/F
The apparent volume of distribution during the terminal phase following extravascular administration, 
based on the fraction of dose absorbed. Vz/f = Dose/(AUC0-∞*λz) following single dose. Vz/f = 
Dose/(AUC*λz) following multiple dose.
Whole blood samples of approximately 3 mL will be collected for measurement of plasma 
concentrations of tepotinib and metabolites, as specified in the Schedule of Activities. Samples 
for rich PK sampling (safety run-in only) will be obtained at Cycle 1 Day 1 and Cycle 1 Day 15 
(at predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after tepotinib administration). 
Samples for sparse PK sampling will be obtained at Cycle 1 Day 1 and Cycle 2 Day 1 (at 
predose, 1.5, and 4 hours after tepotinib administration). The actual date and time (24-hour 
clock time) of each sample will be recorded to calculate actual time elapsed since the prior dose 
administration.
The quantification of tepotinib and metabolites in plasma will be performed using a validated 
method. Concentrations will be used to evaluate the PK of tepotinib.
Whole blood samples of approximately 3 mL will be collected for measurement of plasma 
concentrations of osimertinib and metabolites, as specified in the Schedule of Activities. Time 
points for PK sampling are the same as described for tepotinib. The actual date and time 
(24-hour clock time) of each sample will be recorded to calculate actual time elapsed since the 
prior dose administration.
The quantification of osimertinib and metabolites in plasma will be performed using a validated 
assay method. Concentrations will be used to evaluate the PK of osimertinib.
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For participants in the safety run-in, a maximum total blood volume for PK analysis of 250 mL 
will not be exceeded. For participants in the overall study a maximum total blood volume for 
PK analysis of 80 mL will not be exceeded.
Remaining samples collected for analyses of tepotinib and osimertinib concentrations may also 
be used to evaluate safety or efficacy aspects related to concerns arising during or after the 
study.
Details on collected blood volumes, processes for collection and shipment of these samples are 
in the Laboratory Manual. Retention time and possible analyses of samples after the end of 
study are specified in the respective ICF.
Concentrations and clinical data from this study will be merged with available data from other 
clinical studies to perform the respective Population PK analyses and the analysis results will 
be reported separately from the clinical study report.
8.6
Pharmacodynamics
Refer to Section 8.8 for biomarker assessments. No specific pharmacodynamic assessments will 
be carried out.
8.7
Pharmacogenetics
Where local regulations and IRB/IEC allow, a blood sample will be collected for DNA analysis 
from consenting participants.
Participation in pharmacogenetic research is optional.
Participants who do not wish to participate in the pharmacogenetic research may still participate 
in the study.
In the event of DNA extraction failure, a replacement sample for pharmacogenetic testing may 
be requested from the participant. Additional informed consent will not be required to obtain a 
replacement sample.
Appendix 6 provides further information on pharmacogenetic research.
8.8
Biomarkers
Collection of participant samples for biomarker research is either a mandatory or optional part of 
this study and is governed by the appropriate ICF. 
MET amplification status must be assessed centrally by FISH (TBx) and centrally by blood-based 
next generation sequencing (LBx) in participants with EGFRm+ NSCLC with documented relapse 
on previous first-line osimertinib.
MET amplification status for enrolment can be also be locally assessed by FISH (TBx) on material 
collected after progression on first-line osimertinib. For a local TBx FISH MET positive test to be 
acceptable for eligibility, the following criteria must be met:
1. The TBx FISH assay cut-off for MET amplification meets the criteria specified by the 
Study Sponsor. Specifically, a MET gene copy number ≥ 5 and/or a MET/CEP7 ratio 
≥2 will be regarded as MET FISH positive. 
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2. The local FISH assay must evaluate both MET gene copy number and MET/CEP7 
ratio.Sites must provide the information on the local FISH assay used.
3. Sites must provide during Prescreening or Screening the minimum required tumor tissue 
for central confirmation of MET amplification. Central confirmation is not mandated 
prior to the start of study treatment.
Please see Section 4.1 for the assignment of the participants to the investigation treatment based 
on the test used for defining MET amplification status.
The following participant samples for biomarker research are required and will be collected from 
all participants in this study, as specified in the Schedule of Activities:
For central testing, tumor biopsy (TBx) taken after progression on first-line osimertinib will be 
used to determine the MET amplification status by central FISH testing at Prescreening.
For central confirmation, tumor biopsy (TBx) taken after progression on first-line osimertinib 
must be provided during Prescreening or Screening for participants enrolled using local FISH 
(TBx) results. 
For central testing, blood taken at Prescreening and after progression on first-line osimertinib,
will be used to determine MET amplification status using central blood-based next generation 
sequencing (LBx). 
If available and allowed locally, tissue collected after progression on first-line osimertinib is 
recommended to be provided from all participants for central next generation sequencing TBx 
MET amplification testing. Material is to be collected during prescreening or screening. Further 
technical details are described in the appropriate laboratory manual. 
Blood for on-treatment ctDNA samples (optional for participants in China).
Blood for exploratory biomarker evaluation (optional for participants in China).
Further technical details are described in the appropriate laboratory manual. 
Optional sample for biomarker research may be collected from the participants when possible, 
where local regulations and IRB/IEC allow and if consent was given:
Blood for optional pharmacogenetic testing (refer to Section 8.7 and Appendix 6)
Mandatory and optional blood samples will be tested for a possible link between biomarkers and 
the combined activity of tepotinib and osimertinib to evaluate antitumor activity and resistance of 
biomarkers including, but not limited to, markers of MET pathway activation (eg, HGF levels and 
MET mutations), and other relevant oncogenic pathways.
Details on tumor tissue requirements and blood volume collected, processes for collection and 
shipment of these samples can be found in a central Laboratory Manual. The Sponsor will store 
the samples in a secure storage space with adequate measures to protect confidentiality. Retention 
time and possible analyses of samples after the end of study are specified in the respective ICF.
8.9
Immunogenicity Assessments
Not applicable.
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9
Statistical Considerations
Details of the statistical analyses will be described in a separate Integrated Analysis Plan (IAP).
Regularly performed SMC assessments will be based on participant profiles. Interim analyses for 
the regular IDMC meetings will be a subset of the full set of tables, figures, and listings which will 
be prepared for the clinical study report (CSR). Details will be specified in the IAP and the IDMC 
charter.
The primary analysis will be conducted once all participants in the primary analysis set 
(participants with advanced or metastatic EGFRm+ NSCLC and MET amplification, determined 
centrally by FISH) have either been treated with the recommended Phase II dose of tepotinib and 
osimertinib for at least 9 months, died or have prematurely discontinued study intervention for any 
reason, whichever comes first.
The final analysis will be done 3 years after the last participant’s first dose or when all participants 
have discontinued study intervention and two thirds of the participants have died, whichever comes 
first.
9.1
Statistical Hypotheses
No formal statistical hypotheses are being tested in this study. In particular there will be no formal 
comparison between the tepotinib and osimertinib combination arm and the tepotinib monotherapy 
arm. Descriptive statistics and graphical representations will be used to summarize the data. All 
data are displayed in listings.
9.2
Sample Size Determination
Safety run-in
A BOIN approach (Yuan 2016) with maximum 12 participants will be applied for the safety run-
in. No formal sample size calculation was performed for this study period. 
Combination treatment
The TATTON and INSIGHT studies (Sequist 2020; Cheng 2018) indicate encouraging antitumor 
activity in EGFRm+ NSCLC patients who have relapsed to previous EGFR TKI, with centrally 
confirmed MET amplification status. This justifies the choice of the MET amplified positive 
population as centrally assessed by FISH for the primary analysis. 
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An ORR of at least 50% is expected for the osimertinib and tepotinib combination in participants 
who have progressed on prior first-line osimertinib, as a confirmed BOR of PR or CR based on 
independent review. There is only limited data available to support this assumption. This 
assumption is based on an ORR of 67% observed in the subset of patients with MET amplified, 
NSCLC having received tepotinib and gefitinib after relapse on one prior EGFR TKI treatment 
(INSIGHT study, Cheng 2018) and also considers ORRs observed in the TATTON study after 
relapse to one prior EGFR TKI of 64% to 67% with the combination of osimertinib plus savolitinib 
(Sequist 2020). 
While there is current controversy regarding reduced efficacy of checkpoint inhibitors in patients 
with EGFRm+ NSCLC (Soo 2018), chemotherapy regimens commonly tend to show slightly 
increased response rates in this selected population as indicated by ORRs of 34% and 31% with 
platinum doublet chemotherapy regimens in second-line treatments (Soria 2015, Ahn 2017). Based 
on these historical control data, an ORR of 35% is proposed as standard of care effect. 
Assuming a true ORR of 50% for the combination treatment, a sample size of 80 patients in the 
primary analysis set leads to a 78% probability to observe a lower bound of the exact 2-sided 95% 
confidence interval of above 35%.
Monotherapy treatment
No formal sample size calculation was done for the monotherapy arm. A total number of 
12 participants will be included in the tepotinib monotherapy arm. This leads to a precision of the 
ORR estimates as shown in Table 4.
Table 4
Confidence limits for the objective response rates in the monotherapy 
arm
Monotherapy arm (n=12)
Observed ORR
Corresponding exact 2-sided 95% CI
1/12 (8.3%)
0.2% - 38.5%
2/12 (16.7%)
2.1% - 48.4%
3/12 (25.0%)
5.5% - 57.2%
4/12 (33.3%)
9.9% - 65.1%
5/12 (41.7%)
15.2% - 72.3%
6/12 (50.0%)
21.1% - 78.9%
CI: confidence interval; ORR: objective response rate.
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Total number of participants
Enrollment will continue until 80 participants are included in the primary analysis set, ie,
80 participants with advanced or metastatic EGFRm+ NSCLC and MET amplification, determined 
centrally by FISH, are included into the tepotinib and osimertinib combination treatment arm. 
It is anticipated that approximately 120 participants will be enrolled overall in the study. 
9.3
Populations for Analyses
The analysis populations are specified below. The final decision to exclude participants from any 
analysis population will be made during a data review meeting prior to database lock.
All participants who provided informed consent for Prescreening/Screening will be analyzed in 
terms of participant disposition only. 
Analysis Set
Description
Full Analysis Set (FAS)/Safety Analysis 
Population (SAF)
All participants, who were administered any dose of any study 
intervention. Analyses will consider participants as treated and 
will be performed per treatment arm (and per dose level, in case 
multiple dose ranges were applied). 
Analyses of safety and efficacy will be based on this analysis 
set.
Primary Analysis Set for Efficacy (Primary FAS)
The primary analysis set for efficacy will consist of all FAS 
participants with advanced or metastatic EGFRm+ NSCLC and 
MET amplification, determined centrally by FISH. This analysis 
set supports the primary objective of the study.
Safety Run-In Analysis Set (SRIAS)
The SRIAS will include all participants treated in safety run-in 
who receive at least 75% of the tepotinib and osimertinib 
planned dose and complete the DLT period (3 weeks after start 
of treatment with study intervention), or who experience a DLT 
during the DLT period regardless of the received amount of 
each study intervention.
PK Analysis Set
All participants, who receive at least one dose of study 
intervention, have no clinically important protocol deviations or 
important events affecting PK, and provide at least one 
measurable post-dose concentration. 
The PK population will include all participants:
Who have completed all study periods without any relevant 
protocol deviations and factors likely to affect the comparability 
of PK results.
With adequate study intervention compliance
With evaluable PK data, ie, non-missing values for primary 
endpoints in each study period.
If participants received prohibited concomitant therapy or 
medicines, as specified in Section 6.5, they will be excluded 
from the PK population. Relevant decisions will be made before 
database lock.
All PK analyses will be based on this analysis set.
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9.4
Statistical Analyses
Details of the statistical analyses will be described in a separate IAP.
Continuous variables will be summarized using descriptive statistics, ie, number of participants 
with non-missing values (n), mean, median, standard deviation, 2-sided 95% CIs where 
appropriate, 25th and 75th percentiles, minimum, and maximum.
Qualitative variables and rates will be summarized by counts and percentages along with 2-sided 
exact Clopper-Pearson 95% CIs. Unless otherwise stated, the calculation of proportions will be 
based on the sample size of the analysis set of interest. Counts of missing observations will be 
included in the denominator and presented as a separate category.
In general, the last measurement prior to first administration of study intervention will serve as the 
baseline measurement.
In order to provide overall estimates of the treatment effects, data will be pooled across sites. The 
factor site will not be considered in statistical models or for subgroup analyses because of the high 
number of participating sites and the anticipated small number of participants enrolled at each site.
The independent review will be performed by an IRC which will conduct an independent review 
of the tumor assessment images of all participants using the same criteria based on a separate 
charter outlining details of the review process.
Non-compartmental computation as well as descriptive statistical analyses of PK parameters will 
be performed using the software Phoenix® WinNonlin® 6.3 or higher (Certara, L.P., Princeton, 
New Jersey) or equivalent software. All other statistical analyses will be performed using SAS® 
Version 9.2 or higher.
9.4.1
Efficacy Analyses
Primary and secondary efficacy endpoints will be analyzed by treatment arm for all participants in 
the FAS in accordance to the test (central or local TBx, or central LBx) used to define their MET 
amplification positivity. 
T+ denotes a positive central test based on tissue biopsy (FISH) and L+ denote a positive central 
test based on liquid biopsy. The combined T+/L+ set denotes a positive central test based either
on tissue or based on liquid or based on both tests.
All analyses will be done for T+, L+ as well as for the combined set T+/L+.
The following efficacy analysis sets are defined:

