A Double-blind, Placebo Controlled, Randomized, Phase II Study Evaluating the Efficacy and Safety of Capmatinib and Spartalizumab vs Capmatinib and Placebo as 1st Line Treatment for Advanced NSCLC Patients With MET exon14 Skipping Mutations
Phase: PHASE2
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development
INC280 (carpmatinib), PDR001 (spartalizumab)
Clinical Trial Protocol CINC280J12201 / NCT04323436
A double-blind, placebo controlled, randomized, phase II 
study evaluating the efficacy and safety of capmatinib 
(INC280) and spartalizumab (PDR001) combination therapy 
versus capmatinib and placebo as first line treatment for 
locally advanced or metastatic non-small cell lung cancer 
patients with MET exon 14 skipping mutations
Document type:
Amended Clinical Trial Protocol
EUDRACT number:
2019-003097-11
Version number:
v01 (Clean)
Clinical trial phase:
II
Release date:
13-Oct-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 1 (13-Oct-2021).............................................................................................13
Protocol summary..............................................................................................................18
1
Introduction........................................................................................................................23
1.1
Background............................................................................................................23
1.1.1
Overview of capmatinib (INC280)........................................................26
1.1.2
Overview of spartalizumab (PDR001)..................................................28
1.1.3
Overview of combination therapy.........................................................30
1.2
Purpose...................................................................................................................32
2
Objectives, related endpoints and estimands .....................................................................33
2.1
Primary estimand ...................................................................................................36
2.2
Secondary estimand ...............................................................................................37
3
Study design.......................................................................................................................38
4
Rationale ............................................................................................................................41
4.1
Rationale for study design......................................................................................41
4.2
Rationale for dose/regimen and duration of treatment...........................................42
4.3
Rationale for choice of combination and comparator drugs..................................42
4.3.1
Rationale for choice of combination .....................................................42
4.3.2
Rationale for choice of comparator drugs .............................................43
4.4
Purpose and timing of interim analyses.................................................................43
4.5
Risks and benefits ..................................................................................................44
4.5.1
Capmatinib ............................................................................................44
4.5.2
Spartalizumab........................................................................................45
4.5.3
Capmatinib combined with spartalizumab............................................46
4.6
Rationale for public health emergency mitigation procedures ..............................47
5
Population ..........................................................................................................................47
5.1
Inclusion criteria ....................................................................................................47
5.2
Exclusion criteria ...................................................................................................49
6
Treatment...........................................................................................................................52
6.1
Study treatment ......................................................................................................52
6.1.1
Investigational drugs .............................................................................52
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6.1.2
Additional study treatments...................................................................52
6.1.3
Treatment arms......................................................................................52
6.1.4
Treatment duration ................................................................................53
6.2
Other treatment(s) ..................................................................................................54
6.2.1
Concomitant therapy .............................................................................54
6.2.2
Prohibited medication............................................................................56
6.3
Subject numbering, treatment assignment, randomization....................................57
6.3.1
Subject numbering.................................................................................57
6.3.2
Treatment assignment, randomization...................................................58
6.4
Treatment blinding.................................................................................................58
6.5
Dose modification..................................................................................................60
6.5.1
Dose modification .................................................................................60
6.5.2
Follow-up for toxicities.........................................................................76
6.6
Additional treatment guidance...............................................................................78
6.6.1
Treatment compliance ...........................................................................78
6.6.2
Emergency breaking of assigned treatment code ..................................78
6.7
Preparation and dispensation .................................................................................79
6.7.1
Handling of study treatment and additional treatment ..........................79
6.7.2
Instruction for prescribing and taking study treatment..........................80
7
Informed consent procedures.............................................................................................82
8
Visit schedule and assessments..........................................................................................83
8.1
Screening................................................................................................................96
8.1.1
Molecular pre-screening........................................................................96
8.1.2
Main screening ......................................................................................96
8.1.3
Information to be collected on screening failures .................................97
8.2
Subject demographics/other baseline characteristics.............................................97
8.3
Efficacy..................................................................................................................98
8.3.1
Tumor imaging......................................................................................98
8.3.2
Overall survival ...................................................................................101
8.4
Safety ...................................................................................................................101
8.4.1
Physical examination...........................................................................101
8.4.2
Vital signs............................................................................................102
8.4.3
Height and weight................................................................................102
8.4.4
Performance status...............................................................................102
8.4.5
Laboratory evaluations........................................................................102
8.4.6
Electrocardiogram (ECG)....................................................................105
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8.4.7
Pregnancy and assessments of fertility................................................106
8.4.8
Appropriateness of safety measurements ............................................107
8.5
Additional assessments ........................................................................................107
107
8.5.2
Pharmacokinetics.................................................................................108
111
9
Study discontinuation and completion.............................................................................114
9.1
Discontinuation....................................................................................................114
9.1.1
Discontinuation of study treatment .....................................................114
9.1.2
Withdrawal of informed consent.........................................................115
9.1.3
Lost to follow-up.................................................................................116
9.1.4
Early study termination by the sponsor...............................................116
9.2
Study completion and post-study treatment.........................................................116
9.2.1
End of Study........................................................................................116
9.2.2
Post treatment follow-up .....................................................................117
10 Safety monitoring and reporting......................................................................................117
10.1
Definition of adverse events and reporting requirements....................................117
10.1.1
Adverse events.....................................................................................117
10.1.2
Serious adverse events.........................................................................119
10.1.3
SAE reporting......................................................................................120
10.1.4
Pregnancy reporting.............................................................................121
10.1.5
Reporting of study treatment errors including misuse/abuse ..............122
10.2
Additional Safety Monitoring..............................................................................122
10.2.1
Adverse events of special interest .......................................................122
10.2.2
Data Monitoring Committee................................................................123
10.2.3
Steering Committee.............................................................................123
11 Data collection and database management ......................................................................124
11.1
Data collection .....................................................................................................124
11.2
Database management and quality control ..........................................................124
11.3
Site monitoring.....................................................................................................125
12 Data analysis and statistical methods...............................................................................125
12.1
Analysis sets.........................................................................................................126
12.2
Subject demographics and other baseline characteristics ....................................128
12.3
Treatments............................................................................................................128
12.4
Analysis of the primary endpoint(s) / estimand(s)...............................................128
12.4.1
Efficacy endpoint(s) / estimand(s).......................................................128
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12.5
Analysis of secondary endpoints / estimands ......................................................132
12.5.1
Key secondary endpoint (Part 2: Randomized Part) ...........................132
12.5.2
Other secondary endpoint(s)................................................................134
140
12.7
Interim analyses ...................................................................................................140
12.8
Sample size calculation........................................................................................142
12.8.1
Primary endpoint(s).............................................................................142
12.8.2
Key secondary objective......................................................................144
13 Ethical considerations and administrative procedures.....................................................144
13.1
Regulatory and ethical compliance......................................................................144
13.2
Responsibilities of the investigator and IRB/IEC................................................145
13.3
Publication of study protocol and results.............................................................145
13.4
Quality Control and Quality Assurance...............................................................145
13.5
Participant Engagement .......................................................................................145
14 Protocol adherence...........................................................................................................146
14.1
Protocol amendments...........................................................................................146
15 References........................................................................................................................147
16 Appendices.......................................................................................................................154
16.1
Appendix 1: Guidelines for Response, Duration of Overall Response, TTF, 
TTP, Progression-Free Survival, and Overall Survival based on RECIST 1.1 ...154
16.1.1
Introduction .........................................................................................155
16.1.2
Efficacy assessments ...........................................................................155
16.1.3
Efficacy definitions .............................................................................165
16.1.4
Data handling and programming rules ................................................175
180
182
182
192
195
195
16.3
Appendix 3: Drugs that are prohibited or to be used with caution ......................202
16.4
Appendix 4: Cockcroft-Gault formula for GRF estimate....................................204
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List of tables
Table 2-1
Objectives and related endpoints...........................................................33
Table 6-1
Investigational drugs .............................................................................52
Table 6-2
Dose reduction steps for capmatinib .....................................................61
Table 6-3
Dose modifications of capmatinib and spartalizumab/placebo and 
recommended clinical management for Adverse Events ......................62
Table 6-4
Clinical and diagnostic assessments for LFT abnormalities .................77
Table 6-5
Dose and treatment schedule.................................................................80
Table 8-1
Assessment Schedule - Part 1 (Single Arm Run-in Part) – obsolete 
upon approval of protocol amendment 01.............................................85
Table 8-1b
Assessment Schedule - Part 1 (Single Arm Run-in Part) – 
applicable upon approval of protocol amendment 01 ...........................90
Table 8-2
Assessment Schedule - Part 2 (Randomized part) - obsolete since 
Part 2 will not be initiated .....................................................................92
Table 8-3
Imaging Assessment Collection Plan....................................................98
Table 8-4
ECOG Performance Status..................................................................102
Table 8-5
Laboratory Assessments......................................................................103
Table 8-6
Local ECG collection plan ..................................................................106
Table 8-7
Capmatinib pharmacokinetic blood collection log for extensive PK 
collection (first 15 subjects of Part 1)..................................................108
Table 8-8
Capmatinib pharmacokinetic blood collection log for non-
extensive PK collection (remaining subjects of Part 1 and all Part 2 
subjects)...............................................................................................109
Table 8-9
Spartalizumab pharmacokinetic 
 blood 
collection log for extensive PK sample collection (first 15 subjects 
of Part 1) - obsolete upon approval of protocol amendment 01..........109
Table 8-10
Spartalizumab/placebo pharmacokinetic 
 
blood collection log for non-extensive PK collection (remaining 
subjects of Part 1 and all Part 2 subjects) - obsolete upon approval 
of protocol amendment 01...................................................................110
 
111
 
112
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse........................................................................................122
Table 12-1
Non-compartmental pharmacokinetic parameters...............................138
Table 12-2
Estimated timelines for interim and final PFS analyses an 
simulated power...................................................................................141
Table 12-3
Design operating characteristics..........................................................142
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Table 16-1
Response criteria for target lesions......................................................161
Table 16-2
Response criteria for non-target lesions ..............................................163
Table 16-3
Overall lesion response at each assessment.........................................165
Table 16-4
Overall lesion response at each assessment: patients with non-
target disease only ...............................................................................172
Table 16-5
Options for event dates used in PFS, TTP, duration of response........173
184
185
187
188
Table 16-10
Overall lesion response for a time-point based on consideration of 
target lesions, non-target lesions and new lesions...............................190
Table 16-11
Capmatinib: drugs to be used with caution during co-
administration......................................................................................202
Table 16-12
Capmatinib: prohibited drugs..............................................................203
List of figures
Figure 3-1
Study design ..........................................................................................38
Figure 3-2
Study design Part 1................................................................................39
Figure 3-3
Study design Part 2................................................................................40
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List of abbreviations
ADA
Antidrug Antibody
AE
Adverse Event
AESI
AEs of Special Interest
AJCC
American Joint Committee on Cancer
ALK
Anaplastic Lymphoma Kinase
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
APTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
BID
Bis In Die/twice a day
BIRC
Blinded Independent Review Committee
BLQ
Below the Limit of Quantitation
BOR
Best Overall Response
BUN
Blood Urea Nitrogen
CMV
Cytomegalovirus
CNS
Central Nervous System
CR
Complete Response
CRA
Clinical Research Associate
CRO
Contract Research Organization
CSR
Clinical Study Report
CT
Computerized Tomography
CTCAE
Common Terminology Criteria for Adverse Events 
CTT
Clinical Trial Team
CV
Coefficient of Variation
d
Day(s)
DBP
Diastolic Blood Pressure
DCR
Disease Control Rate
DDI
Drug-Drug Interaction
DILI
Drug-Induced Liver Injury
dl
Deciliter
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee
DOR
Duration of Response
EBV
Epstein-Barr Virus
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form 
EDC
Electronic Data Capture
EGFR
Epidermal Growth Factor Receptor
ELISA
Enzyme-Linked Immunosorbent Assay
EORTC
European Organization for Research and Treatment of Cancer
EOT
End Of Treatment
FAS
Full Analysis Set
FDA
Food and Drug Administration (US)
FPAS
Full Pharmacokinetic Analysis Set
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FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GFR
Glomerular Filtration Rate
GGT
Gamma-Glutamyl Transferase
GI
Gastrointestinal 
GLP
Good Laboratory Practice
h
Hour
HBV
Hepatitis B Virus
hCG
Human Chorionic Gonadotropin
HCC
Hepatocellular Carcinoma
Hgb
Hemoglobin
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
HR
Hazard Ratio
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IG
Immunogenicity 
ILD
Interstitial Lung Disease
IN
Investigator Notification
INR
International Normalized Ratio
IO
Immuno-Oncology
irAE
Immune-related adverse event
IRB
Institutional Review Board
IRT
Interactive Response Technology
iv
intravenous
KM
Kaplan-Meier
LDH
Lactate Dehydrogenase
LFT
Liver Function Test 
LLN
Lower Limit of Normal
LLOQ
Lower Limit Of Quantification
mAb
Monoclonal Antibody
MedDRA
Medical Dictionary for Regulatory Activities 
METΔex14
MET exon 14 skipping
min.
Minute(s)
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NSAIDs
Nonsteroidal Anti-Inflammatory Drugs
NSCLC
Non-Small Cell Lung Cancer
NTI
Narrow Therapeutic Index
ORR
Overall Response Rate
OS
Overall Survival 
PAS
Pharmacokinetic Analysis Set
PD-1
Programmed cell Death protein 1
PD-L1
Programmed Death-Ligand 1
PFS
Progression-Free Survival
 
