A Phase II, Multicenter, Two-cohort Study of Oral MET Inhibitor Capmatinib in Chinese Adult Patients With EGFR Wild-type (wt), ALK Rearrangement Negative, MET Exon 14 Skipping Mutations, Advanced Non-small Cell Lung Cancer (NSCLC) Who Are Treatment Naive or Failed One or Two Prior Lines of Systemic Therapy
Phase: PHASE2
Conditions: Non-Small Cell Lung Cancer (NSCLC)
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development
INC280/Capmatinib
Clinical Trial Protocol CINC280A2204 / NCT04677595
A phase II, multicenter, two-cohort study of oral MET 
inhibitor capmatinib in Chinese adult patients with EGFR 
wild-type (wt), ALK rearrangement negative, MET exon 14 
skipping mutations, advanced non-small cell lung cancer 
(NSCLC) who are treatment naive or failed one or two prior 
lines of systemic therapy
Document type:
Amended Protocol Version
EUDRACT number:
Not applicable
Version number:
03 (Clean)
Clinical Trial Phase:
II
Release date:
07-Jul-2022 (content final)
Property of Novartis 
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.0 (31-Jan-2020)

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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................13
Amendment 03 (07-Jul-2022) ...........................................................................................15
Amendment 02 (18-May-2021).........................................................................................20
Amendment 01 (19-Jun-2020) ..........................................................................................24
Protocol summary..............................................................................................................25
1
Introduction .......................................................................................................................30
1.1
Background............................................................................................................30
1.1.1
Overview of capmatinib (INC280) .......................................................31
1.2
Purpose ..................................................................................................................33
2
Objectives, endpoints and estimands.................................................................................33
2.1
Primary estimands .................................................................................................34
2.2
Secondary estimands .............................................................................................35
3
Study design ......................................................................................................................35
4
Rationale............................................................................................................................37
4.1
Rationale for study design .....................................................................................37
4.2
Rationale for dose/regimen and duration of treatment ..........................................38
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................39
4.4
Purpose and timing of interim analyses/design adaptations..................................39
4.5
Risks and benefits..................................................................................................39
4.5.1
Capmatinib............................................................................................40
4.6
Rationale for Public Health Emergency mitigation procedures ............................40
5
Study Population ...............................................................................................................41
5.1
Inclusion criteria ....................................................................................................41
5.2
Exclusion criteria...................................................................................................42
6
Treatment...........................................................................................................................45
6.1
Study treatment......................................................................................................45
6.1.1
Investigational drug...............................................................................45
6.1.2
Additional study treatments ..................................................................45
6.1.3
Treatment arms/group ...........................................................................45
6.1.4
Guidelines for continuation of treatment ..............................................46
6.1.5
Treatment duration................................................................................46

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6.2
Other treatment(s)..................................................................................................47
6.2.1
Concomitant therapy.............................................................................47
6.2.2
Prohibited medication ...........................................................................50
6.3
Participant numbering, treatment assignment, randomization ..............................51
6.3.1
Participant numbering...........................................................................51
6.3.2
Treatment assignment, randomization ..................................................51
6.4
Treatment blinding.................................................................................................52
6.5
Dose escalation and dose modification..................................................................52
6.5.1
Dose modifications................................................................................52
6.5.2
Treatment interruption and treatment discontinuation..........................57
6.5.3
Follow-up for toxicities.........................................................................58
6.6
Additional treatment guidance...............................................................................64
6.6.1
Treatment compliance...........................................................................64
6.6.2
Emergency breaking of assigned treatment code..................................64
6.7
Preparation and dispensation.................................................................................64
6.7.1
Handling of study treatment and other treatment..................................65
6.7.2
Instruction for prescribing and taking study treatment .........................65
7
Informed consent procedures ............................................................................................66
8
Visit schedule and assessments .........................................................................................68
8.1
Molecular pre-screening........................................................................................76
8.2
Screening ...............................................................................................................76
8.2.1
Eligibility screening ..............................................................................77
8.2.2
Information to be collected on screening failures.................................77
8.3
Participant demographics/other baseline characteristics .......................................78
8.4
Efficacy assessments .............................................................................................79
8.4.1
Tumor imaging assessments .................................................................79
8.4.2
Appropriateness of efficacy assessments..............................................83
8.4.3
Overall survival.....................................................................................83
8.5
Safety.....................................................................................................................84
8.5.1
Laboratory evaluations..........................................................................85
8.5.2
Electrocardiogram (ECG) .....................................................................86
8.5.3
Pregnancy and assessments of fertility .................................................87
8.5.4
Appropriateness of safety measurements..............................................88
8.6
Additional assessments..........................................................................................88
8.6.1
Patient reported outcomes (PRO)..........................................................88
8.6.2
Pharmacokinetics ..................................................................................90

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8.6.3
Biomarkers............................................................................................91
9
Discontinuation and completion........................................................................................92
9.1
Discontinuation from study treatment and from study..........................................92
9.1.1
Discontinuation from study treatment...................................................92
9.1.2
Participant discontinuation from the study ...........................................93
9.1.3
Lost to follow-up...................................................................................93
9.2
Withdrawal of informed consent and exercise of participants’ data privacy 
rights ......................................................................................................................93
9.3
Study completion and post-study treatment ..........................................................94
9.3.1
Follow-up for safety evaluations...........................................................94
9.3.2
Efficacy follow-up and PROs ...............................................................95
9.3.3
Survival follow-up ................................................................................95
9.4
Early study termination by the Sponsor.................................................................95
10 Safety monitoring, reporting and committees ...................................................................96
10.1
Definition of adverse events and reporting requirements......................................96
10.1.1
Adverse events ......................................................................................96
10.1.2
Serious adverse events ..........................................................................98
10.1.3
SAE reporting........................................................................................99
10.1.4
Pregnancy reporting ............................................................................100
10.1.5
Reporting of study treatment errors including misuse/abuse..............100
10.2
Additional safety monitoring...............................................................................101
10.3
Committees..........................................................................................................101
10.3.1
Steering committee..............................................................................101
11 Data collection and database management......................................................................101
11.1
Data collection.....................................................................................................101
11.2
Database management and quality control..........................................................102
11.3
Source documents................................................................................................102
12 Data analysis and statistical methods ..............................................................................103
12.1
Analysis sets ........................................................................................................103
12.1.1
Full analysis set (FAS)........................................................................103
12.1.2
Full analysis set – brain metastases (FAS-BM)..................................103
12.1.3
Safety set .............................................................................................103
12.1.4
Pharmacokinetics analysis set.............................................................104
12.1.5
Evaluable set .......................................................................................104
12.2
Participant demographics and other baseline characteristics...............................104
12.3
Treatments ...........................................................................................................104

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12.4
Analysis supporting primary objectives ..............................................................104
12.4.1
Definition of primary endpoint(s).......................................................104
12.4.2
Statistical model, hypothesis, and method of analysis........................105
12.4.3
Handling of intercurrent events of primary estimand .........................105
12.4.4
Handling of missing values/censoring/discontinuation ......................105
12.4.5
Sensitivity analyses .............................................................................105
12.4.6
Supplementary analysis.......................................................................105
12.4.7
Supportive analyses.............................................................................105
12.5
Analysis supporting secondary objectives...........................................................106
12.5.1
Efficacy and/or pharmacodynamic endpoint(s) ..................................106
12.5.2
Safety endpoints..................................................................................108
12.5.3
Pharmacokinetics ................................................................................110
12.5.4
DNA....................................................................................................110
12.5.5
Biomarkers..........................................................................................110
12.5.6
Pharmarcokinetics/Pharmacodynamics relationships.........................111
12.5.7
Patient reported outcomes...................................................................111
12.6
Analysis of exploratory endpoints.......................................................................112
12.7
Interim analyses...................................................................................................112
12.8
Sample size determination...................................................................................112
12.8.1
Primary endpoint(s).............................................................................112
13 Ethical considerations and administrative procedures ....................................................113
13.1
Regulatory and ethical considerations.................................................................113
13.2
Publication of study protocol and results.............................................................114
13.3
Quality control and quality assurance..................................................................114
13.4
Participant Engagement.......................................................................................114
13.5
Data Protection ....................................................................................................114
14 Protocol adherence ..........................................................................................................115
14.1
Protocol amendments...........................................................................................115
15 References .......................................................................................................................116
16 Appendices ......................................................................................................................120
16.1
Appendix 1: Guidelines for Response, Duration of Overall Response, TTF, 
TTP, Progression-Free Survival, and Overall Survival (based on RECIST 1.1) 120
16.1.1
Introduction.........................................................................................122
16.1.2
Efficacy assessments...........................................................................122
16.1.3
Efficacy definitions .............................................................................131
16.1.4
Data handling and programming rules................................................141

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16.1.5
References (available upon request) ...................................................145
16.2
Appendix 2: Guidelines for Response Assessment in Neuro-oncology 
(RANO) for Brain Metastases (BM) ...................................................................146
16.2.1
Introduction.........................................................................................148
16.2.2
Efficacy assessments...........................................................................148
16.2.3
Efficacy definitions .............................................................................157
16.2.4
References...........................................................................................162
List of tables
Table 2-1
Objectives and related endpoints ..........................................................33
Table 4-1
Rationale for study design.....................................................................38
Table 6-1
Investigational drug...............................................................................45
Table 6-2
Drugs to be used with caution during co-administration with 
capmatinib.............................................................................................49
Table 6-3
Drugs prohibited while on study...........................................................50
Table 6-4
Drugs with a known risk of torsades de pointes prohibited while on 
study......................................................................................................50
Table 6-5
Dose reduction steps for capmatinib.....................................................53
Table 6-6
Criteria for dose reduction / interruption and re-initiation / 
permanent discontinuation of capmatinib treatment for adverse 
drug reactions........................................................................................53
Table 6-7
Follow-up evaluations for selected toxicities........................................58
Table 6-8
Specific assessments to rule out possible causes of LFT 
abnormalities.........................................................................................63
Table 8-1
Allowable window for participant assessments ....................................68
Table 8-2
Assessment schedule.............................................................................70
Table 8-3
Imaging assessment collection plan......................................................80
Table 8-4
Assessments & specifications ...............................................................84
Table 8-5
ECOG performance status.....................................................................85
Table 8-6
Local clinical laboratory parameters collection plan ............................86
Table 8-7
Local ECG collection plan....................................................................87
Table 8-8
Pharmacokinetic blood collection log...................................................90
Table 8-9
Biomarker sample collection plan.........................................................91
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .......................................................................................101
Table 12-1
Objective response rate (ORR) and 95% lower limit of confidence 
interval (LLCI) (%) in study CINC280A2201....................................112
Table 12-2
Operating characteristics for cohort 1.................................................112

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Table 12-3
Operating characteristics for cohort 2.................................................113
Table 16-1
Response criteria for target lesions .....................................................127
Table 16-2
Response criteria for non-target lesions..............................................129
Table 16-3
Overall lesion response at each assessment ........................................130
Table 16-4
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................138
Table 16-5
Options for event dates used in PFS, TTP, DOR................................139
Table 16-6
Response assessment of target lesions................................................152
Table 16-7
Response assessment of non-target lesions.........................................152
Table 16-8
Overall Lesion Response at each assessment......................................154
Table 16-9
CNS and non-CNS response assessment ............................................156
Table 16-10
Overall Lesion Response at each assessment: Participant with only 
non-target disease at baseline..............................................................160
List of figures
Figure 3-1
Study design..........................................................................................36

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List of abbreviations
ADL
Activities of Daily Living
AE(s)
Adverse Event(s)
AESI
Adverse Event of Special Interest
ALK
Anaplastic Lymphoma Kinase
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANA
Antinuclear Antibodies
ANC
Absolute Neutrophil Count
Anti-HBc
Anti-Hepatitis B core antibody
ASMA
Anti-Smooth Muscle Antibody 
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
ATP
Adenosine Triphosphate
AUC
Area Under Curve
AUCinf
Area under the plasma (serum, or blood) concentration versus time curve from time 
zero to infinity
BAL
Bronchoalveolar Lavage
BCG
Bacillus Calmette-Guerin
BCRP
Breast Cancer Resistance Protein
b.i.d
Bis In Die/twice daily
BIRC
Blinded Independent Review Committee
BOIR
Best Overall Intracranial Response
BOR
Best Overall Response
BUN
Blood Urea Nitrogen
CAP
Chest Abdomen Pelvis
CDx
Companion Diagnostic
CFR
Code of Federal Regulation
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
Cmax
Maximum (peak) concentration of drug in plasma
CMO&PS 
Chief Medical Office and Patient Safety
CMV
Cytomegalovirus
CNS
Central Nervous System
CO
Country Organization
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
Coronavirus disease of 2019.
CR
Complete Response
CRA
Clinical Research Associate
CRO
Contract Research Organization
CRS
Case Retrieval Strategy
CSCO
Chinese Society of Clinical Oncology
CSR
Clinical Study Report
CT
Computerized Tomography
CTCAE
Common Terminology Criteria for Adverse Events

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ctDNA
Circulating Tumor DNA
CTT
Clinical Trial Team
CV
Coefficient of Variation
CYP1A2
Cytochrome P450 1A2
CYP3A
Cytochrome P450 3A
DBP
Diastolic Blood Pressure
DCR
Disease Control Rate
DDI
Drug-Drug Interactions
DILI
Drug-Induced Liver Injury
DLCO
Diffusing capacity of the Lungs for Carbon monoxide
DLTs
Dose-Limiting Toxicities
DNA
Deoxyribonucleic Acid
DOIR
Duration Of Intracranial Response
DOR
Duration Of Response
EBV
Epstein-Barr Virus
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report/Record Form
EDC
Electronic Data Capture
EGFR
Epidermal Growth Factor Receptor
EMA
European Medicines Agency
EORTC
European Organization for Research and Treatment of Cancer
EOT
End of Treatment
EQ VAS
EuroQoL visual analogue scale
EQ-5D-5L
EuroQoL-5 Dimension-5 Level
ERCP
Endoscopic Retrograde Cholangio-Pancreatography
eSource
Electronic Source
EU
European Union
FAS
Full Analysis Set
FAS-BM
Full Analysis Set - Brain Metastases
FDA
Food and Drug Administration
FDG-PET
Fluorodeoxyglucose Positron Emission Tomography
FFPE
Formalin Fixed Paraffin Embedded
FPFV
First Patient First Visit
FUP
Follow-Up
GCN
Gene Copy Number
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony-Stimulating Factor
GGT
Gamma-Glutamyl Transferase
GI
Gastro-Intestinal
GLDH
Glutamate Dehydrogenase
GM-CSF
Granulocyte-Macrophage Colony-Stimulating Factor
HA
Health Authorities
HAV
Hepatitis A
HBsAg
Hepatitis B virus surface Antigen

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HBV
Hepatitis B
HCV
Hepatitis C
HEV
Hepatitis E
Hgb
Hemoglobin
HGF
Hepatic Growth Factor
HIV
Human Immunodeficiency Virus
HR
Hazard Ratio
HRQoL
Health-Related Quality of Life
HSV
Herpes Simplex Virus
i.v.
Intravenous
IB
Investigator’s Brochure
IC
Inhibitory Concentration
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
ID
Identity
IDCR
Intracranial Disease Control Rate
IEC
Independent Ethics Committee
IgA
Immunoglobulin A
IgE
Immunoglobulin E
IgG
Immunoglobulin G
IgM
Immunoglobulin M
ILD
Interstitial Lung Disease
IMP
Investigational Medicinal Product
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS
Intrauterine System
KM
Kaplan-Meier
LC/MS/MS
Liquid Chromatography coupled to tandem Mass Spectrometry
LC13
Lung Cancer 13 (specific module of EORTC QLQ)
LFT
Liver Function Test 
LLCI
Lower Limit of Confidence Interval
LLN
Lower Limit of Normal
LLOQ
Lower Limit Of Quantification
LPLV
Last Patient Last Visit
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities 
MET
Mesenchymal Epithelial Transition
METΔex14
MET exon 14-skipping
MRI
Magnetic Resonance Imaging
NCCN FACT-FBrSI
National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy 
- Brain Symptom Index
NCI
National Cancer Institute

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NDA
New Drug Application
NSCLC
Non-Small Cell Lung Cancer
NTI
Narrow Therapeutic Index
OIRR
Overall Intracranial Response Rate
ORR
Overall Response Rate
OS
Overall Survival
PAS
Pharmacokinetic Analysis Set
PBPK
Physiology-Based Pharmacokinetics
pCO2
Partial pressure of carbon dioxide in blood
PD
Progressive Disease
PD-1
Programmed cell Death protein 1
PD-L1
Programmed Death-Ligand 1
PET
Positron Emission Tomography
PFS
Progression-Free Survival
PFT
Pulmonary Function Tests
P-gp
Permeability-GlycoProtein
PK
Pharmacokinetic(s)
PLT
Platelets
pO2
Partial pressure of oxygen in blood
PR
Partial Response
PRO
Patient Reported Outcomes
PS
Performance Status
PT
Prothrombin Time
QLQ
Quality of Life Questionnaire
QMS 
Quality Management System
QoL
Quality of Life
QT
Quick Test
QTcF
QT interval corrected by Fridericia’s formula
R Value
ALT/ALP x ULN
RANKL
Receptor Activator of Nuclear factor Kappa-B Ligand
RANO-BM
Response Assessment in Neuro-Oncology Brain Metastases
RAP
Report and Analysis Plan 
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
Ribonucleic Acid
ROS1
Proto-oncogene tyrosine-protein kinase ROS (Reactive Oxygen Species)
RP2D
Recommended Phase II Dose
RT-PCR
Reverse Transcription Polymerase Chain Reaction
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SC
Steering Committee
SD
Stable Disease
Site No.
Site Number
SMQ
Standardized MedDRA (Medical dictionary for regulatory activities) Query
SOP
Standard Operating Procedures

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SUSAR
Suspected Unexpected Serious Adverse Reaction
TdP
Torsades de Pointes
TKI
Tyrosine Kinase Inhibitor
Tmax
Maximum drug concentration
TSH
Thyroid Stimulating Hormone
TTE
Time To Event
TTIR
Time to Intracranial Response
TTR
Time To Response
ULN
Upper Limit of Normal
US
United States
WHO
World Health Organization 
WHS
White coat Syndrome / White coat Hypertension
wt
Wild-type

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Glossary of terms
Additional treatment
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. any background 
therapy).
Assessment
A procedure used to generate data required by the study.
Clinical Trial Team
A group of people responsible for the planning, execution and reporting of all clinical 
trial activities. Examples of team members include the Study Lead, Medical Monitor, 
Trial Statistician etc.
Coded Data
Personal Data which has been de-identified by the investigative center team by 
replacing personal identifiers with a code.
Cohort
A group of individuals who share a common exposure, experience or characteristic, or 
a group of individuals followed-up or traced over time.
Control drug
A study intervention (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug.
Cycles
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g., q21 days).
Discontinuation from 
study
Point/time when the participant permanently stops receiving the study treatment and 
further protocol required assessments or follow-up, for any reason. No specific 
request is made to stop the use of their samples or data.
Discontinuation from 
study treatment
Point/time when the participant permanently stops receiving the study treatment for 
any reason (prior to the planned completion of study intervention administration, if 
any). Participant agrees to the other protocol required assessments including follow-
up. No specific request is made to stop the use of their samples or data.
Dosage
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg once a 
day, 400 mg twice daily).
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study data using 
data collection systems, such as Web-based applications, interactive voice response 
systems and clinical laboratory interfaces. EDC includes the use of Electronic Case 
Report Forms (eCRFs) which are used to capture data transcribed from source 
data/documents used at the point of care.
End of the clinical trial
The end of the clinical trial is defined as the last visit of the last participant
Enrollment
Point/time of participant entry into the study at which main informed consent must be 
obtained. The action of enrolling one or more participants.
Estimand
As defined in the ICH E9(R1) addendum, estimand is a precise description of the 
treatment effect reflecting the clinical question posed by the trial objective. It 
summarizes at a population-level what the outcomes would be in the same 
participants under different treatment conditions being compared. Attributes of an 
estimand include the population, variable (or endpoint) and treatment of interest, as 
well as the specification of how the remaining intercurrent events are addressed and a 
population-level summary for the variable.
Investigational drug/ 
treatment
The drug whose properties are being tested in the study.
Medication number
A unique identifier on the label of medication kits.
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy).
Participant
A trial participant (a patient). "Participant" terminology is used in the protocol whereas 
term "Subject" is used in data collection.
Participant number
A unique number assigned to each participant upon signing the informed consent. 
This number is the definitive, unique identifier for the participant and should be used to 
identify the participant throughout the study for all data collected, sample labels, etc.

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Patient-Reported 
Outcome (PRO)
A measurement based on a report that comes directly from the participant 
about the status of a participant's health condition without amendment or 
interpretation of the participant's report by a clinician or anyone else.
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the study phases and will be used in clinical 
trial database setup and eventually in analysis.
Personal data
Participant information collected by the Investigator that is coded and transferred to 
Novartis for the purpose of the clinical trial. This data includes participant identifier 
information, study information and biological samples.
Remote
Describes any trial activities performed at a location that is not the investigative site. 
Rescreening
If a participant fails the initial screening and is considered as a Screen Failure, he/she 
can be invited once for a new Screening visit after medical judgment and as specified 
by the protocol.
Screen Failure
A participant who did not meet one or more criteria that were required for participation 
in the study.
Source 
Data/Document
Source data refers to the initial record, document, or primary location from where data 
comes. The data source can be a database, a dataset, a spreadsheet or even hard-
coded data, such as paper or eSource.
Stage of cancer
The extent of a cancer in the body. Staging is usually based on the size of the tumor, 
whether lymph nodes contain cancer, and whether the cancer has spread from the 
original site to other parts of the body.
Start of the clinical 
trial
The start of the clinical trial is defined as the signature of the informed consent by the 
first participant.
Study treatment
Any drug or combination of drugs or intervention administered to the study participants 
as part of the required study procedures; includes investigational drug(s), control(s) or 
background therapy
Treatment arm/group 
A treatment arm/group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts.
Variable (or endpoint)
The variable (or endpoint) to be obtained for each participant that is required to 
address the clinical question. The specification of the variable might include whether 
the participant experiences an intercurrent event.
Withdrawal of 
consent
Withdrawal of consent from the study occurs when the participant explicitly requests to 
stop use of their data and/or biological samples AND no longer wishes to receive 
study treatment, AND does not agree to further protocol required assessments. This 
request should be in writing (depending on local regulations) and recorded in the 
source documentation. This request should be distinguished from a request to 
discontinue the study. Other study participant’s privacy rights are described in the 
corresponding informed consent form.

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Amendment 03 (07-Jul-2022)
Amendment rationale 
As of the release date of this amendment, 22 participants have been enrolled, 15 in the cohort I 
and 7 in the cohort II. Of these 13 are on treatment and 9 discontinued study treatment.
The main purpose of this amendment is to clarify that the centralized METΔex14 data from 
tumor tissue analysis may be utilized towards development of an in vitro diagnostic test for 
METΔex14, such as a companion diagnostic. In addition to the blood collected at C1D1, 
remnant tissue material or extracted nucleic acid material from tumor tissue samples collected 
for centralized METΔex14 testing may also be used towards companion diagnostic 
development purposes (dependent on health authority approval).
Furthermore, an additional eligibility criterion was added to exclude participants who received 
live vaccines within 30 days prior to the first dose of study treatment, and to add live vaccines 
as prohibited concomitant therapy while a participant is dosed with the study treatment and for 
30 days after the last dose of study treatment. Patients with advanced NSCLC with METΔex14 
mutation are typically an elderly and vulnerable patient population (Awad et al 2019). Based 
on the vaccine risk assessment undertaken for this patient population, these patients may be less 
immunocompetent due to the multiple confounding factors such as advanced age, advanced 
stage of NSCLC and prior exposure to antineoplastic therapy. Hence, live vaccines are not 
recommended in this patient population. The exclusion criteria and guidance on use of live 
vaccines as concomitant medications have been updated accordingly.
Also, in exclusion criteria, additional instructions have been added and some rewording done 
for improved clarity (including clarification based on health authority feedback).
Finally, the SAE reporting criteria have been detailed in accordance with current regulatory 
requirements based on health authority feedback. Initial and follow-up SAE must be notified to 
Novartis safety immediately, without undue delay, but under no circumstances later than within 
24 hours of learning of its occurrence. (Note: if more stringent, local regulations regarding 
reporting timelines prevail).
Other editorial revisions and text corrections were made throughout the protocol for 
clarification, where required.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletion and red underlined font for insertions.
The following changes have been implemented and the protocol has been updated to reflect all 
significant changes below based on the current Novartis protocol template version 5.0 used as 
reference:
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IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.

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Amendment 02 (18-May-2021)
Amendment rationale 
As of the release date of this amendment, 1 participant has been pre-screened and no participants 
have been treated in this study.
This amendment is triggered by the release of the results of the analytical validation of a specific 
11-1 PCR assay used to test for METΔex14 mutation status. 
This amendment includes the following revisions: 

Adequate number of fresh-cut tumor tissue slides required to be submitted to the Novartis 
designated laboratory to test for METΔex14 mutation status. All tissue samples need to 
have >20% tumor content per slide.

If resection sample, 5 slides requested initially and if sufficient tumor material is not
found to perform the METΔex14 mutation analysis, additional slides (not exceeding a 
total of 10 slides overall) will be requested.

If core needle biopsy, 10 slides requested per participant. This change is based on the 
11-1 PCR assay validation results that showed the need of 5 to10 slides with minimum 
of 20% of tumor content for generating adequate RNA input for the assay. Tissue 
samples with low tumor content (i.e. less than 20% tumor content) may not be evaluable 
for METΔex14 mutation analysis.

Only slides can be submitted, not blocks

Removal of mandatory band testing as part of hematology assessment

New section added for public health emergencies as rationale for Public Health Emergency 
mitigation procedures

Estimand language added due to recent decision to include estimand framework in every 
protocol moving forward aimed for Chana’s State Food and Drug Administration 
(CFDA China)

Alignment with most recent one CTP version 4 protocol template where required
Changes to the protocol
The assessment of the benefit-risk concluded the absence of additional risks related to 
COVID-19.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
The following sections of the protocol were changed:
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IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
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Amendment 01 (19-Jun-2020) 
Amendment rationale 
As of the release date of this amendment, no participants have been screened or treated in this 
study.
This amendment addresses the following revisions: 

Decreased the number of tumor tissue slides required to be submitted to the Novartis 
designated laboratory to test for METΔex14 mutation status from at least 10 slides to 5 slides 
per participant

Novartis guidelines released on Response Assessment in Neuro-oncology (RANO) for 
Brain Metastases (BM). Guidelines have been added as an appendix to the protocol to 
support the secondary endpoint assessing intracranial anti-tumor activity of capmatinib in 
participants with Central Nervous System (CNS) lesions

Update of the definitions of duration of response (DOR), time to intracranial response 
(TTIR) and duration of intracranial response (DOIR) to align with the RANO-BM 
guidelines (Appendix 2)
Changes to the protocol
The following sections of the protocol were changed:
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol are non-substantial and do not require IRB/IEC 
approval prior to implementation.
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Protocol summary
Protocol number
CINC280A2204
Full Title
A phase II, multicenter, two-cohort study of oral MET inhibitor capmatinib in 
Chinese adult patients with EGFR wild-type (wt), ALK rearrangement 
negative, MET exon 14 skipping mutations, advanced non-small cell lung 
cancer (NSCLC) who are treatment naive or failed one or two prior lines of 
systemic therapy
Brief title
Study of efficacy and safety of capmatinib in Chinese patients with EGFR 
wild-type (wt), ALK rearrangement negative, MET exon 14 skipping 
mutations, advanced NSCLC
Sponsor and Clinical Phase
Novartis, Phase II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
This phase II study is designed to support capmatinib new drug application 
(NDA) in China as a monotherapy in patients with MET mutated, 
advanced/metastatic NSCLC who are treatment naive (cohort 1) or failed one 
or two prior lines of systemic therapy (cohort 2).
Primary Objective(s) 
The primary objective is to evaluate the antitumor activity of capmatinib, as 
measured by overall response rate (ORR) by blinded independent review 
committee (BIRC) assessment per RECIST 1.1, by cohort.
Secondary Objectives
The secondary objectives are the following:

To evaluate duration of response (DOR) as assessed by BIRC per 
RECIST 1.1, by cohort

To evaluate ORR and DOR by Investigator assessment per RECIST 1.1, 
by cohort

To evaluate time to response (TTR), disease control rate (DCR) and 
progression-free survival (PFS) by Investigator and by BIRC assessment
per RECIST 1.1, by cohort

To evaluate overall survival (OS), by cohort

To assess intracranial anti-tumor activity of capmatinib in participants with 
Central Nervous System (CNS) lesions at baseline by BIRC by evaluating 
overall intracranial response rate (OIRR), intracranial disease control rate 
(IDCR), time to intracranial response (TTIR), duration of intracranial 
response (DOIR) by BIRC as per RANO-BM criteria

To evaluate the association between MET mutation status as measured 
in circulating tumor Deoxyribonucleic Acid (ctDNA) at baseline with 
capmatinib efficacy by evaluating ORR, DOR and PFS per RECIST 1.1 
for participants by MET mutation status assessed in ctDNA at baseline, 
both by BIRC and Investigator

To characterize the pharmacokinetics (PK) of capmatinib by evaluating 
the steady state Ctrough and steady state 0.5-1.5 hour and 3-5 hours 
post-dose concentrations

To evaluate capmatinib safety profile by assessing the incidence of 
adverse events (AEs) and serious adverse events (SAEs), change in vital 
signs, laboratory results (hematology, chemistry, and urinalysis) and ECG

To assess the effect of capmatinib on patient-reported disease-related 
symptoms, functioning, and health-related quality of life (HRQoL) by 
evaluating the change from baseline in European Organization for 
Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire (QLQ)-C30 and Lung Cancer 13 (LC13), EuroQoL-5 
Dimension-5 Level (EQ-5D-5L)

To assess the effect of capmatinib on patient-reported symptoms of brain 
metastases by evaluating the change from baseline to each visit in 
symptoms of brain metastases, with the NCCN FACT-FBrSI

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Study design
This is an open-label, multicenter two-cohort phase II study. Cohort 1 will 
include treatment naive participants and Cohort 2 participants who failed one 
or two prior lines of therapy in the advanced stage (stage IIIB, IIIC or IV).
Study population
Approximately 35 Chinese adult participants with EGFR wt (EGFR mutations 
that predict sensitivity to EGFR therapy, including, but not limited to exon 19 
deletions and exon 21 L858R substitution mutations), ALK rearrangement 
negative, advanced (stage IIIB, IIIC or IV) NSCLC disease harboring MET
exon 14-skipping (METΔex14) mutations as determined by a Novartis central 
molecular laboratory will be treated in this study. The 1L cohort includes 
approximately 15 participants and 2/3L cohort includes approximately 20 
participants.
Key Inclusion criteria

Chinese adult ≥ 18 years old at the time of informed consent

Histologically confirmed stage IIIB, IIIC or IV NSCLC at the time of study 
entry, not amenable to curative surgery or radiation or multi-modality 
therapy

Histologically or cytologically confirmed diagnosis of NSCLC that is:

EGFR wt: The EGFR wt status (EGFR mutations that predict sensitivity 
to EGFR therapy, including, but not limited to exon 19 deletions and 
exon 21 L858R substitution mutations) must be documented in the 
participant source documents before the participant can be consented 
for pre-screening for METΔex14 mutation status

AND ALK rearrangement negative: The ALK rearrangement negative 
status must be documented in the participant source documents before 
the participant can be consented for pre-screening for METΔex14
mutation status

AND either: 

Cohort 1: Treatment naive participants with METΔex14 mutations, or

Cohort 2: Pre-treated participants with METΔex14 mutations

Cohort 1: participants must not have received any systemic therapy for 
advanced/metastatic disease (stage IIIB, IIIC or IV NSCLC). Neo-adjuvant 
and adjuvant systemic therapies will not count as one prior line of 
treatment if relapse occurred > 12 months from the end of the neo-
adjuvant or adjuvant systemic therapy.

Cohort 2: participants must have failed one or two prior lines of systemic 
therapy for advanced/metastatic disease (stage IIIB, IIIC or IV NSCLC). 
Treatment failure is defined as documented disease progression or 
intolerance to treatment. Maintenance therapy given after first line 
chemotherapy will be considered as part of the first line if given to 
participants with documented response or stable disease before starting 
the maintenance therapy. Neoadjuvant and adjuvant systematic therapies 
will count as one prior line of treatment if relapse occurred within 12 
months from the end of the neo-adjuvant or adjuvant systemic therapy.

At least one measurable lesion according to response evaluation criteria 
in solid tumors (RECIST) v1.1. Any lesions which have been subjected to 
percutaneous therapies or radiotherapy should not be considered 
measurable, unless the lesion has clearly progressed since the procedure.
Key Exclusion criteria

Prior treatment with any MET inhibitor or HGF-targeting therapy.

Participants with known hypersensitivity to any of the excipients of 
capmatinib (i.e. crospovidone, mannitol, microcrystalline cellulose, 
povidone, sodium lauryl sulfate, magnesium stearate, colloidal silicon 
dioxide, and various coating premixes).

Participants with known druggable molecular alterations (such as ROS1 
translocation or BRAF mutation, etc.) which might be a candidate for 
alternative targeted therapies as applicable per local regulations and 
treatment guidelines.

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
Participants with symptomatic central nervous system (CNS) metastases 
who are neurologically unstable or have required increasing doses of 
steroids within the 2 weeks prior to study entry to manage CNS symptoms. 
If participants are treated with corticosteroids for endocrine deficiencies or 
tumor-associated symptoms other than CNS related, dose must have 
been stabilized (or decreasing) for at least 5 days before first dose of 
capmatinib.

Presence or history of carcinomatous meningitis.

Presence or history of a malignant disease other than NSCLC that has 
been diagnosed and/or required therapy within the past 3 years. 
Exceptions to this exclusion include the following: completely resected 
basal cell and squamous cell skin cancers, and completely resected 
carcinoma in situ of any type.

Presence or history of interstitial lung disease or interstitial pneumonitis, 
including clinically significant radiation pneumonitis affecting activities of 
daily living (ADL) or requiring therapeutic intervention.
Study treatment
Capmatinib (INC280)
Efficacy assessments

Tumor assessment by RECIST 1.1 performed at screening/baseline and 
then every 6 weeks (+/- 7 days) from Cycle 3 Day 1 with capmatinib until 
disease progression as determined by Investigator and confirmed by 
BIRC. Participant who continues on study treatment beyond RECIST-
defined PD (determined by Investigator and confirmed by BIRC) will 
continue to have tumor assessments as per regular visit schedule.

