A Randomized, Open Label, Multicenter Phase II Study Evaluating the Efficacy and Safety of Capmatinib (INC280) Plus Pembrolizumab Versus Pembrolizumab Alone as First Line Treatment for Locally Advanced or Metastatic Non-small Cell Lung Cancer With PD-L1≥ 50%
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer (NSCLC)
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development
INC280/Capmatinib
Clinical Trial Protocol CINC280I12201 / NCT04139317
A randomized, open label, multicenter phase II study 
evaluating the efficacy and safety of capmatinib (INC280) 
plus pembrolizumab versus pembrolizumab alone as first 
line treatment for locally advanced or metastatic non-small 
cell lung cancer with PD-L1≥ 50%
Document type:
Amended Protocol Version
EUDRACT number:
2019-002660-27
Version number:
v03 (Clean)
Clinical trial phase:
II
Release date:
21-Apr-2021
Property of Novartis 
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 2.0 (01-Aug-2018)
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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 3 (21-Apr-2021) ............................................................................................13
Amendment 2 (17-Feb-2020) ............................................................................................17
Amendment 1 (05-Nov-2019) ...........................................................................................19
Protocol summary..............................................................................................................20
1
Introduction........................................................................................................................23
1.1
Background............................................................................................................23
1.1.1
MET and capmatinib (INC280).............................................................24
1.1.2
Combination of capmatinib with a checkpoint inhibitor.......................27
1.2
Purpose...................................................................................................................28
2
Objectives and endpoints...................................................................................................29
3
Study design.......................................................................................................................30
4
Rationale ............................................................................................................................31
4.1
Rationale for study design......................................................................................31
4.2
Rationale for dose/regimen and duration of treatment...........................................31
4.3
Rationale for choice of combination drugs............................................................32
4.4
Purpose and timing of interim analyses.................................................................32
4.5
Risks and benefits ..................................................................................................32
4.6
Rationale for public health emergency mitigation procedures ..............................33
5
Population ..........................................................................................................................33
5.1
Inclusion criteria ....................................................................................................33
5.2
Exclusion criteria ...................................................................................................35
6
Treatment...........................................................................................................................38
6.1
Study treatment ......................................................................................................38
6.1.1
Investigational and control drugs ..........................................................38
6.1.2
Additional study treatments...................................................................39
6.1.3
Treatment arms......................................................................................39
6.1.4
Treatment duration ................................................................................39
6.2
Other treatment(s) ..................................................................................................40
6.2.1
Concomitant therapy .............................................................................40
6.2.2
Prohibited medication............................................................................43
6.3
Subject numbering, treatment assignment, randomization....................................44
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6.3.1
Subject numbering.................................................................................44
6.3.2
Treatment assignment, randomization...................................................44
6.4
Treatment blinding.................................................................................................45
6.5
Dose escalation and dose modification..................................................................45
6.5.1
Dose modifications................................................................................45
6.5.2
Follow-up for toxicities.........................................................................53
6.6
Additional treatment guidance...............................................................................59
6.6.1
Treatment compliance ...........................................................................59
6.6.2
Emergency breaking of assigned treatment code ..................................59
6.7
Preparation and dispensation .................................................................................59
6.7.1
Handling of study treatment..................................................................60
6.7.2
Instruction for prescribing and taking study treatment..........................60
7
Informed consent procedures.............................................................................................62
8
Visit schedule and assessments..........................................................................................64
8.1
Screening................................................................................................................71
8.1.1
Information to be collected on screening failures .................................71
8.2
Subject demographics/other baseline characteristics.............................................72
8.3
Efficacy..................................................................................................................72
8.3.1
Efficacy assessments .............................................................................72
8.3.2
Appropriateness of efficacy assessments ..............................................75
8.4
Safety .....................................................................................................................75
8.4.1
Laboratory evaluations..........................................................................76
8.4.2
Electrocardiogram (ECG)......................................................................77
8.4.3
Pregnancy and assessments of fertility..................................................78
8.4.4
Appropriateness of safety measurements ..............................................78
8.5
Additional assessments ..........................................................................................78
8.5.1
Pharmacokinetics and immunogenicity assessments ............................78
81
9
Study discontinuation and completion...............................................................................83
9.1
Discontinuation......................................................................................................83
9.1.1
Discontinuation of study treatment .......................................................83
9.1.2
Withdrawal of informed consent...........................................................84
9.1.3
Lost to follow-up...................................................................................85
9.1.4
Early study termination by the sponsor.................................................85
9.2
Study completion and post-study treatment...........................................................85
9.2.1
End of study...........................................................................................85
9.2.2
Follow up...............................................................................................86
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10 Safety monitoring and reporting........................................................................................87
10.1
Definition of adverse events and reporting requirements......................................87
10.1.1
Adverse events.......................................................................................87
10.1.2
Serious adverse events...........................................................................89
10.1.3
SAE reporting........................................................................................90
10.1.4
Pregnancy reporting...............................................................................90
10.1.5
Reporting of study treatment errors including misuse/abuse ................91
10.2
Additional Safety Monitoring................................................................................91
10.2.1
Data Monitoring Committee..................................................................91
10.2.2
Steering Committee...............................................................................92
11 Data collection and database management ........................................................................92
11.1
Data collection .......................................................................................................92
11.2
Database management and quality control ............................................................92
11.3
Site monitoring.......................................................................................................93
12 Data analysis and statistical methods.................................................................................94
12.1
Analysis sets...........................................................................................................94
12.1.1
Full Analysis Set....................................................................................94
12.1.2
Per-Protocol Set.....................................................................................94
12.1.3
Safety Set...............................................................................................94
12.1.4
Pharmacokinetic Analysis Sets..............................................................95
12.2
Subject demographics and other baseline characteristics ......................................95
12.3
Treatments..............................................................................................................95
12.4
Analysis of the primary endpoint(s).......................................................................96
12.4.1
Efficacy endpoints.................................................................................96
12.5
Analysis of secondary endpoints............................................................................97
12.5.1
Efficacy and/or pharmacodynamic endpoint(s).....................................97
12.5.2
Safety endpoints ....................................................................................98
12.5.3
Pharmacokinetics.................................................................................100
101
101
101
102
102
102
12.7
Interim analyses ...................................................................................................102
12.8
Sample size calculation........................................................................................102
13 Ethical considerations and administrative procedures.....................................................104
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13.1
Regulatory and ethical compliance......................................................................104
13.2
Responsibilities of the investigator and IRB/IEC................................................104
13.3
Publication of study protocol and results.............................................................104
13.4
Quality Control and Quality Assurance...............................................................104
14 Protocol adherence...........................................................................................................105
14.1
Protocol amendments...........................................................................................105
15 References........................................................................................................................106
16 Appendices.......................................................................................................................110
16.1
Appendix 1: Guidelines for Response, Duration of Overall Response, TTF, 
TTP, Progression-Free Survival, and Overall Survival (based on RECIST 1.1).110
16.1.1
Introduction .........................................................................................111
16.1.2
Efficacy assessments ...........................................................................111
16.1.3
Efficacy definitions .............................................................................121
16.1.4
Data handling and programming rules ................................................132
16.1.5
References (available upon request)....................................................136
137
137
137
140
16.3
Appendix 3: Bayesian model set-up and prior specifications..............................140
16.3.1
Statistical model ..................................................................................140
16.3.2
Prior specifications..............................................................................140
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List of tables
Table 2-1
Objectives and related endpoints...........................................................29
Table 4-1
Rationale for study design.....................................................................31
Table 6-1
Investigational and control drugs ..........................................................38
Table 6-2
Capmatinib: drugs to be used with caution during co-
administration – obsolete upon approval of protocol amendment 03 ...42
Table 6-3
Capmatinib: Prohibited medications – obsolete upon approval of 
protocol amendment 03.........................................................................44
Table 6-4
Drugs with a known risk of Torsades de Pointes – obsolete upon 
approval of protocol amendment 03......................................................44
Table 6-5
Dose reduction steps for capmatinib – obsolete upon approval of 
protocol amendment 03.........................................................................47
Table 6-6
Criteria for dose reduction / interruption and re-initiation of 
capmatinib treatment for adverse drug reactions – obsolete upon 
approval of protocol amendment 03......................................................47
Table 6-7
Follow-up evaluations for selected toxicities – obsolete upon 
approval of protocol amendment 03......................................................53
Table 6-8
Dose and treatment schedule.................................................................61
Table 8-1
Allowable visit windows.......................................................................65
Table 8-2
Assessment Schedule – obsolete upon approval of protocol 
amendment 03 .......................................................................................66
Table 8-2b
Assessment Schedule – applicable upon approval of protocol 
amendment 03 .......................................................................................70
Table 8-3
Imaging Assessment Collection Plan – not mandated upon 
approval of protocol amendment 03......................................................72
Table 8-4
Assessments & Specifications – not mandated upon approval of 
protocol amendment 03.........................................................................75
Table 8-5
ECOG Performance Status....................................................................76
Table 8-6
Laboratory Assessments – not mandated upon approval of protocol 
amendment 03 .......................................................................................76
Table 8-7
Capmatinib pharmacokinetic blood collection log for the first 8 
enrolled subjects in combination treatment arm – obsolete upon 
approval of protocol amendment 03......................................................79
Table 8-8
Capmatinib pharmacokinetic blood collection log for rest of 
subjects other than first 8 enrolled subjects in combination 
treatment arm – obsolete upon approval of protocol amendment 03 ....80
Table 8-9
Pembrolizumab pharmacokinetic and immunogenicity blood 
collection log – obsolete upon approval of protocol amendment 03.....80
 
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Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse..........................................................................................91
Table 12-1
Non-compartmental pharmacokinetic parameters...............................101
Table 12-2
Operating characteristics for scenarios with 96 subjects and 50 
events at the primary analysis..............................................................103
Table 16-1
Response criteria for target lesions......................................................117
Table 16-2
Response criteria for non-target lesions ..............................................119
Table 16-3
Overall lesion response at each assessment.........................................121
Table 16-4
Overall lesion response at each assessment: patients with non-
target disease only ...............................................................................129
Table 16-5
Options for event dates used in PFS, TTP, duration of response........130
139
Table 16-7
Probabilities to declare a success under various scenarios..................145
List of figures
Figure 3-1
Study Design .........................................................................................30
Figure 16-1
Full prior distribution for capmatinib + pembrolizumab PFS.............141
Figure 16-2
Full prior distribution for pembrolizumab PFS...................................143
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List of abbreviations
Ab
Antibody
ADA
Antidrug antibodies
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
APTT
Activated partial thromboplastin time
ASCO
American Society for Clinical Oncology 
AST
Aspartate aminotransferase
ATP
Adenosine triphosphate
AUC
Area under the curve
BAL
Bronchoalveolar lavage
BCRP
breast cancer resistance protein
b.i.d.or BID
bis in die/twice a day/ twice daily
BMI
Body mass index
BUN
Blood urea nitrogen
CNS
Central nervous system
CR
Complete response
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSR
Clinical study report
CT
Computed tomography
CTC
Common Terminology Criteria
CTT
Clinical Trial Team
CV
coefficient of variation
DBP
Diastolic blood pressure 
DCR
Disease control rate
DDI
Drug-drug interactions
DILI
Drug-induced liver injury
DLCO
Diffusing capacity corrected for hemoglobin
DMC
Data Monitoring Committee
DOR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic data capture
ELISA
Enzyme-linked immunosorbent assay
EOT
End of treatment
eSAE
Electronic serious adverse event
ESMO
the European Society for Medical Oncology
eSource
Electronic source
FAS
Full analysis set
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
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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
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HIV
Human Immunodeficiency Virus
HGF
Hepatocyte growth factor
HR
Hazard ratio
IB
Investigator’s Brochure
ICF
Informed consent form
IUD
Intrauterine device
IUS
Intrauterine system
IEC
Independent Ethics Committee
IG
Immunogenicity
ILD
Interstitial lung disease
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent-to-treat
i.v.
intravenous
LDH
lactate dehydrogenase
LFTs
Liver function tests 
LLN
lower limit of normal
LLOQ
lower limit of quantification
mg
milligram(s)
mL
milliliter(s)
MRI
Magnetic resonance imaging
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
NCCN
National Comprehensive Cancer Network
NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
PD
Pharmacodynamic(s)
PET
Positron emission tomography
PFS
Progression-free survival
PFT
Pulmonary function tests
PK
Pharmacokinetic(s)
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p.o.
oral(ly)
PPS
Per-Protocol Set
PR
Partial response
PT
prothrombin time
PTT
Partial Thromboplastin Time
Q2W
Once every 2 weeks
Q3W
Once every 3 weeks
QMS
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
RECIST
Response Evaluation Criteria In Solid Tumors
RP2D
Recommended phase two dose
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SBP
Systolic blood pressure
SC
Steering Committee
SD
standard deviation or stable disease
SmPC
Summary of Product Characteristics
SpO2
Oxygen saturation
TKI
Tyrosine kinase inhibitor
TMB
Tumor Mutational Burden
TPS
Tumor proportion score
TSH
Thyroid Stimulation Hormone
TTR
Time-to-response
ULN
upper limit of normal
VATS
Video-assisted thoracic surgery
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 subject 
Cohort
A specific group of subjects 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 subject 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 subject or 
at a later point in time as defined by the protocol 
Enrollment
Point/time of subject entry into the study at which informed consent must 
be obtained 
Investigational drug
The drug whose properties are being tested in the study
Medication number
A unique identifier on the label of medication kits
Other treatment
Treatment that may be needed/allowed during the conduct of the study 
(i.e. concomitant or rescue therapy)
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 subjects with established 
disease and in those with newly-diagnosed disease
Patient
An individual with the condition of interest for the study
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and 
will be used in clinical trial database setup and eventually in analysis
Personal data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples. 
Premature subject 
withdrawal
Point/time when the subject 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
Randomization 
number
A unique identifier assigned to each randomized subject
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Screen Failure
A subject 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 
(Electronic Source)
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 subject
Study treatment
Any single drug or combination of drugs or intervention administered to 
the subject as part of the required study procedures
Study treatment 
discontinuation
When the subject 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 
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject and 
should be used to identify the subject throughout the study for all data 
collected, sample labels, etc.
Treatment arm
A treatment arm defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts.
Variable
A measured value or assessed response that is determined from specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study
Withdrawal of study 
consent (WoC)
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer and does not allow any further 
collection of personal data 
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Amendment 3 (21-Apr-2021)
Amendment rationale
The main purpose of this amendment is to modify the study conduct and data analysis following 
the enrollment halt on 21-Jan-2021 due to lack of tolerability observed in the capmatinib plus 
pembrolizumab arm. The decision to halt enrollment, supported by the Data Monitoring 
Committee (DMC), was made based on the observation that subjects who receive capmatinib 
plus pembrolizumab combination treatment had higher rates of SAEs/AEs, leading to dose 
interruption and/or discontinuation of both study treatments compared to subjects in the 
pembrolizumab single agent arm.
Immediately following the enrollment halt, below procedural changes have been performed:

Capmatinib treatment was discontinued in subjects on the combination arm. All 
ongoing subjects continue to receive single-agent pembrolizumab, a registered and 
commercialized treatment for the study indication. 

Randomization information was released to the clinical trial team.

Termination of capmatinib PK sample collection, effective 21-Jan-2021

Termination of pembrolizumab PK/IG sample collection as per memorandum dated 
04-Feb-2021
This protocol amendment incorporates significant changes as follow:

To simplify the study procedures,  
-
As pembrolizumab is a registered and commercialized treatment for the study 
indication, the efficacy and safety assessments will be performed as per each 
institution's standard of care. The efficacy and safety assessment results (except 
reporting of adverse events, see next bullet point) will no longer be captured in 
the eCRF. Centralized collection of imaging data will not be performed.
-
The reporting of adverse events, including serious adverse events, and associated 
concomitant medication will remain to be captured in the eCRF until 30 days 
following the last administration of study treatment.

To refine the definition of end of study as the earliest occurrence of one of the 
following:
-
discontinued study treatment and completed the safety FU or
-
died or
-
withdrawn consent or
-
been lost to follow-up.

To allow earlier disbandment of DMC, as an independent review of safety and 
efficacy data will not be required after the release of randomization information to the 
study team.
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
To cancel the originally planned administrative interim analysis when approximately 
30 PFS events have been observed and the primary analysis when 50 PFS events have 
been observed, and adjust the planned data analysis and statistical methods: 
-
The analysis of primary efficacy endpoints will now be based on Kaplan-Meier 
analysis of PFS of the two treatment arms. Halting of further enrolment, 
discontinuation of capmatinib in subjects on the combination arm and the 
stopping of efficacy data collection as of this amendment would make the 
previously planned Bayesian PFS analyses uninterpretable.
-
The definition of PFS endpoint is updated to consider censoring of subjects 
before the start of a subsequent anti-neoplastic therapy, as it is considered more 
appropriate for NSCLC patients. 
-
For subjects on the combination arm, PFS and BOR will also be censored before 
the date of sponsor’s decision to discontinue capmatinib, as hereafter the 
treatment will be switched to pembrolizumab alone. In addition, to explore the 
potential lasting effect of capmatinib, supportive analyses on PFS and BOR will 
also be performed based on all available tumor assessments irrespective of 
sponsor’s decision to discontinue capmatinib. 
This protocol amendment will also incorporate the following changes: 

To allow flexibility when conducting palliative radiotherapy during the study, 
radiotherapy with palliative intent, including but not limited to analgesic purposes or 
for lytic lesions at risk of fracture, may be carried out if required.

To align pembrolizumab handling and treatment with the drug’s approved label,
-
The recommended treatment modifications and follow up for toxicities will refer 
to locally approved label for pembrolizumab. 
-
Treatment beyond disease progression with pembrolizumab will not be allowed 
as part of this study.

Since all ongoing subjects continue to receive single-agent pembrolizumab, a 
registered and commercialized treatment for the study indication, subjects are allowed 
to be transitioned to commercial pembrolizumab and discontinued from the study.

Single-agent pembrolizumab is a well-established standard treatment for the study 
indication, therefore disease progression follow-up and survival follow-up will not be 
performed. Information on antineoplastic therapies after study treatment 
discontinuation will not be collected.

The assessment of benefit/risk concluded the absence of additional risks related to 
COVID-19. To ensure subject safety and trial integrity during a public health 
emergency, mitigation procedures are added in the relevant sections. 
Other minor changes and corrections are made throughout the protocol for consistency and/or 
clarification.
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Study update
As of 21-Jan-2021 when enrollment was halted, 76 out of the targeted 96 subjects had been 
randomized, including 51 subjects in capmatinib plus pembrolizumab arm and 25 subjects in 
pembrolizumab alone arm. As of 15-Mar-2021, 50 subjects are ongoing in this trial with single-
agent pembrolizumab treatment. 
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Protocol Summary: updated Population, Study treatment and Data analysis

Section 3: added a footnote to indicate capmatinib treatment discontinuation

Section 4.4: added that the planned administrative interim analysis will not be performed

Section 4.5: added the assessment for pembrolizumab single agent treatment

Section 4.6: added this new section Rationale for public health emergency mitigation 
procedures

Section 6.1: added conditions for pembrolizumab treatment continuation and 
discontinuation

Section 6.1.4.1: added that treatment beyond disease progression will no longer be 
allowed

Section 6.2.1.1: updated the condition when radiotherapy is allowed

Section 6.4: added that randomization information was released to CTT after enrollment 
halt

Section 6.5.1: added that recommended treatment modifications for pembrolizumab 
should refer to the locally approved label and removed former Table 6-5

Section 6.5.2: added that toxicity follow-up should refer to the locally approved label of 
pembrolizumab

Section 7 and Section 8: added mitigation procedures under public health emergency

Section 8: added Table 8-2b for updated assessment schedule

Section 8.2: added the purpose of collecting subject race and ethnicity information

Section 8.3 and Section 8.4: added that efficacy and safety assessments will be performed 
as per each institution’s standard of care, and that imaging data will no longer be centrally 
collected

Section 8.5.1 and Section 8.5.2: added that PK/IG 
 sample collection has 
been terminated

Section 9.1.1: updated the condition for discontinuation of study treatment, and the 
procedures after treatment discontinuation 

Section 9.2.1: updated the definition of end of study

Section 9.2.2.1: added that antineoplastic therapies since discontinuation of study 
treatment will not be collected

Section 9.2.2.2 and Section 9.2.2.3: added that disease progression follow-up and survival 
follow-up will not be performed
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
Section 10.2.1: added that DMC will be disbanded since randomization information has 
been released to CTT 

Section 12: removed the primary analysis planned to be performed prior to the final CSR, 
and clarified the analysis of all primary and secondary endpoints will be performed after 
the end of the study

Section 12.1.2: removed the definition of Per-Protocol Set (PPS) since no supportive 
analysis based on PPS will be performed 

Section 12.4.1: removed the statement of primary objectives and updated the primary 
endpoint estimation.

Section 12.4.1.2: updated the statistical analysis method to be used for the primary 
analysis of the primary endpoint PFS

Section 12.4.1.3: changed the definitions of primary analyses of PFS regarding the 
censoring of the patient before the start of a subsequent anti-neoplastic therapy or the 
discontinuation of capmatinib due to sponsor’s decision 

Section 12.4.1.4: updated the supportive analyses for the primary endpoint

Section 12.5: updated the secondary efficacy endpoint estimation

Section 12.5.1: added the censoring rules for the definitions of BOR, TTR and DOR.

Section 12.5.3: updated the PK parameters for capmatinib and pembrolizumab

Section 12.7: removed the planned administrative interim analysis 
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
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Amendment 2 (17-Feb-2020) 
Amendment rationale
The main purpose of this amendment is to address Health Authorities’ requests as listed below:

To add background clinical pharmacology information for capmatinib

To exclude patients with active infection or history of allogeneic tissue/organ 
transplantation and to provide the recommended treatment modifications for 
pembrolizumab in details, in order to align with the EU Summary of Product 
Characteristics (SmPC) for pembrolizumab

To interrupt capmatinib treatment in case of hypersensitivity reactions, as SAEs of 
hypersensitivity have been reported as suspected to be related to study treatment in the 
capmatinib IB

To clarify that SAE reporting is required for any progression of malignancy suspected to 
be related to study treatment and meeting the SAE definition 

To conduct a safety review by DMC after the first 6 randomized patients have been 
followed up for at least 6 weeks from randomization or have discontinued earlier 
In addition, after a recent occurrence of a case of myocarditis, the dose modification guidelines 
for protocols using capmatinib in combination with PD-1 inhibitors have been updated to 
mandate permanent discontinuation of study treatment in case of myocarditis grade ≥2 or other 
cardiac event grade ≥3. The recommended clinical management guidelines in case of such an 
event have also been provided.
Also, to align with clinical practice, if a patient’s HCV antibody (Ab) test is negative, then 
further HCV RNA testing is not required. 
Other minor changes and corrections were made throughout the protocol for consistency and/or 
clarification.
Study update
As of 22-Jan-2020, one patient is being screened and no subject has been treated in this trial.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Section 1.1.1: added background clinical pharmacology information for capmatinib 

Section 5.2: excluded patients with active infection or history of allogeneic tissue/organ 
transplantation

Section 6.2.1.1: removed “while taking capmatinib” to clarify that the permitted 
concomitant medications apply to all subjects

Section 6.5.1: 

added recommendation in case the causality of toxicity cannot be clearly attributed

added Table 6-5 Recommended treatment modifications for pembrolizumab
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
Table 6-7: 

clarified definition of grade 3 and 4 febrile neutropenia as per CTCAE v5.0

added dose modifications for capmatinib in case of myocarditis or other cardiac event

added dose modifications for capmatinib in case of hypersensitivity reaction

Section 7: listed the informed consents included in this study

Section 8.3.1: corrected the baseline imaging assessment period from prior to “the first 
dose of study treatment” to prior to “randomization”

Table 8-6: specified HBcAb should test for IgG, added HCV Ab as a hepatitis marker, and 
clarified when HBV DNA and HCV RNA tests are not required. 

Section 10.1.1: clarified progression of malignancy must be reported as an SAE if the 
investigator considers it is related to study treatment and meets the SAE definition

Section 10.2.1: added a safety review by DMC after the first 6 randomized patients have 
been followed up for at least 6 weeks from randomization or have discontinued earlier

Section 12.7: clarified that development decisions will be made by a Novartis Committee 
based on interim analysis results 
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
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Amendment 1 (05-Nov-2019)
Amendment rationale 
The main purpose of this amendment is to address Health Authorities’ requests to provide 
specific recommendations of concomitant medications to treat diarrhea and nausea toxicities.
In addition, free T3 testing was removed from thyroid function monitoring, and total T3 will be 
tested if abnormal thyroid function is suspected. This change is made to be in line with standard 
clinical practice.  
Unintended references to central ECG monitoring for cardiac toxicity follow up were removed 
to reflect the study conduct.
Other minor changes and corrections were made throughout the protocol for consistency and/or 
clarification.
Study update
As of 05-Nov-2019, no subjects have been screened or treated in this trial.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Table 6-7: The descriptions of central ECG were removed. Follow-up evaluations for 
toxicities “Diarrhea” and “Nausea and Vomiting” were updated. 

