Conditions: Non-small Cell Lung Cancer
Keywords: Mesenchymal Epithelial Transition (MET) MET exon 14 skipping mutation High MET amplification Neoadjuvant Prior to surgery Adjuvant After surgery INC280 MET inhibition adult capmatinib
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 4
Healthy volunteers: no

Brief summary:
This study was planned to determine if neoadjuvant capmatinib could improve the major pathological response (MPR) in patients with Stage IB-IIIA, N2 and selected IIIB (T3N2 or T4N2) lung cancers with Mesenchymal Epithelial Transition (MET) exon 14 mutations and/or high MET amplification beyond those achieved with surgery, chemotherapy, and radiation. Treatment was to be continued with capmatinib in the adjuvant setting to evaluate the potential clinical benefit of extended therapy.

The purpose of this study is to determine if neoadjuvant capmatinib can improve outcomes in participants with stages I-IIIA non-small cell lung cancer with MET exon 14 mutations and/or high MET amplification beyond those achieved with surgery, chemotherapy, and radiation.

Detailed description:
This was a Phase II, two cohort, two stage study of capmatinib given for 8 weeks (2 cycles) prior to surgical resection, followed by three-year capmatinib treatment in adjuvant setting. Surgery had to be performed up to 2 weeks after the last dose of neoadjuvant study treatment.

There were 2 molecularly defined cohorts enrolled in parallel:

* Cohort A: MET exon 14 skipping mutations, irrespective of MET GCN or
* Cohort B: high level MET amplification (MET: GCN ≥ 10 by FISH or FoundationOne CDx NGS using tumor tissue).

Approximately 42 participants were aimed to be enrolled in the study, with 21 participants per cohort. This was planned to obtain 38 evaluable participants, 19 per each cohort. Participants who had both MET exon 14 skipping mutations and high-level MET amplification were planned to be enrolled into Cohort A. An evaluable subject received the neoadjuvant treatment and subsequently underwent surgery, resulting in a pathological response.

The study recruitment was prematurely discontinued due to significant recruitment challenges leading to termination of the study. The challenges included the rarity of the mutation and site initiation delays caused by staff shortages associated with COVID-19. As a result, only 4 subjects were enrolled and treated in Cohort A.

Arms:
arm 1: The study treatment started on Cycle 1 Day 1 with the first administration of capmatinib 400 mg twice a day (b.i.d.). The participants were planned to receive study treatment for a maximum of 3 years following surgery or until early discontinuation. arm 2: The study treatment started on Cycle 1 Day 1 with the first administration of capmatinib 400 mg twice a day (b.i.d.). The participants were planned to receive study treatment for a maximum of 3 years following surgery or until early discontinuation.

Interventions: intervention 1: capmatinib
Intervention descriptions: intervention 1: 150 mg and 200 mg tablets for oral administration

Protocol document:
Prot_000.pdf: 
Novartis Medical Affairs 
INC280 (capmatinib) 
Clinical Trial Protocol CINC280AUS12 / NCT04926831
Phase II trial of neoadjuvant and adjuvant capmatinib in participants with 
stages IB-IIIA, N2 and selected IIIB (T3N2 or T4N2) NSCLC with MET exon 14 
skipping mutation or high MET amplification – Geometry-N
Document type: 
Clinical Trial Protocol 
Version number: 
01 Clean (Amended Protocol) 
Clinical Trial Phase: 
II 
Release date: 
17-Mar-2023
Property of Novartis  
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 4.0 (15-Feb-2021) 


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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 ............................................................................................................... 11 
Amendment 1 (17-Mar-2023) ........................................................................................... 14 
Protocol summary .............................................................................................................. 16 
1 
Introduction ....................................................................................................................... 19 
1.1 
Background ........................................................................................... 19 
1.2 
Purpose .................................................................................................. 21 
2 
Objectives and endpoints ................................................................................................... 21 
2.1 
Primary estimand(s) .............................................................................. 22 
2.2 
Secondary estimands ............................................................................. 23 
3 
Study design ...................................................................................................................... 23 
4 
Rationale ............................................................................................................................ 24 
4.1 
Rationale for study design ..................................................................... 24 
4.2 
Rationale for dose/regimen and duration of treatment .......................... 25 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs…... ............................................................................................................. 25 
4.4 
Purpose and timing of interim analyses/design adaptations ................. 25 
4.5 
Risks and benefits ................................................................................. 25 
4.5.1 
Capmatinib ............................................................................................ 26 
4.6 
Rationale for Public Health Emergency mitigation procedures ............ 26 
5 
Study Population ............................................................................................................... 27 
5.1 
Inclusion criteria .................................................................................... 27 
5.2 
Exclusion criteria .................................................................................. 28 
6 
Treatment ........................................................................................................................... 30 
6.1 
Study treatment ..................................................................................... 30 
6.1.1 
Investigational drug ............................................................................... 30 
6.1.2 
Supply of study treatment ..................................................................... 31 
6.1.3 
Treatment group .................................................................................... 31 
6.1.4 
Guidelines for continuation of treatment .............................................. 31 
6.1.5 
Treatment duration ................................................................................ 32 
6.2 
Other treatment(s) ................................................................................. 32 
6.2.1 
Concomitant therapy ............................................................................. 32 
6.2.2 
Prohibited medication ........................................................................... 34 


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6.3 
Participant numbering, treatment assignment, randomization .............. 34 
6.3.1 
Participant numbering ........................................................................... 34 
6.3.2 
Treatment assignment ........................................................................... 34 
6.4 
Treatment blinding ................................................................................ 35 
6.5 
Dose modifications ................................................................................ 35 
6.5.1 
Treatment interruption and treatment discontinuation .......................... 41 
6.5.2 
Follow-up for toxicities ......................................................................... 42 
6.6 
Additional treatment guidance .............................................................. 49 
6.6.1 
Treatment compliance ........................................................................... 49 
6.7 
Preparation and dispensation................................................................. 49 
6.7.1 
Handling of study treatment .................................................................. 49 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 50 
7 
Informed consent procedures ............................................................................................ 51 
8 
Visit schedule and assessments ......................................................................................... 52 
8.1 
Screening ............................................................................................... 60 
8.1.1 
Eligibility screening .............................................................................. 60 
8.1.2 
Information to be collected on screening failures ................................. 61 
8.2 
Participant demographics/other baseline characteristics ....................... 61 
8.3 
Efficacy ................................................................................................. 62 
8.3.1 
Efficacy assessments ............................................................................. 62 
8.4 
Safety..................................................................................................... 63 
8.4.1 
Laboratory evaluations .......................................................................... 64 
8.4.2 
Coagulation ........................................................................................... 66 
8.4.3 
Pulmonary Function Tests (PFT) .......................................................... 66 
8.4.4 
Electrocardiogram (ECG) ..................................................................... 66 
8.4.5 
Pregnancy and assessments of fertility ................................................. 67 
8.4.6 
Appropriateness of safety measurements .............................................. 68 
8.5 
Additional assessments ......................................................................... 68 
8.5.1 
Surgery related information .................................................................. 68 
 
 68 
8.6 
Follow up evaluations ........................................................................... 69 
8.6.1 
Safety follow up .................................................................................... 69 
9 
Discontinuation and completion ........................................................................................ 70 
9.1 
Discontinuation from study treatment and from study ......................... 70 
9.1.1 
Discontinuation from study treatment ................................................... 70 
9.1.2 
Discontinuation from study ................................................................... 71 


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9.1.3 
Withdrawal of informed consent/Opposition to use data/biological 
samples .................................................................................................. 71 
9.1.4 
Lost to follow-up ................................................................................... 72 
9.1.5 
Early study termination by the sponsor ................................................. 72 
9.2 
Study completion and post-study treatment .......................................... 72 
10 Safety monitoring and reporting ........................................................................................ 73 
10.1 
Definition of adverse events and reporting requirements ..................... 73 
10.1.1 
Adverse events ...................................................................................... 73 
10.1.2 
Serious adverse events .......................................................................... 74 
10.1.3 
SAE reporting........................................................................................ 75 
10.1.4 
Pregnancy reporting .............................................................................. 76 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 77 
10.2 
Additional Safety Monitoring ............................................................... 77 
10.2.1 
Steering Committee ............................................................................... 77 
11 Data Collection and Database management ...................................................................... 78 
11.1 
Data collection ...................................................................................... 78 
11.2 
Database management and quality control ........................................... 78 
11.3 
Site monitoring ...................................................................................... 78 
12 Data analysis and statistical methods ................................................................................ 79 
12.1 
Analysis sets .......................................................................................... 79 
12.1.1 
Full Analysis Set ................................................................................... 79 
12.1.2 
Safety Set .............................................................................................. 80 
 
 80 
12.2 
Participant demographics and other baseline characteristics ................ 80 
12.3 
Treatments ............................................................................................. 80 
12.4 
Analysis of the primary endpoint(s)/estimand(s) .................................. 80 
12.4.1 
Definition of primary endpoint(s)/estimand(s) ..................................... 81 
 
 81 
12.4.3 
Handling of intercurrent events of primary estimand ........................... 81 
12.4.4 
Handling of missing values/censoring/discontinuation ........................ 82 
12.4.5 
No imputation will be performed for the missing data.  Sensitivity 
and Supportive analyses for primary endpoint/estimand(s) .................. 82 
12.5 
Analysis of secondary endpoints ........................................................... 82 
12.5.1 
Secondary Efficacy endpoint(s) ............................................................ 82 
12.5.2 
Safety endpoints .................................................................................... 83 
 
 85 
 
 85 


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 85 
12.7 
Interim analyses .................................................................................... 86 
 
 86 
 
 86 
13 Ethical considerations and administrative procedures ...................................................... 86 
13.1 
Regulatory and ethical compliance ....................................................... 86 
13.2 
Responsibilities of the investigator and IRB/IEC ................................. 86 
13.3 
Publication of study protocol and results .............................................. 87 
13.4 
Quality Control and Quality Assurance ................................................ 87 
13.5 
Participant Engagement ........................................................................ 87 
14 Protocol adherence ............................................................................................................ 87 
14.1 
Protocol amendments ............................................................................ 88 
15 References ......................................................................................................................... 89 
16 Appendices ........................................................................................................................ 93 
16.1 
Appendix 1: List of concomitant medications for participants on 
capmatinib………….. .............................................................................................................. 93 
16.2 
Appendix 2: Guidelines for Response, Duration of Overall 
Response, TTF, TTP, Progression-Free Survival, and Overall Survival (based on 
RECIST 1.1)………… ............................................................................................................. 95 
16.2.1 
Introduction ........................................................................................... 95 
16.2.2 
Efficacy assessments ............................................................................. 95 
16.2.3 
Efficacy definitions ............................................................................. 105 
16.2.4 
Data handling and programming rules ................................................ 115 
 


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List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 21 
Table 6-1 
Investigational and control drug ............................................................ 31 
Table 6-2 
Dose reduction steps for capmatinib ..................................................... 36 
Table 6-3 
Criteria for dose reduction / interruption and re-initiation/ 
permanent discontinuation of capmatinib treatment for adverse 
drug reactions ........................................................................................ 36 
Table 6-4 
Follow-up evaluations for selected toxicities ........................................ 42 
Table 6-5 
Follow up on potential drug-induced liver injury (DILI) cases ............ 48 
Table 6-6 
Dose and treatment schedule ................................................................. 51 
Table 8-1 
Assessment schedule ............................................................................. 53 
Table 8-2 
Imaging Assessment Collection Plan .................................................... 63 
Table 8-3 
Safety Assessments ............................................................................... 64 
Table 8-4 
ECOG performance status ..................................................................... 64 
Table 8-5 
Laboratory Assessments ........................................................................ 65 
 
 69 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 77 
Table 16-1 
Medications that require caution when concomitantly used with 
capmatinib ............................................................................................. 93 
Table 16-2 
Capmatinib: prohibited drugs ................................................................ 94 
Table 16-3 
Response criteria for target lesions ..................................................... 100 
Table 16-4 
Response criteria for non-target lesions .............................................. 103 
Table 16-5 
Overall lesion response at each assessment ........................................ 104 
Table 16-6 
Overall lesion response at each assessment: participants with non-
target disease only ............................................................................... 112 
Table 16-7 
Options for event dates used in PFS, TTP, duration of response ........ 113 
 


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List of figures 
Figure 3-1 
Study design .......................................................................................... 24 


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List of abbreviations 
AE 
Adverse Event 
AJCC 
American Joint Committee on Cancer  
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BCRP 
Breast Cancer Resistance Protein  
b.i.d. 
bis in die/twice a day 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CLIA 
Clinical Laboratory Improvement Amendments  
CMO&PS  Chief Medical Office and Patient Safety 
CO 
Country Organization 
CO2 
Carbon Dioxide 
CQA 
Clinical Quality Assurance 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CT 
Computerized Tomography  
CTC 
Common Terminology Criteria 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
DIN 
Drug Inducted Nephrotoxicity 
DQF 
Data Query Form 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
EDC 
Electronic Data Capture 
EGFR 
Epidermal Growth Factor Receptor 
ERCP 
Endoscopic Retrograde Cholangiopancreatography 
eSAE 
Electronic Serious Adverse Event 
eSource 
Electronic Source 
FDA 
Food and Drug Administration 
FEV 
Forced Expiratory Volume  
FISH 
Fluorescence in situ hybridization  
FSH 
Follicle Stimulating Hormone 
GCN 
Gene Copy Number  
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyl Transferase 
h 
Hour 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B Virus 


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HCV 
Hepatitis C Virus 
hCG 
Human Chorionic Gonadotropin 
HED 
Human Equivalent Dose 
HEOR 
Health Economics & Outcomes Research  
HIV 
Human immunodeficiency virus 
HGF 
Human Growth Factor  
i.v. 
intravenous 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals 
for Human Use 
IEC 
Independent Ethics Committee 
ILD 
Interstitial Lung Disease 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
LDH 
lactate dehydrogenase 
LFT 
Liver Function Test  
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
MedDRA 
Medical dictionary for regulatory activities  
MET 
Mesenchymal Epithelial Transition  
METex14 
MET exon 14 skipping 
mg 
milligram(s) 
mL 
milliliter(s) 
MPR 
Major Pathologic Response  
MRI 
Magnetic Resonance Imaging  
Nab 
Neutralizing antibody 
NCI 
National Cancer Institute  
NGS 
Next Generation Sequencing  
p.o. 
oral(ly) 
PA 
posteroanterior 
PC 
Personal Computer 
PD 
Pharmacodynamic(s) 
PET 
Positron Emission Tomography  
PFT 
Pulmonary Function Test(s) 
PK 
Pharmacokinetic(s) 
PS 
Performance Status  
PT 
Prothrombin Time 
QD 
Once a day 
QMS  
Quality Management System 
QTcF 
QT interval corrected by Fridericia’s formula 


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R Value 
ALT/ALP x ULN 
RAP 
The Report and Analysis Plan  
RBC 
Red Blood Cell(s) 
RDC 
Remote Data Capture 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RoW  
Rest of World 
s.c. 
subcutaneous 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
sCR 
serum creatinine 
SD 
standard deviation 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SoC 
Standard of Care 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TKI 
Tyrosine Kinase Inhibitor  
TBL 
Total Bilirubin Level  
ULN 
Upper Limit of Normal 
UTI 
Urinary Tract Infection 
WBC 
White Blood Cell(s) 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 


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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 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant  
Cohort 
A specific group of participants fulfilling certain criteria and generally treated at 
the same time 
Control drug 
A study drug (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., q28 days) 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day) 
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 paper source forms 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 or 
at a later point in time as defined by the protocol  
Enrollment 
Point/time of participant entry into the study at which informed consent must 
be obtained  
eSource (DDE) 
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and case report forms (eCRFs) into one application, 
allowing for the real time collection of clinical trial information to sponsors and 
other oversight authorities, as appropriate 
Estimand  
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. 
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation or 
the existence of the measurements associated with the clinical question of 
interest. 
Investigational 
drug/ treatment 
The drug whose properties are being tested in the study 
Sequence  
number 
A unique medication number on the label of each bottle of medication  
Mis-randomized 
participants 
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study  
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy) 


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Part  
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose part 
and a multiple dose part, or a part in participants with established disease and 
in those with newly-diagnosed disease 
Participant 
A trial participant (can be a healthy volunteer or a patient) 
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. 
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 
Perpetrator drug 
A drug which affects the pharmacokinetics of the other drug 
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. 
Premature 
participant 
withdrawal 
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned 
Enrollment 
number 
A unique identifier assigned to each enrolled participant 
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 in 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 
Study treatment 
discontinuation 
When the participant permanently stops taking any of the study drug(s) prior to 
the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation  
Treatment 
arm/group  
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts. 
Treatment of 
interest 
The treatment of interest and, as appropriate, the alternative treatment to 
which comparison will be made. These might be individual interventions, 
combinations of interventions administered concurrently, e.g. as add-on to 
standard of care, or might consist of an overall regimen involving a complex 
sequence of interventions. This is the treatment of interest used in describing 
the related clinical question of interest, which might or might not be the same 
as the study treatment. 