CNS lesions assessed by BIRC based on Response Assessment in 
Neuro-Oncology Brain Metastases (RANO-BM) criteria.

Survival status collected every 12 weeks regardless of treatment 
discontinuation reason (except if consent is withdrawn or participant is lost 
to follow-up) until death, lost to follow-up, or withdrawal of consent for 
survival follow-up.
Pharmacokinetic 
assessments
The following PK blood samples for capmatinib will be collected for all 
participants:
Cycle 2 Day 1, pre-dose
Cycle 2 Day 1, anytime within 0.5-1.5 hour post-dose
Cycle 2 Day 1, anytime within 3-5 hours post-dose
Cycle 3 Day 1, pre-dose
Key safety assessments

Laboratory assessments including hematology, chemistry, coagulation 
and urinalysis

Physical examination

Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)

Vital signs and body weight

Electrocardiogram (ECG)

Collection of AEs and SAEs
Other assessments

Patient Reported Outcomes (PRO): EORTC QLQ-C30, EORTC QLQ-
LC13, EQ-5D-5L and NCCN FACT-FBrSI
Data analysis
Primary endpoint
The primary endpoint is the ORR by cohort as per the blinded independent 
review committee (BIRC) review. ORR is defined as the proportion of 
participants with best overall response (BOR) of complete response (CR) or 
partial response (PR) according to RECIST 1.1.
The primary analysis will be performed using full analysis set (FAS). The 
primary efficacy endpoint ORR will be estimated and the exact 95% confidence 
interval (CI) (Clopper and Pearson 1934) will be provided by cohort. 
Secondary endpoints

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Duration of response (DOR): DOR only applies to participants whose BOR
is complete response (CR) or partial response (PR) according to RECIST 1.1 
based on tumor response data. The start date is the date of first documented 
response of CR or PR (i.e. the start date of response, not the date when 
response was confirmed), and the end date is defined as the date of the first 
documented progression or death due to any cause.
DOR will be assessed as per BIRC review and by Investigator assessment for 
FAS. Participants continuing without progression or death due to any cause
will be censored at the date of their last adequate tumor assessment.
ORR by Investigator assessment: The evaluation of ORR will be also 
conducted based on Investigator assessment. ORR will be estimated and the 
exact binomial 95% CI will be provided by cohort.
Time to Response (TTR): TTR is defined as the time from the date of start of 
study drug to the first documented response of either complete response (CR) 
or partial response (PR), which must be subsequently confirmed (although 
date of initial response is used, not date of confirmation). TTR will be evaluated 
as per BIRC and also by Investigator review and according to RECIST 1.1.
Disease control rate (DCR): DCR is defined as the proportion of participants 
with a BOR of complete response (CR), or partial response (PR), or an overall 
response of stable disease (SD). DCR will be assessed as per BIRC as well 
as Investigator assessment according to RECIST 1.1.
DCR and its 95% exact confidence interval will be presented for each cohort 
using FAS.
Progression-free survival (PFS): PFS is defined as the time from the date of 
first dose of capmatinib to the date of the first documented progression 
according to RECIST 1.1, or death due to any cause. If a participant has no 
progression or death, the participant is censored at the date of last adequate 
tumor assessment. The analysis of PFS will be performed as per BIRC and 
per Investigator review.
Overall survival (OS): OS is defined as the time from date of first treatment 
to date of death due to any cause. If a participant is not known to have died, 
then OS will be censored at the latest date the participant was known to be 
alive (on or before the cut-off date).
All time to event (TTE) variables (DOR, TTR, PFS, OS) distribution will be 
estimated using the Kaplan-Meier method, and the Kaplan-Meier curves, 
medians, and 95% confidence intervals of the medians (in months) along with 
25th and 75th percentile will be presented for each cohort using FAS.
Overall intracranial response rate (OIRR): OIRR is calculated based on 
response assessments in the brain for participants having measurable and/or 
non-measurable brain metastases at baseline. OIRR is the proportion of 
participants with a confirmed best overall intracranial response (BOIR) of CR 
or PR per RANO-BM criteria as assessed by BIRC review. OIRR calculated 
based on the data from the FAS-BM and the corresponding 95% CI based on 
the exact binomial distribution (Clopper and Pearson 1934) will be presented 
by cohort.
Intracranial disease control rate (IDCR): IDCR is calculated based on 
response assessments in the brain for participants having measurable and/or 
non-measurable brain metastases at baseline. IDCR is the proportion of 
participants with a confirmed BOIR of CR or PR or SD (or non-CR/non-PD) 
per RANO-BM criteria as assessed by BIRC review. IDCR calculated based 
on the data from the FAS-BM and the corresponding 95% CI based on the 
exact binomial distribution (Clopper and Pearson 1934) will be presented by 
cohort.
Time to intracranial response (TTIR): TTIR is defined as the time from the 
date of the start of study treatment to the date of the first documented 
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by the BIRC review, which must be subsequently confirmed (date of initial 
response is used, not date of confirmation).
Participants without a confirmed intracranial CR or PR will be censored at the 
study-maximum follow-up time (i.e. LPLV−FPFV) for participants with an 
intracranial PFS event (intracranial progression or death due to any cause), or 
at the date of the last adequate tumor assessment in brain for participants 
without an intracranial PFS event.
All participants in the FAS-BM will be included in TTIR calculations. Median 
TTIR with corresponding 95% CI, and 25th and 75th percentiles 
(Brookmeyer and Crowley 1982, Klein and Moeschberger 1997) will be 
presented. TTIR will be summarized using the Kaplan-Meier (KM) method, 
based on data from the FAS-BM. KM estimates for TTIR proportions at specific 
time points, along with 95% CI (Greenwood’s formula, Kalbfleisch and
Prentice 2002) will also be provided.
Duration of intracranial response (DOIR): DOIR only applies to participants 
whose BOIR is CR or PR per RANO-BM criteria as assessed by BIRC review. 
DOIR is defined as the time from the date of first documented intracranial 
response of either CR or PR to the date of first documented intracranial 
progression per RANO-BM criteria or the date of death due to any cause.
DOIR will be summarized using the KM method. Median DOIR, with 
corresponding 95% CI, and 25th and 75th percentiles (Brookmeyer and
Crowley 1982, Klein and Moeschberger 1997) will be presented. KM 
estimates for DOIR proportions at specific timepoints, along with95% CI 
(Greenwood's formula, Kalbfleisch and Prentice 2002) will also be provided.
The Pharmacokinetic Analysis Set (PAS) will be used in all pharmacokinetic 
data analysis and PK summary statistics. Descriptive summary statistics of 
plasma concentration will be provided by cohort and by visit/sampling time 
point. Summary statistics will include mean (arithmetic and geometric), 
Standard Deviation, coefficient of variation (CV)% (arithmetic and geometric), 
median, minimum and maximum.
Evaluation of capmatinib safety profile will be performed by analyzing safety 
data such as AEs, ECG, vital and laboratory data.
The association between METΔex14 mutation status as measured in ctDNA 
at baseline with ORR, DOR and PFS will be established using Kaplan-Meier 
curve, by cohort separately provided the number of participants be considered 
large enough. Median survival together will their 95% confidence intervals will 
be reported. 95% CI will be generated for ORR using Fisher exact test. 
Descriptive statistics for continuous data will be used to summarize EORTC 
QLQ-C30/LC13, EQ-5D-5L, and NCCN FACT-FBrSI scores at each 
scheduled assessment time point by FAS. The scores will be displayed as 
mean profiles by cohort/sub-cohort, presented over time. The number of 
participants completing the questionnaires and the number of missing or 
incomplete assessments will be summarized for each scheduled assessment 
time point. 
Key words
INC280, capmatinib, MET, NSCLC

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1
Introduction
1.1
Background
Lung cancer is the most common cancer type worldwide, with an estimated 2.1 million new 
cases in 2018, representing 11.6% of all new cancers. It is also the most common cause of death 
from cancer, with 1.8 million deaths representing 18.4% of the total deaths from cancer
(Bray et al 2018). In China, lung cancer is both the most common cancer and the most leading 
cause of cancer-related deaths. There were 733,300 new cases of lung cancer (85.0% were 
non-small cell lung cancer) and 610,200 patients died of lung cancer in China in 2015 
(Chen et al 2016).
Mechanisms of oncogenesis in lung cancer have been largely deciphered over the past 20 years.
Epidermal Growth Factor Receptor (EGFR) mutations, Anaplastic Lymphoma Kinase (ALK)
translocations and Proto-oncogene tyrosine-protein kinase Reactive Oxygen Species (ROS1)
rearrangements in NSCLC have approved targeted therapies in China (CSCO guidelines for
primary lung cancer,2019). Besides these well-established oncogenic drivers, Mesenchymal 
Epithelial Transition (MET) is recognized as a promising molecular target. MET is a tyrosine 
kinase receptor and MET pathway can be dysregulated by several mechanisms including MET
mutation, gene amplification, overexpression, and autocrine/paracrine stimulation by its ligand 
Hepatic Growth Factor (HGF) (Birchmeier et al 2003, Comoglio et al 2018). Activated MET
promotes tumor cell growth, survival, invasion and metastasis, as well as tumor angiogenesis, 
resulting in poor clinical outcomes (Christensen et al 2005, Liu X et al 2008). MET exon 14 
skipping mutations (MET mutated or METex14 mutated thereafter) remove the juxtamembrane 
domain of MET, leading to protein stabilization and oncogenic activation (Kong-Beltran et al
2006, Togashi et al 2015, Lu et al 2017). Globally, MET mutations leading to exon 14 skipping 
have been reported in 2-3% of NSCLC with adenocarcinoma histology and in ~1% of NSCLC 
with other histologies; notably no overlap between MET mutations and either EGFR mutations 
or ALK translocation is expected (TCGA Research Network 2014, Awad et al 2016, Tong et al
2016, Ou et al 2016). In China, it is reported as a rare alteration in 0.4-1.3% (Liu SY et al 2016,
Zheng et al 2016, Wen et al 2019, Zhu et al 2019) of Chinese NSCLC patients.
Chinese Society of Clinical Oncology (CSCO) guidelines recommend platinum-doublet 
chemotherapy as first-line standard of care and single agent chemotherapy as second-line 
standard of care for treatment of advanced/metastatic NSCLC (CSCO guidelines for primary
lung cancer, 2019) who are EGFR, ALK and ROS1 negative. Outcomes of chemotherapies in 
both first-line setting with standard platinum-doublet chemotherapy (with or without 
maintenance treatment) and second-line setting with single agent remain poor. For locally 
advanced/metastatic NSCLC in the treatment naive setting, chemotherapy observed a median 
progression-free survival (PFS) of 5-7 months and overall survival (OS) of 10-16 months 
(Scagliotti et al 2008, Ciuleanu et al 2009, Ettinger et al 2010, Paz-Ares et al 2012). For pre-
treated setting, the reported response rates to second-line chemotherapy also with other single 
agent chemotherapeutics have generally been < 11% with median PFS and OS generally below 
4 and 11 months, respectively (de Marinis and Grossi 2008, Weiss and Stinchcombe 2013). 
Besides, Chinese MET mutant patients are characterized as elderly compared with the 
unselected NSCLC patient population (Zheng et al 2016). Treatment with chemotherapy is 
challenging in such a patient population limiting the available treatment options.

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Treatment landscape for advanced NSCLC has been reshaped by immunotherapy which is now 
an established treatment option both in the pre-treated and in the treatment naive setting as 
single agent. In China, two immunotherapies (Programmed cell Death protein 1 [PD-1]
inhibitors [nivolumab, pembrolizumab]) have been approved recently. On 15-Jun-2018
nivolumab was approved in the pre-treated setting of EGFR wt and ALK-negative advanced 
NSCLC. ORR (overall response rate) is 16.6% (nivolumab) vs 4.2% (docetaxel) in Checkmate-
078 study (mainly Chinese), with median OS of 12.0 months vs 9.6 months (Hazard Ratio [HR]
0.68 (97.7% Confidence Interval [CI]: 0.52-0.90)) and median PFS of 2.8 months vs 2.8 months 
(HR 0.77 (95% CI: 0.62-0.95) (Wu et al 2019). On 28-Mar-2019 pembrolizumab plus 
pemetrexed+cisplatin was approved in first-line EGFR wt and ALK negative non-squamous 
advanced NSCLC. Several PD-1/Programmed Death-Ligand 1 (PD-L1) therapies are under 
clinical development in NSCLC with non-oncogenic drivers. However, to date, efficacy to
immunotherapy in lung cancer patients harboring a MET exon 14 skipping (METΔex14)
alteration is still limited. Recent preliminary data showed that, similar to EGFR-mutated and 
ALK-translocated NSCLCs, patients with MET mutated NSCLC do not seem to benefit from 
treatment with immunotherapy (Sabari et al 2018, Awad et al 2019).
Promising efficacy data have also been seen in patients with MET mutated NSCLC treated with 
MET inhibitors, including capmatinib (Frampton et al 2015, Jenkins et al 2015, Mendenhall and 
Goldman 2015, Paik et at 2015, Waqar et al 2015, Liu X et al 2016, Schrock et al 2016,
Awad et al 2019, Wolf et al 2019, Drilon et al 2020).
Capmatinib is a small adenosine triphosphate (ATP) competitive, orally bioavailable, highly 
potent, and selective reversible inhibitor of the MET receptor tyrosine kinase (Liu X et al 2011,
Baltschukat et al 2019). GEOMETRY mono-1 [CINC280A2201], a phase II study in MET
dysregulated NSCLC to treat capmatinib, reported its efficacy and safety data in MET mutated 
cohorts. Capmatinib achieved a 40.6% ORR (95% CI: 28.9-53.1) in 2/3L cohort and 67.9% (95% 
CI: 47.6-84.1) in 1L cohort by blinded independent review committee (BIRC) assessment. 
Median duration of response (DOR) per BIRC is 9.72 months in 2/3L cohort and 11.14 months 
in 1L cohort (Wolf et al 2019).
Currently, there is no approved targeted therapy for patients with METΔex14 mutated NSCLC 
in China. MET mutation defines a distinct subset of Chinese NSCLC patients characterized by 
female, non-smoker, and older age (Zheng et al 2016). Available treatment options are very 
limited as introduced above. Considering tolerability of chemotherapy in elderly patients and
limited unknown efficacy response to immunotherapy, a MET inhibitor, capmatinib, is needed 
to be developed in Chinese NSCLC harboring MET exon 14 mutation.
1.1.1
Overview of capmatinib (INC280)
1.1.1.1
Non-clinical experience
Capmatinib possesses potent inhibitory activity against the MET kinase in vitro [inhibitory 
concentration (IC)50 = 0.6 nM], and is highly specific for MET with approximately 1,000 times 
or greater selectivity when compared to more than 400 other kinases or mutant kinase variants 
(Fujino et al 2019). Potent activity of blocking MET activation has been observed in cell-based 
biochemical and functional assays that measure MET-mediated signal transduction, as well as 
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In MET-dependent, mouse tumor models (including lung cancer models), capmatinib exhibits 
dose-dependent antitumor activity and causes tumor regression at well-tolerated doses that 
exceeded IC90 coverage (Liu X et al 2011). Importantly, plasma levels of capmatinib correlate 
with both the dose administered and the extent of tumor growth inhibition in vivo.
In MET/HGF-driven tumor models grown as xenografts in mice, oral dosing of capmatinib 
demonstrated significant in vivo activity in blocking both MET phosphorylation and tumor 
growth. Activation of MET in such responsive models is either due to strong MET
overexpression (mostly because of gene amplification, e.g. in gastric or hepatocellular 
carcinoma) or HGF secretion resulting in an autocrine loop (e.g. in glioblastoma).
For further details, please refer to the latest version of the [capmatinib Investigator’s Brochure].
1.1.1.2
Clinical experience
Capmatinib has been extensively tested in both healthy volunteers and cancer patients. As of 
the safety cut-off date of 27-Sep-2019, more than 780 participants with solid tumors have been 
treated with capmatinib as a single agent, and more than 690 participants have received 
capmatinib in combination with other therapies. The recommended phase II dose (RP2D) for 
capmatinib as a single agent has been determined to be 400 mg twice daily (b.i.d.) in tablet 
formulation [capmatinib Investigator’s Brochure]. 
The most frequent adverse events (AEs) suspected to be related to capmatinib of any grade 
reported in study [CINC280A2201], reference study for the safety profile of capmatinib 
monotherapy (n=334), across study cohorts and irrespective of MET mutational status, were 
edema peripheral (41.6%), nausea (33.2%), blood creatinine increased (19.5%), vomiting 
(18.9%), fatigue (13.8%), decreased appetite (12.6% and diarrhea (11.4%) and the majority 
were Grade 1/2. The Grade 3/4 AEs suspected to be related to capmatinib in the 
[CINC280A2201] study included edema peripheral (7.5%) and lipase increased (5.1%), alanine 
aminotransferase increased (4.8%), amylase increased (3.0%), fatigue (3.0%), aspartate 
aminotransferase increased (2.4%), nausea and vomiting (1.8%), decreased appetite (0.9%), 
constipation (0.6%), and diarrhea (0.3%) [capmatinib Investigator’s Brochure].
Efficacy data for capmatinib single agent in previously treated patients with locally advanced 
or metastatic NSCLC harboring MET 14 exon skipping mutation have been reported in the 
group 4 of phase II GEOMETRY 1 study [CINC280A2201]: as of 15-Apr-2019, RECIST 1.1 
confirmed major responses (including a complete response) evaluated by BIRC were observed 
in 28 out of 69 (ORR 40.6%, [95% CI: 28.9-53.1]) evaluable patients (defined as those with at 
least one post-baseline tumor assessment or have discontinued treatment at the time of the data 
cut-off) and median DOR was 9.72 months [95% CI: 5.55-12.98]. Median PFS was 5.42 months 
[95% CI: 4.17-6.97]. Moreover, major intracranial responses were observed in 7 out of 13 
evaluable patients with brain metastasis at baseline. Four patients had complete resolution of 
lesion (Wolf et al 2019). Based on these data, capmatinib received breakthrough therapy 
designation for treatment of treatment naive and pre-treated NSCLC patients with METΔex14 
mutations from the United States (US) Food and Drug Administration (FDA). FDA also granted 
an orphan drug designation to capmatinib for treatment of patients with MET dysregulated 
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Pharmacokinetics (PK) data collected in clinical trials showed that capmatinib is rapidly 
absorbed after oral administration with a median time to reach maximum drug concentration 
(Tmax) ranging from 1 to 2 hours for tablets. The elimination half-life estimated from study 
[CINC280X1101] ranged from 3.5 to 6.3 hours across the cohorts. Steady state is achieved by 
day 3 of 400 mg twice daily dosing. Accumulation in capmatinib exposure following repeated 
administration of 400 mg b.i.d. tablets is low, with geometric mean accumulation ratio of 
1.39-fold in the single agent [CINC280A2201] study. The mean plasma exposure increase is 
roughly dose proportional for capmatinib tablet from 200 to 400 mg b.i.d..
The PK and safety of capmatinib administered with food has been evaluated in cancer patients 
in study [CINC280A2108]. No significant difference in exposure was seen when capmatinib 
was given under fasted conditions or with food. The safety profile was similar to that of study 
[CINC280A2201], with no dose-limiting toxicities (DLTs) observed. Given the above, 
capmatinib may be administered with or without food.
Capmatinib is a moderate Cytochrome P450 1A2 (CYP1A2) inhibitor [CINC280A2103] and
an inhibitor of Permeability-GlycoProtein (P-gp) and Breast Cancer Resistance Protein (BCRP)
transporter [CINC280A2105]. Therefore, CYP1A2 substrates, P-gp substrates, and BCRP 
substrates where minimal concentration changes may lead to serious adverse reactions should 
be avoided. If co-administration is unavoidable, decrease the dosage of CYP1A2 substrates, P-
gp substrates, or BCRP substrates in accordance with the approved prescribing information.
When co-administered with the strong Cytochrome P450 3A (CYP3A) inhibitor itraconazole, 
capmatinib Area Under Curve (AUC) increased by approximately 42% without any change in 
Maximum (peak) concentration of drug in plasma (Cmax). When co-administered with the strong 
CYP3A inducer rifampicin, capmatinib AUC and Cmax decreased by 67% and 56%, respectively 
[CINC280A2102]. Hence, adverse reactions during co-administration of capmatinib with 
strong CYP3A inhibitors should be closely monitored, in addition, strong CYP3A inducers 
should be avoided in participants treated with capmatinib.
For further details, please refer to the latest version of the [capmatinib Investigator’s Brochure].
1.2
Purpose
This phase II registration China alone study will assess efficacy and safety of capmatinib in
Chinese participants to support capmatinib new drug application (NDA) in China as a 
monotherapy in patients with MET mutated, advanced/metastatic NSCLC who are treatment 
naive or failed one or two prior lines of systemic therapy.
2
Objectives, endpoints and estimands
Table 2-1
Objectives and related endpoints
Objectives
Endpoints
Primary objective
Endpoints for primary objective

To evaluate the antitumor activity of capmatinib, 
as measured by overall response rate (ORR) by 
blinded independent review committee (BIRC) 
assessment, by cohort

ORR, proportion of participants with a best overall 
response (BOR) defined as complete response or 
partial response (CR+PR) by BIRC assessment per 
RECIST 1.1
Secondary objectives
Endpoints for secondary objectives

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Objectives
Endpoints

To evaluate duration of response (DOR) as 
assessed by BIRC, by cohort

DOR, calculated as the time from the date of the first 
documented CR or PR by BIRC per RECIST 1.1 to 
the first documented progression or death due to 
any cause for participants with PR or CR

To evaluate ORR and DOR by Investigator 
assessment, by cohort

ORR (CR+PR) and DOR per RECIST 1.1 by 
Investigator assessment

To evaluate time to response (TTR), disease 
control rate (DCR) and progression-free survival 
(PFS) by Investigator and by BIRC assessment, 
by cohort

All calculated per RECIST 1.1, both by BIRC and 
Investigator:

TTR, calculated as the time from first dose of 
capmatinib to first documented response (CR+PR) 
for participants with PR or CR

DCR, calculated as the proportion of participants 
with BOR of CR, PR, or SD

PFS, defined as time from first dose of capmatinib to 
progression or death due to any cause

To evaluate overall survival (OS), by cohort

OS, defined as time from first dose of capmatinib to 
death due to any cause

To assess intracranial anti-tumor activity of 
capmatinib in participants with Central Nervous 
System (CNS) lesions at baseline by BIRC

Overall 
intracranial 
response 
rate 
(OIRR),
intracranial disease control rate (IDCR), time to 
intracranial response (TTIR), duration of intracranial 
response (DOIR) by BIRC as per RANO-BM criteria

To evaluate the association between METΔex14
mutation status as measured in ctDNA at 
baseline with capmatinib efficacy

ORR, DOR and PFS per RECIST 1.1 for participants 
by METΔex14 mutation status assessed in ctDNA at 
baseline, both by BIRC and Investigator

To 
characterize 
the 
pharmacokinetics 
of 
capmatinib

Steady state Ctrough and steady state 0.5-1.5 hour 
and 3-5 hours post-dose concentrations

To evaluate capmatinib safety profile

Incidence of adverse events (AEs) and serious 
adverse events (SAEs), change in vital signs, 
laboratory results (hematology, chemistry, and 
urinalysis) and ECG

To assess the effect of capmatinib on patient-
reported disease-related symptoms, functioning, 
and health-related quality of life (HRQoL)

Change from baseline in European Organization for 
Research and Treatment of Cancer (EORTC) QLQ-
C30 and LC13, EuroQoL-5 Dimension-5 Level (EQ-
5D-5L)

To assess the effect of capmatinib on patient-
reported symptoms of brain metastases

Change from baseline to each visit in symptoms of 
brain metastases, with the NCCN FACT-FBrSI
2.1
Primary estimands
The primary scientific question of interest is: what is the effect of capmatinib in inducing 
radiological response in Chinese participants with METΔex14 mutation, regardless of study 
treatment discontinuation and prior to start of new antineoplastic therapy?
The primary estimand will be described by the following five attributes:
1. The population is the adult Chinese participants with EGFR wild-type (wt), ALK 
rearrangement negative, MET exon 14 skipping mutations advanced non-small cell lung 
cancer (NSCLC) who are either treatment naive or failed one or two prior lines of systemic 
therapy
2. The treatment attribute is the oral dose of capmatinib 400 mg administered twice daily (b.i.d.) 
i.e. total dose of 800 mg daily

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3. The variable is the best overall response (BOR) defined as the best response recorded from 
the date of treatment start until disease progression/recurrence (taking as reference for PD, 
the smallest measurement recorded since the treatment started) based on BIRC per RECIST 
1.1. prior to start of any antineoplastic therapy
4. The intercurrent events of interest are:
a. The treatment discontinuation for any reason: tumor assessment data collected 
irrespectively of treatment discontinuation will be included to derive BOR (treatment 
strategy)
b. Start of antineoplastic therapy: if any antineoplastic therapy is taken and any response 
after the antineoplastic therapy will be considered as non-responder (composite strategy)
c. Any public health emergency as declared by local or regional authorities i.e. pandemic, 
epidemic or natural disaster: assessment collected irrespectively of those events will be 
included to derive BOR (treatment policy strategy)
5. The summary measure is the overall best overall response rate (ORR) and its exact 95% 
confidence interval (CI) (Clopper and Pearson 1934) will be provided by cohort.
2.2
Secondary estimands
Not applicable.
3
Study design
This is an open-label, multicenter two-cohort phase II study to evaluate the efficacy and safety 
of single-agent capmatinib in Chinese participants with EGFR wt (EGFR mutations that predict 
sensitivity to EGFR therapy, including, but not limited to exon 19 deletions and exon 21 L858R 
substitution mutations), ALK rearrangement negative, MET exon 14 skipping mutated 
advanced/metastatic NSCLC.
Approximately 35 participants aged 18 or over will be treated in this study in two separate 
cohorts. Cohort 1 will include approximately 15 treatment naive participants and Cohort 2 
approximately 20 participants who failed one or two prior lines of therapy in the advanced stage
(refer to Section 12.8.1). Each participant will receive 400 mg capmatinib tablet b.i.d..
Refer to Figure 3-1 for an overview of the study design.

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Figure 3-1
Study design
Pre-Screening:
Participants must sign a Molecular Pre-Screening Informed Consent Form (ICF) prior to any 
study specific molecular pre-screening evaluations.
In order to be considered eligible for the study, participants must have METΔex14 mutation 
confirmed by a Novartis-designated central laboratory (refer to Section 8.1).
A Subject Number (Subject No.) will be assigned to each participant and the Investigator or 
designated staff will provide the requested identifying information to register the participant in
the Interactive Response Technology (IRT) system.

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Screening:
Participants must sign an Informed Consent Form (ICF) prior to any study specific screening 
evaluations and as early as 28 days prior to the start of study treatment.
Following completion of all required screening procedures (refer to Section 8.2) and verifying 
participant eligibility, the Investigator or designated staff will confirm participant eligibility in 
IRT system.
Treatment:
Study treatment will begin on Cycle 1 Day 1 with the first administration of study treatment. 
Participants will continue treatment until reasons for discontinuation of study treatment are met 
(Section 9.1.1).
Participants will be evaluated radiologically at screening/baseline then every 6 weeks to assess 
treatment response until PD by RECIST 1.1 as assessed by the Investigator and confirmed by 
BIRC.
An end of treatment (EOT) visit will be performed when participants permanently discontinue 
study treatment.
Post-treatment Follow-Up (FUP) (Safety, Efficacy and PRO Follow-Up):
After treatment discontinuation, all participants will be followed for safety evaluations as 
outlined in details in Section 6.5.2 and Section 9.3.1 during the safety follow-up period. 
Participants will be followed for safety up to 30 days after the last dose of study drug. If a new 
antineoplastic therapy is initiated after study treatment, safety follow-up will focus on events 
suspected to be related to study treatment only.
In addition to the 30-day safety follow-up, participants who discontinue study treatment without 
prior documented PD, will continue efficacy assessments (Efficacy Follow-up) during the post-
treatment follow-up until documented PD by RECIST 1.1 as assessed by the Investigator and 
confirmed by BIRC, participant withdrawal of consent, physician's decision, lost to follow-up, 
death, or study is terminated by the sponsor as outlined in Section 8.4.1.4 and 
Section 9.3.2. For these participants, participants-reported outcomes (PRO) will also continue 
to be collected electronically (PRO Follow-up) until documented progression.
Survival Follow-up:
After study treatment discontinuation due to PD or post-treatment follow-up phase 
discontinuation due to other reasons except PD, the participant’s survival status will be collected 
every 12 weeks (via phone calls) as part of the survival follow-up phase (Section 9.3.3).
Every effort should be made to comply with the survival follow-up schedule and ensure 
collection of participant survival data.
4
Rationale
4.1
Rationale for study design
Details on the rationale for the study design is described in the Table 4-1 below.

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Table 4-1
Rationale for study design 
Study Design Aspect
Rationale
Study population
The study will enroll Chinese adult patients with EGFR wt, ALK 
rearrangement negative, MET exon 14 skipping mutations, 
advanced NSCLC who are treatment naive or failed one or two 
prior lines of systemic therapy. Participants must be MET
inhibitor naive.
Participants with targetable oncogenic drivers (such as EGFR-
sensitizing mutations, or ALK translocation) will be excluded as 
approved targeted therapies for such patients exist. For more 
details on study population, please refer to Section 5.
Single arm
This is a very rare patient population with high unmet medical 
need and with no previously conducted study globally with good 
efficacy and safety data. A single arm study is therefore justified 
and will satisfy the health authorities (HA) requirement for 
registration.
Two-cohort study 

Cohort 1: Treatment naive participants with METΔex14
mutated NSCLC who did not receive any systemic therapy for 
advanced/metastatic disease.

Cohort 2: Pre-treated participants with METΔex14 mutated 
NSCLC who failed one or two prior lines of systemic therapy 
for advanced/metastatic disease.
Comparator treatment
Not applicable.
Open-label
Not applicable.
Stratification factors
Not applicable.
Randomization
Not applicable.
Treatment beyond disease progression
This is to ensure those participants (in either cohort) who are 
clinically stable, tolerate the treatment, and are deriving clinical 
benefit can continue to receive treatment. Timely follow-up after 
the initial PD will ensure that participants with confirmed/rapid 
progression will be discontinued and can initiate adequate 
subsequent therapies.
4.2
Rationale for dose/regimen and duration of treatment
Based on the PK and safety data, capmatinib 400 mg b.i.d. in tablet formulation was declared 
to be the recommended phase II dose (RP2D) [CINC280X2102]. Furthermore, robust efficacy 
has been demonstrated in both 2/3L and 1L MET mutant NSCLC participants at this dose level 
[CINC280A2201]. In addition, sustained target coverage was expected at this dose as 96% of 
participants can maintain capmatinib plasma concentration above IC95 for MET inhibition 
during the dosing interval [Population PK report]. For further details, please refer to the latest 
version of the [capmatinib Investigator’s Brochure].
 
 
 
 
 
 
 
CCI

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In this study, capmatinib 400 mg b.i.d. orally will be administered. Duration of treatment is 
continuous until disease progression or other reasons for drug discontinuation. Treatment with 
capmatinib may be continued beyond RECIST1.1-defined PD (as assessed by the Investigator 
and confirmed by BIRC) if considered by the Investigator to be in the best interest of the 
participant and as long as no new anticancer treatment is initiated.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Not applicable.
4.4
Purpose and timing of interim analyses/design adaptations
Not applicable.
4.5
Risks and benefits
The participants enrolled in this study will have stage IIIB, IIIC (not amenable to surgery, 
radiation or multi-modality therapy) or stage IV NSCLC. Given the clinical and molecular 
characteristics of METΔex14 mutated NSCLC, participants have fewer therapeutic options and 
the established standard of care has limited benefit in this patient population.
Capmatinib is one experimental treatment that has shown so far a manageable safety profile and 
clinically meaningful activity in this population (please refer to Section 1.1). Participants 
enrolled in the current study will have the possibility of receiving a potentially efficacious 
treatment for a currently unmet medical need. 
The protocol includes specific eligibility criteria (Section 5), monitoring visits and assessments, 
dose modification and stopping rules, and recommended guidelines for treatment of expected 
toxicities, including identification and management of study-drug induced AEs. Recommended 
guidelines for prophylactic or supportive treatment of expected toxicities, including the 
management of study-drug induced AEs (e.g. infusion reaction, pneumonitis), are provided in 
Section 6.5.
The risk to participants in this trial will be minimized by compliance with the eligibility criteria 
and study procedures, as well as by close clinical monitoring and oversight. As with any clinical 
study, there may be unforeseen risks with the study treatment, which could be serious. The 
specific risks for capmatinib is discussed in Section 4.5.1. For further details, refer to the 
toxicity data provided in the current [capmatinib Investigator’s Brochure].
Women of child-bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study and must agree that in order to participate in the study they must adhere to the 
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contraception requirements outlined in the exclusion criteria. If there is any question that the 
participant will not reliably comply, they should not be entered or continue in the study.
Therefore, the overall safety risk to participants enrolled in this study is considered manageable, 
based on the available clinical safety data for capmatinib, along with the eligibility criteria and 
monitoring measures implemented in this study.
4.5.1
Capmatinib
Based upon the clinical experience with capmatinib to date, the overall risk-benefit assessment 
of capmatinib is considered favorable. The data from study [CINC280A2201] show that 
capmatinib is generally well tolerated and has a manageable safety profile. The safety profile 
in the METΔex14 mutated NSCLC population is consistent with the safety profile of capmatinib 
across multiple clinical studies.
The most frequent adverse events (AEs) on treatment with capmatinib monotherapy include 
peripheral edema, nausea, increased blood creatinine, vomiting, fatigue, decreased appetite, and 
diarrhea.
In addition, pancreatic events (e.g. amylase and lipase increase), and liver function test (LFT) 
alterations (alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) and/or 
bilirubin increase) have been observed in participants treated with capmatinib. To date, a direct 
toxic effect of capmatinib on pancreas cannot be definitively identified. Caution is 
recommended when capmatinib is administered in combination with other drugs with a known 
risk of hepatotoxicity.
Pneumonitis and Interstitial Lung Disease (ILD) have been reported from both capmatinib 
single agent and combination studies with EGFR tyrosine kinase inhibitors (TKIs), including 
events with fatal outcomes. Investigators are advised to carefully monitor participants for signs 
and symptoms of pneumonitis and implement dose modification and follow-up evaluations 
described in the protocol in all capmatinib studies, both single agent and in combination studies.
Finally, capmatinib has shown photosensitization potential in in vitro and in vivo assays. The 
Investigators should recommend the use of precautionary measures against ultraviolet exposure 
to the participants during treatment with capmatinib (e.g. use of sunscreen, protective clothing 
and avoid sunbathing or using a solarium intensively).
For 
further 
information 
on 
potential 
toxicities, 
please 
refer 
to 
the 
current 
[capmatinib Investigator’s Brochure].
4.6
Rationale for Public Health Emergency mitigation procedures
In the event of a public health emergency as declared by local or regional authorities (i.e. 
pandemic, epidemic or natural disaster), mitigation procedures may be required to ensure 
participant safety and trial integrity and are listed in relevant sections of the study protocol. 
Notification of the public health emergency should be discussed with Novartis prior to 
implementation of mitigation procedures, and permitted/approved by local or regional health 
authorities and ethics committees as appropriate.