Table 8-2, 8-6: Modified the thyroid panel. 

Section 15 References: A newly cited reference was added.
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.
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Protocol summary
Protocol number
CINC280I12201
Full Title
A randomized, open-label, multicenter phase II study evaluating the 
efficacy and safety of capmatinib (INC280) plus pembrolizumab versus 
pembrolizumab alone as first line treatment for locally advanced or 
metastatic non-small cell lung cancer with PD-L1≥ 50% 
Brief title
Study of efficacy and safety of capmatinib in combination with 
pembrolizumab versus pembrolizumab alone in subjects with non-small 
cell lung cancer with PD-L1≥ 50%
Sponsor and Clinical 
Phase
Novartis, Phase II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose is to evaluate the efficacy and safety of the combination of 
capmatinib with pembrolizumab compared to pembrolizumab alone as 
first-line treatment for subjects with locally advanced or metastatic 
NSCLC who have PD-L1 expression ≥ 50% and have no EGFR mutation 
or ALK rearrangement. 
Capmatinib has demonstrated immunomodulatory activities when 
combined with an anti-PD1 antibody in preclinical tumor models 
irrespective of MET dysregulation. The combination of capmatinib with 
checkpoint inhibitors has been established to be tolerable and could 
provide additional clinical benefit to the subjects.
Primary Objective(s) 
To evaluate the efficacy of capmatinib plus pembrolizumab in 
comparison to pembrolizumab alone by assessing progression-free 
survival (PFS) based on local investigator assessment per RECIST 1.1.
Secondary Objectives
Objective 1: To evaluate the anti-tumor activity of capmatinib plus 
pembrolizumab in comparison to pembrolizumab alone, by assessing 
Objective response rate (ORR), disease control rate (DCR), time-to-
response (TTR) and duration of response (DOR) based on local 
investigator assessment as per RECIST 1.1 and overall survival (OS).
Objective 2: To characterize the safety profile of capmatinib plus 
pembrolizumab and pembrolizumab alone, by assessing the incidence 
and severity of AEs and SAEs, AEs leading to dose interruption, dose 
reduction and dose discontinuation.
Objective 3: To characterize the pharmacokinetics (PK) of capmatinib 
and pembrolizumab by measuring the PK parameters and concentration. 
Objective 4: To evaluate the prevalence and incidence of 
immunogenicity of pembrolizumab by assessing the antidrug antibodies 
(ADA) prevalence at baseline and ADA incidence on treatment of 
pembrolizumab.
Study design
This is a randomized, open-label, multicenter, phase II study evaluating 
the efficacy and safety of capmatinib plus pembrolizumab in comparison 
to pembrolizumab alone.  Subjects in both treatment arms will receive up 
to 35 cycles (~24 months) of study treatment.
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Population
The study will include male or female adult subjects diagnosed with 
advanced or metastatic, squamous or non-squamous non-small cell lung 
cancer (NSCLC), without EGFR or ALK alteration and with PD-L1 high 
expression (TPS≥ 50%) with no prior treatment for their metastatic or 
advanced disease.
Approximately 96 subjects will be randomized including 64 subjects in 
capmatinib plus pembrolizumab arm and 32 subjects in pembrolizumab 
alone arm. 
The study enrollment has been halted since 21-Jan-2021, when 76 
subjects had been randomized, including 51 subjects in capmatinib plus 
pembrolizumab arm and 25 subjects in pembrolizumab alone arm.
Key Inclusion criteria

Histologically confirmed and documented locally advanced stage 
III or stage IV NSCLC (per AJCC/IASLC v.8) for treatment in the 
first-line setting. Treatment with chemotherapy and/or radiation 
as part of neoadjuvant/adjuvant therapy (other than 
immunotherapies) is allowed as long as therapy was completed 
at least 6 months prior to the diagnosis of advanced or 
metastatic disease.

Both EGFR wild type status and ALK-negative rearrangement 
(tumor with BRAF V600 mutation or ROS-1 rearrangement will 
be excluded, if required by local guidelines)

High PD-L1 expression (TPS ≥ 50%).

At least one lesion evaluable by RECIST 1.1

ECOG performance status ≤ 1

Have adequate organ function
Key Exclusion criteria

Prior treatment with a MET inhibitor or HGF-targeting therapy

Prior immunotherapy (e.g. anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CTLA-4 antibody, or any other antibody or drug specifically 
targeting T-cell co-stimulation or immune checkpoint pathways).

Have known hypersensitivity to any of the excipients of 
capmatinib (crospovidone, mannitol, microcrystalline cellulose, 
povidone, sodium lauryl sulfate, magnesium stearate, colloidal 
silicon dioxide, and various coating premixes) or monoclonal 
antibodies.

Have untreated symptomatic central nervous system (CNS) 
metastases.

Have received or will receive a live vaccination within 4 weeks 
prior to first dose of study treatment.

Active hepatitis B or C
Study treatment

Capmatinib (INC280) plus pembrolizumab 

Pembrolizumab alone
Following the study enrollment halt, capmatinib treatment has been 
discontinued in all subjects. Ongoing subjects are treated with 
pembrolizumab alone.
Efficacy assessments

Tumor response assessment per RECIST 1.1 

Survival assessment 
Pharmacokinetic 
assessments

Concentration and pharmacokinetic (PK) parameters 

Pembrolizumab Immunogenicity (IG) 
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Key safety 
assessments

Monitoring of laboratory assessments in blood and urine

Adverse event monitoring

Pregnancy tests in blood and urine
Other assessments 
Data analysis
 The analysis of primary efficacy endpoints will be based on Kaplan-
Meier curves for PFS as well as estimated median PFS along with their 
two-sided 95% confidence intervals for each treatment arm. The full 
analysis set (FAS) will be used.
The secondary endpoints (overall response rate (ORR), disease control 
rate (DCR), time to response (TTR), duration of response (DOR) and 
overall survival (OS) will be analyzed based on FAS and presented by 
treatment arms. 
Aggregated safety data analysis will be performed and reviewed by the 
Data monitoring committee (DMC) on a regular basis. The first review 
will occur after the first 6 randomized patients have been followed up for 
at least 6 weeks from randomization or have discontinued earlier. The 
second review will occur after the first 12 randomized patients have been 
followed up for at least 6 weeks from randomization or have 
discontinued earlier. Subsequent reviews on safety data will be 
conducted every 6 months. Following the enrollment halt, the 
randomization information was released for internal data review and to 
address Health Authorities’ queries.  As a result, independent data 
review will not be performed and DMC will be disbanded. 
Key words
INC280, capmatinib, pembrolizumab, NSCLC, PD-L1, EGFR wild type, 
ALK, MET inhibitor, squamous, non-squamous
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1
Introduction
1.1
Background
Lung cancer is the leading cause of cancer death. In 2012, an estimated 1.8 million people were 
diagnosed with lung cancer globally, resulting in 1.6 million deaths (Ferlay et al 2015). In 2019, 
an estimated 228,150 new cases (116,440 in men and 111,710 in women) will be diagnosed in 
the United States, and 142,670 deaths are estimated because of the disease (Siegel et al 2019). 
Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are the two main types 
of lung cancer, accounting for 80-85% and 10-15% of cases respectively. The majority (70%) 
of NSCLC patients present with advanced disease (Molina et al 2008). Only 25-30% of subjects 
present with surgically resectable disease, and only half of them are disease-free at 5 years 
(Molina et al 2008, Maeda et al 2010, American Community Survey 2012). For early-stage 
NSCLC (stage I, selected node negative IIA), surgery is the treatment of choice. For patients 
with locally advanced NSCLC (inoperable stage II (node positive) and stage III disease), 
concurrent chemoradiation is the recommended treatment. (O’Rourke et al 2010, Curran et al 
2011, Sause et al 2000). Patients with advanced/metastatic NSCLC without targetable 
oncogenic drivers are usually treated with chemotherapy and immunotherapy. Patients with 
targetable alterations (such as sensitizing EGFR mutations, ALK rearrangement, BRAF V600E 
mutation, ROS-1 rearrangement, and NTRK gene fusion) are treated with targeted treatments 
(NCCN v15 2019).
The median overall survival of metastatic NSCLC patients treated with platinum–based doublet 
chemotherapy as first-line chemotherapy is 11-14 months (Gandhi et al 2018, Paz-Ares et al 
2018, Mok et al 2019). Maintenance therapy with pemetrexed is used in non-squamous NSCLC 
treatment to prolong response to therapy for responding patients or those whose disease is stable 
after first-line therapy. (Alimta®USPI 2004) (Alimta®SmPC 2009).
Immunotherapy has further shaped the treatment landscape of advanced NSCLC patients, both 
in the pretreated and treatment-naive setting. Monoclonal antibodies that block the interactions 
between PD-1 and immune suppressing ligands, PD-L1 and PD-L2 (nivolumab, durvalumab, 
pembrolizumab, and atezolizumab) have demonstrated significant activity as monotherapy and 
superiority over single agent chemotherapy in pretreated NSCLC (Novello et al 2016, 
Langer et al 2016, Antonia et al 2018). 
Durvalumab has been approved as consolidation therapy for patients with unresectable stage III 
NSCLC patients whose disease has not progressed following concurrent chemoradiation 
(Antonia et al 2018).
Pembrolizumab has been approved as a single agent in the first-line treatment of PD-L1 
expressing, locally advanced and metastatic NSCLC. The approval was based on the results of 
KEYNOTE-042 study (Mok et al 2019), a randomized, open-label, controlled, phase 3 study, 
comparing pembrolizumab with chemotherapy for previously untreated, PD-L1 ≥ 1%, locally 
advanced or metastatic NSCLC, which do not harbor EGFR or ALK aberrations. Survival 
benefit of pembrolizumab monotherapy over chemotherapy is seen in this study (mOS 16.7 vs 
12.1 months), but the result was largely driven by patients with high PD-L1 expression 
(TPS ≥ 50%) (mOS 20.0 vs 12.2 months). KEYNOTE-024, a randomized, open label, phase 3 
study, comparing pembrolizumab to platinum-based chemotherapies in previously untreated, 
stage IV NSCLC, with high PD-L1 expression, demonstrated that a high level of PD-L1 
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expression (TPS ≥ 50%) predicts response to pembrolizumab (Reck et al 2016). Approximately 
30% 
of 
advanced 
NSCLC 
patients 
have 
PD-L1 
high 
expression 
tumor 
(TPS ≥ 50%). Pembrolizumab has also been approved in combination with pemetrexed and 
platinum-doublet chemotherapy as first-line treatment of patients with metastatic 
non-squamous NSCLC, with no EGFR or ALK genomic tumor aberrations (Gandhi et al 2018), 
and in combination with carboplatin and either paclitaxel or albumin-bound paclitaxel as 
first-line treatment of patients with metastatic squamous NSCLC (Paz-Ares et al 2018).
Nivolumab has been approved for patients who have previously received chemotherapy for both 
squamous and non-squamous lung cancer on the basis of two randomized phase III trials 
(Borghaei et al 2015, Brahmer et al 2015) that demonstrated superior OS for nivolumab over 
docetaxel in both squamous and non-squamous NSCLC. In the first-line setting, nivolumab was 
not superior to platinum-based doublet chemotherapy in patients with PD-L1 ≥ 1% based on 
CheckMate-026 study (Carbone et al 2017). A second study, CheckMate-227, demonstrated 
Progression Free Survival (PFS) improvement of the combination of nivolumab and ipilimumab 
over chemotherapy in patients with high tumor mutational burden NSCLC (regardless of PD-
L1 levels) (Hellmann et al 2018).
Atezolizumab has been approved for previously treated NSCLC with progression on or 
following a platinum-containing regimen based on superior OS over docetaxel chemotherapy 
(Rittmeyer et al 2017) regardless of the PD-L1 expression and of the histology. In first-line 
treatment for non-squamous advanced NSCLC patients, atezolizumab in combination with 
bevacizumab plus platinum-based chemotherapy demonstrated PFS benefit over bevacizumab 
plus chemotherapy (Socinski et al 2018) with an improvement in OS (Socinski et al 2018) 
regardless of PD-L1 expression and EGFR or ALK genetic aberration. Additionally, these 
studies did not demonstrate any significant OS or PFS benefit in this setting between the 
additions of either atezolizumab or bevacizumab to a platinum-based chemotherapy. 
In first-line treatment of squamous NSCLC the addition of atezolizumab to carboplatin plus 
nab-paclitaxel in a phase III trial, IMpower 131, demonstrated a PFS benefit and the OS data is 
still awaited (Jotte et al 2018).  
1.1.1
MET and capmatinib (INC280)
In human malignant disease, 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 
promote proliferation, survival, motility and angiogenesis (Christensen et al 2005). 
Capmatinib is a small adenosine triphosphate (ATP) competitive, orally bioavailable, highly 
potent, and selective reversible inhibitor of the MET receptor tyrosine kinase (Liu et al 2011, 
Baltschukat et al 2019). In preclinical studies, capmatinib treatment induced tumor regression in 
cancer models with MET exon 14 skipping mutation, MET amplification, MET overexpression, or 
HGF-mediated autocrine MET activation (Liu et al 2011, Baltschukat et al 2019). 
Besides the role of MET in cancer, pre-clinical studies suggest that MET and its ligand 
hepatocyte growth factor (HGF) also function in immune cells, where MET activity leads to 
immunosuppression (Molnarfi et al 2015). Several mechanisms of MET/HGF-mediated 
immune suppression have been reported. For example, HGF was found to attract 
immunosuppressive MET-positive neutrophils to tumor and draining lymph nodes, which can 
be prevented by inhibition of MET on neutrophils using capmatinib (Glodde et al 2017). 
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In addition, activation of MET through HGF was found to drive the differentiation of dendritic 
cells towards a “tolerogenic” (i.e. immunosuppressive) phenotype (Rutella et al 2006), 
suggesting that MET inhibition could have a positive immunomodulatory effect on the 
activation of T cells by dendritic cells. Furthermore, it has also been reported that MET is 
expressed on a subset of cytotoxic T lymphocytes, suppressing their function when activated 
by HGF (Benkhoucha et al 2017). These observations demonstrate an immunomodulatory 
potential of MET and HGF by directly acting on immune cells, irrespective of MET 
dysregulation in the tumor. Consequently, MET inhibitors may restore immune cell function.
In support of this concept, two independent studies (Glodde et al 2017 and RD-2017-00370) 
using syngeneic mouse models representing several cancer types revealed that capmatinib can 
enhance T cell-mediated antitumor immunity when combined with anti-PD1 or other immuno-
oncology regimens. Importantly, capmatinib single agent activity was minimal or absent in all 
tested models. The capmatinib + anti-PD1 studies carried out at Novartis RD-2017-00370 
showed that combination treatment led to increased T cell infiltration as well as a higher cure 
rate than either single agent. Higher cure rates were also seen by (Glodde et al 2017), who 
proposed a reactive production of HGF in the inflamed tumor microenvironment, which led to 
recruitment of immunosuppressive MET-positive neutrophils. Prevention of this negative 
feedback loop by capmatinib was suggested to explain the combination benefit. However, the 
additional mechanisms involving MET-positive immune cells discussed above could also 
contribute to the observed enhancement of anti-tumor immunity when adding capmatinib to 
immuno-oncology treatments.
Clinical observations further support the hypothesis that HGF-mediated MET activation is 
immunosuppressive. In melanoma patients treated with anti-PD1 antibodies, an increase of 
serum HGF during treatment was seen in a subset of non-responders, but not in responders 
(Glodde et al 2017), which could be indicative of the HGF-mediated immunosuppressive 
feedback loop that was observed in mouse models. Furthermore, another study found that high 
baseline levels of serum HGF were associated with worse clinical outcomes of anti-PD1 
treatment in melanoma (Kubo et al 2019).
As of 28-Sep-2018, a total of 1253 cancer subjects and 236 non-cancer subjects have received 
capmatinib. 709 subjects have been treated with capmatinib as a single agent at different doses. 
The Maximum Tolerated Dose (MTD) for capmatinib as single agent was not reached. 
The recommended phase 2 dose (RP2D) for capmatinib as a single agent has been determined 
to be 400 mg twice daily (BID) in tablet formulation. Five hundred and forty-four subjects have 
been treated with capmatinib in combination therapies. Fourteen clinical studies with 
capmatinib are currently ongoing and 16 have been completed. Nineteen subjects have 
experienced 25 Dose Limiting Toxicities (DLTs): 6 subjects were in single agent studies and 
13 were in combination studies. 
Most of the reported adverse events (AEs) are mild or moderate in severity. The most frequent 
AEs suspected to be related to capmatinib of any grade reported in the largest single agent trial 
CINC280A2201 with 302 subjects were peripheral edema (40.4%), nausea (32.8%), increased 
blood creatinine (19.2%), vomiting (19.2%), decreased appetite (13.2%), fatigue (13.2%), and 
diarrhea (11.6%), with most of them being Grade 1/2. 
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The Grade 3/4 AEs suspected to be related to capmatinib in the CINC280A2201 study include 
peripheral edema (6.3%), increased lipase (5.0%), fatigue (3.3%), increased alanine 
aminotransferase (4.0%), vomiting (2.0%), nausea (1.7%), hypophosphataemia (1.7%), and 
increased aspartate aminotransferase (1.7%).
As of 28-Sep-2018, pneumonitis and interstitial lung disease (ILD) have been reported from 
both capmatinib single agent studies and combination studies with EGFR TKIs 
(Tyrosine kinase inhibitors), including events with fatal outcomes. In capmatinib single agent 
study CINC280A2201, 6 patients (2.0%) experienced suspected pneumonitis of any grade. 
Three patients (1.0%) experienced Grade 3/4 pneumonitis (1 with a fatal outcome) and two 
patients (0.7%) experienced Grade 3/4 interstitial lung disease and reported as suspected to be 
related to capmatinib treatment. All patients had multiple contributing factors including prior 
radiotherapy and prior therapy with checkpoint inhibitors, concurrent progressive disease of 
NSCLC. Careful monitoring of patients for signs and symptoms of pneumonitis in capmatinib 
studies is suggested, especially in combination studies with EGFR TKIs.
Recent clinical studies indicate that MET exon 14 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 2017). Based on the primary 
analysis of INC280A2201 study, single agent capmatinib has been designated with 
breakthrough therapy in patients with locally advanced or metastatic non-small cell lung cancer 
(NSCLC) harboring MET exon-14 skipping mutations. Overall response rate were 68% (95% 
CI: 47.6%-84.1%, N=28) for treatment-naive patients, and 41% (95% CI: 28.9%-53.1%, N=69) 
for previously treated patients. For more information, please refer to the current 
capmatinib Investigator’s Brochure. Overall, preclinical and early clinical data indicate that 
capmatinib has a manageable safety profile.
Pharmacokinetics (PK) data collected in clinical trials showed that capmatinib is rapidly 
absorbed after oral administration with a median time to reach maximum drug concentration 
(Tmax) ranging from 1 to 2 hours for tablets. The elimination half-life estimated from study 
CINC280X1101 ranged from 3.5 to 6.3 hours across the cohorts. Accumulation in capmatinib 
exposure following repeated administration of 400 mg BID tablets is low, with geometric mean 
accumulation ratio of 1.39-fold in the single agent CINC280A2201 study. The mean plasma 
exposure increase is roughly dose proportional for capmatinib tablet from 200 to 400 mg BID. 
The PK and safety of capmatinib administered with food has been evaluated in cancer patients 
in study CINC280A2108.  No significant difference in exposure was seen when capmatinib was 
given under fasted conditions or with food. The safety profile was similar to that of study 
CINC280A2201, with no dose-limiting toxicities (DLTs) observed. Given the above, 
capmatinib may be administered with or without food.
Capmatinib is a moderate CYP1A2 inhibitor and an inhibitor of P-gp, BCRP and MATE 
transporter.
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When co-administered with the strong CYP3A4 inhibitor itraconazole, capmatinib AUC 
increased by approximately 40% without any change in Cmax. When co-administered with the 
strong CYP3A4 inducer rifampicin, capmatinib AUC and Cmax decreased by 66% and 56%, 
respectively CINC280A2102. These findings suggest that capmatinib is not a sensitive substrate 
of CYP3A4.For further details, please refer to the latest version of the capmatinib Investigator’s 
Brochure.
1.1.2
Combination of capmatinib with a checkpoint inhibitor
There are several ongoing studies investigating the safety and efficacy of the combination of 
capmatinib and checkpoint inhibitors. Capmatinib is being studied with nivolumab in NSCLC 
and with spartalizumab in hepatocellular carcinoma (HCC). These studies have established a 
safety profile for capmatinib combined with checkpoint inhibitors and demonstrated some 
preliminary clinical efficacy. Overall, the safety of capmatinib plus nivolumab in study 
CEGF816X2201C and capmatinib plus spartalizumab in study CINC280X2108 is consistent 
with the safety profile of single agent capmatinib in study CINC280X2102.
1.1.2.1
Combination of capmatinib and nivolumab
The combination of capmatinib and nivolumab has been explored in the study 
CEGF816X2201C, an ongoing phase II, open-label, study of capmatinib in combination with 
nivolumab in adult subjects with advanced NSCLC (either in high cMET, defined as cMET 
IHC 3+ or IHC 2+ & GCN ≥ 5 or MET exon 14 mutations, or low cMET defined as those other 
than high cMET) who have progressed on standard chemotherapy and have not been treated 
with anti-PD(L)1 therapies. As of the data cut-off date of 3-Sep-2018, 44 patients (22 male and 
22 female) have been enrolled and treated with capmatinib 400 mg BID + nivolumab 3 mg/kg 
Q2W. The study has demonstrated the combination is safe and the toxicities are manageable. 
Preliminary data (cutoff by 03-Sep-2018) suggests the combination of capmatinib and 
nivolumab demonstrated higher 6-month PFS rate than that of historical data in nivolumab 
single agent or capmatinib single agent studies (CheckMate-057 and INC280X2102) in the high 
cMET group. Efficacy data (6 months PFS rate) in low cMET group will be analyzed when the 
data is mature. Efficacy signals shown in both high and low cMET groups warrant further 
investigation of capmatinib and checkpoint inhibitor combinations in NSCLC.
1.1.2.2
Combination of capmatinib and spartalizumab
CINC280X2108 is a dose escalation and expansion study evaluating the safety and efficacy of 
capmatinib in combination with spartalizumab (an investigational anti-PD1 antibody). This is 
an ongoing phase Ib/II, open-label, multi-center study of capmatinib in combination with 
spartalizumab or spartalizumab alone for the treatment of patients with advanced HCC who 
have progressed on sorafenib and have not been treated with anti-PD(L)1 therapies. 
As of the data cut-off date of 28-Sep-2018, 48 patients were enrolled in all arms of this study. 
27 patients were enrolled in the dose escalation (phase Ib) part at three different capmatinib 
dose levels (all capmatinib tablets): 200 mg BID capmatinib (N=6), 300 mg BID capmatinib 
(N=10) and 400 mg BID capmatinib (N=11), all in combination with 300 mg Q3W i.v. 
spartalizumab. The RP2D was determined as capmatinib 400 mg BID and spartalizumab 
300 mg Q3W. At the time of the cut-off, eleven patients were enrolled in the spartalizumab 
single agent arm of the phase II part of the study and 10 patients were enrolled into the 
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combination arm of capmatinib and spartalizumab. One phase Ib patient from the 400 mg BID 
capmatinib in combination with spartalizumab 300 mg Q3W cohort experienced a DLT of 
Grade 3 diarrhea which was suspected to be related to the study treatment. Thirty-seven patients 
(77.1%) experienced AEs of any grade which were suspected to be related to the study treatment. 
The most frequent AEs suspected to be related to the study treatment were peripheral edema 
(29.2%), nausea (18.8%), rash (18.8%), vomiting (18.8%), increased alanine aminotransferase 
(16.7%), and pruritus (16.7%), with most of them being Grade 1/2. Eighteen patients (37.5%) 
had Grade 3/4 AEs suspected to be related to study treatment which include increased aspartate 
aminotransferase (6.3%), nausea (4.2%), increased alanine aminotransferase (4.2%), asthenia 
(4.2%), increased lipase (4.2%), acute myocardial infarction (2.1%), adrenal insufficiency 
(2.1%), increased amylase (2.1%), anemia (2.1%), unstable angina (2.1%), increased blood 
bilirubin (2.1%), dehydration (2.1%), diarrhea (2.1%), peripheral edema (2.1%), hypotension 
(2.1%), immune-mediated hepatitis (2.1%), lichen planus (2.1%), liver injury (2.1%), 
neutropenia (2.1%), decreased platelet count (2.1%), pyrexia (2.1%), pruritic rash (2.1%), rash 
(2.1%), skin ulcer (2.1%), and systemic inflammatory response syndrome (2.1%). 
Seven patients (14.6%) experienced the following SAEs suspected to be related to the study 
treatment: acute myocardial infarction, adrenal insufficiency, dehydration, diarrhea, immune-
mediated hepatitis, infusion related reaction, pyrexia, rash pruritic, and blurred vision. The 
combination has been established to be tolerable within a HCC population and the toxicities are 
manageable. Efficacy data is not mature yet.
1.2
Purpose
Pembrolizumab is approved as monotherapy for the first-line treatment of NSCLC patients 
whose tumors have a PD-L1 expression ≥ 50% and no EGFR mutation or ALK rearrangement 
based on the results of KEYNOTE-024 (Reck et al 2016) and KEYNOTE-042 (Mok et al 2019). 
Capmatinib exhibits immunomodulatory activity in preclinical tumor models irrespective of 
MET dysregulation. The combination of capmatinib with checkpoint inhibitors has been 
established to be tolerable and could provide additional clinical benefit compared to the 
treatment of single agent checkpoint inhibitor. This study will evaluate the efficacy and safety 
of capmatinib combined with pembrolizumab in comparison to pembrolizumab as first-line 
treatment for subjects with locally advanced or metastatic NSCLC who have PD-L1 expression 
≥ 50% and have no EGFR mutation or ALK rearrangement. 
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2
Objectives and endpoints
Table 2-1
Objectives and related endpoints 
Objective(s)
Endpoint(s)
Primary Objective(s)
Endpoint(s) for primary objective(s) 
To evaluate the efficacy of capmatinib plus 
pembrolizumab in comparison to 
pembrolizumab alone
Progression-free survival (PFS) based on local 
investigator assessment as per RECIST 1.1
Secondary Objective(s)
Endpoint(s) for secondary objective(s)