PK
Pharmacokinetic(s)
p.o.
Per os/oral(ly)
PR
Partial Response
PRO
Patient Reported Outcome
PS
Performance Status
PT
Prothrombin Time
Q3W
Every three Weeks
Q4W
Every four Weeks
QMS
Quality Management System
QoL
Quality of Life
QTcF
QT interval corrected by Fridericia’s formula
RANO-BM
Response Assessment in Neuro-Oncology Brain Metastases
RECIST
Response Evaluation Criteria In Solid Tumors
RP2D
Recommended phase II dose
R Value
ALT/ALP x ULN
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SC
Steering Committee
SD
Standard Deviation
SOC
Standard Of Care
SS
Safety Set
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBIL
Total Bilirubin 
TdP
Torsades de Pointes
TKI
Tyrosine Kinase Inhibitors
TSH
Thyroid Stimulation Hormone
TTR
Time to Response
ULN
Upper Limit of Normal
WoC
Withdrawal of Consent
wt
Wildtype
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Glossary of terms
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 
Cycles
Number and timing or recommended repetitions of therapy are usually expressed 
as number of days (e.g., 28 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/ 
treatment
The drug whose properties are being tested in the study
Medication number
A unique identifier on the label of medication kits
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)
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
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
Stage of cancer
The extent of a cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has spread 
from the original site to other parts of the body
Start of the clinical trial
The start of the clinical trial is defined as the signature of the informed consent by 
the first 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 depending on the study 
design)
Subject number
A unique number assigned to each subject upon signing the informed consent 
form. 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.
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Treatment arm/group 
A treatment arm/group 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 1 (13-Oct-2021)
Amendment rationale
The main purpose of this protocol amendment is to modify the study conduct and data analysis 
following the sponsor’s decision to halt study enrollment on 28-Jul-2021, as communicated to 
Health Authorities as per local requirements. The enrollment halt decision was based on lack 
of tolerability observed in capmatinib and spartalizumab combination treatment in the run-in 
part (Part 1) of the trial.
Immediately following the enrollment halt, below procedural changes have been performed:

All ongoing subjects were discontinued from spartalizumab treatment and continue to 
receive single agent capmatinib, given the proven tolerability and efficacy of capmatinib 
monotherapy in this study indication.

Enrolled subjects who had not started study treatment were to receive capmatinib single 
agent treatment from the start
 
Due to the change in the study treatment following spartalizumab discontinuation, this study 
can no longer appropriately assess the clinical activity of the combination. Therefore, data 
collection requirements will be simplified and the study objectives will be updated, as follows:

The centralized review of study imaging which was put in place to provide blinded and 
independent efficacy assessment of the combination treatment is no longer required. 
 

As blinded and independent tumor assessments will no longer be performed, the primary 
endpoint of the study will be amended to ORR by investigator assessment as per 
RECIST 1.1, 
. The primary endpoint analysis will be based on the 
estimation of ORR and hypothesis testing of ORR will not be performed. 

PFS and DCR by investigator assessment will be the study secondary endpoints. PFS will 
be reported using Kaplan Meier analysis. 
 
 
The secondary estimand constructed for DOR is no longer applicable.

In order to capture any potential delayed treatment effect of the combination, BOR and PFS 
will take into account all available tumor assessments irrespective of spartalizumab 
discontinuation due to any reason including sponsor decision. The intercurrent events of the 
primary estimand were updated accordingly.

 

 
 
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To reduce the assessment burden for trial subjects, the frequency of radiological assessments 
will be reduced to every 12 weeks after at least 2 post-baseline tumor assessments have been 
obtained. Tumor assessment follow-up, survival follow-up and information on antineoplastic 
therapies after study treatment discontinuation will not be collected.
The end of study definition was updated to ensure that subjects, who had received at least one 
dose of spartalizumab, will complete all required safety assessments up to 150 days from the 
last dose of spartalizumab treatment and will have at least 2 post-baseline tumor assessments 
obtained for the purpose of the primary outcome measure, in case another clinical study or an 
alternative treatment option becomes available to continue capmatinib provision.
This protocol amendment will also incorporate the following changes:

Based on available data, capmatinib is not expected to have any clinically relevant effect on 
QTc (capmatinib Investigator’s Brochure); drugs with known risk of Torsade de Pointes 
(TdP) were therefore removed from the list of capmatinib prohibited concomitant 
medications.

Since capmatinib monotherapy has proven tolerability and efficacy in this study indication, 
dose re-escalation of capmatinib after dose reduction will be allowed. The criteria for dose 
re-escalation of capmatinib was added.

As all ongoing subjects are treated with single agent capmatinib after spartalizumab 
discontinuation, dose modification guidance and recommended follow-up for toxicities 
which specifically apply to capmatinib monotherapy were added. The guidance for 
follow-up on potential drug-induced liver injury (DILI) cases was also updated.

To allow flexibility in administering supportive treatment for bone metastasis and 
cancer-related pain, the protocol was updated to allow limited-field radiotherapy for 
analgesic purposes or for lytic lesions at risk of fracture. Bisphosphonates or receptor 
activator of nuclear factor kappa-B ligand (RANKL) inhibitor for pre-existing bone 
metastases are also now permitted.

Following the emergence and availability of COVID-19 vaccines worldwide, the protocol 
language in relation to vaccination conduct during the study was updated to clarify the use 
of live vaccines.

The assessment of benefit/risk concluded the absence of additional risks related to 
COVID-19. To ensure subject safety and trial integrity in the event of public health 
emergency, mitigation procedures to ensure participant safety were added in relevant 
sections.
Other minor changes and corrections are made throughout the protocol for consistency and/or 
clarification.
Study Update
As of 28-Jul-2021 when enrollment was halted, 28 patients were treated with capmatinib plus 
spartalizumab and 3 patients were in screening in the run-in part (Part 1) of the study. 
The patients who were on combination treatment have discontinued spartalizumab and are 
continuing on capmatinib single agent since the enrollment halt. The patients who were in 
screening at the time of the enrollment halt have started receiving capmatinib single agent 
treatment. As of 06-Sep-2021, 19 patients were still on treatment with capmatinib.
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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 has been updated according to the changes made in the main text of the 
protocol

Section 1.1.1, Overview of capmatinib (INC280): Addition of reference to the approval of 
capmatinib

Section 1.1.1.2, Clinical experience: Addition of MATE to the list of transporters inhibited 
by capmatinib amd addition of results of capmatinib QT analysis

Table 2-1, Objectives and related endpoints:

Primary endpoint (Part 1) was updated to ORR by investigator assessment

 
 

Section 2.1, Primary estimand in Part 1 was updated

Section 2.2, Secondary estimand: in part 1 is no longer applicable

Section 3, Study design:

Addition of footnote indicating spartalizumab treatment discontinuation

It was clarified that tumor assessment follow up and survival follow up will not be 
performed

Section 3 and Section 4.1, Rationale for study design: Update of primary endpoint to ORR 
by investigator assessment

Section 3, Section 4.1 and Section 4.4, Purpose and timing of interim analyses: Removal 
of information regarding Part 2 initiation

Section 4.5.3, Capmatinib combined with spartalizumab: Update of the risk benefit 
following enrollment halt and spartalizumab discontinuation

Section 4.6: Rationale for public health emergency mitigation procedures was added

Section 6.1.3, Treatment arms and Section 6.7.2, Instructions for prescribing and taking 
study treatment: was clarified that following enrollment halt spartalizumab was 
discontinued

Section 6.2.1, Concomitant therapy: The use of bisphosphonates or RANKL inhibitor 
treatment of bone metastases and permitted radiotherapy were clarified

Section 6.2.1.1, Permitted concomitant therapy: Description of concomitant therapies 
requiring caution and/or action was aligned with other capmatinib clinical trials. No new 
class added

Section 6.2.2, Prohibited medication: The use of palliative radiotherapy and live vaccine 
was clarified

Section 6.2.2.1, Capmatinib: prohibited medication: Drugs with known risk of Torsade de 
Pointes (TdP) have been removed from the list of prohibited concomitant medications for 
capmatinib, section reworded to align with other capmatinib studies
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
Section 6.5.1, Dose modifications:

It was clarified that following spartalizumab discontinuation, only capmatinib 
guidance is applicable

Dose modification language for capmatinib monotherapy and language to permit re-
escalation of capmatinib was added

Section 6.5.2, Follow-up for toxicities:

It was clarified that for subjects who are transferred to another clinical study or 
alternative treatment option to continue capmatinib treatment at end of study, no 
further safety data will be collected as part of this study.

Table 6-3 was updated with criteria for dose reduction/ interruption and re-initiation and 
follow-up of toxicities, to align with other capmatinib studies

Section 6.5.2.1, Follow-up on potential drug-induced liver injury (DILI) cases: Guidance 
for follow up of DILI cases was aligned with other capmatinib studies

Section 6.7.1.1 was updated to include language related to destruction of unused study 
drug at site.

Section 7, Informed consent procedures and Section 8, Visit schedule and assessments: 
Addition of mitigation procedures under public health emergency

Table 8-1b was added with a simplified assessments schedule for Part 1 and replaces 
Table 8-1

Section 8.2, Subject demographics/other baseline characteristics: Information for 
collection of race and ethnicity data was added 

Section 8.3.1, Tumor imaging: It was clarified that frequency of imaging assessments is 
reduced to every 12 weeks once trial subjects have obtained at least 2 post-baseline tumor 
assessments. In addition,  study imaging will no longer be submitted for central imaging 
review

Section 8.3.1.3, Confirmation of disease progression by BIRC is no longer applicable

Section 8.3.2: Overall survival is no longer applicable

Section 8.5.1, Patients reported outcomes: Clarification that PROs will no longer be 
collected

Section 8.5.2, Pharmacokinetics: Language to allow use of residual PK samples for 
 analyses was added and it was clarified that PK and 
IG sampling for spartalizumab is no longer applicable
 

Section 9.2.1, End of study: Clarification of end of study for subjects who transfer to 
another clinical study or an alternative treatment option

Section 9.2.2, Post treatment follow-up: Removal of tumor assessment follow-up and 
survival follow-up

Setion 9.2.2.1, Safety follow-up: Removal of 150 day follow up visit, PK and IG and PRO 
assessments

Section 10.1.3, SAE reporting: clarification about SAE reporting was added 
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
Section 10.2.2, Data monitoring committee (DMC): It was clarified that following 
enrollment halt, the DMC section is no longer applicable

Section 12, Data analysis and statistical methods:

It was clarified that following the study enrollment halt during Part 1, Part 2 will not 
be initiated

Reporting details of CSR was updated

Section 12.4.1.2, Statistical hypothesis, model, and method of analysis: Hypothesis testing 
for ORR was removed and clarifed that subjects who had not received one of the 
investigational drugs at all would be excluded from the efficacy analysis.

Section 12.4.1.3, Handling of intercurrent events of primary estimand: updating the way to 
handle intercurrent events for Part 1

Section 12.4.1.4, Handling of missing values/censoring/discontinuations: it was clarified 
that subjects without confirmed CR/PR would be considered as non-responders.