Primary analysis set:
o
T+ participants, treated with the recommended Phase II dose of tepotinib and 
osimertinib or tepotinib monotherapy.
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
Secondary analysis sets: 
o
L+ participants, treated with the recommended Phase II dose of tepotinib and 
osimertinib or tepotinib monotherapy.
o
Combined T+/L+ participants, treated with the recommended Phase II dose of 
tepotinib and osimertinib or tepotinib monotherapy.
The efficacy outcome of participants who are detected to be MET amplification positive by local 
TBx but are negative based on central TBx and LBx, will only be listed. 
Participants from the initial safety run-in who are treated with the recommended dose for the main 
treatment part will be included in the above analysis sets in accordance with the test with which 
they were defined to be MET amplification positive (central or local TBx, or LBx) and the 
treatment eligibility criteria of Version 2 of the Study Protocol (progression on first-line 
osimertinib).
Additionally, efficacy results for participants in the primary analysis set will be provided split by 
C797X status.
Intracranial response will be analyzed for potential participants with brain metastases as target 
lesions.
The following table specifies the definitions and analysis methods by endpoint, further details as 
well as further potential subgroup analyses will be specified in the IAP.
Endpoint
Definitions and Statistical Analysis Methods
Primary
Objective response 
(confirmed CR or PR) 
determined according to 
RECIST Version 1.1 as 
per IRC 
Participants are identified as having an objective response if they achieve either a 
confirmed CR or PR from first administration of study treatment to first observation of 
PD. Confirmation needs to take place by a tumor assessment at least 4 weeks (28 days) 
after the tumor assessments initially indicating CR or PR.
Objective response rate (confirmed CR or PR) and the corresponding 2-sided exact 
Clopper-Pearson 95% CI will be presented. Corresponding summaries of BOR will also 
be provided.
Secondary
Objective response 
(confirmed CR or PR) 
determined according to 
RECIST Version 1.1, as 
per Investigator
Participants are identified as having an objective response if they achieve either a 
confirmed CR or PR from first administration of study treatment to first observation of 
PD. Confirmation needs to take place by a tumor assessment at least 4 weeks (28 days) 
after the tumor assessments initially indicating CR or PR.
Objective response rate (confirmed CR or PR) and the corresponding 2-sided exact 
Clopper-Pearson 95% CI will be presented. Corresponding summaries of BOR will also 
be provided.
Confirmed CR by IRC 
and by Investigator 
Participants are identified as having a confirmed CR if they achieve a confirmed CR 
from first administration of study treatment to first observation of PD. Confirmation 
needs to take place by a tumor assessment at least 4 weeks (28 days) after the tumor 
assessments initially indicating CR.
Complete response rate (confirmed CR) and the corresponding 2-sided exact Clopper-
Pearson 95% CI will be presented.
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Endpoint
Definitions and Statistical Analysis Methods
Duration of response by 
IRC and by Investigator
For participants with objective response, duration of response is the time from when the 
CR/PR (whichever is first) criteria are first met until PD or death due to any cause within 
126 days of the last tumor assessment, whichever occurs first.
Duration of response data will be censored on the date of the last adequate tumor 
assessment for participants who do not have an event (PD or death) or for participants 
with an event after 126 days of the last tumor assessment. Participants who do not have 
a tumor assessment after objective response will be censored at the date CR/PR criteria 
are first met.
Duration of response will be summarized descriptively. Kaplan-Meier plots as well as 
the corresponding number of events, 1st and 3rd quartile (Q1 and Q3), median, minimum 
and maximum from the Kaplan-Meier product-limit estimates of the survival function 
and survival rates at 3, 6, 9, 12, 15, and 18 months together with corresponding 95% CI 
will be presented.
Disease control 
(confirmed CR + PR or 
SD lasting at least 
12 weeks) by IRC and by 
Investigator
Participants are identified as having objective disease control if they achieve either a 
confirmed CR or PR (confirmation needs to take place by a tumor assessment at least 
4 weeks [28 days] after the tumor assessments initially indicating CR or PR), or stable 
disease (SD) lasting at least 12 weeks (84 days).
Disease control rate and the corresponding 2-sided exact Clopper-Pearson 95% CI will 
be presented.
Progression free survival 
by IRC and by 
Investigator
Progression free survival (PFS) is defined as the time (in months) from first 
administration of study treatment to the date of the first documentation of PD or death 
due to any cause within 126 days of the last tumor assessment, whichever occurs first. 
PFS data will be censored on the date of the last evaluable tumor assessment for 
participants who do not have an event (PD or death) or for participants with an event 
more than 126 days after the last tumor assessment. Participants who do not have a 
baseline tumor assessment or who do not have any post baseline tumor assessments 
will be censored at the date of the start of study treatment.
PFS will be summarized descriptively. Kaplan-Meier plots as well as the corresponding 
number of events, first and third quartile (Q1 and Q3), median, minimum and maximum 
from the Kaplan-Meier product-limit estimates of the survival function and survival rates 
at 3, 6, 9, 12, 15, and 18 months together with corresponding 95% CI will be presented.
PFS will only be analyzed for participants treated with the tepotinib and osimertinib 
combination.
Overall survival 
Overall survival is defined as the time (in months) from first administration of study
treatment to the date of death. 
For participants not known to be deceased at time of analysis, OS time will be censored 
at the last date the participant was known to be alive before data cutoff.
Overall survival will be summarized descriptively. Kaplan-Meier plots as well as the 
corresponding number of events, first and third quartile (Q1 and Q3), median, minimum 
and maximum from the Kaplan-Meier product-limit estimates of the survival function 
and survival rates at 3, 6, 9, 12, 15, and 18 months together with corresponding 95% CI 
will be presented.
Overall survival will only be analyzed for participants treated with the tepotinib and 
osimertinib combination.
Patient Reported 
Outcomes 
Patient reported outcomes (EQ 5D 5L, EORTC QLQ-C30, NSCLC-SAQ) will be 
descriptively summarized in tabular and/or graphic format, as appropriate to the data.
Tertiary/Exploratory
Intracranial response 
(CR or PR) by IRC
Participants with brain metastases as target lesions are identified as having an 
intracranial response if they achieve either a confirmed CR or PR from first 
administration of study treatment to first observation of PD. Confirmation needs to take 
place by a tumor assessment at least 4 weeks (28 days) after the tumor assessments 
initially indicating CR or PR.
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Endpoint
Definitions and Statistical Analysis Methods
Intracranial response rate (confirmed CR or PR) and the corresponding 2-sided exact 
Clopper-Pearson 95% CI will be presented. The denominator for intracranial response 
rate will be the number of participants with brain metastases as target lesions.
9.4.2
Safety Analyses
All safety analyses will be performed on the SAF. All analyses will be presented by treatment arm 
and by dose level, if applicable, and participants will be analyzed as treated.
The safety analyses will also be done purely descriptively.
Endpoint
Statistical Analysis Methods
Primary (for the safety 
run-in)
Occurrence of DLTs
Refer to Section 4.1 for the definition of DLTs
The number and percentage of participants in the DLT analysis set during the DLT 
observation period will be tabulated.
Secondary
Occurrence of AEs and 
treatment-related AEs 
and deaths during the 
study
Adverse events will be coded according to the latest available version of the Medical 
Dictionary for Regulatory Activities. Severity of AEs will be graded using the 
NCI-CTCAE (v5.0) toxicity grades. AEs related to study intervention will be defined as 
any AE considered as related to tepotinib and/or osimertinib. Missing classifications 
concerning study intervention relationships will be considered related to the study 
intervention.
Any TEAEs will be summarized, ie, those events that are emergent during treatment 
having been absent prior to treatment or worsened relative to the pretreatment state 
and with onset dates occurring within the first dosing day of study intervention until 
30 days after the last dose of study intervention (or switch over to combination 
treatment, whichever occurs first for the tepotinib monotherapy arm). Adverse events 
occurring after switch over will be described separately, details will be specified in the 
IAP.
Following subtypes of TEAEs will be presented in summaries and tables according to 
System Organ Classes and Preferred Terms:

TEAEs 

SAEs 

TEAEs related to tepotinib and/or osimertinib

SAEs related to tepotinib and/or osimertinib

NCI-CTCAE Grade 3 or higher TEAEs

NCI-CTCAE Grade 3 or higher TEAEs related to tepotinib and/or osimertinib

TEAEs leading to tepotinib and/or osimertinib interruptions

TEAEs leading to permanent tepotinib and/or osimertinib discontinuation

TEAEs leading to deaths.

AESIs
Deaths during the study will also be presented in summaries and tables.
Adverse events of special interest are defined as events suggestive of drug-induced 
liver injury including hepatic/liver failure and hepatitis (non-infectious) and are 
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Endpoint
Statistical Analysis Methods
collected in an expedited manner in the Global Drug Safety database for close 
monitoring.
Laboratory variables
Descriptive summaries over time of actual (absolute) laboratory values and changes 
from baseline will be presented. Gradable laboratory results will be classified by grade 
according to NCI-CTCAE (v5.0); non-gradable parameters will be classified as normal, 
high or low. Shift tables will be presented where applicable.
Vital signs, body weight, 
ECOG
Increase/decrease in vital signs (body temperature, heart rate, blood pressure and 
respiratory rate), ECOG performance status and body weight will be categorized and 
summarized descriptively in shift tables from Baseline to minimum and maximum on-
treatment values.
ECG
Clinically significant, abnormal findings from 12-lead ECG during the treatment phase 
will be presented descriptively. Change from Baseline to worst on-treatment value will 
be summarized descriptively for the QTcF interval in accordance to ICH E14 criteria.
In the safety run-in, a BOIN design will support dose decisions starting with a tepotinib dose of 
500 mg with the option to decrease to 250 mg as well as the option for re-escalation, with a target 
toxicity rate of 30% and a maximum number of 12 participants.
Participants who terminated study intervention will be summarized by primary reason for 
intervention discontinuation.
All deaths, deaths within 30 days after the last dose of study intervention, deaths within 60 days 
after the first dose of study intervention, split by primary reasons for death, will be tabulated.
Clinically significant, abnormal findings from the physical examination are to be reported as AEs. 
Separate summaries of the physical examination during and after study intervention will not be 
provided.
9.4.3
Other Analyses
PK and biomarker exploratory analyses will be specified in the IAP finalized before database lock. 
Integrated analyses across studies, such as the population PK analysis and pharmacodynamic 
analyses will be presented separately from the main CSR.
9.4.4
Sequence of Analyses
During the course of the study, the following steps are implemented:
Two SMC meetings to assess safety and PK during safety run-in.
Regular interim analyses for the IDMC to assess safety and efficacy of the participants after the 
safety-run in. Details will be specified in the IAP and the IDMC charter.
These analyses are planned to be performed 90 days after 12 T+ participants have received the 
first dose of combination treatment, 90 days after 24 T+ participants in the combination 
treatment group and 12 T+ participants in the monotherapy have received the first dose of study 
intervention (ie, enrolment into monotherapy is completed), then 90 days after 48 T+ 
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participants and 90 days after 72 T+ participants have received first combination dose as well 
as 90 days after complete enrollment of T+ participants.
Primary analysis, conducted once all participants in the primary analysis set have either been 
treated with the recommended Phase II dose of tepotinib in combination with osimertinib for at 
least 9 months, died, or have prematurely discontinued study intervention for any reason, 
whichever comes first.
Final analysis, done at the time point at which all participants have discontinued study 
intervention and two thirds of the participants have died, or after 3 years after the last 
participant’s first dose, whichever occurs first.
In addition to the analyses described above, further interim analyses at time points that are not 
specified in the protocol may be performed.
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10
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Leonetti A, Sharma S, Minari R, et al. Resistance mechanisms to osimertinib in EGFR-mutated 
non-small cell lung cancer. Br J Cancer. 2019; 121: 725-37.
Mezquita L, Varga A, Planchard D. Safety of osimertinib in EGFR-mutated non-small cell lung 
cancer. Expert Opin Drug Saf. 2018;17:1239-48.
Mok TS, Wu Y-L, Ahn M-J, et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive 
Lung Cancer. N Engl J Med. 2017;376:629-40.
National Comprehensive Cancer Network. NSCLC (Version 3.2019). https: // www.nccn.
org/professionals/physician_gls/pdf/nscl.pdf. Accessed February 20, 2019.
Ou SI, Agarwal N, Ali SM. High MET amplification level as a resistance mechanism to 
osimertinib (AZD9291) in a patient that symptomatically responded to crizotinib treatment post-
osimertinib progression. Lung Cancer. 2016;98:59-61.
Papadimitrakopoulou VA, Wu YL, Han JY, et al. Analysis of resistance mechanisms to 
osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study. Ann Oncol. 
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Planchard D, Brown KH, Kim DW, et al. Osimertinib Western and Asian clinical 
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Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall Survival with Osimertinib in 
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Sequist LV, Han JY, Ahn MJ, et al. Osimertinib plus savolitinib in patients with EGFR mutation-
positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase 
inhibitors: interim results from a multicentre, open-label, phase 1b study. The Lancet Oncology. 
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Shi P, Oh YT, Zhang G, et al. Met gene amplification and protein hyperactivation is a mechanism 
of resistance to both first and third generation EGFR inhibitors in lung cancer treatment.Cancer 
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Soria JC, Wu YL, Nakagawa K, et al. Gefitinib plus chemotherapy versus placebo plus 
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Small-Cell Lung Cancer. N Engl J Med. 2018;378:113-25.
Soo RA, Lim SM, Syn NL, et al. Immune checkpoint inhibitors in epidermal growth factor receptor 
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11
Appendices
Appendix 1
Abbreviations 
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area Under the Concentration-time Curve
BCRP
Breast Cancer Resistance Protein
BOIN
Bayesian Optimal Interval Design
BOR
Best Overall Response
CI
Confidence Interval
CR
Complete Response
CrCl
Creatinine Clearance
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE v5.0
Common Terminology Criteria for Adverse Events Version 5.0
ctDNA
Circulating tumor Deoxyribonucleic Acid
CYP3A4
Cytochrome P450 3A4
DLT
Dose-limiting Toxicity
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EGFR
Epidermal Growth Factor Receptor
EGFRm+
Epidermal Growth Factor Receptor Mutation Positive
EoT
End of Treatment
EQ-5D-5L
EuroQol Five Dimension Five Level Scale
FAS
Full Analysis Set
FIH
First-in-Human
GCP
Good Clinical Practice
HGF
Hepatocyte Growth Factor
IAP
Integrated Analysis Plan
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
ILD
Interstitial Lung Disease
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IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRC
Independent Review Committee
IVRS
Interactive Voice Response System
LBx
Liquid Biopsy
MET
Mesenchymal-epithelial Transition Factor 
MRI
Magnetic Resonance Imaging
NCI
National Cancer Institute 
NSCLC
Non-small Cell Lung Cancer
NSCLC-SAQ
Non-small Cell Lung Cancer Symptom Assessment Questionnaire
ORR
Objective Response Rate
PD
Progressive Disease
PFS
Progression-free Survival
P-gp
P-glycoprotein
PK
Pharmacokinetics
PR
Partial Response
PRO
Patient Reported Outcomes
Q1
1st Quartile
Q3
3rd Quartile
QLQ-C30
EORTC Core Quality of Life Questionnaire
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Phase II Dose
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SD
Stable Disease
SMC
Safety Monitoring Committee
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE
Treatment-emergent Adverse Event
TKI
Tyrosine Kinase Inhibitor
ULN
Upper Limit of Normal
US
United States
WOCBP
Woman/Women of Childbearing Potential
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Appendix 2
Study Governance
Financial Disclosure
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information, as requested, for the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. This information 
is required during the study and for 1 year after completion of the study.
Informed Consent Process
To enroll in this study, participants will first need to sign a Prescreening informed consent 
form (ICF). Once signed, Mesenchymal-epithelial Transition Factor (MET) amplification 
status will be assessed by liquid biopsy. Participants with positive MET amplification and 
who had progressed on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor
(TKI) treatment should continue with the EGFR TKI beyond progression, until they either 
receive the experimental treatment as defined in this study or in the case of ineligibility, a 
follow-up treatment as discussed with their physician. In case of eligibility, participants 
should sign a second ICF at Screening.
The Investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions on the study.
Participants must be informed that their participation is voluntary.
Participants will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50; the Japanese ministerial ordinance on Good Clinical Practice 
(GCP); local regulations; ICH guidelines; Health Insurance Portability and Accountability 
Act (HIPAA) requirements, where applicable; and the IRB/IEC or study center.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF.
If the ICF is updated during their participation in the study, participants must be re-consented 
to the most current, approved version.
A copy of the ICF(s) must be provided to the participant.
The original signed and dated consent will remain at the Investigator’s site and must be 
safely archived so that it can be retrieved at any time for monitoring, auditing, and inspection 
purposes.
Participants who are rescreened are required to sign a new ICF. 
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Data Protection
The Sponsor will assign a unique identifier to participants after obtaining their informed 
consent. All participant records or datasets transferred to the Sponsor will contain the 
identifier only; participant names or any identifiable information will not be transferred.
The Sponsor must inform participants that their personal study-related data will be used per 
local data protection and privacy laws. The level of disclosure must also be explained to the 
participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other Sponsor-appointed, authorized personnel, by 
appropriate IRB/IEC members, and by regulatory authority inspectors. All such persons will 