To evaluate the anti-tumor activity of 
capmatinib plus pembrolizumab in 
comparison to pembrolizumab alone

To characterize the safety profile of 
capmatinib plus pembrolizumab and 
pembrolizumab alone

To characterize the pharmacokinetics 
of capmatinib and pembrolizumab 

To evaluate the prevalence and 
incidence of immunogenicity of 
pembrolizumab 

Objective response rate (ORR), disease control 
rate (DCR), time-to-response (TTR) and duration 
of response (DOR) based on local investigator 
assessment as per RECIST 1.1 and overall 
survival (OS)

Incidence and severity of AEs and SAEs, AEs 
leading to dose interruption, dose reduction and 
dose discontinuation

Pharmacokinetic parameters and concentration

Antidrug antibodies (ADA) prevalence at baseline 
and ADA incidence on treatment of 
pembrolizumab
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Objective(s)
Endpoint(s)
3
Study design
This is a randomized, open-label, multicenter, phase II study evaluating the efficacy and safety 
of capmatinib plus pembrolizumab in comparison to pembrolizumab alone as first line 
treatment for locally advanced or metastatic non-small cell lung cancer with PD-L1 expression 
≥ 50%, MET unselected, EGFR wild type and ALK negative. 
The study will enroll approximately 96 subjects in a ratio of 2:1 (capmatinib plus 
pembrolizumab vs pembrolizumab alone). The study will be stratified by histology (squamous 
vs non-squamous NSCLC). 
Figure 3-1
Study Design
** Following the study enrollment halt, capmatinib treatment has been discontinued in all subjects. 
Ongoing subjects are treated with pembrolizumab alone.
**
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4
Rationale
4.1
Rationale for study design
The rationale for the study design is described in the table below.
Table 4-1
Rationale for study design 
Study Design Aspect
Rationale
Randomization and the ratio 2:1
A randomized trial can eliminate bias in treatment 
assignment. 
The randomization ratio of 2:1 also increases the 
chances for subjects to receive the innovative 
combination of immunotherapy and immunomodulatory 
agent, which exhibits preclinical/clinical synergistic 
effect with immunotherapy. It will also allow for 
increased chance to detect adverse events with the 
capmatinib and pembrolizumab combination. 
Furthermore, the analysis power could be increased by 
utilizing historical data on the control arm.    
Randomization stratification factors:
Histology (squamous vs. non-squamous)
The stratification factor has been selected to balance 
potential predictive and/or prognostic factors between 
the two arms:
Although anti-PD-1/PD-L1 activity is observed in both 
squamous and non-squamous histology, the magnitude 
of benefit and the absolute outcomes may differ slightly 
in the two histologies (Brahmer et al 2015, 
Borghaei et al 2015, Herbst et al 2016, Reck et al 2016, 
Herzberg et al 2017), therefore randomization is 
stratified based on tumor histology.
4.2
Rationale for dose/regimen and duration of treatment
The safety of the combination of capmatinib with a checkpoint inhibitor was confirmed in two 
studies (CINC280X2108 and CEGF816X2201C), and the RP2D of capmatinib was determined 
as 400 mg p.o BID. For details, please refer to Section 1.1.2. No DDI on drug exposure was 
observed in the two studies. 
Pembrolizumab monotherapy has been approved by the FDA and in many countries for 
advanced/metastatic NSCLC. The recommended dose per pembrolizumab label is 200 mg 
administered as an intravenous infusion Q3W until disease progression, unacceptable toxicity, 
or up to 24 months in subjects without disease progression. 
The dosing regimen for this study is set at the recommended dose of pembrolizumab and the 
RP2D of capmatinib as a combination therapy. Subjects will receive study treatment up to 
35 cycles (~24 months) or discontinue earlier due to other reasons. Refer to Section 9.1 for 
details about discontinuation.  
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4.3
Rationale for choice of combination drugs
Inhibition of MET by capmatinib can enhance T cell mediated antitumor immunity in multiple 
mouse tumor models treated with anti-PD1 antibodies or other immuno-oncology regimens, as 
discussed in more detail above (Section 1.1.1; Glodde et al 2017 and RD-2017-00370). 
While the mechanism underlying this combination benefit has not yet been fully elucidated, 
several pre-clinical observation suggest an immunosuppressive effect of MET / HGF directly 
on immune cells, which can be prevented by capmatinib. 
Pembrolizumab monotherapy has been approved in many countries for advanced/metastatic 
NSCLC as first-line treatment. Pembrolizumab demonstrated survival benefit in OS and PFS 
over chemotherapy (Reck et al 2016, Mok et al 2019), but there is still room for improvement. 
The combination of capmatinib with checkpoint inhibitors has been established as tolerable and 
the toxicities are manageable. Preliminary clinical efficacy signals observed in EGF816X2201C 
study warrant further investigation for this chemotherapy-free regimen in NSCLC. Based on 
the preclinical and clinical data, combination of capmatinib and pembrolizumab is considered 
safe and is expected to provide clinical benefit to the subjects in this study.  
4.4
Purpose and timing of interim analyses
Following approval of protocol amendment 03, the planned administrative interim analysis will 
not be performed. 
4.5
Risks and benefits
Advanced/metastatic NSCLC is an incurable disease. Patients treated with chemotherapy have 
a life expectancy of approximately 11-14 months (Gandhi et al 2018, Paz-Ares et al 2018, 
Mok et al 2019). Recent studies showed pembrolizumab monotherapy demonstrated superior 
PFS and OS over chemotherapy in patients with PD-L1 ≥ 50% and whose tumors do not have 
EGFR mutation or ALK rearrangement (Refer to Section 1.1). The combination of 
pembrolizumab with platinum-doublet chemotherapy yields higher response rates compared to 
pembrolizumab monotherapy, but also produces higher chemotherapy-related toxicities, 
particularly myelosuppression. 
Adding capmatinib to pembrolizumab provides a chemotherapy-free regimen and potential 
survival benefit for its synergistic anti-tumor effect, which has been seen in preclinical 
non-MET driven tumor models. The safety profiles of capmatinib and pembrolizumab as 
monotherapies are well characterized respectively. The combination of capmatinib with 
checkpoint inhibitors has been established to be tolerable in 2 ongoing studies CINC280X2108 
(see Section 1.1.2.2) and CEGF816X2201C (see Section 1.1.2.1). 
Risks in this study can be mitigated by subjects complying with eligibility criteria and study 
procedures, close monitoring for subject safety, and periodic safety data review by the DMC, 
as specified in Section 10.2. Appropriate eligibility criteria and stopping rules are included in 
this protocol. Guidance for prophylactic or supportive treatment for expected toxicities, 
including the management of treatment-related AEs, (e.g. infusion reaction, pneumonitis) are 
provided in Section 6.5. The risk-benefit ratio is expected to be favorable to the combination 
therapy.
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Following the study enrollment halt, capmatinib treatment was discontinued in all subjects. No 
additional risk is expected from treatment with pembrolizumab alone in ongoing patients.
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 
with Novartis prior to implementation of mitigation procedures, and measures should be 
permitted/approved by local or regional Health Authorities and Ethics Committees as 
appropriate.
5
Population
The study population will include adult subjects diagnosed with advanced or metastatic, 
squamous or non-squamous non-small cell lung cancer (NSCLC), without EGFR or ALK 
alteration and with PD-L1 high expression (TPS ≥ 50%).
The investigator must ensure that only subjects who meet all the following inclusion and none 
of the exclusion criteria are offered treatment in the study.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Must have provided written informed consent prior to any screening procedures 
2. Male/female patients ≥ 18 years of age at the time of informed consent. For Japan only: 
written consent is necessary both from the patient and his/her legal representative if he/she 
is under the age of 20 years.
3. Histologically confirmed and documented locally advanced stage III (not candidates for 
surgical resection or definitive chemo-radiation) or stage IV (metastatic) NSCLC (per 
AJCC/IASLC v.8) for treatment in the first-line setting

Treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant 
therapy (other than immunotherapies) is allowed as long as therapy was completed at 
least 6 months prior to the diagnosis of advanced or metastatic disease. 
4. Histologically or cytologically confirmed diagnosis of NSCLC that is both EGFR wild 
type status and ALK- negative rearrangement status:

Subjects with NSCLC of pure squamous cell histology can enter screening without 
EGFR mutation or ALK rearrangement testing or result; however, patients with pure 
squamous cell histology who are known to have sensitizing EGFR mutations (such as 
but not limited to identified in exons 19, 20, or 21) or ALK rearrangements will be 
excluded.

Subjects with known BRAF V600 mutation or ROS-1 rearrangement will be 
excluded, if required by local guidelines
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5. Have an archival tumor sample or newly obtained tumor biopsy with high PD-L1 
expression (TPS ≥ 50%) determined by IHC using FDA approved PD-L1 IHC 22C3 
PharmDx assay at a local laboratory or at a Novartis designated central laboratory.

The archival samples must be most recently available FFPE block or cut tissue 
sections from the block. Tissue sections must NOT be older than 5 months from the 
time of sectioning. Archival samples obtained prior to any systemic anti-neoplastic 
therapy (such as adjuvant therapy) will NOT be acceptable.

If local laboratory testing of PD-L1 as described above is not available, a newly 
obtained tumor biopsy or an archival tumor sample is required to confirm the 
eligibility. 
6. ECOG performance status score ≤ 1
7. Have at least 1 measurable lesion by RECIST 1.1; a previously irradiated lesion may only  
be counted as a target lesion if there is clear sign of progression since the irradiation
8. Must have recovered from all toxicities related to prior systemic therapy to grade ≤ 1 
(CTCAE v5.0). Exception to this criterion: subjects with any grade of alopecia
9. Must have adequate organ function including the following laboratory values at the 
screening visit:

Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (without growth factor support)

Platelets ≥ 100 × 109/L (without growth factor support or transfusion)

Hemoglobin (Hgb) ≥ 9 g/dL (4 weeks without transfusions or erythropoietin)

Calculated creatinine clearance (using Cockcroft-Gault formula) ≥ 45 mL/min 

Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN)

Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 3 × ULN

Alkaline phosphatase (ALP) ≤ 5.0 × ULN

International Normalized Ratio (INR) or Prothrombin Time (PT) and Activated 
Partial Thromboplastin Time (aPTT) or Partial Thromboplastin Time (PTT) ≤ 1.5 × 
ULN unless the subject is receiving anticoagulant therapy

Asymptomatic serum amylase ≤ grade 2. Subjects 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

Fasting plasma glucose ≤ 160 mg/dL (≤ 8.9 mmol/L) 

Subjects must have the following laboratory values within the laboratory normal 
limits or corrected to within normal limits with supplements during screening:

Potassium

Magnesium

Phosphorus

Total calcium (corrected for serum albumin)
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5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Prior treatment with a MET inhibitor or HGF-targeting therapy
2. Prior immunotherapy (e.g. anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or 
any other antibody or drug specifically targeting T-cell co-stimulation or immune 
checkpoint pathways).
3. Have known hypersensitivity to any of the excipients of capmatinib (crospovidone, 
mannitol, microcrystalline cellulose, povidone, sodium lauryl sulfate, magnesium stearate, 
colloidal silicon dioxide, and various coating premixes).
4. History of severe hypersensitivity reactions to other monoclonal antibodies, which in the 
opinion of the investigator may pose an increased risk of serious infusion reaction.
5. Have untreated symptomatic central nervous system (CNS) metastases. Subjects are 
eligible if CNS metastases have been adequately treated with radiotherapy or surgery and 
remained stable for >2 weeks after treatment. The subjects must have been off steroids 
7 days prior to study treatment
6. Presence or history of a malignant disease, other than NSCLC, that has been diagnosed 
and/or required therapy within the past 3 years. Exceptions to this exclusion include the 
following: completely resected basal cell and squamous cell skin cancers, and completely 
resected carcinoma in situ of any type.
7. Presence or history of interstitial lung disease or interstitial pneumonitis, including 
clinically significant radiation pneumonitis (i.e. affecting activities of daily living or 
requiring therapeutic intervention).
8. Clinically significant, uncontrolled heart diseases.

Unstable angina within 6 months prior to screening

Myocardial infarction within 6 months prior to screening

History of documented congestive heart failure (New York Heart Association 
functional classification III-IV)

Uncontrolled hypertension defined by a systolic blood pressure (SBP) ≥ 160 mmHg 
and/or diastolic blood pressure (DBP) ≥ 100 mmHg, with or without antihypertensive 
medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior 
to screening

Ventricular arrhythmias

Supraventricular and nodal arrhythmias not controlled with medication

Other cardiac arrhythmia not controlled with medication

QTcF (QT interval corrected by Fridericia’s formula) ≥ 470 ms on the screening ECG 
(as mean of triplicate ECG)

Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome
9. Prior palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting study treatment.
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10. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior 
(2 weeks for resection of brain metastases) to starting study treatment or who have not 
recovered from side effects of such procedure. Video-assisted thoracic surgery (VATS) 
and mediastinoscopy are not counted as major surgery and subjects can be enrolled in the 
study ≥ 1 week after the procedure.
11. 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).
12. Concomitant medication(s) with a “Known Risk of Torsades de Point (TdP)” per 
www.qtdrugs.org that cannot be discontinued or replaced by safe alternative medication.
13. Receiving treatment with strong inducers of CYP3A4 that cannot be discontinued at least 
1 week prior to the start of treatment with capmatinib and for the duration of the study.
14. Systemic chronic steroid therapy (>10 mg/day prednisone or equivalent) or any 
immunosuppressive therapy 7 days prior to planned date of first dose of study treatment. 
Topical, inhaled, nasal and ophthalmic steroids, mineralocorticoids (e.g., fludrocortisone) 
for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for 
adrenocortical insufficiency are allowed.
15. Participation in a prior investigational study (drug or device) within 30 days prior to first 
dose of study treatment or within 5 half-lives of the investigational product, whichever is 
longer, or those who are expected to receive any other investigational drug or device 
during the conduct of the study.
16. Other severe, acute, or chronic medical or psychotic conditions or laboratory 
abnormalities that in the opinion of the investigator may increase subject's risk associated 
with study participation, or that may interfere with the interpretation of study results.
17. Have received or will receive a live vaccination within 4 weeks prior to first dose of study 
treatment. Seasonal flu vaccines that do not contain live vaccine are permitted.
18. Active hepatitis B or C: 

Active hepatitis B is defined by positive HBsAg and detectable HBV DNA level in 
serum by PCR-based method. Subjects with serologic evidence of chronic HBV 
infection but have an HBV viral load below the limit of quantification can be enrolled 
with concurrent viral suppressive therapy. 

Active hepatitis C is defined by quantitative HCV RNA results greater than the lower 
limits of detection of the assay.
19. Known history of testing positive for Human Immunodeficiency Virus (HIV) infections. 
For countries where known HIV status is mandatory: test HIV status during screening 
using a local test.
20. Active, known, or suspected autoimmune disease or documented history of autoimmune 
disease. Subjects with vitiligo, controlled type I diabetes mellitus on stable insulin, 
residual autoimmune-related hypothyroidism only requiring hormone replacement, or 
psoriasis not requiring systemic treatment are permitted.
21. Any other condition that would, in the investigator’s judgment, contraindicate subject’s 
participation in the clinical study due to safety concerns or compliance with clinical study 
procedures, e.g. intestinal obstruction, unable to swallow medication, social/ 
psychological issues, etc.
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22. Pregnant or breast-feeding (lactating) women, or women who plan to become pregnant or 
breast-feed during the study, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive hCG laboratory 
test.
23. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective contraception during the study 
and through 120 days after the last dose of pembrolizumab and 7 days after the last dose 
of capmatinib. Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. 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 6 weeks before 
taking study treatment. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment.

Sterilization of the female study subject’s male partner, where the male partner was 
vasectomized at least 6 months before the screening.

Use of oral (estrogen and progesterone), injected or implanted combined 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.
If using oral contraception, women should have been stabilized on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate (generally age from 40 to 59 years), history of vasomotor symptoms 
(e.g. hot flush)) in the absence of other medical justification or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal 
ligation at least 6 weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child-bearing potential.
24. Sexually active males unless they use a condom during intercourse while taking 
capmatinib and for 7 days after stopping capmatinib, and should not father a child in this 
period. A condom is required to be used also by vasectomized men in order to prevent 
delivery of study treatments via seminal fluid.
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the informed consent form 
(ICF).
25. Active infection requiring systemic intravenous therapy.
26. Known history of allogeneic tissue/organ transplantation.
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6
Treatment
6.1
Study treatment
In this study, “study treatment” refers to capmatinib plus pembrolizumab or pembrolizumab 
alone. “investigational drug” refers to the Novartis study drug, capmatinib (INC280). 
Pembrolizumab may be considered as “investigational drug” following local regulations. 
Novartis Global Clinical Supply (GCS) or its designee will provide capmatinib as 150 mg and 
200 mg tablets as individual subject supply, packaged in bottles. Medication labels will comply 
with the legal requirements of each country and be printed in the local language. Storage 
conditions are described in the medication label.
Pembrolizumab will be procured or prescribed locally according to local practice and 
regulations, or supplied by Novartis country organizations. Handling and storage of 
pembrolizumab will follow the instructions in the package insert. 
Following approval of protocol amendment 03, subjects who remain in the study may continue 
to receive pembrolizumab treatment as per investigator's discretion until unacceptable toxicity, 
or disease progression, or up to 35 cycles of treatment, whichever occurs first. In countries 
where pembrolizumab is approved and available for the study indication, subjects may be 
transitioned to commercial pembrolizumab and discontinued from the study. 
6.1.1
Investigational and control drugs
The first dose of study treatment (capmatinib plus pembrolizumab or pembrolizumab alone) is 
given on Day 1 of Cycle 1. Cycle 1 Day 1 should occur no later than 3 days after randomization 
registration into the IRT (Interactive Response Technology) system.
All dosages prescribed and administered to subjects and all dose interruptions and changes 
during the study must be recorded on the study treatment eCRF (electronic Case Report/Record 
Form). Refer to Section 6.7.2 for study treatment prescribing and administration information.
Table 6-1
Investigational and control drugs 
Investigational and 
control drugs 
Pharmaceutical 
Dosage Form
Route of 
Administration
Drug package
Supplier 
(global 
or local)
Capmatinib (INC280) 
150 mg or 200 mg
Film-coated tablet
Oral use
Open-label 
subject 
specific; bottles
Global
Pembrolizumab
100mg/4mL (25 mg/mL)
Solution in vial for 
infusion 
Intravenous use
Refer to local 
drug package
Local
Pembrolizumab
50 mg
Lyophilized 
powder in vial for 
reconstitution for 
infusion 
Intravenous use
Refer to local 
drug package
Local
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6.1.2
Additional study treatments
Not applicable.
6.1.3
Treatment arms
Subjects will be assigned to one of the following two treatment arms in a ratio of 2:1. 
A complete cycle of treatment is defined as 21 days of an infusion of pembrolizumab, with or 
without continuous capmatinib treatment. 

Capmatinib 400 mg (tablets) orally twice daily (BID) followed by pembrolizumab 200 mg 
intravenously (i.v.) on day 1 of each cycle, every 21 days.

Pembrolizumab 200 mg intravenously (i.v.) alone every 21 days. 
6.1.4
Treatment duration
Subjects in both treatment arms will receive up to 35 cycles (~24 months) of study treatment. 
Subjects may be discontinued from study treatment earlier due to other reasons. Refer to 
Section 9.1 for details about discontinuation.  
6.1.4.1
Treatment beyond disease progression
Following approval of protocol amendment 03, treatment with pembrolizumab will strictly 
adhere to the drug’s approved label for the study indication. Accordingly, pembrolizumab may 
be administered until disease progression, unacceptable toxicity, or up to 35 cycles in subjects 
without disease progression, whichever occurs first. Treatment beyond disease progression will 
no longer be allowed as part of this study.
Subjects who have documented disease progression per RECIST 1.1 can remain on study 
treatment if they meet all the following criteria after documented discussion and agreement 
between the investigator and the Novartis medical monitor. Subjects are to be informed by the 
investigator of the options to continue study treatment as well as of other therapeutic options 
and their benefits, should they exist.

Clinical benefit per investigator's judgement (e.g. tumor shrinkage at other sites or 
symptomatic improvement)

Continuation of treatment beyond initial progression will not delay an imminent 
intervention to prevent serious complications of disease progression

Subject exhibits adequate tolerance to study treatment

Subject performance status is stable

Absence of symptoms and signs (including worsening of clinically relevant laboratory 
values) indicating disease progression
Subjects who meet the above criteria and continue study treatment beyond initial disease 
progression per RECIST 1.1 (see Section 16.1) 
 
 and continue all study procedures as outlined in Table 8-2.
In case of clinical deterioration or suspicion of disease progression, a follow-up imaging 
assessment should be performed promptly rather than waiting for the next scheduled assessment. 
 
 
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Please refer to Section 8.3 for additional information on RECIST 1.1 
.
6.2
Other treatment(s)
In general, for subjects taking capmatinib, the use of any concomitant medication/therapy 
deemed necessary for the care of the subject (e.g. such as anti-emetics, anti-diarrhea) is 
permitted (see Section 6.2.1), except when specifically prohibited (see Section 6.2.2). 
For the concomitant/prohibited therapies when taking pembrolizumab, please refer to the 
locally approved label.
The subject must be told to notify the investigator about any new medications he/she takes after 
the start of the study treatment. All medications (excluding study treatment), blood transfusions, 
surgeries and procedures (including physical therapy) administered after the subject has signed 
inform consent form until 30 days after the last dose of study treatment will be recorded in the 
appropriate eCRF. Medications include not only physician prescribed medications, but also all 
over-the counter medications, herbal medications, food supplements and vitamins.
The following restrictions apply during the entire duration of the study:

No other investigational therapy should be given to subjects

No anticancer agents other than the study treatment (capmatinib and pembrolizumab) 
should be given to subjects. 
6.2.1
Concomitant therapy
6.2.1.1
Permitted concomitant therapy
Subjects are permitted to use the following medications.

Oral or topical antibiotics

Medications to prevent or treat nausea, vomiting or diarrhea

Growth factors (e.g. G-CSF, GM-CSF, erythropoietin, platelets growth factors, etc.) are 
allowed per investigator’s judgement and per local guidelines.

Treatment with bisphosphonates for pre-existing bone metastases is permitted, if clinically 
indicated, and following existing local guidelines. Treatment with bisphosphonates should 
preferably begin before the study treatment is initiated, but can also be initiated during 
therapy only if absence of radiological bone disease progression is well documented 
(in this case, the reason for its use must be clearly documented; i.e. “pre-existing, 
non-progressing, bone metastases”).