Section 12.5.2.1, Efficacy endpoint(s): Removed ORR, OS, DOR and TTR
 
 

Section 12.7, Interim analyses: it was clarified that no formal interim analysis is planned 
for Part 1 of the study

Section 13.5 Participant engagement language was included

Table 16-13, Drugs with known risk of TdP was removed
Other minor changes and corrections were made throughout the protocol for consistency and/or 
clarification.
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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Protocol summary
Protocol number
INC280J12201
Full Title
A double-blind, placebo controlled, randomized, phase II study evaluating 
the efficacy and safety of capmatinib (INC280) and spartalizumab 
(PDR001) combination therapy versus capmatinib and placebo as first line 
treatment for locally advanced or metastatic non-small cell lung cancer 
(NSCLC) patients with MET exon 14 skipping (METΔex14) mutations
Brief title
Study of efficacy and safety of capmatinib in combination with 
spartalizumab in naive patients with EGFR wild type (wt), ALK 
rearrangement negative advanced NSCLC, harboring METΔex14 
mutations.
Sponsor and Clinical 
Phase
Novartis, Phase II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this study is to evaluate the efficacy and safety of 
capmatinib in combination with spartalizumab in treatment naive patients 
with EGFR wt, ALK rearrangement negative advanced NSCLC, harboring 
METΔex14 mutations.
A run-in part (Part 1) will be conducted to determine the anti-tumor activity 
and safety of capmatinib in combination with spartalizumab. Upon review 
of safety data and confirmation of anti-tumor activity in Part 1, the 
randomized part (Part 2) will be initiated to compare the efficacy and 
safety of capmatinib plus spartalizumab to capmatinib plus placebo.
Combined treatment of METΔex14 mutated NSCLC with capmatinib and 
spartalizumab is expected to result in improved efficacy compared to each 
single agent due to direct targeting of an oncogenic driver (MET) as well 
as more efficient stimulation of an anti-tumor immune response than with 
PD-1 blockade alone.
Primary Objective(s) 
Run-in part (Part 1):

To evaluate the anti-tumor activity of capmatinib in combination with 
spartalizumab as measured by overall response rate (ORR) by 
investigator assessment according to RECIST 1.1
Randomized part (Part 2):

To compare the efficacy of capmatinib plus spartalizumab to 
capmatinib plus placebo by assessing Progression Free Survival 
(PFS) by BIRC according to RECIST 1.1
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Secondary Objectives
Run-in part (Part 1):

To assess safety and tolerability of capmatinib in combination with 
spartalizumab

To further evaluate the anti-tumor activity of capmatinib in 
combination with spartalizumab

To evaluate the PK of capmatinib and spartalizumab
Randomized part (Part 2)

To compare OS of capmatinib in combination with spartalizumab 
versus capmatinib plus placebo

To assess safety and tolerability of capmatinib in combination with 
spartalizumab versus capmatinib plus placebo

To further evaluate the anti-tumor activity of capmatinib in 
combination with spartalizumab versus capmatinib plus placebo

To evaluate patient reported outcomes of capmatinib in combination 
with spartalizumab versus capmatinib plus placebo

To evaluate the PK of capmatinib and spartalizumab

 
Study design
This study consists of two parts:

A single arm run-in part of capmatinib in combination with 
spartalizumab (Part 1).

A randomized double-blind placebo controlled part (Part 2) of 
capmatinib in combination with spartalizumab versus capmatinib 
plus placebo (randomization ratio 2:1). Randomization will be 
stratified by presence or absence of brain metastasis at baseline (as 
assessed by investigator per RECIST 1.1) and PD-L1 expression 
(<1%, 1-49%, ≥50%). Treatment cross-over is not allowed.
Following the study enrollment halt during Part 1, Part 2 will not be 
initiated.
Population
This study will include adult male and female patients with stage IIIB, IIIC 
or IV NSCLC harboring METΔex14 mutations, who have not received 
prior systemic therapy for advanced/metastatic disease.
Approximately 270 subjects will be treated in the study: ca. 30 in Part 1 
and ca. 240 randomized in Part 2.
Key Inclusion criteria

Histologically confirmed locally advanced or metastatic NSCLC which 
is EGFR wt, ALK rearrangement negative and METΔex14 mutated

No prior systemic therapy for advanced/metastatic disease (neo-
adjuvant/adjuvant treatment completed > 12 months before relapse 
are permitted)

Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

Measurable disease as per RECIST 1.1

Known PD-L1 tumor expression status (applicable to Part 2 only)
Key Exclusion criteria

Prior treatment with a PD-1/PD-L1 inhibitor, MET inhibitor or HGF 
inhibitor

Presence of symptomatic CNS metastases or requiring local CNS-
directed therapy (radiotherapy or surgery), or increasing doses of 
corticosteroids 2 weeks prior to study entry
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
Impaired cardiac function or clinically significant cardiac disease

Presence or history of interstitial lung disease, non-infectious 
pneumonitis or interstitial pneumonitis, including clinically significant 
radiation pneumonitis

History of allogenic bone marrow or solid organ transplant

Radiotherapy to lung fields ≤ 4 weeks or to any other anatomic site ≤ 
2 weeks prior to start of study treatment (palliative radiotherapy for 
bone lesions is allowed)
Study treatment
Run-in part (Part 1):

Capmatinib 400 mg p.o. BID plus spartalizumab 400 mg iv Q4W
Randomized part (Part 2):

Arm 1: capmatinib 400 mg p.o. BID plus spartalizumab 400 mg iv 
Q4W

Arm 2: capmatinib 400 mg p.o. BID plus spartalizumab matching 
placebo iv Q4W
A complete cycle of treatment is defined as 28 days of continuous 
capmatinib treatment and an infusion of spartalizumab or placebo every 
28 days.
Efficacy assessments

Radiological tumor assessment by investigator assessment as per 
RECIST 1.1 at screening and every 8 weeks, then every 12 weeks 
when at least 2 post-baseline radiological tumor assessments have 
been performed.
Pharmacokinetic 
assessments 

Concentrations and derived PK parameters of capmatinib and 
spartalizumab

Antidrug antibodies (ADA) prevalence at baseline and ADA 
incidence on treatment with spartalizumab
Key safety 
assessments

Physical examination

ECOG performance status

Vital signs

Performance status

Laboratory assessments, including hematology, chemistry, thyroid 
function and coagulation