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5
Study Population
Approximately 35 adult participants with EGFR wt (EGFR mutations that predict sensitivity to 
EGFR therapy, including, but not limited to exon 19 deletions and exon 21 L858R substitution 
mutations), ALK rearrangement negative, advanced (stage IIIB, IIIC or IV, referencing 
CSCO guidelines for primary lung cancer, 2019) NSCLC disease harboring METΔex14 
mutations as determined by a Novartis central molecular laboratory will be treated in this study. 
The 1L cohort includes approximately 15 participants and 2/3L cohort includes approximately 
20 participants.
Participants enrolled in the study are not permitted to participate in additional, parallel, 
investigational drug or device studies.
The Investigator or designee must ensure that only participants who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study.
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study
2. Chinese adult ≥ 18 years old at the time of informed consent
3. Histologically confirmed stage IIIB, IIIC or IV NSCLC at the time of study entry, not 
amenable to curative surgery or radiation or multi-modality therapy (according to staging 
definition in CSCO guidelines for primary lung cancer, 2019).
4. Histologically or cytologically confirmed diagnosis of NSCLC that is:

EGFR wt: The EGFR wt status (EGFR mutations that predict sensitivity to EGFR 
therapy, including, but not limited to exon 19 deletions and exon 21 L858R substitution 
mutations) must be documented in the participant source documents before the 
participant can be consented for pre-screening for MET mutation status

AND ALK rearrangement negative: The ALK rearrangement negative status must be 
documented in the participant source documents before the participant can be consented 
for pre-screening for MET mutation status

AND either: 

Cohort 1: Treatment naive participants with MET mutations, or

Cohort 2: Pre-treated participants with MET mutations
5. Cohort 1: participants must not have received any systemic therapy for advanced/metastatic 
disease (stage IIIB, IIIC or IV NSCLC). Neo-adjuvant and adjuvant systemic therapies will 
not count as one prior line of treatment if relapse occurred > 12 months from the end of the 
neo-adjuvant or adjuvant systemic therapy.
Cohort 2: participants must have failed one or two prior lines of systemic therapy for 
advanced/metastatic disease (stage IIIB, IIIC or IV NSCLC). Treatment failure is defined 
as documented disease progression or intolerance to treatment. Maintenance therapy given 
after first line chemotherapy will be considered as part of the first line if given to participants 
with documented response or stable disease (SD) before starting the maintenance therapy. 
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relapse occurred within 12 months from the end of the neo-adjuvant or adjuvant systemic 
therapy.
6. At least one measurable lesion according to RECIST v1.1. Any lesions which have been 
subjected to percutaneous therapies or radiotherapy should not be considered measurable, 
unless the lesion has clearly progressed since the procedure.
7. Participants must have recovered from all toxicities related to prior anticancer therapies to 
grade ≤ 1 (Common Terminology Criteria for Adverse Events (CTCAE) version 5.0). 
Participants with any grade of alopecia are allowed to enter the study.
8. Participants must have adequate organ function including the following laboratory values 
at the screening visit:

Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without growth factor support

Platelets (PLT) ≥ 75 x 109/L

Hemoglobin (Hgb) ≥ 9 g/dL

Calculated creatinine clearance (using Cockcroft-Gault formula) ≥ 45 mL/min

Total bilirubin ≤ 1.5 x Upper Limit of Normal (ULN)

Aspartate transaminase (AST) ≤ 3 x ULN, except for participants with liver metastasis, 
who may only be included if AST ≤ 5 x ULN

Alanine transaminase (ALT) ≤ 3 x ULN, except for participants with liver metastasis, 
who may only be included if ALT ≤ 5 x ULN

Alkaline phosphatase (ALP) ≤ 5.0 x ULN

Asymptomatic serum amylase ≤ 5 x ULN (grade ≤2). Participants with grade 1 or grade 
2 serum amylase at the beginning of the study must be confirmed to have no signs 
and/or symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-amylase, 
abnormal imaging findings of pancreas, etc.)

Serum lipase ≤ ULN
9. ECOG performance status (PS) ≤1
10. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1. Prior treatment with any MET inhibitor or HGF-targeting therapy.
2. Participants with known hypersensitivity to any of the excipients of capmatinib 
(i.e. crospovidone, mannitol, microcrystalline cellulose, povidone, sodium lauryl sulfate, 
magnesium stearate, colloidal silicon dioxide, and various coating premixes).
3. Participants with known druggable molecular alterations (such as ROS1 translocation or 
BRAF mutation, etc.) which might be a candidate for alternative targeted therapies as 
applicable per local regulations and treatment guidelines.
4. Participants with symptomatic central nervous system (CNS) metastases who are 
neurologically unstable or have required increasing doses of steroids within the 2 weeks 
prior to study entry to manage CNS symptoms. If participants are treated with
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related, dose must have been stabilized (or decreasing) for at least 5 days before first dose 
of capmatinib.
5. Presence or history of carcinomatous meningitis.
6. Presence or history of a malignant disease other than NSCLC that has been diagnosed and/or 
required therapy within the past 3 years. Exceptions to this exclusion include the following: 
completely resected basal cell and squamous cell skin cancers, and completely resected 
carcinoma in situ of any type.
7. Presence or history of interstitial lung disease or interstitial pneumonitis, including 
clinically significant radiation pneumonitis affecting activities of daily living or requiring 
therapeutic intervention.
8. Concomitant medication(s) with a “Known Risk of Torsades de Pointes” per //.qtdrugs.org 
that cannot be discontinued or replaced by safe alternative medication.
9. Clinically significant, uncontrolled heart disease such as:

Unstable angina within 6 months prior to screening

Myocardial infarction within 6 months prior to screening

History of documented congestive heart failure (New York Heart Association 
functional classification III-IV)

Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg 
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without antihypertensive 
medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior 
to screening. If white coat syndrome (WHS) is suspected, blood pressure measurements 
may be repeated.

Ventricular arrhythmias

Supraventricular and nodal arrhythmias not controlled with medication

Other cardiac arrhythmia not controlled with medication

Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome, or QT interval corrected by Fridericia’s formula (QTcF) ≥ 470 ms on the 
screening ECG (as mean of triplicate ECG)
10. Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting capmatinib or participants 
who have not recovered from radiotherapy-related toxicities. For all other anatomic sites 
(including radiotherapy to thoracic vertebrae and ribs), radiotherapy ≤ 2 weeks prior to 
starting capmatinib or participants who have not recovered from radiotherapy-related 
toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting capmatinib is 
allowed.
11. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior (2 
weeks for resection of brain metastases) to starting capmatinib or who have not recovered 
from side effects of such procedure. Thoracoscopy for biopsy and mediastinoscopy will not 
be counted as major surgery and participants can be enrolled in the study ≥ 1 week after the 
procedure.
12. Participants receiving treatment with strong inducers of CYP3A and cannot be discontinued 
at least 1 week prior to the start of treatment with capmatinib and for the duration of the 
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13. Impairment of gastro-intestinal (GI) function or GI disease that may significantly alter the 
absorption of capmatinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, 
or malabsorption syndrome).
14. Unable or unwilling to swallow tablets as per dosing schedule.
15. Substance abuse, active infection (including active hepatitis B and C, participants whose 
disease is controlled under antiviral therapy are eligible, and human immunodeficiency 
virus (HIV) history positive) or other severe, acute, or chronic medical or psychotic 
conditions or laboratory abnormalities that in the opinion of the Investigator may increase 
the risk associated with study participation, or that may interfere with the interpretation of 
study results.
16. Applicable to Cohort 2 only: Previous anti-cancer and investigational agents within 4 weeks 
or ≤ 5 x half-life of the agent (whichever is shorter) before first dose of capmatinib. If 
previous treatment is a monoclonal antibody, then the treatment must be discontinued at 
least 4 weeks before first dose of capmatinib. If previous treatment is an oral targeted agent, 
then the treatment must be discontinued at least 5 x half-life of the agent.
17. Pregnant or nursing (lactating) women.
18. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception while 
taking study treatment and for 7 days after stopping medication. Highly effective 
contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception.

Female bilateral tubal ligation, female sterilization (have had surgical bilateral 
oophorectomy with or without hysterectomy) or total hysterectomy at least six weeks 
before taking study treatment. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow-up hormone level 
assessment.

Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant

Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), 
or other forms of hormonal contraception that have comparable efficacy (failure rate < 
1%), for example hormone vaginal ring or transdermal hormone contraception.
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal if they have had 12 months of natural (spontaneous) 
amenorrhea with an appropriate clinical profile (e.g. age-appropriate history of vasomotor 
symptoms). Women are considered not of child-bearing potential if they are post-
menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), 
total hysterectomy or bilateral tubal ligation at least six weeks prior to enrollment on study. 
In the case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow-up hormone level assessment is she considered to be not of child-
bearing potential.

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19. Sexually active males unwilling to use a condom during intercourse while taking study 
treatment and for 7 days after stopping study treatment. A condom is required for all
sexually active male participants to prevent them from fathering a child AND to prevent 
delivery of study treatment via seminal fluid to their partner. In addition, male participants 
must not donate sperm for the time period specified above.
If local regulations are more stringent than the contraception methods listed above to 
prevent pregnancy, local regulations apply and will be described in the ICF.
20. Participants who received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, 
oral polio, bacillus Calmette-Guerin (BCG), yellow fever, varicella, TY21a typhoid 
vaccines and live COVID-19 vaccines) within 30 days prior to the first dose of study 
treatment.
6
Treatment
6.1
Study treatment
For this study, the investigational drug is capmatinib. The drug will be labeled and provided to 
sites by Novartis in compliance with legal requirements in China.
6.1.1
Investigational drug
The study treatment begins on Cycle 1 Day 1 with the first administration of capmatinib.
Cycle 1 Day 1 should occur on the day of confirmation of participant eligibility into the IRT
system or no later than 3 days after this confirmation.
Capmatinib can be administered with or without food. The morning and the evening doses 
should be taken 12 (± 4) hours apart, although 12-hour interval is highly recommended. The 
morning dose should be taken the same time each morning. If a dose is not taken within 4 hours 
of the planned dosing time, the missed dose should not be replaced.
Table 6-1
Investigational drug
Investigational Drug
(Name and Strength)
Treatment Form 
or 
Pharmaceutical 
Dosage Form
Route of 
Administration
Presentation
Sponsor 
(global or 
local)
Capmatinib (INC280) 
150 mg or 200 mg
Film-coated tablet
Oral use
Open-label, participant 
specific bottles
Global
All doses prescribed and dispensed to the participants, and all dose changes during the study 
must be recorded on the appropriate electronic Case Report Form (eCRF). Refer to 
Section 6.7.2 for study drug prescribing and administration information and to Section 6.5.1 for 
dose modification information.
6.1.2
Additional study treatments
No other treatment beyond investigational drug is included in this trial.
6.1.3
Treatment arms/group
Participants will be assigned to one of the following cohorts:

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
Cohort 1: Treatment naive participants with METΔex14 mutations

Cohort 2: Pre-treated participants with METΔex14 mutations
All participants, regardless of the cohort they belong to, will be treated with capmatinib as 
described below:

Capmatinib 400 mg (tablets) orally b.i.d. with or without food

Capmatinib will be given as continuous daily dosing, and the first dose is administered at 
the study center

A complete cycle of treatment is defined as 21 days of continuous capmatinib treatment.
6.1.4
Guidelines for continuation of treatment
Participant should continue to receive the study treatment until one or more criteria for treatment 
discontinuation described in Section 9.1.1 are met.
Guidelines on the management of common capmatinib associated toxicities and dose 
modification instructions are provided in Section 6.5.1.
6.1.5
Treatment duration
Participants should continue to receive the study treatment until one or more criteria for 
treatment discontinuation described in Section 9.1.1 are met.
Participants may continue treatment beyond disease progression as per RECIST 1.1 criteria
(as assessed by the Investigator and confirmed by BIRC) if, in the judgment of the Investigator, 
there is evidence of clinical benefit and the participant wishes to continue on the study treatment. 
Criteria for treatment beyond progression are described in Section 6.1.5.1.
At the end of the study, every effort will be made to continue provision of study treatment 
outside this study through an alternative setting to participants who in the opinion of the 
Investigator are still deriving clinical benefit, where permitted by and in accordance with local 
laws and regulations.
6.1.5.1
Treatment beyond disease progression
Clinical data indicate that participants may derive benefit from continuing study treatment 
despite initial evidence of disease progression.
Participants treated with capmatinib will be permitted to continue study treatment beyond initial 
disease progression as per RECIST 1.1 criteria (as assessed by Investigator and confirmed by 
BIRC) provided they meet the following criteria:

Evidence of clinical benefit assessed by Investigator

No rapid radiological or clinical progression

Tolerance to study treatment

Should not jeopardize critical interventions to treat/prevent severe complications, or prevent 
participants from receiving adequate care

Participant performance status is stable

Participant wishes to continue on the study treatment

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
No new antineoplastic therapy has been initiated
Participants who meet the above criteria and continue treatment beyond initial disease 
progression as per RECIST 1.1 will continue all study procedures as outlined in Section 8. In 
case of clinical deterioration or suspicion of further disease progression, a follow-up imaging 
assessment should be performed promptly rather than waiting for the next scheduled assessment.
Participants who are no longer deriving clinical benefit, or who meet other protocol 
discontinuation criteria must be discontinued.
6.2
Other treatment(s)
No additional treatment beyond investigational drug is provided in this trial. 
6.2.1
Concomitant therapy
In general, concomitant medications and therapies deemed necessary for the supportive care 
(e.g. such as anti-emetics, anti-diarrhea) and safety of the participant are allowed except when 
specifically prohibited (see Section 6.2.2).
The participant must be told to notify the investigational site about any new medications he/she 
takes after signing the main study ICF. All medications (excluding the current study treatment),
surgeries, procedures and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after the participant signs the main study ICF and up to 30 days after 
the last dose of study drugs must be recorded on the appropriate eCRF. For participants with 
brain metastases at baseline, steroid use should be collected on the appropriate eCRF until 
disease progression (as determined by Investigator and confirmed by BIRC). Medications 
include not only physician prescribed medications, but also all over-the counter medications, 
herbal medications, food supplements and vitamins.
The following restrictions apply during the entire duration of the study:

No other investigational therapy should be given to participants

No anticancer agents other than the study medication should be given to participants.
Participants are permitted to use the following medications while taking study drug:

Oral or topical antibiotics

Medications to prevent or treat nausea, vomiting or diarrhea

Growth factors (e.g. granulocyte colony-stimulating factor (G-CSF), granulocyte-
macrophage colony-stimulating factor (GM-CSF), erythropoietin, platelets growth factors, 
etc.) are allowed per the Investigator’s judgement and per local guidelines.

Oxygen therapy and blood products or transfusions

Nutritional support or appetite stimulants

Pain medication
 
 
 
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6.2.1.1
Permitted concomitant therapy requiring caution and/or action
The following medications should be used with caution when concomitantly used with 
capmatinib treatment in this study:

Capmatinib is a moderate CYP1A2 inhibitor. Co-administration of capmatinib increased 
sensitive CYP1A2 probe substrate (caffeine) AUCinf by 134%. Avoid co-administration 
of capmatinib with CYP1A2 substrates where minimal concentration changes may lead to
serious adverse reactions. If co-administration is unavoidable, decrease the CYP1A2 
substrate dosage in accordance with the approved prescribing information.

Co-administration of capmatinib increased P-gp substrate (digoxin) exposure (AUCinf and 
Cmax by 47% and 74%, respectively) and BCRP substrate (rosuvastatin) exposure 
(AUCinf and Cmax by 108% and 204%, respectively). Avoid co-administration of 
capmatinib with P-gp and BCRP substrates where minimal concentration changes may lead 
to serious adverse reactions. If co-administration is unavoidable, decrease the P-gp or BCRP 
substrate dosage in accordance with the approved prescribing information.

Co-administration of capmatinib with a strong CYP3A inhibitor (itraconazole) increased 
capmatinib AUCinf by 42%. There was no change in capmatinib Cmax. Closely monitor 
patients for adverse reactions during co-administration of capmatinib with strong CYP3A 
inhibitors.

Simulations using physiologically-based pharmacokinetic (PBPK) models predicted that 
coadministration of capmatinib with the moderate CYP3A inducer efavirenz (600 mg once 
daily for 20 days) would result in a 44% decrease in capmatinib AUC0-12h and 34% 
decrease in Cmax at steady-state compared to administration of capmatinib alone. Caution 
should be exercised during concomitant use of capmatinib with moderate CYP3A inducers.
Use an alternative medication with no or minimal potential to induce CYP3A during 
coadministration with capmatinib.

Co-administration of capmatinib with proton pump inhibitor (rabeprazole) decreased 
capmatinib AUCinf by 25% and Cmax by 38%. Exercise caution during concomitant use 
of capmatinib with proton pump inhibitors.

As an alternative to proton pump inhibitors, an H2-receptor antagonist or antacid can be 
taken. Capmatinib should be administered at least 3 hours before or 6 hours after an H2-
receptor antagonist. Capmatinib should be administered at least 2 hours before or 2 hours 
after an antacid.
Refer to Table 6-2 for a list of the medications that require caution when concomitantly used 
with capmatinib.
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Table 6-2
Drugs to be used with caution during co-administration with 
capmatinib
Mechanism of Interaction
Drug Name
Strong CYP3A inhibitors
ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira Pak), indinavir/ritonavir, 
tipranavir/ritonavir, ritonavir, cobicistat, indinavir, ketoconazole, 
troleandomycin, telaprevir, danoprevir/ritonavir, eltegravir/ritonavir, 
saquinavir/ritonavir, lopinavir/ritonavir, itraconazole, voriconazole, 
mibefradil, posaconazole, telithromycin, grapefruit juice, conivaptan, 
nefazodone, nelfinavir, idelalisib, boceprevir, atazanavir/ritonavir, 
darunavir/ritonavir
CYP1A2 substrates with NTI
theophylline, tizanidine
Moderate CYP3A inducers
bosentan, dabrafenib, efavirenz, etravirine, genistein, modafinil, nafcillin, 
tipranavir/ritonavir, lopinavir, telotristat
P-gp substrates
afatinib, alfuzosin, aliskiren, alogliptin, ambrisentan, apixaban, apremilast, 
aprepitant, atorvastatin, boceprevir, bosentan, carvedilol, caspofungin, 
ceritinib, colchicine, cyclosporine, dabigatran, digoxin, docetaxel, doxepin, 
doxorubicin, eribulin, everolimus, fentanyl, fexofenadine, fidaxomicin, 
fluvastatin, fosamprenavir, idelalisib, iloperidone, indacaterol, irbesartan, 
lacosamide, lapatinib, levetiracetam, linagliptin, linezolid, loperamide, 
losartan, maraviroc, mirabegron, nadolol, naloxegol, nateglinide, 
nevirapine, nintedanib, olodaterol, paclitaxel, pantoprazole, paroxetine, 
pazopanib, proguanil, posaconazole, pravastatin, ranolazine, ritonavir, 
riociguat, risperidone, rivaroxaban, saquinavir, silodosin, simeprevir, 
simvastatin, sirolimus, sitagliptin, sofosbuvir, sorafenib, tacrolimus, 
telaprevir, tenofovir, ticagrelor, tipranavir, tolvaptan, topotecan, 
umeclidinium, valsartan, vardenafil, vincristine, voriconazole
BCRP substrates
atorvastatin, daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, 
imatinib, methotrexate, paritaprevir, pitavastatin, rosuvastatin, irinotecan, 
ethinyl estradiol, simvastatin, sofosbuvir, sulfasalazine, tenofovir, 
topotecan, venetoclax
Proton pump inhibitors
esomeprazole, pantoprazole, omeprazole, lansoprazole, rabeprazole, 
dexlansoprazole
H2-receptor antagonists
cimetidine, famotidine, nizatidine, ranitidine
Antacids
aluminum hydroxide, aluminum carbonate, calcium hydroxide, calcium 
carbonate, bismuth subsalicylate
Source: The list is adapted from the Novartis Institutes for Biomedical PK Sciences internal memorandum (v01, 
2018): drug-drug interactions (DDI) database, which is compiled primarily from the Indiana University School of 
Medicine’s “Clinically Relevant” Table (medicine.iupui.edu/flockhart/table.htm), the University of Washington’s 
Drug Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction 
Studies”.
This list may not be exhaustive and could be updated periodically. Please refer to the above links for latest 
information.
NTI: narrow therapeutic index
6.2.1.2
Use of bisphosphonates or RANKL inhibitor
Treatment with bisphosphonates or receptor activator of nuclear factor kappa-B ligand 
(RANKL) inhibitor for pre-existing bone metastases is permitted, if clinically indicated, and 
following existing guidelines in China. Treatment with bisphosphonates or RANKL inhibitor 
should preferably begin before the study treatment is initiated, but can also be initiated during 
therapy only if absence of radiological bone disease progression is well documented (in this 
case, the reason for its use must be clearly documented; i.e. “pre-existing, non-progressing, 
bone metastases”).

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6.2.1.3
Local radiotherapy
Localized palliative radiotherapy for pre-existing, painful bone/liver metastases is permitted. 
Local bone radiotherapy for analgesic purposes or for lytic lesions at risk of fracture may be 
carried out if required. It should not be delivered to a target lesion. If palliative radiotherapy is 
initiated after start of study treatment, the reason for its use must be clearly documented and 
progression as per RECIST 1.1 must be ruled out. The study treatment must be interrupted on 
the days of radiotherapy and can be resumed the day after its completion. Caution is advised 
for radiation to fields that include lung tissue. The radiotherapy must be listed on the 
concomitant antineoplastic therapy – radiotherapy eCRF. After documented progression by 
RECIST 1.1, radiotherapy is allowed following the same dose adjustment guidance in case 
capmatinib is continued beyond PD.
6.2.2
Prohibited medication
During the course of the study, participants must not receive other antineoplastic therapies (e.g. 
investigational drugs, devices, chemotherapy, immunotherapies) or any other therapies that may 
be active against cancer.
There are no prohibited therapies during the post-treatment follow-up period.
During the treatment period, co-administration of capmatinib with a strong CYP3A inducer 
(rifampicin) decreased capmatinib AUCinf by 67% and Cmax by 56% Table 6-3 which may 
decrease capmatinib anti-tumor activity. Therefore, concurrent use of strong CYP3A inducers 
are prohibited [capmatinib Investigator’s Brochure]. The prohibited medications of strong 
CYP3A inducer are listed in the Table 6-3 below.
Drugs with a known risk of torsades de pointes (TdP) are prohibited. For identification of drugs 
with known risk of TdP, please refer to Table 6-4.
Table 6-3
Drugs prohibited while on study
Mechanism of Interaction
Drug Name
Strong CYP3A inducer
carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, 
phenytoin, rifabutin, rifampicin, St. John’s wort (Hypericum perforatum)
Source: The list is adapted from the Novartis Institutes for Biomedical PK Sciences internal memorandum (v01, 
Jan 2018): drug-drug interactions (DDI) database, which is compiled primarily from the Indiana University 
School of Medicine’s “Clinically Relevant” Table (medicine.iupui.edu/flockhart/table.htm), the University of 
Washington’s Drug Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug 
Interaction Studies”
This list gets updated periodically. Kindly refer to the above links for latest information.
Table 6-4
Drugs with a known risk of torsades de pointes prohibited while on 
study
Class of medication
Drug Name
With known risk of torsades de 
pointes
amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, 
chloroquine, chlorpromazine, cilostazol, ciprofloxacin, cisapride, citalopram, 
clarithromycin, disopyramide, dofetilide, domperidone, donepezil, 
dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, 
gatifloxacin, halofantrine, haloperidol, ibutilide, levofloxacin, 
levomepromazine, levosulpiride, methadone, moxifloxacin, ondansetron, 
oxaliplatin, papaverine HCl (intra-coronary), pentamidine, pimozide, 

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Class of medication
Drug Name
procainamide, propofol, quinidine, roxithromycin, sevoflurane, sotalol, 
sulpiride, sultopride, terlipressin, terodiline, thioridazine, vandetanib
Check: Crediblemeds.org for the most updated list.
This list gets updated periodically. Kindly refer to the above links for latest information.
Additionally, live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG,
yellow fever, varicella, TY21a typhoid vaccines and live COVID-19 vaccines) must not be 
administered while a participant is on study treatment and for 30 days after the last dose of study 
treatment. Other types of vaccines with other mechanisms of action such as inactivated vaccines, 
messenger Ribonucleic Acid (mRNA) vaccines, Deoxyribonucleic Acid (DNA)-based vaccines 
and viral vector based vaccines are permitted for use.
6.3
Participant numbering, treatment assignment, randomization
6.3.1
Participant numbering
Each participant is identified in the study by a Subject Number (Subject No.), that is assigned 
when the participant signs the molecular pre-screening ICF and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is rescreened. The Participant No. consists of the Site
Number (Site No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the molecular pre-screening ICF, the participant is 
assigned to the next sequential Participant No. available.
At the molecular pre-screening visit, the Investigator or designated staff will contact the IRT 
and provide the requested identifying information for the participant to register him/her into the 
IRT system. Once assigned, the participant No. must not be reused for any other participant. In 
case of re-screening a new participant No. will be assigned to participant through the Clinical 
Data Management System interface and this new participant No. will be provided to IRT for 
registration as re-screened participant.
6.3.2
Treatment assignment, randomization
No randomization will be performed in this study.
Prior to dosing, for all participants who fulfill all inclusion/exclusion criteria, the Investigator 
or his/her delegate will log on to the IRT system and confirm that the participant fulfills all the 
inclusion/exclusion criteria by completing the key eligibility criteria checklist embedded in the 
system. All participants who fulfill all inclusion/exclusion criteria will be assigned to one of the 
cohorts of interest based on prior treatment status results and information will be collected via 
IRT:
Cohort 1: Treatment naive participants with MET mutations regardless of MET gene copy 
number (GCN)
Cohort 2: Pre-treated participants with MET mutations regardless of MET GCN
The IRT will also specify medication number of the bottles of capmatinib (INC280) to be 
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If the participant fails to start treatment for any reason, the reason will be entered into the 
screening disposition eCRF. IRT must be notified within 2 days if the screened participant failed 
to start treatment.
6.4
Treatment blinding
This is an open-label study. Treatment will be open to participants, Investigator staff, persons 
performing the assessments, and the clinical trial team (CTT).
6.5
Dose escalation and dose modification
6.5.1
Dose modifications
For participants who do not tolerate the protocol-specified dosing schedule, dose interruptions, 
and/or reductions are either recommended or mandated in order to allow participants to continue 
the study treatment.
The following guidelines should be considered:
Dose reductions are allowed for capmatinib and should follow the dose reduction steps 
described in Table 6-5 and Table 6-6. For each participant, a maximum of two consecutive dose 
level reductions is allowed after which the participant must be discontinued. Dose reductions 
of capmatinib below 200 mg b.i.d. are not permitted. The lowest dose allowed, 200 mg b.i.d. in 
tablets is expected to be pharmacologically active, as the observed steady state plasma trough 
concentrations ([CINC280X1101], [CINC280X2202], n=6) were above the concentration 
associated with full MET inhibition in xenograft mice models (IC90, 120 nM total concentration).
For participants who do not tolerate the protocol-specified dosing schedule, dose interruptions 
are permitted in order to allow participants to continue the study treatment. All dose 
modifications, interruptions or discontinuations must be based on the worst preceding toxicity 
as graded by the National Cancer Institute (NCI) - CTCAE version 5.0. Any changes must be 
recorded on the dosage administration eCRF page.
A participant must discontinue treatment with capmatinib if, after treatment is resumed at the 
lowest allowed dose (200 mg b.i.d.), the toxicity recurs with the same or worse severity despite 
use of maximal preventive measures as per the institution guidelines for toxicity prevention and 
management.
Unless otherwise indicated in Table 6-6, for grade 1 and tolerable grade 2 treatment-related 
toxicities, participants may continue full doses of capmatinib. For intolerable grade 2 or grade 
3 treatment-related toxicities, dosing should be interrupted until at least resolution to grade 1 
followed by either dose reduction or re-initiation at the same dose level, depending on the type 
of toxicity as described in Table 6-6. For any grade 4 toxicity, except for neutropenia, febrile 
neutropenia, anemia and thrombocytopenia, participants should interrupt capmatinib until 
resolution to grade 1, followed by either dose reduction or treatment discontinuation (refer to
Table 6-6).
Permanent treatment discontinuation is mandatory for specific events indicated as such in 
Table 6-6 or listed in Section 6.5.2. Deviations to mandatory dose discontinuations are not 
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Dose re/escalation of study treatment to previous dose level is allowed only once, and if no AE 
leading to dose modification is observed after at least 1 cycle (3 weeks) of study treatment at 
the reduced dose.
Any planned variance from the guidelines in Table 6-6, in view of participant safety (unless 
there is an urgent need for action) when in the opinion of the Investigator the participant 
continues to experience clinical benefit, should first be discussed and approved by the Novartis 
Medical Lead or designee.
Events not included in the study protocol or the reference guidance documents should be 
managed according to local practices.
Table 6-5
Dose reduction steps for capmatinib
Capmatinib
Starting dose level 0
Dose level - 1
Dose level - 2
400 mg b.i.d.
300 mg b.i.d.
200 mg b.i.d.
Dose reduction should be based on the worst toxicity demonstrated at the last dose.
Dose reduction below 200 mg b.i.d. is not allowed.
Table 6-6
Criteria for dose reduction / interruption and re-initiation / permanent 
discontinuation of capmatinib treatment for adverse drug reactions
Worst toxicity CTCAE Gradea during a cycle of therapy
No toxicity
Maintain dose level
HEMATOLOGICAL
Neutrophil count decreased (ANC) Neutropenia
Grade 1 (ANC < LLN - 1500/mm3; < LLN - 1.5 x 109/L)
Maintain dose level
Grade 2 (ANC < 1500 - 1000/mm3; < 1.5 - 1.0 x 109/L)
Maintain dose level
Grade 3 (ANC < 1000 - 500/mm3; < 1.0 - 0.5 x 109/L)
Omit dose until resolved to ≤ grade 2, then:
If resolved in ≤ 7 days, resume treatment at the 
same dose level
If resolved in > 7 days, then ↓ 1 dose level
Grade 4 (ANC < 500/mm3; < 0.5 x 109/L)
Omit dose until resolved to ≤ grade 2 and then ↓ 1 
dose level
Platelet count decreased (Thrombocytopenia)
Grade 1 (PLT < LLN - 75,000/mm3; < LLN - 75 x 109/L)
Maintain dose level
Grade 2 (PLT < 75,000 - 50,000/mm3; < 75 - 50 x 109/L)
Maintain dose level
Grade 3 (PLT < 50,000 - 25,000/mm3; < 50 - 25 x 109/L)
Omit dose until resolved to ≤ grade 2, then:
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then ↓ 1 dose level
Grade 4 (PLT < 25,000/mm3; < 25 x 109/L)
Omit dose until resolved to ≤ grade 2, then ↓1 dose 
level
Febrile neutropenia (ANC < 1000/mm3 (< 1.0 x 109/L), 
fever > 38.3°C)
Omit dose, then:
If resolved in ≤ 7 days, resume treatment at ↓ 1 
dose level
If resolved in > 7 days, permanently discontinue 
participant from capmatinib treatment
Hemoglobin decreased (Anemia)
Grade 1 (Hgb <LLN - 10.0 g/dL; <LLN - 6.2 mmol/L; 
<LLN – 100 g/L)
Maintain dose level

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Grade 2 (Hgb <10.0 - 8.0 g/dL; <6.2 - 4.9 mmol/L; <100 
– 80 g/L)
Maintain dose level
Grade 3 (Hgb <8.0 g/dL; <4.9 mmol/L; <80 g/L; 
transfusion indicated)
Omit dose until resolved to ≤ grade 2, then:
If resolved in ≤ 7 days, resume treatment at the 
same dose level
If resolved in > 7 days, then ↓ 1 dose level
Grade 4 (Life-threatening consequences; urgent 
intervention indicated)
Omit dose until resolved to ≤ grade 2 and then ↓ 1 
dose level
If toxicity recurs, permanently discontinue 
participant from capmatinib treatment.
RENAL
Serum creatinine
Grade 1 (> ULN - 1.5 x ULN)
Maintain dose level
Grade 2 (> 1.5 - 3.0 x ULN)
Omit dose until resolved to ≤ grade 1 or baseline, 
then resume treatment at the same dose level.
Grade 3 (> 3.0 - 6.0 x ULN)
Omit dose until resolved to ≤ grade 1 or baseline, 
then resume treatment at ↓ 1 dose level.
Grade 4 (> 6.0 x ULN)
Permanently discontinue participant from 
capmatinib treatment
HEPATIC
Isolated Total Bilirubin elevation*
Grade 1 (> ULN - 1.5 x ULN)
Maintain dose level
Grade 2 (> 1.5 - 3.0 x ULN)
Omit dose until resolved to ≤ grade 1, then
If resolved in ≤ 7 days, maintain dose level
If resolved in > 7 days, ↓1 dose level
Grade 3 (> 3.0 - 10.0 x ULN)
Omit dose until resolved to ≤ grade 1, then
If resolved in ≤ 7 days, ↓ 1 dose level
If resolved in > 7 days, permanently discontinue
participant from capmatinib treatment
Grade 4 (> 10.0 x ULN)
Mandatory: Permanently discontinue participant 
from capmatinib treatment
Isolated AST or ALT elevation
Grade 1 (> ULN - 3 x ULN)
Maintain dose level
Grade 2 (> 3.0 - 5.0 x ULN)
Maintain dose level
Grade 3 (> 5.0 - 20.0 x ULN)
Omit dose until resolved to ≤ grade 1 (or ≤ grade 2 
if grade 2 elevation at baseline) then
If resolved in ≤ 7 days, then resume treatment at 
the same dose level
If resolved in > 7 days, resume treatment at ↓ 1 
dose level
Grade 4 (> 20.0 x ULN)
Mandatory: Permanently discontinue participant 
from capmatinib treatment
Combined elevations of AST or ALT and Total Bilirubin b,c,d
For participants with normal baseline ALT and AST and 
total bilirubin value:
AST or ALT > 3.0 x ULN combined with total bilirubin > 
2.0 x ULN without evidence of cholestasis or hemolysis
OR
For participants with elevated baseline AST or ALT or 
total bilirubin value:
Mandatory: Permanently discontinue participant 
from capmatinib treatment