strictly maintain participants’ confidentiality.
Study Administrative
Approximately 100-120 study sites in Europe, Asia, and North America are planned to participate 
in this study.
The Coordinating Investigator listed on the title page represents all Investigators for decisions and 
discussions on this study, per ICH GCP. The Coordinating Investigator will provide expert medical 
input and advice on the study design and execution and is responsible for the review and signoff 
of the clinical study report.
The study will appear in the following clinical studies registries: 
ClinicalTrials.gov: to be confirmed
EudraCT: to be confirmed
Details of structures and associated procedures will be defined in a separate Operations Manual.
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and the following:
Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines
Applicable ICH GCP Guidelines
The Japanese ministerial ordinance on GCP 
Applicable laws and regulations
The Investigator must submit the protocol, protocol amendments (if applicable), ICF, 
Investigator Brochure, and other relevant documents (eg, advertisements) to an IRB/IEC and 
the IRB/IEC must review and approve them before the study is initiated.
The Sponsor initiates the study at a site after obtaining written approval from the Head of 
the study site, based on favorable opinion/approval from the concerned IRB.
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Any protocol amendments (ie, changes to the protocol) will be documented in writing and 
require IRB/IEC approval before implementation of changes, except for changes necessary 
to eliminate an immediate hazard to study participants. When applicable, amendments will 
be submitted to the appropriate Health Authorities.
The Investigator will be responsible for the following:
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently per the IRB’s/IEC’s requirements, policies, and procedures.
Notifying the IRB/IEC of SAEs or other significant safety findings, as required by 
IRB/IEC procedures
Providing oversight of the study conduct at the site and adherence to requirements of 21 
CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations
The protocol and any applicable documentation will be submitted or notified to the Health 
Authorities in accordance with all local and national regulations for each site.
Emergency Medical Support
The Sponsor or designee will provide Emergency Medical Support cards to participants for 
use during the study. These provide the means for participants to identify themselves as 
participating in a clinical study. Also, these give health care providers access to any 
information about this participation that may be needed to determine the course of medical 
treatment for the participant. The information on the Emergency Medical Support card may 
include the process for emergency unblinding (if applicable).
The first point of contact for all emergencies will be the clinical study Investigator caring 
for the participant. Consequently, the Investigator agrees to provide his or her emergency 
contact information on the card. If the Investigator is available when an event occurs, they 
will answer any questions. Any subsequent action (eg, unblinding) will follow the standard 
process established for Investigators.
When the Investigator is not available, the Sponsor provides the appropriate means to contact a 
Sponsor physician. This includes provision of a 24-hour contact number at a call center, whereby 
the health care providers will be given access to the appropriate Sponsor physician to assist with 
the medical emergency and to provide support for the potential unblinding of the participant 
concerned.
Clinical Study Insurance and Compensation to Participants
The Sponsor is entirely responsible for AEs that are associated with this study and cause damage 
to the health of the participants, except for AEs caused by an intentional and/or significant 
deviation on the part of the Investigator, the study site, and/or the participant. The Sponsor takes 
out insurance to fulfill the responsibility.
Insurance coverage will be provided for each country participating in the study. Insurance 
conditions shall meet good local standards, as applicable.
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Clinical Study Report
After study completion, the Sponsor will write a CSR in consultation with the Coordinating 
Investigator and any Steering Committee or other relevant study-appointed committees or groups.
Publication
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows Merck to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. Per standard 
editorial and ethical practice, the Sponsor will generally support publication of multicenter 
studies only in their entirety and not as individual site data. In this case, a coordinating 
Investigator will be designated by agreement.
Authorship will be determined by agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data
Any publications and presentations of the results either in whole or in part, by Investigators or 
their representatives will require review by the Sponsor before submission. The Sponsor will not 
suppress publication but maintains the right to delay publication to protect intellectual property 
rights.
Posting of data on ClinicalTrials.gov and EudraCT is planned and will occur 12 months after the 
last visit, or scheduled procedure, or another appropriate date to meet applicable requirements.
Data Quality Assurance
All participant study data will be recorded on printed or electronic CRFs or transmitted to 
the Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible 
for verifying that data entries are complete, accurate, legible, and timely by physically or 
electronically signing the CRF. Details for managing CRFs are in the Operations Manual.
For PRO data (eg, QoL and pain assessments), ePRO will be used.
The Investigator must maintain accurate documentation (source data) that supports the 
information in the CRF.
The Investigator must permit study-related monitoring, quality assurance audits, IRB/IEC 
review, and regulatory agency inspections and provide direct access to the study file and 
source data.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are in the Monitoring Plan.
The Sponsor or designee is responsible for data management of this study, including quality 
checking of the data and maintaining a validated database. Database lock will occur once 
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quality control and quality assurance procedures have been completed. PDF files of the 
CRFs will be provided to the Investigators at study completion.
Study monitors will perform ongoing source data verification to confirm that data in the CRF 
are accurate, complete, and verifiable; that the safety and rights of participants are being 
protected; and that the study is being conducted per the currently approved protocol and any 
other study agreements, ICH GCP, the Japanese ministerial ordinance on GCP, and all 
applicable regulatory requirements.
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion, unless local regulations, 
institutional policies, or the Sponsor requires a longer retention. No records may be 
destroyed during the retention period without the Sponsor’s written approval. No records 
may be transferred to another location or party without the Sponsor’s written notification.
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.
The Investigator must keep a paper or electronic file (medical file and original medical 
records) at the site for each study participant. The file must identify each participant, contain 
the following demographic and medical information for the participant, and should be as 
complete as possible:
Participant’s full name, date of birth, sex, height, and weight
Medical history and concomitant diseases
Prior and concomitant therapies (including changes during the study)
Study identifier (ie, the Sponsor’s study number) and participant’s study number.
Dates of entry into the study (ie, signature date on the informed consent) and each visit to 
the site
Any medical examinations and clinical findings predefined in the protocol
All AEs
Date that the participant left the study, including any reason for early withdrawal from 
the study or study intervention, if applicable.
All source data must be filed (eg, CT or MRI scan images, ECG recordings, and laboratory 
results). Each document must have the participant number and the procedure date; ideally, 
printed by the instrument used for the procedure. As necessary, medical evaluation of these 
records should be performed, documented, signed, and dated by the Investigator. 
Data recorded on printed or electronic CRFs that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
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The study monitors will use printouts of electronic files for source data verification. These 
printouts must be signed and dated by the Investigator and kept in the study file.
Source documents are stored at the site for the longest possible time permitted by the 
applicable regulations, and/or as per ICH GCP guidelines, whichever is longer. The 
Investigator (in Japan, a record retainer designated by the Head of the study site) ensures
that no destruction of medical records is performed without the Sponsor’s written approval.
Definition of what constitutes source data is found in the Monitoring Plan.
Study and Site Start and Closure
First Act of Recruitment
The study start date is the date when the clinical study will be open for recruitment
The first act of recruitment is when the first site is opened and will be the study start date.
Study Closure and Site Termination
The Sponsor reserves the right to close the study site or terminate the study at any time and 
for any reason. 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 site closure 
visit has been completed.
The Investigator may initiate 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:
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines
Inadequate recruitment of participants by the Investigator
Discontinuation of further development of the Sponsor’s compound
If the study is prematurely terminated or suspended, the Sponsor will promptly inform 
the Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The Investigator will promptly inform the 
participants and assure appropriate participant therapy and/or follow-up.
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Appendix 3
Contraception
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile, as specified below.
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before the first dose of study intervention, consider additional evaluation.
A WOCBP is not:
1. Premenarchal
2. A premenopausal female with 1 of the following:
Documented hysterectomy
Documented bilateral salpingectomy
Documented bilateral oophorectomy
Documentation can come from the site personnel’s review of the female’s medical records, 
medical examination, or medical history interview.
For a female with permanent infertility due to an alternate medical cause other than the above, 
(eg, Mullerian agenesis, androgen insensitivity), Investigator discretion applies to determine 
study entry.
3. A postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.