Oxygen therapy and blood products or transfusions
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
Nutritional support or appetite stimulants

Pain medication

Radiotherapy with palliative intent, including but not limited to analgesic purposes or for 
lytic lesions at risk of fracture, may be carried out if required.
6.2.1.2
Permitted concomitant therapy requiring caution and/or action for the 
treatment of capmatinib plus pembrolizumab 
Capmatinib is a moderate CYP1A2 inhibitor. Coadministration of capmatinib increases 
sensitive CYP1A2 probe substrate (caffeine) AUC (Area under the curve) by 135% 
CINC280A2103. The dose of CYP1A2 substrates with narrow therapeutic index may need to 
be reduced when used concurrently with capmatinib as capmatinib may increase their exposure. 
Consult the product information of concomitant drug for dose adjustment.
Coadminstration of capmatinib increased Pgp substrate (digoxin) exposure (AUC and Cmax by 
47% and 74%, respectively) and breast cancer resistance protein (BCRP) substrate 
(rosuvastatin) exposure (AUC and Cmax by 108% and 204%, respectively) CINC280A2105. 
Monitor subjects closely for symptoms of increased exposure to Pgp or BCRP substrates. 
Consult the concomitant Pgp or BCRP substrate product information when considering dose 
adjustment.
Coadministrating capmatinib with strong CYP3A4 inhibitor (itraconazole) increases 
capmatinib AUC by 40%. There is no change in capmatinib Cmax. Execute caution when using 
a strong CYP3A4 inhibitor concurrently with capmatinib CINC280A2102. The effect of the 
moderate CYP3A4 inducer, efavirenz, administered at 600 mg q.d. on the single or multiple 
dose capmatinib PK in patients was simulated using the PBPK model. The model predicted a 
weak effect of 45% reduction in capmatinib AUC0-12 and 34% reduction in Cmax at steady 
state DMPK R1701418-Table 6.9.
In healthy subjects, multiple doses of an oral proton pump inhibitor (PPI), rabeprazole at 20 mg 
once daily resulted in a modest reduction in the extent of capmatinib absorption with a 37.5% 
decrease in Cmax and a decrease of 25.2% in AUCinf. A similar result was observed in a small 
number of subjects A2108 with concomitant PPI use. Caution should be exercised during 
concomitant use with PPIs. 
Capmatinib should be taken at least 3 hours before or 6 hours after an H2-receptor antagonist, 
and at least 2 hours before or 2 hours after an antacid.
Refer to Table 6-2 below for a list of the medications (presented by mechanism of interaction) 
that require caution when concomitantly used with capmatinib. 
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Table 6-2
Capmatinib: drugs to be used with caution during co-administration – 
obsolete upon approval of protocol amendment 03
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, 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
CYP1A2 substrate with 
NTI
theophylline, tizanidine
P-gp substrates
afatinib, alfuzosin, aliskiren, alogliptin, ambrisentan, apixaban, 
apremilast, aprepitant, atorvastatin, , boceprevir, bosentan, carvedilol, 
caspofungin, ceritinib, colchicine, cyclosporine, dabigatran, digoxin, 
docetaxel, doxepin, doxorubicin, eribulin, everolimus, fentanyl, 
fexofenadine, fidaxomicin, fluvastatin, fosamprenavir, idelalisib, 
iloperidone, indacaterol, irbesartan, lacosamide, lapatinib, 
levetiracetam, linagliptin, linezolid, loperamide, losartan, maraviroc, 
mirabegron, nadolol, naloxegol, nateglinide, nevirapine, nevirapine, 
nintedanib, olodaterol, paclitaxel, pantoprazole, paroxetine, pazopanib, 
proguanil, posaconazole, pravastatin, ranolazine, ritonavir, riociguat, 
risperidone, rivaroxaban, saquinavir, silodosin, simeprevir, simvastatin, 
sirolimus, sitagliptin, sofosbuvir, sorafenib, tacrolimus, telaprevir, 
tenofovir, ticagrelor, tipranavir, tolvaptan, topotecan, umeclidinium, 
valsartan, vardenafil, vincristine, voriconazole
BCRP substrates
atorvastatin daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, 
imatinib, methotrexate, paritaprevir, pitavastatin, rosuvastatin, 
irinotecan, ethinyl estradiol, simvastatin, sofosbuvir, sulfasalazine, 
tenofovir, topotecan, venetoclax
Proton pump inhibitor
esomeprazole, pantoprazole, omeprazole, lansoprazole, rabeprazole, 
dexlansoprazole
H2-receptor antagonists
ranitidine, nizatidine, famotidine, cimetidine
Antacids
aluminum hydroxide, aluminum carbonate, calcium hydroxide, calcium 
carbonate, bismuth subsalicylate
Source: The list is adapted from the Novartis Institutes for Biomedical PK Sciences internal memorandum (v01, 
2018): drug-drug interactions (DDI) database, which is compiled primarily from the Indiana University School of 
Medicine’s “Clinically Relevant” Table (medicine.iupui.edu/flockhart/table.htm), the University of Washington’s 
Drug Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction 
Studies”.
This may not be an exhaustive list and will be updated periodically.
NTI: narrow therapeutic index
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6.2.2
Prohibited medication
During the course of the study, subjects must not receive other additional investigational drugs, 
devices, chemotherapy, or any other therapies that may be actively against cancer or that are 
intended to modulate an immune response, however, limited-field palliative radiotherapy may 
be allowed as a concomitant therapy (see Section 6.2.1). 
For the prohibited medications when using pembrolizumab, the use of systemic steroid therapy 
(at doses greater than 10 mg/day prednisone or equivalent) and other immunosuppressive drugs 
is not allowed, except for:

Prophylactic use for subjects with imaging contrast dye allergy.

Replacement-dose steroids (defined as 10 mg/day (or lower dose) of prednisone or 
equivalent dose of corticosteroids) in the setting of adrenal insufficiency. 

Transient exacerbations of chronic inflammatory conditions such as COPD. Steroids must 
be reduced to 10 mg/day (or lower dose) of prednisone or equivalent dose of 
corticosteroids prior to the next treatment with pembrolizumab. 

The treatment of study treatment-related infusion reactions or study treatment-related 
irAEs. Steroids must be reduced to ≤10 mg/day of prednisone or equivalent dose of 
corticosteroids prior to the next study treatment administration.
For other prohibited medications for subjects treated with pembrolizumab, please follow local 
guidelines as per standard of care and product labels. 
For  subjects treated with capmatinib, strong CYP3A4 inducer (rifampicin) decreases 
capmatinib AUC by 67% and Cmax by 56% CINC280A2102, and therefore concurrent use of 
strong CYP3A4 inducers should be prohibited as decreased capmatinib exposure may lead to 
reduced efficacy. 
Drugs with a known risk of TdP are prohibited during treatment with capmatinib plus 
pembrolizumab. For identification of drugs with known risk of TdP, please refer to 
www.qtdrugs.org (refer to Table 6-4).
The prohibited medications are listed in the Table 6-3 below.
For the capmatinib plus pembrolizumab treatment, all prohibited medications should not be 
taken. If a subject is only taking pembrolizumab, the prohibited medications when using 
pembrolizumab merely need to be prohibited. If a subject is only taking capmatinib, the 
prohibited medications when using capmatinib merely need to be prohibited.
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Table 6-3
Capmatinib: Prohibited medications – obsolete upon approval of 
protocol amendment 03
Mechanism of 
Interaction
Drug Name
Strong CYP3A4 
inducer
carbamazepine, enzalutamide, lumacaftor, phenobarbital, phenytoin, 
rifabutin, rifampicin, mitotane, 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 
(medicine.iupui.edu/flockhart/table.htm), the University of Washington’s Drug Interaction Database 
(druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction Studies”
This may not be an exhaustive list, which will be updated periodically.
Table 6-4
Drugs with a known risk of Torsades de Pointes – obsolete upon 
approval of protocol amendment 03
TdP Risk
Generic Names
Known
amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, chloroquine, 
chlorpromazine, cilostazol, ciprofloxacin, cisapride, citalopram, clarithromycin, 
disopyramide, dofetilide, domperidone, donepezil, dronedarone, droperidol, 
erythromycin, escitalopram, flecainide, fluconazole, gatifloxacin, halofantrine, 
haloperidol, ibutilide, levofloxacin, levomepromazine, levosulpiride, methadone, 
moxifloxacin, ondansetron, oxaliplatin, papaverine HCl (intra-coronary), 
pentamidine, pimozide, procainamide, propofol, quinidine, roxithromycin, 
sevoflurane, sotalol, sulpiride, sultopride, terlipressin, terodiline, thioridazine, 
vandetanib
Check crediblemeds.org/healthcare-providers/drug-list for the most updated list.
This may not be an exhaustive list, which will be updated periodically.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the subject is assigned to the next sequential Subject 
No. available.
6.3.2
Treatment assignment, randomization
Prior to dosing, all eligible subjects will be randomized via Interactive Response Technology 
(IRT) to one of the treatment arms. The investigator or his/her delegate will contact the IRT 
after confirming that the subject fulfills all the inclusion/exclusion criteria. The IRT will assign 
a randomization number to the subject, which will be used to link the subject to a treatment 
arm.  
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The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by a delegate under Novartis supervision, using a validated 
system that automates the random assignment of subject numbers to randomization numbers. 
These randomization numbers are linked to the different treatment arms.
Randomization will be stratified by the subject’s histology (squamous vs. non-squamous).
The randomization scheme for subjects will be reviewed and approved by a member of the 
Novartis Randomization Office.
6.4
Treatment blinding
Treatment will be open to subjects, investigator staff and persons performing the assessments. 
The Clinical Trial Team (CTT) will not have access to the randomized treatment from the time 
of randomization until database lock for the primary analysis. Randomization data will be kept 
strictly confidential until the time of unblinding, and will not be accessible by anyone else 
involved in the study with the following exceptions: independent biostatistician and 
programmer who will perform Data Monitoring Committee (DMC) analysis, PK 
bioanalyst, modeler and modeling programmer. The study bioanalyst will receive a copy of the 
randomization schedule to facilitate analysis of the samples. The CTT, investigators and site 
personnel will not have access to any aggregated efficacy and safety results by treatment arm 
until the primary analysis. While the CTT will have access to the dose administration record, 
the randomization codes and full randomization list will be kept strictly confidential from the 
CTT until primary analysis.  
Following the enrollment halt, the randomization information was released to the CTT for 
internal data review and to address Health Authorities’ queries. 
6.5
Dose escalation and dose modification
Dose escalations are not permitted.
6.5.1
Dose modifications
For subjects who do not tolerate the protocol-specified dosing schedule, dose interruptions 
and/or reductions are either recommended or mandated in order to allow subjects to continue 
the study treatment.
In situations where the causality of toxicity cannot be clearly attributed to one of the study drugs 
(capmatinib or pembrolizumab), dose modification recommendations for both study drugs 
should be followed.
There are no dose reductions allowed in this study for pembrolizumab. Dose interruptions for 
pembrolizumab are permitted. Please refer to local pembrolizumab labels for recommended 
treatment modifications for pembrolizumab.
For clinical management of suspected immune-related adverse event (irAE) and corresponding 
dose modification requirements, reference to consensus management guidelines is 
recommended such as those provided in the National Comprehensive Cancer Network (NCCN) 
Guidelines for the Management of Immunotherapy-Related Toxicities (available at: 
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https://www.nccn.org/professionals/physician_gls/default.aspx#immunotherapy), 
the 
American Society for Clinical Oncology (ASCO) clinical practice guideline for Management 
of Immune-Related Adverse Events in Subjects Treated With Immune Checkpoint Inhibitor 
Therapy (Brahmer et al 2018) or the European Society for Medical Oncology (ESMO) Clinical 
Practice Guidelines for Management of Toxicities from Immunotherapy (Haanen et al 2017).  
Consider early referral to specialists with expertise in the diagnosis and management of 
immune-related AEs to thoroughly investigate events of uncertain etiology. 
Events not included in the study protocol or the reference guidance documents should be 
managed per institutional preference. 
Dose reductions and interruptions are permitted for capmatinib. These dose modifications are 
summarized in Table 6-6. Deviations to mandatory dose interruptions and/or reductions are not 
allowed. Permanent treatment discontinuation for capmatinib is mandatory for specific events 
indicated as such in Table 6-6.
Capmatinib dose reduction will follow the dose reduction steps described in Table 6-5 . For 
each subject, a maximum of two dose level modifications are allowed after which the subject 
must be discontinued from treatment with capmatinib. The lowest dose allowed, 200 mg BID 
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 subject must discontinue treatment with capmatinib if, after treatment is 
resumed at the lowest allowed dose (200 mg BID), the toxicity recurs with the same or worse 
severity despite use of maximal preventive measures as per the institution guidelines for toxicity 
prevention and management.
Unless otherwise indicated in Table 6-6, for grade 1 and tolerable grade 2 treatment-related 
toxicities, subjects may continue full doses of study treatment. For intolerable grade 2 or grade 
3 treatment-related toxicities, dosing should be interrupted until at least resolution to grade 1 
followed by either dose reduction or re-initiation at the same dose level, depending on the type 
of toxicity as described in Table 6-6. For any grade 4 toxicity, subjects should interrupt study 
treatment until resolution to grade 1, followed by either dose reduction or treatment 
discontinuation (refer to Table 6-6).
Any planned variance from the guidelines in Table 6-6, in view of subject safety (unless there 
is an urgent need for action) when in the opinion of the investigator the subject continues to 
derive clinical benefit, should first be discussed and approved by the Novartis medical monitor.
Overall, AEs are to be graded according to NCI-CTCAE v5.0 (http://ctep.cancer.gov). All dose 
reductions and interruptions and the reason for the dose reductions/interruptions must be 
documented in the eCRF.
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Table 6-5
Dose reduction steps for capmatinib – obsolete upon approval of 
protocol amendment 03
Starting dose level - 0
Dose level - 1
Dose level - 2
Capmatinib
400 mg BID
300 mg BID
200 mg BID
Dose reduction should be based on the worst toxicity demonstrated at the last dose.
Dose reduction below 200 mg BID is not allowed
Table 6-6
Criteria for dose reduction / interruption and re-initiation of 
capmatinib treatment for adverse drug reactions – obsolete upon 
approval of protocol amendment 03
Dose modifications for capmatinib
Worst toxicity CTCAEa Grade
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 × 109/L)
Maintain dose level
Grade 2 (ANC < 1500 - 1000/mm3; 
< 1.5 - 1.0 × 109/L)
Maintain dose level
Grade 3 (ANC < 1000 - 500/mm3;
 < 1.0 - 0.5 × 109/L)
Interrupt dose until resolved to ≤ grade 2, then:
If resolved in ≤ 7 days, resume treatment at 
the same dose level
If  not resolved within  7 days, then ↓ 1 dose 
level
Grade 4 (ANC < 500/mm3;
< 0.5 × 109/L)
Interrupt dose until resolved to ≤ grade 2 and 
then ↓ 1 dose level
Platelet count decreased (Thrombocytopenia)
Grade 1 (PLT < LLN - 75,000/mm3; 
< LLN - 75 × 109/L)
Maintain dose level
Grade 2 (PLT < 75,000 - 50,000/mm3; < 75 - 50 × 
109/L)
Maintain dose level
Grade 3 (PLT < 50,000 -25,000/mm3; < 50 – 25 × 
109/L)
Interrupt dose until resolved to ≤ grade 2, then:
If resolved in ≤ 7 days, then maintain dose 
level 
If  not resolved within  7 days, then ↓ 1 dose 
level
Grade 4 (PLT < 25,000/mm3; 
< 25 × 109/L)
Interrupt dose until resolved to ≤ grade 2, then 
↓1 dose level
Febrile neutropenia 
( Grade 3: ANC < 1000/mm3 38.3°C or a sustained 
temperature of ≥38°C for more than one hour; 
Grade 4: Life-threatening consequences; urgent 
intervention indicated)
Interrupt dose, then:
If resolved in ≤ 7 days, resume treatment at ↓ 
1 dose level
If  not resolved within  7 days, discontinue 
subject from study drug treatment
Hemoglobin decreased (Anemia)
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Dose modifications for capmatinib
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)
Interrupt 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
Interrupt dose until resolved to ≤ grade 2 and 
then ↓ 1 dose level
If toxicity recurs, discontinue subject from 
study drug treatment.
RENAL
Serum creatinine
Grade 1 (> ULN - 1.5 × ULN)
Maintain dose level
Grade 2 (> 1.5 - 3.0 × ULN)
Interrupt dose until resolved to ≤ grade 1 or 
baseline, then resume treatment at the same 
dose level.
Grade 3 (> 3.0 - 6.0 × ULN)
Interrupt dose until resolved to ≤ grade 1 or 
baseline, then resume treatment at ↓ 1 dose 
level.
Grade 4 (> 6.0 × ULN)
Permanently discontinue subject from study 
drug treatment
HEPATIC
Isolated Total Bilirubin elevation*
Grade 1 (> ULN - 1.5 × ULN)
Maintain dose level
Grade 2 (> 1.5 - 3.0 × ULN)
Interrupt dose until resolved to ≤ grade 1, then
If resolved in ≤ 7 days, maintain dose level 
If  not resolved within  7 days, ↓1 dose level
Grade 3 (> 3.0 - 10.0 × ULN)
Interrupt dose until resolved to ≤ grade 1, then
 If resolved in ≤ 7 days, ↓ 1 dose level
If resolved in > 7 days, permanently 
discontinue subject from study drug treatment 
Grade 4 (> 10.0 × ULN)
Mandatory: Permanently discontinue subject 
from study drug treatment
Isolated AST or ALT elevation
Grade 1 (> ULN - 3 × ULN)
Maintain dose level
Grade 2 (> 3.0 - 5.0 × ULN)
Maintain dose level
Or consider to interrupt dose until resolved to 
≤ grade 1, then maintain dose level
Grade 3 (> 5.0 - 20.0 × ULN)
Interrupt 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
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Dose modifications for capmatinib
If  not resolved within 7 days, resume 
treatment at ↓ 1 dose level
Grade 4 (> 20.0 × ULN)
Mandatory: Permanently discontinue subject 
from study drug treatment
Combined elevations  of AST or ALT and Total Bilirubinb,c,d
For subjects with normal baseline 
ALT and AST and total bilirubin value:
AST or ALT > 3.0 × ULN combined  with total 
bilirubin >2.0 × ULN without evidence of cholestasis
OR
For subjects with elevated baseline AST or ALT or 
total bilirubin value:
(AST or ALT > 2 × baseline AND
 > 3.0 × ULN) OR (AST or ALT 
>8.0 × ULN), whichever is lower, combined with 
(total bilirubin >2 × baseline AND > 2.0 × ULN)
Mandatory: Permanently discontinue subject 
from study drug treatment
CARDIAC
Myocarditis or other cardiac event
Recommended clinical management of myocarditis grade ≥ 2 or other cardiac event grade ≥ 3: 
Initiate systemic corticosteroids (prednisone or equivalent) at a dose of 1-2 mg/kg QD and consult 
with a cardiologist (hospitalization as indicated)
Grade 1
Maintain dose level of study drug treatment (pembrolizumab 
can be continued)
Myocarditis grade ≥ 2 
Permanently discontinue subject from study drug treatment 
(pembrolizumab should also be discontinued)
Other cardiac event grade ≥ 3
Permanently discontinue subject from study drug treatment 
(pembrolizumab should also be discontinued)
Electrocardiogram QT corrected (QTc) interval prolonged
Grade 1 (QTcF 450-480 ms)
Grade 2 (QTcF 481-500 ms)
Maintain dose level
Grade 3 (QTcF ≥ 501 ms on at least two separate 
ECGs)
Omit dose until resolved to ≤ grade 2, then:
If resolved in ≤ 7 days, resume treatment at 
the same dose level
If  not resolved within  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 subject from study 
drug treatment
GASTROINTESTINAL
Pancreatitis
Grade 2
Maintain dose level
Grade ≥ 3
Mandatory: Permanently discontinue subject 
from study drug treatment
Asymptomatic amylase and/or lipase elevation (If symptomatic elevations of any grade, discontinue 
CAPMATINIB permanently)
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Dose modifications for capmatinib
Grade 1 (> ULN - 1.5 × ULN)
Maintain dose level
Grade 2 (> 1.5 - 2.0 × ULN)
Maintain dose level
Grade 3 (> 2.0 - 5.0 × ULN)
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 × ULN)
Permanently discontinue subject from study 
drug treatment
Diarrhea**
Grade 1 (despite appropriate 
anti-diarrheal medication)
Maintain dose level
Grade 2 (despite maximal 
anti-diarrheal medication)
Interrupt dose until resolved to ≤ grade 1, then 
maintain dose level.
If diarrhea returns as ≥ grade 2, then interrupt 
dose until resolved to ≤ grade 1, then resume 
treatment at↓ 1 dose level
Grade 3 or 4 (despite appropriate 
anti-diarrheal medication)
Interrupt 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)
Interrupt dose until resolved to ≤ grade 1, then 
maintain dose level.
Grade 3 (despite appropriate 
anti-emetics)
Interrupt dose until resolved to ≤ grade 1, 
then↓  1 dose level
Grade 4 (despite appropriate 
anti-emetics)
Interrupt dose until resolved to ≤ grade 1, then 
↓ 1 dose level
Nausea
Grade 1 (despite appropriate 
anti-emetics)
Maintain dose level
Grade 2 (despite appropriate 
anti- emetics)
Maintain dose level 
Or consider to interrupt dose until resolved to 
≤ grade 1, then maintain dose level 
Grade 3 (despite appropriate 
anti-emetics)
Interrupt 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
Interrupt dose until resolved to grade ≤ 1, then:
If resolved in ≤ 7 days, then↓resume treatment 
at 1 dose level.
If  not resolved within  7 days (despite 
appropriate skin toxicity therapy), then 
discontinue subject from study drug treatment
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Grade 4, despite skin toxicity therapy
Permanently discontinue subject from study 
drug treatment
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
ILD/Pneumonitis
Monitor subjects for pulmonary symptoms indicative of ILD/pneumonitis. In addition, withhold 
capmatinib for acute onset of new or progressive unexplained pulmonary symptoms, such as 
dyspnea, cough and fever and during diagnostic workup for ILD/pneumonitis to exclude alternative 
causes such as, but not limited to infections, lymphangitic carcinomatosis, cardiogenic edema, or 
pulmonary hemorrhage.
Grade 1
Interrupt capmatinib during diagnostic workup 
for ILD/Pneumonitis. Exclude infections and 
other etiologies. 
In presence of diagnosis of ILD/Pneumonitis 
after diagnostic workup, it is mandatory to 
permanently discontinue capmatinib. 
Only in the absence of a diagnosis of 
ILD/Pneumonitis, study drug may be restarted 
at the same dose. 
If it recurs after resumption of study drug 
permanently discontinue capmatinib.
Grade 2
Mandatory: interrupt capmatinib during 
diagnostic work up for ILD/pneumonitis until 
improvement to ≤ Grade 1.  Exclude infections 
and other etiologies.
In presence of diagnosis of ILD/Pneumonitis 
after diagnostic workup, it is mandatory to 
permanently discontinue capmatinib. 
Only in the absence of a diagnosis of 
ILD/Pneumonitis, 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 
recur after resumption of study drug at 
decreased dose, permanently discontinue 
capmatinib
Grade 3 or 4
Mandatory: permanently discontinuestudy 
drug.
Treat with IV steroids as clinically indicated. 
Oxygen therapy as indicated
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Fatigue/ Asthenia
Grade 1
Maintain dose level
Grade 2
Maintain dose level 
Or consider to interrupt dose until resolved to 
≤ grade 1, then maintain dose level
Grade 3
Omit dose until resolved to ≤ grade 1, then:
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If resolved in ≤ 7 days, resume treatment at 
same dose level If resolved
 in > 7 days, resume treatment at↓ 1 dose 
level
Peripheral edema
Grade 1
Maintain dose level
Grade 2
Maintain dose level 
Or consider to interrupt dose until resolved to 
≤ grade 1, then maintain dose level
Grade 3
Discontinue dose until resolved to ≤ Grade 1, 
then↓1 dose level
Grade 4
Discontinue CAPMATINIB
Hypersensitivity
If a suspected hypersensitivity case occurs, investigators should interrupt capmatinib while ruling 
out other possibilities and evaluating the severity of the patient’s hypersensitivity. Management of 
the symptoms of hypersensitivity should follow Table 6-6 unless investigators decide permanent 
discontinuation of capmatinib is indicated.
Other adverse events
Grade 1 or 2
Maintain dose level, consider to initiate 
appropriate support medication.
For any intolerable grade 2 (e.g.: limiting 
instrumental ADL), consider omitting the dose 
until resolved to ≤ grade 1, then↓ 1 dose level.
Grade 3
Interrupt dose until resolved to ≤ grade 2, 
then↓ 1 dose level
Grade 4
Interrupt dose and then discontinue from study 
drug treatment
All dose modifications should be based on the worst preceding toxicity. 
a Common Toxicity Criteria for Adverse Events (CTCAE Version 5.0).
b “Combined” defined as total bilirubin increase to the defined threshold concurrently with ALT/AST 
increase to the defined threshold
c “Cholestasis” defined as: ALP elevation (> 2.0 × ULN and R value (ALT/ALP in × ULN) < 2.0) in 
subjects without bone metastasis, or elevation of ALP liver fraction in subjects with bone metastasis
d If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please 
follow the instructions for isolated elevation of total bilirubin and isolated elevation of AST/ALT, and 
take a conservative action based on the degree of the elevations (e.g. discontinue treatment at the 
situation when omit dose is needed for one parameter and discontinue treatment is required for 
another parameter). After all elevations resolve to the defined thresholds that allow treatment re-
initiation, re-start the treatment either at the same dose or at one dose lower if meeting a criterion for 
dose reduction.
* Note: If total bilirubin > 3.0 × 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. Please refer to Table 6-7 for recommended medications.
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*** During the whole duration of treatment with CAPMATINIB, the subject is recommended to use 
precautionary measures against ultraviolet exposure (e.g., use of sunscreen, protective clothing and 
avoid sunbathing or using a solarium intensively.
6.5.2
Follow-up for toxicities
Following approval of protocol amendment 03, please refer to the locally approved 
pembrolizumab label and follow each institution’s standard of care to ensure adequate 
monitoring and follow-up of toxicities. The content of Section 6.5.2 below and Table 6-7 are 
no longer applicable.
Subjects whose treatment is interrupted or permanently discontinued due to an adverse event or 
clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for four weeks, and 
subsequently at approximately four week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts such as ophthalmologists, endocrinologists, 
dermatologists, psychiatrists etc. should be consulted as deemed necessary. All subjects must 
be followed for AEs and SAEs after discontinuation of pembrolizumab and capmatinib.  
Recommendations for follow-up evaluations of selected toxicities for subjects receiving 
capmatinib refer to Table 6-7. 
The emergence of irAE may be anticipated based on the mechanism of action of 
immunomodulatory therapies. Serologic, histologic (tumor sample) and immunological 
assessments should be performed as deemed appropriate by the investigator locally to verify 
the immune-related nature of the AE and to exclude alternative explanations. 
Subjects whose treatment is temporarily interrupted or permanently discontinued due to an AE 
or abnormal laboratory value must be followed until resolution or stabilization of the event, 
whichever comes first, including all study assessments appropriate to monitor the event.
An unscheduled assessment should be performed in all cases below where toxicity monitoring 
is recommended more frequently than defined by the schedule of assessments. 
Subsequent monitoring must be performed as per the regular visit schedule.
Table 6-7
Follow-up evaluations for selected toxicities – obsolete upon approval 
of protocol amendment 03
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.
Subjects 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
Total bilirubin CTCAE Grade 1:
Monitor liver function tests (LFTs) per protocol or more frequently 
if clinically indicated
Total bilirubin CTCAE Grade 2:
Weekly monitoring of LFTs, or more frequently if clinically 
indicated, until resolved to ≤ 1.5 ×ULN
Total bilirubin CTCAE Grade 3:
Weekly monitoring of LFTs, or more frequently if clinically 
indicated, until resolved to ≤ 1.5 × ULN. If resolved in > 7 days, 
after discontinuing the subject from capmatinib permanently, the 
subject should be monitored weekly (including LFTs), or more 
frequently if clinically indicated, until total bilirubin have resolved 
to baseline or stabilization over 4 weeks
Total bilirubin CTCAE Grade 4:
After discontinuing the subject from capmatinib permanently, the 
subject should be monitored weekly (including LFTs), or more 
frequently if clinically indicated, until total bilirubin has resolved to 
baseline or stabilization over 4 weeks
Isolated AST/ALT elevation
AST/ALT CTCAE Grade 2 elevation:
For subjects with baseline value ≤ 3.0 × 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 × ULN
For subjects with baseline value  > 3.0 - 5.0 × 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 × ULN:

For subjects with baseline value ≤ 3.0 × 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 × ULN

For subjects with baseline value  > 3.0 - 5.0 × 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 × ULN
For AST/ALT elevation > 10.0 - 20.0 × ULN:
Repeat LFTs as soon as possible, preferably within 48-72 hours 
from awareness of the abnormal results; monitor LFTs weekly, or 
more frequently if clinically indicated, until resolved to ≤ baseline
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TOXICITY
FOLLOW-UP EVALUATION
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
Combined elevations of AST or ALT and total bilirubin:
After discontinuing the subject 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, GGT (Gamma-glutamyl 
transferase), total bilirubin (fractionated (direct and indirect), if 
total bilirubin > 2.0 × ULN), and alkaline phosphatase 
(fractionated (quantification of isoforms), if alkaline phosphatase 
> 2.0 × 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:
Perform an analysis of serum potassium, calcium, phosphorus, 
and magnesium, and if below lower limit of normal, correct with 
supplements to within normal limits.
Review concomitant medication usage for the potential to inhibit 
CYP3A4/5 (Table 6-3) and/or to prolong the QT-interval 
().
Perform a repeat ECG within one hour of the first QTcF of ≥501 
ms.
If QTcF remains ≥ 501 ms, repeat ECG as clinically indicated, but 
at least once daily until the QTcF returns to < 501 ms.
Repeat ECGs 7 days and 14 days (and then every 21 days) after 
dose resumption for all subjects 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 patient with 
QTcF prolongation should be maintained on study.
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TOXICITY
FOLLOW-UP EVALUATION
GASTROINTESTINAL
Diarrhea
Investigate potential concomitant medication, food or comorbidity 
driven causes of diarrhea (including infectious causes) and 
remedy these causes if possible (e.g. discontinuation of 
concomitant medication, dietary modification, treatment of 
comorbidity).
The subject 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. For the treatment of diarrhea, it is recommended 
to follow “the recommended guidelines for the treatment of 
cancer treatment-induced diarrhea” (Benson et al 2004). 
For example:
For uncomplicated diarrhea (grade 1 or 2 without complicating 
signs or symptoms), loperamide given at a standard dose (e.g. 
initial administration of 4 mg, then 2 mg every 2-4 hours, 
maximum of 16 mg/day), along with oral hydration and dietetic 
measures should be considered. Note: complicating signs or 
symptoms include: moderate to severe cramping, decreased 
performance status, fever, neutropenia, frank bleeding or 
dehydration.
For complicated diarrhea (all grade 3 or 4, grade 1-2 with 
complicating signs or symptoms), management should involve 
intravenous (IV) fluids, and consider treatment with octreotide (at 
starting dose of 100 to 150 µg sub-cutaneous t.i.d or 25 to 50 µg 
IV) and antibiotics (e.g. fluoroquinolone) should be given.
Subjects needing loperamide should be followed for side effects 
of loperamide as its exposure may be increased in the presence 
of capmatinib.
Nausea and Vomiting
The investigator should consider/investigate potential 
concomitant medication, food or comorbidity driven causes of 
nausea and/or vomiting and remedy these causes if possible 
(e.g. discontinuation of concomitant medication, dietary 
modification, treatment of comorbidity).
Individualized supportive and anti-emetic treatment should be 
initiated, as appropriate, at the first signs and/or symptoms of 
these AEs. In subjects with vomiting, the subject should be 
monitored for signs of dehydration and instructed to take 
preventive measures against dehydration.
For the treatment of nausea and/or vomiting, it is recommended 
to follow the ASCO Clinical Practice Guideline 
(Hesketh et al 2017) or NCCN Clinical Practice Guidelines 
(NCCN Guidelines Version 1.2019 Antiemesis).
Drugs listed as prohibited medication (see Section 6.2.2) should 
not be used. Aprepitant should be used with caution 
(see Section 6.2.1.2) for subjects whose nausea and vomiting 
cannot be managed with other agents permitted on study. 
Subjects needing aprepitant should be followed for side effects of 
aprepitant as its exposure may be increased in the presence of 
capmatinib.
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TOXICITY
FOLLOW-UP EVALUATION
SKIN TOXICITY
Rash and Photosensitivity
CTCAE grade 1
Consider initiating  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  initiating 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 testsa - if normal at baseline, repeat every 
8 weeks

Bronchoscopy with biopsy and/or BAL recommendedc
Symptomatic therapy including corticosteroids if clinically 
indicated (1 to 2 mg/kg/day prednisone or equivalent as clinically 
indicated)b
CTCAE Grade 3 or 4
CT scan (high-resolution with lung windows).

Clinical evaluation and laboratory work-up for infection

Consult pulmonologist.

Pulmonary function testsa-if abnormal, repeat every 8 weeks 
until normalized.

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.
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TOXICITY
FOLLOW-UP EVALUATION

If IV steroids followed by high dose oral steroids does not 
reduce initial symptoms within 48 to 72 hours, consider non- 
corticosteroid immunosuppressive medication.
*Note: this table refers only to the evaluation schedule to monitor selected toxicities. Refer to 
Table 6-5 Dose reduction steps for capmatinib for dose modifications required for applicable toxicities
**Note: except if the subject is Grade 2 at baseline in which case: it is ≥ CTCAE grade 3
a PFT (Pulmonary function tests) to include: diffusing capacity 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 hemorrhage, opportunistic infections, cell count + determination lymphocyte CD4/8 
count where possible.
t.i.d = Three times a day.
6.5.2.1
Follow up on potential drug-induced liver injury (DILI) cases
Subjects with transaminase increase combined with TBIL increase may be indicative of 
potential DILI and should be considered as clinically important events. 
The threshold for potential DILI may depend on the subject’s baseline AST/ALT and TBIL 
value; subjects meeting any of the following criteria will require further follow-up as outlined 
below:

For subjects with normal ALT and AST and TBIL value at baseline: AST or ALT >3.0 × 
ULN combined with TBIL > 2.0 × ULN

For subjects with elevated AST or ALT or TBIL value at baseline: (AST or ALT > 2 × 
baseline AND > 3.0 × ULN) OR (AST or ALT > 8.0 × ULN), combined with (TBIL > 2 × 
baseline AND > 2.0 × ULN)
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 × ULN with R value < 2 in subjects without bone metastasis, or elevation 
of ALP liver fraction in subjects with bone metastasis.In the absence of cholestasis, these 
subjects should be immediately discontinued from study treatment, and repeat LFTs as soon as 
possible, preferably within 48 hours from the awareness of the abnormal results. The evaluation 
should include laboratory tests, detailed history, physical assessment, and the possibility of liver 
metastasis or new liver lesions, obstructions/compressions, etc.

Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR, and alkaline phosphatase.

A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, and history of any pre-existing 
liver conditions or risk factors, should be collected.
Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is performed 
in the study.
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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,” thus, meet the definition of SAE and reported as SAE using the term “potential 
drug-induced liver injury.” All events should be followed up with the outcome clearly 
documented.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
Capmatinib will be dispensed via IRT as specified in Section 6.7 following the schedule in 
Table 8-2. When capmatinib is taken orally at home, the investigator must promote compliance 
by instructing the subject to take the capmatinib exactly as prescribed and by stating that 
compliance is necessary for the subject’s safety and the validity of the study. The subject must 
also be instructed to contact the investigator if he/she is unable for any reason to take capmatinib 
as prescribed. Compliance will be assessed by the investigator and/or study personnel at each 
visit using tablet counts and information provided by the subject. This information should be 
captured in the source document at each visit. 
Pembrolizumab will be administered at the investigational site following the local practice and 
instructions in package insert. The date and time of all pembrolizumab administrations during 
the study and any deviations from the protocol treatment schedule will be captured by the 
investigator staff or delegates in the source document at each administration visit. 
All pembrolizumab infused and returned must be recorded in the Drug Accountability Log.
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all subjects 
in both treatment arms, as detailed in the pharmacokinetics section (Section 8.5.1).
6.6.2
Emergency breaking of assigned treatment code
Not applicable.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
drugs section (Section 6.1.1).
Capmatinib
A unique medication number is printed on the label of capmatinib.
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s) for capmatinib. The study medication has a 
2-part label (base plus tear-off label). Immediately before dispensing the medication kit to the 
subject, site personnel will detach the outer part of the label from the packaging and affix it to 
the source document.
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Pembrolizumab
Pembrolizumab will be supplied locally as commercially available by the site pharmacy or by 
Novartis country organization. Preparation and dispensation should follow the locally approved 
package insert and local practice.
6.7.1
Handling of study treatment
Study treatment supplied by Novartis must be received by a designated person at the study site, 
handled and stored safely and properly and kept in a secured location to which only the 
investigator and designated site personnel have access. Upon receipt, all study treatment must 
be stored according to the instructions specified on the labels and in the Investigator’s Brochure. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. Also, for capmatinib provided by Novartis, they will include storage conditions for the 
study treatment but no information about the subject, except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatments supplied by Novartis in a drug accountability log. Monitoring of drug accountability 
will be performed by monitors during site visits and at the completion of the trial. Subjects 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 as appropriate during the course of the study, the investigator 
will return a copy of the completed drug accountability log to the Novartis monitor or to the 
Novartis address provided in the investigator folder at each site. 
The unused study treatments supplied by Novartis can be destroyed at the local Novartis facility 
or third party, as appropriate, or locally at the site only if permitted by local regulations and 
authorized by Novartis. 
Pembrolizumab supplied locally by investigational sites should be handled following the local 
practice.
6.7.2
Instruction for prescribing and taking study treatment
All dosages prescribed and dispensed to subjects and all dose changes during the study must be 
recorded on the Dosage Administration Record eCRF.
All kits of capmatinib assigned by the IRT will be recorded in the IRT system.
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Table 6-8
Dose and treatment schedule
Capmatinib
Capmatinib tablets will be administered orally on a continuous twice daily (BID) dosing 
schedule, from Day 1 until Day 21 of each 21-day cycle. The starting dose of capmatinib will 
be 400 mg BID (total daily dose: 800 mg) on a flat scale of mg/day and not individually adjusted 
by weight or body surface area. The investigator must instruct the subject to take the study drug 
exactly as prescribed.

Subjects should be instructed to take capmatinib at approximately the same time each day 
starting from Cycle 1 Day 1. The morning and the evening doses should be taken 12 (± 4) 
hours apart, although a 12-hour interval is highly recommended. If a dose is not taken 
within 4 hours of the planned dosing time, the missed dose should not be replaced. 

Subjects should be instructed to swallow the tablets whole and not to chew them.

Capmatinib can be taken with or without food. Each dose of capmatinib should be taken 
with a glass of water.

On days of co-administration of capmatinib with pembrolizumab, the subject should be 
instructed to take the dose of capmatinib in the clinic. Capmatinib will be administered 
prior to the pembrolizumab infusion along with its pre-medication (if pre-medication is 
necessary). The sequence will allow consistent time of daily dosing for capmatinib. 
Subjects should receive pembrolizumab at least one hour after capmatinib administration.

On days that blood PK samples are obtained, the subject should take the dose in the clinic 
after pre-dose PK samples and prior to post-dose PK samples (if applicable), when 
instructed by the study staff. The exact time of drug administration should be recorded in 
the appropriate eCRF. If a subject vomits within 4 hours of capmatinib dosing, the time of 
vomiting should be recorded on the eCRF. If vomiting occurs during the course of 
treatment, then no re-dosing of capmatinib is allowed before the next scheduled dose.

During the whole duration of treatment with capmatinib, the subject is recommended to 
use precautionary measures against ultraviolet exposure (e.g., use of sunscreen, protective 
clothing, avoid sunbathing or using a solarium).
The orally administered film-coated tablet formulation will be provided in two strengths of 
150 mg and 200 mg free base equivalent. For the list of excipients, please refer to the current 
capmatinib Investigator’s Brochure.
Investigational/ Control 
Drug
  Dose
Frequency 
and/or Regimen
Capmatinib
150 mg or 200 mg
-
400 mg orally - 2 × 200 mg 
-
If dose is reduced to 300 mg- 2 × 150 mg 
-
If dose is reduced to 200 mg- 1 × 200 mg 
Twice daily 
(21 day cycles)
Pembrolizumab
100 mg/4mL (25 mg/mL)
200mg - 2 × 100 mg vials
Once every 21 
days
Pembrolizumab
50 mg (lyophilized)
200 mg- 4 × 50 mg vials
Once every 21 
days
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Pembrolizumab
Pembrolizumab (100 mg concentrate for solution for infusion or 50 mg lyophilized power for 
reconstitution for infusion) will be administered intravenously at 200 mg once every 21 days. 
Further instructions for the preparation, administration and infusion durations of 
pembrolizumab should follow the locally approved package insert.
Study treatment schedule adjustment
After the first dose, there will be a ±4-day window for the administration of pembrolizumab in 
the subsequent cycles.  If a dose cannot be administered within the planned window due to any 
unresolved AEs, the dose on that cycle should be skipped. The subsequent dose should be 
administered in the next scheduled cycle or when the AE has been resolved/recovered for dose 
continuation as specified in Section 6.5.1. 
In the combination therapy, if one of the study drugs is permanently discontinued due to any 
unresolved AEs, the other study drug can be continued. For more details of treatment duration, 
please refer to Section 6.1.4.
If a subject requires a dose interruption of pembrolizumab for >12 consecutive weeks or 
capmatinib for > 6 consecutive weeks from last dose of the study treatment due to any 
unresolved AEs related to study drug(s), the subject must discontinue the study drug. 
However, if the subject is continuously deriving clinical benefit and, in the opinion of the 
investigator, it is in the subject’s best interest to remain on study treatment, the subject may 
restart the study treatment after documented agreement with Novartis.
7
Informed consent procedures
Eligible subjects 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 subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject 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). Laboratory and radiological studies which were done 
prior to obtaining consent as part of the subject's clinical standard of care within the acceptable 
screening window may be used for screening purposes. The process of obtaining informed 
consent must be documented in the subject 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.
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Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB) for capmatinib and package insert for pembrolizumab. 
This information will be included in the subject informed consent and should be discussed with 
the subject during the study as needed. Any new information regarding the safety profile of the 
investigational drug that is identified between IB updates will be communicated as appropriate, 
for example, via an investigator notification or an aggregate safety finding. New information 
might require an update to the informed consent and then must be discussed with the subject.
The following informed consents are included in this study:

Main study consent, which also includes:

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 Follow-up Consent for the pregnant subjects

As applicable, Pregnancy Follow-up Consent for the pregnant partner of male subjects
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 subjects 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.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain a standard 
written informed consent due to limits that prevent an on-site visit, Investigator may conduct 
the informed consent discussion remotely (e.g. telephone, videoconference) if allowable by a 
local Heath Authority.
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.).
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8
Visit schedule and assessments
Following approval of protocol amendment 03, the efficacy and safety assessments will be 
performed as per each institution's standard of care. The assessment schedule in Table 8-2 will 
no longer be applicable and will be replaced by Table 8-2b.  
The Assessment Schedule (Table 8-2) lists all of the assessments when they are performed. 
All data obtained from these assessments must be supported in the subject’s source 
documentation.
Subjects should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-2) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. Subjects who prematurely discontinue the study 
for any reason should be scheduled for a visit as soon as possible, at which time all of the 
assessments listed for the final visit will be performed. At this final visit, all dispensed 
investigational product should be reconciled, and the adverse event and concomitant 
medications recorded on the eCRF.
During the course of the study visits, test procedures should occur on schedule whenever 
possible as per allowable visit windows specified in Table 8-1 below.
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 allowed by local Health Authority and depending on operational capabilities, phone 
calls or virtual contacts (e.g. tele consult) 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
Allowable visit windows 
Visit name
Window
Screening
Day -28 to Day -1
Cycle 1 Day 1
Within 3 days after randomization in IRT
Day 1 of the subsequent cycles 
± 4 Days
PK/IG/PD sampling
Refer to tables in Section 8.5.1 
Tumor assessments
± 7 Days
EOT
≤ 7 Days after decision of discontinuation of study 
treatment
Safety follow up assessment
± 7 Days 
Survival follow- up
± 14 Days
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Table 8-2
Assessment Schedule – obsolete upon approval of protocol amendment 03
Period
Screening
Treatment
Follow-up
Visit Name
Screening
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Subsequ
ent 
cycles
(Up to 35 
cycles)
EOT
Safety 
Disease 
progression
Survival 
Day
-28 to -1
1
1
1
1
1
1
1
-
30
-
Every 12 
weeks
Obtain informed consent
X
IRT registration
X
(Screening 
& 
randomizat
ion)
X 
(for capmatinib dispensing only)
Collection of local PD-L1 
expression data
X1
Demography
X
Inclusion/exclusion criteria
X
Diagnosis, stage and 
grade of cancer
X
Relevant medical 
history/current medical 
conditions
X
Prior anti-neoplastic 
therapies (medications, 
surgery, radiotherapy)
X
Prior/Concomitant 
Medications
X
X (concomitant medications to be collected from consent until 30 days after last dose of study 
treatment or start of new antineoplastic medication (ANP), whichever is sooner.
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Period
Screening
Treatment
Follow-up
Visit Name
Screening
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Subsequ
ent 
cycles
(Up to 35 
cycles)
EOT
Safety 
Disease 
progression
Survival 
Day
-28 to -1
1
1
1
1
1
1
1
-
30
-
Every 12 
weeks
Smoking history
X
Physical Exam 
S
S (Refer to Table 8-4)
Height
X
Weight
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
X
X
ECG
X
X (If clinically indicated)
Hematology
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
Coagulation
X
X (if clinically indicated)
Thyroid panel including 
free T4 and TSH and total 
T3 if abnormal thyroid 
function is suspected
X
X
X
X
X  (Every 
other 
cycle 
from 
Cycle 7)
X
Urinalysis
X
X (if clinically indicated)
Hepatitis markers
X
X (if clinically indicated)
HIV testing if
locally required
S
S (if clinically indicated)
Serum pregnancy test
S2 
S
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Period
Screening
Treatment
Follow-up
Visit Name
Screening
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Subsequ
ent 
cycles
(Up to 35 
cycles)
EOT
Safety 
Disease 
progression
Survival 
Day
-28 to -1
1
1
1
1
1
1
1
-
30
-
Every 12 
weeks
Urine Pregnancy Test
S
S
S
S
S
S
S
Tumor evaluation as per 
RECIST 1.1 
  
X
X  (Refer to Table 8-3)
Adverse Events
X
X
Obtain Pathology report (if 
available) if submitting an 
archival tumor sample
S
Capmatinib PK Sampling7
X6
X
X
Pembrolizumab PK and 
Immunogenicity 
Sampling7
X
X
X
X
X (every 
6 cycles)
X
X8
Study drug administration
pembrolizumab
X
X
X
X
X
X
X
Study drug administration
X (continuous dosing, BID)
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Period
Screening
Treatment
Follow-up
Visit Name
Screening
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Subsequ
ent 
cycles
(Up to 35 
cycles)
EOT
Safety 
Disease 
progression
Survival 
Day
-28 to -1
1
1
1
1
1
1
1
-
30
-
Every 12 
weeks
Capmatinib
Antineoplastic therapies 
since discontinuation of 
study treatment
X
Survival follow up
X
X = assessment to be recorded in the clinical database or received electronically from a vendor
S = assessment to be recorded in the source documentation only
1. Only applicable for subjects with local PD-L1 TPS data available for study eligibility. The PD-L1 TPS data tested locally should be recorded in 
eCRF
2. Within 72 hours prior to first dose of study treatment
 
 
 
6. Only the first eight subjects enrolled into the treatment arm with capmatinib need to take the intensive PK samples specified in Table 8-7. Refer to 
Table 8-8 for the rest of subjects. 
7. If subjects experience an SAE or AE leading to the discontinuation of the study treatment, an unscheduled PK blood sample should be obtained 
whenever possible
8. Only when subjects who return to the site for safety follow up assessment
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Table 8-2b
Assessment Schedule – applicable upon approval of protocol amendment 03
Visit Name
Treatment Phase - all cycles until end of study treatment or 35 cycles 
EOT
30-Day Safety 
Follow-up
Adverse Events
X (continuous) 
Concomitant Medications
X (continuous, until 30 days after last dose of study treatment or start of new antineoplastic medication, 
whichever is sooner)
Study drug administration pembrolizumab
X (day 1 of every cycle)
X = assessment to be recorded in the clinical database 
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8.1
Screening
The study IRB/IEC (Institutional Review Board/Independent Ethics Committee) approved 
informed consent form must be signed and dated before any screening procedures are performed, 
except for laboratory and radiological evaluations which were performed as part of the subject’s 
clinical standard of care within the acceptable screening window.
Subjects will be evaluated against study inclusion and exclusion criteria and safety assessments 
(refer to Table 8-2). Screening assessments must be repeated if performed outside of the 
specified screening window (Table 8-1). Subjects must meet all inclusion and none of the 
exclusion criteria at screening in order to be eligible for the study.
As part of the screening procedures patients PD-L1 status must be established to determine 
eligibility. If the local lab has available data meeting the criteria outlined in Section 5.1 this 
may be accepted. In the event data meeting this criteria is not available, the subject’s tumor 
must be tested at a local or central laboratory using the assay specified in Section 5.1.
Laboratory test result(s) or symptoms that do not satisfy the eligibility criteria may be repeated 
or treated during the screening visit window. In the event that the repeated laboratory test(s) 
cannot be performed within 28 days from the original screening visit, or do not meet the 
eligibility criteria, or other eligibility criteria have changed and are not met anymore, the subject 
is considered a screen failure.
It is permissible to re-screen a subject if s/he fails the initial screening; however, each case must 
be discussed and agreed with the Sponsor on a case-by-case basis. A new ICF needs to be signed 
if the investigator chooses to re-screen the subject after a subject has screen failed. A new 
subject number will be assigned to the subject. The rescreen form will have to be completed in 
the electronic Case Report Form (eCRF) to provide the original subject number. All required 
screening activities must be performed when the subject is re-screened for participation in the 
study. An individual subject may only be re-screened once for the study. Once the number of 
subjects screened and enrolled is likely to ensure target enrollment, the Sponsor may close the 
study to further screening. In such case, screen failure subjects will not be permitted to re-screen.
8.1.1
Information to be collected on screening failures
Subjects who sign an informed consent form and are subsequently found to be ineligible will 
be considered a screen failure. The reason for screen failure should be entered on the applicable 
eCRF. The demographic information, informed consent, and Inclusion/Exclusion pages must 
also be completed for screen failure subjects. No other data will be entered into the clinical 
database for subjects who are screen failures, unless the subject experienced a serious adverse 
event (SAE) during the screening phase (see Section 10.1.3 for SAE reporting details). Adverse 
events that are not SAEs will be followed by the investigator and collected only in the source 
data. If the subject fails to be randomized, the IRT must be notified within 2 days. 
Subjects who are randomized but fail to start treatment, e.g. subjects randomized in error, will 
be considered as early terminators. The reason for early termination should be recorded on the 
appropriate eCRF.
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8.2
Subject demographics/other baseline characteristics
Subject demographics and baseline characteristic data are to be collected from all subjects. 
Smoking history and relevant medical history/current medical condition present before signing 
the informed consent will be recorded. Investigators will have the discretion to record abnormal 
test findings on the appropriate CRF whenever in their judgment, the test abnormality occurred 
prior to the informed consent signature. 
Country-specific regulations should be considered for the collection of demographics and 
baseline characteristics in alignment with CRF.
Wherever allowable by local laws and regulations, subject race and ethnicity are collected and 
analyzed to assess the diversity of the study population as required by certain Health Authorities 
and may be used to identify variations in safety or efficacy due to these factors.
8.3
Efficacy
Following approval of protocol amendment 03, all efficacy assessments are to be performed 
according to each institution’s standard of care, and the requirements detailed in Table 8-3 are 
no longer mandated. Additional scans may be done at the investigator’s discretion. Efficacy 
data will not be captured on the eCRFs and there will be no central collection of imaging data. 
8.3.1
Efficacy assessments
Tumor response will be assessed locally according to the Novartis guideline version 3.2 
(Section 16.1) based on RECIST 1.1 (Eisenhauer et al 2009) 
. 
The imaging assessment collection plan is presented in Table 8-3. 
Imaging data will be centrally collected and checked for quality by an imaging Contract 
Research Organization (CRO) designated by Novartis. The local investigator’s assessment will 
be used for the primary endpoint analysis and for treatment decision making. Central review of 
the imaging data may be performed if deemed necessary.
Table 8-3
Imaging Assessment Collection Plan – not mandated upon approval 
of protocol amendment 03
Procedure
Screening/Baseline
During Treatment/Follow-
up
CT* of the chest and abdomen 
(with intravenous contrast 
enhancement)
Mandated
Every 9 weeks through 45 
weeks and every 12 weeks 
thereafter 
 