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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. 
Victim drug  
The drug that is affected by the drug-drug interaction 
Withdrawal of 
study consent 
(WoC) 
Withdrawal of consent from the study occurs only when a participant does not 
want to participate in the study any longer and does not allow any further 
collection of personal data  




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• Section 9.2: Clarified study completion definition. 
 
• Section 12.4.3: Removed intercurrent events for primary estimand and added 
intercurrent events for the supplementary estimand.   
• Section 12.4.4: clarified that for the primary estimand, only participants with non-
missing MPR will be considered for the MPR evaluation and for the supplementary 
estimands, patients with missing MPR values will be considered non-responders. 
• Section 12.5.1: Clarified that best overall response will be determined at the 
assessments performed prior to surgery. Due to timepoint of assessment, and need for 
patients to proceed to surgery, there will not be a confirmatory response assessment 4 
weeks later.  
• Section 12.5.2: Clarified safety follow up is 30 days 
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 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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1 
Introduction 
1.1 
Background 
An estimated 2.2 million people were diagnosed globally with lung cancer in 2020 and there 
were 1.8 million deaths from this disease (Globocan 2020). The number of new lung cancer 
cases is expected to grow by about 70% over the next 2 decades (Globocan 2020).  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 2019, approximately 142,670 deaths due to lung 
cancer are expected in the United States (US) (Siegel et al 2019) and 280,000 in the European 
Union (Malvezzi et al 2019).  Despite apparently curative surgery, approximately 50% of stage 
IB and 70% of stage II NSCLC patients will relapse and eventually die of their disease. Given 
the current limited survival of patients with NSCLC, even in early stages of disease, new 
treatment options are needed. Neoadjuvant and adjuvant treatments are used to eradicate 
micrometastatic disease and minimize the risk of relapse. 
A meta-analysis based upon seven trials involving 988 patients suggested that neoadjuvant 
chemotherapy (platinum-based chemotherapy-cisplatin or carboplatin, combined with other 
agents) improved OS in patients with NSCLC when given preoperatively (five-year survival 
20% versus 14% without neoadjuvant chemotherapy). This improvement in survival is similar 
to that observed in the meta-analyses of predominantly adjuvant chemotherapy 
(Burdette-Radoux and Muss 2006, Scagliotti et al 2012, Chuang et al 2017). The neoadjuvant 
setting offers the possibility for the identification of surrogate clinical and biological markers 
that may correlate with response to therapy and in some cases long-term outcome. In addition, 
preoperative therapy may be a useful platform for the development of new targeted therapies. 
Efficient strategies to evaluate promising agents in early phase development are essential for 
rapid progress in lung cancer treatment and prevention. Several studies have shown 
preoperative systemic therapy to be safe prior to surgical resection of NSCLC with no difference 
in extent of surgical procedures performed, operative morbidity and mortality 
(Depierre et al 2002, Gilligan et al 2007, Scagliotti et al 2012). 
Activating mutations in Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma 
Kinase (ALK) translocations are molecular drivers in NSCLC and their presence is strongly 
predictive of superior response to EGFR and ALK Tyrosine Kinase Inhibitors (TKIs) when 
compared to standard chemotherapy. For participants harboring EGFR activating mutations and 
ALK translocations, targeted therapies have become the standard of care (SoC) in both 
treatment-naive 
and 
pretreated 
participants 
(Ettinger et al 2010, 
Sequist et al 2013, 
Zhou et al 2011, 
Fukuoka et al 2011, 
Shaw and Engelman 2013, 
Shaw et al 2013, 
Rosell et al 2012, Solomon et al 2014, NCCN 2020). The success of EGFR and ALK TKIs 
highlights the importance of identifying specific molecular drivers of NSCLC and appropriately 
direct targeted agents to specific patient populations. Similarly, other TKIs directed at rare 
targets like ROS1 translocations and BRAF V600 mutations are now available for subsets of 
participants harboring these oncogenic drivers (Solomon et al 2014, Hamanishi et al 2016). 
The potential for prolonged and meaningful clinical response, by targeting these oncogenic 
drivers, delays the need for chemotherapy or other treatments. 
In human cancer, the MET pathway is frequently dysregulated, triggering a diverse set of 
signaling cascades (including the RAS-MAPK as well as the PI3K-AKT pathway), which 


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promote 
proliferation, 
survival, 
motility 
and 
angiogenesis 
of 
tumor 
cells 
(Christensen et al 2005). Several mechanisms have been identified through which the MET 
pathway becomes aberrantly activated in cancer, including MET exon 14 skipping (METex14) 
mutations, MET gene amplification, chromosomal rearrangements leading to MET fusion 
proteins, MET receptor overexpression, and autocrine or paracrine activation of MET by its 
ligand Hepatocyte Growth Factor (HGF). METex14 mutations and MET amplification are 
currently the most studied MET dysregulations in NSCLC, being evaluated as predictors of 
response to MET inhibitors. 
The presence of METex14 mutations leads to loss of the juxtamembrane domain of the receptor, 
which causes protein stabilization and oncogenic activation (Kong-Beltran et al 2006).  Next 
generation sequencing of tumor specimens has identified many different variants resulting in 
exon 14 skipping. These variants are rare and collectively found at a frequency of 2-4% in lung 
cancer 
(Frampton et al 2015, Schrock et al 2016, Schrock et al 2016). 
Recent 
clinical 
observations suggest that such mutations are predictors of response to capmatinib and other 
MET 
targeting 
agents 
(Frampton et al 2015, 
Paik et al 2015, 
Jenkins et al 2015, 
Mendenhall and Goldman 2015, 
Waqar et al 2015, Liu et al 2015, 
Schuler et al 2016, 
Drilon 2016, Cedrés et al 2018, Wolf et al 2018).  
In NSCLC, MET dysregulation has been found to be a negative prognostic factor 
(Guo et al 2014, Landi et al 2017, Awad et al 2019), particularly when both MET amplification 
and mutation occur in the same tumor (Awad et al 2019).  Activation of the MET pathway is 
associated with many cancers and can be caused by MET exon 14 skipping mutation 
(METex14), overexpression and gene amplification. METex14 occur in 3–4% and MET 
amplifications in 1–6% of patients with NSCLC (Paik et al 2015, Saigi et al. 2018, Guo et al. 
2019). Subsequent treatment options are limited, because MET mutations are known to be 
mutually exclusive of other established oncogenic molecular drivers in NSCLC and mostly 
occur in elderly participants (more than two-thirds > 65 years) (Schrock et al 2016), in whom 
triplet combinations of platinum doublet and IO may often not be feasible due to poor 
tolerability compared to younger participants with less comorbidities. In addition, participants 
with MET exon14 mutated NSCLC appear to have a relatively higher incidence of BM that in 
the 
general 
NSCLC population 
(up 
to 
40%) 
(Wolf et al 2018, 
Awad et al 2019, 
Awad et al 2019).  
There have been promising efficacy data in clinical studies with MET inhibitors, including 
capmatinib, in participants whose tumors harbor METex14 mutations, confirming the value of 
this class of mutations in predicting the response to targeted therapies directed against MET.  
The GEOMETRY mono-1 study was a multiple-cohort, phase 2 study evaluating capmatinib in 
364 patients with MET-dysregulated advanced NSCLC. Patients were assigned to cohorts on 
the basis of previous lines of therapy and MET status (MET exon 14 skipping mutation or MET 
amplification according to gene copy number in tumor tissue. Among patients with NSCLC 
with a MET exon 14 skipping mutation, overall response was observed in 41% (95% confidence 
interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously 
and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the 
median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 
5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated 
patients with MET amplification who had a gene copy number of less than 10 (overall response 


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in 7 to 12% of patients). Among patients with MET amplification and a gene copy number of 
10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated 
patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. 
The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 
45%); these events were mostly of grade 1 or 2.  Capmatinib is approved for targeted therapy 
for 
participants 
with 
METex14 
mutated 
NSCLC 
tumors 
(Frampton et al 2015, 
Jenkins et al 2015, 
Liu et al 2016, 
Mendenhall and Goldman 2015, 
Paik et al 2015, 
Waqar et al 2015, 
Drilon 2016, 
Schuler et al 2016, 
Wolf et al 2017, 
Wolf et al 2018, 
Wolf et al 2019). 
1.2 
Purpose 
Activation of the MET pathway is associated with many cancers and can be caused by MET 
exon 14 skipping mutation (METex14), overexpression and gene amplification. METex14 
occur in 3–4% and MET amplifications in 1–6% of participants with NSCLC (Paik et al 2015, 
Saigi et al. 2018, Guo et al. 2019).  Capmatinib is approved in the United States for the treatment 
of metastatic NSCLC with METex14 mutation and has an adverse event profile that is 
manageable and not expected to complicate surgery (Wolff et al. 2019, Paik et al 2020). The 
current study will determine if neoadjuvant capmatinib can improve the major pathological 
response (MPR) in participants with stages IB-IIIA, N2 and selected IIIB (T3N2 or T4N2) lung 
cancers with MET exon 14 mutations and/or high MET amplification beyond those achieved 
with surgery, chemotherapy, and radiation.  Treatment will continue with capmatinib in the 
adjuvant setting to evaluate the potential clinical benefit of extended therapy and allow longer 
follow up in order to assess disease free survival 
 
2 
Objectives and endpoints 
Objectives and related endpoints are described in Table 2-1 below. 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
To determine the MPR in resection specimens following 
neoadjuvant capmatinib in 2 cohorts. Cohort A: MET exon 
14 skipping mutation, irrespective of MET GCN; Cohort B: 
High MET amplification (MET: GCN ≥ 10) 
MPR rate in each cohort based on 
local review, defined as the percentage 
of participants with ≤ 10% residual 
viable cancer cells 
Secondary objective(s) 
Endpoint(s) for secondary 
objective(s) 
To assess overall response rate post neoadjuvant 
treatment with capmatinib in each cohort  
Overall response rate (ORR) based on 
local investigator assessment per 
RECIST 1.1 
To determine the complete pathologic response following 
neoadjuvant capmatinib therapy in each cohort 
Complete pathologic response (pCR) 
rate based on local review  
To evaluate safety and tolerability of capmatinib 
Type, frequency and severity of AEs 
[CTCAE] v5.0), vital signs and 
laboratory abnormalities 


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Objective(s) 
Endpoint(s) 
To assess disease free survival with adjuvant therapy with 
capmatinib  
 
Disease free survival rate at 24, 36, 
and 60 months  
 
2.1 
Primary estimand(s) 
The following are scientific questions for both the two cohorts: 
The primary scientific question of interest is to determine if neoadjuvant treatment effect of 
capmatinib followed by surgical resection and adjuvant treatment effect of capmatinib can 
improve clinical outcome, major pathological response (MPR) in patients with IB-IIIA, N2 and 
selected IIIB (T3N2 or T4N2) lung cancers with MET exon 14 mutations and/or high MET 
amplification, regardless of study treatment discontinuation, beyond those achieved with 
surgery, chemotherapy, and radiation and before start of any new anti-neoplastic therapy. 
 
 
 


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The justification for targeting this treatment effect for both Cohort A and Cohort B is that it will 
enable us to evaluate the MPR even after treatment is discontinued, but avoid potential 
confounding effects of any other therapies or any new anti-neoplastic therapy. 
For more detailed definitions, please refer to the Section 12.4.2. 
The primary estimand is characterized by the following attributes: 
1. Population: Newly diagnosed participants with clinical stages IB-IIIA, N2 and selected IIIB 
(T3N2 or T4N2) lung cancers with MET exon 14 mutations and/or high level MET 
amplification (MET: GCN ≥ 10). 
2. Treatment: Capmatinib (INC280) in the neoadjuvant and adjuvant setting at a dose of 400 
mg b.i.d (tablets for oral use). 
3. Variable: Major pathologic response (MPR) rate, defined as the proportion of evaluable 
participants with ≤ 10% residual viable cancer cells. MPR rate will be assessed in each 
cohort via local review for primary analysis. 
4. Intercurrent events:  The intercurrent events of interest are: 
• The treatment discontinuation for any reason: Tumor assessment data collected 
irrespectively of treatment discontinuation until start of antineoplastic therapy will be 
included to derive MPR (composite strategy). 
• Start of any other antineoplastic therapy:  If any other antineoplastic therapy is taken, 
any subsequent assessment will be excluded from the MPR assessment (hypothetical 
strategy). 
• Any public health emergency as declared by local or regional authorities i.e. pandemic, 
epidemic or natural disaster (treatment policy strategy) 
Details on how to handle the intercurrent events and strategy applied are provided in Section 
12.4.3 
5. Summary measure: proportion of subjects with MPR. 
2.2 
Secondary estimands 
No secondary estimands planned in this study. 
3 
Study design 
This is a phase II, two-cohort, two-stage, study of capmatinib given for 8 weeks (2 cycles) prior 
to surgical resection, followed by three years capmatinib treatment in adjuvant setting.  Surgery 
should be performed up to 2 weeks after the last dose of neoadjuvant study treatment. Please 
contact the sponsor if surgery will be beyond the 2 week window.  
There will be 2 molecularly defined cohorts enrolling in parallel: Cohort A: MET exon 14 
skipping mutations, irrespective of MET GCN or Cohort B:  high level MET amplification 
(MET: GCN ≥10 by FISH or FoundationOne CDx NGS using tumor tissue).  
 
 Participants who have both MET exon 14 skipping mutations and high level 






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The risk to participants in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring, and, as with any clinical study, there 
may be unforeseen risks with the study treatment, which could be serious. The specific risks for 
capmatinib are discussed below.
 