A high follicle-stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in a female not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, more than 1 FSH measurement is required in the 
postmenopausal range.

A female on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if she wishes to 
continue her HRT during the study. Otherwise, she must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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Contraception Guidance:
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methods That Have Low User Dependency

Implantable progestogen-only hormone contraception associated with inhibition of ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomized partner: a highly effective contraceptive method provided that the partner is the sole sexual 
partner of a WOCBP, and the absence of sperm has been confirmed. Otherwise, use an additional highly 
effective method of contraception. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation

Oral

Intravaginal

Transdermal

Injectable

Progestogen-only hormone contraception associated with inhibition of ovulation

Oral

Injectable

Sexual abstinence: a highly effective method only if defined as refraining from intercourse during the entire 
period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study.
Notes:
Contraceptive use by men or women is consistent with local regulations on the use of contraceptive methods for 
clinical study participants.
Highly effective methods are those with a failure rate of <1% per year when used consistently and correctly. 
Typical use failure rates differ from those when used consistently and correctly.
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive 
methods are limited to those which inhibit ovulation as the primary mode of action.
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom cannot be used together (due to risk of failure with friction).
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Appendix 4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definitions
Adverse Event
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, 
regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, regardless if it is considered related to the medicinal 
product.
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigator is required to grade the severity or toxicity of each AE.
Investigators will reference the National Cancer Institute - Common Terminology Criteria for AEs 
(CTCAE), version 5.0 (publication date: 27 November 2017), a descriptive terminology that can 
be used for AE reporting.
A general grading (severity/intensity; hereafter referred to as severity) scale is provided at the 
beginning of the above referenced document, and specific event grades are also provided.
If the severity for an AE is not specifically graded by NCI-CTCAE, the Investigator is to use the 
general NCI-CTCAE definitions of Grade 1 through Grade 5, using his or her best medical 
judgment.
The 5 general grades are:
Grade 1 or Mild
Grade 2 or Moderate
Grade 3 or Severe 
Grade 4 or Life-threatening 
Grade 5 or Death 
Any clinical AE with severity of Grade 4 or 5 must also be reported as an SAE. However, a 
laboratory abnormality of Grade 4, such as anemia or neutropenia, is considered serious only if the 
condition meets one of the serious criteria specified below.
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the outcome of this specific event and death will 
not be recorded as separate event. Only, if no cause of death can be reported (eg, sudden death, 
unexplained death), the death per se might then be reported as an SAE.
Investigators must also systematically assess the causal relationship of AEs to study intervention 
(including any other non-study interventions, radiation therapy, etc.) using the following 
definitions. Decisive factors for the assessment of causal relationship of an AE to the study 
intervention include, but may not be limited to, temporal relationship between the AE and the study 
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intervention, known side effects of study intervention, medical history, concomitant medication, 
course of the underlying disease, and study procedures.
Unrelated:
Not reasonably related to the study intervention. AE could not medically 
(pharmacologically/clinically) be attributed to the study intervention under study 
in this clinical study protocol. A reasonable alternative explanation must be 
available.
Related:
Reasonably related to the study intervention. AE could medically 
(pharmacologically/clinically) be attributed to the study intervention under study 
in this clinical study protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (eg, on an ECG trace) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead to 
study intervention discontinuation or are considered otherwise medically important by the 
Investigator. If a laboratory abnormality fulfills these criteria, the identified medical condition (eg,
anemia or increased ALT) must be reported as the AE rather than the abnormal value itself.
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:
Results in death
Is life-threatening. Life-threatening refers to an event in which the participant is at risk of 
death at the time of the event, not an event that hypothetically might have caused death if it 
was more severe.
Requires inpatient hospitalization or prolongs an existing hospitalization
Results in persistent or significant disability or incapacity
Is a congenital anomaly or birth defect
Is otherwise considered to be medically important. Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be considered as SAEs 
when, based upon appropriate medical judgment, they may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias, or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.
For the purposes of reporting, any suspected transmission of an infectious agent via a study 
intervention is also considered an SAE, as specified below for reporting SAEs, AESIs, and DLTs.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify study intervention or procedures (eg, an 
overnight stay to facilitate intravenous therapy) are not considered SAEs. However, all events 
leading to unplanned hospitalizations or unplanned prolongation of an elective hospitalization (ie,
undesirable effects of any administered treatment) must be documented and reported as SAEs.
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Events Not to Be Considered as AEs/SAEs
Medical conditions present at the initial study visit that do not worsen in severity or frequency 
during the study are defined as Baseline Medical Conditions and are not to be considered AEs.
AE/SAEs Observed in Association with Disease Progression
Progression of the disease/disorder being studied assessed by measurement of lesions on 
radiographs or other methods as well as associated clinical signs or symptoms (including 
laboratory abnormalities) should not be reported as an (S)AE, unless the participant’s general 
condition is more severe than expected for the participant’s condition and/or unless the outcome 
is fatal within the adverse event reporting period, as defined in Section 8.3.2 (Method of Detecting 
Adverse Events and Serious Adverse Events)
Adverse Events of Special Interest

Adverse events suggestive of drug-induced liver injury including
o
Hepatic/liver failure
o
Hepatitis (non-infectious).
Other Adverse Events to be Reported Following a Specialized Procedure 
Any overdose is recorded in the eCRF and reported to drug safety in an expedited manner. 
Overdoses are reported on a SAE Report Form.
The Investigator must notify the Sponsor/designee in an expedited manner of any pregnancy 
using the Pregnancy Report Form, which must be transmitted by the same process specified 
for SAE.
Each event meeting the criteria of a DLT must be recorded in the CRF within 24 HOURS 
after becoming aware of the event. Serious DLTs must be reported in an expedited manner 
as SAEs.
Recording and Follow-Up of AE and/or SAE
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates and also onset and resolution times, when it is important to assess the time of AE 
onset relative to the recorded study intervention administration time), its severity, its causal 
relationship with the study intervention, any other potential causal factors, any treatment given or 
other action taken, including dose modification or discontinuation of the study intervention, and 
its outcome. In addition, serious cases should be identified, and the appropriate seriousness criteria 
documented. If an AE constitutes a DLT this is documented accordingly.
Specific guidance is in the CRF Completion and Monitoring Conventions provided by the Sponsor.
Reporting Serious Adverse Events, Adverse Events of Special Interest and Dose Limiting 
Toxicities
Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 HOURS after becoming aware of the event) inform the 
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Sponsor or its designee using the electronic SAE report form in the Electronic Data Capture (EDC) 
system.
Reporting of SAEs using a paper report form is required as a back-up method only for an EDC 
system failure. Names, addresses, and telephone and fax numbers will be included on the paper 
form. All information from the paper form must be transcribed into the electronic form as soon as 
the system becomes available.
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, an electronic SAE report form must be completed immediately thereafter.
Relevant pages from the CRF may be provided in parallel (eg, medical history, concomitant drugs). 
Additional documents may be provided by the Investigator, if available (eg, laboratory results, 
hospital report, autopsy report). 
The Investigator must respond to any request for follow-up information (eg, additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for initial 
reports. This is necessary to ensure prompt assessment of the event by the Sponsor or designee and 
(as applicable) to allow the Sponsor to meet strict regulatory timelines associated with expedited 
safety reporting obligations.
Requests for follow-up will usually be made via the study monitor, although in exceptional 
circumstances the drug safety department may contact the Investigator directly to obtain further 
information or to discuss the event.
Adverse Events of Special Interest
In the event of a nonserious AESI, the Investigator will notify the Sponsor/designee by completing 
the electronic AESI Report Form in the EDC system within 24 HOURS after becoming aware of 
the event. Serious AESIs must be reported in an expedited manner as SAEs, as outlined above.
Reporting of non-serious AESIs using a paper report form is required as a back-up method only 
for an EDC system failure. Names, addresses, and telephone and fax numbers will be included on 
the paper report form. All information from the paper form must be transcribed into the electronic 
form as soon as the system becomes available.
Dose-Limiting Toxicities
Each event meeting the criteria of a DLT, as specified in Section 4.1, must be recorded in the CRF 
within 24 HOURS after becoming aware of the event. Serious DLTs must be reported in an 
expedited manner as SAEs, as outlined above.
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Appendix 5
Clinical Laboratory Tests
Table 5
Protocol-Required Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelets
Mean Corpuscular 
Volume
WBC Count with 
Differential:

Neutrophils

Lymphocytes

Monocytes

Eosinophils

Basophils
Reticulocytes
Hemoglobin
MCH
Hematocrit
Biochemistry
Blood Urea 
Nitrogen
Potassium
Aspartate 
Aminotransferase
Bilirubin
Creatinine
Sodium
Alanine Aminotransferase
Total Protein
Glucose
Calcium (Total 
Calcium and 
Calculated [or 
Adjusted] and/or 
Ionized [or free] 
Calcium)
Alkaline phosphatase
Serum Cystatin (for 
sites where the test is 
available)
Total Amylase
Lipase
Gamma-glutamyl 
transpeptidase
Albumin
Coagulation
aPTT (sec or 
ratio)
PT (sec or ratio)
INR (%)
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1 (Discontinuation of Study Intervention).
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by 
dipstick

Microscopic examination (if blood or protein is abnormal). 
Other Screening 
Tests

FSH (if not a WOCBP only)