CT* of pelvis (with intravenous 
contrast enhancement)
Mandated
Only if lesions were 
documented at screening; 
follow the same schedule 
as CT of the chest and 
abdomen, or if clinically 
indicated
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Procedure
Screening/Baseline
During Treatment/Follow-
up
CT or MRI of the brain
Mandated
Only if lesions were 
documented at screening; 
follow the same schedule 
as CT/MRI of the chest and 
abdomen, or if clinically 
indicated
Whole body bone scan
Mandated
Only if clinically indicated
Localized bone CT, MRI or x-ray
Mandated for any lesions 
identified on the whole body bone 
scan that are not visible on the 
CT/MRI of the chest, abdomen 
and pelvis
Only if lesions were 
documented at screening; 
follow the same schedule 
as CT/MRI of the chest and 
abdomen, or if clinically 
indicated
CT or MRI of other 
metastatic sites (e.g., neck)
If clinically indicated
Only if lesions were 
documented at screening, 
follow the same schedule 
as CT/MRI of the chest and 
abdomen , or if clinically 
indicated
Photography with scale/ruler (for 
any skin lesion)
If clinically indicated ( for any skin 
lesions present)
Only if lesions were 
documented at screening, 
follow the same schedule 
as CT/MRI of the chest and 
abdomen, or if clinically 
indicated
*: If CT is not feasible, refer to the below part “Baseline imaging assessment” for details.
Baseline imaging assessments
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).
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 as the baseline images for this study. Any imaging assessments obtained after 
randomization will not be considered baseline. Refer to Table 8-3 for a list of imaging 
assessments required at baseline. 
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 (MRI is not 
recommended due to respiratory artifacts, however if CT is not feasible per local regulations, 
MRI can be performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen and 
pelvis should be performed.
Brain MRI or CT must be completed at baseline. Contrast enhanced brain MRI is preferred, 
however, if MRI contrast is contraindicated, then MRI without contrast or CT with/without 
contrast is acceptable.
A whole body bone scan should be performed per institutional standard of care (e.g., Tc-99 
bone scan, whole body bone MRI, Fluorodeoxyglucose positron emission tomography 
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(FDG-PET) or sodium fluoride (NaF) PET). Localized CT, MRI or X-rays should be acquired 
for all skeletal lesions identified on the screening whole body bone scan, which are not visible 
on the chest, abdomen and pelvis CT/MRI.
If clinically indicated, CT or MRI of other areas (e.g., neck) of disease as appropriate should be 
performed.
If skin lesions are present at screening, color photography should be acquired using a digital 
camera in clear focus, including a scale/ruler, in such a way that the size of the lesion(s) can be 
determined from the photograph.
Any potentially measurable lesion that has been previously treated with radiotherapy should be 
considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable 
lesion.
Chest X-rays and ultrasound should not be used to measure tumor lesions.
Post-baseline imaging assessments
Imaging assessments as described in Table 8-3 should be performed at the time points specified 
using the same imaging modality used at baseline, irrespective of study treatment interruption 
or actual dosing (see Table 8-2). Imaging assessments for response evaluation will be performed 
every 9 weeks (+/- 7 days) through 45 weeks and every 12 weeks (+/- 7 days) thereafter until 
disease progression, death, lost to follow-up or withdrawal of consent. Imaging assessments 
should be scheduled using the randomization date as the reference date (not the date of the 
previous tumor assessment) and should be respected regardless of whether treatment with study 
treatment is temporarily withheld or unscheduled assessments performed.
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a subject, as necessary. 
Clinical suspicion of disease progression at any time requires a physical examination and 
imaging assessments to be performed promptly rather than waiting for the next scheduled 
imaging assessment.
Each lesion that is measured at baseline must be measured by the same method (either same 
imaging method or by photography, including a metric ruler) and when possible, the same local 
radiologist/physician throughout the study so that the comparison is consistent. If an off-
schedule imaging assessment is performed because progression is suspected, subsequent 
imaging assessments should be performed in accordance with the original imaging schedule.
Combined PET/CT may be used only if the CT is of similar diagnostic quality as a 
CT performed without PET, including the utilization of IV contrast media. At the discretion of 
the Investigators, FDG-PET scans may be performed to document progressive disease per 
RECIST 1.1 (Section 16.1). 
The coded medical images will be used primarily for analysis as described in this protocol; 
however, the images may also be used for the development and evaluation of new analysis 
methods directly related to the area of research that this study covers.
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8.3.2
Appropriateness of efficacy assessments
The efficacy assessments selected are standard for this indication/subject population. 
Additional information can be found in Section 16.1 and Section 16.2.
8.4
Safety
Following approval of protocol amendment 03, all safety assessments are to be performed 
according to each institution’s standard of care, and the requirements detailed in Table 8-4 and 
Table 8-6 are no longer mandated. The results of safety assessments will not be captured on the 
eCRFs. However, clinically significant findings must be recorded as AEs on the eCRFs. 
Reporting of AEs, including SAEs, will continue to ensure Sponsor’s oversight of safety. 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to the AE Section 10.1.1.
Table 8-4
Assessments & Specifications – not mandated upon approval of 
protocol amendment 03
Assessment
Specification
Physical 
examination
Physical examination will be performed according to Table 8-2.
At Screening and Cycle 1 Day 1 prior to treatment, a complete physical 
examination will be performed and will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities and neurological.
After Cycle 1 Day 1 onwards, a short physical examination will be performed (it will 
include the examination of general appearance and vital signs).
Clinically relevant findings that were present prior to signing informed consent 
must be recorded on the appropriate eCRF that captures medical history. 
Significant new findings that begin or worsen after informed consent which meet 
the definition of an Adverse Event must be recorded as an adverse event.
For Japan only: oxygen saturation (SpO2) will be measured by pulse oximetry for 
Japanese subjects every time physical examination is performed as indicated in 
Table 8-2. The results of SpO2 will be recorded only in the source documentation.
Vital signs
Vital signs include blood pressure (supine position preferred when ECG is 
collected), pulse measurement, and body temperature. 
They will be measured at screening and at subsequent time points as specified in 
Table 8-2.
Height and 
weight
Height 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 8-2.
Performance 
status
The performance status will be assessed according to the Eastern Cooperative 
Oncology Group (ECOG) Performance Status Scale as specified in Table 8-5 
following the schedule given in Table 8-2.
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Table 8-5
ECOG Performance Status
Grade
ECOG status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Death
8.4.1
Laboratory evaluations
All laboratory parameters assessed for safety purpose will be evaluated locally. Additional time 
points should be added as deemed necessary per the investigator's best judgment to make sure 
the toxicity profile is sufficiently characterized and dose adjustments are performed to 
safeguard the safety of the subject. 
Laboratory values obtained during the screening to assess the subject’s eligibility will not be 
required to be repeated prior to dosing (except serum pregnancy test if not done within 72 hours 
prior to treatment start, and hematology/chemistry if not done within 7 days prior to treatment 
start) unless deemed clinically necessary by the investigator and/or required as per local 
institutional policies. The time windows granted for laboratory evaluations are identical to the 
corresponding visit time windows for each visit (refer to Table 8-1) except as stated above.
The investigator is responsible for reviewing all laboratory reports for subjects in the study and 
evaluating any abnormalities for clinical significance.
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate.
Table 8-6
Laboratory Assessments – not mandated upon approval of protocol 
amendment 03
Test Category
Test Name
Hematology
Hemoglobin, Platelets, Hematocrit, White blood cells, Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils, Other)
Chemistry
Albumin, Alkaline Phosphatase, ALT, Amylase, AST, Calcium, Creatinine, Total 
Bilirubin, Direct Bilirubin, Indirect Bilirubin, GGT, Lipase, Magnesium, Sodium, 
Potassium, fasting Glucose (non- fasting glucose allowed post-baseline), Blood 
Urea Nitrogen (BUN) or Urea, Bicarbonate, Uric Acid, Lactate dehydrogenase 
(LDH), Phosphorus, Creatine kinase, Total Cholesterol
Urinalysis
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, 
Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
If dipstick is abnormal then perform local laboratory Microscopic Panel (Red 
Blood Cells, White Blood Cells, Casts, Crystals, Bacteria, Epithelial cells)
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Test Category
Test Name
Coagulation
International normalized ratio (INR) or Prothrombin Time (PT), and Activated 
Partial Thromboplastin Time (APTT) or Partial Thromboplastin Time (PTT)
Thyroid
TSH (Thyroid Stimulation Hormone), Free T4 and total T3 if abnormal thyroid 
function is suspected
Hepatitis* 
markers
HBV-DNA, HBsAg, HBsAb, HBcAb (IgG), HCV Ab, HCV RNA-PCR 
HIV testing
HIV antibody where locally required
Pregnancy Test
Refer to Section 8.4.3 
*If HBsAg, HBsAb and HBcAb are all negative, HBV DNA test is not required; if HCV Ab is negative, 
HCV RNA test is not required.
8.4.2
Electrocardiogram (ECG)
Following approval of protocol amendment 03, ECGs are to be performed according to each 
institution's standard of care.
Electrocardiograms (ECGs) must be recorded after 10 minutes rest in the supine position to 
ensure a stable baseline. The preferred sequence of cardiovascular data collection during study 
visits is ECG collection first, followed by vital signs, and blood sampling. The Fridericia QT 
correction formula (QTcF) should be used for clinical decisions.
Triplicate 12-lead ECGs are to be collected with ECG machines available locally at the site. 
The individual ECGs should be recorded approximately 2 minutes apart. The mean QTcF value 
for each visit will be calculated from the triplicate ECGs for each subject. ECGs will be 
performed at screening and at the discretion of the investigator at any time and as clinically 
indicated during the study conduct. 
For any ECGs with subject safety concerns, two additional ECGs must be performed to confirm 
the safety finding. A monitoring or review process should be in place for clinically significant 
ECG findings throughout the study and especially at screening before administration of study 
treatment. Any identifier details must be redacted e.g. subject initials, date of birth.
If a clinically significant ECG abnormality is identified at the site (e.g. severe arrhythmia, 
conduction abnormality of QTcF > 500 ms), the ECG is repeated to confirm the diagnosis. If the 
subject is hemodynamically compromised, the investigator or a medically qualified person must 
initiate appropriate safety procedures without delay (for example cardioversion).
Clinically significant abnormalities must be recorded on the eCRF as either medical 
history/current medical conditions or adverse events as appropriate.
Interpretation of the tracing must be made by a qualified physician and documented on the ECG. 
Each ECG tracing should be labeled with the study number, subject initials (where regulations 
permit), subject number, date, and kept in the source documents at the study site. Clinically 
significant abnormalities present at screening should be reported on the appropriate eCRF. 
Clinically significant findings must be discussed with Novartis prior to enrolling the subject in 
the study. New or worsened clinically significant findings occurring after informed consent 
must be recorded as AEs.
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8.4.3
Pregnancy and assessments of fertility
A condom is required for all sexually active male participants receiving capmatinib to prevent 
them from fathering a child AND to prevent delivery of capmatinib via seminal fluid to their 
partner. In addition, male participants receiving capmatinib should not donate sperm for the 
time period specified in Section 5.2.
In case of a positive urine pregnancy test, additional tests must be performed to confirm 
pregnancy and if confirmed, the reporting requirements as described in Section 10.1.4, must be 
followed. If a subject becomes pregnant, study treatment must be stopped immediately. If a 
pregnancy test (urine or serum) is positive, but the subject is thought not to be pregnant, study 
drug should be stopped until it is determined that the test was falsely positive, and pregnancy is 
excluded.
Assessments of Fertility
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:
1. Surgical bilateral oophorectomy without a hysterectomy
2. 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 subject regardless of reported reproductive/menopausal status 
at screening/baseline.
8.4.4
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/subject population.
8.5
Additional assessments
8.5.1
Pharmacokinetics and immunogenicity assessments
Blood samples will be collected from all subjects for the analysis of plasma capmatinib and 
serum pembrolizumab concentrations, as well as for immunogenicity (IG) analysis. 
 
 
 
Following enrollment halt and the release of the memorandum on 04-Feb-2021, collection of 
PK and IG samples is terminated. 
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8.5.1.1
Pharmacokinetic and immunogenicity blood collection and handling 
The exact date and clock times of drug administration and PK blood draw will be recorded on 
the appropriate eCRF page. If vomiting occurs within 4 hours following capmatinib 
administration on the day of post dose PK blood sampling, the clock time of vomiting should 
be recorded in the dosage administration PK eCRF page.
Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in 
a forearm vein. A total of 3 mL of blood will be collected at specified time points for capmatinib 
analysis in plasma. Another 6 mL of blood will be collected for pembrolizumab and IG analysis 
in serum. Blood samples should be collected from the arm opposite from the investigational 
drug infusion, or from another site. Refer to the study's laboratory manual for detailed 
instructions for the collection, handling, and shipment of PK and IG samples. If subjects 
experience an SAE or AE leading to the discontinuation of the study treatment, an unscheduled 
PK blood sample should be obtained whenever possible. The date and time of the last dose and 
the time of PK blood draw should be recorded. 
8.5.1.2
Pharmacokinetic sampling for capmatinib
PK blood samples for capmatinib are outlined in Table 8-7 and Table 8-8. The subjects who 
will be involved in the early safety review will collect more extensive PK samples in Cycle 2 
compared to subjects who will not be involved in the early safety review. All subjects will 
provide a pre-dose PK sample and a post-dose PK sample between 1-4 hours on C3D1 and 
C4D1. 
Table 8-7
Capmatinib pharmacokinetic blood collection log for the first 8 
enrolled subjects in combination treatment arm – obsolete upon 
approval of protocol amendment 03
Cycle
Day
Scheduled Time point (h)
Analytes
2
1
Pre-dosea
PK
2
1
1 (±10 minutes)
PK
2
1
2 (±15 minutes)
PK
2
1
4 (±30 minutes)
PK
2
1
8 (±2 hours)
PK
3
1
Pre-dosea
PK
3
1
Anytime between 1-4h
PK
4
1
Pre-dosea
PK
4
1
Anytime between 1-4h
PK
Unscheduled 
 
Anytime
PK
a Take samples immediately prior to administration of capmatinib
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Table 8-8
Capmatinib pharmacokinetic blood collection log for rest of subjects 
other than first 8 enrolled subjects in combination treatment arm – 
obsolete upon approval of protocol amendment 03
Cycle
Day
Scheduled Time (h)
Analytes
2
1
Pre-dosea
PK
2
1
Anytime between 1-4h
PK
3
1
Pre-dosea
PK
3
1
Anytime between 1-4h
PK
4
1
Pre-dosea
PK
4
1
Anytime between 1-4h
PK
Unscheduled 
 
anytime
PK
a Take samples immediately prior to administration of capmatinib
8.5.1.3
Pharmacokinetic and immunogenicity sampling for pembrolizumab
Blood samples for pembrolizumab PK and IG analysis will be collected for both capmatinib 
plus pembrolizumab arm and pembrolizumab alone arm as outlined in Table 8-9. PK and IG 
samples will be collected also at the end of treatment visit and in the event of a clinically 
significant AE (such as infusion reaction/anaphylaxis) or if IG is suspected. After the cut-off 
for the primary analysis is reached, no additional PK and IG samples will be collected for the 
subjects still ongoing in the study.
Table 8-9
Pembrolizumab pharmacokinetic and immunogenicity blood 
collection log – obsolete upon approval of protocol amendment 03
Cycle
Day
Scheduled Time Point 
(h)
Analytes
1
1
Pre-dosea
PK/IG
2
1
Pre-dosea
PK/IG
3
1
Pre-dosea
PK/IG
6
1
Pre-dosea
PK/IG
Every 6 cycles after C6D1 until 
discontinuation of study treatment
1
Pre-dosea
PK/IG
EOT
anytime
PK/IG
30-day safety follow-upb
anytime
PK/IG
Unscheduled 
 
anytime
PK/IG
a Take samples immediately prior to infusion of pembrolizumab
b For subjects who return to the site for safety follow up assessment
8.5.1.4
Analytical method
Pharmacokinetic samples for capmatinib will be quantified using validated LC/MS/MS assays. 
The assay to quantify and assess the pembrolizumab PK and IG will be a validated 
homogeneous ELISA (Enzyme-linked immunosorbent assay).  
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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a subject can be initiated by either the subject or the 
investigator.
The investigator must discontinue study treatment for a given subject if he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances:

Subject/guardian decision

Any situation in which study participation might result in a safety risk to the subject.

Pregnancy

Death
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Following approval of protocol amendment 03, in countries where pembrolizumab is approved 
and available for the study indication, subjects may be transitioned to commercial 
pembrolizumab and discontinued from the study.
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information.
Subjects 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 withdraw of informed consent section). Where possible, they should return 
for the assessments indicated in the assessment schedule. 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 subject/pre-designated contact as specified in the lost to follow-up section. This 
contact should preferably be done according to the study visit schedule.
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

new / concomitant treatments

Adverse events/Serious adverse events. 
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment of capmatinib. The discontinuation of pembrolizumab is not required to be recorded 
in IRT.
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
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 subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
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.
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For US and Japan: 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 
informed consent form.
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
9.1.3
Lost to follow-up
For subjects 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.
9.1.4
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 subjects 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 subject welfare and safety. 
Should early termination be necessary, subjects must be seen as soon as possible (provide 
instruction for contacting the subject, when the subject should stop taking drug, when the 
subject should come in for a final visit) and treated as a prematurely withdrawn subject. 
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 subject’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
9.2.1
End of study
Following the study enrollment halt, the end of the study is defined as the earliest occurrence 
of one of the following:
- discontinued study treatment and completed the safety FU or
- died or
- withdrawn consent or
- been lost to follow-up. 
See Section 12 Data Analysis and statistical methods for details of timing of the final reporting 
of data.
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9.2.2
Follow up
9.2.2.1
Safety follow-up
All subjects receiving study treatment must have safety evaluations for 30 days after the last 
dose of study treatment. The 30 day safety follow-up can be done by telephone call or visit. 
Concomitant medications will be collected until the 30-day safety follow-up has been 
completed or the start of a new antineoplastic therapy, whichever occurs first. A PK and 
immunogenicity sample should be collected at the 30-day safety follow up visit as described in 
Section 8.5.1. If the 30-day safety evaluation is conducted by phone, samples do not need to be 
collected.
Data collected should be added to the Adverse Events CRF, the antineoplastic therapies since 
discontinuation of study treatment CRF, the Concomitant Medications CRF and the PK/IG CRF. 
For female subjects of child bearing potential, pregnancy tests will be performed as outlined in 
Section 8.4.3.
As of 04-Feb-2021, collection of PK and IG samples is terminated. Following approval of 
protocol amendment 03, antineoplastic therapies since discontinuation of study treatment will 
not be collected.
9.2.2.2
Disease progression follow-up
Following approval of protocol amendment 03, disease progression follow-up will not be 
performed.
All subjects who discontinue study treatment for any reason other than death or disease 
progression as per RECIST 1.1 should return for tumor assessments at the intervals specified in 
Table 8-2 until documented disease progression, death, lost to follow-up or withdrawal of 
consent (Section 8.3.1).
If patients refuse to return for these visits or are unable to do so, every effort should be made to 
contact them or a knowledgeable informant by telephone to determine if the patient had disease 
progression. Once the follow-up for disease progression period has ended, the appropriate 
disposition eCRF should be completed.
9.2.2.3
Survival follow-up
Following approval of protocol amendment 03, survival follow-up will not be performed. 
Subjects will enter the survival follow-up period once they complete the safety follow-up and/or 
disease progression follow-up after treatment discontinuation (whichever is longer). Subjects 
will then be contacted by telephone every 12 weeks to follow up on their survival status. Any 
new antineoplastic therapies that have been started since the last contact date will also be 
collected during these phone calls.
Information on all subsequent therapies received for NSCLC, if any, after study treatment has 
been completed, will be collected (including start date, stop date, and date of progression if 
any).
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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 subject or 
clinical investigation subject 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 subject 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 subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject 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):
1. the severity grade according to the Common Terminology Criteria for Adverse Events 
(CTCAE) v 5.0.

Grade 1 to 4 will be used to characterize the severity of the Adverse Event. If CTCAE 
grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening (corresponding respectively to Grades 1 - 4) will be used.
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject
3. its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported
4. whether it constitutes an SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. action taken regarding with study treatment
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All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose reduced/increased

Drug interrupted/withdrawn
6. its outcome 
If the event worsens, the event should be reported a second time in the eCRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 AEs only, if improvement to a lower 
grade is determined, a new entry for this event should be reported in the eCRF noting the start 
date when the event improved from having been Grade 3 or Grade 4.
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
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 AE 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 assessments 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 1.1 criteria for solid tumors), should not be reported as a 
serious adverse event. However, if the progression of malignancy is considered to be related to 
study treatment as per Investigator’s assessment and meets the SAE definition, the event should 
be reported as a serious adverse event.
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.
Information about adverse drug reactions for the investigational drug can be found in the 
capmatinib Investigator’s Brochure or the locally approved package insert of pembrolizumab.
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 subjects with 
the underlying disease.
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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
Life-threatening in the context of an SAE refers to a reaction in which the subject 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 subject’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of an SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject 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 subject 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 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.
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10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety within 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.
The following SAE reporting time frames apply: 
1. Screen Failures (e.g. a subject who is screened but is not randomized): SAEs occurring 
after the subject has provided informed consent until the time the subject is deemed a 
Screen Failure must be reported to Novartis. 
2. Randomized OR treated Subjects: SAEs collected from a subject signs ICF until 30 days 
after the subject has discontinued or 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.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment, a Novartis Chief Medical 
Office and Patient Safety (CMO & PS) Department associate may urgently require further 
information from the investigator for health authority reporting. Novartis may need to issue an 
Investigator Notification (IN) to inform all investigators involved in any study with the same 
study treatment that this SAE has been reported.
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 period of safety follow up should only be reported to 
Novartis Safety if the investigator suspects a causal relationship to study treatment.
10.1.4
Pregnancy reporting
Pregnancies
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Novartis 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 any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported.
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Pregnancy outcomes should be collected for the female partners of any males who took 
capmatinib in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
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, subject 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
Yes, even if not 
associated with an 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
Data Monitoring Committee
This study will include a data monitoring committee (DMC), which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will be responsible to review safety data. 
The first review will occur after the first 6 randomized patients have been followed up for at 
least 6 weeks from randomization or have discontinued earlier. The second review will occur 
after the first 12 randomized patients have been followed up for at least 6 weeks from 
randomization or have discontinued earlier. Subsequent reviews on safety data will be 
conducted every 6 months. The DMC will also assess the data from the interim analysis as 
mentioned in Section 4.4. The interim analysis (planned and unplanned if any) will be 
conducted by an independent statistician and independent programmer supporting the DMC. 
The CTT, investigator staff, persons performing the assessments and subjects will not have 
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access to the interim data and results of the analysis. However, the key results will be shared by 
the DMC with a Novartis Committee as specified in the DMC charter.
Specific details regarding composition, responsibilities, data monitoring and meeting frequency, 
and documentation of DMC reports, minutes, and recommendations will be described in a 
separate DMC charter that is established between the sponsor and the DMC.
Following the enrollment halt, the randomization information was released for internal data 
review and to address Health Authorities’ queries.  As a result, independent data review will 
not be performed and the DMC will be disbanded.
10.2.2
Steering Committee
A Steering Committee (SC) will be established comprising investigators participating in the 
trial. 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 the SC Charter.
11
Data collection and database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the 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 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 subject 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.
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Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology.
Randomization codes and data about capmatinib dispensed to the subject and all dosage changes 
will be tracked using Interactive Response Technology (IRT). The data will be used for analyses 
specified in Section 12.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 
and statistician. 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 meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. 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 subject records, the accuracy of data capture / data 
entry, the adherence to the protocol and to GCP, 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 Trial 
Monitoring 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 subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographics and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on the CRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
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 subjects will be disclosed.
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12
Data analysis and statistical methods
The analysis of all primary and secondary endpoints will be performed after the end of the 
study.
Data from participating centers in this protocol will be combined, so that an adequate number 
of subjects will be available for analysis. Study data will be reported in the final clinical study 
report (CSR) based on all subjects’ data up to the time of the completion of the study. There will 
be no additional CSR.
All summaries, listings, figures and analyses will be performed by treatment arm, unless 
otherwise specified. Additional summaries by histological type (squamous vs. non-squamous) 
or other subject subgroups may be produced as relevant for selected endpoints.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
distributions (e.g., 25th and 75th percentiles) may also be presented.
Screen failure subjects, as described in Section 8.1, and the reasons for not starting the study 
treatment will be reported in a listing, but will not be included in any analyses.
Details of the statistical analysis and data reporting will be provided 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) comprises all subjects to whom study treatment has been assigned 
by randomization. According to the intent-to-treat (ITT) principle, subjects will be analyzed 
according to the treatment they have been assigned to during the randomization procedure. 
All efficacy endpoints will be analyzed based on the FAS population. 
12.1.2
 Per-Protocol Set
Not applicable.
12.1.3
Safety Set
The Safety set includes all subjects who received at least one dose of study treatment (either 
one in the combination arm). Subjects will be classified according to treatment received, where 
treatment received is defined as:

the treatment assigned if it was received at least once, or

the first treatment received when starting therapy with study treatment if the assigned 
treatment was never received.
All safety endpoints will be analyzed based on the safety set.
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12.1.4
 Pharmacokinetic Analysis Sets
The capmatinib pharmacokinetic analysis set (INC-PAS) includes all subjects who provide at 
least one blood sample providing measurable capmatinib PK data. For a concentration to be 
evaluable, subjects are required to:

receive the planned treatments prior to sampling

(for pre-dose samples) not to vomit within 4 hours after the last dosing of capmatinib prior 
to sampling; (for post-dose samples) not to vomit within 4 hours after the dosing of 
capmatinib.