Women of childbearing 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 
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. 
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 of study [INC280A2201] show that capmatinib 
is generally well tolerated and has a manageable safety profile. The safety profile in the 
METex14 mutated NSCLC population is consistent with the safety profile of capmatinib across 
multiple clinical studies. In the context of the significant clinical benefit observed for this 
participant population with limited effective therapeutic options, the overall safety profile is 
acceptable, and the benefit/risk favorable. 
The most frequent safety findings on treatment with capmatinib monotherapy include 
peripheral oedema, nausea, increased blood creatinine, vomiting, fatigue, decreased appetite, 
and diarrhea. 
In addition, pancreatic events (e.g. amylase and lipase increase), and liver function test 
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 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). 
4.6 
Rationale for Public Health Emergency mitigation procedures 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 


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with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate. 
5 
Study Population 
Newly diagnosed participants with clinical stages IB-IIIA and select IIIB lung cancers with 
MET exon 14 mutations and/or high level MET amplification (MET: GCN ≥ 10). The presence 
of MET exon 14 mutations can be determined by any assay conducted in a CLIA certified 
laboratory.  High level MET amplification can be determined by FISH in a CLIA certified 
laboratory or FoundationOne CDx NGS (other NGS-based methods without adjusting for tumor 
content % cannot be accepted).  All participants will be deemed to be both operable and 
resectable by the thoracic surgeon who will perform surgery upon completion of neoadjuvant 
capmatinib. 
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. Adult ≥ 18 years of age at the time of informed consent.  
3. Histologically confirmed NSCLC stage IB-IIIA, N2 and selected IIIB (T3N2 or T4N2) 
(per AJCC 8th edition), deemed suitable for primary resection by treating surgeon (T4 
tumors with mediastinal organ invasion are not eligible for enrollment). 
4. Participant must have MET exon 14 mutation and/or high level MET amplification (MET: 
GCN ≥ 10) as determined by a CLIA certified laboratory.  High level MET amplification 
must be identified by FISH in a CLIA certified laboratory or FoundationOne CDx NGS 
(other NGS-based methods without adjusting for tumor content % cannot be accepted). 
5. Participants must be eligible for surgery and scheduled for surgical resection within 
approximately 2 weeks after the last dose of neoadjuvant study treatment. 
6. 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 ≥ 100 x 109/L 
• Hemoglobin (Hgb) ≥ 9 g/dL 
• Calculated creatinine clearance (using Cockcroft-Gault formula) ≥ 45 mL/min 
• Total bilirubin (TBIL) ≤ 1.5 ULN (upper limit of normal) 
• Aspartate transaminase (AST) ≤ 3 x ULN 
• Alanine transaminase (ALT) ≤ 3 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 


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• Alkaline phosphatase (ALP) ≤ 5.0 x ULN 
7. Participant must have adequate cardiovascular and respiratory function to be submitted to 
surgical procedure as assessed per local clinical practice, including: 
• Adequate pulmonary function to be eligible for surgical resection. Postoperative 
predicted forced expiratory volume in 1 second (FEV1) and diffusion capacity must 
be ≥ 40% and/or maximal oxygen consumption (VO2 max) should be > 10 
mL/kg/min.  
8. ECOG PS of 0 or 1. 
9. Willing and able to comply with scheduled visits, treatment plan and laboratory tests. 
10. Participants must have a life expectancy of at least 3 months. 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Participants with unresectable or metastatic disease. All participants should have brain 
imaging (either MRI brain or CT brain with contrast) prior to enrollment to exclude brain 
metastasis. 
2. Presence or history of a malignant disease 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. 
3. Prior treatment with any MET inhibitor or HGF-targeting therapy. 
4. Participants with other known oncogenic driver alterations. 
5. History of or current interstitial lung disease or pneumonitis, including clinically 
significant radiation pneumonitis (i.e., affecting activities of daily living or requiring 
therapeutic intervention). 
6. Clinically significant, uncontrolled heart disease and/or recent cardiac event, such as: 
• Unstable angina or myocardial infarction within 6 months prior to screening 
• History of documented congestive heart failure (CHF) (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 anti- 
hypertensive 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 
• QTcF ≥ 470 ms on the screening ECG (as mean of triplicate ECG) 
7. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior to 
starting study treatment, or who have not recovered from side effects of such procedure. 
Video- assisted thoracic surgery (VATS) and mediastinoscopy for diagnostic and/or 


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staging purposes will not be counted as major surgery and participants can be enrolled in 
the study ≥1 week after the procedure. 
8. Participants receiving treatment with strong inducers of CYP3A and cannot be 
discontinued at least 1 week prior to the start of treatment and for the duration of the 
study. 
9. Prior systemic anti-cancer therapy (chemotherapy, immunotherapy, biologic therapy, 
vaccine) or investigational agents for NSCLC within the past 3 years.   
10. Impairment of GI function or GI disease that may significantly alter the absorption of 
capmatinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or 
malabsorption syndrome). 
11. Unable or unwilling to swallow tablets as per dosing schedule 
12. Participants receiving unstable or increasing doses of corticosteroids. If participants are on 
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. 
13. Participants receiving treatment with any enzyme-inducing anticonvulsant that cannot be 
discontinued at least 1 week before first dose of capmatinib, and for the duration of the 
study. Participants on non-enzyme-inducing anticonvulsants are eligible. 
14. Substance abuse, active infection 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.   
15. Participants with known hypersensitivity to capmatinib and any of the excipients of 
capmatinib (crospovidone, mannitol, microcrystalline cellulose, povidone, sodium lauryl 
sulfate, magnesium stearate, colloidal silicon dioxide, and various coating premixes). 
16. Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome. 
17. Any other condition that would, in the Investigator’s judgment, contraindicate 
participant’s participation in the clinical study due to safety concerns or compliance with 
clinical study procedures, e.g., active infection (including active hepatitis B and C, SARS-
CoV-2), inflammation, intestinal obstruction, unable to swallow medication, social/ 
psychological issues, etc. 
18. Pregnant or nursing (lactating) women. 
19. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective contraception during the study 
and for 7 days after stopping treatment.  Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before 
taking study treatment. In case of oophorectomy alone, only when the reproductive 
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• Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that patient 
• Use of oral, 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 and not of childbearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. 
age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least 
six weeks before study entry. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by laboratory assessment is she 
considered not of childbearing potential. Medical documentation of oophorectomy, 
hysterectomy, or bilateral tubal ligation must be retained as source documents. Subsequent 
hormone level assessment to confirm the woman is not of child-bearing potential must 
also be available as source documentation in the following cases: 
• Surgical bilateral oophorectomy without a hysterectomy 
• Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, Follicle-stimulating hormone (FSH) testing 
is required of any female participant regardless of reported reproductive/menopausal status at 
screening/baseline. 
When non-child-bearing potential status is determined during the study, further pregnancy 
testing will not be continued. If local requirements dictate otherwise, local regulations should 
be followed. 
20. Sexually active males unless they use a condom during intercourse while taking drug and 
for 7 days after stopping treatment and should not father a child in this period. A condom 
is required to be used also by vasectomized men as well as during intercourse with a male 
partner in order to prevent delivery of the drug via semen 
6 
Treatment 
6.1 
Study treatment 
The investigational drug to be used in this study is capmatinib, as described in Table 6-1. The 
study treatment is defined as capmatinib administered orally as a single agent.  
Capmatinib will be labeled and provided to sites by Novartis in compliance with US regulations. 
6.1.1 
Investigational drug 
The study treatment begins on Cycle 1 Day 1 with the first administration of capmatinib.  All 
dosages prescribed and dispensed to the participant and all dose changes during the study must 


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be recorded on the dose administration electronic Case Report/Record Form (eCRF). Refer 
to Section 6.7.2  for study drug prescribing and administration information. 
Table 6-1 
Investigational and control drug 
Investigational 
Drug 
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
Capmatinib 
(INC280) 150 mg 
or 200 mg 
Film-coated tablet 
Oral use 
Open-label 
bottles 
Sponsor (local) 
 
6.1.2 
Supply of study treatment 
Capmatinib 150 mg or 200 mg will be supplied by the sponsor (Novartis). 
Storage conditions are described in the medication label. Medication labels will comply with 
the legal requirements of the country and be printed in the local language. 
During the COVID-19 pandemic that limits or prevents on-site study visits, delivery of IMP 
directly to a participant’s home is generally permitted in the event the Investigator has decided 
that an on-site visit by the participant is no longer appropriate 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. Implementation will need to be discussed with Novartis. 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 3-months supply. In this case, regular phone 
calls or virtual contacts (every 4 weeks or less frequently) will occur between the site and the 
participant for instructional purposes, safety monitoring, and discussion of the participant´s 
health status until the participants can again visit the site. 
6.1.3 
Treatment group  
All participants in this study will be treated with capmatinib 400 mg orally b.i.d. 
A complete cycle of treatment is defined as 28 days of continuous capmatinib treatment.  
Participants will be assigned to each cohort based on their biomarker status (either METex14 
or high level MET amplification or both).  See Section 3 for cohort definitions.   
6.1.4 
Guidelines for continuation of treatment  
For guidelines on the management of common capmatinib associated toxicities and dose 
modification instructions see Section Section 6.5 
Participants should continue to receive the study treatment until one or more criteria for 
treatment discontinuation described in Section 9.1.1 are met or until treatment completion has 
occurred.    


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6.1.5 
Treatment duration 
Participants will continue to receive study treatment for a maximum of three years following 
surgery or until early discontinuation (see Section 9.1.1).  All participants must have an EOT 
& Safety follow-up visit per the assessment schedule, Table 8-1.   
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
In general, the use of any concomitant medications and therapies deemed necessary for the 
supportive care (e.g. such as anti-emetics, anti-diarrheal) 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 the start of the study treatment. All medications (excluding study treatment and prior 
antineoplastic treatments), blood transfusions, surgeries and procedures (including physical 
therapy) administered within 28 days prior to the first dose administration of study drug through 
30 days after the last dose of study drug will be recorded in the Concomitant Medications or 
Surgical and Medical Procedures eCRF, respectively. Medications include not only physician 
prescribed medications, but also all over-the counter medications, herbal medications, food 
supplements and vitamins. In addition, corticosteroid use will be documented on the appropriate 
eCRF until disease progression (as determined by investigator and confirmed by BIRC). Please 
refer to Section 9.2. 
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 with 
exception to adjuvant chemotherapy per Section 6.2.1.1 
• No radiotherapy 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 
• Oxygen therapy and blood products or transfusions 
• Nutritional support or appetite stimulants 
• Pain medication 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
enrolling a participant or allowing a new medication to be started. If the participant is already 
enrolled, contact Novartis to determine if the participant should continue participation in the 
study. 
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject is enrolled into the study must be recorded in 
the appropriate eCRF. 


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6.2.1.1 
Adjuvant chemotherapy  
Standard postoperative adjuvant chemotherapy, consisting of a platinum-based doublet for 4 
cycles is allowed.  For patients receiving adjuvant chemotherapy no more than 26 weeks can 
elapse between surgery and start of adjuvant capmatinib.    
Chemotherapy regimen, dosing, start and stop dates must be recorded in the eCRF.  
6.2.1.2 
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: 
• Strong CYP3A inhibitors: Co-administrating capmatinib with strong CYP3A inhibitor 
(itraconazole) increased capmatinib AUCinf by 42%. There was no change in capmatinib 
Cmax. Closely monitor participants for adverse reactions during coadministration of 
capmatinib with strong CYP3A inhibitors.  
• Moderate CYP3A inducers: 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. 
• Certain CYP1A2 substrates with narrow therapeutic index (NTI):  Capmatinib is a 
moderate CYP1A2 inhibitor. Coadministration of capmatinib increased sensitive CYP1A2 
probe substrate (caffeine) AUCinf by 134%. Avoid coadministration of capmatinib with 
CYP1A2 substrates where minimal concentration changes may lead to serious adverse 
reactions. If coadministration is unavoidable, decrease the CYP1A2 substrate dosage in 
accordance with the approved prescribing information. 
• P-gp and BCRP substrates: Coadminstration 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 
coadministration of capmatinib with P-gp and BCRP substrates where minimal 
concentration changes may lead to serious adverse reactions. If coadministration is 
unavoidable, decrease the P-gp or BCRP substrate dosage in accordance with the 
approved prescribing information. 
• Proton pump inhibitors: Coadministration 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.  
• H2-receptor antagonists and antacids: 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 16-1 for a list of the medications that require caution when concomitantly used 
with capmatinib.  If a medication listed in Section 16.1 appears on both the list of prohibited 


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and the list of medications to be used with caution (Table 16-1 and Table 16-2), the medication 
is prohibited. 
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 with exception to adjuvant chemotherapy per Section 6.2.1.1.  
Participants enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies while on treatment. 
There are no prohibited therapies during the post-treatment follow-up period. 
Capmatinib: prohibited medication 
Strong CYP3A inducers: Co-administration of capmatinib with strong CYP3A inducer 
(rifampicin) decreases capmatinib AUCinf by 67% and Cmax by 56% [CINC280A2102], 
which may decrease capmatinib anti-tumor activity. Therefore, concurrent use of strong 
CYP3A inducers are prohibited. 
Additionally, live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, 
BCG, yellow fever, varicella, TY21a typhoid vaccines and COVID 19 vaccines) should not be 
administered while a participant is on study treatment and for 30 days after the last dose of study 
treatment. 
Capmatinib prohibited medications are listed in Table 16-2.  
6.3 
 Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a participant Number (participant No.), that is 
assigned when the participant is first enrolled for pre-screening and is retained as the primary 
identifier for the participant throughout his/her entire participation in the trial. The participant 
No. consists of the Center Number (Center No.) (as assigned by Novartis to the investigative 
site) with a sequential participant number suffixed to it, so that each participant is numbered 
uniquely across the entire database. Upon signing the ICF, the participant is assigned to the next 
sequential participant No. available to the investigator through the Clinical Data Management 
System interface.  Once assigned, the Participant No. must not be reused for any other 
participant and the Participant No. for that individual must not be changed. 
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No. 
6.3.2 
Treatment assignment 
Participants will be assigned to a cohort based on their mutational status. All eligible 
participants will receive treatment with capmatinib. 
All participants who fulfill all inclusion/exclusion criteria will be assigned to one of the cohorts 
of interest and information will be collected.   


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Cohort A 
 Cohort A 
includes eligible participants with MET exon 14 skipping mutations.  Participants who have 
both MET exon 14 skipping mutations and high level MET amplification (MET: GCN ≥10 by 
FISH or FoundationOne CDx NGS using tumor tissue) should be enrolled into Cohort A.   Total 
enrollment to a cohort will depend on the decision to expand the cohort.  See Section 3 for the 
study design.   
Cohort B 
 Cohort B will 
include eligible participants with high level MET amplification (MET: GCN ≥ 10).  Total 
enrollment to a cohort will depend on the decision to expand the cohort.  See Section 3 for the 
study design.    
The study treatment phase begins on Cycle 1 Day 1 with the first administration of capmatinib. 
Cycle 1 Day 1.   
6.4 
Treatment blinding 
This is an open-label study, therefore treatment assignment will be known to participants, 
investigator staff, persons performing the assessments, and the Novartis representatives from 
the Clinical Trial Team. 
6.5 
Dose modifications 
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 NCI Clinical Toxicity Criteria (NCI-CTCAE version 5.0). Any changes must 
be recorded on the dose administration eCRF page. 
Dose reductions are allowed for capmatinib and should follow the dose reduction steps 
described in Table 6-2 and Table 6-3. 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). 
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 6-3, 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 


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followed by either dose reduction or re-initiation at the same dose level, depending on the type 
of toxicity as described in Table 6-3. 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 6-3). 
Permanent treatment discontinuation is mandatory for specific events indicated in Table 6-3. 
Deviations to mandatory dose discontinuations are not allowed. 
All interruptions or changes to study drug administration must be recorded in 
the dose administration eCRF. 
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 (4 weeks) of study treatment at 
the reduced dose. 
Any planned variance from the guidelines in Table 6-3, 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. All dose changes must be recorded on the appropriate 
eCRF.  
Table 6-2 
Dose reduction steps for capmatinib  
  
Starting dose level 0 
Dose level −1 
Dose level -2 
capmatinib 
400 mg b.i.d 
300 mg b.i.d 
200 mg b.i.d 
Note: dose reduction should be based on the worst toxicity demonstrated at the last dose.  Dose 
reduction below 200 mg is not allowed. 
 