Serum human chorionic gonadotropin (hCG) pregnancy test (as needed for a WOCBP).
All study-required laboratory assessments will be performed by a local laboratory. It is required 
that these local laboratories are certified, perform and document interlaboratory testing at 
regular time intervals and provide a list of normal range laboratory values including units as 
defined by international system of units. For sites in China, laboratory assessments (e.g., 
lipase) can be performed in local or central laboratories, based on the availability in the local 
laboratories.
MCH: mean corpuscular hemoglobin; WCB: white blood cells; aPTT: Activated partial thromboplastin time; PT: 
Prothrombin time; INR: Prothrombin Intl. Normalized Ratio; WOCBP: woman of childbearing potential.
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Appendix 6
Pharmacogenetics
Use/Analysis of DNA
Genetic variation may impact a participant’s response to therapy, susceptibility to, and 
severity and progression of disease. Variable response to therapy may be due to genetic 
determinants that impact study intervention absorption, distribution, metabolism, and 
excretion; mechanism of action of the study intervention; disease etiology; and/or molecular 
subtype of the disease being treated.
DNA samples will be analyzed for a better understanding of the mode of action of tepotinib 
and potential resistance occurring under tepotinib treatment. Additional analyses may be 
conducted if it is hypothesized that this may help further understand the clinical data.
In addition, DNA samples will be used for research related to resistance occurring under 
osimertinib treatment, a better understanding of MET inhibition in EGFR resistant NSCLC. 
They may also be used to develop tests or assays, including diagnostic tests related to 
tepotinib or osimertinib treatment, mechanism of action of tepotinib, EGFR resistant 
NSCLC and other conditions in the context of NSCLC. Pharmacogenetic research may 
consist of the analysis of one or more candidate genes or the analysis of genetic markers 
throughout the genome (as appropriate).
The results of pharmacogenetic analyses may be reported in the CSR or in a separate study 
summary.
Details on blood volume collected, processes for collection and shipment of these samples 
can be found in the Laboratory Manual. The Sponsor will store the DNA samples in a secure 
storage space with adequate measures to protect confidentiality.
Retention time and possible analysis of DNA sample after the study ends are specified in the 
respective ICF.
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Appendix 7
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1
The text below was obtained from the following reference: Eisenhauer et al. New response 
evaluation criteria in solid tumors: revised RECIST guideline (Version 1.1). Eur J Cancer.2009;
45:228-47.
Definitions
Response and progression will be evaluated in this study using the international criteria proposed 
by the RECIST Committee (Version 1.1). Changes in only the largest diameter (unidimensional 
measurement) of the tumor lesions are used in the RECIST criteria. Note: Lesions are either 
measurable or non-measurable using the criteria provided below. The term “evaluable” in 
reference to measurability will not be used because it does not provide additional meaning or 
accuracy.
Measurable Disease
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the plane 
of measurement is to be recorded) with a minimum size of: 
10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice 
thickness and a minimum of 10 mm)
10 mm caliper measurement by clinical exam (when superficial)
20 mm by chest X-ray (if clearly defined and surrounded by aerated lung).
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At Baseline and in Follow-up, only the short axis will be measured 
and followed.
Non-measurable Disease
All other lesions (or sites of disease), including small lesions (longest diameter ≥10 to < 15 mm 
with conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable 
disease. Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques are 
all non-measurable.
Bone lesions:
Bone scan, PET scan, or plain films are not considered adequate imaging techniques to measure 
bone lesions. However, these techniques can be used to confirm the presence or disappearance 
of bone lesions.
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Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.
Blastic bone lesions are non-measurable.
Cystic lesions:
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts.
Cystic lesions thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same participant, these are preferred for selection as target lesions.
Lesions with prior local treatment:
Tumor lesions situated in a previously irradiated area, or in an area subjected to other local 
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Study protocols should detail the conditions under which such lesions 
would be considered measurable.
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at Baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as 2 dimensions in the plane in which the image is 
obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition may 
be axial, sagittal, or coronal). The smaller of these measures is the short axis. For example, an 
abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm and qualifies 
as a malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) should 
be considered non-target lesions. Nodes that have a short axis < 10 mm are considered non-
pathological and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
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sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
Non-target Lesions
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at Baseline. Measurements are not required, and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’). 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
Baseline evaluations should be performed as close as possible to the treatment start and never more 
than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at Baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical examination.
No photographs, no skin lesion measurement by calipers and no measurements on chest X-ray will 
be done in this study.
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5 mm or less. As is described in Appendix II of the 
original source article cited above, when CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable 
in certain situations (eg, for body scans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from 1 assessment to the next. 
If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI 
is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in 
selected instances.
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies 
are obtained or to determine relapse in studies where recurrence following complete response or 
surgical resection is an endpoint.
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Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit; however, they must normalize for a participant
to be considered in complete response. Because tumor markers are disease specific, instructions 
for their measurement should be incorporated into protocols on a disease specific basis. Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and prostate-specific antigen 
response (in recurrent prostate cancer), have been published. In addition, the Gynecologic Cancer 
Intergroup has developed CA-125 progression criteria which are to be integrated with objective 
tumor assessment for use in first-line studies in ovarian cancer.
Cytology, histology: These techniques can be used to differentiate between partial response and 
complete response (CR) in rare cases if required by protocol (eg, residual lesions in tumor types 
such as germ cell tumors, where known residual benign tumors can remain). When effusions are 
known to be a potential adverse event (AE) of treatment (eg, with certain taxane compounds or 
angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment can be considered if the measurable tumor has met criteria 
for response or stable disease (SD) in order to differentiate between response (or SD) and 
progressive disease (PD).
RESPONSE CRITERIA
Evaluation of Target Lesions
CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-
target) must have reduction in short axis to < 10 mm.
Partial response: At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 
mm. (Note: the appearance of 1 or more new lesions is also considered progression). 
SD: Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the Baseline examination), even 
if the nodes regress to below 10 mm on study. This means that when lymph nodes are included as 
target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria are met, 
since a normal lymph node is defined as having a short axis of < 10 mm. Case report forms (CRFs) 
or other data collection methods may therefore be designed to have target nodal lesions recorded 
in a separate section where, in order to qualify for CR, each node must achieve a short axis 
< 10 mm. For partial response, SD, and PD, the actual short axis measurement of the nodes is to 
be included in the sum of target lesions.
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Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and 
non-nodal) recorded at Baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm). However, sometimes lesions or lymph 
nodes which are recorded as target lesions at Baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
‘too small to measure’. When this occurs, it is important that a value be recorded on the eCRF. If 
it is the opinion of the radiologist that the lesion has likely disappeared, the measurement should 
be recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned. (Note: It is less likely that this rule will be 
used for lymph nodes since they usually have a definable size when normal and are frequently 
surrounded by fat, such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be assigned in 
this circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness). The measurement of these lesions is 
potentially non-reproducible; therefore, providing this default value will prevent false responses 
or progressions based upon measurement error. To reiterate, however, if the radiologist is able to 
provide an actual measure, that should be recorded, even if it is below 5 mm.
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such 
that they are no longer separable, the vector of the longest diameter in this instance should be the 
maximal longest diameter for the ‘coalesced lesion’.
Evaluation of Non-target Lesions
While some non-target lesions may actually be measurable, they need not be measured and instead 
should be assessed only qualitatively at the time points specified in the protocol. 
CR: Disappearance of all non-target lesions and normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
PD: Unequivocal progression (see comments below) of existing non-target lesions. (Note: the 
appearance of 1 or more new lesions is also considered progression). 
When the participant also has measurable disease. In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in the presence of SD or partial response in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A 