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[AST or ALT > 3 x baseline] OR [AST or ALT > 8.0 x 
ULN], whichever is lower, combined with [total bilirubin > 
2 x baseline AND > 2.0 x ULN] without evidence of 
cholestasis or hemolysis
METABOLIC
Amylase and/or lipase elevation
Grade 1 (> ULN - 1.5 x ULN)
Maintain dose level
Grade 2 (> 1.5 - 2.0 x ULN; >2.0 - 5.0 x ULN and 
asymptomatic)
Maintain dose level
Grade 3 (> 2.0 - 5.0 x ULN with signs or symptoms; >5.0 
x ULN and asymptomatic)
Omit the dose until resolved to ≤ grade 2, then
If resolved in ≤ 14 days, resume treatment at the 
same dose level
If resolved in > 14 days, then ↓ 1 dose level
Grade 4 (> 5.0 x ULN with signs or symptoms)
Permanently discontinue participant from 
capmatinib treatment
CARDIAC
Electrocardiogram QT corrected (QTc) interval prolonged
Grade 1 (QTcF 450-480 ms)
Maintain dose level
Grade 2 (QTcF 481-500 ms)
Maintain dose level
Grade 3 (QTcF ≥ 501 ms on at least two separate 
ECGs)
Omit dose until resolved to ≤ grade 2, then:
If resolved in ≤ 7 days, resume treatment at the 
same dose level
If resolved in > 7 days, then ↓ 1 dose level
Grade 4 (QTcF ≥ 501 or > 60 ms change from baseline 
and Torsades de pointes or polymorphic ventricular 
tachycardia or signs/symptoms of serious arrhythmia)
Permanently discontinue participant from 
capmatinib treatment
GASTROINTESTINAL
Pancreatitis
Grade 2
Maintain dose level
Grade ≥ 3
Mandatory: Permanently discontinue participant 
from capmatinib treatment
Diarrhea**
Grade 1 (despite appropriate anti-diarrheal medication)
Maintain dose level
Grade 2 (despite maximal anti-diarrheal medication)
Omit dose until resolved to ≤ grade 1, then 
maintain dose level.
If diarrhea returns as ≥ grade 2, then omit dose 
until resolved to ≤ grade 1, then resume treatment 
at ↓ 1 dose level
Grade 3 or 4 (despite appropriate anti-diarrheal 
medication)
Omit dose until resolved to ≤ grade 1, then resume 
treatment at ↓ 1 dose level
Vomiting
Grade 1 (despite appropriate anti-emetics)
Maintain dose level
Grade 2 (despite appropriate anti-emetics)
Omit dose until resolved to ≤ grade 1, then 
maintain dose level.
If vomiting returns as ≥ grade 2, then omit dose 
until resolved to ≤ grade 1, then ↓ 1 dose level
Grade 3 (despite appropriate anti-emetics)
Omit dose until resolved to ≤ grade 1, then ↓ 1 
dose level
Grade 4 (despite appropriate anti-emetics)
Omit dose until resolved to ≤ grade 1, then ↓ 1 
dose level

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Nausea
Grade 1 or 2 (despite appropriate anti-emetics)
Maintain dose level
Grade 3 (despite appropriate anti-emetics)
Omit dose until resolved to ≤ grade 1, then ↓ 1 
dose level
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Rash/photosensitivity***
Grade 1
Maintain dose level.
Grade 2
Maintain dose level.
Grade 3, despite skin toxicity therapy
Omit dose until resolved to grade ≤ 1, then:
If resolved in ≤ 7 days, then resume treatment at ↓ 
1 dose level
If resolved in > 7 days (despite appropriate skin 
toxicity therapy), then permanently discontinue 
participant from capmatinib treatment
Grade 4, despite skin toxicity therapy
Omit dose and permanently discontinue participant 
from capmatinib treatment
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Interstitial Lung Disease (ILD) /Pneumonitis
Monitor participants for pulmonary symptoms indicative of ILD/Pneumonitis. In addition, withhold capmatinib for 
acute onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever and 
during diagnostic workup for ILD/Pneumonitis to exclude alternative causes such as, but not limited to 
infections, lymphangitic carcinomatosis, cardiogenic edema, or pulmonary hemorrhage.
Grade 1
Interrupt capmatinib during diagnostic workup for 
ILD/Pneumonitis. Exclude infections and other 
etiologies.
In presence of diagnosis of ILD/Pneumonitis after 
diagnostic workup, it is mandatory to permanently 
discontinue capmatinib.
Only in the absence of a diagnosis of 
ILD/Pneumonitis, capmatinib may be restarted at 
the same dose.
If it recurs after resumption of capmatinib, 
permanently discontinue capmatinib.
Grade 2
Mandatory: Interrupt capmatinib dose during 
diagnostic workup for ILD until improvement to ≤ 
Grade 1. Exclude infections and other etiologies.
In presence of diagnosis of ILD/Pneumonitis after 
diagnostic workup, it is mandatory to permanently 
discontinue capmatinib.
Only in the absence of a diagnosis of 
ILD/Pneumonitis, capmatinib may be restarted 
following these guidelines: 

If resolves to ≤ Grade 1 in ≤ 7 days reduce 
capmatinib by 1 dose level

If fails to resolve to ≤ Grade 1 within 7 days or 
recurs after resumption of capmatinib
at 
decreased dose, permanently discontinue 
capmatinib
Grade 3 and Grade 4
Mandatory: Permanently discontinue capmatinib
Treat with intravenous (i.v.) steroids as clinically 
indicated. Oxygen therapy as indicated
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

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Fatigue/ Asthenia
Grade 1 or 2
Maintain dose level
Grade 3
Omit dose until resolved to ≤ grade 1, then:
If resolved in ≤ 7 days, resume treatment at same 
dose level
If resolved in > 7 days, resume treatment at↓ 1 
dose level
Peripheral edema
Grade 1 or 2
Maintain dose level
Grade 3
Omit dose until resolved to ≤ Grade 1, then ↓ 1 
dose level
Grade 4
Permanently discontinue capmatinib treatment
Other adverse events
Grade 1 or 2
Maintain dose level, consider to initiate appropriate 
support medication.
For any intolerable grade 2 (e.g.: limiting 
instrumental ADL), consider omitting the dose until 
resolved to ≤ grade 1, then restart either at same 
dose or ↓ 1 dose level.
Grade 3
Omit dose until resolved to ≤ grade 1, then↓ 1 dose 
level
Grade 4
Permanently discontinue participant from 
capmatinib treatment
LLN: Lower Limit of Normal / ULN: Upper Limit of Normal
All dose modifications should be based on the worst preceding toxicity
a Common Toxicity Criteria for Adverse Events (CTCAE Version 5.0).
b “Combined” defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST increase to 
the defined threshold.
c “Cholestasis” defined as: ALP elevation (> 2.0 x ULN and R value (ALT/ALP in x ULN) < 2.0) in participants 
without bone metastasis, or elevation of ALP liver fraction in participants with bone metastasis.
d If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the 
instructions for isolated elevation of total bilirubin and isolated elevation of AST/ALT, and take a conservative 
action based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is 
needed for one parameter and discontinue treatment is required for another parameter). After all elevations 
resolve to the defined thresholds that allow treatment re-initiation, re-start the treatment either at the same 
dose or at one dose lower if meeting a criterion for dose reduction.
* Note: If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as 
the aetiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear and 
haptoglobin determination), then ↓ 1 dose level and continue treatment at the discretion of the Investigator.
** Note: antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt 
diarrhea.
*** During the whole duration of treatment with capmatinib, the participant is recommended to use precautionary 
measures against ultraviolet exposure (e.g., use of sunscreen, protective clothing and avoid sunbathing or 
using a solarium intensively.
6.5.2
Treatment interruption and treatment discontinuation
If the administration of capmatinib is temporarily interrupted for reasons other than toxicity up 
to 21 days, then treatment with capmatinib may be resumed at the same dose. If the treatment 
with capmatinib is withheld due to toxicity, the dose modification guidelines in Table 6-5
should be followed. In any case, scheduled visits and all assessments (including tumor 
assessments) should continue to be performed, as described in Table 8-2.

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If the treatment with capmatinib is withheld for more than 21 consecutive days (counting from 
the first day when a dose was interrupted), then study treatment should be permanently 
discontinued. Under exceptional circumstances, when the Investigator believes that continuing 
treatment may still derive clinical benefit for the participant, study treatment may be resumed. 
However, the Investigator must discuss and receive approval from Novartis Medical Lead or 
designee prior to continuing study treatment and rational should be captured in the source 
documents.
Participants who discontinue the study due to a study drug related AE or an abnormal laboratory 
value must be followed as described in Section 6.5.3.
6.5.3
Follow-up for toxicities
All participants will be followed for safety until 30 days after the last dose of capmatinib. 
Participants whose treatment is temporarily interrupted or permanently discontinued due to an 
AE or abnormal laboratory value must be followed until resolution or stabilization of the event, 
whichever comes first, including all study assessments appropriate to monitor the event.
An unscheduled assessment should be performed in all cases below where toxicity monitoring 
is recommended more frequently than defined by the schedule of assessments. Subsequent 
monitoring must be performed as per the regular visit schedule.
Table 6-7
Follow-up evaluations for selected toxicities
TOXICITY
FOLLOW-UP EVALUATION
HEMATOLOGICAL
Febrile neutropenia,
Neutropenia ≥ CTCAE grade 3
Thrombocytopenia ≥ CTCAE grade 3
Anemia ≥ CTCAE grade 3
Test weekly (or more frequently if clinically indicated) until ≤ 
CTCAE grade 2.
Perform physical exam for check on bruising in case of major 
thrombocytopenia.
RENAL
Serum creatinine ≥ CTCAE grade 2
Test weekly (or more frequently if clinically indicated) until ≤ 
CTCAE grade 1 or baseline.
Participants will be instructed to increase hydration until 
resolution to ≤ CTCAE grade 1 or baseline.
HEPATIC
Isolated total bilirubin elevation
Total bilirubin CTCAE Grade 1:
Monitor LFTs per protocol or more frequently if clinically 
indicated
Total bilirubin CTCAE Grade 2:
Weekly monitoring of LFTs, or more frequently if clinically 
indicated, until resolved to ≤ 1.5 x ULN
Total bilirubin CTCAE Grade 3:
Weekly monitoring of LFTs, or more frequently if clinically 
indicated, until resolved to ≤ 1.5 x ULN. If resolved in > 7 days, 
after discontinuing the participant from capmatinib permanently, 
the participant should be monitored weekly (including LFTs), or 
more frequently if clinically indicated, until total bilirubin have 
resolved to baseline or stabilization over 4 weeks
Total bilirubin CTCAE Grade 4:

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After discontinuing the participant from capmatinib permanently, 
the participant should be monitored weekly (including LFTs), or 
more frequently if clinically indicated, until total bilirubin has
resolved to baseline or stabilization over 4 weeks
Isolated AST/ALT elevation
AST/ALT CTCAE Grade 2 elevation:
For participants with baseline value ≤ 3.0 x ULN: repeat LFTs as 
soon as possible, preferably within 48-72 hours from awareness 
of the abnormal results; if abnormal lab values are confirmed 
upon the repeat test, then monitor LFTs weekly, or more 
frequently if clinically indicated, until resolved to ≤ 3.0 x ULN
For participants with baseline value > 3.0 – 5.0 x ULN: monitor 
LFTs per protocol or more frequently if clinically indicated
AST/ALT CTCAE Grade 3 elevation:
For AST/ALT elevation > 5.0 - 10.0 x ULN:
For participants with baseline value ≤ 3.0 x ULN: repeat LFTs as 
soon as possible, preferably within 48-72 hours from awareness 
of the abnormal results; monitor LFTs weekly, or more frequently 
if clinically indicated, until resolved to ≤ 3.0 x ULN
For participants with baseline value > 3.0 – 5.0 x ULN: repeat 
LFTs as soon as possible, preferably within 48-72 hours from 
awareness of the abnormal results; if abnormal lab values are 
confirmed upon the repeat test, then monitor LFTs, weekly, or 
more frequently if clinically indicated, until resolved to ≤ 5.0 x 
ULN
For AST/ALT elevation > 10.0 - 20.0 x ULN:
Repeat LFTs as soon as possible, preferably within 48-72 hours 
from awareness of the abnormal results; monitor LFTs weekly, 
or more frequently if clinically indicated, until resolved to ≤ 
baseline
AST/ALT CTCAE Grade 4 elevation:
Repeat LFTs as soon as possible, preferably within 48-72 hours 
from awareness of the abnormal results; monitor LFTs weekly, 
or more frequently if clinically indicated, until resolved to 
baseline or stabilization over 4 weeks.
Combined elevations in ALT and/or AST 
with concurrent total bilirubin increase, in 
the absence of cholestasis or hemolysis
Combined elevations of AST or ALT and total bilirubin:
After discontinuing the participant from capmatinib permanently, 
repeat LFTs as soon as possible, preferably within 48 hours 
from awareness of the abnormal results, then with weekly 
monitoring of LFTs, or more frequently if clinically indicated, until 
AST, ALT, or bilirubin have resolved to baseline or stabilization 
over 4 weeks.
Core LFTs consist of ALT, AST, Gamma-Glutamyl Transferase 
(GGT), total bilirubin (fractionated [direct and indirect], if total 
bilirubin > 2.0 x ULN), and alkaline phosphatase (fractionated 
[quantification of isoforms], if alkaline phosphatase > 2.0 x ULN.)
METABOLIC
Amylase or lipase ≥ CTCAE grade 3
Test weekly (or more frequently) until ≤ CTCAE grade 2.
A Computerized Tomography (CT) scan or equivalent imaging 
procedure to assess the pancreas, liver, and gallbladder is 
recommended within 7 days of the first occurrence of any ≥ 
CTCAE grade 3 result, to exclude disease progression or 
potential other liver or pancreatic disease.
CARDIAC
≥ CTCAE grade 3
Test weekly (or more frequently) until ≤ CTCAE grade 2.

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QTcF ≥ 501 ms (CTCAE grade 3)
When QTcF ≥ 501 ms (CTCAE grade 3), perform the following:
Perform an analysis of serum potassium, calcium, phosphorus, 
and magnesium, and if below lower limit of normal, correct with 
supplements to within normal limits.
Review concomitant medication usage for the potential to 
prolong the QT-interval.
Check compliance with correct dose and administration of 
capmatinib.
Perform a repeat ECG within one hour of the first QTcF of 
≥501 ms.
If QTcF remains ≥ 501 ms, repeat ECG as clinically indicated, 
but at least once daily until the QTcF returns to < 501 ms.
Repeat ECGs 7 days and 14 days (and then every 21 days) 
after dose resumption for all participants who had therapy 
interrupted due to QTcF ≥ 501 ms.
If QTcF of ≥ 501 ms recurs, repeat ECGs as described above.
Notes:
The Investigator should contact the Novartis Medical Lead or 
designee regarding any questions that arise if a participant with 
QTcF prolongation should be maintained on study.
GASTROINTESTINAL
Diarrhea
Investigate potential concomitant medication, food or 
comorbidity driven causes of diarrhea (including infectious 
causes) and remedy these causes if possible (e.g. 
discontinuation of concomitant medication, dietary modification, 
treatment of comorbidity).
The participant should be monitored for signs of dehydration and 
instructed to take preventive measures against dehydration as 
soon as diarrhea occurs. Antidiarrheal medication must be 
initiated at the first sign of abdominal cramping, loose stools or 
overt diarrhea. Concomitant medication for the treatment of 
diarrhea should follow local practice and the Investigator’s best 
judgment and may follow “the recommended guidelines for the 
treatment of cancer treatment-induced diarrhea”
(Benson et al 2004). For example:
For uncomplicated diarrhea (grade 1 or 2 without complicating 
signs or symptoms), loperamide given at a standard dose (e.g. 
initial administration of 4 mg, then 2 mg every 2-4 hours, 
maximum of 16 mg/day), along with oral hydration and dietetic 
measures should be considered. Note: complicating signs or 
symptoms include: moderate to severe cramping, decreased 
performance status, fever, neutropenia, frank bleeding or 
dehydration.
For complicated diarrhea (all grade 3 or 4, grade 1-2 with 
complicating signs or symptoms), management should involve 
intravenous (IV) fluids, and consider treatment with octreotide (at 
starting dose of 100 to 150 µg sub-cutaneous tid or 25 to 50 µg 
IV) and antibiotics (e.g. fluoroquinolone) should be given.
Nausea and Vomiting
The Investigator should consider/investigate potential 
concomitant medication, food or comorbidity driven causes of 
nausea and/or vomiting and remedy these causes if possible 
(e.g. discontinuation of concomitant medication, dietary 
modification, treatment of comorbidity).
Individualized supportive and anti-emetic treatment should be 
initiated, as appropriate, at the first signs and/or symptoms of 
these AEs. In participants with vomiting, the participant should 

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be monitored for signs of dehydration and instructed to take 
preventive measures against dehydration.
Concomitant medication for the treatment of nausea and/or 
vomiting should follow local practice and the Investigator’s best 
judgment.
SKIN TOXICITY
Rash and Photosensitivity
CTCAE grade 1
Consider to initiate appropriate skin toxicity therapy (such as 
antihistamines, topical corticosteroids and low-dose systemic 
corticosteroids)
CTCAE grade 2
Initiate/intensify appropriate skin toxicity therapy (such as 
antihistamines, topical corticosteroids and low-dose systemic 
corticosteroids).
≥CTCAE grade 3
Intensify appropriate skin toxicity therapy and monitor weekly or 
more frequently until resolved to grade ≤ 2
Peripheral edema
CTCAE grade≤2
Consider to initiate conservative measures such as leg 
elevation, compression stockings, and dietary salt modification 
as clinically indicated.
CTCAE grade≥3
Initiate/intensify conservative measures
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
ILD/Pneumonitis
CTCAE Grade 1
CT scan (high-resolution with lung windows) recommended, with 
serial imaging to monitor for resolution or progression- re-image 
at least every 3 weeks
Monitor for symptoms every 2-3 days - Clinical evaluation and 
laboratory work-up for infection
Monitoring of oxygenation via pulse oximetry recommended
Consultation of pulmonologist recommended
CTCAE Grade 2
CT scan (high-resolution with lung windows)
• Monitor symptoms daily, consider hospitalization
• Clinical evaluation and laboratory work up for infection
• Consult pulmonologist
• Pulmonary function tests a - if normal at baseline, repeat every 
8 weeks
• Bronchoscopy with biopsy and/or BAL recommended c
Symptomatic therapy including corticosteroids if clinically 
indicated (1 to 2 mg/kg/day prednisone or equivalent as clinically 
indicated) b
CTCAE Grade 3 and Grade 4
CT scan (high-resolution with lung windows)
Clinical evaluation and laboratory work-up for infection
Consult pulmonologist
Pulmonary function testsa-if < normal, repeat every 8 weeks until 
≥ normal
Bronchoscopy with biopsy and/or BAL if possiblec
Treat with i.v steroids (methylprednisolone 125 mg) as indicated. 
When symptoms improve to ≤ Grade 1, a high dose oral steroid 
(prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg 
every 4 hours)b.
If i.v. steroids followed by high dose oral steroids does not 
reduce initial symptoms within 48 to 72 hours, consider non-
corticosteroid immunosuppressive medication

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a PFT (Pulmonary function tests) to include: diffusing capacity of the lungs for carbon monoxide (DLCO)
corrected for hemoglobin; spirometry; resting oxygen saturation.
Guideline for significant deterioration in lung function: Decrease in spirometry and/or DLCO of 30% and/or O2 
saturation ≤ 88% at rest on room air.
b Duration and dose of course of corticosteroids will vary according to circumstances but should be as limited 
as possible. Consider tapering dosage at end.
c If bronchoscopy is performed, bronchoalveolar lavage (BAL) should be done where possible to exclude 
alveolar hemorrhage, opportunistic infections, cell count + determination lymphocyte CD4/8 count where 
possible.
6.5.3.1
Follow-up on potential drug-induced liver injury cases
Participants with transaminase increase combined with total bilirubin increase may be 
indicative of potentially severe drug-induced liver injury (DILI) and should be considered as 
clinically important events and assessed appropriately to establish the diagnosis. The required 
clinical information, as detailed below, should be sought to obtain the medical diagnosis of the 
most likely cause of the observed laboratory abnormalities.
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and total 
bilirubin value; participants meeting any of the following criteria will require further follow-up 
as outlined below:

For participants with normal ALT and AST and total bilirubin value at baseline: AST or 
ALT > 3.0 x ULN combined with total bilirubin > 2.0 x ULN

For participants with elevated AST or ALT or total bilirubin value at baseline: [AST or 
ALT >3.0 x baseline] OR [ALT or AST > 8.0 x ULN], whichever is lower, combined with 
[total bilirubin > 2.0 x baseline AND > 2.0 x ULN]
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed to be the cause of liver injury.
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre-
existing liver conditions or risk factors, should be collected.
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, gamma-
glutamyl transferase (GGT), prothrombin time (PT)/ International Normalized Ratio (INR), 
alkaline phosphatase, albumin, and creatine kinase. If available, testing of Glutamate 
Dehydrogenase (GLDH) is also recommended.
Evaluate status of liver metastasis (new or exacerbation) or vascular occlusion – e.g. using 
computerized tomography (CT), magnetic resonance imaging (MRI), or duplex sonography.
Perform relevant examinations (Ultrasound or MRI, Endoscopic Retrograde Cholangio-
Pancreatography (ERCP) as appropriate, to rule out an extrahepatic cause of cholestasis. 
Cholestasis (is defined as an ALP elevation > 2.0 x ULN with R value < 2 in participants without 
bone metastasis, or elevation of the liver-specific ALP isoenzyme in participants with bone 
metastasis).
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. In clinical 

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situations where it is suspected that ALP elevations are from an extrahepatic source, the GGT 
can be used if available. GGT may be less specific than ALP as a marker of cholestatic injury, 
since GGT can also be elevated by enzyme induction or by ethanol consumption. It is more 
sensitive than ALP for detecting bile duct injury.
Table 6-8 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule out possible alternative causes of observed LFT abnormalities.
Table 6-8
Specific assessments to rule out possible causes of LFT 
abnormalities
Disease
Assessment
Hepatitis A (HAV), Hepatitis B
(HBV), Hepatitis C (HCV), 
Hepatitis E (HEV)
Immunoglobulin M (IgM) anti-HAV; Hepatitis B virus surface Antigen 
(HBsAg), IgM & Immunoglobulin G (IgG) anti-Hepatitis B core antibody
(anti-HBc), HBV DNA; anti-HCV, HCV RNA, IgM & IgG anti-HEV, HEV 
RNA
Cytomegalovirus (CMV)
Herpes Simplex Virus (HSV)
Epstein-Barr Virus (EBV) infection
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis
Antinuclear Antibodies (ANA) & Anti-Smooth Muscle Antibody (ASMA)
titers, total IgM, IgG, Immunoglobulin E (IgE), Immunoglobulin A (IgA)
Alcoholic hepatitis
Ethanol history, GGT, mean corpuscular volume (MCV), CD-transferrin
Nonalcoholic steatohepatitis
Ultrasound or MRI
Hypoxic/ischemic hepatopathy
Medical history: acute or chronic congestive heart failure, hypotension, 
hypotension, hypoxia, hepatic venous occlusion. Ultrasound or MRI.
Biliary tract disease
Ultrasound or MRI, ERCP as appropriate.
Wilson disease (if <40 yrs old)
Ceruloplasmin
Hemochromatosis
Ferritin, transferrin
Alpha-1-antitrypsin deficiency
Alpha-1-antitrypsin
Other causes should also be considered based upon participants’ medical history 
(hyperthyroidism / thyrotoxic hepatitis – T3, T4, thyroid stimulating hormone (TSH); cardio 
vascular disease / ischemic hepatitis – ECG, prior hypotensive episodes; Type 1 diabetes
mellitus/ glycogenic hepatitis).
Obtain PK sample to determine exposure to study treatment and metabolites.
Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” i.e. >50% likely, if it appears greater than all other possible causes 
of liver injury combined. The term “treatment-induced” indicates probably caused by the 
treatment, not by something else, and only such a case can be considered a DILI case and should 
be reported as a serious adverse event (SAE).
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” and thus, meet the definition of SAE and should be reported as SAE using the term 
“potential treatment-induced liver injury.” All events should be followed up with the outcome 
clearly documented.

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6.6
Additional treatment guidance
6.6.1
Treatment compliance
Each time the study treatment is to be administered, IRT needs to be accessed for the medication 
(kit) number. The date of all study drug administered during the study and any deviations from 
the protocol treatment schedule will be captured by the Investigator staff or by field monitor on 
the appropriate study treatment dispensing form.
The Investigator must promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the participant’s 
safety and the validity of the study. The participant must also be instructed to contact the 
Investigator if he/she is unable for any reason to take the study treatment as prescribed.
Compliance will be assessed by the Investigator and/or study personnel at each visit using pill 
counts and information provided by the participant. This information should be captured in the 
source documents at each visit. All study drug dispensed and returned must be recorded in a 
drug accountability log. Compliance to the protocol will be assessed by the field monitor at 
each visit and the information provided by the pharmacist or by the Investigator. Exposure to 
the study treatment will be based on the amount of drug administered.
Pharmacokinetic parameters will be determined in all participants treated with capmatinib, as 
detailed in pharmacokinetics section (Section 8.6.2).
6.6.2
Emergency breaking of assigned treatment code
Not applicable. Study is open-label.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
drug section (Section 6.1.1).
The Investigator or responsible site personnel must instruct the participant (or caregiver) to take 
the study treatment as per protocol. Study treatment will be dispensed to the participant by 
authorized site personnel only. All dosages prescribed to the participant and all dose changes 
during the study must be recorded on the study treatment eCRF.
A unique medication number is printed on the study medication label.
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the IRT and obtaining the medication number(s). The study medication has a 2-part 
label (base plus tear-off label), immediately before dispensing the medication kit to the 
participant, site personnel will detach the outer part of the label from the packaging and affix it 
to the source document.
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
(i.e. pandemic, epidemic or natural disaster) that limits or prevents on-site study visits, delivery 
of Investigational Medicinal Product (IMP) directly to a participant's home may be permitted 
(if allowed by local or regional health authorities and ethics committees as appropriate) in the 
event the Investigator has decided that an on-site visit by the participant is no longer appropriate 

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or possible, and that it is in the interest of the participant's health to administer the study 
treatment even without performing an on-site visit. The dispatch of IMP from the site to the 
participant’s home remains under the accountability of the Investigator. Each 
shipment/provisioning will be for a maximum of 30-day supply. In this case, regular phone calls 
or virtual contacts (every 3 weeks or more frequently if needed) will occur between the site and 
the participant for instructional purposes, safety monitoring, investigation of any adverse events, 
ensuring participants continue to benefit from treatment, and discussion of the participant's 
health status until the participants can resume visits at the study site.
6.7.1
Handling of study treatment and other treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the Investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the [capmatinib Investigator’s Brochure].
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization (CO) Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number.
The Investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Participants will be 
asked to return all unused study treatment and packaging at the end of the study or at the time 
of discontinuation of study treatment. The site may destroy and document destruction of unused 
study treatment, drug labels and packaging as appropriate in compliance with site processes, 
monitoring processes, and per local regulation/guidelines. Otherwise, at the conclusion of the 
study, and as appropriate during the course of the study, the Investigator will return all unused 
study treatment, packaging, drug labels, and a copy of the completed drug accountability log to 
the Novartis monitor or to the Novartis address provided in the Investigator folder at each site.
6.7.1.2
Handling of other treatment
Not applicable.
6.7.2
Instruction for prescribing and taking study treatment
The Investigator or responsible site personnel must instruct the participant or caregiver to take 
the study treatment as per protocol.
Capmatinib tablets will be administered orally on a continuous b.i.d. dosing schedule from Day 
1 to Day 21 of each 21 day cycle. The starting dose of capmatinib will be 400 mg b.i.d. (total 
daily dose = 800 mg) on a flat scale of mg/day and not individually adjusted by weight or body 
surface area.
A complete cycle of treatment is defined as 21 days of twice daily treatment with capmatinib. 

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
Including days of PK sampling, participants should take 400 mg of capmatinib tablets b.i.d.
at approximately the same time each day starting at Cycle 1 Day 1.

Each dose of capmatinib is to be taken with a glass of water (at least 8 ounces -
approximately 250 mL) and consumed over as short a time as possible (i.e., not slower than 
1 tablet every 2 minutes).

Participants should be instructed to swallow the tablets whole and not to chew them.

Capmatinib can be administered with or without food. The morning and the evening dose 
should be taken 12 (± 4) hours apart, although a 12-hour interval is highly recommended. 
The morning dose should be taken at the same time each morning. If a dose is not take 
within 4 hours of the planned dosing time, the missed dose should not be replaced.

On days when PK blood samples are to be collected, participants will be instructed to hold 
their dose until arrival at the study center, unless participant visit is more than 4 hours post 
standard visit time. Capmatinib will be administered at the site in the morning prior to the 
post-dose PK sample blood draws supervised by a member of the research team. The pre-
dose PK samples will be taken right before capmatinib administration. The exact time of 
drug administration should be recorded in the appropriate eCRF. Food consumption prior 
to capmatinib administration should be recorded in the appropriate eCRF. If a participant
vomits within 4 hours of capmatinib dosing, the time of vomiting should be recorded on the 
eCRF.

Participants should be instructed not to make up for missed doses or partial doses (i.e., when 
the entire dose is not taken as instructed). A missed or partial dose will be defined when the 
full dose is not taken within 4 hours of the scheduled twice daily dosing. If that occurs, then 
the dose (or part of the remaining dose) should not be taken and dosing should restart with 
the next scheduled dose. If vomiting occurs, no attempt should be made to replace the 
vomited dose before the next scheduled dose.

During the whole duration of treatment with capmatinib, the participant is recommended to 
use precautionary measures against ultraviolet exposure (e.g., use of sunscreen, protective 
clothing, avoid sunbathing or using a solarium).
7
Informed consent procedures
The Investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant or their legally authorized representative (defined as per local 
regulation) and answer all questions regarding the study.
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representatives will be required to sign a statement of informed consent that meets 
the requirements of 21 Code of Federal Regulation (CFR) 50, local regulations, International 
Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use
(ICH) guidelines, privacy and data protection requirements, where applicable, and the 
Institutional Review Board (IRB)/ Independent Ethics Committee (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.

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A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative (defined as per local regulation).
Participants who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional additional research. The Investigator or authorized designee will explain to each 
participant the objectives of the additional research, which include the use of samples for in 
vitro diagnostic test (e.g. companion diagnostic [CDx]) development. Participants will be told 
that they are free to refuse to participate and may withdraw their consent at any time and for 
any reason during the storage period. A separate signature will be required to document a 
participant’s agreement to allow any remaining specimens to be used for additional research. 
Participants who decline to participate in this optional additional research will document this.
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/ IEC-approved informed consent.
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her level of understanding. If the participant is capable of doing so, he/she 
must indicate agreement by personally signing and dating the written informed consent 
document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents.
Information about common side effects already known about the investigational treatment can 
be found in the [capmatinib Investigator's Brochure]. This information will be included in the 
participant informed consent and should be discussed with the participant upon obtaining 
consent and also during the study as needed. Any new information regarding the safety profile 
of the investigational treatment that is identified between Investigator’s Brochure (IB) updates 
will be communicated as appropriate, for example, via an Investigator Notification (IN) or an 
aggregate safety finding. New information might require an update to the informed consent and 
then must be discussed with the participant.
The following informed consents are included in this study:

Molecular pre-screening informed consent

Main study informed consent, which also included:

A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study

Optional consent for activities that may be done outside of the study site

As applicable, Pregnancy Outcomes Reporting Consent for female participants or the 
female partners of any male participants who took study treatment

Patient information sheet for female partners of any male participants who took study 
treatment

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A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
(i.e. pandemic, epidemic or natural disaster) that may challenge the ability to obtain a standard 
written informed consent due to limits that prevent an on-site visit, Investigator may conduct 
the informed consent discussion remotely (e.g. telephone, videoconference) if allowable by a 
local health authority.
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.).
8
Visit schedule and assessments
The assessment schedule (Table 8-2) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the participant’s source 
documentation.
Written informed consent must be obtained before any study specific assessments are 
performed. Main screening evaluations and baseline radiological tumor assessments should be 
performed within 28 days of treatment start. All visits are to be scheduled according to the
appropriate number of calendar days from Cycle 1 Day 1 of study drug administration. Visit 
windows per Table 8-1 are allowed.
Table 8-1
Allowable window for participant assessments
Visit name
Window allowed
Screening
28 days to -1 day from first dose of study treatment
C1D1
Within 3 days after confirmation of eligibility in IRT system
C1D15
± 1 day
C2D1
± 3 days
C3D1
± 3 days
Day 1 visit of all subsequent cycles
± 3 days
Imaging evaluations
± 7 days
PROs assessments
± 7 days
EOT
≤ 7 days after stopping study treatment
30-Day Safety FUP
+ 7 days
Survival FUP
± 14 days
Every effort must be made to follow the schedule of assessments within the windows outlined 
in the protocol. If a given visit is out of window, the next visit should be performed with 
reference to the day of first dose in order to get the participant back on schedule. If an off-
schedule imaging assessment is performed, subsequent imaging assessments should be 
performed in accordance with the original imaging schedule. Missed or rescheduled visits 
should not lead to automatic discontinuation. 

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The “X” in the table denotes the assessments to be recorded in the clinical database or received 
electronically from a vendor. The “S” in the table denotes the assessments that are only in the 
participant’s source documentation and do not need to be recorded in the clinical database.
PRO measure(s) must be completed before any clinical assessments are performed at any given 
visit.
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
(i.e. pandemic, epidemic or natural disaster) that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the Investigator as 
the situation dictates. If allowable by a local health authority, national and local regulations and 
depending on operational capabilities, phone calls or virtual contacts (e.g. tele consultation) or 
visits by site staff/off-site healthcare professional(s) staff to the participant’s home, can replace 
certain protocol assessments, for the duration of the disruption until it is safe for the participant 
to visit the site again. If the Investigator delegates tasks to an off-site healthcare professional, 
the Investigator must ensure the individual(s) is/are qualified and appropriately trained to 
perform assigned duties. The Investigator must oversee their conduct and remain responsible 
for the evaluation of the data collected.