Table 6-3 
Criteria for dose reduction / interruption and re-initiation/ permanent 
discontinuation of capmatinib treatment for adverse drug reactions 
Dose modifications for capmatinib 
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 


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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 study drug 
treatment 
Hemoglobin decreased (Anemia) 
Grade 1 (Hgb < LLN - 10.0 g/dL; < LLN - 6.2 
mmol/L; < LLN - 100 g/L) 
Maintain dose level 
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   
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 study drug 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 study 
drug treatment 
HEPATIC 
Isolated Total bilirubin elevation* 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level 


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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 capmatinib  
Grade 4 (> 10.0 x ULN) 
Permanently discontinue participant from study 
drug 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 bilirubinb,d 
For participants with normal baseline ALT and 
AST and TBL value: 
AST or ALT > 3.0 x ULN combined with TBL > 
2.0 x ULN without evidence of cholestasisc  
Or hemolysis 
OR 
For participants with elevated baseline AST or 
ALT or TBL value: 
[AST or ALT > 3 x baseline] OR [AST or ALT > 
8.0 x ULN], whichever is lower, combined with 
[TBL > 2 x baseline AND > 2.0 x ULN] 
Mandatory: Permanently discontinue participant 
from study drug treatment 
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 and with signs or 
symptoms) 
Permanently discontinue participant from study 
drug treatment 
CARDIAC 
Electrocardiogram QT corrected (QTc) interval prolonged 
Grade 1 (QTcF 450-480 ms) and 
Maintain dose level 


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Grade 2 (QTcF 481-500 ms) 
 
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 study 
drug treatment 
GASTROINTESTINAL 
Pancreatitis 
Grade 2 
Maintain dose level 
Grade ≥ 3 
Permanently discontinue participant from study 
drug treatment 
Diarrhea** 
Grade 1 (despite maximal 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 maximal 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 
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 


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• 
If resolved in > 7 days (despite appropriate 
skin toxicity therapy), then permanently 
discontinue participant from study drug 
treatment 
Grade 4, despite skin toxicity therapy 
Omit dose and permanently discontinue 
participant from study drug treatment 
RESPIRATORY 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 absence of diagnosis of 
ILD/Pneumonitis, study drug may be restarted at 
the same dose. 
If it recurs after restarting of study drug, 
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 absence of diagnosis of 
ILD/Pneumonitis, study drug may be restarted 
following these guidelines: 
• 
If resolves to ≤ Grade 1 in ≤ 7 days reduce 
study drug by 1 dose level 
• 
If fails to resolve to ≤ Grade 1 within 7 days 
or recurs after resumption of study drug at 
decreased dose, permanently discontinue 
capmatinib 
Grade 3 and Grade 4 
Permanently discontinue study drug 
Treat with IV steroids as clinically indicated. 
Oxygen therapy as indicated. 
Fatigue/ Asthenia (General disorders and administration site conditions) 
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 


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Peripheral edema  
Grade 1 or 2 
Maintain dose level 
Grade 3 
Discontinue dose until resolved to ≤ Grade 1, 
then ↓ 1 dose level 
Grade 4 
Permanently discontinue study drug 
Other AEs 
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 
the same dose or ↓ 1 dose level. 
Grade 3 
Omit dose until resolved to ≤ grade 1, then ↓ 1 
dose level 
Grade 4 
Permanently discontinue study drug 
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: TBL 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 TBL do not meet the defined thresholds, please follow 
the instructions for isolated elevation of TBL 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 TBL > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as 
the etiology 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. 
6.5.1 
Treatment interruption and treatment discontinuation  
If the administration of capmatinib is temporarily interrupted for reasons other than toxicity, 
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 6-3 & 
Table 6-2 should be followed. In any case, scheduled visits and all assessments (including tumor 
assessments) should continue to be performed, as described in Table 8-1. 
If the treatment with capmatinib is withheld for more than 21 consecutive days (counting from 
the first day when a dose was interrupted), excluding the surgical and adjuvant chemotherapy 


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window specified below, then capmatinib should be permanently discontinued. Under 
exceptional circumstance, 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 capmatinib treatment. 
Participants who discontinue the study due to a study drug related AE or an abnormal laboratory 
value must be followed as described in Section 6.5.2. 
After the 8 week neoadjuvant treatment with capmatinib, participants are to undergo surgical 
resection.  Participants should undergo within 2 weeks after last dose of neoadjuvant 
capmatinib.  In addition, participants may receive adjuvant chemotherapy prior to re-starting 
capmatinib at the discretion of the investigator.  For patients who do not receive adjuvant 
chemotherapy no more than 10 weeks should elapse from the date of surgery and the start of 
adjuvant capmatinib.  For patients who do receive adjuvant chemotherapy, see Section 6.2.1.1 
for the dosing window.  If participants for any reason cannot re-start capmatinib therapy within 
the specified windows, then study treatment must be permanently discontinued.  
Participants who discontinue the study due to a surgery related AE must complete the EOT visit 
and safety follow-up visit.    
6.5.2 
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 a 
toxicity 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. Please refer to Table 6-4 for 
follow-up evaluations for selected toxicities. 
Table 6-4 
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. 


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TOXICITY 
FOLLOW-UP EVALUATION 
HEPATIC 
Isolated Total bilirubin elevation 
TBL CTCAE Grade 1:  
• 
Monitor LFTs per protocol or more frequently if clinically 
indicated 
TBL CTCAE Grade 2:  
• 
Weekly monitoring of LFTs, or more frequently if clinically 
indicated, until resolved to ≤ 1.5 x ULN 
TBL 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 TBL have resolved to baseline 
or stabilization over 4 weeks 
TBL CTCAE Grade 4:  
• 
After discontinuing the participant from capmatinib 
permanently, the participant should be monitored weekly 
(including LFTs), or more frequently if clinically indicated, 
until TBL have 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 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 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; 


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TOXICITY 
FOLLOW-UP EVALUATION 
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 AST or ALT and 
Total bilirubin elevation without 
cholestasis or hemolysis 
• 
Combined elevations of AST or ALT and TBL:  
• 
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), TBL (fractionated [direct and 
indirect], if TBL > 2.0 x ULN), and ALP (fractionated 
[quantification of isoforms], if ALP > 2.0 x ULN.) 
METABOLIC 
Asymptomatic amylase or 
lipase ≥ CTCAE grade 3 
• 
Test weekly (or more frequently) until ≤ CTCAE grade 2. 
• 
A 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. 
QTcF ≥ 501 ms (CTCAE grade 
3) 
• 
When QTcF ≥ 501 ms (CTCAE grade 3), perform the 
following:  
• 
Request an immediate manual read of the ECG. 
• 
Perform an analysis of serum potassium, calcium, 
phosphorus, and magnesium, and if below lower limit of 
normal (LLN), 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. 


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TOXICITY 
FOLLOW-UP EVALUATION 
• 
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. 
• 
If the ECG report shows a QTcF ≥ 501 ms (not 
previously documented on the site machine), contact the 
participant and instruct him/her to suspend capmatinib 
and return for a repeat ECG as soon as possible. 
Conduct a manual read of the repeat ECG immediately, 
and the above guidance followed. 
GASTROINTESTINAL 
Diarrheal 
• 
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 PS, 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 


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TOXICITY 
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(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 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 institute 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 


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TOXICITY 
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CTCAE Grade 3 and Grade 4 
• 
Computerized Tomography (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 IV 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 IV steroids followed by high dose oral steroids does not 
reduce initial symptoms within 48 to 72 hours, consider non-
corticosteroid immunosuppressive medication 
a PFT (Pulmonary function tests) to include: diffusing capacity of lungs for carbon monoxide 
corrected for hemoglobin (DLCO); 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 haemorrhage, opportunistic infections, cell count + determination lymphocyte 
CD4/8 count where possible. 
6.5.2.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Participants with transaminase increase combined with Total bilirubin (TBL) increase may be 
indicative of potentially severe 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 TBL 
value; participants meeting any of the following criteria will require further follow-up as 
outlined below: 
• For participants with normal ALT and AST and TBL value at baseline: AST or ALT > 3.0 
x ULN combined with TBL > 2.0 x ULN 
• For participants with elevated AST or ALT or TBL value at baseline: [AST or ALT >3.0 x 
baseline] OR [ALT or AST > 8.0 x ULN], whichever is lower, combined with [TBL > 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 as 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. 


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Laboratory tests should include ALT, AST, TBL, direct and indirect bilirubin, GGT, GLDH, 
prothrombin time (PT)/INR, ALP, albumin, and creatine kinase. 
Evaluate status of liver metastasis (new or exacerbation) or vascular occlusion – e.g. using CT, 
MRI, or duplex sonography. 
Perform relevant examinations (Ultrasound or MRI, 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 
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 (livertox.nih.gov/rucam.html). 
Table 6-5 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule out possible alternative causes of observed LFT abnormalities. 
Table 6-5 
Follow up on potential drug-induced liver injury (DILI) cases 
Disease 
Assessment 
Hepatitis A, B, C, 
E 
• 
IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, Hepatitis B Virus (HBV) DNA; 
anti-HCV, Hepatitis C Virus (HCV) RNA, IgM & IgG anti-HEV, HEV RNA 
CMV, HSV, EBV 
infection 
• 
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV 
Autoimmune 
hepatitis 
• 
ANA & ASMA titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
• 
Ethanol history, GGT, MCV, CD-transferrin 
Nonalcoholic 
steatohepatitis 
• 
Ultrasound or MRI 
Hypoxic/ischemic 
hepatopathy 
• 
Medical history: acute or chronic CHF, hypotension, hypoxia, hepatic 
venous occlusion. Ultrasound or MRI. 
Biliary tract 
disease 
• 
Ultrasound or MRI, ERCP as appropriate. 
Wilson disease (if 
<40 yrs old) 
• 
Caeruloplasmin 
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 Stimulation Hormone (TSH); CVD / 
ischemic hepatitis – ECG, prior hypotensive episodes; T1D / glycogenic hepatitis). 
Obtain PK sample to determine exposure to study treatment and metabolites. 


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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 an 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. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
The date and time of study treatment administration during the study and any deviations from 
the protocol treatment schedule will be captured 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. 
Treatment 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 document at each visit. All study treatment dispensed and returned must 
be recorded in a drug accountability log. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described in Section 6.1.1 
A unique medication number (sequence number) is printed on the study medication label per 
bottle, as well as a unique packaging control number (PCN) per batch/labeling operation.  
6.7.1 
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. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance.  
Medication labels will be in the local language and comply with the legal requirements of the 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication kit 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 


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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. 
At the conclusion of the study, and if appropriate during the course of the study, the investigator 
will destroy all unused study treatment, packaging, drug labels, and provide a copy of the 
completed drug accountability log to the study monitor.  If the investigator cannot destroy these 
items compliantly, they may be returned to the study monitor or to the Novartis address 
provided in the investigator folder at each site.  
The study drugs supply can be destroyed locally at the site only if permitted by local regulations 
and authorized by Novartis.  
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 28 of each 28 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 28 days of b.i.d. treatment with 
capmatinib. The investigator must instruct the participant to take the study drug exactly as 
prescribed. All dosages prescribed and dispensed to the participant and all dose changes during 
the study must be recorded on the dose administration eCRF. 
• 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 
• 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). 


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Table 6-6 
Dose and treatment schedule 
Investigational / Control Drug 
(Name and Strength) 
Dose 
Frequency and/or Regimen 
Capmatinib (150 mg or 200 mg 
tablets)  
400 mg orally (2x 200 mg 
tablets)  
 
Twice daily (28 day cycles)  
7 
Informed consent procedures  
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 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. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
This information will be included in the 
participant informed consent and should be discussed with the participant during the study as 
needed. 
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: 
• Main study 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 
• As applicable, Pregnancy Outcomes Reporting Consent for female participants or the 
female partners of any male participants who took study treatment 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information. 


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A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the participant’s source 
documentation. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. Participants who discontinue the treatment should 
be scheduled for the end of treatment visit as soon as possible, and attend the follow-up visits 
as indicated in the Assessment Schedule.  At this visit, all dispensed investigational product 
should be reconciled, and the adverse event and concomitant medications recorded on the CRF. 
Each treatment cycle is 28 days. Screening evaluations should be performed within ≤ 28 days 
of Cycle 1 Day 1 (except for the pregnancy test which has to be performed within 72 hours 
before the first dose & PFTs which can occur within 3 months of starting neoadjuvant 
treatment). Laboratory assessments performed as part of the screening evaluations that are 
within 72 hours of the first dose of study treatment are not required to be repeated on the first 
day of dosing (Cycle 1 Day 1). 
During the course of the study visits, test and/or procedures should occur on schedule whenever 
possible. A visit window of +/- 3 days is allowed for study procedures (including treatment 
administration). A window of +/- 7 days from the planned visit date is allowed for imaging 
evaluations. Note: if a treatment cycle is delayed at any time during the study, all study visits 
and safety and efficacy assessments should continue according to the appropriate number of 
calendar days measured from Day 1 of the previous cycle, or more often if clinically indicated.  
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 and depending on operational 
capabilities, phone calls, virtual contacts (e.g. tele consult) or visits by site staff/ home nursing 
staff to the participant´s home, can replace on-site study visits, for the duration of the disruption 
until it is safe for the participant to visit the site again.  
 


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Table 8-1 
Assessment schedule  
Period 
Screening 
Treatment 
Surgery  
 
 
Treatment 
Follow-up 
Cycle 
Cycle 1 
Cycle 2 
Cycle 3 & beyond up to 
3 years 
Visit Name 
Screening 
Treatment 
C1D1 
Treatment 
C2D1 
Surgery 
Post-surgery Treatment 
C3D1 
Treatment 
C4D1 & 
beyond 
EOT 
30 day safety 
follow up 
Days/months 
-28 to -1 
1 
28 
 Within 2 
weeks from 
last dose of 
capmatinib6 
2 weeks from 
date of 
surgery9 
10-26 
weeks from 
surgery3 
Every 3 
months 
when 
applicable  
30 days post last 
dose of 
capmatinib 
Informed consent 
X 
Demography 
X 
MET status 
confirmation 
X 
Inclusion / 
Exclusion criteria 
X 
Medical 
history/current 
medical conditions 
 
X 
Smoking history 
X 


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Period 
Screening 
Treatment 
Surgery  
 
 
Treatment 
Follow-up 
Cycle 
Cycle 1 
Cycle 2 
Cycle 3 & beyond up to 
3 years 
Visit Name 
Screening 
Treatment 
C1D1 
Treatment 
C2D1 
Surgery 
Post-surgery Treatment 
C3D1 
Treatment 
C4D1 & 
beyond 
EOT 
30 day safety 
follow up 
Days/months 
-28 to -1 
1 
28 
 Within 2 
weeks from 
last dose of 
capmatinib6 
2 weeks from 
date of 
surgery9 
10-26 
weeks from 
surgery3 
Every 3 
months 
when 
applicable  
30 days post last 
dose of 
capmatinib 
Diagnosis, stage 
and grade of 
cancer 
 
X 
 
 
 
 
 
 
 
Histopathology 
assessment, 
(squamous or non-
squamous) 
 
X 
 
 
 
 
 
 
 
Physical 
Examination 
S 
S 
S 
 
S 
S 
S 
S 
S 
ECOG 
Performance status 
X 
X 
X 
 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
 
X 
X 
X 
X 
Body Weight 
X 
X 
X 
 
X 
X 
X  
X  
Body Height 
X 
 
 
 
 
 
 
 


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Period 
Screening 
Treatment 
Surgery  
 
 
Treatment 
Follow-up 
Cycle 
Cycle 1 
Cycle 2 
Cycle 3 & beyond up to 
3 years 
Visit Name 
Screening 
Treatment 
C1D1 
Treatment 
C2D1 
Surgery 
Post-surgery Treatment 
C3D1 
Treatment 
C4D1 & 
beyond 
EOT 
30 day safety 
follow up 
Days/months 
-28 to -1 
1 
28 
 Within 2 
weeks from 
last dose of 
capmatinib6 
2 weeks from 
date of 
surgery9 
10-26 
weeks from 
surgery3 
Every 3 
months 
when 
applicable  
30 days post last 
dose of 
capmatinib 
Electrocardiogram 
(ECG) 
X 
X2 
 
If clinically indicated 
X 
Pulmonary function 
tests (PFT) 
X4 
 
 
X5 
X 
 
 
 
 
Hematology blood 
sample 
X 
X 
X 
 
X 
X 
X 
X 
X 
Chemistry blood 
sample 
X 
X 
X 
 
X 
X 
X 
X 
X 
Coagulation panel  
X 
 
If clinically indicated 
 
Urinalysis (dipstick) 
X 
X 
X 
 
 
X 
X 
 


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Period 
Screening 
Treatment 
Surgery  
 
 
Treatment 
Follow-up 
Cycle 
Cycle 1 
Cycle 2 
Cycle 3 & beyond up to 
3 years 
Visit Name 
Screening 
Treatment 
C1D1 
Treatment 
C2D1 
Surgery 
Post-surgery Treatment 
C3D1 
Treatment 
C4D1 & 
beyond 
EOT 
30 day safety 
follow up 
Days/months 
-28 to -1 
1 
28 
 Within 2 
weeks from 
last dose of 
capmatinib6 
2 weeks from 
date of 
surgery9 
10-26 
weeks from 
surgery3 
Every 3 
months 
when 
applicable  
30 days post last 
dose of 
capmatinib 
Prior/concomitant 
medications 
X 
X (Continuous from 28 days prior to starting treatment until 30 day safety follow-up or start of new antineoplastic 
medication (ANP), whichever is sooner) 
Non-drug therapies 
and procedures 
X 
X (Continuous from 28 days prior to starting treatment until 30 day safety follow-up or start of new antineoplastic 
medication (ANP), whichever is sooner) 
Adverse Events 
X (Continuous until ≥ 30 days after the last dose of INC280) 
Serious Adverse 
Events 
X (Continuous until ≥ 30 days after the last dose of INC280) 
Serum pregnancy 
test 
S (within 72 
hours prior 
to first dose) 
 
 
 
 
 
 
S11 
S11 
Urine pregnancy 
test11  
 
S 
 
 
S 
S 
 


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Period 
Screening 
Treatment 
Surgery  
 
 
Treatment 
Follow-up 
Cycle 
Cycle 1 
Cycle 2 
Cycle 3 & beyond up to 
3 years 
Visit Name 
Screening 
Treatment 
C1D1 
Treatment 
C2D1 
Surgery 
Post-surgery Treatment 
C3D1 
Treatment 
C4D1 & 
beyond 
EOT 
30 day safety 
follow up 
Days/months 
-28 to -1 
1 
28 
 Within 2 
weeks from 
last dose of 
capmatinib6 
2 weeks from 
date of 
surgery9 
10-26 
weeks from 
surgery3 
Every 3 
months 
when 
applicable  
30 days post last 
dose of 
capmatinib 
Surgery 
 
 
X 
 
 
PET-CT (with 
diagnostic quality 
CT)  
X10  
 
 
CT/MRI – Chest   
X10 
X, To be 
performed 
within 7 days 
prior to 
surgery 
 
X, At the initiation of adjuvant therapy (chemotherapy or 
capmatinib) and every 12 weeks for the first year of 
treatment, every 26 weeks thereafter7 
Brain MRI 
X 
 
If clinically indicated 
Whole body bone 
scan 
 
If clinically indicated 
 
Tumor sample from 
surgery1 
X 
 
 
 
 


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Period 
Screening 
Treatment 
Surgery  
 
 
Treatment 
Follow-up 
Cycle 
Cycle 1 
Cycle 2 
Cycle 3 & beyond up to 
3 years 
Visit Name 
Screening 
Treatment 
C1D1 
Treatment 
C2D1 
Surgery 
Post-surgery Treatment 
C3D1 
Treatment 
C4D1 & 
beyond 
EOT 
30 day safety 
follow up 
Days/months 
-28 to -1 
1 
28 
 Within 2 
weeks from 
last dose of 
capmatinib6 
2 weeks from 
date of 
surgery9 
10-26 
weeks from 
surgery3 
Every 3 
months 
when 
applicable  
30 days post last 
dose of 
capmatinib 
MPR 
X 
 
 
 
 
Adjuvant 
chemotherapy8   
 
 
X 
 
 
 
Study drug 
administration 
(capmatinib) 
X (continuous twice daily 
(BID) dosing) 
 
 
X (continuous twice daily 
(BID) dosing) 
 
 
Antineoplastic 
therapies since 
discontinuation of 
study treatment 
 
 
 
 
 
 
 
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 Lymph nodes might be requested if collected, see Table 8-6 for number of unstained slides.  