12-lead ECGs

Monthly pregnancy testing for women of child-bearing potential

Adverse events (AEs), the severity, the relationship to study 
treatment and the seriousness
Data analysis
Run-in part (Part 1)
The primary objective is to evaluate the anti-tumor activity of capmatinib 
in combination with spartalizumab, as measured by ORR by investigator 
assessment according to RECIST 1.1.
Participants who did not receive one of the investigational drugs at all will 
be excluded from the efficacy analysis.
No formal interim analysis is planned..
Randomized part (Part 2)
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Following the study enrollment halt, Part 2 will not be initiated.
The primary objective is to evaluate whether spartalizumab in addition to 
capmatinib prolongs PFS by BIRC according to RECIST 1.1 compared to 
capmatinib plus placebo.
The following null and alternative hypothesis will be tested to address the 
primary efficacy objective:
H01: θ1 ≥1 vs H11:  θ1 < 1
Where 𝜃1 is the PFS hazard ratio (HR) (capmatinib in combination with 
spartalizumab versus capmatinib plus placebo). The primary efficacy 
analysis to test these hypotheses and compare the two treatment groups 
will  be based on a  stratified log-rank test at an overall one-sided 2.5% 
significance level.
The stratification will be based on the stratification factors assigned at  
randomization (i.e. presence or absence of brain metastasis at baseline 
and PD-L1 expression [<1%,or 1-49%, or ≥50%]). Analysis will be based 
on the Full Analysis Set (FAS) population according to the randomized 
treatment group and strata assigned at randomization.
The PFS analysis will be performed as a part of a two-look group 
sequential design using a Lan-DeMets alpha spending function with 
O’Brien-Fleming type stopping boundary to control the type I error 
probability. The primary intent of this interim analyses is to report early 
outstanding efficacy results in terms of PFS. The interim analysis for PFS 
is planned after approximately 145 PFS events (i.e. at approximately 75% 
information fraction) have been documented.
PFS will be summarized using the Kaplan-Meier (KM) method. Median 
PFS, with corresponding 95% CI, and 25th and 75th percentiles will be 
presented by treatment group. The hazard ratio for PFS will be estimated, 
along with its 95% confidence interval, using a stratified Cox proportional 
hazard model using the same stratification factors as for the log-rank test.
The key secondary objective is to evaluate whether spartalizumab when 
added to capmatinib prolongs OS compared to capmatinib plus placebo.
A hierarchical testing procedure will be adopted and the statistical test for 
OS will be performed only if the primary efficacy endpoint PFS is 
statistically significant. A similar hypothesis and model will be used to 
address the key secondary efficacy endpoint for OS.
A maximum of four analyses are planned for OS. The OS analysis will be 
performed as a part of a four-look group sequential design using a Lan-
DeMets alpha spending function with O’Brien-Fleming type stopping 
boundary to control the type 1 error probability.
At the time of the interim and primary PFS analysis, interim OS analyses 
for a possible early significance claim will be performed. An additional 
interim OS analysis will be performed when approximately 167 deaths 
(85% of the deaths) have been observed, in case the time gap between 
the final analysis for PFS and for OS is longer than 1 year. A final OS 
analysis will be performed when approximately 197 deaths have been 
observed. A hierarchical testing approach will be used to control the 
overall type I error, where OS will only be formally tested and interpreted 
if the primary analysis for PFS is statistically significant. If PFS is not 
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statistically significant at either the interim PFS analysis or final PFS 
analysis, the third interim OS analysis and final OS analysis will not be 
performed.
Additional details on the interim analyses for PFS and OS are provided in 
Section 12.7.
Refer to Section 12.4.1 and Section 12.5.1 for details on censoring, 
intercurrent events, as well as sensitivity and supplementary analyses that 
will be performed for the primary and key secondary efficacy endpoints.
Key words
INC280, PDR001, capmatinib, spartalizumab, NSCLC, EGFR wt, ALK 
rearrangement negative, MET inhibitor, MET exon 14 skipping mutation
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1
Introduction
1.1
Background
Lung cancer is the most common cancer type worldwide, with an estimated 2.1 million new 
cases worldwide in 2018, representing 11.6% of all new cancers. It is also the most common 
cause of death from cancer, with 1.8 million deaths representing 18.4% of the total deaths from 
cancer (Bray et al 2018). In 2019, approximately 142,670 deaths due to lung cancer are expected 
in the United States (US) (Siegel et al 2019) and 280,000 in the European Union 
(Malvezzi et al 2019).
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. 
MET mutations leading to exon 14 skipping have been reported in approximately 2% to 4% of 
the NSCLC population (TCGA 2014, Frampton et al 2015, Paik et al 2015, Awad 2016, 
Campbell et al 2016, Schrock et al 2016, Tong et al 2016, Lu et al 2017, Benayed at al 2019).
Activating mutations in EGFR and ALK translocations are molecular drivers in NSCLC and 
their presence is strongly predictive of superior response to EGFR and ALK Tyrosine Kinase 
Inhibitors (TKIs) when compared to standard chemotherapy. For subjects harboring EGFR 
activating mutations and ALK translocations, targeted therapies have become the standard of 
care in both treatment-naive and pretreated patients (Ettinger et al 2010, Zhou et al 2011, 
Fukuoka et al 2011, 
Rosell et al 2012, 
Sequist et al 2013, 
Shaw and Engelman 2013, 
Shaw et al 2013, Solomon et al 2014, NCCN 2018). The success of EGFR and ALK TKIs 
highlights the importance of identifying specific molecular drivers of NSCLC and appropriately 
direct targeted agents to specific patient populations. Similarly, other TKIs directed at rare 
targets like ROS1 translocations and BRAF V600 mutations are now available for subsets of 
patients harboring these oncogenic drivers. (Solomon et al 2014, Hamanishi et al 2016). 
The potential for prolonged and meaningful clinical response, by targeting these oncogenic 
drivers, delays the need for chemotherapy or other treatments.
Current treatment options for advanced NSCLC patients are systemic chemotherapy and 
Immuno-Oncology (IO) therapy (Gettinger and Lynch 2011, Hirsch et al 2016, 
Morgensztern and Herbst 2016, Reck et al 2016), unless a patient has a “druggable molecular 
driver” and hence is a candidate for targeted therapy (NCCN 2019). Compared to systemic 
chemotherapy, targeted therapies are associated with improved progression-free survival (PFS) 
and quality of life (QoL) in patients with advanced NSCLC (Solomon et al 2014, 
Yang et al 2016, Brahmer et al 2017, Hida et al 2017, Reck 2018).
Treatment options for patients with advanced NSCLC with no established molecular driver (e.g. 
ALK gene rearrangements, ROS1 rearrangements, sensitizing EGFR mutations and BRAF 
V600E point mutations) are based on IO, either as monotherapy or in combination with 
platinum doublets (Planchard et al 2018, NCCN 2019). Single-agent IO treatment is considered 
as first-line treatment in patients whose tumors have programmed death-ligand 1 (PD-L1) expression 
> 50%, and in pretreated patients irrespective of PD-L1 expression (Planchard et al 2018, 
NCCN 2019). The programmed cell death protein 1 (PD-1) inhibitor pembrolizumab is also 
approved by FDA as monotherapy for first-line treatment of advanced NSCLC whose tumors 
express PD-L1 (tumor proportion score (TPS) ≥ 1%). A combination of IO treatment with 
platinum doublets may be considered as first-line treatment irrespective of tumor PD-L1 
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expression (Garon et al 2015, Reck et al 2016, Gandhi et al 2018, Hellmann et al 2018, 
Paz-Ares et al 2018, Sheela et al 2018, Socinski et al 2018, Heinhuis et al 2019). 
Alternatively, systemic chemotherapy without the addition of IO treatment is an option for patients 
not eligible for single agent or combination IO therapy (Fossella et al 2000, Schiller et al 2002, 
Lilenbaum et al 2005, Pujol et al 2005, Scagliotti et al 2008, Scagliotti et al 2014, 
Malhotra et al 2017).
Outcomes of treatment with platinum-doublet chemotherapy remain poor for locally 
advanced/metastatic NSCLC in the treatment-naive setting, with a median PFS of 5-7 months 
and OS of 10-16 months (Scagliotti et al 2008, Ciuleanu et al 2009, Ettinger et al 2010, 
Paz-Ares et al 2012).
Patients with NSCLC tumors harboring molecular drivers have limited benefit from IO 
treatments as single agent or in combination with chemotherapy and and should receive 
IO-based therapies only after exhausting the benefit from the appropriate targeted therapy 
(Mazieres et al 2019).
In human cancer, the MET pathway is frequently dysregulated, triggering a diverse set of 
signaling cascades (including the RAS-MAPK as well as the PI3K-AKT pathway), which promote 
proliferation, survival, motility and angiogenesis of tumor cells (Christensen et al 2005). 
Several mechanisms have been identified through which the MET pathway becomes aberrantly 
activated in cancer, including MET exon 14 skipping (METΔex14) mutations, MET gene 
amplification, chromosomal rearrangements leading to MET fusion proteins, MET receptor 
overexpression, and autocrine or paracrine activation of MET by its ligand HGF. METΔex14 
mutations and MET amplification are currently the most studied MET dysregulations in 
NSCLC, being evaluated as predictors of response to MET inhibitors.
The presence of METΔex14 mutations lead to loss of the juxtamembrane domain of the receptor, 
which causes protein stabilization and oncogenic activation (Kong-Beltran et al 2006). 
Next generation sequencing of tumor specimens has identified many different variants resulting 
in exon 14 skipping. These variants are rare and collectively found at a frequency of 2-4% in 
lung cancer (Frampton et al 2015, Schrock et al 2016). Recent clinical observations suggest that 
such mutations are predictors of response to capmatinib and other MET targeting agents 
(Frampton et al 2015, Paik et al 2015, Jenkins et al 2015, Mendenhall and Goldman 2015, 
Waqar et al 2015, Liu et al 2015, Schuler et al 2016, Drilon 2016, Cedres et al 2018, 
Wolf et al 2018).
In NSCLC, MET dysregulation has been found to be a negative prognostic factor 
(Guo et al 2014, Landi et al 2017, Awad et al 2019), particularly when both MET amplification 
and mutation occur in the same tumor (Awad et al 2019).
Currently, there is no approved targeted therapy for patients with METΔex14 mutated NSCLC 
tumors. Treatment options are limited, because MET mutations are known to be mutually 
exclusive of other established oncogenic molecular drivers in NSCLC and mostly occur in 
elderly patients (more than two-thirds > 65 years, Schrock et al 2016), in whom triplet 
combinations of platinum doublet and IO treatment may often not be feasible due to poor 
tolerability compared to younger patients with less comorbidities.
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To date, data on the efficacy of IO therapies in MET mutated NSCLC are limited and mostly 
based on retrospective analyses for anti-PD1 single agent treatment. These indicate a moderate 
benefit from IO therapy irrespective of the line of therapy with Overall Response Rates (ORR) 6-20% 
and median PFS below 2 months, without significantly improved efficacy in tumors with PD-L1 
expression ≥ 50% or high tumor mutation burden (TMB) (Sabari et al 2017, Sabari et al 2018, 
Awad et al 2019, Baba et al 2019, Mazieres et al 2019).
There have been promising efficacy data in clinical studies with MET inhibitors, including 
capmatinib, in patients whose tumors harbor METΔex14 mutations , confirming the value of 
this class of mutations in predicting the response to targeted therapies directed against MET 
(Frampton et al 2015, Jenkins et al 2015, Mendenhall and Goldman 2015, Paik et al 2015, 
Waqar et al 2015, Drilon 2016, Liu et al 2016, Schuler et al 2016, Wolf et al 2017, 
Wolf et al 2018, Wolf et al 2019).
The combination of targeted and IO therapies may represent an opportunity to improve outcome 
for METΔex14 mutated NSCLC. The rationale for such a combination is two-fold: while 
targeted therapy against a molecular driver yields rapid responses in a high percentage of 
patients, IO therapy can lead to durable clinical benefit. Therefore, combining targeted and IO 
therapies may have the potential to result in deep and durable responses in many patients. 
Emerging data from the COMBI-i trial in BRAF-mutant melanoma, where the kinase inhibitors 
dabrafenib and trametinib are combined with the anti-PD-1 antibody spartalizumab, appear to 
support this concept (Long et al 2019).
Besides the role of MET as an oncogenic driver, preclinical studies suggest that MET and its 
ligand hepatocyte growth factor (HGF) have important functions in immune cells, with MET 
activity leading to immunosuppression (Molnarfi et al 2015). Several mechanisms of 
MET/HGF-mediated immune suppression have been proposed. HGF was found to attract 
immunosuppressive MET-positive neutrophils to tumor and draining lymph nodes, and 
inhibition of MET by capmatinib was shown to prevent this (Glodde et al 2017). 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 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 direct 
actions on immune cells, irrespective of MET dysregulation in the tumor and suggest that MET 
inhibitors may restore immune cell function.
Clinical observations further support the hypothesis that HGF-mediated MET activation is 
immunosuppressive: in melanoma patients treated with anti-PD-1 antibodies, an increase of 
serum HGF during treatment was seen in a subset of non-responders, but not in responders 
(Glodde et al 2017), indicative of an HGF-mediated immunosuppressive feedback loop similar 
to that observed in mouse models. Likewise, another study found that high baseline levels of 
serum HGF were associated with worse clinical outcomes of anti-PD-1 treatment in melanoma 
(Kubo et al 2019).
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In summary, targeting METΔex14 mutated NSCLC with a MET inhibitor (such as capmatinib) 
and an IO therapy (such as spartalizumab) may lead to deep and durable responses in a high 
percentage of patients based on multiple complementary mechanisms.
1.1.1
Overview of capmatinib (INC280)
Capmatinib (INC280) 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 METΔex14 mutations, MET amplification, MET 
overexpression, or HGF-mediated autocrine MET activation. Addition of capmatinib to anti-PD-1 
or other IO treatments led to enhanced anti-tumor efficacy in multiple syngeneic mouse models, none 
of which exhibited any tumor biomarkers of MET dysregulation (Glodde et al 2017 and 
RD-2017-00370). Efficacy of capmatinib monotherapy in patients with advanced or metastatic 
NSCLC harboring METΔex14 mutations has been demonstrated in the ongoing pivotal study 
CINC280A2201 (Wolf et al 2019, see also Section 1.1.1.2). Based on these data, capmatinib 
received approval for the treatment of treatment-naive and pretreated NSCLC patients with 
METΔex14 mutations regardless of line of treatment from the US Food and Drug 
Administration (FDA) and from the Pharmaceuticals and Medical Devices Agency (PMDA) in 
Japan. FDA and the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan also 
granted an orphan drug designation to capmatinib for treatment of patients with MET 
dysregulated NSCLC.
1.1.1.1
Non-clinical experience
Capmatinib has potent inhibitory activity against the MET kinase in vitro [inhibitory 
concentration (IC)50 = 0.13 ± 0.05 nM in a biochemical assay], and is highly specific for MET 
with approximately 1,000-fold or greater selectivity over more than 400 other human kinases 
or mutant variants thereof (Baltschukat et al 2019). Potent inhibitory activity has also been 
observed in cell-based assays that measure MET-mediated signal transduction, as well as 
MET-dependent cell proliferation, survival, and migration.
Preclinical data support the use of capmatinib as single agent in NSCLC, gastric cancer, 
hepatocellular carcinoma, and glioblastoma. MET dependency in preclinical models from these 
cancer types was either due to strong MET overexpression (mostly as a consequence of gene 
amplification, observed in lung, gastric or hepatocellular carcinoma), or MET mutations leading 
to exon 14 skipping (lung cancer), or HGF secretion resulting in an autocrine loop 
(glioblastoma). In such MET-dependent mouse tumor models, oral dosing of capmatinib led to 
a block of MET phosphorylation, dose-dependent antitumor activity, and tumor regression at 
well-tolerated doses (Liu et al 2011, Baltschukat et al 2019). Studies in a MET / HGF 
co-expressing mechanistic model indicated that plasma levels of capmatinib correlate with both 
the dose administered and the extent of tumor growth inhibition in vivo, and that optimal anti-
tumor activity is associated with an exposure that achieves >90% of MET inhibition over the 
entire dosing interval (Liu et al 2011).
Collectively, the data suggest that capmatinib possesses potent in vitro and in vivo biological 
and pharmacologic activities, and further support its clinical development as a potentially 
effective oral treatment for human cancers with MET dysregulation.
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For further details, please refer to the [capmatinib Investigator’s Brochure].
1.1.1.2
Clinical experience
Capmatinib has been extensively tested in both cancer and non-cancer subjects. As of the safety 
cut-off date of 27-Sep-2019, more than 780 subjects with solid tumors have been treated with 
capmatinib as a single agent, and more than 690 subjects have received capmatinib in 
combination with other therapies. The recommended phase II dose (RP2D) for capmatinib as a 
single agent has been determined to be 400 mg BID in tablet formulation.
The most frequent AEs suspected to be related to capmatinib of any grade reported in study 
CINC280A2201, reference study for the safety profile of capmatinib monotherapy (n=334), 
across study cohorts and irrespective of MET mutational status, were edema peripheral (41.6%), 
nausea (33.2%), blood creatinine increased (19.5%), vomiting (18.9%), fatigue (13.8%), 
decreased appetite (12.6%  and diarrhea (11.4%), and the majority were Grade 1/2. 
The Grade 3/4 AEs suspected to be related to capmatinib in the CINC280A2201 study included 
edema peripheral (7.5%) and lipase increased (5.1%), alanine aminotransferase increased 
(4.8%), amylase increased (3.0%), fatigue (3.0%), aspartate aminotransferase increased (2.4%), 
nausea and vomiting (1.8%), decreased appetite (0.9%), constipation (0.6%), and diarrhea 
(0.3%).
In the global, prospective, multi-cohort, single arm, open label Phase II study CINC280A2201 
single agent capmatinib was evaluated in 97 subjects with METΔex14 mutated advanced 
NSCLC including 28 treatment-naive (first-line), and 69 pretreated (2nd/3rd line) subjects. 
The primary analysis demonstrated clinical benefit irrespective of the line of treatment. In first 
line, ORR was 67.9% (95% CI: 47.6, 84.1), with confirmed Complete Response (CR) in 1 (3.6%) 