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Table 8-2
Assessment schedule
Period
Screening
Treatment
Post-Treatment FUP
Survival 
FUP
Visit Name
Molecular 
Pre-
Screening
Screening Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
beyond
EOT
30-Day 
Safety 
FUP
Efficacy 
and PRO 
FUP
End of 
Post-
Treatment 
FUP
Survival 
FUP
Days
-
-28 to -1
Day 1
Day 15
Day 1
Day 1
Day 1
-
-
-
-
-
Molecular pre-
screening 
informed consent
X
Collection of
EGFR and ALK
status
X
Information on 
prior local testing 
for METΔex14
mutation status
X
Archival tumor or 
newly obtained 
tumor biopsy
(preferred) sample
for central 
confirmation of 
METΔex14
mutation status 
(via a validated 
test) and to
support CDx
development
X
IRT pre-screening 
registration
X
Main informed 
consent
X

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Period
Screening
Treatment
Post-Treatment FUP
Survival 
FUP
Visit Name
Molecular 
Pre-
Screening
Screening Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
beyond
EOT
30-Day 
Safety 
FUP
Efficacy 
and PRO 
FUP
End of 
Post-
Treatment 
FUP
Survival 
FUP
Days
-
-28 to -1
Day 1
Day 15
Day 1
Day 1
Day 1
-
-
-
-
-
Demography
X
IRT eligibility 
check
S
IRT registration
X
X
X
X
X
X
Inclusion / 
Exclusion criteria
X
X
Medical 
history/current 
medical conditions
X
Diagnosis and 
stage of cancer
X
Smoking history
X
Prior 
antineoplastic 
therapy (meds, 
surgery, radiation)
X
Prior/concomitant 
medications
Continuously from 28 days prior to first dose until 30 days after last dose of study treatment
X1,2
Physical 
examination, 
including 
neurological 
exams
S
If clinically indicated
Targeted physical 
examination
S
S
S
S
S
Performance 
status (ECOG)
X
X
X
X
X
X
X1

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Period
Screening
Treatment
Post-Treatment FUP
Survival 
FUP
Visit Name
Molecular 
Pre-
Screening
Screening Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
beyond
EOT
30-Day 
Safety 
FUP
Efficacy 
and PRO 
FUP
End of 
Post-
Treatment 
FUP
Survival 
FUP
Days
-
-28 to -1
Day 1
Day 15
Day 1
Day 1
Day 1
-
-
-
-
-
Body Height
X
Body Weight
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
HIV history
S
Hematology
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
Coagulation
X
If clinically indicated
Urinalysis with 
microanalysis
X
If clinically indicated
Pregnancy Test 
(serum)
S
S
Pregnancy test 
(urine)
S
S
S
S
CT scan or MRI of 
chest, abdomen
X
C3D1 and then every 
6 weeks
EOT scan not 
required if previous 
scan was performed ≤ 
28 days
Every 6 
weeks
Pelvis CT or MRI
X
C3D1 and every 6 
weeks (if positive at 
baseline) or if clinically 
indicated
If positive at baseline 
or if clinically 
indicated. EOT scan 
not required if 
previous scan was 
performed within ≤28 
days
Every 6 
weeks (if 
positive at 
baseline) 
or if 
clinically 
indicated
Brain MRI (Brain 
CT is acceptable if 
X
C3D1 and every 6 
weeks (if positive at 
If positive at baseline 
or if clinically 
indicated. EOT scan 
Every 6 
weeks (if 
positive at 

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Period
Screening
Treatment
Post-Treatment FUP
Survival 
FUP
Visit Name
Molecular 
Pre-
Screening
Screening Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
beyond
EOT
30-Day 
Safety 
FUP
Efficacy 
and PRO 
FUP
End of 
Post-
Treatment 
FUP
Survival 
FUP
Days
-
-28 to -1
Day 1
Day 15
Day 1
Day 1
Day 1
-
-
-
-
-
MRI contrast is 
contraindicated)
baseline) or if clinically 
indicated
not required if 
previous scan was 
performed within ≤28 
days
baseline) 
or if 
clinically 
indicated
Whole body bone 
scan
X
If clinically indicated
If 
clinically 
indicated
Localized bone 
CT, MRI or x-ray 
(for any lesions 
identified on the 
whole body bone 
scan that are not 
visible on chest/ 
abdomen or pelvis 
(CAP) CT or MRI)
Only if 
lesions on 
whole 
body scan 
that are 
not visible 
on the 
CAP scans
C3D1 and every 6 
weeks (if positive at 
baseline) or if clinically 
indicated
If positive at baseline 
or if clinically 
indicated. EOT scan 
not required if 
previous scan was 
performed within ≤28 
days
Every 6 
weeks (if 
positive at 
baseline) 
or if 
clinically 
indicated
CT or MRI of other 
metastatic sites 
(e.g. neck)
Only if 
other 
metastatic 
sites 
suspected
C3D1 and every 6 
weeks (if positive at 
baseline) or if clinically 
indicated
If positive at baseline 
or if clinically 
indicated. EOT scan 
not required if 
previous scan was 
performed within ≤28 
days
Every 6 
weeks (if 
positive at 
baseline) 
or if 
clinically 
indicated
Color photography 
(for skin lesions)
Only if skin 
lesions
C3D1 and every 6 
weeks (if positive at 
baseline) or if clinically 
indicated
If positive at baseline 
or if clinically 
indicated. EOT scan 
not required if 
previous scan was 
performed within ≤28 
days
Every 6 
weeks (if 
positive at 
baseline) 
or if 
clinically 
indicated

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Period
Screening
Treatment
Post-Treatment FUP
Survival 
FUP
Visit Name
Molecular 
Pre-
Screening
Screening Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
beyond
EOT
30-Day 
Safety 
FUP
Efficacy 
and PRO 
FUP
End of 
Post-
Treatment 
FUP
Survival 
FUP
Days
-
-28 to -1
Day 1
Day 15
Day 1
Day 1
Day 1
-
-
-
-
-
Adverse Events
Continuously from signing of main ICF until 30 days after last dose of study treatment
Serious Adverse 
Events
Continuously from signing of pre-screening ICF until 30 days after last dose of study treatment. Before 
signing of screening ICF, only SAEs suspected to be causally related to a study procedure are 
captured
SAEs related to study treatment only
Electrocardiogram 
(ECG)
X
X3
X3,4
X
PROs (EORTC 
QLQ-C30, EORTC 
LC13, EQ-5D-5L 
and NCCN Fact-
FBrSI)
X
Starting at Cycle 3 
and then every 6 
weeks
X
Every 6 
weeks
Capmatinib 
administration
Continuous twice daily dosing [b.i.d.]
Plasma collection 
for assessment of 
METΔex14 status 
and development 
of a liquid CDx
X3
Food 
administration
X
Blood for 
capmatinib PK
X3,5
X3
Antineoplastic 
therapies (meds, 
surgery, radiation) 
since 
discontinuation of 
study drug
X
X
X
X
X

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Period
Screening
Treatment
Post-Treatment FUP
Survival 
FUP
Visit Name
Molecular 
Pre-
Screening
Screening Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
beyond
EOT
30-Day 
Safety 
FUP
Efficacy 
and PRO 
FUP
End of 
Post-
Treatment 
FUP
Survival 
FUP
Days
-
-28 to -1
Day 1
Day 15
Day 1
Day 1
Day 1
-
-
-
-
-
Disposition
X
X
X
Survival (survival 
information can be 
obtained via 
telephone contact)
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 Only for participants with brain metastasis at baseline
2 Only for steroids 
3 Pre-dose
4 Post-dose, 2 hours
5 Post-dose, 0.5-1.5 hour, 3-5 hours

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8.1
Molecular pre-screening
In order to be considered eligible for the study, participants must have METΔex14 mutation 
confirmed by a Novartis-designated central laboratory. If a participant's MET mutation status is 
known via a local result, confirmation by a Novartis-designated central laboratory is required 
to confirm eligibility prior to starting study treatment but participant can commence screening.
Confirmation by the Novartis-designated central laboratory will be by a RT-PCR (a real time 
Reverse Transcription (RT) Polymerase Chain reaction (PCR) test that detects exon 14-deleted 
MET messenger Ribonucleic Acid (RNA) derived from formalin fixed, paraffin-embedded 
human tissue) to confirm eligibility prior to starting study treatment but participant can 
commence screening.
All participants will be asked to sign and date an IRB/IEC approved “Molecular pre-screening 
informed consent form” before their tumor sample is sent for testing to the Novartis-designated 
central laboratory. Freshly cut slides from a newly obtained tumor biopsy (preferred) or archival 
tumor tissue should be submitted to the Novartis designated laboratory to test for METΔex14 
mutation status. The resulting METΔex14 data and remaining tumor tissue material (upon the 
approval from health authorities) may be used in the development of an in vitro diagnostic test
for METΔex14, such as a CDx.
Archival tumor tissue obtained at the time of diagnosis of NSCLC or any time since is 
acceptable. If more than one archival tissue sample is available, tissue from the most recent 
biopsy is preferred. Samples obtained from bone metastases and cytology samples are not 
acceptable. All tissue samples need to have >20% tumor content per slide.

If resection sample, 5 slides are requested per participant initially and if sufficient tumor 
material is not found to perform the METΔex14 mutation analysis, additional slides (not 
exceeding a total of 10 slides overall) will be requested.

If core needle biopsy, 10 slides are requested per participant.
If a newly obtained biopsy is provided, the remaining tissue from pre-screen failure samples 
will be returned to the site.
The pre-screening results from central testing for all tested participants (whether the participant 
is eligible or not for the study) will be communicated to the respective study center.
If confirmed that the participant’s tumor harbors the required mutation, the participant will be 
able to proceed for study specific screening procedures following signature of the main ICF.
8.2
Screening
The study IRB/IEC approved informed consent form must be signed and dated before any 
screening procedures are performed, except for laboratory and radiological evaluations which 
were performed as part of the participant's clinical standard of care within the acceptable 
screening window.
Participants will be evaluated against study inclusion and exclusion criteria and safety
assessments (refer to Table 8-2). Screening assessments must be repeated if performed outside 
of the specified screening window (Table 8-1). Participants must meet all inclusion and none 
of the exclusion criteria at screening in order to be eligible for the study.

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Laboratory assessments of hematology/chemistry performed as part of the screening 
evaluations done within 7 days prior to Cycle 1 Day 1 will not be required to be repeated in 
Cycle 1 Day 1, unless deemed clinically necessary by the Investigator. Serum pregnancy test is 
preferentially within 72 hours prior to treatment start. Urine pregnancy test on Cycle 1 Day 1 
will not be required if serum pregnancy test is done within 72 hours prior to Cycle 1 Day 1.
Laboratory test result(s) or symptoms that do not satisfy the eligibility criteria may be repeated 
or treated during the screening visit window. In the event that the repeated laboratory test(s) 
cannot be performed within 28 days from the original screening visit, or do not meet the 
eligibility criteria, or other eligibility criteria have changed and are not met anymore, the 
participant is considered a screening failure.
Re-screening of a participant who has failed screening may be allowed. In such cases, a new 
ICF must be signed. A new participant number will be assigned to the participant. The re-screen 
form will have to be completed in the eCRF and in IRT to provide the original participant 
number.
All required screening assessments must be repeated if they do not meet the allowed time 
window for screening when the participant is re-screened for participation in the study. An 
individual participant can only be re-screened once for the study.
Once the number of participants enrolled is likely to ensure target number of treated participants, 
the Sponsor may close the study to further screening. In this case, the participants who screen 
failed will not be permitted to re-screen.
Participants who are screened and eligibility confirmed in IRT system, but fail to start treatment
for any reason, the reason should be recorded on the appropriate disposition eCRF.
8.2.1
Eligibility screening
Following registering in the IRT for screening, participant eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
Please refer and comply with detailed guidelines in the IRT manual.
8.2.2
Information to be collected on screening failures
A screen failure occurs when a participant who consents to participate in the clinical study is 
subsequently found to be ineligible and therefore not entered in the study treatment. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAE.
Participants who sign the molecular pre-screening ICF, or the molecular pre-screening and main 
ICFs and are subsequently found to be ineligible will be considered as screen failures and data 
will be handled in the same manner.
The reason for screen failure should be recorded on the appropriate disposition eCRF (screening 
phase disposition). 
The following eCRF pages must be completed for screening failure patients: 

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
ALK and EGFR status as per participant’s record

Information on prior local testing for MET mutation status (if available) 

Tumor samples collection (archival or newly obtained) for central confirmation of MET
mutation status

NSCLC diagnosis and extent of disease, including:

Date of diagnosis and stage of NSCLC

Site of active disease

Characteristics of disease

Screening phase disposition

Demography

Informed consent

Inclusion/Exclusion Criteria

Withdrawal of consent (if applicable)

Death (if applicable)
No other data will be entered into the clinical database for participants who are screen failures, 
unless the participant experienced a SAE during the screening period (see SAE section for 
reporting details). For molecular pre-screening failures, only SAEs possibly related to a study 
procedure (i.e. tumor biopsy collection) will be reported to the Novartis Safety group. Data and 
samples collected from participants prior to screen failure may still be analyzed, unless the 
participant withdraws the consent of using the data and samples by writing (or having the legal 
representative /guardian written) to the Investigators.
Participants who sign an informed consent form and are considered eligible but fail to be started 
on treatment for any reason will be considered an early terminator. The reason for early 
termination should be captured on the appropriate disposition Case Report Form.
8.3
Participant demographics/other baseline characteristics
Participant demographic and baseline characteristic data that need to be collected on all 
participants at screening include:

Demography (age, gender)

Other background or relevant medical history (including smoking history) / (serious)
adverse events

Cancer characteristics including diagnosis, history, extent of cancer, baseline tumor 
mutation status (EGFR, ALK and MET), prior antineoplastic therapies (medications, 
radiation, surgeries), and for participants eligible for cohort 2, the date of progression prior 
to study entry

Tumor imaging assessments

Other assessments to be completed for the purpose of determining eligibility (ECOG 
performance status, complete physical examination, vital signs, hematology, chemistry, 
coagulation studies, urinalysis, HIV testing [only recorded in source documentation], serum 
pregnancy test for women of child-bearing potential [only recorded in source 
documentation], and 12-Lead ECG)

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
Prior and current concomitant medications and surgical and medical procedures
Data to be collected on C1D1 pre-dose include:

Patient Reported Outcomes (PROs)

12-Lead ECG
8.4
Efficacy assessments
Planned time points for all efficacy assessments are provided in Section 8 Visit schedule and 
assessments.
8.4.1
Tumor imaging assessments
Tumor response will be assessed locally and centrally according to the Novartis guideline 
version 3.2 (Section 16.1) based on RECIST 1.1 (Eisenhauer et al 2009). In addition, CNS 
lesions will be assessed centrally according to the Novartis guideline version 1 based on 
Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria
(Section 16.2).
The imaging assessment collection plan is presented in Table 8-3. Details of the central review 
process will be described in the independent review charter.
Participants should have at least one documented measurable lesion at study entry per 
RECIST 1.1.
Imaging data will be centrally collected and checked for quality by an imaging Contract 
Research Organization (CRO) designated by Novartis. The results of the central evaluations 
will be used for primary analysis purposes. The local Investigator’s assessment will be used for 
the secondary endpoint analysis and treatment decision making. 
Although the study will use an Independent Central Radiology Review to measure tumor 
response, the decision to enroll the participant will be made based on the judgment of the 
Investigator and local radiologist.
Information regarding prior interventions (e.g. radiotherapy), pre-existing radiographic findings 
that mimic metastatic disease at baseline/screening and prior interventions should be 
transmitted to the imaging CRO via the Baseline Clinical Form along with the baseline images 
for review by the independent radiologist. Once the participant is enrolled, the baseline imaging 
data should be sent within 2 business days by the study site to the Independent Central 
Radiology Reviewer for imaging assessments. Sites must ensure the data entered on the form 
is consistent with the data entered in the clinical database.
Information regarding cytology results should be transmitted to the imaging CRO via the 
Cytology Form for all visits, when applicable, for review by the independent radiologist. Sites 
must ensure the data entered on the form is consistent with the data entered in the clinical 
database.
Information regarding ECOG performance status and corticosteroid dose as compared to 
baseline should be transmitted to the imaging CRO for review by a neuro-radiologist.

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Details regarding collection and shipment of additional information required for imaging 
assessment including RANO-BM assessment by BIRC will be described in the imaging manual 
provided by the designated CRO.
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
(i.e. pandemic, epidemic or natural disaster) that limits or prevents on-site study visits, the 
collection of images (e.g. change of imaging center or imaging frequency) may be modified by 
Novartis and will be communicated to the Investigator.
Table 8-3
Imaging assessment collection plan
Procedure
Screening/Baseline*
During Treatment/Follow-up
Chest and abdomen CT or MRI 
(with intravenous contrast 
enhancement)
Mandated
Mandated
Starting at Cycle 3: every 6 
weeks (+/- 7 days) thereafter until 
PD determined using RECIST 1.1 
by the Investigator and confirmed 
by BIRC
End of treatment: scan not 
required if previous scan was done 
within 28 days
Post Treatment Follow-Up: for 
participants with EOT for reason 
other than disease progression, 
withdrawal of consent or death will 
continue collect imaging and follow 
the same rule of every 6 weeks 
(+/- 7 days) thereafter until PD.
Pelvis CT or MRI (with intravenous 
contrast enhancement)
Mandated
Only if lesions were documented at 
screening; follow the same 
schedule as CT/MRI of the chest 
and abdomen, or if clinically 
indicated
Brain MRI with intravenous 
contrast enhancement
Mandated
Only if lesions were documented at 
screening; follow the same 
schedule as CT/MRI of the chest 
and abdomen, or if clinically 
indicated.
Whole body bone scan
Mandated
If clinically indicated
Localized bone CT, MRI or x-ray
Mandated for any lesions identified 
on the whole body bone scan that 
are not visible on the chest, 
abdomen and pelvis CT or MRI
Only if lesions were documented at 
screening; follow the same 
schedule as CT/MRI of the chest 
and abdomen, or if clinically 
indicated.
Color photography (with 
scale/ruler)
Mandated for any skin lesions 
present
Only if lesions were documented at 
screening; follow the same 
schedule as CT/MRI of the chest 
and abdomen, or if clinically 
indicated
CT or MRI of other metastatic sites 
(e.g. neck)
If other metastatic sites are 
suspected
Only if lesions were documented at 
screening; follow the same 
schedule as CT/MRI of the chest 
and abdomen, or if clinically 
indicated
*Preferably 7 days prior to first dose, however, scans within 28 days of first dose are acceptable

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8.4.1.1
Baseline imaging assessments
Imaging assessments will be performed at screening/baseline within 28 days of start of 
treatment (preferably Day -7 to Day -1 prior to Cycle 1 Day 1).
Any imaging assessments already completed during the regular work-up of the participant 
within 28 days prior to start of treatment, including before signing the main study ICF, can be 
considered as the baseline images for this study. Any imaging assessments obtained after first 
dose of study treatment cannot be considered baseline images. The following assessments are 
required at screening:

Chest, abdomen, and pelvis CT or MRI

Brain MRI

Whole body bone scan

Localized bone CT, MRI, or x-ray, for any lesions identified on the whole body bone scan 
that are not visible on the chest, abdomen, and pelvis CT or MRI

Color photography for any skin lesions present

CT or MRI of other metastatic sites (e.g. neck), if clinically indicated
If a participant is known to have a contraindication to CT intravenous contrast media or 
develops a contraindication during the trial, a non-contrast CT of the chest (MRI is not 
recommended due to respiratory artifacts; however, if CT is not feasible per local regulations, 
MRI can be performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen and 
pelvis should be performed.
Regardless of the suspicion of brain metastases at baseline, contrast enhanced brain MRI must
be completed for all participants unless MRI contrast is contraindicated. If MRI contrast is 
contraindicated, then MRI without contrast or CT with/without contrast is acceptable.
A whole body bone scan should be performed per institutional standard of care [e.g. Tc-99m
bone scan, whole body bone MRI, 18F-fluorodeoxyglucose positron emission tomography 
(FDG-PET), or 18F-sodium fluoride (NaF) positron emission tomography (PET)]. Localized 
CT, MRI, or x-rays should be acquired for all skeletal lesions identified on the screening whole 
body bone scan, which are not visible on the chest, abdomen or pelvis CT/MRI.
If clinically indicated, CT or MRI of other areas (e.g. neck) of disease, as appropriate, should
be performed.
If skin lesions are present at screening, color photography should be acquired using a digital 
camera in clear focus, including a scale/ruler, in such a way that the size of the lesion(s) can be 
determined from the photograph.
Any potentially measurable lesion that has been previously treated with radiotherapy should be 
considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable 
lesion.
Chest x-rays and ultrasound should not be used to measure tumor lesions.

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8.4.1.2
Post-baseline imaging assessments
Imaging assessments as described in Table 8-3 should be performed using the same imaging 
modality used at baseline, irrespective of study treatment interruption or actual dosing
see (Table 8-2). Imaging assessments for response evaluation will be performed started at Cycle 
3 every 6 weeks (+/- 7 days) thereafter until disease progression, death, lost to follow-up or 
withdrawal of consent/opposition to use data. Imaging assessments should be scheduled using 
the date of first dose of study treatment as the reference date (not the date of the previous tumor 
assessment) and should be respected regardless of whether treatment with study treatment is 
temporarily withheld or unscheduled assessments performed. If an unscheduled imaging 
assessment is performed because progression is suspected, subsequent imaging assessments 
should be performed in accordance with the original imaging schedule.
Additional imaging assessments may be performed at any time during the study at the 
Investigator’s discretion to support the efficacy evaluations for a participant, as necessary. 
Clinical suspicion of disease progression at any time requires a physical examination and 
imaging assessments to be performed promptly rather than waiting for the next scheduled 
imaging assessment.
Each lesion that is measured at baseline must be measured by the same method (either same 
imaging method or by photography, including a metric ruler) and when possible, the same local 
radiologist/physician throughout the study so that the comparison is consistent.
Combined PET/CT may be used only if the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of i.v. contrast media. At the discretion of the 
Investigators, FDG-PET scans may be performed to document progressive disease (PD) per 
RECIST 1.1 (Section 16.1).
All study imaging (including any off-schedule imaging studies) should be submitted to the 
designated imaging CRO for quality control and central review.
8.4.1.3
Confirmation of disease progression by BIRC
Time points at which progression is determined locally
All participants who have disease progression determined by the local Investigator require an 
expedited central review. Rapid image transmission to the imaging CRO may be accomplished 
by transferring the images electronically, e.g. via the Internet. In all instances, the process at the 
imaging CRO will ensure that the central reviewers remain blinded to the results of the local 
assessment and the expedited nature of the review. The Investigator seeking an expedited 
review to confirm the disease progression seen locally must indicate this request to the imaging 
CRO on a designated form or by alternative means. The imaging will undergo expedited central 
review (within 5 business days from the time of image receipt at the imaging CRO and once all 
applicable queries are resolved) and the results of the central review will be communicated to 
the site. While the Investigator is awaiting the results of the central review, it is preferable that 
the participant continue on study treatment. However, during this time, the Investigator should 
do whatever is medically necessary for his/her participant.
If the central review determines disease progression, then the participant will discontinue study 
treatment and subsequent tumor assessments are no longer required.

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If the central review does not determine disease progression, the participant should continue 
receiving the study treatment until disease progression has been determined by the BIRC or, as 
a minimum requirement, until at least one additional tumor assessment has been completed, 
unless there is a medical need (i.e. rapid progression or clinical deterioration) for an immediate 
change in therapy.
Participants will continue to have imaging performed as per protocol (Table 8-2) until the 
central review determines disease progression.
The imaging vendor will ensure that the central reviewers involved are blinded to the expedited 
status of the reading.
Time points without locally determined progression
All imaging time points without locally determined progression will be read on an ongoing, 
non-expedited basis as detailed in the imaging manual to be provided by the designated imaging 
CRO and independent review charter. Results of these readings will not be communicated to 
the sites.
Treatment beyond disease progression
Following determination of disease progression, if the Investigator believes the participant may 
derive benefit from continuing study treatment, the participant will be permitted to continue 
treatment beyond initial disease progression as per RECIST 1.1. Please see Section 6.1.5.1 for 
additional information.
8.4.1.4
Efficacy follow-up imaging assessments
For participants who discontinue treatment for reasons other than initial disease progression as 
per RECIST 1.1, tumor assessments must continue to be performed as outlined in Table 8-2. 
Please refer to Section 9.3.2 for additional information.
8.4.2
Appropriateness of efficacy assessments
Tumor assessments every 6 weeks are consistent with the standard clinical practice. Chinese 
Society of Clinical Oncology (CSCO) guidelines for NSCLC recommend response assessment 
every 6-12 weeks and respect assessment frequency defined in clinical trials by drug evaluation 
needs.
Conducting tumor evaluations more than this frequency may expose a participant to an 
unnecessary treatment if disease progression takes place between infrequent assessments.
8.4.3
Overall survival
All participants will enter the survival follow-up period once they complete the safety follow-
up and efficacy follow-up after treatment discontinuation (whichever is longer). Survival status 
will be collected every 12 weeks regardless of treatment discontinuation reason (except if 
consent is withdrawn or participant is lost to follow-up) until death, lost to follow-up, or 
withdrawal of consent for survival follow-up.

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Additional survival assessments may be performed outside the 12 weeks follow-up schedules 
if a survival update is required for an interim assessment to meet safety or regulatory needs.
Survival information can be obtained via phone, and information will be documented in the 
source documents and relevant eCRFs. Information on the therapies received for NSCLC, if 
any, after study treatment has been completed will be collected, as well as the SAEs suspected 
to be related to study treatment.
8.5
Safety
Safety will be monitored by assessing physical examination, Eastern Cooperative Oncology 
Group (ECOG) Performance Status, vital signs, body weight, ECG, Patient reported outcomes
(PRO), laboratory assessments including hematology, chemistry, coagulation and urinalysis, as 
well as collecting AEs at every visit. Clinically relevant findings that were present prior to 
signing informed consent must be recorded on the appropriate eCRF that captures medical 
history. Significant new findings that begin or worsen after informed consent which meet the 
definition of an AE must be recorded as an AE. For details on AE collection and reporting, refer 
to AE Section 10.1.1.
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
(i.e. pandemic, epidemic or natural disaster) that limits or prevents on-site study visits, regular 
phone or virtual calls can occur (every 3 weeks or more frequently if needed) for safety 
monitoring and discussion of the participant´s health status until it is safe for the participant to 
visit the site again.
Table 8-4
Assessments & specifications
Assessment
Specification
Physical examination
Significant findings that were present prior to the signing of informed consent 
must be included as medical history on the participant’s eCRF. Significant new 
findings that begin or worsen after informed consent must be recorded as an 
AE on the appropriate eCRF.
Physical examination
At screening, a complete physical examination will be performed and will 
include the examination of general appearance, skin, neck (including thyroid), 
eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, and a basic nervous system evaluation. More frequent 
examinations may be performed at the discretion of the Investigator and if 
medically indicated. Information about the physical examination must be 
present in the source documentation.
Targeted physical examination
A targeted physical exam will be performed at day 1 of each cycle during 
treatment and at EOT as indicated in Table 8-2, except where a complete 
physical examination is required (see above). It will include at least the 
examination of general appearance and vital signs (blood pressure [SBP and 
DBP] and pulse). If indicated based on symptoms, additional exams will be 
performed.
Information for all physical examinations must be included in the source 
documentation at the study site and additionally reported in appropriate eCRF 
pages for blood pressure (SBP and DBP), vital signs, height and weight. For 

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Assessment
Specification
participants with brain metastasis neurological status will also be evaluated at 
the time of radiological assessments.
Vital signs
Vital signs include blood pressure (supine position preferred when ECG is 
collected), pulse measurement, and body temperature. They will be measured 
at screening and at subsequent time points as specified in Table 8-2.
Height and weight
Height in centimeters (cm) will be measured at screening. Body weight in 
kilogram (kg) (in indoor clothing, but without shoes) will be measured at 
screening and at subsequent time points as specified in Table 8-2.
Performance status
The performance status will be assessed according to the Eastern Cooperative 
Oncology Group (ECOG) Performance Status Scale as specified in Table 8-5
and following the schedule given in Table 8-2.
The Eastern Cooperative Oncology Group (ECOG) performance status scale will be used as 
described in Table 8-5 following the schedule given in Table 8-2.
Table 8-5
ECOG performance status
Grade
ECOG Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
8.5.1
Laboratory evaluations
Local laboratories will be used for the analysis of all scheduled and unscheduled hematology, 
chemistry, coagulation, urinalysis with microanalysis, and pregnancy test to assess the 
participant's eligibility and safety monitoring (as detailed in Table 8-2 and Table 8-6). 
Additional time points should be added as deemed necessary as per the Investigators best 
judgment to make sure dose adjustments are performed to safeguard the safety of the participant. 
Additional results from unscheduled laboratory evaluations should be recorded in the 
appropriate Unscheduled Visit eCRF.
Laboratory assessments of hematology/chemistry performed as part of the screening 
evaluations done within 7 days prior to Cycle 1 Day 1 will not be required to be repeated on 
Cycle 1 Day 1, unless deemed clinically necessary by the Investigator. Serum pregnancy test is 
preferentially within 72 hours prior to treatment start. Urine pregnancy test on Cycle 1 Day 1 
will not be required if serum pregnancy test is done within 72 hours prior to Cycle 1 Day 1. The 
time windows granted for laboratory evaluations are identical to the corresponding visit time 
windows for each visit (refer to Table 8-1) except as stated above.
If at any time a participant has a laboratory parameter obtained from a different (outside) 
laboratory, Novartis must be provided with a copy of the certification and a tabulation of the 
normal ranges and units for this laboratory. The results of all local laboratory results will be 
recorded in the appropriate eCRF. The Investigator is responsible for reviewing all laboratory 
reports for participants and evaluating any abnormalities for clinical significance.

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As per Section 4.6, during a public health emergency as declared by local or regional authorities' 
(i.e. pandemic, epidemic or natural disaster), that limits or prevents on-site study visits, if 
participants cannot visit the site for protocol-specified safety lab assessments, an alternative lab 
(local) collection site may be used.
Table 8-6
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, White blood cells, Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands (optional, if clinically 
indicated), Other)
Chemistry
Albumin, Alkaline phosphatase, ALT, Amylase, AST, Creatinine, Creatinine 
Clearance, Total Bilirubin, Direct Bilirubin (only if total bilirubin is ≥ grade 2), Gamma-
glutamyl-transferase (GGT), Lipase, Calcium, Magnesium, Sodium, Potassium, 
Phosphate (inorganic phosphorus), fasting Glucose (non-fasting allowed post-
baseline), Blood Urea Nitrogen (BUN) or Urea
Bicarbonate or arterial blood gas analysis (i.e. partial pressure of oxygen in blood 
(pO2), partial pressure of carbon dioxide in blood (pCO2) and pH): (optional, if 
clinically indicated)
Chloride and Uric Acid: at screening and thereafter optional, if clinically indicated.
Urinalysis
Microscopic panel (Red Blood Cells, White Blood Cells, Casts, Crystals, Bacteria, 
Epithelial cells)
Coagulation
International normalized ratio (INR) and Prothrombin time (PT), or Quick Test (QT)
Pregnancy Test
A serum pregnancy test must be performed at screening before C1D1 (preferentially 
≤72 hours before C1D1) and at EOT.
A urine pregnancy test should be performed at Day 1 of every cycle.
For women considered to be post-menopausal and not of child-bearing potential, 
pregnancy testing is not required.
If a serum pregnancy test is required as per local practice at day 1 of every cycle, the 
urine pregnancy test does not need to be repeated.
8.5.2
Electrocardiogram (ECG)
Electrocardiograms (ECGs) must be recorded after 10 minutes rest in the supine position to 
ensure a stable baseline/according to the ECG Investigator manual. The preferred sequence of 
cardiovascular data collection during study visits is ECG collection first, followed by vital signs, 
and blood sampling.
Standard 12 lead ECG will be performed as per Table 8-7.
The individual ECGs should be recorded approximately 2 minutes apart. The Fridericia QT 
correction formula (QTcF) should be used for clinical decisions. The mean QTcF value for each 
visit will be calculated from the triplicate ECGs for each participant.
For any ECGs with participant safety concerns, two additional ECGs must be performed to 
confirm the safety finding. A monitoring or review process should be in place for clinically 
significant ECG findings throughout the study and especially at baseline before administration 
of study treatment.
Clinically significant abnormalities must be recorded on the eCRF as either medical 
history/current medical conditions or AEs as appropriate.

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ECGs are to be collected with machines available at the site. Interpretation of the tracing must 
be made by a qualified physician and documented on the appropriate eCRF. Each ECG tracing 
should be labeled with the study number, participant number, date, and kept in the source 
documents at the study site. Clinically significant abnormalities present at screening should be 
reported on the appropriate eCRF. Clinically significant findings must be discussed with 
Novartis prior to enrolling the participant in the study. New or worsened clinically significant 
findings occurring after informed consent must be recorded as AEs.
Additional, unscheduled, safety ECGs may be repeated at the discretion of the Investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically significant 
findings should be collected in triplicate. Local cardiologist ECG assessment may also be 
performed at any time during the study at the discretion of the Investigator.
Table 8-7
Local ECG collection plan
Cycle
Day
Time
ECG Type
Screening
Day -28 to Day -1
Anytime
12 Lead, triplicate
Cycle 1
Day 1
Pre-dose
12 Lead, triplicate
Cycle 2
Day 1
Pre-dose
12 Lead, triplicate
Cycle 2
Day 1
Post-dose 2 hours
12 Lead, triplicate
End of Treatment
Anytime
12 Lead, triplicate
Unscheduled
Anytime if clinically indicated
12 Lead, triplicate
8.5.3
Pregnancy and assessments of fertility
Participants are required to use highly effective methods of contraception during the study and 
for the follow-up time period as specified in Section 5.2. For a definition of highly effective 
contraception, assessment of fertility (males and females), and the definition of post-
menopausal, please refer to Section 5.2.
All pre-menopausal women who are not surgically sterile will have a serum pregnancy test 
preferentially within 72 hours prior to the first dose of study treatment and at the end of 
treatment.
Urine pregnancy tests will be required to be performed on Day 1 of every cycle.
In case of a positive urine pregnancy result, the participant must contact the Investigator 
immediately and the study treatment must be stopped until additional tests are performed to 
confirm pregnancy (including a confirmatory serum pregnancy test).
Male participants must notify the Investigator in case their partner becomes pregnant during the 
treatment period. See Section 10.1.4 for pregnancy reporting.
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
(i.e. pandemic, epidemic or natural disaster) that limits or prevents on-site study visits, if 
participants cannot visit the site to have serum pregnancy tests, urine pregnancy test kits may 
be used. Relevant participants can perform the urine pregnancy test at home and report the result 
to the site. It is important that participants are instructed to perform the urine pregnancy test 
first and only if the test result is negative proceed with the administration of the study treatment. 
A communication process should be established with the participant so that the site is informed 
and can verify the pregnancy test results (e.g. following country specific measures).