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2 pre-dose  
3 No more than 26 weeks or 10 weeks can elapse between surgery and start of adjuvant capmatinib for patients who have or have not received 
adjuvant chemotherapy, respectively.  
4 Within 3 months before starting neoadjuvant capmatinib  
5 After neoadjuvant capmatinib but before surgery  
6 Delay to the surgical procedure beyond 2 weeks is acceptable, but should be avoided.  Please contact the sponsor if surgery will be beyond 
the 2 week window. 
7 Post-surgery scan schedule to start with initiation of any adjuvant treatment, chemotherapy or capmatinib. 
8Standard postoperative adjuvant chemotherapy, consisting of a platinum-based doublet for 4 cycles is allowed.  No more than 26 weeks can 
elapse between surgery and start of adjuvant capmatinib.    
9 Post-surgery visit to be approximately 2 weeks from date of surgery in alignment with practice guidelines.  
10  Chest CT/MRI or PET-CT (with diagnostic quality CT) is required at baseline. 
11 For women of child-bearing potential only  
 
 A visit window of +/- 3 days is allowed for study procedures (including treatment administration). A window of +/- 7 days from the 
planned visit date is allowed for imaging evaluations 
 


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8.1 
Screening 
Molecular pre-screening 
Eligible participants must have METex14 mutation and/or high level MET amplification (MET: 
GCN ≥ 10) determined  by a  CLIA certified laboratory from formalin fixed, paraffin-embedded 
human tissue.  Participant's METex14 mutation will be determined locally at a CLIA-certified 
laboratory compliant with LCMC4 master screening protocol.  High level MET amplification 
(MET: GCN ≥ 10) must be determined by FISH in a CLIA certified laboratory or 
FoundationOne CDx NGS. Other NGS-based methods for determining gene copy number 
without adjusting for tumor content % are currently not accepted.  Confirmation by a Novartis-
designated central laboratory is not required to confirm eligibility prior to enrollment.  
Molecular pre-screening results will be captured in the eCRF.  
Screening 
The study IRB/IEC approved ICF must be signed and dated before any screening procedures 
are performed, except for laboratory, PFTs and radiological evaluations which were performed 
as part of the participant’s clinical SoC within the acceptable screening window. 
Participants will be evaluated against study inclusion and exclusion criteria and undergo safety 
assessments (refer to Table 8-1). Screening assessments must be repeated if performed outside 
of the specified screening window (Section 8). Participants must meet all inclusion and none of 
the exclusion criteria at screening in order to be eligible for the study. 
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. 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. 
8.1.1 
Eligibility screening 
The investigator is responsible to ensure only participants who meet all inclusion and do not 
meet any exclusion criteria are included in the study. 
Participant eligibility will be checked by the sponsor once all screening procedures are 
completed. The eligibility check form will be sent from the site to the sponsor via email for 
evaluation. Upon confirmation of eligibility, the sponsor will return the signed eligibility check 
form via email to the site. The investigator site will then be allowed to start treatment to the 
participant.  


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8.1.2 
Information to be collected on screening failures 
Participants who sign an ICF and subsequently found to be ineligible prior to start of treatment 
will be considered a screen failure. The reason for screen failure should be recorded on the 
appropriate CRF. The demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for screen failure participants. No other data will be entered into 
the clinical database for participants who are screen failures, unless the subject experienced a 
SAE during the screening phase (see SAE section for reporting details). If a screen failure 
experiences AEs that are not SAEs will be followed by the investigator and collected only in 
the source data. If the subject fails to be enrolled, the sponsor must be notified within 2 days of 
the screen fail via e-mail that the subject did not initiate treatment.  
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed. In case of re-screening, a new participant ID will be generated, 
however, site has to provide original participant ID in respective eCRF to link the two 
participants for reporting and validation. All required screening activities must be performed 
when the participant is re- screened for participation in the study. An individual participant may 
only be re-screened once for the study. Once the number of participants screened and enrolled 
is likely to ensure target enrollment, 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 enrolled and fail to start treatment, e.g. participants enrolled in error, will 
be considered an early terminator. The reason for early termination should be recorded on the 
appropriate eCRF. 
8.2 
Participant demographics/other baseline characteristics 
Participant demographic and baseline characteristic data are to be collected on all participants. 
Relevant medical history/current medical conditions present before signing the informed 
consent will be recorded. Investigators will have the discretion to record abnormal test findings 
on the appropriate eCRF whenever, in their judgment, the test abnormality occurred prior to the 
informed consent signature. 
Data to be collected on participant characteristics at screening include: 
• Demography (age, gender, race and ethnicity, or as allowed by local regulations). 
Participant race and ethnicity are collected and analyzed to identify variations in safety or 
efficacy due to these factors as well as to assess the diversity of the study population as 
required by Health Authorities. 
• Other background or relevant medical history (including smoking history)/ (serious) 
adverse events, prior and current concomitant medications, prior antineoplastic therapies 
(medications, radiation, surgeries)  
• Cancer characteristics including diagnosis, history, extent of cancer, MET mutation status, 
prior antineoplastic therapies (medications, radiation, surgeries).   
• Tumor imaging assessments 
• Other assessments to be completed for the purpose of determining eligibility (ECOG 
performance status, complete physical examination [only recorded in source 
documentation], vital signs, height, weight, hematology, blood chemistry, coagulation 


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studies, urinalysis,  serum pregnancy test [only recorded in source documentation], and 
12-Lead ECG) 
• Pulmonary function tests  
• Prior and current concomitant medications and surgical and medical procedures 
8.3 
Efficacy 
8.3.1 
Efficacy assessments 
Major Pathological Response (MPR)  
Response will be assessed locally at the time of surgery (by number of subject with ≤10% 
residual viable tumor cells). MPR assessment in tumor samples will be collected at time of 
resection.  MPR rate as assessed by the number of participants with ≤ 10% residual viable 
cancer cells and will be assessed locally.  In addition, the local MPR assessment will be 
confirmed centrally.  All formalin-fixed, paraffin embedded (FFPE) tumor tissues collected at 
surgery must be submitted, detailed instructions for sample collection and processing will be 
included in the central lab manual. 
Radiologic  
The following assessments are required at screening/baseline: 
• Chest CT/MRI or  PET-CT (with diagnostic quality CT)   
• Brain  MRI/CT 
• Whole body bone scan, if clinically indicated 
In the neoadjuvant setting imaging assessments will be performed at screening/baseline within 
28 days of start of treatment (Day -28 to Day -1 prior to Cycle 1 Day 1) and within 7 days prior 
surgery.  See Table 8-1.  Tumor response will be assessed locally based on RECIST 1.1.   
Any imaging assessments already completed during the regular work-up of the subject within 
28 days prior to start of treatment, including before signing the main study ICF, can be 
considered the baseline images for this study.   
In the adjuvant setting imaging assessments will begin with the initiation of any adjuvant 
treatment, chemotherapy or capmatinib, and are to be performed every 12 weeks for the first 
year of treatment and then every 26 weeks thereafter during adjuvant treatment.  First disease 
recurrence must be radiologically confirmed by the investigator. In case of non-conclusive 
radiological evidence, a biopsy should be performed to confirm recurrence.  If a biopsy is not 
feasible, the subject will be followed up until recurrence can be confirmed as per protocol 
(radiologically conclusive and/or biopsy). The intervals between imaging assessments across 
all study phases should be respected as described above regardless of whether study 
treatment is temporarily withheld or if unscheduled assessments are performed.  A 
window of ±7 days is permitted is permitted to take into account scheduling over holidays. 
For any antineoplastic therapy, surgery, or radiotherapy initiated after the start of study 
treatment the reason for its use must be clearly documented.  


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A whole body bone scan (e.g. Tc-99m bone scan, sodium fluoride PET [NaF-PET] bone scan) 
can be done to identify location of recurrence in bone tissue. If bone metastases were identified 
by a bone scan, it has to be confirmed histologically (preferred) or radiographically (by CT, 
MRI or FDG-PET-CT) if biopsy confirmation is unsafe. 
All MRI and CT of the chest should be done with contrast unless contraindicated. If a subject 
is known to have a contraindication to CT intravenous (IV) contrast media or develops a 
contraindication during the trial, a non-contrast CT of the chest (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 chest should be performed. 
MRI or CT of brain with contrast is required at screening.  Contrast enhancement should be 
used for all subsequent imaging unless contraindicated for the subject. 
Findings from radiological evaluations (evaluation of suspicion of recurrence or unconfirmed 
findings) will be recorded in the eCRF. 
Table 8-2 
Imaging Assessment Collection Plan 
Procedure 
Screening/Baseline 
& Pre-operative  
During Adjuvant 
Treatment 
Survival follow-up 
Chest CT/MRI with 
contrast or PET-CT* 
*with diagnostic 
quality CT; allowed at 
baseline only  
Mandated 
Mandated, every 12 
weeks (+/- 7 days) for 
the first year of 
adjuvant treatment and 
every 26 weeks 
thereafter.  
Not applicable 
Brain MRI/CT 
Mandated at 
screening, if clinically 
indicated pre-
operative  
If clinically indicated  
Not applicable  
Whole body bone 
scan 
If clinically indicated 
If clinically indicated 
(new bone pain or other 
symptoms of bone 
metastases) 
Not applicable 
Unscheduled CT or 
MRI of involved area, 
upon any signs or 
symptoms of 
recurrence 
Not applicable 
Upon suspected 
recurrence 
Not applicable 
8.4 
Safety 
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 may limit or prevent on-site study 
visits regular phone or virtual calls can occur for safety monitoring and discussion of the 
participant´s health status until it is safe for the participant to visit the site again. 
For details on AE collection and reporting, refer to Section 10.1. 


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Table 8-3 
Safety Assessments 
Assessment 
Specification 
Physical 
examination 
A complete physical examination must be performed at screening and later as 
clinically indicated and will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, vascular, and neurological assessments.  
A targeted (short) physical exam will be performed as per schedule in Table 8-1 
and will include the examination of general appearance and vital signs (blood 
pressure and pulse). 
More frequent examinations may be performed at the discretion of the 
investigator and if medically indicated. Information for all physical examinations 
must be included in the source documentation at the study site. Clinically relevant 
findings that are present prior to signing informed consent must be recorded on 
the appropriate eCRF that captures medical history. Significant findings made 
after signing informed consent which meet the definition of an AE must be 
recorded as an AE. 
 
Vital signs 
Vital signs include blood pressure (supine position preferred when ECG is 
collected), pulse measurement, respiratory rate, and body temperature. 
Vital signs will be measured at screening and at subsequent time points as 
specified in Table 8-1. 
Height and 
weight 
Height will be measured at screening. 
Body weight (in indoor clothing, but without shoes) will be measured at screening 
and at subsequent time points as specified in Table 8-1. 
Performance 
status (PS) 
The Eastern Cooperative Oncology Group (ECOG) performance status will be 
assessed according to the PS scale as specified in Table 8-4 following the 
schedule given in Table 8-1. 
Performance status 
Table 8-4 
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 
8.4.1 
Laboratory evaluations 
The results of the laboratory tests performed locally will be recorded in the eCRF. 
Novartis must be provided with a copy of the normal ranges and certification of the all 
laboratories used to assess participants’ safety during study conduct. The investigator is 


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responsible for reviewing all laboratory reports for participants in the study and evaluating any 
abnormalities for clinical significance. 
At any time during the study up to the safety follow-up visit, abnormal laboratory parameters 
which are clinically relevant and require an action to be taken with study treatment (e.g., require 
dose modification and/or interruption of study treatment, lead to clinical symptoms or signs, or 
require therapeutic intervention), whether specifically requested in the protocol or not, will be 
recorded on the AE eCRF page. The severity of laboratory data will be graded using the 
Common Terminology Criteria for Adverse events (CTCAE) v5.0. (See Section 10.1 for 
additional information.) Additional analyses are left to the discretion of the investigator. 
As per Section 4.6, if participants cannot visit the site for protocol specified safety lab 
assessments, an alternative lab (local) collection site may be used.   
Table 8-5 
Laboratory Assessments 
Test 
Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, White blood cells (WBC), Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands, Other (absolute value 
preferred, percentages are acceptable unless indicated otherwise) 
Chemistry 
Albumin, ALP, ALT, AST, Gamma-glutamyl-transferase (GGT),  Calcium, 
Magnesium, Phosphorus, Sodium, Potassium, Creatinine, Creatine kinase, 
Creatinine Clearance, Direct Bilirubin (only if TBL is ≥ grade 2), TBL, Blood Urea 
Nitrogen (BUN) or Urea, Amylase, Lipase, fasting Glucose (non-fasting glucose 
allowed post-baseline) 
Bicarbonate, Chloride and Uric Acid: at screening and thereafter if clinically 
indicated. 
Urinalysis 
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, Leukocytes 
esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen) 
If dipstick is abnormal then perform Microscopic Panel (Red Blood Cells, WBC, 
Casts, Crystals, Bacteria, Epithelial cells) 
Coagulation  
Prothrombin time (PT) or Quick Test (QT), International normalized ratio [INR])  
Pregnancy 
Test 
A serum pregnancy test must be performed at screening within ≤ 72 hours before 
first dose of study treatment, then the schedule of serum and urine pregnancy tests 
should be performed as indicated in Table 8-1 and Section 8.4.5.  If local 
requirements dictate otherwise, local regulations should be followed. 
8.4.1.1 
Hematology 
Hematology tests are to be performed according to the visit schedule outlined in Table 8-1. For 
details of the hematology panel refer to Table 8-5. Hematology should be assessed on the actual 
scheduled day, even if study drug is being withheld. 
Hematology lab tests done as part of screening assessments ≤ 3days prior to first dose of study 
treatment do not need to be repeated. 
Additional results from unscheduled hematology lab evaluations should be recorded on the 
appropriate unscheduled visit eCRF. 