(for pre-dose sample) have the sample collected before the next dose administration and 
9-15 hours after the last dose administration.
The pembrolizumab pharmacokinetic analysis set (Pembro-PAS) includes all subjects who 
provide at least one blood sample providing measurable pembrolizumab PK data. For a 
concentration to be evaluable, subjects are required to:

have received one of the planned pembrolizumab treatments prior to sampling.

(for pre-dose samples) have the sample collected before the next dose administration.

The immunogenicity (IG) set includes two parts: IG prevalence set and IG incidence set:

The IG prevalence set includes all subjects in the FAS with a determinant baseline IG 
sample or at least one determinant post-baseline IG sample.

The IG incidence set includes all subjects in the IG prevalence set with a determinant 
baseline IG sample and at least one determinant post-baseline IG sample.
Note: Some subject’s data may not be adequate for the reliable estimation of some PK 
parameters. These cases will be identified and their PK parameters will be excluded from the 
relevant summaries. The criteria of exclusion will be listed in the SAP.
All endpoints related to pharmacokinetics will be analyzed based on the PAS analysis set, unless 
otherwise specified.
12.2
Subject demographics and other baseline characteristics
Demographics and other baseline data (including disease characteristics) will be listed and 
summarized descriptively by treatment arm for the FAS.
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term by treatment arm. 
12.3
Treatments
The Safety set will be used for the analyses below. 
The duration of exposure in weeks of capmatinib and pembrolizumab, as well as the dose 
intensity (computed as the ratio of actual cumulative dose received and actual duration of 
exposure) and the relative dose intensity (computed as the ratio of dose intensity and planned 
dose intensity) will be summarized by means of descriptive statistics using the safety set.
The duration of exposure will also be presented for each study drug.
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The number of subjects with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by treatment arm and all dosing data will 
be listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed by subject and summarized by anatomical therapeutic chemical 
classification system (ATC) term and treatment arm.
12.4
Analysis of the primary endpoint(s)
12.4.1
Efficacy endpoints
The primary endpoint of this study is the progression-free survival (PFS). Estimation of PFS 
will be provided by treatment arm, based on the FAS population.
12.4.1.1 Definition of primary endpoint(s)
PFS is defined as the time from the date of randomization to the date of the first documented 
progression or death due to any cause. PFS will be assessed via local review according to 
RECIST v1.1 (see Section 16.1 for further details). Censoring conventions are provided below 
in Section 12.4.1.3. 
12.4.1.2 Statistical hypothesis, model, and method of analysis 
Kaplan-Meier curves for PFS as well as estimated median PFS along with their two-sided 95% 
confidence intervals will be presented for each treatment arm. The FAS will be used.
12.4.1.3 Handling of missing values/censoring/discontinuations
PFS will be censored at the date of the last adequate tumor assessment prior to the earliest of 
analysis cut-off date, the start of a subsequent anti-neoplastic therapy (if any), the date of 
sponsor’s decision to discontinue capmatinib (applicable only to subjects on the combination 
arm), or if the event occurred after two or more missing tumor assessments. Clinical progression 
without objective radiological evidence will not be considered as documented disease 
progression. Subjects should be followed for documented progression after discontinuation of 
treatment for such clinical progression.  The date of last adequate tumor assessment is the date 
of the last tumor assessment with overall lesion response of CR, PR or SD before an event or a 
censoring reason has occurred. If no post-baseline assessments are available (before an event 
or a censoring reason occurred), the date of treatment randomization will be used.
The number of subjects censored and reasons for censoring will be summarized by treatment 
arm using descriptive statistics.
More details will be provided in the SAP.
12.4.1.4 Sensitivity and Supportive analyses
To further explore the potential lasting effect of capmatinib, a supportive analysis of PFS will 
be performed without censoring data before the date of sponsor’s decision to discontinue 
capmatinib. Kaplan-Meier curves for such PFS as well as estimated median PFS along with 
their two-sided 95% confidence intervals will be presented for each treatment arm.
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12.5
Analysis of secondary endpoints
The secondary efficacy endpoints are ORR, DCR, TTR, DOR as per RECICT 1.1 and OS. 
Estimation of all the secondary endpoints will be provided by treatment arms based on the FAS. 
All relative listings, tables and figures will be presented by treatment arm, unless otherwise 
specified. 
12.5.1
Efficacy and/or pharmacodynamic endpoint(s)
Objective response rate (ORR)
ORR is defined as the proportion of subjects with a best overall response (BOR) of CR or PR 
as per local review and according to RECIST 1.1.
BOR is defined as the best response recorded from the start of the treatment until disease 
progression/recurrence as per local review and according to RECIST v1.1. In particular, any 
subsequent tumor assessment after the date of sponsor’s decision to discontinue capmatinib 
(applicable only to subjects on the combination arm), will be excluded from the BOR derivation.
In addition, to explore the potential lasting effect of capmatinib, a supportive analysis of BOR 
will be performed with including tumor assessments after sponsor’s decision to discontinue 
capmatinib. 
Disease control rate (DCR)
DCR is defined as the proportion of subjects with a best overall response (BOR) of CR, PR or 
SD as per local review and according to RECIST 1.1.
Time-to-response (TTR)
TTR applies to all subjects. For responders, TTR is defined as the time from the date of 
randomization to the first documented response of either CR or PR, which must be subsequently 
confirmed (although date of initial response is used, not date of confirmation). For non-
responders, TTR will be censored at the last adequate tumor assessment date if no PFS event, 
otherwise, TTR will be calculated as the censored time from the first visit of the first subject to 
the last visit of the last subject. 
Duration of response (DOR)
DOR only applies to subjects for whom best overall response is complete response (CR) or 
partial response (PR). DOR is defined as the time between the date of first documented response 
(CR or PR) and the date of first documented progression or death due to underlying cancer. 
If progression or death due to any reasons has not occurred by the date of the cut-off, then the 
subject will be censored following the same rules defined for PFS in Section 12.4.1.3.
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Overall survival (OS)
OS is defined as the time from randomization to date of death due to any cause. If a subject is 
not known to have died by the date of the cut-off, OS will be censored at the last date the subject 
was known to be alive. Additional considerations may be made for the handling of the patients 
who continue to receive therapy beyond RECIST v1.1 PD.
ORR and DCR will be summarized along with their accompanying 95% confidence interval. 
TTR, DOR and OS will be summarized using the Kaplan-Meier estimators for the medians 
along with their accompanying 95% confidence intervals. Kaplan-Meier curves will also be 
provided.
Individual lesion measurements, overall response assessments per RECIST 1.1 as well as BOR 
will be listed by subject and assessment date.
12.5.2
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment arm.
The overall observation period will be divided into three mutually exclusive segments:
Pre-treatment period:

from day of subject’s first informed consent to the day before first administration of study 
treatment
On-treatment period:

Single agent arm: from date of first administration of study treatment to 30 days after date 
of last actual administration of any study treatment (including start and stop date).

Combination arm: from date of first administration of any study drug to 30 days after date 
of last actual administration of any study drug (including start and stop date). 
Post-treatment period:

Single agent arm: starting at day 31 after last administration of study treatment.

Combination arm: starting at day 31 after the last administration of study treatment.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).
The on-treatment period lasts from the date of first administration of study treatment to 30 days 
after the date of the last actual administration of any study treatment.
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Adverse events
All information obtained on adverse events will be displayed by treatment arm and subject. 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. The incidence of treatment-emergent 
adverse events (new or worsening from baseline) will be summarized by system organ class 
and or preferred term, severity (based on CTCAE grades), type of adverse event, relation to 
study treatment. Serious adverse events and non-serious adverse events during the on-treatment 
period will be tabulated. All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths, and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged.
Vital signs
The following will be reported:

Summary of notable vital sign values
Table with descriptive statistics at baseline, one or several post-baseline time points and change 
from baseline to this/these post-baseline time points
12-lead ECG

12-lead ECGs including PR, QRS, QT, QTcF intervals and heart rate (HR) will be 
obtained for each subject during the study. ECG data will be read and interpreted locally.

A listing of these subjects will be produced (by treatment arm).
Clinical laboratory evaluations
All laboratory data will be listed by treatment arm, subject, and visit/time and if normal ranges 
are available abnormalities will be flagged. Summary statistics will be provided by treatment 
and visit/time. Shift tables using the low/normal/high/ (low and high) classification will be used 
to compare baseline to the worst on-treatment value.
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used.
For laboratory tests where grades are not defined by CTCAE v5.0, results will be categorized 
as low/normal/high based on laboratory normal ranges.
The following summaries will be generated separately for hematology, and biochemistry tests:

Listing of all laboratory data with values flagged to show the corresponding CTCAE v5.0 
grades if applicable and the classifications relative to the laboratory normal ranges
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For laboratory tests where grades are defined by CTCAE v5.0

Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject will be 
counted only once for the worst grade observed post-baseline.

Shift tables using CTCAE v5.0 grades to compare baseline to the worst on-treatment value
For laboratory tests where grades are not defined by CTCAE v5.0,

Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value.
In addition to the above-mentioned tables and listings, other exploratory analyses, for example, 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the SAP.
Other safety evaluations
Any other safety information collected will be listed and notable values will be flagged. Any 
statistical tests performed to explore the data will be used only to highlight any interesting 
comparisons that may warrant further consideration.
Immunogenicity
Immunogenicity will be characterized descriptively by tabulating anti-drug antibodies (ADA) 
prevalence at baseline and ADA incidence on-treatment. The impact of immunogenicity on PK, 
safety, and efficacy will be explored. Further details will be specified in the SAP. 
12.5.3
Pharmacokinetics
All pharmacokinetic data analysis and PK summary statistics will be based on the PAS 
population.
Capmatinib and pembrolizumab concentration data will be listed by treatment, subject, and 
visit/sampling time point. Descriptive summary statistics will be provided by treatment and 
visit/sampling time point, including the frequency (n, %) of concentrations below the lower 
limit of quantification (LLOQ) and reported as zero.
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. Concentrations below LLOQ will be treated as 
zero in summary statistics and for PK parameter calculations.
Pharmacokinetic parameters (e.g. Ctrough, Cmax, AUC) for all PK-evaluable patients will be 
listed by treatment and subject. For capmatinib, PK parameters include but may be not limited 
to those listed in Table 12-1. For pembrolizumab, PK parameters will include but may not be 
limited to Ctrough. Descriptive summary statistics will include mean (arithmetic and geometric), 
SD, and CV (arithmetic and geometric), median, minimum, and maximum. An exception to this 
is Tmax where median, minimum, and maximum will be presented. Missing data will not be 
imputed and will be treated as missing.
 
  
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Table 12-1
Non-compartmental pharmacokinetic parameters
AUClast
The AUC from time zero to the last measurable analyte (capmatinib or pembrolizumab) 
concentration sampling time (tlast) (mass × time × volume-1)
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount × time 
× volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (mass × volume-1)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time)
12.5.3.1 Handling of missing values/censoring/discontinuations
Missing values for any PK parameters or concentrations will not be imputed and will be treated 
as missing. Below the limit of quantitation (BLQ) values will be set to zero by the bioanalyst 
and will be displayed in the listings as zero and flagged. BLQ values will be treated as missing 
for the calculation of the geometric means and geometric CV%.
12.5.3.2 Population pharmacokinetic analysis
If data permit, a mixed-effects model may be applied to the pembrolizumab and/or capmatinib 
concentration-time data to generate post hoc estimates of pharmacokinetic parameters using 
software such as NONMEM to characterize pembrolizumab and/or capmatinib exposure.  
 
 
 Data from this and other studies may be pooled for analysis.
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12.7
Interim analyses
Not applicable.
12.8
Sample size calculation
Sample size calculation was based on simulations for various scenarios on treatment outcome, 
number of subjects included, number of events at the time-point of the originally planned 
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primary analysis using the Bayesian model defined in Section 16.3, which will no longer be 
performed. 
The evaluation of the success criteria was based on the HR of the PFS (capmatinib plus 
pembrolizumab vs pembrolizumab alone) after the time-point of risk change in the assumed 
two-piece exponential distributions (HR2) used in the Bayesian model (in order to account for 
potential delayed effects).
The success criteria used for the evaluation of the efficacy of the simulation samples are the 
following:

At least 50% confidence level that HR2 ≤0.7

At least 90% confidence level that HR2<1
Approximately 96 subjects will be enrolled in the study, randomized with ratio 2:1 (capmatinib 
plus pembrolizumab: pembrolizumab alone). In this calculation, a 6% rate of early drop-out 
before 1st post-baseline assessment as well as a 10% risk of drop-out rate per year on treatment 
has been taken into consideration.
Regarding the enrolment plan of the study, we assume that 3 subjects will be accrued at the first 
month after FPFV, 6 at the second, 12 at the third, 14 at the fourth and 15 subject per month for 
all the following months until approximately 96 subject are enrolled.
The reported median PFS for pembrolizumab alone as first-line therapy for NSCLC subjects 
with PD-L1≥ 50% was 10.3 months in KEYNOTE-024 study (Reck et al 2016) and 7.1 months 
in KEYNOTE-042 (Mok et al 2019). It is therefore reasonable to assume that the median PFS 
of pembrolizumab is between 7.1 and 10.3 months. We expect around 50% reduction in the 
hazard rate of PFS in capmatinib plus pembrolizumab, after the time-point of risk change in the 
assumed two-piece exponential distributions.   
Table 12-2 presents the operating characteristics of the Bayesian model with different outcome 
scenarios keeping stable the total sample size (96 subjects) and the number of total PFS events 
(50) required at the time-point of the primary analysis. With this combination reasonable 
operating characteristics can be achieved. Description of operating characteristics of alternative 
sample size can be found in Section 16.3. 
Table 12-2
Operating characteristics for scenarios with 96 subjects and 50 events 
at the primary analysis
Scenarios 
(Capmatinib plus pembrolizumab vs. pembrolizumab)
PFS in months (Hazard ratio) 
Probability of 
Success
7.1 vs. 7.1 months (HR2=1)
0.110
8.5 vs. 8.5 months (HR2=1)
0.160
10.3 vs. 10.3 months (HR2=1)
0.196
12.8 vs. 8.5 months (HR2=0.598)
0.716
12 vs. 7.1 months (HR2=0.505)
0.850
15 vs. 8.5 months (HR2=0.496)
0.855
18.5 vs. 10.3 months (HR2=0.501)
0.840
HR2: Hazard ratio after the risk change in the two-piece exponential distributions
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13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g. 
advertisements) and any other written information to be provided to subjects. 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.
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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 subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject 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 subject 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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References
References are available upon request.
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chemoradiotherapy in stage III NSCLC. N Engl J Med; 379(24):2342-50.
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Models of Non-Small Cell Lung Cancer and Other Cancer Types with Defined Mechanisms 
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Benkhoucha M, Molnarfi N, Kaya G, et al (2017) Identification of a novel population of 
highly cytotoxic c-Met-expressing CD8+ T lymphocytes. EMBO Rep.; 18(9): 1545-58.
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of cancer treatment-induced diarrhea. J. Clin. Oncol: 22(14):2918-26.
Borghaei H, Paz-Ares L, Horn L, et al (2015) Nivolumab versus Docetaxel in Advanced 
Non-squamous Non-Small-Cell Lung Cancer. N Engl J Med; 373(17):1627-39.
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immunity. Future Oncol; 11(9):1307-26.
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Non-Small-Cell Lung Cancer. N Engl J Med; 2415-26.
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Cancer Patient With a Germline BRCA1 Mutation. J Natl Cancer Inst; 110(8):914-7.
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characterization of inhibitors for therapeutic intervention. Cancer Lett; 225(1):1-26.
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stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. Natl Cancer Inst; 
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tumours: Revised RECIST guideline (version 1.1). Eur J Cancer; 45(2):228-47.
Ferlay J, Soerjomataram I, Dikshit R, et al (2015) Cancer incidence and mortality worldwide: 
sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer; 136(5):E359-86.
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Frampton GM, Ali SM, Rosenzweig M, et al (2015) Activation of MET via diverse exon 14 
splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET 
inhibitors. Cancer Discov; 5(8):850-9.
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in Metastatic Non-Small-Cell Lung Cancer. N. Engl. J. Med.; 378: 2078-92.
Glodde N, Bald T, van den Boorn-Konijnenberg D, et al (2017) Reactive Neutrophil 
Responses Dependent on the Receptor Tyrosine Kinase c-MET Limit Cancer Immunotherapy. 
Immunity; 47(4):789-802.e9.
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immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 
Ann. Oncol ; 28(4): iv119-iv142.
Hellmann MD, Ciuleanu TE, Pluzanski A, et al (2018) Nivolumab plus Ipilimumab in Lung 
Cancer with a High Tumor Mutational Burden. N Engl J Med; 378: 2093-104.
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treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a 
randomised controlled trial. Lancet; 387(10027):1540-50.
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Cell Lund Cancer. Oncologist; 22(1):81-8
Hesketh PJ, Kris MG, Basch E, et al (2017) Antiemetics: American Society of Clinical 
Oncology Clinical Practice Guideline Update. Journal of Clinical Oncology; 35: 3240-61.
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.
Jotte RM, Cappuzzo F, Vynnychenko I et al (2018) IMpower131: Primary PFS and safety 
analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-
paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. 
ASCO Abstract #LBA9000.
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with response to anti-PD-1 antibody therapy in patients with metastatic melanoma. J Dermatol 
Sci; 93(1):33-40.
Langer CJ, Gadgeel SM, Borghaei H, et al (2016) Carboplatin and pemetrexed with or 
without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a 
randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol; 17(11): 
1497-508.
Liu H, Wu Q, Liu Y, et al (2015) Prognostic significance of 
β1,6-Nacetylglucosaminyltransferase V expression in patients with hepatocellular carcinoma. 
Jpn. J. Clin. Oncol; 45:844-53.
Liu X, Wang Q, Yang G, et al (2011) A novel kinase inhibitor, INCB28060, blocks c-MET 
dependent signaling, neoplastic activities, and cross-talk with EGFR and HER-3. Clin Cancer 
Res.; 17(22): 7127-38.
Maeda R, Yoshida J, Hishida T, et al (2010) Late recurrence of non-small cell lung cancer 
more than 5 years after complete resection: incidence and clinical implications in patient 
follow-up. Chest; 138(1): 145-50.
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Mendenhall MA, Goldman JW (2015) MET-Mutated NSCLC with Major Response to 
Crizotinib. J Thorac Oncol; 10(5): e33-4.
Mok T, Wu Y, Kudaba I, et al (2019). Pembrolizumab versus chemotherapy for previously 
untreated, PD-L1-expressing, locally advanced or metastatic non-small cell lung cancer 
(KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet; 
393(10183):1819-30. 
Molina JR, Yang P, Cassivi SD, et al (2008) Non-small cell lung cancer: epidemiology, risk 
factors, treatment, and survivorship. Mayo Clin Proc; 83(5): 584-94.
Molnarfi N, Benkhoucha M, Funakoshi H, et al (2015) Hepatocyte growth factor: A regulator 
of inflammation and autoimmunity. Autoimmun Rev.; 14(4): 293-303.
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Control 
Clin Trials; 9(1):11-8.
NCCN (v5, 2019) Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer.
Novello S, Barlesi F, Califano R, et al (2016) Metastatic non-small-cell lung cancer: ESMO 
Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol; 
27(5):v1-v27.
O’Rourke N, Roqué I Figuls M, Farré Bernadó N, et al (2010) Concurrent chemoradiotherapy 
in non-small cell lung cancer. Cochrane Database Syst Rev; 6::CD002140.
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; 
5(8): 842-9.
Paz-Ares L, Luft A, Vicente D, et al (2018), Pembrolizumab plus chemotherapy for squamous 
non-small-cell lung cancer. N Engl J Med; 379: 2040-51.
Reck M, Rodríguez-Abreu D, Robinson AG, et al (2016) Pembrolizumab versus 
Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med; 
375(19):1823-33.
Rittmeyer A, Barlesi F, Waterkamp D, et al (2017) Atezolizumab versus docetaxel in patients 
with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre 
randomised controlled trial. Lancet; 389(10066):255-65.
Rutella S, Danese S, Leone G (2006) Tolerogenic dendritic cells: cytokine modulation comes 
of age. Blood; 108(5):1435-40.
Sause W, et al (2000) Final results of phase III trial in regionally advanced unresectable non-
small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology 
Group, and Southwest Oncology Group. Chest; 117:358-64.
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 p. suppl; abstr 9067.
Siegel RL, Miller KD, Jemal A. (2019) Cancer statistics, 2019. CA Cancer J Clin; 69(1):-34.
Socinski MA, Jotte RM, Cappuzzo F, et al (2018) Atezolizumab for First-Line Treatment of 
Metastatic Nonsquamous NSCLC. N Engl J Med; 2288-301.
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The Cancer Genome Atlas (TCGA) Research Network (2014) Comprehensive molecular 
profiling of lung adenocarcinoma (2014). Nature; 511(7511):543-50.
Waqar SN, Morgensztern D, Sehn J (2015) MET Mutation Associated with Responsiveness to 
Crizotinib. J Thorac Oncol; 10(5): e29-31.
Wolf J, Han J, Nishio M, et al (2017) GEOMETRY Mono-1: Phase II, Multicenter Study of 
MET Inhibitor Capmatinib (INC280) in EGFR Wt, MET-Dysregulated Advanced NSCLC p. 
poster. 
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16
Appendices
16.1
Appendix 1: Guidelines for Response, Duration of Overall 
Response, TTF, TTP, Progression-Free Survival, and Overall 
Survival (based on RECIST 1.1)
Harmonization of Efficacy Analysis of Solid Tumor Studies
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
Authors (Version 3.2):
Authors (Version 3.1):
 
Authors (Version 3):
 
 
Authors (Version 2):
 
Authors (Version 1):
 
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Glossary
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
DFS
Disease-free survival
eCRF
Electronic Case Report Form
FPFV
First patient first visit
GBM
Glioblastoma multiforme
MRI
Magnetic resonance imaging
LPLV
Last patient last visit
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable disease
SOD
Sum of Diameter
TTF
Time to treatment failure
TTP
Time to progression
UNK
Unknown
16.1.1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 16.1.2 and the definition of best response in 
Section 16.1.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and res for determination of best response. Section 16.1.3.2 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 16.1.4.1 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the SAP to provide further details needed for programming.
16.1.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247.
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16.1.2.1 Definitions
16.1.2.1.1
Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.
Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should be confirmed 
by cytology/histology.
For patients without measurable disease see Section 16.1.3.2.9.
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 10 mm 
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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16.1.2.1.2
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations. Guidance on how patients with just non-measurable disease at baseline will 
be evaluated for response and also handled in the statistical analyses is given in 
Section 16.1.3.2.8.
16.1.2.2 Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v.) contrast.
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.