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Assessments of Fertility
A woman is considered of childbearing potential from menarche and until becoming
postmenopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Medical documentation of 
oophorectomy, hysterectomy, or tubal ligation must be retained as source documents. A 
postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause and an appropriate clinical profile.
In absence of the medical documentation, confirming permanent sterilization, or if the post-
menopausal is not clear, the Investigator should use his medical judgment to appropriately 
evaluate the fertility state of the woman and document it in the source document.
8.5.4
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/participant population.
8.6
Additional assessments
8.6.1
Patient reported outcomes (PRO)
A PRO is a measurement based on a report that comes from the study participant about the 
status of a participant’s health condition without interpretation of the participant’s report by 
anyone else. A PRO can be measured by self-report or by interview, provided that a trained 
interviewer records only the participant’s response. Symptoms or other unobservable concepts 
known only to the participant (e.g. pain severity or nausea) can only be captured by PRO 
measures. PROs can also assess the participant's perspective on functioning or activities that 
may also be observable by others.
The European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire (EORTC-QLQ-C30, and QLQ-LC13), the EuroQoL 5-level instrument (EQ-5D-
5L, tablet version) and the NCCN FACT-Brain Symptom Index version 2.0 (NCCN-FACT-
FBrSI) will be used to evaluate patient-reported outcome measures of health-related quality-of-
life, functioning, disease symptoms, treatment-related adverse experiences, and global health 
status. The EORTC QLQ-C30 and QLQ-LC13 are frequently used in clinical trials of 
participants with advanced or metastatic lung cancer (Aaronson et al 1993).
The EORTC QLQ-C30 is a questionnaire developed to assess the quality of life of cancer 
patients which has been translated and validated into 81 languages and has been used in more 
than 3,000 studies worldwide. The questionnaire contains 30 items and is composed of both 
multi-item scales and single-item measures based on the patients experience over the past week. 
These include five scales (physical, role, emotional, cognitive and social functioning), three 
symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, 
appetite loss, constipation, diarrhea and financial impact) and a global health status/Quality of 
Life (QoL) scale. All of the scales and single-item measures range in score from 0 to 100. A 
high scale score represents a higher response level. Thus a high score for a functional scale 
represents a high / healthy level of functioning; a high score for the global health status / QoL 
represents a high QoL, but a high score for a symptom scale/item represents a high level of 

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symptomatology/problems. All scoring will follow the scoring procedures defined by the 
EORTC Scoring Manual (Fayers 2001).
The QLQ-LC13 is used in conjunction with the EORTC QLQ-C30 and provides information 
on an additional 13 items specifically related to lung cancer. The five domains of the LC13 
include pain, dyspnea, coughing and hemotoposis, and are based on their presence over the past 
week. All but the pain domain are scored on a 4 point Likert scale ranging from “not at all” to 
“very much”. Pain is score based on its presence, hence yes or no. A higher score indicates a 
higher presence of symptoms (Bergman et al 1994).
The EQ-5D-5L is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal 
(The EuroQol Group 1990). The EQ-5D 5L is designed for self-completion by respondents and 
takes only a few minutes to complete. Instructions to respondents are included in the 
questionnaire. The EQ-5D-5L consists of 2 pages – the descriptive system and the EuroQoL
visual analogue scale (EQ VAS) (Herdman et al 2011). The descriptive system comprises 5 
dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each 
with 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme 
problems. The participant is asked to indicate his/her health state by ticking (or placing a cross) 
in the box against the most appropriate statement in each of the 5 dimensions. This decision 
results in a 1-digit number expressing the level selected for that dimension. The EQ VAS 
records the participant’s self-rated health on a 20 cm vertical, visual analogue scale with 
endpoints labeled ‘the best health you can imagine’ and ‘the worst health you can imagine’
(Rabin and de Charro 2001).
The NCCN FACT-Brain Symptom Index version 2.0 (NCCN-Fact-FBrSI) symptom module 
will be used to explore changes in symptoms associated with potential brain metastases in this 
study. The NCCN FACT-FBrSI was adapted from the previously developed FACT-Brain 
module. The symptoms module contains 24 items with a recall period of the past 7 days. The 
participant responds to 24 statements and indicates to what extent it applies to them on a 5-point 
Likert response scale from “not at all” to “very much.” (Lai et al 2014).
PRO data collection will be collected using an electronic device. All PRO assessments should 
be administered in the participant’s local language and according to the Visit Evaluation 
Schedule in Table 8-2, prior to any tests, treatments or receipt of results from any test to avoid 
biasing the participant’s perspective. The PRO questionnaires should be completed at Cycle 1 
Day 1, Cycle 3 Day 1 and then every 6 weeks while the participant is on treatment, at the end 
of treatment visit, and at the post-treatment follow-up visits if the participant is still followed 
for efficacy. All PRO questionnaires will also be accessible during unscheduled visits and can 
be completed at Investigator/site team discretion.
Participants should be given sufficient space and time to complete all study questionnaires, and 
all administered questionnaires should be reviewed for completeness. If missing responses are 
noted, participants should be encouraged to complete any missing responses. Attempts should 
be made to collect responses to all questionnaires for all participants, including from those who 
discontinue prior to the end of treatment or follow-up visit, however, if participants refuse to 
complete questionnaires, this should be documented in study source records. A participant’s 

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refusal to complete study questionnaires is not a protocol deviation. The participant should be 
made aware that completed measure(s) are not reviewed by the Investigator/ study personnel.
8.6.2
Pharmacokinetics
Blood samples for PK evaluation will be collected from all treated participants participating in 
the study.
 
Complete dosing information, including the date and time of actual blood draw and time of the 
last study drug dose prior to the sampling, should be obtained on all sampling days and recorded 
on the PK eCRF and/or CRO requisition form(s).
If vomiting occurs within 4 hours following capmatinib administration on the day of post dose 
PK blood sampling, PK sample collection is at site’s discretion. If PK sample collection is done,
the clock time of vomiting should be recorded in the dosage administration PK eCRF page.
8.6.2.1
Pharmacokinetic blood collection and handling
PK blood samples for capmatinib will be collected for all the participants as outlined in
Table 8-8.
Table 8-8
Pharmacokinetic blood collection log
Cycle
Day
Scheduled Time Point
Dose Identity (ID)
following trough 
PK sampling
Dose ID prior to 
trough PK
sampling
PK 
Sample 
No
2
1
Pre-dose1
1
102
101
2
1
Anytime within 0.5-1.5 hour
post-dose
1
102
2
1
Anytime within 3-5 hours
post-dose
1
103
3
1
Pre-dose1
2
202
104
Unscheduled
Anytime3
1001+3
1 Take samples immediately prior to administration of capmatinib. 
2 Dose reference IDs with two digits refer to the dose administered and dosing time of the last dose prior to 
collection of the corresponding PK sample.
3 Sample numbers for any unscheduled blood collection for capmatinib will be labeled sequentially starting with 
1001.
Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in 
a forearm vein. A total of 3 mL of blood will be collected at specified time points for capmatinib 
analysis in plasma. Refer to the study's laboratory manual for detailed instructions for the 
collection, handling, and shipment of PK samples.
If participants experience a SAE or an AE leading to the discontinuation of the study treatment, 
an unscheduled PK blood sample should be obtained whenever possible. The date and time of 
the last dose and the time of PK blood draw should be recorded.
8.6.2.2
Analytical method
Pharmacokinetic samples for capmatinib will be quantified using validated liquid 
chromatography tandem-mass spectrometry (LC/MS/MS) assays.
CCI

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8.6.3
Biomarkers
Biomarker assessments in tumor
Archival or newly acquired core or excisional biopsy (preferred) are required as part of the 
molecular pre-screening portion of this trial to test for METΔex14 mutation. Residual tumor 
sample material (upon the approval of health authorities) and resulting METΔex14 test data 
may be used to support development of an in vitro diagnostic test for METΔ ex14, such as a 
CDx test. No tissue will be collected in this study for exploratory analyses.
Biomarker assessments in blood
Blood samples will be collected at Cycle 1 Day 1 to assess the association of 
METΔex14mutation status in ctDNA isolated from blood plasma with capmatinib (INC280) 
efficacy, how well the METΔex14 status can be detected in blood as compared to tumor tissue
and potentially also for development of a liquid biopsy in vitro diagnostic test for METΔex14, 
such as a CDx test.
Biomarker sample collection information should be recorded on the appropriate eCRF and/or 
Central Laboratory paper requisition form(s). The details must be specified in the protocol.
Table 8-9
Biomarker sample collection plan
Sample Type
Volume
Visit
Time point
Tumor samples
Mandatory for eligibility
Formalin fixed paraffin 
embedded (FFPE) tissue 
slides from either a newly 
obtained biopsy 
(preferred) or from an
archival biopsy taken at
time of NSCLC diagnosis 
or any time since; to 
determine METΔex14
status for eligibility and to 
support CDx 
development
5-10 fresh-cut slides (with 
minimum of 20% tumor 
content per slide).
• If resection sample, 5 
slides requested initially 
and if there is not 
sufficient tumor material 
found to perform the MET 
exon 14 mutation 
analysis, additional slides 
(not exceeding a total of 
10 slides overall) will be 
requested. 
• If core needle biopsy, 
10 slides requested.
Pre-Screening
Requires participant’s 
written consent on the 
Molecular Pre-screening 
ICF
Prior to main screening
Blood samples
Mandatory
Blood (for plasma
extraction) for METΔex14
analysis and to support 
CDx development
2x10 mL
Cycle 1 Day 1
Pre-dose

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9
Discontinuation and completion
9.1
Discontinuation from study treatment and from study
9.1.1
Discontinuation from study treatment
Discontinuation from study treatment for a participant occurs when study treatment is 
permanently stopped for any reason (prior to the planned completion of study treatment 
administration, if any) and can be initiated by either the participant or the Investigator.
The Investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being.
Discontinuation from study treatment is required under the following circumstances:

Participant/guardian decision

Investigator decision

Pregnancy (see Section 10.1.4)

Any situation in which continued study participation might result in a safety risk to the 
participant

Disease progression per RECIST 1.1 as determined by Investigator and confirmed by BIRC. 
In some circumstances participants may be allowed to continue to receive study treatment 
beyond disease progression as per RECIST 1.1. These participants will continue 
assessments as outlined in Table 8-2 or Table 8-3, as applicable, and will complete the EOT 
visit only after permanent discontinuation of study treatment

AE requiring permanent discontinuation of study treatment (see Section 6.5.1)

Protocol deviation that results in a significant risk to participant's safety

Withdraw of consent (see Section 9.2)

Study is terminated by the sponsor (see Section 9.4)

Death

Lost to follow-up (see Section 9.1.3)
If discontinuation from study treatment occurs, the Investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation from study treatment and 
record this information.
Participants who discontinue from study treatment agree to return for the end of treatment and 
follow-up visits indicated in the Assessment Schedule (Table 8-2).
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule.
The Investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment.
In some circumstances participants may be allowed to continue to receive study treatment 
beyond disease progression as per RECIST 1.1 criteria. These participants will continue 

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assessments as outlined in the assessments section, and will complete the EOT visit only after 
permanent discontinuation of study treatment.
9.1.2
Participant discontinuation from the study
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason.
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in the assessment table (refer to Section 8).
9.1.3
Lost to follow-up
For participants whose status is unclear because they fail to appear for study visits or fail to 
respond to any site attempts to contact them without stating an intention to discontinue from 
study treatment or discontinue from study or withdraw consent (or exercise other participants’ 
data privacy rights), the Investigator must show "due diligence" by documenting in the source 
documents steps taken to contact the participant, e.g. dates of telephone calls, registered letters, 
etc. A participant should not be considered as lost to follow-up until due diligence has been 
completed.
9.2
Withdrawal of informed consent and exercise of participants’ 
data privacy rights
Withdrawal of consent/opposition to use of data and/or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and when a participant:

Explicitly requests to stop use of their data
and

No longer wishes to receive study treatment
and

Does not want any further visits or assessments (including further study-related contacts)
This request should be as per local regulations (e.g. in writing) and recorded in the source 
documentation.
Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g. to respond to data queries) and potentially other country-specific restrictions. It is therefore 
very important to ensure accurate recording of withdrawal vs. discontinuation based on the 
protocol definitions of these terms.
In this situation, the Investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their
consent/exercise data privacy rights and record this information. The Investigator shall clearly 
document if the participant has withdrawn his/her consent for the use of data in addition to a 
study discontinuation.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.

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Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up.
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/exercise data privacy rights should be made as detailed in the assessment table (refer 
to Section 8).
Further details on withdrawal of consent or the exercise of participants' data privacy rights are 
included in the corresponding informed consent form.
9.3
Study completion and post-study treatment
For individual participant: Study completion is reached when participant completes all post-
treatment follow-up (including 30-day safety follow-up and tumor assessment until PD, 
whichever is longer). The appropriate disposition eCRF must be completed, giving the date and 
reason of post-treatment follow-up discontinuation. After this, participant can enter survival 
follow-up.
For the study: Study completion is defined as the earliest occurrence of one of the following:

All participants have discontinued study treatment and completed the safety follow-up and 
at least 75% of the participants have died, withdrawn consent or are lost to follow-up.

Another clinical study becomes available that can continue to provide capmatinib in this 
participant population, and all participants ongoing are transferred to that clinical study. 
Note: For participants who transfer to another clinical study or an alternative treatment 
option to continue provision of study treatment, the follow-up for safety, disease progression 
and survival will not be performed.

If the primary analysis of ORR or secondary analysis of PFS does not demonstrate treatment 
benefit, the follow-up for OS will end, in this case the end of the study will be when all 
participants have discontinued treatment and completed the safety follow-up, or have 
withdrawn consent or are lost to follow-up.
At the end of the study, every effort will be made to continue provision of study treatment 
outside this study through an alternative setting to participants who in the opinion of the
Investigator are still deriving clinical benefit.
Details on the timing of the primary analysis and final reporting of data are provided in 
Section 12.
9.3.1
Follow-up for safety evaluations
Regardless of the reason for discontinuation from study treatment (see Section 9.1.1), 
participants will be contacted for a safety follow-up 30 days (+ 7 days) after the last dose of
capmatinib. At this time, the Investigator will record any AEs/SAEs that may have occurred 
after discontinuation of study treatment and/or follow on resolution of ongoing AEs.
If the participant begins any post-treatment antineoplastic medication before the 30-day safety 
follow-up period is complete, the collection of new SAEs and AEs unrelated to capmatinib will 
stop, and, thereafter, only suspected AEs and suspected SAEs will continue to be collected up 
to day 30. Suspected SAEs will continue to be collected beyond the 30-day safety follow-up.

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AEs, concomitant medications and antineoplastic therapies since discontinuation of study 
treatment will be recorded on the appropriate eCRF during this follow-up period.
For participants who transfer to another Novartis clinical study or Novartis treatment setting,
the 30-day safety follow-up will no longer be performed within the present protocol.
9.3.2
Efficacy follow-up and PROs
All participants who discontinue treatment with capmatinib for any reason other than disease 
progression according to RECIST 1.1 as determined by Investigator and confirmed by BIRC, 
death, withdrawal of consent for further assessments or lost to follow-up will continue to have 
tumor assessments as per their current schedule until disease progression is confirmed by BIRC, 
death, withdrawal of consent for further assessments, lost to follow-up or study terminated by 
the sponsor. Participants will also continue to complete PRO questionnaires following the same 
schedule as that for tumor assessments (as per Table 8-2).
When a participant discontinued from efficacy follow-up, the appropriate disposition eCRF 
must be completed, giving the date and reason of discontinuation, as per Table 8-2.
Information on new antineoplastic therapy initiated since discontinuation of study treatment 
will be collected on the appropriate eCRF during this follow-up period.
9.3.3
Survival follow-up
Participants will enter the survival follow-up period once they complete the 30-day safety 
follow-up and efficacy follow-up (if applicable) after treatment discontinuation (whichever is 
longer). Participants will then be contacted by telephone every 12 weeks to follow-up on their 
survival status. Any new antineoplastic therapies that have been started since the last contact 
date will also be collected during these phone calls.
Every effort should be made to comply with the survival follow-up schedule and ensure 
collection of participant survival data.
9.4
Early study termination by the Sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination (but not limited to):

Unexpected, significant, or unacceptable safety risk to participants enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data

Discontinuation of study treatment development
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a participant who discontinued from study treatment. The Investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the participant’s interests. The Investigator or Novartis depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.

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10
Safety monitoring, reporting and committees
10.1
Definition of adverse events and reporting requirements
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found 
respectively in Section 10.1.1 and Section 10.1.2.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.1.3.
10.1.1
Adverse events
An AE is any untoward medical occurrence (e.g. any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a clinical investigation 
participant after providing written informed consent for participation in the study. Therefore, 
an AE may or may not be temporally or causally associated with the use of a medicinal 
(investigational) product.
The Investigator has the responsibility for managing the safety of individual participant and 
identifying AEs.
Novartis qualified medical personnel will be readily available to advise on trial-related medical 
questions or problems.
For participants whose MET mutation status is unknown and who sign the molecular pre-
screening ICF, AEs which occur after signature of this consent will only be captured if they 
meet the definition of serious as outlined in Section 10.1.2 and are reported to be causally related 
with study procedures (e.g. an invasive procedure such as biopsy). Once the main study ICF is 
signed, all AEs per the descriptions below will be captured as AEs.
Participants whose MET mutation status is known will sign the main study ICF.
The occurrence of AEs must be sought by non-directive questioning of the participant at each 
visit during the study. AEs also may be detected when they are volunteered by the participant 
during or between visits or through physical examination findings, laboratory test findings, or 
other assessments.
AEs must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2):
1. The Common Toxicity Criteria (CTC) AE grade (version 5.0).
AEs will be assessed and graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0.

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If CTCAE grading does not exist for an AE, the severity of mild, moderate, severe, life-
threatening and fatal, corresponding to grades 1 - 5, will be used. CTCAE grade 5 (death) will 
be used in this study and information about deaths will be collected through a Death eCRF.
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant
3. Its duration (start and end dates or ongoing) and the outcome must be reported
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. Action taken regarding with study treatment.
All AEs must be treated appropriately. Treatment may include one or more of the following:

Dose not changed

Dose Reduced/increased

Drug interrupted/permanently discontinued
6. Its outcome
If the event worsens the event should be reported a second time in the eCRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 AEs only, if improvement to a lower 
grade is determined, a new entry for this event should be reported in the eCRF noting the start 
date when the event improved from having been Grade 3 or Grade 4.
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant.
AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms.
AE monitoring should be continued for at least 30 days following the last dose of study 
treatment.
Once an AE is detected, it must be followed until its resolution or until it is judged to be not 
recovered/not resolved (e.g. continuing at the end of the study), and assessment must be made 
at each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the interventions required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors or as per Cheson's guidelines for 
hematological malignancies), should not be reported as a SAE, except if the Investigator 
considers that progression of malignancy is related to study treatment.
AEs separate from the progression of malignancy (for example deep vein thrombosis at the time 
of progression or hemoptysis concurrent with finding of disease progression) will be reported 
as per usual guidelines used for such events with proper attribution regarding relatedness to the 
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Information about adverse drug reactions for the investigational drug can be found in the 
[capmatinib Investigator's Brochure].
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease.
10.1.2
Serious adverse events
An SAE is defined as any AE [appearance of (or worsening of any pre-existing)] undesirable 
sign(s), symptom(s), or medical conditions(s) which meets any one of the following criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect, fetal death or a congenital abnormality or 
birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the participant’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 

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do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines).
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered SAE irrespective 
if a clinical event has occurred.
10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety immediately, without undue delay, but under no 
circumstances later than within 24 hours of obtaining knowledge of the events (Note: If more 
stringent, local regulations regarding reporting timelines prevail). Detailed instructions 
regarding the submission process and requirements are to be found in the Investigator folder 
provided to each site. Information about all SAEs is collected and recorded on the eSAE with 
paper backup Serious Adverse Event Report Form; all applicable sections of the form must be 
completed in order to provide a clinically thorough report. If a new antineoplastic therapy is 
initiated during the 30-day safety follow-up period, only SAEs suspected to be related to the 
study treatment will be collected in the Adverse Events eCRF.

Screen Failures (e.g. a participant who is screened but is not treated): SAEs occurring after 
the participant has provided informed consent until the time the participant is deemed a 
Screen Failure must be reported to Novartis.

Treated Participants: Only SAEs suspected to be causally related to a study procedure are 
captured between the time participant signs molecular pre-screening ICF and signs the main 
ICF. All SAEs are collected between the time the participant signs the main ICF until 30 
days after the participant has permanently stopped study treatment.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
Investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event.
If the SAE is not previously documented in the [capmatinib Investigator’s Brochure] or Package 
Insert (new occurrence) and is thought to be related to the study treatment, a Novartis Chief 
Medical Office and Patient Safety (CMO&PS) Department associate may urgently require 
further information from the Investigator for health authority reporting. Novartis may need to 
issue an IN to inform all Investigators involved in any study with the same study treatment that 
this SAE has been reported.

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Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with European Union 
(EU) Guidance 2011/C 172/01 or as per national regulatory requirements in China.
SAE collection will start upon signing the molecular pre-screening ICF. SAEs will only be 
reported if the event is suspected to be causally related to a study procedure as assessed by the 
Investigator (e.g. an invasive procedure such as biopsy). SAEs will be followed until resolution 
or until clinically relevant improvement or stabilization. If the main ICF is not signed (e.g. 
molecular screen failure), SAE collection ends 30 days after the last study related procedure.
Any SAEs experienced after the 30-day period following the last administration of study 
treatment should only be reported to Novartis Safety if the Investigator suspects a causal 
relationship to study treatment, unless otherwise specified by local law/regulations.
10.1.4
Pregnancy reporting
Pregnancies
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the Investigator to collect and report information regarding the pregnancy. 
To ensure participant safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded and reported by the Investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment and
pregnancy outcome. Any SAE experienced during pregnancy must be reported.
If a female partner of a male trial participant who took study treatment in this study becomes 
pregnant, pregnancy outcomes should be collected. Consent to report information regarding 
these pregnancy outcomes should be obtained from the mother.
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery.
Women of childbearing potential should be advised to use highly effective contraception
methods while they are receiving study treatment and up to 7 days after capmatinib treatment 
has been stopped.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (European Medicines Agency (EMA) definition).

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Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE. Study 
treatment errors and uses outside of what is foreseen in the protocol, misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an AE/SAE 
within 24 hours of Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
eCRF (Yes/No)
Document in AE eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with an 
AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with an 
AE/SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
10.2
Additional safety monitoring
Not applicable.
10.3
Committees
10.3.1
Steering committee
A steering committee (SC) will be established comprising Investigators participating in the trial 
and/or key opinion leaders in NSCLC and Novartis representatives from the Clinical Trial Team.
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also
develop recommendations for publications of study results including authorship rules. The 
details of the role of the Steering Committee will be defined in a Steering Committee charter.
11
Data collection and database management
11.1
Data collection
Designated Investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the Electronic Data Capture (EDC) system until they have been trained. 

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Automatic validation programs check for data discrepancies in the eCRFs, allow modification 
and/or verification of the entered data by the Investigator staff.
The Investigator/designee is responsible for assuring that the data (entered into eCRFs) is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
Investigator must certify that the data entered are complete and accurate.
After final database lock, the Investigator will receive copies of the participant data for 
archiving at the investigational site.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated Investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Dates of screenings, screen failures and study completion, as well as data about all study 
treatment (s) dispensed to the participant and all dosage changes will be tracked using an 
Interactive Response Technology (IRT). The system will be supplied by a vendor, who will also 
manage the database. The data will be sent electronically to Novartis (or a designated CRO) at 
specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis development management.
11.3
Source documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF or entered in the eCRF 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.
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. The Investigator must also keep the original 

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informed consent form signed by the participant (a signed copy is given to the participant). 
Definition of what constitutes source data and its origin can be found in monitoring guidelines.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. Study monitors will perform ongoing source data verification 
to confirm that data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH Good Clinical Practice (GCP), and all applicable 
regulatory requirements.
Key study personnel must be available to assist the field monitor during these visits. Continuous 
remote monitoring of each site’s data may be performed by a centralized Novartis Clinical 
Research Associate (CRA) organization. Additionally, a central analytics organization may 
analyze data & identify risks & trends for site operational parameters, and provide reports to 
Novartis clinical teams to assist with trial oversight.
12
Data analysis and statistical methods
Primary safety and efficacy analysis will be conducted on all participant data by cohort when 
all treated participants in that cohort have completed at least 6 cycles of treatment (18 weeks) 
unless a participant has discontinued treatment earlier. These data will be summarized in the 
primary Clinical Study Report (CSR). In case of one cohort finishes earlier than the other, the 
primary CSR may be written based on data from that cohort only. Once the second cohort is 
complete another CSR may be written.
All available data from all participants up to this cutoff date will be analyzed.
12.1
Analysis sets
12.1.1
Full analysis set (FAS)
The full analysis set (FAS) comprises all participants to whom study treatment has been 
assigned and who received at least one dose of capmatinib. Unless otherwise specified, all 
efficacy analyses will be performed using FAS.
12.1.2
Full analysis set – brain metastases (FAS-BM)
The full analysis set - brain metastases (FAS-BM) comprises all participants in the FAS who 
have measurable and/or non-measurable brain metastases at baseline.
12.1.3
Safety set
The Safety Set includes all participants who received at least one dose of capmatinib. Unless 
otherwise specified, all safety data will be analyzed by Safety Set.

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12.1.4
Pharmacokinetics analysis set
The pharmacokinetic analysis set (PAS) consists of all participants who received at least one 
dose of capmatinib and had at least one evaluable post-baseline capmatinib concentration 
measurement.
The definition of an evaluable PK concentration will be specified in the statistical analysis plan
(SAP).
12.1.5
Evaluable set
The evaluable set comprises all participants in FAS who have at least one post-baseline tumor 
assessment after treatment.
12.2
Participant demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by cohort for the FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation), median, minimum, and maximum will be presented. For selected 
parameters, 25th and 75th percentiles will also be presented.
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term, by cohort using FAS.
12.3
Treatments
The safety set will be used for the analyses below.
The actual dose and duration in days of capmatinib as well as the dose intensity (computed as 
the ratio of total dose received and actual duration) and the relative dose intensity (computed as 
the ratio of dose intensity and planned dose received/planned duration), will be listed and 
summarized by cohort. Dose reductions and dose interruptions (including the reasons for these) 
will be listed and summarized by cohort.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized according to the Anatomical Therapeutic Chemical (ATC)
by cohort.
12.4
Analysis supporting primary objectives
12.4.1
Definition of primary endpoint(s)
The primary endpoint is the ORR by cohort as per BIRC review. ORR is defined as the 
proportion of participants with best overall response (BOR) of complete response (CR) or 
partial response (PR) according to RECIST 1.1.

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12.4.2
Statistical model, hypothesis, and method of analysis
The primary analysis will be performed on the FAS. The primary efficacy endpoint ORR will 
be estimated and the exact 95% confidence interval (CI) (Clopper and Pearson 1934) will be 
provided by cohort.
The study is based on estimation of the endpoint and therefore no statistical hypothesis will be 
performed.
12.4.3
Handling of intercurrent events of primary estimand
Tumor assessment data collected irrespective of treatment discontinuation until the start of new 
anti-cancer therapy will be included to derive BOR.
If any antineoplastic therapy is taken, any response after the antineoplastic therapy will be 
considered as non-responder. In case of any missed visit in the event of a public health 
emergency as declared by local or regional authorities (i.e. pandemic, epidemic or natural 
disaster), the subsequent assessments will be included for the BOR calculation.
12.4.4
Handling of missing values/censoring/discontinuation 
Confirmed PR or CR reported prior to any additional anticancer therapy will be considered as 
responses in the calculation of the ORR irrespective of the number of missed assessments before 
response.
Participants with a BOR of ‘Unknown’ per RECIST 1.1 will be considered as non-responders 
when estimating ORR and DCR.
Participants who have disease progression and continue to receive study drug after progression 
will qualify for PD at the time of progression and will be counted as PD in the derivation of 
efficacy endpoints. For additional details, please ref to RECIST 1.1 guideline (Section 16).
12.4.5
Sensitivity analyses
Sensitivity analysis will be performed for DOR and PFS. In the sensitivity analysis of DOR and 
PFS, for participants who receive antineoplastic therapy, the event will be censored at the last 
tumor assessment prior to the antineoplastic therapy.
12.4.6
Supplementary analysis
No supplementary analysis will be provided.
12.4.7
Supportive analyses
ORR by BIRC will be summarized by evaluable sets to support the primary analysis.

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12.5
Analysis supporting secondary objectives
12.5.1
Efficacy and/or pharmacodynamic endpoint(s)
Duration of response (DOR)
DOR only applies to participants whose BOR is complete response (CR) or partial response 
(PR) according to RECIST 1.1 based on tumor response data. The start date is the date of first 
documented response of CR or PR (i.e. the start date of response, not the date when response 
was confirmed), and the end date is defined as the date of the first documented progression or 
death due to any cause. DOR will be assessed as per BIRC review and by Investigator 
assessment for both FAS and evaluable sets.
Participants continuing without progression or death due to any cause will be censored at the 
date of their last adequate tumor assessment. Participants without a post-baseline tumor 
assessment will be censored at the time of the first treatment.
ORR by Investigator assessment
The evaluation of ORR will be also conducted based on Investigator assessment. ORR will be 
estimated and the exact binomial 95% CI will be provided by cohort.
Time to Response (TTR)
TTR is defined as the time from the date of start of study drug to the first documented response 
of either complete response (CR) or partial response (PR), which must be subsequently 
confirmed (although date of initial response is used, not date of confirmation). TTR will be 
evaluated as per BIRC and also by Investigator review and according to RECIST 1.1.
Participants without a confirmed CR or PR will be censored at the study-maximum follow-up 
time (i.e. first patient first visit (FPFV) to last patient last visit (LPLV)) for participants with a 
PFS event (i.e. disease progression or death due to any cause), or at the date of the last adequate 
tumor assessment for participants without a PFS event.
Disease control rate (DCR)
DCR is defined as the proportion of participants with a BOR of complete response (CR), or 
partial response (PR), or an overall response of stable disease (SD). DCR will be assessed as 
per BIRC as well as Investigator assessment according to RECIST 1.1.
DCR and its 95% exact confidence interval will be presented for each cohort using FAS.
Progression-free survival (PFS)
The analysis in this section refers to the PFS as per BIRC and per Investigator review.
PFS is defined as the time from the date of first dose of capmatinib to the date of the first 
documented progression according to RECIST 1.1, or death due to any cause. If a participant 
has no progression or death, the participant is censored at the date of last adequate tumor 
assessment. Definition of last adequate tumor assessment is provided in Section 16.1.

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PFS will be summarized using the Kaplan-Meier (KM) method, based on data from the FAS. 
Median PFS, with corresponding 95% CI, and 25th and 75th percentiles (Brookmeyer and 
Crowley 1982, Klein and Moeschberger 1997) will be presented. KM estimates for PFS 
proportions at specific timepoints, along with 95% CI (Greenwood’s formula, Kalbfleisch and 
Prentice 2002) will also be provided.
Overall survival (OS)
OS is defined as the time from date of first treatment to date of death due to any cause. If a 
participant is not known to have died, then OS will be censored at the latest date the participant 
was known to be alive (on or before the cut-off date).
All time to event (TTE) variables (DOR, TTR, PFS, OS) distribution will be estimated using 
the Kaplan-Meier method, and the Kaplan-Meier curves, medians, and 95% confidence 
intervals of the medians (in months) along with 25th and 75th percentile will be presented for 
each cohort using FAS.
Overall intracranial response rate (OIRR)
OIRR is calculated based on response assessments in the brain for participants having 
measurable and/or non-measurable brain metastases at baseline. OIRR is the proportion of 
participants with a confirmed best overall intracranial response (BOIR) of CR or PR per RANO-
BM criteria as assessed by BIRC review.
OIRR calculated based on the data from the FAS-BM and the corresponding 95% CI based on 
the exact binomial distribution (Clopper and Pearson 1934) will be presented by cohort.
Intracranial disease control rate (IDCR)
IDCR is calculated based on response assessments in the brain for participants having 
measurable and/or non-measurable brain metastases at baseline. IDCR is the proportion of 
participants with a confirmed BOIR of CR or PR or SD (or non-CR/non-PD) per RANO-BM 
criteria as assessed by BIRC review.
IDCR calculated based on the data from the FAS-BM and the corresponding 95% CI based on 
the exact binomial distribution (Clopper and Pearson 1934) will be presented by cohort.
Time to intracranial response (TTIR)
TTIR is defined as the time from the date of the start of study treatment to the date of the first 
documented intracranial response of either CR or PR per RANO-BM criteria as assessed by the 
BIRC review, which must be subsequently confirmed (date of initial response is used, not date 
of confirmation).
All participants in the FAS-BM will be included in TTIR calculations. Participants without a 
confirmed intracranial CR or PR will be censored at the study-maximum follow-up time (i.e. 
LPLV−FPFV) for participants with an intracranial PFS event (intracranial progression or death 
due to any cause), or at the date of the last adequate tumor assessment in brain for participants 
without an event. 

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Median TTIR with corresponding 95% CI, and 25th and 75th percentiles (Brookmeyer and 
Crowley 1982, Klein and Moeschberger 1997) will be presented. TTIR will be summarized 
using the KM method, based on data from the FAS-BM. KM estimates for TTIR proportions at 
specific time points, along with 95% CI (Greenwood’s formula, Kalbfleisch and Prentice 2002) 
will also be provided.
Duration of intracranial response (DOIR)
DOIR only applies to participants whose confirmed BOIR is CR or PR per RANO-BM criteria 
as assessed by the BIRC review. DOIR is defined as the time from the date of first documented 
intracranial response of either CR or PR to the date of the first documented intracranial 
progression per RANO-BM criteria as assessed by BIRC review or date of death due to any
cause.
Participants with a confirmed intracranial CR or PR will be censored if they have disease 
progression in organs other than brain and have no scans in brain after that. The censoring date 
will be the date of the last adequate tumor assessment in brain.
DOIR will be summarized using the KM method. Median DOIR, with corresponding 95% CI, 
and 25th and 75th percentiles (Brookmeyer and Crowley 1982, Klein and Moeschberger 1997) 
will be presented. KM estimates for DOIR proportions at specific timepoints, along with 95%
CI (Greenwood's formula, Kalbfleisch and Prentice 2002) will also be provided.
12.5.2
Safety endpoints
12.5.2.1 Analysis set and grouping for the analysis
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
cohort.
The overall observation period will be divided into three mutually exclusive segments:
1. Pre-treatment period: from day of participant’s informed consent to the day before first dose 
of study medication
2. On-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
3. Post-treatment period: starting at day 31 after last dose of study medication.
12.5.2.2 Adverse events
All information obtained on AEs will be displayed by cohort and participants.
The number (and percentage) of participants with treatment emergent AEs (events started on or 
after the first dose of study medication) will be summarized in the following ways:

by primary system organ class and preferred term.

by primary system organ class, preferred term and maximum severity.

by Standardized MedDRA Query (SMQ) and preferred term.
Separate summaries will be provided for study medication related AEs, death, SAEs, other 
significant AEs leading to discontinuation.