subject and Partial Response (PR) in 18 subjects (64.3%). The median Duration of Response 
(DOR) was 11.14 months (95% CI: 5.55, NE). Among the 19 responders, 13 subjects (68.4%) 
had responses that were maintained for ≥ 6 months and for 7 subjects (36.8%) responses were 
maintained for ≥ 12 months. The Kaplan-Meier estimated event-free rate was 73.0% (95% CI: 
46.7, 87.8) at 6 months and 47.3% (95% CI: 22.6, 68.6) at 12 months. The median PFS was 
9.69 months (95% CI: 5.52, 13.86) with estimated PFS rates at 6 and 12 months of 70.4% (95% 
CI: 49.4 83.9) and 49.7% (95% CI: 29.3, 67.1), respectively. Preliminary evidence of 
intracranial activity was seen in pretreated and in treatment naive subjects (Anon 2019, 
Wolf et al 2019).
Pharmacokinetics (PK) data collected in clinical trials showed that capmatinib was rapidly 
absorbed after oral administration with a median time to reach maximum drug concentration 
(Tmax) ranging from 1 to 2 hours for tablets. The terminal 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 
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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 and BCRP transporters. 
Substrates of CYP1A2, P-gp, and/or BCRP should be avoided in instances where minimal 
concentration changes may lead to serious adverse reactions. If coadministration is unavoidable, 
the dosage of CYP1A2 substrates, P-gp substrates, or BCRP substrates should be decreased in 
accordance with the approved prescribing information. In vitro, capmatinib inhibits renal 
transporter MATE1 and MATE2K with a Ki of 0.28 μM. Coadministration of capmatinib may 
increase the exposure of MATE1 and MATE2K substrates.
When co-administered with the strong CYP3A4 inhibitor itraconazole, capmatinib AUC 
increased by approximately 42% without any change in Cmax. When co-administered with the 
strong CYP3A4 inducer rifampicin, capmatinib AUC and Cmax decreased by 67% and 56%, 
respectively (CINC280A2102). Hence, strong CYP3A4 inhibitors are to be used with caution 
and strong CYP3A4 inducers are prohibited in subjects treated with capmatinib.
Capmatinib did not prolong the QT interval to any clinically relevant extent. Following a dose 
of 400 mg twice daily in clinical studies, no participant had a post-baseline QTcF interval value 
greater than 500 msec. A concentration-QT analysis showed that the estimated mean QTcF 
increase from baseline was 1.33 msec with upper bound 90% confidence interval (CI) of 
2.58 msec at the mean steady-state Cmax following 400 mg twice daily dosing.
For further details, please refer to the latest version of the capmatinib Investigator’s Brochure.
1.1.2
Overview of spartalizumab (PDR001)
Spartalizumab (PDR001) is a monoclonal antibody (mAb) directed against human PD-1. PD-1 
is a critical immune-checkpoint receptor that is expressed on CD4 and CD8 T cells upon 
activation (Freeman 2008). Engagement of PD-1 by its ligands, PD-L1 and PD-L2, transduces 
a signal that inhibits T-cell proliferation, cytokine production, and cytolytic function 
(Riley 2009). During tumorigenesis, cancer cells from a wide range of tumor types exploit 
immune checkpoint pathways, such as PD-1/PD-L1, to avoid detection by the adaptive immune 
system (Murphy 2011). Inhibitors of immunological checkpoints, including PD-1 and PD-L1 
mAbs, have demonstrated significant antitumor activity in patients with various solid tumors.
For further details please refer to the latest [spartalizumab Investigator’s Brochure].
1.1.2.1
Non-clinical experience
Spartalizumab is a high-affinity, ligand-blocking, humanized immunoglobulin G4 (IgG4) 
antibody directed against PD-1 that blocks the binding of PD-L1 and PD-L2, and enhances 
interleukin-2 production in ex-vivo lymphocyte stimulation assays. It does not cross-react with 
rodent PD-1; therefore, toxicology studies were performed only in cynomolgus monkeys where 
there was acceptable cross-reactivity with monkey PD-1. Repeated administration of 
spartalizumab to monkeys was tolerated at all doses tested up to 100 mg/kg/week for 5 weeks 
in the GLP toxicology single-agent study. No test article-related in-life, mortality, organ weight 
changes, or macroscopic findings were noted. There were no spartalizumab-related effects seen 
in any of the safety pharmacology endpoints assessed (cardiovascular, neurobehavioral, and 
respiratory). Macrophage infiltrates into the splenic white pulp were observed in animals given 
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100 mg/kg/week and mononuclear cell infiltrates, often associated with fibrosis, around the 
injection site blood vessel (saphenous vein) in a few animals given ≥25 mg/kg/week. 
These spartalizumab-related microscopic changes were fully reversible after an eight week 
recovery. Additionally, mostly low grade mononuclear infiltrates in the vascular and 
perivascular space in several tissues of main and recovery treated animals and in recovery 
controls were observed but with a slightly higher incidence in treated animals. No evidence of 
parenchymal damage was associated with the vascular/perivascular changes in any of the 
organs examined and the changes were not associated with any frank tissue injury. 
Dose-proportional exposure to spartalizumab in each dose group was confirmed. Anti-drug 
antibodies (ADA) to spartalizumab were observed in some spartalizumab treated cynomolgus 
monkeys. A trend of reduced drug exposure was observed in these ADA-positive animals. 
Based on the toxicology studies with spartalizumab as a single-agent, the Highest Non-Severely 
Toxic Dose (HNSTD) dose is 100 mg/kg.
For further details, please refer to the latest spartalizumab Investigator’s Brochure, as well as 
Section 4.5.1 (Risks and Benefits) and Section 6.5 (Dose Modification) of the protocol.
1.1.2.2
Clinical experience
To date, more than 1200 patients across 23 Novartis sponsored clinical studies have been treated 
with spartalizumab. Of these, more than 500 patients were exposed to spartalizumab single 
agent.
The available safety data from these clinical studies indicate that spartalizumab is generally 
well tolerated. In the dose escalation phase of the first-in-man study CPDR001X2101 in patients 
with advanced solid tumors, no Dose Limiting Toxicities were reported. The preliminarily 
identified safety risks associated with spartalizumab are consistent with and characteristic of 
agents that inhibit the PD-1 receptor, and an advanced cancer population investigated in the 
respective trials. Severe immune-related adverse events (irAEs) were infrequent and typically 
manageable with dose interruption and use of immunosuppressive treatment or other supportive 
therapy as clinically indicated; discontinuations due to irAEs were rare.
In study CPDR001X2101, spartalizumab single-agent was administered as an intravenous 
infusion over 30 minutes at doses ranging from 1 to 10 mg/kg on an every 2 weeks (Q2W) 
schedule or at 3 and 5 mg/kg every 4 weeks (Q4W) schedules. Approximately dose-proportional 
increase in exposure (C1D1 AUC0-336) was observed with doses from 1 to 10 mg/kg and no 
DLTs were observed. Accumulation of approximately 2.1-3.4-fold was observed with Q2W 
dosing and 1.6-2.2-fold with Q4W dosing. Population PK analysis indicated that 
weight-adjusted or flat dosing lead to similar exposure range Therefore, a flat dosing scheme 
was selected which has the added advantage of convenience and less risk for medication errors. 
Two recommended phase II dosing regimens have been established: 300 mg Q3W and 400 mg 
Q4W flat dosing schedules. A flat dose of 400 mg Q4W or 300 mg Q3W is expected to achieve 
a mean steady-state Ctrough value higher than the ex vivo EC50 for antigen-stimulated IL-2 
production, a translational biomarker for PD-1 blockade (Patnaik et al 2015). Based on the 
safety profile observed in study CPDR001X2101 and the expected Ctrough values, 400 mg 
Q4W is expected to be a safe and efficacious dose. Based on the available PK and safety data, 
the recommended phase 2 dose (RP2D) of spartalizumab has been declared as 400 mg i.v. Q4W 
or 300 mg i.v. Q3W for combination treatment regimens.
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Based on pooled safety data from four studies comprising 513 patients treated with single agent 
spartalizumab across different regimen (400 mg Q4W [n=382], 300 mg Q3W [n=59] and 
1-10 mg/kg Q2W or Q4w [n=76]) and various advanced solid tumors types (i.e. mainly 
non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), 
anaplastic thyroid carcinoma, neuroendocrine tumors and nasopharyngeal carcinoma), the most 
common AEs (>10%), all grades, regardless of relationship with study treatment included: 
fatigue (23.6%), decreased appetite (19.7%), anemia (19.1%), nausea (19.1%), dyspnea 
(18.9%), cough (17.2%), pyrexia (16.0%), constipation (15.4%), diarrhea (13.8%), vomiting 
(12.9%), asthenia (11.5%) and abdominal pain (11.3%). Most common AEs (>3%), all grades, 
suspected to be study drug related included fatigue (13.1%), hypothyroidism (6.4%), nausea 
(6.2%), decreased appetitive (5.8%), diarrhea (5.7%), rash (5.5%), pruritus (4.9%), pyrexia 
(4.7%), asthenia (4.3%), anemia (3.7%), AST increase (3.5%) and ALT increase (3.1%).
Most common SAEs (>1%), all grades, regardless of relationship with study treatment were 
dyspnea (3.5%), pleural effusion (2.5%), abdominal pain (2.3%), pneumonia (2.3%), pyrexia 
(1.8%), hypercalcemia (1.6%), anemia (1.4%), sepsis (1.4%) and vomiting (1.2%); there were 
no SAEs suspected to be study drug related that occurred in more than 1% of patients.
AEs of special interest (AESI) for spartalizumab include endocrinopathies, colitis, skin 
reactions, hepatitis, nephritis, pneumonitis and other immune-related AEs (irAEs), and infusion 
reactions.
For further details, please refer to the latest version of the spartalizumab Investigator’s Brochure 
as well as Section 4.5.2  (Risks and Benefits) and Section 6.5 (Dose Modifications) of the 
protocol.
1.1.3
 Overview of combination therapy
1.1.3.1
Non-clinical experience
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 
anti-tumor immunity when combined with anti-PD-1 or other IO regimens. Importantly, 
capmatinib single agent activity was minimal or absent in all tested models, consistent with the 
fact that none of these models harbored any MET-activating alteration. The capmatinib + 
anti-PD-1 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 upon addition of capmatinib to immune therapies were also seen in a second, 
independently performed series of studies with syngeneic mouse models (Glodde et al 2017). 
As a mechanistic explanation, a reactive production of HGF in the inflamed tumor 
microenvironment, leading to recruitment of immunosuppressive MET-positive neutrophils, 
has been proposed. Prevention of this negative feedback loop by capmatinib might explain the 
benefit of the combination treatment. Further, the additional mechanisms involving 
MET-positive immune cells discussed above (Section 1.1) may also contribute to the observed 
enhancement of anti-tumor immunity when adding capmatinib to IO treatments.
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1.1.3.2
Clinical experience
The combination of capmatinib with a PD-1 inhibitor, either nivolumab or spartalizumab, is 
currently being evaluated in clinical trials. Overall, no significant drug-drug interactions (DDI) 
have been observed in these studies from pharmacokinetic assessment in the relative 
populations. For safety and efficacy data, refer to Section 1.1.3.2.1 and Section 1.1.3.2.2.
1.1.3.2.1 Combination of Capmatinib and Nivolumab in NSCLC
The combination of capmatinib and the PD-1 inhibitor nivolumab is currently being explored 
in study CEGF816X2201C. This ongoing study is a phase II, open-label trial of capmatinib in 
combination with nivolumab in adult subjects with advanced IO therapy-naive NSCLC with 
“MET-high” status (defined as cMET IHC 3+, or IHC 2+ & Gene Copy Number (GCN) ≥ 5, 
or MET exon 14 mutations) or “MET-low” status (defined as not meeting the criteria for 
MET-high). As of 10-Sep-2019, 46 patients have been enrolled and treated with capmatinib 
400 mg BID + nivolumab 3 mg/kg q2 weeks.
Overall, the safety profile of the combination was manageable. Forty-six patients (100%) 
experienced AEs of any grade, regardless of causality. The most common AEs of any grade 
were nausea (54.3%), vomiting (39.1%), blood creatinine increased (32.6%), edema peripheral 
(32.6%), increased amylase (32.6%), asthenia (32.6%), lipase increased (28.3%), decreased 
appetite (26.1%), diarrhea (23.9%), pyrexia (23.9%), hypoalbuminaemia (23.9%) and anaemia 
(21.7%); the majority of AEs were Grade 1/2.
Forty-three patients (93.5%) experienced AEs of any grade suspected to be related to study 
treatment. The most frequent AEs of any grade suspected to be related to study treatment were 
nausea (52.2%), edema peripheral (32.6%); increased blood creatinine (30.4%), vomiting 
(26.1%), increased amylase (26.1%), decreased appetite (23.9%), diarrhoea (23.9%), asthenia 
(23.9%) and lipase increased (23.9%); the majority of AEs were Grade 1/2.
For further details, please refer to the capmatinib Investigator’s Brochure.
These preliminary data support the tolerable combination of capmatinib with a PD-1 inhibitor 
in NSCLC.
1.1.3.2.2 Combination of Capmatinib and Spartalizumab
Capmatinib in combination with spartalizumab is currently being evaluated in three studies: 
1) a dose escalation and expansion study CINC280X2108 in subjects with hepatocellular 
carcinoma (HCC), 2) a randomized phase II study in subjects with advanced NSCLC that have 
progressed following treatment with one platinum-doublet and one PD-1 inhibitor 
(CINC280D2201), and 3) a phase II platform study in subjects with advanced melanoma 
(CPDR001J2201). While enrollment is completed in study CINC280X2108, it is still ongoing 
in the other two studies; therefore no data are currently available from studies CINC280D2201 
and CPDR001J2201. For additional information, please refer to the current capmatinib 
Investigator’s Brochure.
CINC280X2108 is an ongoing phase Ib/II, open-label, multi-center study of capmatinib in 
combination with spartalizumab versus spartalizumab alone, in advanced IO treatment-naive 
HCC after sorafenib failure.
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As of 01-Sep-2019, a total of 89 patients have been enrolled in the study. Twenty-seven patients 
were treated in the dose escalation part (phase Ib) at three dose levels: 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 spartalizumab. The RP2D was determined to be capmatinib 400 mg BID in 
combination with spartalizumab 300 mg Q3W. Thirty patients were enrolled into the 
spartalizumab single agent arm of the phase II part of the study and 32 patients were enrolled 
into the combination arm of capmatinib and spartalizumab.
Only data from patients treated with capmatinib in combination with spartalizumab are 
described below (Phase Ib and Phase II, N=59 patients). Fifty-five patients (93.2%), 
experienced AEs of any grade. The most common AEs, regardless of causality were: edema 
peripheral (47.5%), nausea (40.7%), decreased appetite (32.2%), pyrexia (32.2%), diarrhoea 
(28.8%), asthenia (27.1%), alanine aminotransferase increased (23.7%), aspartate 
aminotransferase increased (23.7%), blood bilirubin increased (23.7%), hypoalbuminemia 
(23.7%) and vomiting (23.7%). The majority of AEs were grade 1/2.
Forty-nine patients (83%) experienced AEs of any grade, suspected to be related to study 
treatment. The most frequent AEs suspected to be related to study treatment were nausea 
(30.5%), edema peripheral (28.8%), vomiting (23.7%) and decreased appetite (20.3%). 
The majority of AEs were Grade 1/2.
Forty-one patients (69.5%) experienced Grade 3/4 AEs regardless of causality. Twenty-nine 
patients (49.1%) had Grade 3/4 AEs suspected to be related to study treatment, the most 
frequent AEs suspected include asthenia (10.2%), aspartate aminotransferase increased (6.8%) 
and lipase increased (6.8%).
At least one SAE regardless of causality has been reported for 19 patients (32.2%). Nine patients 
(15.2%) experienced the following SAEs suspected of being related to study treatment. 
For further details please refer to the capmatinib Investigator’s Brochure.
The safety data support combining capmatinib with spartalizumab in NSCLC patients in the 
current protocol. However, as no data exist for the combination in treatment-naive METΔex14 
NSCLC, this study has been designed with a single arm open label run-in part preceding the 
randomized part.
1.2
Purpose
The purpose of this study is to evaluate the efficacy and safety of capmatinib in combination 
with spartalizumab in treatment naive patients with EGFR wt, ALK rearrangement negative 
advanced NSCLC, harboring METΔex14 mutations.
METΔex14 mutated NSCLC is rare, occurring in 2-4% of the total NSCLC population. 
METΔex14 mutations are associated with poor prognosis and poor response to standard 
therapies, including immunotherapy. Based on this, and on the promising data with single agent 
capmatinib demonstrated in the treatment of naive subjects, capmatinib can be considered the 
appropriate therapy for this population.
An ongoing phase II study in the METΔex14 mutated NSCLC population CINC280A2201 
showed single agent efficacy for capmatinib monotherapy in both treatment-naive and 
previously treated subjects. ORR by BIRC was 67.9% (95% CI: 47.6, 84.1) in the treatment-
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naive setting, with a median DOR of 11.14 months (95% CI: 5.55, NE) and a median PFS by 
BIRC of 9.69 months (Anon 2019, Wolf et al 2019).
If tolerable, combination of targeted and IO therapies in a molecularly selected indication has 
the potential to result in clinical efficacy that is superior to the targeted therapy alone 
(Long et al 2019, see also Section 1.1). MET inhibitors may be a particularly attractive type of 
targeted therapy for combination with IO agents, since the MET signaling pathway is suggested 
to have a role in immune modulation, and preclinical data indicate that capmatinib has 
synergistic effects with checkpoint inhibitors (Section 1.1.3.1).
By combining capmatinib with spartalizumab in METΔex14 mutated NSCLC, we expect 
improved efficacy compared to direct targeting of the oncogenic driver by capmatinib 
monotherapy, because spartalizumab can promote an additional anti-tumor immune response 
that may be further enhanced by the immunomodulatory effect of capmatinib. This study will 
be the first to evaluate the activity of capmatinib in combination with a PD-1 inhibitor in 
METΔex14 mutated NSCLC in the treatment-naive setting.
2
Objectives, related endpoints and estimands
Objectives and related endpoints are described in Table 2-1 below.
Table 2-1
Objectives and related endpoints
Objectives
Endpoints
Primary Objectives
Endpoints for primary objectives
Run-in part
To evaluate the anti-tumor activity of 
capmatinib in combination with spartalizumab
Overall Response Rate (ORR) by investigator 
assessment as per RECIST 1.1
Randomized part
To compare the efficacy of capmatinib in 
combination with spartalizumab versus 
capmatinib plus placebo
Progression Free survival (PFS) by BIRC as per 
RECIST 1.1
Key Secondary Objective
Endpoint for key secondary objective
Randomized part
To compare overall survival of capmatinib in 
combination with spartalizumab versus 
capmatinib plus placebo
Overall survival (OS)
Other Secondary Objectives
Endpoints for other secondary objectives
Run-in part