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8.4.1.2 
Chemistry 
Clinical chemistry tests are to be performed according to the visit schedule outlined in Table 8-
1. For details of the biochemistry panel see Table 8-5. Chemistry tests should be assessed on 
the actual scheduled day, even if study drug is being withheld. 
Chemistry lab tests done as part of screening assessments ≤ 3 days prior to the first dose of 
study treatment do not need to be repeated. 
Additional results from unscheduled chemistry lab evaluations should be recorded in eCRF as 
unscheduled visit. 
8.4.1.3 
Urinalysis 
Dipstick measurements will be performed as per Table 8-5 and according to the schedule of 
assessments (Table 8-1). Any significant findings on dipstick will be followed up with 
microscopic evaluation and recorded on the appropriate eCRF page. 
8.4.2 
Coagulation  
Coagulation tests outlined in Table 8-5 will be performed according to the visit schedule 
outlined in Table 8-1. 
8.4.3 
Pulmonary Function Tests (PFT) 
PFTs must have been performed within 3 months of planned resection and repeated at screening 
if clinically indicated, and should include lung volumes, spirometry, and diffusion capacity.  
Abnormal PFTs may be further evaluated with quantitative ventilation/perfusion scanning or 
cardiopulmonary exercise testing.  Additional PFTs should be performed according to the visit 
schedule outlined in Table 8-1. 
Any PFTs already completed during the regular work-up of the subject within 3 months prior 
to start of treatment, including before signing the main study ICF, can be considered the baseline 
PFTs for this study.   
8.4.4 
Electrocardiogram (ECG) 
Standard triplicate 12 lead ECG assessments will be performed during screening, pre-dose 
Cycle 1, day 1, and at end of treatment (see Table 8-1).   
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. 
Clinically significant ECG abnormalities present at screening should be reported on the 
appropriate CRF. New or worsened clinically significant findings occurring after informed 
consent must be recorded as adverse events. 


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8.4.5 
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 and the definition of post-menopausal, and for a definition of assessment of 
fertility (males and females), please see Section 5.2. 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 should not donate 
sperm for the time period specified above. 
A woman is considered of child bearing potential from menarche and until becoming post-
menopausal 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 status 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. 
All women of child bearing potential will have a serum pregnancy test within 72 hours prior to 
the first dose of study treatment. hCG may also be considered a tumor marker, therefore if hCG 
levels are detected, another blood sample at least 4 days later must be taken to assess the kinetics 
of the increase, and a transvaginal ultrasound must be performed to rule out pregnancy. 
Additional pregnancy testing might be performed if requested by local requirements.  
For women of child-bearing potential, urine pregnancy tests will be required to be performed 
on day 1 of cycles 1,2,3 and 4 and then every 3 cycles (at each study visit) until the end of 
treatment with capmatinib.  In addition, a serum pregnancy test will be performed at the end of 
treatment and during the safety follow-up.    
If participants cannot visit the site to have serum pregnancy tests 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, 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). 
Women of child-bearing potential will be instructed to contact the site immediately at any time 
during the study (on-treatment or during follow-up) should they have a positive pregnancy test. 
In case of positive urine pregnancy testing, additional testing must be performed to confirm the 
pregnancy, and, if confirmed, follow the reporting requirements as described in Section 10.1.4. 
A positive pregnancy test requires immediate discontinuation of study treatment. If a positive 
pregnancy test is performed in between study visits, the participant must immediately notify the 
investigator. Male participants must notify the investigator in case their partner is confirmed 


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with positive pregnancy test results during the treatment period. See Section 10.1.4 for 
pregnancy reporting. 
Local pregnancy test and associated results will not be collected on the eCRF. 
8.4.6 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population. 
8.5 
Additional assessments  
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, or if visits by site staff 
to a participant’s home are not feasible the collection of samples may be modified by Novartis 
and will be communicated to the Investigator. 
8.5.1 
Surgery related information 
The surgery should be performed as per local guidelines/clinical practice. The following surgery 
instructions are general recommendations and should only be considered as a guidance.   
• Mediastinal lymph node staging by endobronchial ultrasound or mediastinoscopy is 
encouraged. 
• Resection may be accomplished by open or minimally invasive techniques (i.e. 
clamshell or hemiclamshell incision, robot assisted thoracic surgery, sternotomy, 
thoracotomy, or video assisted thoracic surgery/thoracoscopy). 
• Pathologic complete resection of the primary tumor (R0 resection) should be performed. 
Anatomic resection by bilobectomy, lobectomy, pneumonectomy, or segmentectomy is 
strongly preferred. Wedge (nonanatomic) resection can be done for very small (2 cm or 
less) tumors located peripherally where at least a 1 cm margin in all directions is 
possible. 
• Hilar and mediastinal lymph node dissection or sampling should be performed. For right 
sided resections, lymph nodes for levels 4R, 7, 10R, and 11R, and for left sided 
resections lymph nodes from levels 5/6, 7, 10L, and 11L should be dissected or sampled. 
Surgery related information, including safety-related, will be collected on the appropriate eCRF 
page. 


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8.6 
Follow up evaluations 
8.6.1 
Safety follow up 
All subjects will be followed for AEs and SAEs for at least 30 days following the EOT visit.  
At the end of this period, the investigator should assess and discuss with the subject any AEs 
observed and concomitant medications taken since discontinuation of study treatment. Subjects 
whose treatment is permanently discontinued due to an AE (clinical or based on abnormal 
laboratory value) must be followed until resolution or stabilization of the event, whichever 


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comes first. In case of an abnormal laboratory value, blood tests should be repeated until 
resolution or stabilization. See Table 8-1 for list of assessments to be performed at safety follow-
up visit.  
If a new antineoplastic therapy is initiated after discontinuation of study treatment, only SAEs 
suspected to be related to study treatment will be collected in the Adverse Events eCRF. 
9 
Discontinuation and completion 
9.1 
Discontinuation from study treatment and from study  
9.1.1 
Discontinuation from study treatment   
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study drug administration) 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 recurrence  
• AE requiring permanent discontinuation of study treatment (see Table 6-3) 
• Protocol deviation that results in a significant risk to participant's safety 
• Withdraw of consent (see Section 9.1.3) 
• Study is terminated by the sponsor (see Section 9.1.5) 
• Death 
• Lost to follow-up (see Section 9.1.4) 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information. 
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 9.1.3). Where possible, they should return for the EOT 
assessments indicated in Table 8-1 and safety follow-up. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made 
to contact the participant/pre-designated contact as specified in the lost to follow-up section. 
This contact should preferably be done according to the study visit schedule. 


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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. 
After study treatment discontinuation, in abbreviated visits, the data mentioned in Table 8-1 
should be collected at clinic visits or via telephone/email contact. 
9.1.2 
Discontinuation from 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 
Withdrawal of informed consent/Opposition to use data/biological 
samples  
Participants may voluntarily withdraw consent/oppose to use data/biological samples to 
participate in the study for any reason at any time. WoC/opposition to use data/biological 
samples occurs only when a participant: 
• Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) 
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 in writing (depending on local regulations) and recorded in the source 
documentation. 
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 his/her 
consent/opposition to use data/biological samples and record this information.  
Where consent to the use of personal and coded data is not required, the participant therefore 
cannot withdraw consent; however, they still retain the right to object to the further collect or 
use of their personal data.  
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.  
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study discontinuation.  If the 
participant agrees a final evaluation at the time of the participant’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the Assessment 
Table.  


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Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until the time of withdrawal) according to applicable 
law. 
All biological samples not yet analyzed at the time of withdrawal may still be used for further 
testing/analysis in accordance with the terms of this protocol and of the ICF.  No new Personal 
Data (including biological samples) will be collected following withdrawal of 
consent/opposition 
9.1.4 
Lost to follow-up  
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed. Participants lost to follow up should be recorded as such on the 
appropriate eCRF page. 
9.1.5 
 Early study termination by the sponsor  
The study can be terminated by Novartis at any time. 
Reasons for early termination: 
• 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 drug 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:   Novartis will provide instruction for 
contacting the participant, when the participant should stop taking drug, when the participant 
should come in for a final visit(s) that the safety follow up period must be completed and which 
visits to be performed.  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 sponsor depending on local regulation will be 
responsible for informing IRBs/IECs of the early termination of the trial. 
9.2 
 Study completion and post-study treatment  
For participants, study completion is defined as when the subject has completed the 30 day 
safety follow-up.   
Final analysis will be performed when all the participants complete the treatment period or 
discontinue early, and final CSR will be written.   
Participants will continue to receive study treatment until reasons for discontinuation of study 
treatment are met in Section 9.1.1 or treatment completion. In addition, participants may 
voluntarily withdraw from the study treatment or may be taken off the study treatment at the 
discretion of the investigator at any time.  


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10 
Safety monitoring and reporting  
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (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 adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events 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.   
Adverse events 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): 
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0. 
• 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 
• Its duration (start and end dates or ongoing) and the outcome must be reported 
• Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
• Action taken regarding with study treatment. All adverse events must be treated 
appropriately. Treatment may include one or more of the following: 
o Dose not changed 
o Dose Reduced/increased 
o Drug interrupted/permanently discontinued  
• Its outcome (not recovered/not resolved; recovered/resolved; recovered/resolved with 
sequelae; fatal or unknown). 
 


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If the event worsens the event should be reported a second time in the CRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if 
improvement to a lower grade is determined a new entry for this event should be reported in 
the CRF 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. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (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), should not be reported as a serious adverse event, 
except if the investigator considers that progression of malignancy is related to study treatment. 
Adverse events separate from the progression of malignancy (i.e. 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 drug. 
 
Abnormal laboratory values or test results constitute adverse events 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 adverse event [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 


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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 
• 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 
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 serious adverse 
event 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, under no 
circumstances later than 24 hours of learning of its occurrence. Detailed instructions regarding 
the submission process and requirements are to be found in the investigator folder provided to 
each site. 


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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 AE eCRF. 
The following SAE reporting timeframes apply: 
• 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. 
• Enrolled OR Treated Participants: All SAEs collected between time participant signs 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 
within 24 hours of the investigator receiving the follow-up information. 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. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the 30 day follow-up period should only be reported to Novartis 
Safety if the investigator suspects a causal relationship to study treatment. 
10.1.4 
Pregnancy reporting 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent from 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 at 1, 3 (for a live birth only) and 12 (for a live birth only) months after the estimated 
date of delivery 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 
any pregnancy outcome. Any SAE experienced during pregnancy must be reported. 


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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. 
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 (EMA definition). 
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 CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. 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 
CRF (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 even if not 
associated with an AE 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
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 SC will be defined in a SC charter. 


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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 EDC system until they have been trained. 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 (recorded on CRFs) (entered 
into eCRF) 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 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
At the conclusion of a non-IRT study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused supplies to Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis.  Any changes to 
the database after that time can only be made after written agreement by Novartis development 
management. 
11.3 
Site monitoring  
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis/delegated CRO representative will review the protocol and data capture requirements 
(i.e. eSource DDE or eCRFs) with the investigators and their staff. During the study, 
Novartis employs several methods of ensuring protocol and GCP compliance and the 
quality/integrity of the sites’ data. The field monitor will visit the site to check the completeness 
of participant records, the accuracy of data capture / data entry, the adherence to the protocol 


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and to Good Clinical Practice, the progress of enrollment, and to ensure that study treatment is 
being stored, dispensed, and accounted for according to specifications. 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/delegated CRO/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. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
It is planned that the data from all centers participating in the study will be combined, so that 
an adequate number of participants are available for analysis. Novartis and/or a designated 
CRO will perform all analyses. 
All efficacy and safety data will be summarized descriptively for each cohort. Categorical data 
will be presented in frequencies and percentages. For continuous data, descriptive statistics 
(mean, standard deviation, median 25th and 75th percentiles, min and max) will be provided. 
As appropriate, 95% confidence interval will be reported. 
Screen failures and the reasons for not starting the study treatment will be reported in a listing, 
but will not be included in any analysis. 
Further details of the statistical analyses including timing and analysis of each endpoints will 
be fully described in the Statistical Analysis Plan (SAP).Any data analysis carried out 
independently by the investigator should be submitted to Novartis before publication or 
presentation. 
12.1 
Analysis sets 
12.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) is defined as all enrolled participants to whom study treatment has 
been assigned and who received at least one dose of any study treatment (i.e. at least one dose 
of capmatinib administered).  


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12.1.2 
Safety Set 
Same definition as of FAS above in Section 12.1.1. 
 
 
 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively for all participants enrolled in the study. 
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term for all participants. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum and maximum will be presented. Disposition data of 
participants will be listed. 
12.3 
Treatments 
The duration of exposure to capmatinib will be presented in days. Dose intensity will be 
computed as the ratio of actual cumulative dose received and actual duration of exposure. 
Relative dose intensity will be computed as the ratio of dose intensity and planned dose 
intensity. The duration of exposure, dose intensity and relative dose intensity will be 
summarized using descriptive statistics. The duration of exposure will be presented for the 
cohort. Continuous data, mean, standard deviation, median, 25th and 75th percentiles, minimum 
and maximum will be presented. 
The number of participants with dose adjustments (reduction, interruption, or permanent 
discontinuation) and the reasons will be summarized for each cohort. All of the dosing related 
data will be listed. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system. 
Categorical data will be summarized as frequencies and percentages.  
12.4 
Analysis of the primary endpoint(s)/estimand(s) 
The primary objective is to evaluate the major pathologic response (MPR) rate in resection 
specimens following neoadjuvant capmatinib in the two cohorts (A and B). 
Where, Cohort A: Participants with MET exon 14 skipping mutation, irrespective of MET GCN 
and Cohort B: Participants with High MET amplification.  




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 Detail will be discussed in the Statistical Analysis Plan (SAP). 
12.4.4 
Handling of missing values/censoring/discontinuation 
Only participants with non-missing MPR will be considered for the evaluation of MPR 
following neoadjuvant capmatinib therapy. MPR achieved prior to any additional anticancer 
therapy will be considered as responses in the calculation of the MPR irrespective of the number 
of missed assessments before response. 
Participants with a MPR of ‘Unknown’ will be considered as non-responders when estimating 
MPR.  
Participants with no available data will be considered as non-responders when estimating MPR. 
12.4.5 
No imputation will be performed for the missing data.  Sensitivity and 
Supportive analyses for primary endpoint/estimand(s) 
As part of supportive analysis, the following subgroup analyses for the primary efficacy variable 
will be performed to assess the homogeneity of the treatment effect across demographic and 
baseline disease characteristics: 
• Gender (male vs. female) 
• Age (<65 vs.  ≥65 years) 
• ECOG performance status (0 vs. 1) 
• Nodal stage (N0 vs. N1 vs. N2) 
Number and percentage of patients receiving: no adjuvant therapy, standard of care 
chemotherapy alone, and SOC chemotherapy + adjuvant therapy will also be summarized 
As appropriate, a sensitivity analysis will be performed on the primary efficacy evaluating the 
impact of the above intercurrent events, if any.   
Further details will be provided in the SAP. 
12.5 
Analysis of secondary endpoints 
The secondary objectives for the study are to evaluate complete pathologic response (pCR) rate 
following neoadjuvant capmatinib therapy, overall response rate (ORR) and safety and 
tolerability for each cohort. 
12.5.1 
Secondary Efficacy endpoint(s) 
The secondary efficacy endpoints will be assessed using the Full Analysis Set (FAS). The 
following analyses will be performed for each cohort: 
Complete Pathologic response (pCR) rate is defined as the as the proportion of participants 
with no residual viable cancer cells. pCR rate will be assessed via both central and local review. 
pCR rate will be summarized using binomial response rate and its 95% confidence interval will 
be presented for each cohort following neoadjuvant capmatinib therapy using Coppler-Pearson 
method. 


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Overall response rate (ORR) is defined as the proportion of participants with best overall 
response (BOR) of complete response (CR) or partial response (PR) according to RECIST v 
1.1. ORR will be calculated using local investigator review.  
ORR will be summarized using binomial response rate and its 95% confidence interval will be 
presented each cohort using Coppler-Pearson method. 
Disease Free Survival (DFS) is defined as the time from date of end of adjuvant therapy with 
capmatinib to the date of event defined as the recurrence of cancer or death due to any cause. 
Disease free survival will be presented at 24, 36 and 60 months after adjuvant capmatinib 
treatment for each cohort. The disease free survival distribution will be estimated using the 
Kaplan-Meier method, and the estimates of the 25th, median and 75th percentile of the DFS and 
95% confidence intervals will also be presented.  
12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used and data will be presented for each cohort. 
Listings and tables will also be presented by each cohort for all participants. 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from the day of subject’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 the date of 
last actual administration of any study medication. 
3. Post-treatment period: starting at day 31 after last dose of study medication. 
If dates are incomplete in a way that clear assignment to pre-, on-, or post-treatment period 
cannot be made, then the respective data will be assigned to the on-treatment period. Additional 
details to address incomplete AE and/or dosing dates will be addressed in the SAP. 
Additional summaries will be displayed to report deaths, all AEs, AEs related to study 
treatment, all SAEs and SAEs related to study treatment collected up to 30 days after last 
administration of any study treatment. 
Adverse events 
Summary tables for AEs will include only AEs that started or worsened during on-treatment 
periods, the treatment-emergent AEs and will be presented for each cohort. 
The incidence of treatment-emergent AEs will be summarized by system organ class and 
preferred term, severity (based on CTCAE v 5.0 grades), types of adverse event, and relation to 
study treatment. 
Serious adverse events (SAEs), non-serious adverse events, and adverse events of special 
interest (AESI) during the on-treatment period will be tabulated. 
All reported deaths (on-treatment and post-treatment) will be summarized. 