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A participant with multiple AEs within a primary system organ class is only counted once 
towards the total of the primary system organ class.
AEs which will be counted for a specific treatment period are those which are treatment-
emergent. These events are those with an onset after the start of the treatment period, or which 
were present prior to the start of the treatment period but increased in severity, changed from 
being not suspected to being suspected of study treatment relationship, or developed into SAEs 
after the start of the treatment period.
Summary tables for AEs will include only AEs that started or worsened during the on-treatment 
period, the treatment-emergent AEs.
SAEs, non-serious AEs and adverse events of special interest (AESI) based on case retrieval 
strategy (CRS) during the on-treatment period will be tabulated.
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths, and SAEs (including those from the pre and post-treatment periods) will be 
listed and those collected during the pre-treatment and post-treatment period will be flagged.
12.5.2.3 Vital signs
All vital signs data will be listed by cohort, participant, and visit and if ranges are available, 
abnormalities will be flagged. Summary statistics will be provided by cohort and visit/time.
12.5.2.4 12-lead ECG
ECG evaluation will be collected as per visit schedule (see Table 8-2).

PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each 
participant during the study. ECG data will be read and interpreted locally.
All ECG data will be listed by cohort, participant and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by cohort and visit/time.
12.5.2.5 Clinical laboratory evaluations
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 or higher. The calculation of 
CTCAE grades will be based on the observed laboratory values only, clinical assessments will 
not be taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used.
For laboratory tests where grades are not defined by CTCAE, results will be categorized as 
low/normal/high based on laboratory normal ranges.
The following summaries will be generated separately for hematology, biochemistry and 
urinary laboratory tests by cohort:

Listing of all laboratory data with values flagged to show the corresponding CTCAE grades 
if applicable and the classifications relative to the laboratory normal ranges
For laboratory tests where grades are defined by CTCAE:

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
Worst post-baseline CTCAE grade (regardless of the baseline status). Each participant will 
be counted only once for the worst grade observed post-baseline.

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value
For laboratory tests where grades are not defined by CTCAE:

Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value.
In addition to the above mentioned tables and listings, other exploratory analyses, 
 
 
12.5.2.6 Other safety evaluations
Tolerability will be summarized in terms of dose reductions or drug interruption due to an AE 
by cohort.
12.5.3
Pharmacokinetics
The PAS will be used in all pharmacokinetic data analysis and PK summary statistics.
Descriptive summary statistics of plasma concentration will be provided by cohort and by 
visit/sampling time point. Summary statistics will include mean (arithmetic and geometric), 
Standard Deviation, CV% (arithmetic and geometric), median, minimum and maximum.
Capmatinib plasma concentration data will be listed by cohort, participant, and visit/sampling 
time point.
Capmatinib plasma concentration values below the lower limit of quantitation (LLOQ) will be 
displayed in listings as zero with a flag and handled as zero in any calculations of summary 
statistics, but handled as missing for the calculation of the geometric means and their CV.
If data permits, population PK analysis 
.
12.5.4
DNA
Not applicable.
12.5.5
Biomarkers
As a project standard, only biomarker data collected in the clinical database will be analyzed. 
This study is not adequately powered to assess specific biomarker related hypotheses. The 
analyses of biomarkers will be reported in the CSR if data are available at the time of clinical 
database lock and CSR preparation. Otherwise, the results may be reported in a separate report 
document.
There may be circumstances when a decision is made to stop a sample collection, or not perform 
or discontinue the analysis of tumor samples due to either practical or strategic reasons (e.g., 
issues related to the quality and or quantity of samples. Under such circumstances, the number 
of samples may be inadequate to perform a rigorous data analysis and the available data will 
only be listed.
CCI
CCI

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12.5.5.1 Outline of the data analysis
The proposed data analysis will be aligned with the secondary biomarker objective of the 
protocol:

To evaluate the association between MET mutation status as measured in ctDNA at baseline 
with ORR, DOR and PFS upon treatment with capmatinib.
12.5.5.2 Data handling principles
Data handling principles such as handling of missing values, categorization of continuous or 
semi-continuous biomarker, etc. will be described in detail in the SAP.
12.5.5.3 Data analysis principles
12.5.5.3.1
Analysis set
The FAS will be used for all biomarker analyses. Unless otherwise specified, all statistical 
analyses of biomarker data will be performed on participants with biomarker data.
12.5.5.3.2
Basic tables, figures and listings
If the number of participants is considered large enough, the association between MET mutation 
status as measured in ctDNA at baseline with ORR, DOR and PFS will be established using 
Kaplan-Meier curve, by cohort separately. Median survival together will their 95% confidence
intervals will be reported. 95% CI will be generated for ORR using Fisher exact test.
Details of statistical methods will be provided in the SAP.
12.5.5.3.3
Advanced analysis methods
 
12.5.6
Pharmarcokinetics/Pharmacodynamics relationships
Not applicable.
12.5.7
Patient reported outcomes
Patient reported outcomes (PRO) data will be analyzed using the FAS.
The EORTC QLQ-C30/LC13, NCCN FACT-Br Symptom Index symptom module and EQ-
5D-5L questionnaires will be used to collect participant’s PRO data. Scoring and handling of 
missing data from PROs will be conducted according to the respective scoring manual provided 
by the developers (Fayers 2001; Van Reenen M et al 2019).
Descriptive statistics for continuous data will be used to summarize EORTC QLQ-C30/LC13,
EQ-5D-5L, and NCCN FACT-FBrSI at each scheduled assessment time point. The scores will 
be displayed as mean profiles by cohort/sub-cohort, presented over time. The number of 
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participants completing the questionnaires and the number of missing or incomplete 
assessments will be summarized for each scheduled assessment time point.
12.6
Analysis of exploratory endpoints
Not applicable.
12.7
Interim analyses
Not applicable.
12.8
Sample size determination
12.8.1
Primary endpoint(s)
Approximate 35 participants will be treated in this two-cohort study (cohort 1 ~ 15 participants 
and cohort 2~20 participants). With 15 participants in Cohort 1, the lower bound of exact 
binomial 95% CI for observed ORR will be at least 38.4% when observed ORR is 66.7%. 
Similarly, with 20 participants in Cohort 2, the lower bound of exact binomial 95% CI for ORR 
will be ≥ 19.1% when observed ORR is 40%. 
Table 12-1 below shows the results from study [CINC280A2201] which will be used as a 
reference for sample size calculation. 
Table 12-1
Objective response rate (ORR) and 95% lower limit of confidence 
interval (LLCI) (%) in study CINC280A2201
Line
n/N
Point estimate (%)
95% LLCI (%)
1L
19/28
67.9
47.6
2/3L
28/69
40.6
28.9
In study [CINC280A2201], 67.9% ORR and 47.6% of its lower limit of 95% CI were observed 
from 28 participants in the treatment naive cohort. If 10 responders out of 15 participants are 
observed in this study, cohort 1, it will result ORR of 66.7%. The probability of observing ORR 
greater than 47.6% is at least 0.89. With 15 participants, Table 12-2 below shows the probability 
of observing ORR greater than 47.6%.
Table 12-2
Operating characteristics for cohort 1
Sample size
True ORR (%) in 
Chinese participants
Probability (%) that observed ORR > 47.6% 
(lower limit in A2201)
15
50
50.0
55
65.4
60
78.7
65
88.7
70
95.0
75
98.3
Similarly, in study [CINC280A2201], 40.6% ORR and 28.9% of its lower limit of 95% CI were 
observed from 69 participants from the pre-treated cohort. If 8 responders out of 20 participants
are observed in this study, cohort 2, it will result 40% ORR. The probability of observing ORR 

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greater than 28.9% is at least 0.87. With 20 participants, Table 12-3 below shows the probability 
of observing ORR greater than 28.9%.
Table 12-3
Operating characteristics for cohort 2
Sample size
True ORR (%) in 
Chinese participants
Probability (%) that observed ORR > 28.9% 
(lower limit in A2201)
20
25
38.3
30
58.4
35
75.5
40
87.4
45
94.5
50
99.4
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical considerations
This study will be conducted in accordance with the protocol and with 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 Good Clinical Practice (GCP) guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator’s Brochure and other relevant documents 
(e.g. advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate
hazard to study participants.
Protocols and any substantial amendments/modifications to the protocol will require health
authority approval prior to initiation except for changes necessary to eliminate an immediate
hazard to study participants.
The Investigator will be responsible for the following:

Signing a protocol signature page confirming his/her agreement to conduct the study in
accordance with these documents and all of the instructions and procedures found in this
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Quality Assurance representatives, designated agents of Novartis, IRBs/IECs, 
and regulatory authorities as required

Providing written summaries of the status of the study to the IRB/IEC annually or more
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by
IRB/IEC procedures

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
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), European Medical Device Regulation 2017/745 for clinical device 
research (if applicable), and all other applicable local regulations

Inform Novartis immediately if an inspection of the clinical site is requested by a
regulatory authority
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, United States CFR 21), and with 
the ethical principles laid down in the Declaration of Helsinki.
13.2
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last participant last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required health authority websites (e.g. Clinicaltrials.gov, EudraCT etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial Investigator 
meetings.
Any data analysis carried out independently by the Investigator should be submitted to Novartis 
before publication or presentation.
13.3
Quality control and quality assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of Investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal standard operating procedures (SOPs), and are performed according to 
written Novartis processes.
13.4
Participant Engagement
Not applicable.
13.5
Data Protection
Participants will be assigned a unique identifier by Novartis. Any participant records or datasets 
that are transferred to Novartis will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred.

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The participant must be informed that his/her personal study-related data will be used by 
Novartis in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Novartis, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.
Novartis has appropriate processes and policies in place to handle personal data breaches 
according to applicable privacy laws.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an Investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the Investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.

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15
References
References are available upon request
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Awad MM, Leonardi GC, Kravets S, et al (2019) Impact of MET inhibitors on survival among 
patients with non-small cell lung cancer harboring MET exon 14 mutations: a retrospective 
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Amplification and c-Met Overexpression. J Clin Oncol; 34(7):721-30.
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tumours: revised RECIST guideline (version 1.1). Eur J Cancer; 45(2):228-47.
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Netw; 8(7):740-801.
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EORTC QLQ-C30. Eur J Cancer; 37(11):1331-4.
Frampton GM, Ali SM, Rosenzweig M, et al (2015) Activation of MET via diverse exon 14 
splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET 
inhibitors. Cancer Discov; 5(8):850-9.
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14(10):1753-1765.
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five-level version of EQ-5D (EQ-5D-5L). Qual Life Res; 20(10):1727-36.
Jenkins RW, Oxnard GR, Elkin S, et al (2015) Response to Crizotinib in a Patient With Lung 
Adenocarcinoma Harboring a MET Splice Site Mutation. Clin Lung Cancer; 16(5): e101-4.
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Data, Second Edition. NewYork, Springer.
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deletion of met in lung cancer. Cancer Res; 66(1):283-9.
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with primary brain tumors. Value Health; 17(1):62-9.
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Chinese Patients with NSCLC. J Thorac Oncol; 11(9):1503-10.
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Liu X, Yao W, Newton RC, et al (2008) Targeting the c-MET signaling pathway for cancer 
therapy. Expert Opin Investig Drugs; 17(7):997-1011.
Lu X, Peled N, Greer J, et al (2017) MET Exon 14 Mutation Encodes an Actionable Therapeutic 
Target in Lung Adenocarcinoma. Cancer Res; 77(16):4498-4505.
Mendenhall MA, Goldman JW (2015) MET-Mutated NSCLC with Major Response to 
Crizotinib. J Thorac Oncol; 10(5):e33-4.
Ou SI, Agarwal N, Ali SM (2016) High MET amplification level as a resistance mechanism to 
osimertinib (AZD9291) in a patient that symptomatically responded to crizotinib treatment 
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how to use the EQ-5D-5L instrument, Version 3.0. EuroQol Research Foundation.
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Abstract 14P.

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16
Appendices
16.1
Appendix 1: Guidelines for Response, Duration of Overall 
Response, TTF, TTP, Progression-Free Survival, and Overall 
Survival (based on RECIST 1.1)
Document type:
TA Specific Guideline
Document status:
Version 3.2: 16-Feb-2016
Version 3.1: 29-Nov-2011
Version 3: 19-Oct-2009
Version 2: 18-Jan-2007
Version 1: 13-Dec-2002
Release date:
11-Feb-2016
Authors (Version 
3.2):
 
 
Authors (Version 
3.1):
 
 
Authors (Version 3):
 
 
Authors (Version 2):
 
 
Authors (Version 1):
 
PPD
PPD
PPD
PPD
PPD

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Glossary
BOR
Best overall response
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
DFS
Disease-free survival
DOR
Duration of response
eCRF
Electronic Case Report Form
FPFV
First patient first visit
GBM
Glioblastoma multiforme
MRI
Magnetic resonance imaging
LPLV
Last patient last visit
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable disease
SOD
Sum of Diameter
TTF
Time to treatment failure
TTP
Time to progression
UNK
Unknown

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16.1.1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 16.1.2 and the definition of best response in
Section 16.1.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 16.1.3.2 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 16.1.4 of 
this guideline describes data handling and programming rules. This section is to be referred to
in the SAP (Statistical Analysis Plan) to provide further details needed for programming.
16.1.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247.
16.1.2.1 Definitions
16.1.2.1.1
Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.

Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. If 
the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
For patients without measurable disease see Section 16.1.3.2.8
Measurable lesions (both nodal and non-nodal)

Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10 mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5 mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft tissue 
component meets the definition of measurability.

Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 
15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 
10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at baseline, 
regardless of the slice thickness, are normal and not considered indicative of disease.
CCI
CCI

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
Cystic lesions: 

Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no septations, 
and low CT density [water-like] content) 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 
noncystic lesions are present in the same patient, these are preferred for selection as 
target lesions.

Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with 10 
to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging techniques.
16.1.2.1.2
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in 
Section 16.1.3.2.8.
16.1.2.2 Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v.) contrast.
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.

For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-up. 
Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed using 
a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan slice 
thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. If, at 
baseline, a patient is known to have a medical contraindication to CT contrast or develops 
a contraindication during the trial, the following change in imaging modality will be 
accepted for follow-up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis.

A change in methodology can be defined as either a change in contrast use (e.g. keeping the 
same technique, like CT, but switching from with to without contrast use or vice-versa, 

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regardless of the justification for the change) or a major change in technique (e.g. from CT 
to MRI, or vice-versa), or a change in any other imaging modality. A change from 
conventional to spiral CT or vice versa will not constitute a major “change in method” for 
the purposes of response assessment. A change in methodology will result by default in a 
UNK overall lesion response assessment as per Novartis calculated response. However,
another response assessment than the Novartis calculated UNK response may be accepted 
from the investigator or the central blinded reviewer if a definitive response assessment can 
be justified, based on the available information.

FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.

No FDG-PET at baseline with a positive FDG-PET at follow-up:

If new disease is indicated by a positive PET scan but is not confirmed by CT (or some 
other conventional technique such as MRI) at the same assessment, then follow-up 
assessments by CT will be needed to determine if there is truly progression occurring at that 
site. In all cases PD will be the date of confirmation of new disease by CT (or some other 
conventional technique such as MRI) rather than the date of the positive PET scan. If there 
is a positive PET scan without any confirmed progression at that site by CT, then a PD 
cannot be assigned.

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.

Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.

Physical exams: Evaluation of lesions by physical examination is accepted when 
lesions are superficial, with at least 10 mm size, and can be assessed using calipers. 

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions, unless pre-specified by 
the protocol. It is, however, a possible alternative to clinical measurements of 
superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules. US might 
also be useful to confirm the complete disappearance of superficial lesions usually 
assessed by clinical examination.

Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for 
objective tumor evaluation has not yet been fully and widely validated. Their uses in 
this specific context require sophisticated equipment and a high level of expertise that 
may only be available in some centers. Therefore, the utilization of such techniques for 
objective tumor response should be restricted to validation purposes in specialized 
centers. However, such techniques can be useful in confirming complete pathological 
response when biopsies are obtained.

Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian 
cancer, PSA for prostate cancer, alpha-FP, lactate dehydrogenase (LDH) and Beta-hCG 

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for testicular cancer) can be integrated as non-target disease. If markers are initially 
above the upper normal limit they must normalize for a patient to be considered in 
complete clinical response when all lesions have disappeared.

Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment
is required when the measurable tumor has met the criteria for response or stable disease
(SD). Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and SD (an effusion may be a side effect of the treatment) 
or progressive disease (PD) (if the neoplastic origin of the fluid is confirmed).

Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
16.1.2.3 Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs 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) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF (even 
if it resides in the same organ).
Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice thickness 
is not applicable (e.g. clinical examination, photography) should be at least 10 mm in 
longest diameter. See Section 16.1.2.1.1.

Nodal target: See Section 16.1.2.1.1.
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. Each 
target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.

Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of non-
target lesions should be assessed throughout the study; measurements of these lesions are 
not required. Multiple non-target lesions involved in the same organ can be assessed as a 
group and recorded as a single item (i.e. multiple liver metastases). Each non-target lesion 

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identified at baseline must be followed at each subsequent evaluation and documented on 
eCRF.
16.1.2.4 Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 16-1) and non-target lesions (Table 16-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 16-3) as well as the presence or absence of new lesions.
16.1.2.4.1
Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for the
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number.
Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm,
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval.
In other cases where the lesion cannot be reliably measured for reasons other than its size 
(e.g., borders of the lesion are confounded by neighboring anatomical structures), no 
measurement should be entered and the lesion cannot be evaluated.
Nodal lesions
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist.
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness
(but should not be changed with varying CT slice thickness).Actual measurement should be 
given for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval.

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However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination.
16.1.2.4.2
Determination of target lesion response
Table 16-1
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
Complete Response (CR):
Disappearance of all non-nodal target lesions. In addition, any pathological lymph 
nodes assigned as target lesions must have a reduction in short axis to < 10 mm 1
Partial Response (PR):
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of diameter of all measured target lesions, 
taking as reference the smallest sum of diameter of all target lesions recorded at 
or after baseline. In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm 2.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions 
which would qualify for PD.
Unknown (UNK)
Progression has not been documented and one or more target lesions have not 
been assessed or have been assessed using a different method than baseline.3
1.SOD for CR may not be zero when nodal lesions are part of target lesions
2.Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all nodal 
lesions are <10 mm in size. In this case, the target lesion response is CR
3.In exceptional circumstances an UNK response due to change in method could be over-ruled by the investigator 
or central reviewer using expert judgment based on the available information (see Notes on target lesion 
response and methodology change in Section 16.1.2.2).
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following 
possibilities:
The lesion is a new lesion, in which case the overall tumor assessment will be considered as 
PD
The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 16-1 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at or 
after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who have 
not achieved target response of CR. For patients who have achieved CR, please refer to last 
bullet in this section.

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For those patients who have only one target lesion at baseline, the reappearance of the target 
lesion which disappeared previously, even if still small, is considered a PD.
Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit is 
140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, in 
other cases where a PD cannot definitely be attributed, the target lesion response would be 
UNK.
Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal in 
order not to overstate progression should it be based on increase in the size of nodes.
Lesions split: In some circumstances, disease that is measurable as a target lesion at baseline 
and appears to be one mass can split to become two or more smaller sub-lesions. When this 
occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) of the two split 
lesions should be added together and the sum recorded in the diameter field on the case report 
form under the original lesion number. This value will be included in the sum of diameters 
when deriving target lesion response. The individual split lesions will not be considered as 
new lesions, and will not automatically trigger a PD designation.
Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they are 
no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis - nodal 
lesions) of the “merged lesion” should be used when calculating the sum of diameters for 
target lesions. On the case report form, the diameter of the “merged lesion” should be
recorded for the size of one of the original lesions while a size of “0” mm should be entered 
for the remaining lesion numbers which have coalesced.

The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications.

Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all non-
nodal target lesions have disappeared.

Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions.

Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 
10 mm and there is at least 20% increase in sum of the diameters of all nodal target 
lesions relative to nadir with at least 5 mm increase in the absolute sum of the diameters. 

A change in method for the evaluation of one or more lesions will usually lead to an UNK 
target lesion response unless there is progression indicated by the remaining lesions which 
have been evaluated by the same method. In exceptional circumstances an investigator or 
central reviewer might over-rule this assignment to put a non-UNK response using expert 

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judgment based on the available information. E.g. a change to a more sensitive method 
might indicate some tumor shrinkage of target lesions and definitely rule out progression in 
which case the investigator might assign an SD target lesion response; however, this should 
be done with caution and conservatively as the response categories have well defined 
criteria.
16.1.2.4.3
Determination of non-target lesion response
Table 16-2
Response criteria for non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions. In addition, all lymph nodes assigned a 
non-target lesions must be non-pathological in size (< 10 mm short axis)
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.1
Non-CR/Non-PD:
Neither CR nor PD
Unknown (UNK)
Progression has not been documented and one or more non-target lesions have 
not been assessed or have been assessed using a different method than 
baseline2.
1.
The assignment of PD solely based on change in non-target lesions in light of target lesion response of CR, 
PR or SD should be exceptional. In such circumstances, the opinion of the investigator or central reviewer 
does prevail.
2.
It is recommended that the investigator and/or central reviewer should use expert judgment to assign a Non-
UNK response wherever possible (see notes section for more details)
Notes on non-target lesion response

The investigator and/or central reviewer can use expert judgment to assign a non-UNK 
response wherever possible, even where lesions have not been fully assessed or a different 
method has been used. In many of these situations it may still be possible to identify 
equivocal progression (PD) or definitively rule this out (non-CR/Non-PD) based on the 
available information. In the specific case where a more sensitive method has been used 
indicating the absence of any non-target lesions, a CR response can also be assigned.

The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions returned 
to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or there are 
any abnormal nodal lesions (i.e. 10 mm) the response can only be ‘Non-CR/Non-PD’ 
unless there is unequivocal progression of the non-target lesions (in which case response is 
PD) or it is not possible to determine whether there is unequivocal progression (in which 
case response is UNK).

Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable disease 

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at baseline. If there is unequivocal progression of non-target lesion(s), then at least one of 
the non-target lesions must be assigned a status of “Worsened”. Where possible, similar 
rules to those described in Section 16.1.2.4.2 for assigning PD following a CR for the 
non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.
16.1.2.4.4
New lesions
The appearance of a new lesion is always associated with PD and has to be recorded as a new 
lesion in the New Lesion CRF page.

If a new lesion is equivocal, for example 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 
first observation of the lesion

If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 16.1.2.5).

A lymph node is considered as a “new lesion” and, therefore, indicative of PD if the short 
axis increases in size to 10 mm for the first time in the study plus 5 mm absolute increase.
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 16.1.2.2.
16.1.2.5 Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in 
Table 16-3.
Table 16-3
Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overall
lesion response
CR
CR
No
CR1
CR
Non-CR/Non-PD3
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR1
SD
Non-PD and not UNK
No
SD1, 2
UNK
Non-PD or UNK
No
UNK1
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD

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Target lesions
Non-target lesions
New Lesions
Overall
lesion response
1.
This overall lesion response also applies when there are no non-target lesions identified at baseline.
2.
Once confirmed PR was achieved, all these assessments are considered PR.
3.
As defined in Section 16.1.2.4.
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
16.1.3
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 16.1.3.2.8 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
16.1.3.1 Best overall response
The best overall response (BOR) is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). In general, the patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.
The BOR will usually be determined from response assessments undertaken while on treatment. 
However, if any assessments occur after treatment withdrawal the protocol should specifically 
describe if these will be included in the determination of BOR and/or whether these additional 
assessments will be required for sensitivity or supportive analyses. As a default, any 
assessments taken more than 30 days after the last dose of study treatment will not be included 
in the BOR derivation. If any alternative cancer therapy is taken while on study any subsequent 
assessments would ordinarily be excluded from the BOR determination. If response 
assessments taken after withdrawal from study treatment and/or alternative therapy are to be 
included in the main endpoint determination, then this should be described and justified in the 
protocol.
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met.
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed.

For non-randomized trials where response is the primary endpoint, confirmation is needed.

For trials intended to support accelerated approval, confirmation is needed

For all other trials, confirmation of response may be considered optional.

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The BOR for each patient is determined from the sequence of overall (lesion) responses 
according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR prior 
to progression where confirmation not required

SD = at least one SD assessment (or better) > 6 weeks after randomization/start of treatment 
(and not qualifying for CR or PR).

PD = progression 12 weeks after randomization/start of treatment (and not qualifying for 
CR, PR or SD).

UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks)
The time durations specified in the SD/PD/UNK definitions above are defaults based on a 6 
week tumor assessment frequency. However these may be modified for specific indications 
which are more or less aggressive. In addition, it is envisaged that the time duration may also 
take into account assessment windows. E.g. if the assessment occurs every 6 weeks with a time 
window of +/- 7 days, a BOR of SD would require a SD or better response longer than 5 weeks 
after randomization/start of treatment.
Overall lesion responses of CR must stay the same until progression sets in, with the exception 
of a UNK status. A patient who had a CR cannot subsequently have a lower status other than a 
PD, e.g. PR or SD, as this would imply a progression based on one or more lesions reappearing, 
in which case the status would become a PD.
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not 20% increase from previous smallest sum), the objective status 
at that assessment should be SD. Once a confirmed PR was seen, the overall lesion response 
should be considered PR (or UNK) until progression is documented or the lesions totally 
disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable.
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm – 150 mm – 140 mm – 160 mm – 160 mm at the 
subsequent visits. Assuming that non-target lesions did not progress, the overall lesion response 
would be PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for 
this patient. All subsequent assessments are considered PR even if tumor measurements 
decrease only by 20% compared to baseline (200 mm to 160 mm) at the following assessments.

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If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of BOR.
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.
The BOR for a patient is always calculated, based on the sequence of overall lesion responses. 
However, the overall lesion response at a given assessment may be provided from different 
sources:

Investigator overall lesion response

Central Blinded Review overall lesion response

Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review)
The primary analysis of the BOR will be based on the sequence of central blinded 
review/calculated (central) overall lesion responses.
Based on the patients’ BOR during the study, the following rates are then calculated:
Overall response rate (ORR) is the proportion of patients with a BOR of CR or PR. This is 
also referred to as ‘Objective response rate’ in some protocols or publications.
Disease control rate (DCR) is the proportion of patients with a BOR of CR or PR or SD. The 
objective of this endpoint is to summarize patients with signs of “activity” defined as either 
shrinkage of tumor (regardless of duration) or slowing down of tumor growth. 
Clinical benefit rate (CBR) is the proportion of patients with a BOR of CR or PR, or an overall 
lesion response of SD or Non-CR/Non-PD which lasts for a minimum time duration (with a 
default of at least 24 weeks in breast cancer studies). This endpoint measures signs of activity 
taking into account duration of disease stabilization.
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used:
Early progression rate (EPR) is the proportion of patients with PD within 8 weeks of the start 
of treatment.
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be at 
8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with an 
unknown (UNK) assessment at that time point and no PD before, will not be counted as early 
progressors in the analysis but may be included in the denominator of the EPR rate, depending 
on the analysis population used. Similarly when examining overall response and disease control, 
patients with a BOR assessment of unknown (UNK) will not be regarded as “responders” but 
may be included in the denominator for ORR and DCR calculation depending on the analysis 
population (e.g. populations based on an ITT approach).

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16.1.3.2 Time to event variables
16.1.3.2.1
Progression-free survival
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint.
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, PFS is censored at the date of last adequate tumor assessment.
PFS rate at x weeks is an additional measure used to quantify PFS endpoint. It is recommended 
that a Kaplan Meier estimate is used to assess this endpoint. 
16.1.3.2.2
Overall survival
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”).
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive.
16.1.3.2.3
Time to progression
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer.
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment.
16.1.3.2.4
PFS2
A recent EMA guidance (EMA 2012) recommends a substitute end point intermediate to PFS 
and OS called PFS2, a surrogate for OS when OS cannot be measured reliably, which assesses 
the impact of the experimental therapy on next-line treatment. The main purpose of this 
endpoint is to assess long term maintenance strategies, particularly of resensitizing agents and 
where it is necessary to examine the overall “field of influence”.
PFS2, which could be termed PFS deferred, PFS delayed, tandem PFS, or PFS version 2.0, is 
the time from date of randomization/start of treatment to the date of event defined as the first 
documented progression on next-line treatment or death from any cause. The censoring rules 
for this endpoint will incorporate the same principles as those considered for PFS in this 

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document, and in addition may involve other considerations which will need to be detailed in 
the protocol.
Please note that data collection for the PFS2 is limited to the date of progression and not specific 
read of the tumor assessments.
It is strongly recommended that the teams consult regulatory agencies for scientific advice given 
the limited experience with the use of this endpoint in regulatory setting in light of 
methodological issues w.r.t. censoring foreseen.
16.1.3.2.5
Time to treatment failure
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study drug. In some protocols, time to treatment failure 
may be considered as a sensitivity analysis for time to progression. The list of discontinuation 
reasons to be considered or not as treatment failure may be adapted according to the specificities 
of the study or the disease.
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation due 
to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to treatment 
failure for patients who did not experience treatment failure will be censored at last adequate 
tumor assessment.
16.1.3.2.6
Duration of response (DOR)
The analysis of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 
a treatment with a significantly higher response rate had a significantly shorter DOR but where 
this probably primarily reflected selection bias which is explained as follows: It is postulated 
that there are two groups of patients: a good risk group and a poor risk group. Good risk patients 
tend to get into response readily (and relatively quickly) and tend to remain in response after 
they have a response. Poor risk patients tend to be difficult to achieve a response, may have a 
longer time to respond, and tend to relapse quickly when they do respond. Potent agents induce 
a response in both good risk and poor risk patients. Less potent agents induce a response mainly 
in good risk patients only. This is described in more detail by Morgan (1988).
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates... If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis, et al (2008). It should also be stated in the protocol if DOR is 
to be calculated in addition for unconfirmed response.
For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis).

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Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end date 
and censoring is defined the same as that for time to progression.
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen.
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression.
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression.
16.1.3.2.7
Time to response
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed.
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the ORRs, since the same kind of selection bias may be introduced as 
described for DOR in Section 16.1.3.2.5. It is recommended that an analysis of all patients (both 
responders and non-responders) be performed whether or not a “responders only” descriptive 
analysis is presented. Where an inferential statistical comparison is required, then all patients 
should definitely be included in the analysis to ensure the statistical test is valid. For analysis 
including all patients, patients who did not achieve a response (which may have to be a 
confirmed response) will be censored using one of the following options.

At maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the worst 
possible outcome as it means the patient cannot subsequently respond. Since the statistical 
analysis usually makes use of the ranking of times to response it is sufficient to assign the 
worst possible censoring time which could be observed in the study which is equal to the 
maximum follow-up time (i.e. time from FPFV to LPLV)

At last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint.

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16.1.3.2.8
Definition of start and end dates for time to event variables
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number.
In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations.
Start dates
For all “time to event” variables, other than DOR, the randomization/date of treatment start will 
be used as the start date.
For the calculation of DOR the following start date should be used:

Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page).

Date of progression is the first assessment date at which the overall lesion response was 
recorded as PD.

Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the date 
of randomization/start of treatment is used.

Date of next scheduled assessment is the date of the last adequate tumor assessment plus the 
protocol specified time interval for assessments. This date may be used if back-dating is 
considered when the event occurred beyond the acceptable time window for the next tumor 
assessment as per protocol (see Section 16.1.3.2.8).
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.

Date of discontinuation is the date of the end of treatment visit.

Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 

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date. If available, the last known date patient alive from the survival follow-up page is used. 
If no survival follow-up is available, the date of discontinuation is used as last contact date.

Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
16.1.3.2.9
Handling of patients with non-measurable disease only at baseline
It is possible that patients with only non-measurable disease present at baseline are entered into 
the study, either because of a protocol violation or by design (e.g. in Phase III studies with PFS 
as the primary endpoint). In such cases the handling of the response data requires special 
consideration with respect to inclusion in any analysis of endpoints based on the overall 
response evaluations.
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints.
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with non-
measurable disease is derived slightly differently according to Table 16-4.
Table 16-4
Overall lesion response at each assessment: patients with non-target 
disease only
Non-target lesions
New Lesions
Overall lesion response
CR
No
CR
Non-CR/Non-PD1
No
Non-CR/non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
1 As defined in Section 16.1.2.4.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for BOR patients with only non-
measurable disease may be highlighted in an appropriate fashion e.g. in particular by displaying 
the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.
For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease.

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16.1.3.2.10
Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well as addresses
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a patient being lost to follow-up? It is important that the protocol and RAP specify the 
primary analysis in detail with respect to the definition of event and censoring dates and also 
include a description of one or more sensitivity analyses to be performed.
Based on definitions outlined in Section 16.1.3.2.7, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 2005) 
as a reference, the following analyses can be considered:
Table 16-5
Options for event dates used in PFS, TTP, DOR
Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently in the 
protocol or RAP
Outcome
A
No baseline assessment
(1) Date of randomization/start of treatment3
Censored
B
Progression at or before next scheduled 
assessment
(1) Date of progression
(2) Date of next scheduled assessment2
Progressed
Progressed
C1
Progression or death after exactly one
missing assessment
(1) Date of progression (or death)
(2) Date of next scheduled assessment2
Progressed
Progressed
C2
Progression or death after two or more
missing assessments
(1) Date of last adequate assessment2
(2) Date of next scheduled assessment2
(3) Date of progression (or death)
Censored
Progressed
Progressed
D
No progression
(1) Date of last adequate assessment
Censored
E
Treatment discontinuation due to ‘Disease 
progression’ without documented 
progression, i.e. clinical progression 
based on investigator claim
(1) Ignore clinical progression and follow 
situations above 
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
As per above 
situations
Progressed
F
New anticancer therapy given
(1) Ignore the new anticancer therapy and follow 
situations above (ITT approach) 
(2) Date of last adequate assessment prior to new 
anticancer therapy
(3) Date of secondary anti-cancer therapy
(4) Date of secondary anti-cancer therapy
As per above 
situations
Censored
Censored
Event
G
Deaths due to reason other than 
deterioration of ‘Study indication’
(1) Date of last adequate assessment
Censored 
(only TTP and 
DOR)
1.
=Definitions can be found in Section 16.1.3.2.7.
2.
=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in 
Section 16.1.3.2.7.
3.
=The rare exception to this is if the patient dies no later than the time of the second scheduled assessment 
as defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.