modest ‘increase’ in the size of 1 or more non-target lesions is usually not sufficient to quality for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or partial response of target disease will therefore 
be extremely rare.
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When the participant has only non-measurable disease. This circumstance arises in some Phase 
III studies when it is not a criterion of study entry to have measurable disease. The same general 
concept applies here as noted above; however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions 
are truly non-measurable), a useful test that can be applied when assessing participants for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as ‘sufficient 
to require a change in therapy’. If ‘unequivocal progression’ is seen, the participant should be 
considered to have had overall PD at that point. While it would be ideal to have objective criteria
to apply to non-measurable disease, the very nature of that disease makes it impossible to do so; 
therefore, the increase must be substantial.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality, or findings thought 
to represent something other than tumor (eg, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). This is particularly important when the participant’s Baseline lesions 
show partial or complete response. For example, necrosis of a liver lesion may be reported on a 
CT scan report as a ‘new’ cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at Baseline 
is considered a new lesion and will indicate PD. An example of this is the participant who has 
visceral disease at Baseline and while on study has a brain CT or MRI ordered which reveals 
metastases. The participant’s brain metastases are considered to be evidence of PD even if he/she 
did not have brain imaging at Baseline.
If a new lesion is equivocal, eg, because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely 
a new lesion, then progression should be declared using the date of the initial scan.
While fludeoxyglucose positron emission tomography (FDG-PET) response assessments need 
additional studies, it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible ‘new’ disease). New 
lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:
a.
Negative FDG-PET at Baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
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b. No FDG-PET at Baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
Evaluation of Best Overall Response
The best overall response (BOR) is the best response recorded from the start of the study 
intervention until the end of treatment taking into account any requirement for confirmation. On 
occasion, a response may not be documented until after the end of therapy, so protocols should be 
clear if post treatment assessments are to be considered in determination of BOR. Protocols must 
specify how any new therapy introduced before progression will affect best response designation. 
The participant’s BOR assignment will depend on the findings of both target and non-target disease 
and will also take into consideration the appearance of new lesions. Furthermore, depending on 
the nature of the study and the protocol requirements, it may also require confirmatory 
measurement. Specifically, in non-randomized studies where response is the primary endpoint, 
confirmation of partial response or CR is needed to deem either 1 the ‘BOR’. 
The BOR is determined once all the data for the participant is known. Best response determination 
in studies where confirmation of complete or partial response IS NOT required: Best response in 
these studies is defined as the best response across all time points (for example, a participant who 
has SD at first assessment, partial response at second assessment, and PD on last assessment has a 
BOR of partial response). When SD is believed to be best response, it must also meet the 
protocol-specified minimum time from baseline. If the minimum time is not met when SD is 
otherwise the best time point response, the participant’s best response depends on the subsequent 
assessments. For example, a participant who has SD at first assessment, PD at second and does not 
meet minimum duration for SD, will have a best response of PD. The same participant lost to 
follow-up after the first SD assessment would be considered inevaluable.
Target Lesions
Non-target Lesions
New Lesions
Overall Response
CR*
CR
No
CR
CR
CR
Non-CR/non-PD
Not Evaluated
No
No
Partial response
Partial response
Partial response
Non-PD or not all evaluated
No
Partial response
SD
Not all evaluated
Non-PD or not all evaluated
Non-PD
No
No
SD
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR: complete response; NE: not evaluable; SD: stable disease; PD: progressive disease.
See text for more details.
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Note:
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that participants with CR may 
not have a total sum of ‘zero’ on the eCRF. 
In studies where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the study must address how missing 
data/assessments will be addressed in determination of response and progression. For example, in 
most studies, it is reasonable to consider a participant with time point responses of partial 
response-NE-partial response as a confirmed response.
Participants with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of PD at that time should be reported as ‘symptomatic deterioration’. 
Every effort should be made to document objective progression even after discontinuation of 
treatment. Symptomatic deterioration is not a descriptor of an objective response; it is a reason for 
stopping study therapy. 
Conditions that define ‘early progression, early death, and inevaluability’ are study-specific and 
should be clearly described in each protocol (depending on treatment duration, and treatment 
periodicity).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When 
the evaluation of CR depends upon this determination, it is recommended that the residual lesion 
be investigated (fine needle aspirate/biopsy) before assigning a status of CR. The use of FDG-PET 
may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual 
radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and supported by disease specific 
medical literature for the indication. However, it must be acknowledged that both approaches may 
lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the 
next scheduled assessment, progression is confirmed, the date of progression should be the earlier 
date when progression was suspected.
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE
Confirmation
In non-randomized studies where response is the primary endpoint, confirmation of partial 
response and CR is required to ensure the responses identified are not the result of measurement 
error. This will also permit appropriate interpretation of results in the context of historical data 
where response has traditionally required confirmation in such studies. However, in all other 
circumstances, ie, in randomized studies (Phase II or III) or studies where SD or progression are 
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the primary endpoints, confirmation of response is not required since it will not add value to the 
interpretation of the study results. However, elimination of the requirement for response 
confirmation may increase the importance of central review to protect against bias, in particular in 
studies which are not blinded.
In the case of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general not less than 6 to 8 weeks) that is defined in the study protocol.
Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are first met for 
CR/partial response (whichever is first recorded) until the first date that recurrent or PD is 
objectively documented (taking as reference for PD the smallest measurements recorded on study).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease
Stable disease is measured from the start of the treatment (in randomized studies, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD).
The clinical relevance of the duration of SD varies in different studies and diseases. If the 
proportion of participants achieving SD for a minimum period of time is an endpoint of importance 
in a particular study, the protocol should specify the minimal time interval required between 
2 measurements for determination of SD.
Note: The duration of response and SD as well as the progression-free survival are influenced by 
the frequency of follow-up after baseline evaluation. It is not in the scope of this guideline to define 
a standard follow-up frequency. The frequency should take into account many parameters 
including disease types and stages, treatment periodicity, and standard practice. However, these 
limitations of the precision of the measured endpoint should be taken into account if comparisons 
between studies are to be made.
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Appendix 8
Examples of Drugs that Prolong QT Interval and Have a 
Known Risk of Causing Torsade de Pointe
Table 6 provides examples of drugs which prolong QTc and have a known risk for Torsade de 
Pointe. 
Note: This is not an exhaustive list. If you have questions on a drug product not included in this 
list, please consult the prescribing information for the product.
Table 6
Examples of drugs with a known risk for Torsade de Pointe due to QTc 
prolongation
Aclarubicin 
Droperidol
Oxaliplatin
Amiodarone
Erythromycin
Papaverine HCl (Intra-coronary)
Anagrelide
Escitalopram
Pentamidine
Arsenic trioxide
Flecainide
Pimozide
Astemizole
Fluconazole
Probucol
Azithromycin
Gatifloxacin
Procainamide
Bepridil
Grepafloxacin
Propofol
Chloroquine
Halofantrine 
Quinidine
Chlorpromazine
Haloperidol
Roxithromycin
Cilostazol
Hydroquinidine, dihydroquinidine
Sevoflurane
Ciprofloxacin
Ibogaine
Sotalol
Cisapride
Ibutilide
Sparfloxacin
Citalopram
Levofloxacin
Sulpiride
Clarithromycin
Levomepromazine 
(methotrimeprazine)
Sultopride
Cocaine
Levomethadyl acetate 
Terfenadine
Disopyramide
Levosulpiride
Terlipressin
Dofetilide
Mesoridazine
Terodiline
Domperidone
Methadone
Thioridazine
Donepezil
Moxifloxacin
Vandetanib
Dronedarone
Ondansetron
Examples provided are based on information given by www.crediblemeds.org/new-drug-list/ 
(accessed 18 March 2019)
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Appendix 9
Protocol Amendment History
The information for the current amendment is on the title page.
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Appendix 10
Sponsor Signature Page
Study Title:
A Phase II, two-arm study to investigate tepotinib 
combined with osimertinib in MET amplified, advanced 
or metastatic non-small cell lung cancer (NSCLC) 
harboring activating EGFR mutations and having 
acquired 
resistance
to 
prior 
osimertinib 
therapy 
(INSIGHT 2 Study)
Regulatory Agency Identifying 
Numbers:
IND Number: 128073
ClinicalTrials.gov: NCT03940703
European Clinical Trials Database: 2019-001538-33
Clinical Study Protocol Version:
3.0/ 04 May 2021
I approve the design of the clinical study:
____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function/Title:
Institution:
Merck Healthcare KGaA 
Address:
Frankfurter Str. 250, Darmstadt, Germany
Telephone number:
Fax number:
Not applicable
E-mail address:
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PPD
PPD
PPD