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All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those starting during the pre-treatment and post-treatment period will 
be flagged. 
Vital signs 
Data on vital signs will be tabulated and listed for each cohort, notable values will be flagged. 
12-lead ECG 
12- lead ECGs including PR, QRS, QT, QTcF, and HR intervals will be obtained for each 
participant during the study. ECG data will be read and interpreted locally. 
Categorical analysis of QT/QTc interval data based on number of participants meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline 
will be presented for each cohort. In addition, a listing of these participants will be produced. 
All ECG data will be listed by subject and visit/time, abnormalities will be flagged. 
Clinical laboratory evaluations 
Grading of laboratory values will be assigned programmatically as per NCI CTCAE version 
5.0. The calculation of CTCAE v 5.0 grades will be based on the observed laboratory values 
only, clinical assessments will not be taken into account. 
CTCAE v 5.0 grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
Grade 5 will not be applicable. 
For laboratory tests where grades are not defined by CTCAE v 5.0, results will be categorized 
as low/normal/high based on laboratory normal ranges. 
The following listing/summaries will be generated separately for hematology, and biochemistry 
tests: 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE v 5.0 
grades, if applicable and the classifications relative to the laboratory normal ranges. 
For laboratory tests where grades are defined by CTCAE v 5.0: 
• Worse post-baseline CTCAE v 5.0 grade (regardless of the baseline status). Each subject 
will be counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE v 5.0 grades to compare baseline to the worst on-treatment 
value. 
For laboratory tests where grades are not defined by CTCAE v 5.0: 
• Shift tables using the low/normal/high/(low and high) classification to compare baseline to 
the worst on-treatment value. 
 


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Other safety evaluations 
Tolerability 
Tolerability of study drug treatment will be assessed by summarizing the number of treatments 
dose interruptions and dose reductions. Reasons for dose interruption and dose reductions will 
be listed by subject and summarized for each cohort.  
 
 
 




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written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign 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. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
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 patient 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. 
13.4 
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 SOPs, and are performed according to written Novartis processes. 
13.5 
Participant Engagement  
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the timepoints indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis. 
•Thank You letter 
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 


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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. 
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 analysis. Lung Cancer; 133:96-102. 
Benson AB, Ajani JA, Catalano RB, et al (2004) Recommended guidelines for the treatment 
of cancer treatment-induced diarrhea. J. Clin. Oncol; 22(14):2918-26. 
Blumenthal GM, Bunn PA Jr, Chaft JE, et al. (2018) Current Status and Future Perspectives on 
Neoadjuvant Therapy in Lung Cancer. J Thorac Oncol. (12):1818-1831. 
Bray F, Ferlay J, Soerjomataram I, et al (2018) Global cancer statistics 2018: GLOBOCAN 
estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J 
Clin; 68:394-424. 
Burdette-Radoux S, Muss HB (2006) Adjuvant chemotherapy in the elderly: whom to treat, 
what regimen? The Oncologist p. 234-42. 
Cancer Genome Atlas Research N. Comprehensive molecular profiling of lung 
adenocarcinoma. Nature 2014;511:543-50. 
Cedrés S, Felip E, Cruz C, et al (2018) Activity of HSP90 Inhibiton in a Metastatic Lung 
Cancer Patient With a Germline BRCA1 Mutation. J Natl Cancer Inst; 110(8):914-917. 
Christensen JG, Burrows J, Salgia R (2005) c-Met as a target for human cancer and 
characterization of inhibitors for therapeutic intervention. Cancer Lett; 225:1-26. 
Chuang JC, Liang Y, Wakelee HA (2017) Neoadjuvant and Adjuvant Therapy for Non-Small 
Cell Lung Cancer. Hematol. Oncol. Clin. North Am. p. 31-44. 
Depierre A, Milleron B, Moro-Sibilot D, et al (2002) Preoperative chemotherapy followed by 
surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa 
nonsmall-cell lung cancer. J. Clin. Oncol. p. 247-53. 
Drilon A (2016) MET Exon 14 Alterations in Lung Cancer: Exon Skipping Extends Half-
Life. Clin. Cancer Res; 22(12):2832-4. 
Ettinger DS, Akerley W, Bepler G, et al (2010) Non-small cell lung cancer. J Natl Compr 
Canc Netw; 8(7):740-801. 
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; 850-9. 
Fukuoka M, Wu YL, Thongprasert S, et al (2011) Biomarker analyses and final overall 
survival results from a phase III, randomized, open-label, first-line study of gefitinib versus 
carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer 
in Asia (IPASS). J Clin Oncol; 29(21):2866-74. 


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Gilligan D, Nicolson M, Smith I, et al (2007) Preoperative chemotherapy in patients with 
resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 
multicentre randomised trial and update of systematic review. Lancet p. 1929-37. 
Group NM-aC.  (2014) Preoperative chemotherapy for non-small-cell lung cancer: a systematic 
review and meta-analysis of individual participant data. Lancet; 383:1561-71. 
Guo B, Cen H, Tan X, et al. (2014) Prognostic value of MET gene copy number and protein 
expression in patients with surgically resected non-small cell lung cancer: a meta-analysis of 
published literatures. PLoS ONE; 9(6):e99399. 
Guo R, Berry L, Aisner DL, et al. (2019) MET IHC is a Poor Screen for MET Amplification or 
MET exon 14 mutations in Lung Adenocarcinomas: Data from a Tri-Institutional Cohort of the 
Lung Cancer Mutation Consortium. J Thorac Oncol.  
Hamanishi J, Mandai M, Matsumura N, et al. (2016) PD-1/PD-L1 blockade in cancer 
treatment: perspectives and issues. Int J Clin Oncol;21(3):462-73. 
Hellmann MD, Chaft JE, William WN, Jr., et al. (2014) Pathological response after neoadjuvant 
chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major 
pathological response as a surrogate endpoint. Lancet Oncol;15:e42-50. 
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. 
Kong-Beltran M, Seshagiri S, Zha J, et al (2006) Somatic mutations lead to an oncogenic 
deletion of met in lung cancer. Cancer Res; 66(1):283-9. 
Landi L, Chella A, Chiari R, et al (2017) P.1.01-015 Crizotinib in ROS1 Rearranged or MET 
Deregulated Non-Small-Cell Lung Cancer (NSCLC): Final Results of the METROS trial 
[abstract]. J Thorac Oncol; s1898. 
Liu H, Wu Q, Liu Y, et al (2015) Prognostic significance of β1,6-N-
acetylglucosaminyltransferase V expression in patients with hepatocellular carcinoma. Jpn. J 
Clin Oncol; 45(9):844-53. 
Liu X, Jia Y, Stoopler MB, et al (2016) Next-Generation Sequencing of Pulmonary 
Sarcomatoid Carcinoma Reveals High Frequency of Actionable MET Gene Mutations. J Clin 
Oncol; 34(8):794-802. 
Malvezzi M, Carioli G, Bertuccio P, et al (2019) European cancer mortality predictions for 
the year 2019 with focus on breast cancer. Ann Oncol; 30:781-7. 
Mendenhall MA, Goldman JW (2015) MET-Mutated NSCLC with Major Response to 
Crizotinib. J Thorac Oncol; 10(5):e33-4. 
NCCN (2020) Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. 
Paik PK, Drilon A, Fan PD, et al (2015) Response to MET inhibitors in patients with stage IV 
lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov; 
842-9. 


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Paik PK et al. (2020) Tepotinib in Non–Small-Cell Lung Cancer with MET Exon 14 Skipping 
Mutations. NEJM; 383:931-934.  
Pignon JP, Tribodet H, Scagliotti GV, et al. (2008) Lung adjuvant cisplatin evaluation: a pooled 
analysis by the LACE Collaborative Group. J Clin Oncol; 26:3552-9. 
Rosell R, Carcereny E, Gervais R, et al (2012) Erlotinib versus standard chemotherapy as first-
line treatment for European patients with advanced EGFR mutation-positive non-small-cell 
lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol; 
13(3):239-46. 
Saigi M, McLeer-Florin A, Pros E, Nadal E, Brambilla E, Sanchez-Cespedes M. Genetic 
screening and molecular characterization of MET alterations in non-small cell lung cancer. Clin 
Transl Oncol 2018;20:881-8. 
Scagliotti GV, Pastorino U, Vansteenkiste JF, et al (2012) Randomized phase III study of 
surgery alone or surgery plus preoperative cisplatin and gemcitabine in stages IB to IIIA 
nonsmall-cell lung cancer. J. Clin. Oncol. p. 172-8. 
Schrock AB, Frampton GM, Suh J, et al (2016) Characterization of 298 Patients with Lung 
Cancer Harboring MET Exon 14 Skipping Alterations. J Thorac Oncol; 11(9):1493-502. 
Schuler MH, Berardi R, Lim WT, et al (2016) Phase I Study of the Safety and Efficacy of the 
cMET Inhibitor Capmatinib (INC280) in Patients With Advanced cMET+ Non-small Cell 
Lung Cancer [abstract]. J Clin Oncol; suppl; 9067-9067. 
Sequist LV, Yang JC, Yamamoto N, et al (2013) Phase III study of afatinib or cisplatin plus 
pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin 
Oncol; 31(27):3327-34. 
Shaw AT, Engelman JA (2013) ALK in lung cancer: past, present, and future. J Clin Oncol; 
31(8):1105-11. 
Shaw AT, Kim DW, Nakagawa K, et al (2013) Crizotinib versus chemotherapy in advanced 
ALK-positive lung cancer. N Engl J Med; 368(25):2385-94. 
Siegel RL, Miller KD, Jemal A. (2020) Cancer statistics. CA Cancer J Clin. 2020;70(1):7‐30. 
doi:10.3322/caac.21590. 
Solomon BJ, Mok T, Kim DW, et al (2014) First-line crizotinib versus chemotherapy in 
ALK-positive lung cancer. N Engl J Med; 371(23):2167-77. 
Waqar SN, Morgensztern D, Sehn J (2015) MET Mutation Associated with Responsiveness to 
Crizotinib. J Thorac Oncol; 10(5):e29-31. 
Winton T, Livingston R, Johnson D, et al. (2005) Vinorelbine plus cisplatin vs. observationin 
resected non-small-cell lung cancer. N Engl J Med; 352:2589-97. 
Wolf J, Han J, Nishio M, et al (2017) P2.04-005 GEOMETRY Mono-1: Phase II, Multicenter 
Study of MET Inhibitor Capmatinib (INC280) in EGFR wt, MET dysregulated Advanced 
NSCLC [abstract]. S2399:04-005. 


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Wolf J, Baik C, Heist RS, et al (2018) Natural history, treatment (tx) patterns, and outcomes 
in MET dysregulated non-small cell lung cancer (NSCLC) patients (pts) [abstract]. European 
Journal of Cancer; 103S1:PB-066. 
Wolf J, Seto T, Han J-Y, et al (2019) Capmatinib (INC280) in METΔex14-mutated advanced 
non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 
study [abstract]. J Clin Oncol 37; suppl; 9004. 
Wolf J, Seto T, Han J-Y, et al (2020) Capmatinib (INC280) in METΔex14-mutated advanced 
non-small cell lung cancer (NSCLC):  NEJM; 383:944-957. 
Zhou C, Wu YL, Chen G, et al (2011) Erlotinib versus chemotherapy as first-line treatment 
for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, 
CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol; 
12(8):735-42. 
 


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16 
Appendices  
16.1 
Appendix 1: List of concomitant medications for participants on 
capmatinib 
Table 16-1 
Medications that require caution when concomitantly used with 
capmatinib 
Mechanism of 
Interaction 
Drug Name 
Strong CYP3A 
inhibitor 
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,clarithromycin, posaconazole, telithromycin, grapefruit juice, 
conivaptan, nefazodone, nelfinavir, idelalisib, boceprevir, atazanavir/ritonavir, 
darunavir/ritonavir 
Moderate CYP3A 
inducer 
bosentan, dabrafenib, efavirenz, etravirine, genistein, modafinil, nafcillin, 
tipranavir/ritonavir, lopinavir, telotristat, thioridazine 
CYP1A2 substrate 
with NTI 
theophylline, tizanidine 
P-gp substrates 1 
afatinib, alfuzosin, aliskiren, alogliptin, ambrisentan, apixaban, apremilast, 
aprepitant, atorvastatin, azithromycin, boceprevir, bosentan, carvedilol, 
caspofungin, ceritinib, citalopram, colchicine, cyclosporine, dabigatran, 
digoxin, docetaxel, doxepin, doxorubicin, eribulin, everolimus, fentanyl, 
fexofenadine, fidaxomicin, fluvastatin, fosamprenavir, gatifloxacin, idelalisib, 
iloperidone, indacaterol, irbesartan, lacosamide, lapatinib, levetiracetam, 
linagliptin, linezolid, loperamide, losartan, maraviroc, mirabegron, moxifloxacin 
nadolol, naloxegol, nateglinide, nevirapine, nintedanib, olodaterol, paclitaxel, 
pantoprazole, paroxetine, pazopanib, posaconazole, pravastatin, proguanil, 
quinidine, ranolazine, riociguat, risperidone, ritonavir, rivaroxaban, saquinavir, 
silodosin, simeprevir, simvastatin, sirolimus, sitagliptin, sofosbuvir, sorafenib, 
tacrolimus, telaprevir, tenofovir, ticagrelor, tipranavir, tolvaptan, topotecan, 
umeclidinium, valsartan, vardenafil, vincristine, voriconazole 
BCRP substrates 1 
atorvastatin daunorubicin, dolutegravir, doxorubicin, ethinyl estradiol, 
hematoporphyrin, imatinib, irinotecan, methotrexate, mitoxantrone, 
paritaprevir, pitavastatin, rosuvastatin, simvastatin, sofosbuvir, sulfasalazine, 
tenofovir, topotecan, venetoclax 
Proton pump 
inhibitor 
dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, 
rabeprazole 
H2-receptor 
antagonists 
cimetidine, famotidine, nizatidine, ranitidine 
Antacids 
aluminum carbonate, aluminum hydroxide, calcium carbonate, calcium 
hydroxide, 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 (drug-
interactions.medicine.iu.edu/Main-Table.aspx), 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 
mentioned database for the latest information. NTI: narrow therapeutic index 


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1 If coadministration with capmatinib is unavoidable and minimal concentration changes of the drug 
listed may lead to serious adverse reactions, decrease dosage in accordance with the approved 
prescribing information. 
Table 16-2 
Capmatinib: prohibited drugs 
Mechanism of 
Interaction 
Drug Name (generic) 
Strong CYP3A4 
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, 2018): drug-drug interactions (DDI) database, which is compiled primarily from the 
Indiana University School of Medicine’s “Clinically Relevant” Table (drug-
interactions.medicine.iu.edu/Main-Table.aspx), 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 
mentioned databases for the latest information. 
 
 
 


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16.2 
Appendix 2: 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: February 11, 2016 Version 3.1: November 29, 2011 Version 
3: October 19, 2009 Version 2: January 18, 2007 Version 1: December 13, 
2002 
Release date: 
11-Feb-2016 
 
16.2.1 
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 16.2.2 and the definition of best response in 
Section 16.2.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 16.2.3.2 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 16.2.4 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. 
16.2.2 
Efficacy assessments 
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), and revised 
RECIST guidelines (version 1.1) (Eisenhauer et al 2009). 


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16.2.2.1 Definitions 
16.2.2.1.1 
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 participants without measurable disease see Section 16.2.3.2.9. 
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 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm 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. 
• 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. 


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16.2.2.1.2 
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 participants be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how participants with just non-measurable disease at 
baseline will be evaluated for response and also handled in the statistical analyses is given in 
Section 16.2.3.2.9. 
16.2.2.2 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 participants, 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, 
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 


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• 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 10mm 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, LDH and Beta-hCG 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. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (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. 


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16.2.2.3 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 eCRF 
(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 16.2.2.1.1. 
• Nodal target: See Section 16.2.2.1.1. 
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 identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 
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 16-3) and non-target lesions (Table 16-4) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 16-5) as well as the presence or absence of new lesions. 
16.2.2.4.1 
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. 