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Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration.
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1) (ITT) is the recommended approach; events 
documented after the initiation of new cancer therapy will be considered for the primary 
analysis i.e. progressions and deaths documented after the initiation of new cancer therapy 
would be included as events. This will require continued follow-up for progression after the 
start of the new cancer therapy. In such cases, it is recommended that an additional sensitivity 
analysis be performed by censoring at last adequate assessment prior to initiation of new cancer 
therapy.
Option (2), i.e. censoring at last adequate assessment may be used as a sensitivity analysis. If a 
high censoring rate due to start of new cancer therapy is expected, a window of approximately 
8 weeks performed after the start of new cancer therapy can be used to calculate the date of the 
event or censoring. This should be clearly specified in the analysis plan. 
In some specific settings, local treatments (e.g. radiation/surgery) may not be considered as 
cancer therapies for assessment of event/censoring in PFS/TTP/DOR analysis. For example, 
palliative radiotherapy given in the trial for analgesic purposes or for lytic lesions at risk of 
fracture will not be considered as cancer therapy for the assessment of BOR and PFS analyses. 
The protocol should clearly state the local treatments which are not considered as antineoplastic 
therapies in the PFS/TTP/DOR analysis.
The protocol should state that tumor assessments will be performed every x weeks until 
radiological progression irrespective of initiation of new antineoplastic therapy. It is strongly 
recommended that a tumor assessment is performed before the patient is switched to a new 
cancer therapy.

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Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 16-5 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment 
(from baseline)”, with the following definition:

Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment.
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation.
16.1.4
Data handling and programming rules
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates).
16.1.4.1 Study/project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation.
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock).
16.1.4.2 End of treatment phase completion
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc.
The end of treatment visit and its associated assessments should occur within 7 days of the last 
study treatment. 
Patients may discontinue study treatment for any of the following reasons:

Adverse event(s)

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

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
Participant/guardian decision

Progressive disease

Study terminated by the sponsor

Non-compliant with study treatment

No longer requires treatment

Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given)
Death is a reason which “must” lead to discontinuation of patient from trial. 
16.1.4.3 End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up.
Patients may provide study phase completion information for one of the following reasons:

Adverse event

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Participant/guardian decision

Death

Progressive disease

Study terminated by the sponsor
16.1.4.4 Medical validation of programmed overall lesion response
In order to be as objective as possible the RECIST programmed calculated response assessment 
is very strict regarding measurement methods (i.e. any assessment with more or less sensitive 
method than the one used to assess the lesion at baseline is considered UNK) and not available 
evaluations (i.e. if any target or non-target lesion was not evaluated the whole overall lesion 
response is UNK unless remaining lesions qualified for PD). This contrasts with the slightly 
more flexible guidance given to local investigators (and to the central reviewers) to use expert 
judgment in determining response in these type of situations, and therefore as a consequence 
discrepancies between the different sources of response assessment often arise. To ensure the 
quality of response assessments from the local site and/or the central reviewer, the responses
may be re-evaluated by clinicians (based on local investigator data recorded in eCRF or based 
on central reviewer data entered in the database) at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on RECIST 
criteria. This may be queried for clarification. However, the investigator or central reader’s 
response assessment will never be overruled.

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If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 
at that specific assessment is to be kept in a dataset. This must be clearly documented in the 
RAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
16.1.4.5 Programming rules
The following should be used for programming of efficacy results:
16.1.4.5.1
Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
16.1.4.5.2
Incomplete assessment dates
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 16.1.3.2.7). If all measurement dates have 
no day recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
16.1.4.5.3
Incomplete dates for last known date patient alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
16.1.4.5.4
Non-target lesion response
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’.
16.1.4.5.5
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.

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16.1.4.5.6
Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page.
For survival the following censoring reasons are possible:

Alive

Lost to follow-up
For PFS and TTP (and therefore DORs) the following censoring reasons are possible:

Ongoing without event

Lost to follow-up

Withdrew consent

Adequate assessment no longer available*

Event documented after two or more missing tumor assessments (optional, see Table 16-5)

Death due to reason other than underlying cancer (only used for TTP and DOR)

Initiation of new anti-cancer therapy
* Adequate assessment is defined in Section 16.1.3.2.7. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted:

This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off).

The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment.

This reason will also be used to censor in case of no baseline assessment.

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16.1.5
References (available upon request)
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer; 45: 228-47
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465
EMA Guidance: 2012 Guideline on the evaluation of anticancer medicinal products in man
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute; 92: 205-16

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16.2
Appendix 2: Guidelines for Response Assessment in Neuro-
oncology (RANO) for Brain Metastases (BM)
Document type
TA specific guideline
Document status
Version 1: 04-Jun-2020
Release Date
04-Jun-2020
Authors (Version 1)
 
PPD

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List of abbreviations
BM
Brain metastases
BOIR
Best overall intracranial response
CNS
Central Nervous System
CR
Complete response
DCR
Disease Control Rate
DOIR
Duration of Intracranial Response
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
FPFV
First Patient First Visit
IDCR
Intracranial Disease Control Rate
KM
Kaplan-Meier
LD
Longest diameter
LPLV
Last Patient Last Visit
MRI
Magnetic resonance imaging
NCRNPD
Non-CR/Non-PD
NE
Not evaluable
OIRR
Overall Intracranial Response Rate
PD
Progressive disease
PR
Partial response
RANO
Response Assessment in Neuro-Oncology
RANO-BM
Response Assessment in Neuro-Oncology brain metastases criteria
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable disease
TTIR
Time to Intracranial Response

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16.2.1
Introduction
This guideline provides the general principles and application of the Response Assessment in 
Neuro-Oncology for Brain Metastases (RANO-BM) criteria to assess tumor response and to 
derive efficacy endpoints in Novartis oncology brain metastases trials. This guideline is based 
on the publication: “Response assessment criteria for brain metastases: proposal from the 
RANO group” (Lin 2015).
In studies with an endpoint of overall intracranial response rate (OIRR), tumor response will be 
primarily evaluated by the Response Assessment in Neuro-Oncology (RANO) working group 
Brain Metastases criteria, the RANO-BM Criteria (Lin 2015).
The standard response and progression criteria from RANO-BM are relevant for the assessment 
of parenchymal brain metastases only. Leptomeningeal metastases, which are generally not 
radiographically measurable in a reliable and reproducible manner, will be treated as for non-
target lesions.
Similar to RECIST 1.1 (Eisenhauer et al 2009), definitions for radiographical response in 
RANO-BM are based on unidimensional measurements. Participants will undergo gadolinium-
enhanced MRI* assessments for response evaluation as defined in the protocol.
The efficacy assessments described in Section 16.2.2 and the definition of best overall 
intracranial response in Section 16.2.3.1 are based on the RANO-BM criteria but also give more 
detailed instructions and rules for determination of best response. Section 16.2.3.2 is 
summarizing the endpoints and related variables.
The following components will be taken into account when assessing a participant’s overall 
intracranial response at an individual evaluation:

Tumor evaluation for gadolinium-enhanced MRI assessments

Overall lesion response category (CR/PR/PD/SD (or non-CR/non-PD)/NE)

Corticosteroid usage

ECOG performance scale and other clinical evaluation findings
*In this document, the term “MRI” refers to gadolinium-enhanced MRI.
16.2.2
Efficacy assessments
Tumor evaluations are made based on RANO-BM (Lin 2015).
Tumor assessments will be performed according to assessment schedule described in the 
protocol Section 8.
16.2.2.1 Definitions
16.2.2.1.1
Disease measurability
In order to evaluate CNS tumors throughout a study, definitions of measurability are required 
in order to classify lesions appropriately at baseline.

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Measurable disease
Measurable disease is defined as a contrast-enhancing lesion that can be accurately measured 
in at least one dimension, with a minimum size of 10 mm, and is visible on two or more axial 
slices that are preferably 5 mm or less apart with 0 mm skip (and ideally ≥1.5 mm apart with 
0 mm skip). Additionally, although the longest diameter in the plane of measurement is to be 
recorded, the diameter perpendicular to the longest diameter in the plane of measurement should 
be at least 5 mm for the lesion to be considered measurable. If the MRI is performed with thicker 
slices, the size of the measurable lesion at baseline should be at least double the slice thickness. 
Interslice gaps, if present, should also be considered in the determination of the minimum size 
of measurable lesions at baseline.
Non-measurable disease
Non-measurable disease includes all other lesions, including:

Other measurable lesions that cannot be considered as target lesions

lesions with longest dimension less than 10 mm,

lesions with borders that cannot be reproducibly measured,

dural, bony skull metastases,

cystic-only lesions, and

leptomeningeal disease.
Lesions composed of a tumor around a cyst or a surgical cavity are considered non-measurable 
unless there is a nodular component that measures 10 mm or more in longest diameter and 5 mm 
or more in perpendicular plane. The cystic or surgical cavity should not be measured for the 
determination of a response. Non-measurable lesions should all be followed as non-target 
lesions.
16.2.2.1.2
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the participant may be allowed to enter the 
study in some situations (e.g. studies including participants with leptomeningeal disease). 
Guidance on how participants with just non-measurable disease at baseline will be evaluated 
for response is given in Section 16.2.3.4.
16.2.2.2 Methods of tumor measurement – general guidelines
Participants will undergo gadolinium-enhanced MRI assessments for response evaluation as 
defined per protocol. 
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation (mm) using a digital 
measurement tool.

All baseline evaluations should be performed as closely as possible to randomization/start 
of treatment and never more than 28 days before the randomization/start of treatment.

The same method of assessment and technique (gadolinium- enhanced MRI) should be used 
to characterize each identified and reported lesion at baseline and during follow-up.

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16.2.2.2.1
Special Circumstances
In the case of participants who have been treated with stereotactic radiosurgery or 
immunotherapy-based approaches, for whom there has been radiographical evidence of 
enlargement of target and non-target lesions, which do not necessarily represent tumor 
progression, if radiographical evidence of progression exists, but clinical evidence indicates that 
the radiological changes are due to treatment effect (and not due to progression of cancer), 
additional evidence is needed to distinguish between true progression and treatment effect. In 
this case, standard MRI alone is insufficient. Participants can continue on protocol therapy 
pending further investigation with one or more of the following options:

The MRI can be repeated at the next protocol-scheduled assessment or sooner, and generally 
within 6-8 weeks. The investigator can choose a shorter time interval if progressive 
symptoms or other clinical concerns arise.

Continued tumor growth might be consistent with radiographical progression, in which 
case the participant should discontinue the study.

Stabilisation and shrinkage of a lesion can be consistent with treatment effect, in such 
case the participant can stay on study.

For participants with equivocal results even on the next scheduled restaging scan, the 
scan can be repeated again at a subsequent protocol scheduled assessment or sooner, 
although surgery or use of an advanced imaging modality are encouraged. Surgical 
pathology can be obtained via biopsy or resection.

For lesions treated by stereotactic radiosurgery, additional evidence of tumor progression 
or treatment effect (radionecrosis) can be acquired with an advanced imaging modality, such 
as perfusion MRU; magnetic resonance spectroscopy, or 18FLT PET. In addition, clinical 
judgment and involvement of a multidisciplinary team may be required to adjudicate and 
distinguish between radiation necrosis and true progression. Note, that these advanced 
imaging modalities have not been extensively studied with regards to immunotherapy-based 
approaches and therefore cannot be recommended to distinguish between tumor progression 
and immune-related changes at present.

Irrespective of the additional testing obtained, if subsequent testing shows that 
progression has occurred, the date of progression should be recorded as the date of the 
scan at which this issue was first raised.

Participants can also have an equivocal finding on a scan (e.g., as small lesion that is not 
clearly new).

Continued treatment is permissible until the next protocol-scheduled assessment.

If the subsequent assessment shows that progression has indeed occurred, the date of 
progression should be recorded as the date of the initial scan where progression was 
suspected.
16.2.2.3 Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, each lesion is classified at 
baseline as either a target or a non-target lesion:

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Target lesions
All measurable lesions up to a maximum of five CNS lesions should be identified as target 
lesions and recorded and measured at baseline using the longest diameter. Target lesions should 
be selected on the basis of their size (lesions with the longest diameter) and for reproducibility 
of measurement. Each target lesion must be uniquely and sequentially numbered on the eCRF.
For participants with recurrent disease who have multiple lesions, of which only one to two are 
increasing in size, the enlarging lesions should be prioritized as target lesions for the response 
assessment. If lesions not previously treated with local therapies are present, these are preferred 
for selection as target lesions. Lesions with prior local treatment (i.e., stereotactic radiosurgery 
or surgical resections) can be considered measurable if progression has occurred since the time 
of local treatment and if they are > 5 mm in diameter.
A sum of the diameters (longest diameters, LD) for all target lesions will be calculated and 
reported as the baseline sum of longest diameters. The baseline sum of longest diameters will 
be used as reference by which to characterize the objective intracranial tumor response. Each 
target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on the eCRF.
Non-Target lesions
All other CNS lesions should be identified as non-target lesions and should also be recorded at 
baseline. Measurements are not required for non-target lesions and these lesions should be 
classified as present, absent or unequivocal progression during follow-up assessments. Each 
non-target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on the eCRF.
Documentation of previously treated lesions
For previously treated target or non-target lesions, the previous treatment should be documented 
(e.g. stereotactic radiosurgery, whole brain radiotherapy, surgical resection) on the Prior 
antineoplastic therapy eCRF pages.
16.2.2.4 Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated 
(at baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 16-6) and non-target lesions (Table 16-7) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 16-8) as well as the presence or absence of new lesions, 
corticosteroid usage relative to baseline, ECOG performance scale and other clinical evaluation 
findings relative to baseline.
16.2.2.4.1
Follow-up and recording lesions
At each visit and for each lesion the actual date of the MRI which was used for the evaluation 
of each specific lesion should be recorded. This applies to target and non-target lesions as well 

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as new lesions that are detected. At the assessment visit, all of the separate lesion evaluation 
data are examined by the investigator/local reader in order to derive the overall visit response.
16.2.2.4.2
Determination of response/progression
The evaluation of overall intracranial lesion response at each assessment is a composite of the 
target lesion response, non-target lesion response, the presence of new lesions, corticosteroid 
usage relative to baseline, and clinical status as assessed by investigator and supported by the 
ECOG Performance Scale relative to baseline.
Participants (except participants with leptomeningeal disease, see Section 16.2.3.4) who have 
measurable and/or non-measurable disease in the brain at baseline and have received at least 
one dose of therapy will be considered evaluable for response.
All target lesion or non-target lesions must be assessed using the same methods and techniques 
as baseline for CR/PR/SD.
Determination of target lesion response
Target lesions should be assessed quantitatively at each of the time points specified in the 
protocol.
Table 16-6
Response assessment of target lesions
Response Criteria
Evaluation of target lesions
Complete response 
(CR)
Disappearance of all CNS target lesions sustained for at least 4 weeks; with no new 
lesions, no use of corticosteroids, and participant is stable or improved clinically.
Partial response 
(PR)
At least a 30% decrease in the sum of longest diameters of CNS target lesions, 
taking as reference the baseline sum of longest diameters sustained for at least 4 
weeks; no new lesions; stable to decreased corticosteroid dose; stable or improved 
clinically.
Progressive disease 
(PD)
At least a 20% increase in the sum of longest diameters of CNS 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%, at least one 
lesion must increase by an absolute value of 5 mm or more to be considered 
progression.
Stable disease 
(SD)
Neither sufficient shrinkage to qualify for partial response nor sufficient increase to 
qualify for progressive disease.
Not evaluable 
(NE) 
Progression has not been documented and one or more target lesions have not 
been assessed or have been assessed using a different method than baseline
Determination of non-target lesion response
Non-target lesions should be assessed qualitatively at each of the time points specified in the 
protocol.
Table 16-7
Response assessment of non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete response (CR)
Requires all of the following: disappearance of all enhancing CNS non-target 
lesions, no new CNS lesions.
Non-complete response 
or non-progressive 
Persistence of one or more non-target CNS lesion or lesions.

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Response Criteria
Evaluation of non-target lesions
disease (Non-CR/non-
PD)
Progressive disease 
(PD)
Any of the following: unequivocal progression of existing enhancing non-target 
CNS lesions, new lesion(s) (except while on immunotherapy-based treatment), 
CNS lesions. In the case of immunotherapy-based treatment, new lesions alone 
may not constitute progressive disease.
Not evaluable (NE) 
Progression has not been documented and one or more target lesions have not 
been assessed or have been assessed using a different technique than baseline
New lesions
New lesions can appear during treatment. The finding of a new CNS lesion should be 
unequivocal and not due to technical or slice variation. A lesion not present at baseline and 
appearing at any follow-up evaluation timepoint is considered a new lesion.
If the MRI is obtained with slide thickness of 1.5 mm or less, the new lesion should also be 
visible in axial, coronal and sagittal reconstructions of 1.5 mm or thinner projections. If a new 
lesion is equivocal, for example because of its small size (i.e., ≤5 mm), continued therapy can 
be considered, and a follow-up assessment will clarifiy if it really is new disease. If repeated
scans confirm a new lesion, progression should be declared using the date of the initial scan 
showing the new lesion. In the case of immunotherapy-based treatment, however, new lesions 
alone may not constitute progressive disease.
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion eCRF page.
Corticosteroids
The corticosteroids (including medication name, dose and unit, frequency, route, start and end 
date, indication, ongoing, status compared to baseline) used for response determination have to 
be recorded in the eCRF.
The corticosteroids dose at the time of the tumor assessment will be compared with the dose 
taken at the time of the baseline tumor assessment. If the participant is not taking corticosteroids 
at baseline, a zero dose will be considered as the baseline value. If corticosteroids dose is not 
available at baseline, then the baseline dose will be considered unknown. Every effort should 
be made to document the baseline and subsequent corticosteroid doses.
If corticosteroids information is not collected at the intracranial assessment, the most recently 
recorded corticosteroid dose will be considered.
In the absence of clinical deterioration related to the tumor, an increase in corticosteroid dose 
alone should not be used as a sole determinant of progression. Participants with stable imaging 
results and whose corticosteroid dose has increased for reasons other than clinical deterioration 
related to the tumor do not qualify as having stable disease or progression. These participants 
should be observed closely, and if their corticosteroid dose can be reduced back to baseline, 
they will be considered as having stable disease, but if further clinical deterioration related to 
the tumor becomes apparent they will be considered as having progression. The date of 
progression should be the first time point at which corticosteroid dose increase was necessary.

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Clinical Status
Clinical performance status will be evaluated based on the investigators’ opinion and 
complemented by the ECOG performance status scale. At each protocol-specified time point, 
ECOG assessment should occur and intracranial tumor assessment should be coincident with 
ECOG assessment.
Clinical status based on the investigators’ opinion used for response determination has to be 
recorded in the eCRF page.
If ECOG is unknown or not done at the intracranial tumor assessment, the previous ECOG 
assessment could be used for determination of the response.
16.2.2.4.3
Evaluation of overall lesion response
The evaluation of overall intracranial lesion response at each assessment is a composite of the 
target lesion response, non-target lesion response, the presence of new lesions, corticosteroid 
use relative to baseline, and clinical status as assessed by investigator and supported by the 
ECOG Performance Scale as shown below in Table 16-8.
Table 16-8
Overall Lesion Response at each assessment
Criterion 
Complete 
Response
Partial 
Response
Stable 
Disease
Progressive 
Disease
Target Lesions
None
≥ 30% decrease in 
sum LD relative to 
baseline
< 30% decrease 
relative to baseline 
but <20% increase in 
sum LD relative to 
nadir #
≥ 20% increase in 
sum LD relative to 
nadir #
Non-target Lesions §
None
Stable or improved
Stable or improved
Unequivocal PD*
New Lesion(s) †
None
None
None
Present *
Corticosteroids 
compared to baseline
None
Stable or decreased
Stable or decreased
Not applicable ‡
Clinical Status
compared to baseline
Stable or 
Improved
Stable or improved
Stable or improved
Worse*
Requirement for 
Response 
All
All
All
Any ‡
# Nadir: the smallest sum of diameter of all target lesions recorded at or after baseline
§ Non-target lesions response: stable (Non-CR/Non-PD), improved (CR)
* progression occurs when this criterion is met
† A new lesion is one that was not present on prior scans and is visible in minimum two projections.
If a new lesion is equivocal, for example because of its small size, continued therapy can be considered, and 
follow-up assessment will clarify if the new lesion is new disease.
If repeat scans confirm there is definitely a new lesion, progression should be declared using the date of the 
initial scan showing the new lesion. For immunotherapy-based approaches, new lesions alone to do not define 
progression.

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Criterion 
Complete 
Response
Partial 
Response
Stable 
Disease
Progressive 
Disease
‡ Increase in corticosteroids alone will not be taken into account in determining progression in the absence of 
persistent clinical deterioration (see Section 16.2.2.4.2).
Sum LD: sum of longest diameters
Not evaluable (NE) overall lesion response is described in Section 16.2.2.4.3
Corticosteroids (see Section 16.2.2.4.2) and clinical status based on the investigators’ opinion (see
Section 16.2.2.4.2)
Complete response (CR)
All of the following criteria must be met:
1. Complete disappearance of all enhancing target and non-target lesions, sustained for at least 
4 weeks. In the absence of a confirmatory MRI 4 weeks after the criteria for response are 
met, this evaluation will be considered at best stable disease.
2. No new lesions.
3. Participants must either be on no corticosteroids or on physiologic replacement doses only.
4. Stable or improved clinical status per investigator supported ECOG performance status 
scale compared to baseline.
Partial response (PR)
All of the following criteria must be met:
1. Greater than or equal to 30% decrease from baseline in the sum of longest diameters of all 
target lesions sustained for at least 4 weeks. In the absence of a confirmatory scan 4 weeks 
after the criteria for response are met, this evaluation will be considered at best stable disease. 
2. Stable or improved non-target lesions.
3. No new lesions.
4. The corticosteroid dose at the time of the scan evaluation is not greater than the 
corticosteroid dose at the time of the baseline MRI scan.
5. Stable or improved clinical status per investigator supported ECOG performance status 
scale compared to baseline.
Stable disease (SD)
All of the following criteria must be met:
1. Less than 30% decrease from baseline but less than 20% increase from nadir in the sum of 
longest diameters of all target lesions.
2. Does not qualify for CR, PR, or PD.
3. No new lesions.
4. The corticosteroid dose at the time of the scan evaluation is not greater than the 
corticosteroid dose at the time of the baseline MRI scan.
5. Stable or improved clinical status per investigator supported ECOG performance status 
scale compared to baseline.

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Progressive disease (PD)
Any of the following criteria must be met:
1. Greater than or equal to 20% increase in the sum of longest diameters of all target lesions 
relative to nadir.
2. Unequivocal progression of non-target lesions. To achieve unequivocal progression on the 
basis of non-target disease there must be an overall level of substantial worsening on the 
NT disease such that, even in the presence of CR, PR, or SD in target disease, the overall 
tumor burden has increased sufficiently to merit discontinuation of therapy.
3. Any new lesion.
4. Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. 
seizures, medication side effects, complications of therapy, cerebrovascular events, 
infection etc.). The definition of clinical deterioration is at the discretion of the investigator, 
however, it is recommended that a decline in the ECOG performance status, for at least 7 
days, be considered a clinical deterioration unless attributable to co-morbid events or 
changes in corticosteroid dose.
a. Increase in corticosteroids alone will not be taken into account in determining 
progression in the absence of persistent clinical deterioration.
5. Failure to return for evaluation due to death or deteriorating condition unless caused by 
documented non-related disorders.
Not evaluable status (NE)
1. Progressive disease has not been documented and one or more target or non-target lesions 
have not been assessed.
2. Change in method or technique for assessing target and non-target lesions from baseline 
regardless of the justification of the change. E.g. if a participant develops a contraindication 
to MRI intravenous (IV) contrast media during the trial, a non-contrast MRI of the brain 
can be used (if possible); the participants response should only be recorded as Not evaluable 
unless there is progressive disease.
16.2.2.4.4
CNS and non-CNS Response Assessment
At each protocol-specified time point, a response assessment should occur and intracranial 
assessment should be coincident with extracranial and whole body assessment. Table 16-9
shows CNS and non-CNS response assessment.
Note that progressive disease in either compartment (namely, intracranial or extracranial 
compartments) is considered progressive disease overall. Table 16-6 shows the additional 
corticosteroid and clinical status requirements to deem a partial response or a complete response.
Table 16-9
CNS and non-CNS response assessment
CNS (RANO-BM)
Non-CNS (RECIST 1.1)
Complete response, partial response or stable 
disease (or non-CR/Non-PD)
Complete response, partial response or stable disease (or 
non-CR/Non-PD)
Complete response, partial response or stable 
disease (or non-CR/Non-PD)
Progressive Disease 

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CNS (RANO-BM)
Non-CNS (RECIST 1.1)
Progressive Disease
Complete response, partial response or stable disease (or 
non-CR/Non-PD)
Progressive Disease
Progressive Disease
16.2.3
Efficacy definitions
16.2.3.1 Best overall intracranial response
The best overall intracranial response (BOIR) is the best intracranial response recorded from 
the randomization/start of treatment until disease progression/recurrence (taking as reference 
for PD the smallest measurements recorded since the randomization/treatment started) and will 
be determined programmatically based on the investigator/local reader’s assessment of 
response at each time point. 
The best overall intracranial response will usually be determined from response assessments 
undertaken while on treatment. However, if any assessments occur after treatment withdrawal 
the protocol should specifically describe if these will be included in the determination of best 
overall intracranial response and/or whether these additional assessments will be required for 
sensitivity or supportive analyses. As a default, any assessments taken more than 30 days after 
the last dose of study treatment will not be included in the best overall intracranial response 
derivation. If any alternative cancer therapy is taken while on study any subsequent assessments 
would ordinarily be excluded from the best overall intracranial response determination. If 
response assessments taken after withdrawal from study treatment and/or alternative therapy 
are to be included in the main endpoint determination, then this should be described and justified 
in the protocol.
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met.
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed.

For non-randomized trials in which intracranial response is the primary endpoint, 
confirmation of partial response or complete response at least 4 weeks later is necessary to 
deem either one the best overall intracranial response.
The best overall intracranial response for each participant is determined from the sequence of 
overall (lesion) responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR prior 
to progression where confirmation not required

SD = at least one SD assessment (or better) > 6 weeks after randomization/start of treatment 
(and not qualifying for CR or PR).

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
PD = progression ≤ 12 weeks after randomization/start of treatment (and not qualifying for 
CR, PR or SD).

Not evaluable (NE) = all other cases (i.e. not qualifying for confirmed CR or PR and without 
SD after more than 6 weeks or early progression within the first 12 weeks)
The time durations specified in the SD/PD/NE definitions above are defaults based on a 6-8 
week tumor assessment frequency. However these may be modified for specific indications (to 
be more or less aggressive). In addition, it is envisaged that the time duration may also take into 
account assessment windows. E.g. if the assessment occurs every 6 weeks with a time window 
of +/- 7 days, a BOR of SD would require a SD or better response longer than 5 weeks after 
randomization/start of treatment.
16.2.3.2 Endpoints
Based on the participants’ best overall intracranial response during the study, the following 
endpoints are then calculated:
Overall intracranial response rate (OIRR) is the proportion of participants with a confirmed 
best overall intracranial response (BOIR) of CR or PR.
Intracranial Disease control rate (IDCR) is the proportion of participants with a confirmed 
BOIR of CR or PR or SD (or non-CR/Non-PD).
Duration of intracranial response (DOIR): DOIR only applies to participants whose 
confirmed BOIR is CR or PR. DOIR is defined as time from first documented intracranial 
response of either CR or PR to the date of the first documented intracranial progression or date 
of death due to any cause. Participants will be censored if they have disease progression in 
organs other than brain and have no scans in brain after that. The censoring date will be the date 
of the last adequate tumor assessment in brain.
Time to intracranial response (TTIR): TTIR is defined as the time from the date of 
randomization/start of the treatment to the date of the first documented intracranial response of 
either CR or PR, which must be subsequently confirmed (date of initial response is used, not 
date of confirmation).
All participants will be included in TTIR calculations. Participants without a confirmed 
intracranial CR or PR will be censored at the study-maximum follow-up time 
(i.e. LPLV−FPFV) for participants with event (intracranial progression or death due to any 
cause), or at the date of the last adequate intracranial tumor assessment for participants without 
an event.
16.2.3.3 Definitions of dates
Assessment dates
For each assessment, the assessment date is calculated as the latest of all measurement dates if 
the overall lesion response at that assessment is CR/PR/SD/NCRNPD/NE. Otherwise – if 
overall lesion response is progression – the assessment date is calculated as the earliest date of 
all measurement dates at that visit.

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In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations.
Start dates
For the calculation of duration of response the following start date should be used:

Date of first documented response is the assessment date of the first overall lesion response 
of CR / PR when this status is later confirmed. The date of initial response is used, not date 
of confirmation.
End dates
The dates which are used to calculate endpoints are defined as follows:

Date of death due to any cause is the date of death due to “Study indication” or “Other”.

Date of intracranial progression is the first assessment date at which the overall lesion 
response was recorded as progressive disease in the brain.

Date of last adequate intracranial tumor assessment is the date the last tumor assessment in 
brain with overall lesion response of CR, PR or SD was made before an event or a censoring 
reason occurred. In this case the last tumor evaluation date at that assessment is used. If no 
post-baseline assessments in brain are available (before an event or a censoring reason 
occurred) the date of randomization/start of treatment is used.
Secondary anti-cancer therapy date
The date which is used for BOIR determination is defined as follows:

Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy, radiotherapy, or surgery.
16.2.3.4 Handling of participants with only non-measurable disease at baseline
It is possible that participants with only non-measurable disease present at baseline are entered 
into the study, either because of a protocol violation or by design (e.g. enrollment, type of 
disease such as leptomeningeal disease). In such cases the handling of the response data requires 
special consideration with respect to inclusion in any analysis of endpoints based on the overall 
response evaluations.
It is recommended that any participants with only non-measurable disease at baseline should be 
included in the main analysis (Intent-To-Treat approach) of each of these endpoints.
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients with only non-measurable disease should 
also be incorporated in an appropriate manner. The overall response for patients with non-
measurable disease is derived slightly differently according to Table 16-10.

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Table 16-10
Overall Lesion Response at each assessment: Participant with only 
non-target disease at baseline
Criteria 
Complete 
Response
Non-CR/Non-PD
Progressive 
Disease
Non-target Lesions §
None
Stable or improved
Unequivocal PD*
New Lesions †
None
None
Present *
Corticosteroids 
compared to baseline
None
Stable or decreased
Not applicable ‡
Clinical Status
compared to baseline
Stable or Improved
Stable or improved
Worse*
Requirement for 
Response 
All
All
Any ‡
§ Non-target lesions response: stable (Non-CR Non-PD), improved (CR)
* Progression occurs when this criterion is met.
† A new lesion is one that not present on prior scans and is visible in minimum two projections.
If a new lesion is equivocal, for example because of its small size, continued therapy can be considered, and 
follow-up assessment will clarify if the new lesion is new disease.
If repeat scans confirm there is definitely a new lesion, progression should be declared using the date of the 
initial scan showing the new lesion. For immunotherapy-based approaches, new lesions alone to do not define 
progression.
‡ Increase in corticosteroids alone will not be taken into account in determining progression in the absence of 
persistent clinical deterioration (see Section 16.2.2.4.2).
Not evaluable (NE) overall lesion response is described in Section 16.2.2.4.3
Corticosteroids (see Section 16.2.2.4.2) and clinical status based on the investigators’ opinion 
(see Section 16.2.2.4.2)
16.2.3.4.1
Evaluation of overall lesion response
Complete response (CR)
All of the following criteria must be met:
1. Complete disappearance of all non-target lesions, sustained for at least 4 weeks. In the 
absence of a confirmatory MRI 4 weeks after the criteria for response are met, this 
evaluation will be considered at best Non-CR/Non-PD.
2. No new lesions.
3. Participants must either be on no corticosteroids or on physiologic replacement doses only.
4. Stable or improved clinical status per investigator supported ECOG performance status 
scale compared to baseline.
Non-CR/Non-PD
All of the following criteria must be met:
1. Does not qualify for CR or PD.
2. No new lesions.

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3. The corticosteroid dose at the time of the scan evaluation is not greater than the 
corticosteroid dose at the time of the baseline MRI scan.
4. Stable or improved clinical status per investigator supported ECOG performance status 
scale compared to baseline.
Progressive disease (PD)
Any of the following criteria must be met:
1. Unequivocal progression of non-target lesions. To achieve unequivocal progression on the 
basis of non-target disease there must be an overall level of substantial worsening on the 
NT disease.
2. Any new lesion.
3. Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. 
seizures, medication side effects, complications of therapy, cerebrovascular events, 
infection etc.). The definition of clinical deterioration is at the discretion of the investigator, 
however, it is recommended that a decline in the ECOG performance status, for at least 7 
days, be considered a clinical deterioration unless attributable to co-morbid events or 
changes in corticosteroid dose.
a. Increase in corticosteroids alone will not be taken into account in determining 
progression in the absence of persistent clinical deterioration.
4. Failure to return for evaluation due to death or deteriorating condition unless caused by 
documented non-related disorders.
16.2.3.4.2
Best overall intracranial response
The best overall intracranial response for each participant is determined from the sequence of 
overall (lesion) responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required

Non-CR/Non-PD = at least one Non-CR/Non-PD assessment (or better) > 6 weeks after
randomization/start of treatment (and not qualifying for CR)

PD = progression ≤ 12 weeks after randomization/start of treatment (and not qualifying for 
CR or Non-CR/Non-PD).

Not evaluable (NE) = all other cases (i.e. not qualifying for confirmed CR and without Non-
CR/Non-PD after more than 6 weeks or early progression within the first 12 weeks)

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Protocol No. CINC280A2204
16.2.4
References
Eisenhauer EA, Therasse P, Bogaerts J et al (2009). New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer; 45(2):228-47.
Lin N et al. (2015) Response assessment criteria for brain metastases: proposal from the RANO 
group. Lancet Oncology, 16:e270-278.