To assess safety and tolerability of 
capmatinib in combination with 
spartalizumab

Safety: incidence and severity of AEs and 
SAEs, changes in laboratory values, vital signs 
and ECGs. Any clinically significant lab, vital 
signs, ECG abnormalities will be captured as 
an AE

Tolerability: dose interruptions, reductions, and 
dose intensity

To further evaluate the anti-tumor activity 
of capmatinib in combination with 
spartalizumab 

Disease Control Rate (DCR) and PFS by 
investigator assessment as per RECIST 1.1
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Objectives
Endpoints

To evaluate the PK of capmatinib and 
spartalizumab

Concentrations and derived PK parameters of 
capmatinib and spartalizumab
Randomized part

To assess safety and tolerability of 
capmatinib in combination with 
spartalizumab versus capmatinib plus 
placebo

Safety: incidence and severity of AEs and 
SAEs, changes in laboratory values, vital signs 
and ECGs. Any clinically significant lab, vital 
signs, ECG abnormalities will be captured as 
an AE

Tolerability: dose interruptions, reductions, and 
dose intensity

To further evaluate the anti-tumor activity 
of capmatinib in combination with 
spartalizumab versus capmatinib plus 
placebo

PFS by investigator assessment as per 
RECIST 1.1

DCR, DOR, ORR and TTR by BIRC and 
investigator assessment as per RECIST 1.1

To evaluate patient reported outcomes of 
capmatinib in combination with 
spartalizumab versus capmatinib plus 
placebo

Change from baseline in EORTC QLQ-C30, 
QLQ-LC13 and EQ-5D-5L

Time to definitive 10 points deterioration 
symptom scores for pain in chest, coughing and 
dyspnea per QLQ-LC13 questionnaire as three 
primary PRO variables of interest and time to 
definitive deterioration in global health 
status/QoL, shortness of breath and pain per 
EORTC QLQ-C30 as secondary PRO variables 
of interest.

To evaluate the PK of capmatinib and 
spartalizumab

PK concentrations

To evaluate the prevalence and 
incidence of immunogenicity of 
spartalizumab in combination with 
capmatinib

Antidrug antibodies (ADA) prevalence at 
baseline and ADA incidence on treatment with 
spartalizumab
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2.1
Primary estimand
Part 1: Single Arm Run-In Part
The primary scientific  interest is to estimate the effect of capmatinib in combination with 
spartalizumab in terms of overall radiological response by investigator assessment as per 
RECIST 1.1 in first line NSCLC with METΔex14 mutation.
The primary estimand is characterized by the following attributes:
1. Population: adult patients with NSCLC with METΔex14 mutation in first line setting. 
Further details on the population are provided in Section 5.
2. Treatment: capmatinib in combination with spartalizumab without any new anti-neoplatic 
therapy. Further detail about the treatment is provided in Section 6.
3. Variable: Best Overall Response (BOR) defined as the best response recorded from the start 
of the treatment until disease progression/recurrence by investigator assessment as per 
RECIST 1.1
4. Intercurrent events:

Discontinuation of spartalizumab for any reason (treatment policy strategy)

Discontinuation of tumor assessment follow up with approval of protocol amendment 
01 (while on treatment strategy)

Any public health emergency as declared by local or regional authorities, e.g., 
pandemic, epidemic or naturadisaster (treatment policy strategy)

New anti-neoplastic therapy (while on treatment strategy)
Details on how to handle the intercurrent events are provided in Section 12.4.1.3.
5. Summary measure: Proportion of subjects with a confirmed CR/PR as BOR, with its 
corresponding two-sided exact binomial 95% CI.
Part 2: Randomized Part
Following the study enrollment halt, Part 2 will not be initiated.
The primary scientific question of interest is: What is the relative effect of the two treatment 
strategies in prolonging time to radiological progression by BIRC per RECIST 1.1 or death in 
first line NSCLC with MET exon 14 skipping mutation, regardless of study treatment 
discontinuation or start of new anti-neoplastic therapy?
The primary estimand is characterized by the following attributes:
1. Population: adult patients with NSCLC with MET exon 14 skipping mutation in first line 
setting. Further details on the population are provided in Section 5.
2. Treatment: Capmatinib in combination with spartalizumab versus capmatinib in 
combination with placebo. Further detail about the treatment is provided in Section 6.
3. Variable: PFS by BIRC as per RECIST 1.1
4. Intercurrent events:

Discontinuation of study treatment for any reason before radiological progression or 
death due to any cause

New anti-cancer therapy before radiological progression or death due to any cause
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
Radiological progression or death observed after two or more missing tumor 
assessments

Lack of post-baseline tumor assessment
Details on how to handle the intercurrent events are provided in Section 12.4.1.3.
5. Summary measure: PFS hazard ratio (capmatinib plus spartalizumab versus capmatinib plus 
placebo) along with 95% confidence interval, estimated using a Cox proportional hazard 
model stratified by the randomization stratification factors.
2.2
Secondary estimand
Part 1: Single Arm Run-In Part
Following the approval of protocol amendment 01, this section will no longer be applicable.
The secondary scientific question of interest is: What is the effect of capmatinib in combination 
with spartalizumab in improving the duration of the radiological response by BIRC as per 
RECIST 1.1 in first line NSCLC with MET exon 14 skipping mutation, regardless of study 
treatment discontinuation or start of new anti-neoplastic therapy?
The secondary estimand is characterized by the following attributes:
1. Population: adult patients with NSCLC with MET exon 14 skipping mutation in first line 
setting who have had a confirmed response of either CR or PR as assessed by BIRC. 
Further details on the population are provided in Section 5.
2. Treatment: Capmatinib in combination with spartalizumab. Further detail about the 
treatment is provided in Section 6.
3. Variable: Duration of Response (DOR) by BIRC as per RECIST 1.1
4. Intercurrent events:

Discontinuation of study treatment for any reason before radiological progression or 
death due to any cause

New anti-cancer therapy before radiological progression or death due to any cause

Radiological progression or death observed after two or more missing tumor 
assessments
Details on how to handle the intercurrent events are provided in Section 12.5.2.
5. Summary measure: Median DOR with it corresponding 95% CI estimated using Kaplan-
Meier method.
Part 2: Randomized Part
Following the study enrollment halt, Part 2 will not be initiated.
The secondary scientific question of interest is: What is the relative effect of the two treatment 
strategies in prolonging time to death in first line NSCLC with MET exon 14 skipping mutation, 
regardless of study treatment discontinuation or start of new anti-neoplastic therapy?
The key secondary estimand is characterized by the following attributes:
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1. Population: adult patients with NSCLC with MET exon 14 skipping mutation in 1L 
setting. Further details on the population are provided in Section 5.
2. Treatment: Capmatinib in combination with spartalizumab regardless of being followed 
by any standard of care (SOC) versus capmatinib in combination with placebo regardless 
of being followed by any SOC. Further detail about the treatment is provided in Section 6.
3. Variable: OS
4. Intercurrent events:

Discontinuation from study for any reason

New anti-cancer therapy
Details on how to handle the intercurrent events are provided in Section 12.5.1.1
5. Summary measure: OS hazard ratio (capmatinib plus spartalizumab versus capmatinib plus 
placebo) along with 95% confidence interval, estimated using a Cox proportional hazard 
model stratified by the randomization stratification factors.
3
Study design
This is a two-part, multicenter, phase II study to evaluate the efficacy and safety of capmatinib 
in combination with spartalizumab in treatment of naive patients with EGFR wt, ALK 
rearrangement negative advanced NSCLC, harboring METΔex14 mutations.
The study consists of a single arm open label run-in part followed by a double-blind, placebo 
controlled, randomized part.
The study will enroll approximately 270 subjects. An overview of the study design is provided 
in Figure 3-1.
Figure 3-1
Study design
*Following the study enrollment halt in Part 1, spartalizumab treatment has been discontinued and the 
randomized part will not be initiated.
Part 1: Single Arm Run-in Part
Approximately 30 subjects will be treated with the capmatinib and spartalizumab combination 
during the run-in part of the study (Part 1). The primary objective of Part 1 is to assess the ORR 
by investigator assessment as per RECIST 1.1 of the combination of capmatinib with 
spartalizumab.
capmatinib 400mg p.o. BID 
+ spartalizumab 400mg iv 
Q4W 
N= 30 
Run-in part
Arm 1: capmatinib 400mg p.o. BID + 
spartalizumab 400mg iv Q4W
N= 160 
Arm 2: capmatinib 400mg p.o. BID + 
spartalizumab matching placebo iv Q4W
N= 80
Randomized part*
Efficacy and 
safety review 
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Refer to Figure 3-2 for an overview on the study design of Part 1.
Figure 3-2
Study design Part 1
Following the approval of protocol amendment 01, tumor assessment FU and survival FU will 
not be performed
EOT: end of treatment; FU: follow-up
Part 2: Randomized Part
Following the study enrollment halt, Part 2 will not be initiated.
In the randomized part (Part 2), approximately 240 subjects will be randomized in a 2:1 ratio to 
the following treatment arms:

Arm 1: capmatinib plus spartalizumab (n=160) 

Arm 2: capmatinib plus spartalizumab matching placebo (n=80).
The randomization will be stratified by presence or absence of brain metastasis at baseline (as 
assessed by investigator per RECIST 1.1) and PD-L1 expression (<1%, or 1-49%, or ≥50%), 
assessed either locally using Dako PD-L1 IHC 22C3 pharmDx, or at a Novartis-designated 
central lab.
The primary objective of Part 2 is to assess the PFS of the combination of capmatinib plus 
spartalizumab compared to capmatinib plus placebo as determined by BIRC. OS will be 
assessed as the key secondary objective. One interim analysis for PFS and a maximum of three 
interim analyses for OS are planned; the purpose and the timing of these analyses are described 
in Section 4.4.
After the primary analysis of PFS, if the primary endpoint is met, investigators and subjects will 
continue to remain blinded to study treatment and all subjects will continue to be followed for 
OS until the final OS analysis (or earlier if OS reaches statistical significance at any of the 
interim analyses).
Refer to Figure 3-3 for an overview on the study design of Part 2.
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Figure 3-3
Study design Part 2
R: randomization; EOT: end of treatment; FU: follow-up.
Overview of study visit flow (Part 1 and Part 2)
For all subjects tumor molecular pre-requisites will be assessed during screening. EGFR and 
ALK status will be verified based on tests performed locally as part of standard clinical practice, 
while MET mutation status will be assessed at a Novartis-designated central laboratory during 
molecular pre-screening, unless previously determined locally (only local assays agreed by 
Novartis will be accepted). Additional information regarding the molecular pre-screening and 
the main screening are provided respectively in Section 8.1.1 and Section 8.1.2.
Subjects with NSCLC of pure squamous cell histology do not need to be tested for an EGFR 
mutation or ALK rearrangement, however, subjects with pure squamous cell histology already 
known to have EGFR mutations in exons 19 and 21 or ALK-positive rearrangement will be 
excluded. Once all eligibility criteria are confirmed, subjects will receive capmatinib 400 mg 
BID in combination with spartalizumab 400 mg or placebo Q4W in a 28-day cycle.
Subjects will be treated until they experience unacceptable toxicity, disease progression per 
RECIST 1.1 as determined by investigator assessment (with or without confirmation by BIRC), 
and/or treatment is discontinued at the discretion of the investigator or the subject. A complete 
list of the circumstances requiring study treatment discontinuation is provided in Section 9.
Study treatment may be continued beyond disease progression per RECIST 1.1 if, in the 
judgment of the investigator, there is evidence of clinical benefit, and the subject wishes to 
continue on the study treatment (for additional details please refer to Section 6.1.4).
After study treatment discontinuation, an end of treatment visit will be performed, all subjects 
will then enter the safety follow-up period, which will last for 150 days after last dose of 
spartalizumab or 30 days after last dose of capmatinib, whichever is longer. For subjects who 
are transferred to another clinical study or alternative treatment option to continue capmatinib 
treatment at end of study, no further collection of safety data will be required as part of this 
study (for details please refer to Section 9.2.1).
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4
Rationale
4.1
Rationale for study design
This study has been designed as a phase II, multicenter study consisting of two parts.