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Appendix 11
Coordinating Investigator Signature Page
Study Title:
A Phase II, two-arm study to investigate tepotinib 
combined with osimertinib in MET amplified, 
advanced or metastatic non-small cell lung cancer 
(NSCLC) harboring activating EGFR mutations and 
having acquired resistance to prior osimertinib therapy 
(INSIGHT 2 Study)
Regulatory Agency Identifying 
Numbers:
IND Number: 128073
ClinicalTrials.gov: NCT03940703
European Clinical Trials Database: 2019-001538-33
Clinical 
Study 
Protocol 
Version:
3.0/ 04 May 2021
Site Number:
I approve the design of the clinical study, am responsible for the conduct of the study at this site, 
and understand and will conduct it per the clinical study protocol, any approved protocol 
amendments, International Council for Harmonisation Good Clinical Practice (Topic E6) and all 
applicable Health Authority requirements and national laws.
____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function/Title:
Institution:
Address:
Telephone number:
Fax number:
E-mail address:
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Appendix 12
Principal Investigator Signature Page
Study Title:
A Phase II, two-arm study to investigate tepotinib combined 
with osimertinib in MET amplified, advanced or metastatic non-
small cell lung cancer (NSCLC) harboring activating EGFR 
mutations and having acquired resistance to prior osimertinib 
therapy (INSIGHT 2 Study)
Regulatory 
Agency 
Identifying Numbers:
IND Number: 128073
ClinicalTrials.gov: NCT03940703
European Clinical Trials Database: 2019-001538-33
Clinical 
Study 
Protocol Version:
3.0/04 May 2021
Site Number:
I am responsible for the conduct of the study at this site and understand and will conduct it per the 
clinical study protocol, any approved protocol amendments, International Council for
Harmonisation Good Clinical Practice (Topic E6) and all applicable Health Authority 
requirements and national laws.
I also understand that Health Authorities may require the Sponsors of clinical studies to obtain and 
supply details about ownership interests in the Sponsor or Investigational Medicinal Product and 
any other financial ties with the Sponsor. The Sponsor will use any such information solely for 
complying with the regulatory requirements. Therefore, I agree to supply the Sponsor with any 
necessary information regarding ownership interest and financial ties including those of my spouse 
and dependent children, and to provide updates as necessary to meet Health Authority 
requirements.
____________________________________
____________________________
Signature
Date of Signature
Name, 
academic 
degree:
Function/Title:
Institution:
Address:
Telephone number:
Fax number:
E-mail address:
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