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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. 
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. 
16.2.2.4.2 
Determination of target lesion response 
Table 16-3 
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 


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Response Criteria 
Evaluation of 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 16.2.2.2) 
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 progressive disease 
• 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 eCRF and the tumor assessment will remain 
based on the sum of tumor measurements as presented in Table 16-3 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 participants who have not achieved target response of CR. For participants who 
have achieved CR, please refer to last bullet in this section. 
• For those participants 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 


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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 
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 


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16.2.2.4.3 
Determination of non-target lesion response 
Table 16-4 
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 isCR 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 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 16.2.2.4.2 for assigning PD following a CR for 
the non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied. 


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16.2.2.4.4 
New lesions 
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. 
• 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 16.2.2.5). 
• A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to ³ 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 16.2.2.2. 
16.2.2.5 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-
5. 
Table 16-5 
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 
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 16.2.2.4. 
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. 


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16.2.3 
Efficacy definitions 
The following definitions primarily relate to participants who have measurable disease at 
baseline. Section 16.2.3.2.8 outlines the special considerations that need to be given to 
participants with no measurable disease at baseline in order to apply the same concepts. 
16.2.3.1 Best overall response 
The best overall response 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 best overall 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 
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 response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall 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. 
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. 
The best overall response 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) 


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• 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 (³30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not ³20% 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. 
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response. 
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 best overall response 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) 


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The primary analysis of the best overall response will be based on the sequence of 
investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses. 
Based on the participants’ best overall response during the study, the following rates are then 
calculated: 
Overall response rate (ORR) is the proportion of participants with a best overall response 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 participants with a best overall response of 
CR or PR or SD. The objective of this endpoint is to summarize participants 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 participants with a best overall response 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 participants with progressive disease 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 participants 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. Participants 
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, participants with a best overall response 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). 
16.2.3.2 Time to event variables 
16.2.3.2.1 
Progression-free survival 
Usually in all Oncology studies, participants 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, progression-free survival is censored at the date of last adequate 
tumor assessment. 




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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 participants who did not experience treatment failure will be censored at last adequate 
tumor assessment. 
16.2.3.2.6 
Duration of response 
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 duration of 
response but where this probably primarily reflected selection bias which is explained as 
follows: It is postulated that there are two groups of participants: a good risk group and a poor 
risk group. Good risk participants tend to get into response readily (and relatively quickly) and 
tend to remain in response after they have a response. Poor risk participants 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 participants. Less 
potent agents induce a response mainly in good risk participants only. This is described in more 
detail by Morgan (1988). 
It is recommended that an analysis of all participants (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 
participants (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 
duration of response 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 
participants throughout the study is usually taken into account in the analysis). 
Duration of overall response (CR or PR): For participants 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 participants 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. 


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Duration of stable disease (CR/PR/SD): For participants 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. 
16.2.3.2.7 
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 overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 16.2.3.2.6. It is recommended that 
an analysis of all participants (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 participants should definitely be included in the analysis to 
ensure the statistical test is valid. For analysis including all participants, participants 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 participants 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 participants 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. 
16.2.3.2.8 
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. 


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Start Dates 
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date. 
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 (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 progressive disease. 
• 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 16.2.3.2.8). 
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 
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. 
16.2.3.2.9 
Handling of participants with non-measurable disease only 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. 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. 


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It is recommended that any participants 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 
participants with measurable disease at baseline, participants without measurable disease should 
also be incorporated in an appropriate manner. The overall response for participants with non-
measurable disease is derived slightly differently according to Table 16-6. 
Table 16-6 
Overall lesion response at each assessment: participants 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 16.2.2.4. 
In general, the non-CR/non-PD response for these participants is considered equivalent to an 
SD response in endpoint determination. In summary tables for best overall response participants 
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 participants 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 participants with 
only non-measurable disease at baseline, handling participants with a best response of CR as 
“responders” with respect to ORR and all other participants as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
participants with only non-measurable disease at baseline, with possible sensitivity analyses 
which exclude these particular participants. Endpoints such as PFS which are reliant on the 
determination and/or timing of progression can incorporate data from participants with only 
non-measurable disease. 
16.2.3.2.10 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. 


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Based on definitions outlined in Section 16.2.3.2.7, 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 16-7 
Options for event dates used in PFS, TTP, duration of response 
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 
As per above 
situations 
Censored 
Censored 
Event 


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1. =Definitions can be found in Section 16.2.3.2.7. 
2. =After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in 
Section 16.2.3.2.7. 
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. 
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 participants 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 
Situation 
Options for end-date 
(progression or 
censoring)1 
(1) = default unless 
specified differently 
in the protocol or 
RAP 
Outcome 
(3) Date of secondary 
anti-cancer therapy 
(4) Date of secondary 
anti-cancer therapy 
G 
Deaths due to reason 
other than 
deterioration of ‘Study 
indication’ 
(1) Date of last 
adequate assessment 
Censored (only TTP 
and duration of 
response) 


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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. 
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 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. 
16.2.4 
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). 
16.2.4.1 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. 


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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). 
16.2.4.2 End of treatment phase completion 
Participants 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 participants 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.  
Participants may discontinue study treatment for any of the following reasons: 
• Adverse event(s) 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• 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. 
16.2.4.3 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. 
Participants 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 


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• Death 
• Progressive disease 
• Study terminated by the sponsor 
16.2.4.4 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. 
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 participants with documented deterioration 
of symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation. 
16.2.4.5 Programming rules 
The following should be used for programming of efficacy results: 
16.2.4.5.1 
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. 
16.2.4.5.2 
Incomplete assessment dates 
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year. 


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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 16.2.3.2.7). 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. 
16.2.4.5.3 
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. 
16.2.4.5.4 
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)’. 
16.2.4.5.5 
Study/project specific programming 
The standard analysis programs need to be adapted for each study/project. 
16.2.4.5.6 
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 duration of responses) 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 16-7) 
• Death due to reason other than underlying cancer (only used for TTP and duration of 
response) 
• Initiation of new anti-cancer therapy  
* Adequate assessment is defined in Section 16.2.3.2.7. 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 


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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 participants 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. 
 

SAP_001.pdf: 






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 15 
2.14 
Interim analysis ...................................................................................................... 15 
 
 15 
4 
Change to protocol specified analyses .............................................................................. 15 
5 
Appendix ........................................................................................................................... 15 
5.1 
Imputation rules ..................................................................................................... 15 
5.1.1 
Study drug ............................................................................................. 15 
5.1.2 
AE date imputation ............................................................................... 16 
5.1.3 
Concomitant medication date imputation ............................................. 16 
5.2 
AEs coding/grading ............................................................................................... 16 
5.3 
Laboratory parameters derivations ........................................................................ 16 
5.4 
Statistical models ................................................................................................... 16 
5.4.1 
Primary analysis .................................................................................... 16 
5.4.2 
Key secondary analysis ......................................................................... 17 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 17 
6 
Reference ........................................................................................................................... 17 


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List of abbreviations 
 AE 
Adverse Event 
 AESI Adverse Events of Special Interest 
 AJCC American Joint Committee on Cancer  
 ALP 
Alkaline Phosphatase 
 ALT 
Alanine Aminotransferase 
 AST 
Aspartate Aminotransferase 
 ATC 
Anatomical Therapeutic Chemical 
 b.i.d. 
bis in die/twice a day 
 BOR 
best overall response 
 BUN 
Blood Urea Nitrogen 
 CI 
Confidence Interval 
 CLIA 
Clinical Laboratory Improvement Amendments  
 CMD    Concomitant medication 
 CMO&PS Chief Medical Office and Patient Safety 
 CO 
Country Organization 
 CR 
Complete response 
 CRF 
Case Report/Record Form (paper or electronic) 
 CRO 
Contract Research Organization 
 CSR 
Clinical study report 
 CT 
Computerized Tomography  
 CTC 
Common Terminology Criteria 
 DAR  Drug Administration Record 
 DBP 
Diastolic Blood Pressure 
 DFS 
Disease Free Survival 
 ECG 
Electrocardiogram 
 ECOG Eastern Cooperative Oncology Group  
 EOS 
End of Study 
 FAS 
Full Analysis Set 
 FISH Fluorescence in situ hybridization 
 GCN 
Gene Copy Number  
 GPS 
Global programming & statistical environment 
 h 
Hour 
 HGF 
Human Growth Factor  


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 MedDRA Medical dictionary for regulatory activities  
 MET 
Mesenchymal Epithelial Transition  
 METex14 MET exon 14 skipping 
 mg 
milligram(s) 
 mL 
milliliter(s) 
 MPR 
Major Pathologic Response  
 MRI 
Magnetic Resonance Imaging  
 NCI 
National Cancer Institute  
 NGS 
Next Generation Sequencing  
 NSCLC Non-small cell lung cancer 
 ORR 
Overall response rate 
 pCR 
Complete Pathologic response 
 PD 
Pharmacodynamic(s) 
 PDS 
Programming Dataset Specifications 
 PD 
Pharmacodynamic(s) 
 PFT 
Pulmonary Function Test(s) 
 
 PPS 
Per-Protocol Set 
 PR  
Partial response 
 PS 
Performance Status  
 PT 
Preferred term 
 QT 
QT interval 
 QTcF QT interval corrected by Fridericia’s formula 
 RAP 
The Report and Analysis Plan 
 RECIST Response Evaluation Criteria In Solid Tumors 
 SAE 
Serious Adverse Event 
 SAP 
Statistical Analysis Plan 
 SAS 
Statistical Analysis System 
 SBP 
Systolic Blood Pressure 
 SD 
standard deviation 
 SOC 
system organ class 
 TEAE  Treatment Emergent Adverse Events 
 TFLs     Tables, Figures, Listings 
 TKI 
Tyrosine Kinase Inhibitor  
 WHO World Health Organization 








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Study treatment start and end date 
Study treatment start date is defined as the first date when a non-zero dose of study drug is 
administered and recorded on the Drug Administration Record (DAR) CRF page. Similarly, 
study drug end date is defined as the last study drug administration date. 
Study day 
The study day is defined as: 
 •The date of the event (visit date, onset date of an event, assessment date etc.) – study reference 
start date + 1 if event is on or after the study treatment start date; 
•The date of the event (visit date, onset date of an event, assessment date etc.) − study reference 
start date if event precedes the study treatment start date. 
The reference start date for safety assessments (e.g. adverse event onset, laboratory abnormality 
occurrence, vital sign measurement, dose interruption etc.) is the start of study treatment. 
For events prior to study drug start date (e.g., time of diagnosis), study day will be negative and 
calculated as (event date – study drug start date). Note that study drug start date is study day 1.  
Due to the study drug dosing schedule, one month will be considered as 28 days. However, 
for “time since event” data (e.g., medical history), one month will be considered as 365.25/12 
days for events that occurred prior to study Day 1.  
Baseline  
Baseline (e.g. for laboratory parameters), is considered as the last available assessment or value 
before start of the first treatment, unless otherwise stated under the related assessment. For all 
relevant parameters comparisons against baseline will be presented through the report. Further, 
if several assessments are taken on the same day, the last assessment will be used for that time 
point. 
If patients have no value as defined above, the baseline result will be missing. 
Post Baseline assessment 
A post-baseline value refers to a measurement taken in the Treatment phase from Study Day 1 
onwards. For patients who discontinued study treatment, all assessments listed in End of 
Study (EOS) visit will be performed. 
Change from baseline:  
When change from baseline is of interest, the following formula will be used for each scheduled 
visit where baseline and post-baseline values are both available: 
Change from baseline = post-baseline value – baseline value. 
 


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2.2 
Analysis sets 
Full Analysis Set (FAS), Safety Set, 
are defined in the protocol. 
However, as there are limited number of patients recruited in the study, any summary or 
statistical analysis will NOT be performed. Relevant data will be listed for all the patients. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Demographic and other baseline data including disease characteristics will be listed for all 
participants enrolled in the study. 
Relevant medical histories and current medical conditions at baseline will be listed as captured 
in the database for all participants. 
2.3.1 
Patient disposition 
A listing for data on the final status of the patient in the study will be provided. A data listing 
of screened patients who did not take study drug will be also provided with reasons for screening 
failure. 
2.3.2 
Patient demographics and other baseline characteristics 
Listings will be provided for demographic variables for all patients. 
Data to be collected on participant characteristics at screening include: 
• 
Other background or relevant medical history (prior antineoplastic therapies 
(medications, radiation, surgeries)  
• 
Prior antineoplastic therapies (medications, radiation, surgeries).  
• 
Other assessments to be completed for the purpose of determining eligibility (ECOG 
performance status, complete physical examination [only recorded in source documentation], 
vital signs, height, weight, hematology, blood chemistry, coagulation studies, urinalysis and 12-
Lead ECG)  
• 
Prior and current concomitant medications and surgical and medical procedures 
Medical history 
Medical history and current medical conditions will be listed by system organ class and 
preferred term of the Medical Dictionary for Drug Regulatory Affairs (MedDRA) dictionary. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The duration of exposure to capmatinib will be presented in days. All the dosing related data 
will be listed. Due to the limited number of patients recruited to the study analysis will not be 
performed. 


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2.4.2 
Prior, concomitant and post therapies 
Prior and concomitant medications/significant non-drug therapies will be listed in all patients. 
• 
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment.  
• 
Concomitant medications are medications that started on or after the first dose of study 
drug and before 30 days after the last dose of the treatment or started before the first dose of 
study drug and continued after the first dose of study drug. 
Listings will be provided for patients receiving prior and concomitant medication or significant 
non-drug therapy will be presented separately, by Anatomical Therapeutic Classification (ATC) 
class and preferred term. 
Surgical and medical procedures will be listed by primary system organ class and MedDRA 
preferred term. 
All medications (excluding study treatment and prior antineoplastic treatments), blood 
transfusions, surgeries and procedures (including physical therapy) administered within 28 days 
prior to the first dose administration of study drug through 30 days after the last dose of study 
drug will be recorded in the Concomitant Medications or Surgical and Medical Procedures 
eCRF, respectively. Medications include not only physician prescribed medications, but also 
all over-the counter medications, herbal medications, food supplements and vitamins. 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
Due to limited number of patients the primary endpoint will not be analyzed using statistical 
methods mentioned in the protocol. The Residual Viable Tumor assessments data (both local 
and central review), related to the primary endpoint will be listed for all the patients: 
2.5.3 
Handling of missing values/censoring/discontinuations 
Not applicable. 
2.5.4 
Supportive analyses 
Due to the limited number of patients, no statistical analysis will be performed. 
2.6 
Analysis of the key secondary objective 
Not applicable. 




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2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
12- lead ECGs including RR, PR, QRS, QT, QTcF, and HR intervals will be obtained for each 
participant during the study. ECG data will be read and interpreted locally.  
All ECG data will be listed by subject and visit. 
2.8.4.2 
Vital signs 
Vital signs include blood pressure, pulse measurement, respiratory rate, body temperature, 
Height and Body weight.  
Vital signs will be measured at screening and at subsequent time points. Height will be 
measured at screening and Body weight will be measured at screening and at subsequent time 
points. Listings will be presented for all patients. 
2.8.4.3 
ECOG performance status 
The Eastern Cooperative Oncology Group (ECOG) performance status will be assessed 
according to the PS scale as specified in the table below. 
 
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 
2.8.4.4 
Pregnancy Test 
Not applicable. 
 
   
 
 
 
 
 
 
 




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CINC280AUS12 
 
5.1.2 
AE date imputation 
5.1.2.1 
AE Start Date Imputation  
Not applicable. 
5.1.2.2 
AE End Date Imputation  
Not applicable. 
 
5.1.3 
Concomitant medication date imputation 
5.1.3.1 
Concomitant medication start date imputation 
Not applicable. 
5.1.3.2 
Concomitant medication end date imputation 
Not applicable. 
5.1.3.3 
Prior therapies date imputation 
Not applicable. 
5.1.3.4 
Post therapies date imputation 
Not applicable. 
5.1.3.5 
Other imputations 
Not applicable. 
5.2 
AEs coding/grading 
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. 
The verbatim term recorded on CRF will be identified as adverse event and will be coded by 
primary system organ class and preferred term using MedDRA version 20.1 and above. AEs 
will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0. 
 
5.3 
Laboratory parameters derivations 
Not applicable. 
5.4 
Statistical models 
5.4.1 
Primary analysis 
Not applicable. 


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CINC280AUS12 
 
5.4.2 
Key secondary analysis 
Not applicable. 
5.5 
Rule of exclusion criteria of analysis sets  
Not applicable. 
6 
Reference 
1. 
CINC280AUS12--v01-Clinical Trial Protocol_21Mar2023