For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow- 
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis.

A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
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 10 mm size, and can be assessed using calipers.

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions, unless pre-specified by 
the protocol. It is, however, a possible alternative to clinical measurements of 
superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules. US 
might also be useful to confirm the complete disappearance of superficial lesions 
usually assessed by clinical examination.

Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for 
objective tumor evaluation has not yet been fully and widely validated. Their uses in 
this specific context require sophisticated equipment and a high level of expertise that 
may only be available in some centers. Therefore, the utilization of such techniques 
for objective tumor response should be restricted to validation purposes in specialized 
centers. However, such techniques can be useful in confirming complete pathological 
response when biopsies are obtained.

Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian 
cancer, PSA for prostate cancer, alpha-FP, 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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16.1.2.3 Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). Each target lesion must be uniquely and sequentially numbered 
on the CRF (even if it resides in the same organ).
Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 
10 mm in longest diameter. See Section 16.1.2.1.1.

Nodal target: See Section 16.1.2.1.1.
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. 
Each target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.

Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.
16.1.2.4 Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated 
(at baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 16-1) and non-target lesions (Table 16-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 16-3) as well as the presence or absence of new lesions.
16.1.2.4.1
Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number
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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.
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16.1.2.4.2
Determination of target lesion response
Table 16-1
Response criteria for target lesions 
Response Criteria
Evaluation of target lesions
Complete Response 
(CR):
Disappearance of all non-nodal target lesions. In addition, any 
pathological lymph nodes assigned as target lesions must have a 
reduction in short axis to < 10 mm 1
Partial Response (PR):
At least a 30% decrease in the sum of diameter of all target lesions, 
taking as reference the baseline sum of diameters.
Progressive Disease 
(PD):
At least a 20% increase in the sum of diameter of all measured target 
lesions, taking as reference the smallest sum of diameter of all target 
lesions recorded at or after baseline. In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 
mm 2.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR or CR nor an increase in 
lesions which would qualify for PD.
Unknown (UNK)
Progression has not been documented and one or more target lesions 
have not been assessed or have been assessed using a different method 
than baseline.3
SOD for CR may not be zero when nodal lesions are part of target lesions 
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
In exceptional circumstances an UNK response due to change in method could be over-ruled by the 
investigator or central reviewer using expert judgment based on the available information (see 
Notes on target lesion response and methodology change in Section 16.1.2.2).
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following 
possibilities:

The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as 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 CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 16-1 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at 
or after baseline with at least 5 mm increase in the absolute sum of the diameters). 
Proper documentation should be available to support this decision. This applies to patients 
who have not achieved target response of CR. For patients who have achieved CR, please 
refer to last bullet in this section.
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
For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD.

Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK.

Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal 
in order not to overstate progression should it be based on increase in the size of nodes.

Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) 
of the two split lesions should be added together and the sum recorded in the diameter 
field on the case report form under the original lesion number. This value will be included 
in the sum of diameters when deriving target lesion response. The individual split lesions 
will not be considered as new lesions, and will not automatically trigger a PD designation.

Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis - 
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0”mm should 
be entered for the remaining lesion numbers which have coalesced.

The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications.

Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all non- 
nodal target lesions have disappeared.

Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions.

Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 mm 
and there is at least 20% increase in sum of the diameters of all nodal target lesions 
relative to nadir with at least 5 mm increase in the absolute sum of the diameters.
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
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.
16.1.2.4.3
Determination of non-target lesion response
Table 16-2
Response criteria for non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete Response 
(CR):
Disappearance of all non-target lesions. In addition, all lymph nodes 
assigned a non-target lesions must be non-pathological in size (< 10 mm 
short axis)
Progressive Disease 
(PD):
Unequivocal progression of existing non-target lesions.1
Non-CR/Non-PD:
Neither CR nor PD
Unknown (UNK):
Progression has not been documented and one or more non-target 
lesions have not been assessed or have been assessed using a different 
method than baseline2.
1. The assignment of PD solely based on change in non-target lesions in light of target lesion 
response of CR, PR or SD should be exceptional. In such circumstances, the opinion of the 
investigator or central reviewer does prevail.
2. It is recommended that the investigator and/or central reviewer should use expert judgment to 
assign a Non-UNK response wherever possible (see notes section for more details)
Notes on non-target lesion response

The investigator and/or central reviewer can use expert judgment to assign a non-UNK 
response wherever possible, even where lesions have not been fully assessed or a different 
method has been used. In many of these situations it may still be possible to identify 
equivocal progression (PD) or definitively rule this out (non-CR/Non-PD) based on the 
available information. In the specific case where a more sensitive method has been used 
indicating the absence of any non-target lesions, a CR response can also be assigned.

The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e. ≥ 10 mm) the response can only be ‘Non- 
CR/Non-PD’ unless there is unequivocal progression of the non-target lesions (in which 
case response is PD) or it is not possible to determine whether there is unequivocal 
progression (in which case response is UNK).
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
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 16.1.2.4.2 for assigning PD following a CR for 
the non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.
16.1.2.4.4
New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page.

If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion

If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 16.1.2.5).

A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to ≥ 10 mm for the first time in the study plus 5 
mm absolute increase.
FDG-PET: can complement CT scans in assessing progression (particularly possible for ‘new’ 
disease). See Section 16.1.2.2.
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16.1.2.5 Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in 
Table 16-3.
Table 16-3
Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overall lesion response
CR
CR
No
CR1
CR
Non-CR/Non-PD3
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR1
SD
Non-PD and not UNK
No
SD1, 2
UNK
Non-PD or UNK
No
UNK1
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1. This overall lesion response also applies when there are no non-target lesions identified at baseline.
2. Once confirmed PR was achieved, all these assessments are considered PR.
3. As defined in Section 16.1.2.4
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
16.1.3
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 16.1.3.2.8 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
16.1.3.1 Best overall response
The best overall response 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 
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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) > 7 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).

PD = progression ≤ 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).

UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks)
The time durations specified in the SD/PD/UNK definitions above are defaults based on a 
6 week tumor assessment frequency. However these may be modified for specific indications 
which are more or less aggressive. In addition, it is envisaged that the time duration may also 
take into account assessment windows. E.g. if the assessment occurs every 6 weeks with a time 
window of +/- 7 days, a BOR of SD would require a SD or better response longer than 5 weeks 
after randomization/start of treatment.
Overall lesion responses of CR must stay the same until progression sets in, with the exception 
of a UNK status. A patient who had a CR cannot subsequently have a lower status other than a 
PD, e.g. PR or SD, as this would imply a progression based on one or more lesions reappearing, 
in which case the status would become a PD.
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR ( 30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
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at the next assessment (but not  20% increase from previous smallest sum), the objective status 
at that assessment should be SD. Once a confirmed PR was seen, the overall lesion response 
should be considered PR (or UNK) until progression is documented or the lesions totally 
disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable.
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments.
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)
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 patients’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of patients 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 patients with a best overall response of CR or 
PR or SD. The objective of this endpoint is to summarize patients with signs of “activity” 
defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth.
Clinical benefit rate (CBR) is the proportion of patients with a 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:
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Early progression rate (EPR) is the proportion of patients 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 patients who at the specified assessment (in this example the assessment would be at 
8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with an 
unknown (UNK) assessment at that time point and no PD before, will not be counted as early 
progressors in the analysis but may be included in the denominator of the EPR rate, depending 
on the analysis population used. Similarly when examining overall response and disease control, 
patients with a 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).
16.1.3.2 Time to event variables
16.1.3.2.1
Progression-free survival
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint.
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.
PFS rate at x weeks is an additional measure used to quantify PFS endpoint. It is recommended 
that a Kaplan-Meier estimate is used to assess this endpoint.
16.1.3.2.2
Overall survival
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”).
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive.
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16.1.3.2.3
Time to progression
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer.
Time to progression (TTP) is the time from date of randomization/start of treatment to the date of 
event defined as the first documented progression or death due to underlying cancer. If a patient has 
not had an event, time to progression is censored at the date of last adequate tumor assessment.
16.1.3.2.5
Time to treatment failure
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study drug. In some protocols, time to treatment failure 
may be considered as a sensitivity analysis for time to progression. The list of discontinuation 
reasons to be considered or not as treatment failure may be adapted according to the specificities 
of the study or the disease.
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation due 
to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to treatment 
failure for patients who did not experience treatment failure will be censored at last adequate 
tumor assessment.
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16.1.3.2.6
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 patients: a good risk group and a poor risk 
group. Good risk patients tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk patients tend to be difficult to achieve 
a response, may have a longer time to respond, and tend to relapse quickly when they do respond. 
Potent agents induce a response in both good risk and poor risk patients. Less potent agents 
induce a response mainly in good risk patients only. This is described in more detail by 
Morgan 1988.
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates. If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis et al (2008). It should also be stated in the protocol if 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 patients throughout the study is usually taken into account in the analysis).
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed) the start date is the date of first documented response (CR or PR) and the end 
date and censoring is defined the same as that for time to progression.
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen.
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression.
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression.
16.1.3.2.7
Time to response
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed.
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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 16.1.3.2.5. It is recommended that 
an analysis of all patients (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 
is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options:

at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV)

at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint.
16.1.3.2.8
Definition of start and end dates for time to event variables
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number.
In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations.
Start dates
For all “time to event” variables, other than 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.
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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 16.1.3.2.8).
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.

Date of discontinuation is the date of the end of treatment visit.

Date of last contact is defined as the last date the patient was known to be alive. 
This corresponds to the latest date for either the visit date, lab sample date or tumor 
assessment date. If available, the last known date patient alive from the survival follow-up 
page is used. If no survival follow-up is available, the date of discontinuation is used as 
last contact date.

Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
16.1.3.2.9
Handling of patients with non-measurable disease only at baseline
It is possible that patients with only non-measurable disease present at baseline are entered into 
the study, either because of a protocol violation or by design (e.g. in Phase III studies with PFS 
as the primary endpoint). In such cases the handling of the response data requires special 
consideration with respect to inclusion in any analysis of endpoints based on the overall 
response evaluations.
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints.
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with 
non-measurable disease is derived slightly differently according to Table 16-4.
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Table 16-4
Overall lesion response at each assessment: patients with non-target 
disease only
Non-target lesions
New Lesions
Overall lesion response
CR
No
CR
Non-CR/Non-PD1
No
Non-CR/non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
1 As defined in Section 16.1.2.4.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.
For ORR it is recommended that the main ITT analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease.
16.1.3.2.10
Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well as addresses 
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a patient being lost to follow-up? It is important that the protocol and RAP specify the 
primary analysis in detail with respect to the definition of event and censoring dates and also 
include a description of one or more sensitivity analyses to be performed.
Based on definitions outlined in Section 16.1.3.2.7, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 
2005) as a reference, the following analyses can be considered:
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Table 16-5
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
(3) Date of secondary anti-cancer therapy
(4) Date of secondary anti-cancer therapy
As per above 
situations 
Censored
Censored
Event
G
Deaths due to reason 
other than deterioration 
of ‘Study indication’
(1) Date of last adequate assessment
Censored (only 
TTP and 
duration of 
response)
1. Definitions can be found in Section 16.1.3.2.7.
2. After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in 
Section 16.1.3.2.7.
3. The rare exception to this is if the patient dies no later than the time of the second scheduled 
assessment as defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. 
Clearly define if and why options (1) are not used for situations C, E and (if applicable) F.
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Situations C (C1 and C2): Progression or death after one or more missing assessments: 
The primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration.
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1) (ITT) is the recommended approach; events 
documented after the initiation of new cancer therapy will be considered for the primary 
analysis i.e. progressions and deaths documented after the initiation of new cancer therapy 
would be included as events. This will require continued follow-up for progression after the 
start of the new cancer therapy. In such cases, it is recommended that an additional sensitivity 
analysis be performed by censoring at last adequate assessment prior to initiation of new cancer 
therapy.
Option (2), i.e. censoring at last adequate assessment may be used as a sensitivity analysis. If a 
high censoring rate due to start of new cancer therapy is expected, a window of approximately 
8 weeks performed after the start of new cancer therapy can be used to calculate the date of the 
event or censoring. This should be clearly specified in the analysis plan.
In some specific settings, local treatments (e.g. radiation/surgery) may not be considered as 
cancer therapies for assessment of event/censoring in PFS/TTP/DoR analysis. For example, 
palliative radiotherapy given in the trial for analgesic purposes or for lytic lesions at risk of 
fracture will not be considered as cancer therapy for the assessment of BOR and PFS analyses. 
The protocol should clearly state the local treatments which are not considered as antineoplastic 
therapies in the PFS/TTP/DoR analysis.
The protocol should state that tumor assessments will be performed every x weeks until 
radiological progression irrespective of initiation of new antineoplastic therapy. It is strongly 
recommended that a tumor assessment is performed before the patient is switched to a new 
cancer therapy.
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Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 16-5 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment 
(from baseline)”, with the following definition:

Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment.
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation.
16.1.4
Data handling and programming rules
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates).
16.1.4.1 Study/project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation.
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock).
16.1.4.2 End of treatment phase completion
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-up, 
the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc.
The end of treatment visit and its associated assessments should occur within 7 days of the last 
study treatment.
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Patients may discontinue study treatment for any of the following reasons:

Adverse event(s)

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Progressive disease

Study terminated by the sponsor

Non-compliant with study treatment

No longer requires treatment

Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given)
Death is a reason which “must” lead to discontinuation of patient from trial.
16.1.4.3 End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up.
Patients may provide study phase completion information for one of the following reasons:

Adverse event

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

Progressive disease

Study terminated by the sponsor
16.1.4.4 Medical validation of programmed overall lesion response
In order to be as objective as possible the RECIST programmed calculated response assessment 
is very strict regarding measurement methods (i.e. any assessment with more or less sensitive 
method than the one used to assess the lesion at baseline is considered UNK) and not available 
evaluations (i.e. if any target or non-target lesion was not evaluated the whole overall lesion 
response is UNK unless remaining lesions qualified for PD). This contrasts with the slightly 
more flexible guidance given to local investigators (and to the central reviewers) to use expert 
judgment in determining response in these type of situations, and therefore as a consequence 
discrepancies between the different sources of response assessment often arise. To ensure the 
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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 patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
16.1.4.5 Programming rules
The following should be used for programming of efficacy results:
16.1.4.5.1
Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
16.1.4.5.2
Incomplete assessment dates
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 16.1.3.2.8). If all measurement dates have 
no day recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
16.1.4.5.3
Incomplete dates for last known date patient alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
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16.1.4.5.4
Non-target lesion response
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’.
16.1.4.5.5
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
16.1.4.5.6
Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page.
For survival the following censoring reasons are possible:

Alive

Lost to follow-up
For PFS and TTP (and therefore 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 16-5)

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 16.1.3.2.7. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted:

This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off).

The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative 
anti-cancer therapy) has occurred more than the specified period following the last 
adequate assessment.

This reason will also be used to censor in case of no baseline assessment.
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16.1.5
References (available upon request)
Dent S, Zee B (2001) Application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19:785-91.
Eisenhauer EA, Therasse P, Bogaerts J, et al (2009) New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer; 45: 228-47.
Ellis S, Carroll KJ, Pemberton K (2008) Analysis of duration of response in oncology trials. 
Contemp Clin Trials; 29(4): 456-65.
EMA Guidance: 2012 Guideline on the evaluation of anticancer medicinal products in man.
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005.
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007.
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9:11-18.
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, J Natl Cancer Inst; 92:205-16.
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16.3
Appendix 3: Bayesian model set-up and prior specifications 
16.3.1
 Statistical model
For each treatment group, the underlying PFS time (in days) will be modeled using a two-piece 
exponential distribution, which allows the specification of different hazard rates before/after 
the possible delayed effect. The survival function is given by
PFS(t) = exp( ― λi1 ∗t) , if t ≤ri ; 
PFS(t) = exp( ― λi1 ∗ri) ∗exp( ― λi2 ∗(t ― ri)) , if t > ri 
Where t is study day, ri is the risk changing time-point (i.e., the time to the delayed effect), λi1 
and λi2are the hazard rates before/after the delayed effects and i indicates the treatment group, 
i = 1 for capmatinib plus pembrolizumab and i = 2 for pembrolizumab alone. 
The corresponding HR between capmatinib plus pembrolizumab and pembrolizumab alone 
after the delayed effects is λ12/λ22.
In a clinical trial, the time to progression may lie between the assessment at which the event is 
observed and day of the previous assessment+1 when patients have an event of progression. 
It is assumed the time to the event has a uniform distribution within this period.
16.3.2
Prior specifications
Priors for the risk change-point
Gamma priors are used for the time of the risk change-point, ri (i=1, 2). For each treatment 
group the prior is selected such that the mode is 64 days (i.e. three treatment cycles+1 day, the 
planned time of the first post-baseline tumor assessment) and the variance is 20. The resulting 
priors for ri (i=1, 2) are Gamma(206.8, 3.2).
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Priors for the first period
A common prior will be assumed for PFS in the first period (i.e., before the delayed effect) for 
both treatments. Gamma priors are used for λi1 (i=1, 2), selected such that the resulted median 
PFS rate at Day 64 is around 75% (a rate determined from prior data) and the probability of 
PFS rate at Day 64 being less than 50% is approximately 0.05. The resulting priors for λi1 are 
Gamma(2.6, 507.2). 
Full prior for capmatinib + pembrolizumab PFS
Prior for the second period
A weakly informative gamma prior for λ12 is used. The prior is selected such that if the risk 
change-point is 64 days, and the fraction of patients progression free at this point is 75% that 
the overall median PFS is approximately 12 months, with wide credible interval. The resulting 
prior is Gamma(2.6, 1601.1), 
Full prior
Combining the priors for r1, λ11, and λ12 gives the complete specification of the prior of PFS 
for the capmatinib + pembrolizumab arm (Figure 16-1). This is a weakly informative prior with 
median PFS of 10.7 months and a wide 80% credible interval of (3.9, 27.9) months.
Figure 16-1
Full prior distribution for capmatinib + pembrolizumab PFS
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Full prior for pembrolizumab PFS
Priors for the second period
For pembrolizumab alone, a three component mixture of gamma distributions is used for the 
prior for λ22. These components correspond to PFS as reported in the Keynote 024 trial, PFS 
as reported in the Keynote 042 trial, and a weakly informative robustification component to 
represent the case that neither of the prior Keynote trials are representative of PFS as observed 
on this trial. The prior components to represent the prior Keynote trials were selected such that 
under the assumption that the risk change-point is 64 days, and that 75% of patients are 
progression free at this point that the prior median PFS approximates to the reported median 
PFS, and the lower limit of the 95% credible interval lies below the reported lower limit of the 
95% confidence interval for median PFS. The robustification prior component was selected 
such that it has a median lying approximately midway between the reported median PFSs of the 
two Keynote trials, with wide credible interval. Weights are assigned to the three components 
such that the prior Keynote trials are given equal weight, with the robustification component 
having half of the weight assigned to either component corresponding to a Keynote trial.
The resulting mixture Gamma distribution is: 0.4*Gamma(5.0, 2775.0) + 0.4*Gamma(19.0, 
6892.7) + 0.2*Gamma(1.5, 548.8).
Full prior
Combining the priors for r2, λ21, and λ22 gives the complete specification of the prior of PFS 
for the  pembrolizumab arm (Figure 16-2 ). This is a weakly informative prior with median PFS 
of 7.8 months and a wide 80% credible interval of (3.3, 16.1) months.
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Figure 16-2
Full prior distribution for pembrolizumab PFS
Operating characteristics
The operating characteristics for the Bayesian analysis described in Section 12.4.1.2 are 
obtained by performing extensive simulations. 
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16.3.2.1 Generating hypothetical datasets
Let ni denote the sample size for each treatment group, and aj denote the accrual rate in the jth 
accrual month. The values of aj are specified below:
For each treatment group several possible values for the underlying median PFS are specified. 
For each scenario with one of the specified value for the underlying median PFS, the 
hypothetical PFS dataset is generated by the following steps:
1. Set accrual waiting time to 0 for the first patient. Generate accrual waiting times for the 
remaining patients based on equidistance enrolment within each month with the accrual 
rate mentioned in the above table, i.e., 1/aj for patients in the jth accrual month. 
2. Generate a random sample of ni PFS times in unit of day following a two-piece 
exponential distribution with the time-point of risk change as 64 days and the respective 
risks of progression in the first and second periods of λi1 = ― log(0.75)/64 = 0.0045 and 
λi2 =  ― log(0.5/0.75)/(l ― 64), corresponding to a PFS function with PFS rate at the 
time-point of risk change  75% and median PFS of l.
Take a sample of ni × re  patients from the ni patients without replacement, where re is the 
early drop-out rate before the first assessment and is pre-specified as 6.25% in this study. 
Set the corresponding censoring time as 1 day.
3. Generate a random sample of ni ― ni ∗re  censoring times, based on the assumption of an 
exponential distribution corresponding to a drop-out risk of rd = 0.1 per patient year. 
Where censoring time is earlier than event time, the patient follow up time is set to the 
censoring time, and the patient is treated as censored in the subsequent analysis.
4.  For each patient an assessment schedule is generated, based on tumor assessments 
occurring every 9 weeks. A +/- 1 week window is assumed for each assessment, with the 
timing of the assessment distributed uniformly within this window. For each patient with 
an event, it is assumed the event is observed at the next assessment on or after the day of 
the event. For censored patients, the day of censoring is the last assessment on or before 
the day of censoring.  
5. Calculate accrual calendar time (i.e., the cumulative sum of the accrual waiting times 
before the patient enrolled) and scheduled PFS calendar time (i.e., the sum of accrual 
calendar time and the event/censoring occurred time time). Rank the non-censored 
scheduled PFS calendar time from the shortest to the longest. Since the primary analysis 
will be performed after 50 events are observed, the 50th non-censored scheduled PFS 
calendar time will be considered as the day of analysis. 
6. For patients with progression events after the day of analysis, and hence censored in that 
analysis, the censoring time is set to be the day of last assessment on or before the day of 
analysis cut-off.
The steps 1-6 above are repeated to generate a total of 1000 hypothetical datasets for each 
scenario.
Month
1st
2nd
3rd
4th
≥5th
Accrual rate
3
6
12
14
15
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16.3.2.2 Posterior analysis
Given the prior distributions and parameter values specified above, the corresponding posterior 
distributions for each of the 1000 hypothetical datasets are obtained by performing extensive 
MCMC simulations using R package R2jags with 5000 iterations plus a burn-in length of 3000 
for each of two chains. For each pair of posterior values of  λ12 and λ22, the HR after the time-
point of risk change HR2 is calculated as λ12/λ22. The calculated HR from the iterations form 
the posterior distribution for the primary endpoint. The mean, median, standard deviation and 
90%-quantile will be calculated from this posterior distribution. The operating characteristics 
in terms of probability of success among 1000 hypothetical datasets for the above mentioned 
Bayesian study design under different true median PFS for each arm are summarized in the 
following table.
Table 16-7
Probabilities to declare a success under various scenarios
Sample size and primary analysis timing
Scenario
(capmatinib plus 
pembrolizumab vs. 
pembrolizumab)
PFS in months 
(Hazard ratio)
N=75, when 50 
events were 
observed
N=96, when 50 
events were 
observed
N=96, when 60 
events were 
observed
N=105, when 
70 events were 
observed
7.1 vs. 7.1 months 
(HR2=1)
0.110
0.110
0.143
0.096
8.5 vs. 8.5 months 
(HR2=1)
0.135
0.160
0.148
0.158
10.3 vs. 10.3 months 
(HR2=1)
0.155
0.196
0.189
0.174
12.8 vs. 8.5 months 
(HR2=0.598)
0.684
0.716
0.700
0.770
12 vs. 7.1 months 
(HR2=0.505)
0.825
0.850
0.871
0.883
15 vs. 8.5 months 
(HR2=0.496)
0.834
0.855
0.891
0.909
18.5 vs. 10.3 months 
(HR2=0.501)
0.856
0.840
0.888
0.914
Note: The success criteria are defined as at least 50% confidence level that HR≤ 0.7 and at least 90% 
confidence level that HR2<1.
The sample size of 96 patients with the primary analysis timing of 50 events is selected. It is 
the minimum sample size and minimum number of events that ensures at least 70% probability 
to declare success if the underlying HR2<0.6, with controlling the probability to declare success 
under 20% if the underlying HR2=1.
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Compound:
INC280
Document Title:
CINC280I12201: Protocol v03 - A randomized, open label, multicenter
phase II study evaluating the efficacy and safety of capmatinib (INC280) plus
pembrolizumab versus pembrolizumab alone as first line treatment for locally
advanced or metastatic non-small cell lung cancer with PD-L1# 50%
Document Name:
02.01.0201 Protocol - v03
Document Version:
4.0
Username
User ID
Signing Reason
Date
Content Approval
2021-04-26
01:06:48 (UTC)
Document electronically signed
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