Part 1: Single arm run-in part of capmatinib in combination with spartalizumab

Part 2: Randomized part of capmatinib in combination with spartalizumab versus 
capmatinib plus placebo
Following the study enrollment halt during Part 1, Part 2 will not be initiated.
Part 1: Single Arm Run-in Part
Part 1 of the study was designed to assess the efficacy and safety of capmatinib in combination 
with spartalizumab in treatment-naive adult subjects with advanced NSCLC harboring 
METΔex14 mutation. Based on the safety observed during Part 1, the decision was made not 
to open Part 2.
Thirty-one patients were treated in Part 1 of the study.
The primary objective of Part 1 of the study is to evaluate the anti-tumor activity of capmatinib 
in combination with spartalizumab. The primary outcome measure of anti-tumor activity is ORR 
according to RECIST 1.1 and as determined by investigator assessment. ORR is an endpoint that 
can be used to assess earlier the efficacy of a treatment in studies with small sample size 
(FDA-industry guidance 2018). Given the efficacy observed with capmatinib single agent in 
the same patient population (Anon 2019, Wolf et al 2019), ORR can be used as a surrogate 
endpoint to predict the clinical benefit of capmatinib in combination with spartalizumab in the 
context of the single arm run-in part of the study (FDA-industry guidance 2015).
Part 2: Randomized Part
Upon review of safety data and confirmation of anti-tumor activity in Part 1, Part 2 will be 
initiated (see Section 12.8). Part 2 of the study will compare the efficacy and safety of 
capmatinib in combination with spartalizumab versus capmatinib plus placebo in treatment-
naive adult subjects with advanced NSCLC harboring METΔex14 mutation.
Approximately 240 subjects will be randomized in a 2:1 ratio to either capmatinib in 
combination with spartalizumab or capmatinib plus placebo.
Patients will be stratified for tumor PD-L1 expression, a predictor of response to PD-1/PD-L1 
inhibitors, and presence or absence of brain metastases, a strong prognostic factor in NSCLC, 
to identify differential efficacy in the respective stratification groups.
The primary objective of Part 2 of the study is to demonstrate that capmatinib in combination 
with spartalizumab is superior to capmatinib plus placebo in terms of efficacy. The primary 
endpoint is PFS (based on BIRC as per RECIST 1.1), and the key secondary endpoint is OS.
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4.2
Rationale for dose/regimen and duration of treatment
The feasibility of the combination of capmatinib with a checkpoint inhibitor has been confirmed 
in two studies CINC280X2108 and CEGF816X2201C. For details, please refer to 
Section 1.1.3.2.
The combination of capmatinib with spartalizumab has been evaluated in study 
CINC280X2108 conducted in hepatocellular carcinoma (HCC) where the RP2D was declared 
at 400 mg BID for capmatinib in combination with 300 mg spartalizumab Q3W.
In study CPDR001X2101 pharmacokinetic and safety data across tested dose levels supported 
the declaration of two RP2Ds for spartalizumab as single agent: 300 mg Q3W and 400 mg Q4W. 
Based on the population PK model simulations, both regimens are expected to be safe and 
efficacious (for additional information refer to Section 1.1.2.2), therefore two RP2Ds were 
declared to allow more convenient scheduling of treatments for subjects receiving combination 
therapy with spartalizumab.
In this study, the 400 mg Q4W schedule was selected for spartalizumab based on scheduling 
convenience for patients in the setting of advanced NSCLC.
4.3
Rationale for choice of combination and comparator drugs
4.3.1
Rationale for choice of combination
Capmatinib was granted accelerated approval by the FDA in the treatment-naive and in 
pretreated NSCLC with METΔex14 mutations regardless of line of treatment based on safety 
and efficacy data from study CINC280A2201 (Wolf et al 2019). Other trials have demonstrated 
that the combination of capmatinib with spartalizumab is feasible from a safety perspective 
(Section 1.1.3.2.2). Emerging clinical data from a melanoma trial, where direct targeting of the 
oncogenic drive (BRAF) is combined with the immune stimulator spartalizumab, suggests that deep 
and durable responses can be achieved with the concept of combining targeted and IO therapy 
(Long et al 2019).
In addition, inhibition of MET by pharmacological or genetic means can enhance T cell 
mediated anti-tumor immunity in a variety of treatment regimens and mouse tumor models 
(including melanoma lung, breast, and colon cancer models). (Glodde et al 2017) proposed a 
model in which capmatinib counteracts an HGF-driven negative feedback loop in a T cell 
inflamed tumor microenvironment, activated immune cells and/or tumor-associated stroma 
secrete HGF, which is mirrored by an increased serum HGF level. As a consequence, 
MET-positive neutrophils are mobilized and invade tumor and adjacent lymph nodes, where 
they acquire immunosuppressive properties, dampening the T cell response (Glodde et al 2017).
In order to independently reproduce these results, the combination of anti-PD-1 and capmatinib 
was tested in two syngeneic mouse models at Novartis RD-2017-00370. Combination treatment 
led to increased T cell infiltration in the short term, and an improved anti-tumor immune 
response with a higher cure rate than either single agent in the long term. The in vivo studies 
were extended in a second model (cervical carcinoma) that was generated at Novartis in a 
genetically engineered mouse strain with error-prone DNA (deoxyribonucleic acid) replication, 
which also leads to a high mutation burden. Again, addition of capmatinib to anti-PD-1 therapy 
led to an increased cure rate, while the MET inhibitor was largely inactive on its own.
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Besides these direct functional data in mouse models, the reported immunosuppressive effects 
of HGF/MET on dendritic cells and T cells (Section 1.1) further support the rationale for 
combining anti-PD-1 and capmatinib, because both agents have the potential to enhance T cell 
mediated anti-tumor immunity through complementary mechanisms. While inhibition of 
HGF/MET signaling is expected to enhance antigen presentation and T cell stimulation by 
dendritic cells and potentially even increase cytotoxicity of a subset of T cells, anti-PD-1 
antibodies will prevent suppression of T cell function through PD-L1 expressed on tumor cells 
or other immune cells.
Combined treatment with capmatinib and spartalizumab of METΔex14 mutated NSCLC is 
expected to result in improved efficacy compared to each single agent due to direct targeting of 
an oncogenic driver (MET) as well as more efficient stimulation of an anti-tumor immune 
response than with PD-1 blockade alone.
4.3.2
Rationale for choice of comparator drugs
Capmatinib montherapy has shown promising anti-tumor activity in treatment-naive and in 
pretreated NSCLC with METΔex14 mutations in study CINC280A2201. In the first line setting 
ORR was 67.9% (see Section 1.1.1.2), supporting capmatinib single agent as an appropriate 
comparator in first line in this particular subset of NSCLC patients.
Currently available therapies, IO and chemotherapy platinum-doublets, are less effective in the 
METΔex14 population compared to unselected NSCLC and the role of PD-L1 expression as 
predictor of response to IO is less clear (Sabari et al 2017). Triplet/quadruplet combinations of 
chemotherapy and IO are less likely to be tolerated by patients with METΔex14 mutated 
NSCLC who are commonly older and more frail than the general NSCLC population 
(Schrock et al 2016).
In summary, although not yet evaluated in a randomized trial versus IO or chemotherapy due 
to the challenges of conducting such a trial in a very small patient population, the clinical 
efficacy and safety of capmatinib monotherapy in first line METΔex14 mutated NSCLC 
suggests that it is an appropriate comparator for the capmatinib + spartalizumab combination.
4.4
Purpose and timing of interim analyses
Part 1: Single Arm Run-in Part
No formal interim analysis is planned for Part 1 of the study. Based on the safety observed 
during Part 1, the decision was made not to open Part 2.
Part 2: Randomized Part
Following the study enrollment halt during Part 1, Part 2 will not be initiated.
One efficacy interim analysis for PFS is planned when approximately 145 PFS events 
(75% information fraction) have been observed and all subjects have been randomized to the 
study. The primary intent of the efficacy interim analysis is to report early outstanding efficacy 
results in terms of PFS if the pre-specified threshold for significance is crossed.
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At the time of the interim PFS analysis, the first interim analysis for OS will be conducted, and 
at this time approximately 97 deaths (49% information fraction) are expected to be observed. 
A second interim analysis for OS is planned to be conducted at the time of the primary PFS 
analysis when 193 PFS events have been observed, and at this time approximately 146 deaths 
(74% information fraction) are expected to be observed. A third interim analysis for OS is 
planned to be conducted approximately 15 months after the primary PFS analysis, and at this 
time approximately 167 deaths (85% information fraction) are expected to be observed. 
A hierarchical testing procedure will be used in this study where OS is tested only if the 
respective PFS analysis is statistically significant.
Additional details on the interim analyses for PFS and OS are provided in Section 12.7.
4.5
Risks and benefits
All subjects treated in this study will receive capmatinib, which has an established efficacy and 
safety profile in the study population.
In addition, subjects enrolled in this study will have unresectable stage IIIB, IIIC or IV NSCLC 
and no other potentially curative treatment. Given the clinical and molecular characteristics of 
METΔex14 mutated NSCLC, even patients in the treatment naive setting have few therapeutic 
options and the established standard of care has limited benefit in this patient population.
The protocol includes specific eligibility criteria (Section 5), monitoring visits and assessments, 
dose modification and stopping rules, and recommended guidelines for treatment of expected 
toxicities, including identification and management of study-drug induced adverse events. 
Recommended guidelines for prophylactic or supportive treatment of expected toxicities, 
including the management of study-drug induced AEs, (e.g. infusion reaction, pneumonitis) are 
provided in Section 6.5.
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria 
and study procedures, as well as by close clinical monitoring and oversight. As with any clinical 
study, there may be unforeseen risks with the study treatment, which could be serious. 
The specific risks for each compound are discussed below. For further details, refer to the 
toxicity data provided in the capmatinib Investigator's Brochure and in the spartalizumab 
Investigator's Brochure.
Women of child bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study, and agree that, in order to participate in the study, they must adhere to the contraception 
requirements outlined in the exclusion criteria. If there is any lack of clarity about a subject's 
willingness or capability to comply with these requirements, they should not enter or continue 
in the study.
4.5.1
Capmatinib
Based upon the clinical experience with capmatinib to date, the overall risk-benefit assessment 
of capmatinib is considered favorable. The data from study CINC280A2201 show that 
capmatinib is generally well tolerated and has a manageable safety profile. The safety profile 
in the METΔex14 mutated NSCLC population is consistent with the safety profile of 
capmatinib across multiple clinical studies. In the context of the significant clinical benefit 
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observed for this patient population with limited effective therapeutic options, the overall safety 
profile is acceptable, and the benefit/risk favorable (see Section 1.1.1.2).
The most frequent safety findings on treatment with capmatinib monotherapy include peripheral 
edema, nausea, blood creatinine increased, vomiting, fatigue, decreased appetite, and diarrhea.
In addition, pancreatic events (e.g. amylase and lipase increase), and liver function test 
alterations (ALT and/or AST and/or bilirubin increase) have been observed in patients treated 
with capmatinib. To date, a direct toxic effect of capmatinib on pancreas cannot be definitively 
identified. Caution is recommended when capmatinib is administered in combination with other 
anticancer drugs with a known risk of hepatotoxicity.
Pneumonitis and Interstitial Lung Disease (ILD) have been reported from both capmatinib 
single agent and combination studies with EGFR TKIs, including events with fatal outcomes. 
Investigators are advised to carefully monitor subjects for signs and symptoms of pneumonitis 
and implement dose modification and follow-up evaluations described in the protocol in all 
capmatinib studies, both single agent and in combination studies.
Finally, capmatinib has shown photosensitization potential in in vitro and in vivo assays. 
The investigators should recommend the use of precautionary measures against ultraviolet 
exposure to the subjects during treatment with capmatinib (e.g. use of sunscreen, protective 
clothing and avoid sunbathing or using a solarium intensively).
For further information on potential toxicities, please refer to the current capmatinib 
Investigator's Brochure.
4.5.2
Spartalizumab
Spartalizumab is a humanized mAb which belongs to a class of agents known as immune-
checkpoint inhibitors, specifically anti-PD-1. This class of compounds has demonstrated 
significant improvement in efficacy combined with a tolerable and manageable safety profile, 
supporting regulatory approvals in various indications.
Immune-checkpoint inhibitors of this class may be associated with the occurrence of 
immune-related adverse events (irAEs). In general, irAEs can potentially involve every organ 
system but gastrointestinal (GI) (e.g. diarrhea, colitis), dermatologic (e.g. rash, pruritus), hepatic 
(e.g. hepatitis), pulmonary (e.g. pneumonitis), renal (e.g. nephritis) and endocrine toxicities 
(e.g. hypothyroidism, hyperthyroidism, type I diabetes, hypophysitis including hypopituitarism 
and adrenal insufficiency) are typically the most frequent. Other irAEs may rarely include the 
nervous system (e.g. encephalitis, Guillain-Barre syndrome, myasthenia gravis), eye 
(e.g. uveitis, vision changes), musculo-skeletal system (e.g. myositis, arthritis), pancreas 
(e.g. pancreatitis), cardio-vascular system (e.g. vasculitis, myocarditis) or blood system (e.g. 
anemia, cytopenias), and severe skin reactions such as toxic epidermonecrolysis or 
Stevens-Johnson syndrome. Furthermore, complications in patients with bone marrow or solid 
organ transplant have been reported (e.g. organ rejection, severe graft-versus-host disease).
These side effects are generally manageable and reversible with dose interruption and 
administration of corticosteroids and/or other immunosuppressants. However, fatal events have 
been reported in some cases with checkpoint inhibitors; furthermore, some events like 
endocrinopathies may require life-long hormonal replacement. While most irAEs are expected 
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to occur during the treatment with spartalizumab, onset may be delayed and irAEs may also 
occur after discontinuation of study treatment (Spain et al 2016, Hofmann et al 2016, 
Champiat et al 2016, Haanen et al 2017, Brahmer et al 2018). In addition, mAbs can be 
associated with infusion-related reactions some of which can be severe; these are often 
immediate and usually occur within minutes of the exposure to the study drug. Therefore, 
infusions should take place in a facility with appropriate resuscitation equipment available at 
the bedside and a physician readily available, and patients monitored for respective signs and 
symptoms. Patients who experience severe or life-threatening irAEs or infusion reactions may 
need to permanently discontinue spartalizumab (see Section 6.5 for further guidance).
Clinical experience with spartalizumab to date suggests that it can cause irAEs. It is therefore 
important to be vigilant and carefully identify events that may be suggestive of potential irAEs, 
as their appearance may be sub-clinical (for example an asymptomatic laboratory abnormality), 
and early diagnosis is critical for appropriate management and possibly prevent complications. 
Serological, immunological and histological assessments (such as biopsy of the affected tissue) 
should be performed as deemed appropriate by the investigator to verify the potential immune-
mediated nature of the AE and to exclude alternative diagnoses or disease progression. 
Following appropriate and complete evaluation, an empiric trial of corticosteroids may 
contribute to the identification of irAEs.
Refer also to the latest version of the spartalizumab Investigator’s Brochure for additional 
details on clinical and preclinical safety.
4.5.3
Capmatinib combined with spartalizumab
Both capmatinib and spartalizumab are well tolerated as single agents. There is no 
pharmacological or clinical evidence that would anticipate any cumulative, interactive or 
unexpected toxicity of the compounds if given in combination and pharmacokinetic DDI is 
anticipated to be low.
Data from the dose escalation and expansion study CINC280X2108 in subjects with HCC 
confirms that the safety profile of the combination of capmatinib and spartalizumab in this 
disease setting is manageable.
The most frequent safety findings suspected to be related to treatment with the combination 
include peripheral edema, diarrhea, nausea and vomiting, pyrexia, fatigue, asthenia, AST and 
ALT elevations, and pruritus.
In Study CPDR001J2201, one subject with metastatic melanoma experienced myocarditis and 
hepatitis approximately two months after initiation of combination therapy with capmatinib and 
spartalizumab. The subject was treated with prednisolone. At the time of reporting, hepatitis 
was fully recovered and myocarditis was ongoing.
 For further detail on potential adverse events with the combination of capmatinib and 
spartalizumab please refer to Section 1.1.3.2 of this protocol.
A decision to halt study enrollment and to discontinue spartalizumab treatment in all ongoing 
subjects was taken based on the lack of tolerability observed with the combination of capmatinib 
and spartalizumab in Part 1 of this trial. All ongoing subjects may continue to be treated with 
single agent capmatinib. Given that capmatinib has a well established safety profile as 
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monotherapy and a proven benefit in first line NSCLC population with MET exon 14 skipping 
mutation, the risk-benefit balance of the trial subjects is considered favorable.
4.6
Rationale for public health emergency mitigation procedures
In the event of a public health emergency as declared by local or regional authorities, e.g, 
pandemic, epidemic or natural disaster, mitigation procedures may be required to ensure 
participant safety and trial integrity and are listed in relevant sections of the study protocol.
Prior to implementation of mitigation procedures, Novartis should be notified of the public 
health emergency, and the mitigation procedues must be permitted/approved by local or 
regional Health Authorities and Ethics Committees as appropriate.
5
Population
This study will enroll adult male and female patients with stage IIIB, IIIC or IV NSCLC 
harboring METΔex14 mutations, who have not received prior systemic therapy for 
advanced/metastatic disease.
Patients enrolled in the study are not permitted to participate in any additional, parallel, 
investigational drug or device studies.
The investigator or designee must ensure that only patients 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. Able to understand and voluntarily sign the Informed Consent Form (ICF) and ability to 
comply with the study visit schedule and the other protocol requirements. Written 
informed consent must be obtained prior to any study specific procedures that are not part 
of standard of care. If consent cannot be expressed in writing, it must be formally 
documented and witnessed, ideally via an independent trusted witness.
2. Male or female patients must be ≥ 18 years of age.
3. Histologically or cytologically confirmed and documented stage IIIB, IIIC or IV (per 
American Joint Committee on Cancer (AJCC) staging system version 8), unresectable, 
squamous or non-squamous NSCLC which is in addition:
a.
harboring METΔex14 mutations, as determined by central pre-screening assessment 
performed at a Novartis designated laboratory, if not previously determined locally 
(only local assays agreed by Novartis will be accepted).
b. Negative for any mutations that are known to sensitize to EGFR inhibitors, such as 
exon 19 deletions or L858R substitution
c.
Negative for ALK rearrangements
Note: Patients with NSCLC of pure squamous cell histology can enter the study without 
EGFR mutation or ALK rearrangement testing or result; however, patients with pure 
squamous cell histology who are known to have EGFR mutations in exons 19 or 21 or 
ALK rearrangements will be excluded.
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4. Have an archival tumor sample or newly obtained tumor biopsy.
a.
The archival samples must be most recently available FFPE block or cut tissue 
sections from the block.
b. Patients must be suitable and willing to undergo study-required biopsies if there is no 
archival sample available.
5. Patients must not have received any systemic therapy for advanced/metastatic disease 
(stage IIIB, IIIC or IV NSCLC). Neo-adjuvant and adjuvant systemic therapies are 
permitted if relapse occurred > 12 months from the end of therapy.
6. At least one measurable lesion as defined by RECIST 1.1 as per investigator assessment.
7. Patients must have recovered from all toxicities related to prior anticancer therapies to 
grade ≤ 1 (Common Terminology Criteria for Adverse Events [CTCAE] v 5.0). 
Patients with any grade of alopecia are allowed to enter the study.
8. Patients must have adequate organ function including the following laboratory values at 
the screening visit:

Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without growth factor support

Platelets ≥75 x 109/L

Hemoglobin (Hgb) > 9 g/dL

Calculated creatinine clearance (using Cockcroft-Gault formula, see Appendix 4) 
≥ 45 mL/min

Total bilirubin < 1.5 x Upper Limit of Normal (ULN)

Aspartate transaminase (AST) < 3 x ULN, except for patients with liver metastasis, 
who can be included if AST < 5 x ULN

Alanine transaminase (ALT) < 3 x ULN, except for patients with liver metastasis, 
who can be included if ALT < 5 x ULN

Alkaline phosphatase (ALP) < 5 x ULN

Asymptomatic serum amylase increased < grade 2. Patients with grade 1 or grade 2 
serum amylase increased 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 < 1.5 x ULN
9. Eastern Cooperative Oncology Group (ECOG Performance Status (PS) of 0 or 1.
10. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
11. For subjects of Part 2 only: Patients must have known PD-L1 tumor expression status as 
determined by IHC using the Dako PD-L1 IHC 22C3 pharmDx assay at a local laboratory 
or at a Novartis designated central laboratory.
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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 PD-1/PD-L1 inhibitor, MET inhibitor or HGF inhibitor.
2. Patients with 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).
3. 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.
4. Presence of symptomatic CNS metastases, or CNS metastases that require local 
CNS-directed therapy (such as radiotherapy or surgery), or increasing doses of 
corticosteroids 2 weeks prior to study entry. Patients with treated symptomatic brain 
metastases should be neurologically stable (for ≥ 4 weeks post-treatment and prior to 
study entry) and at a dose of ≤ 10 mg per day prednisone or equivalent for at least 2 weeks 
before administration of any study treatment.
5. Presence or history of carcinomatous meningitis.
6. Presence or history of a malignant disease other than NSCLC that has been diagnosed 
and/or required therapy within the past 3 years. Exceptions to this exclusion criterion 
include the following: completely resected basal cell and squamous cell skin cancers, and 
completely resected carcinoma in situ of any type.
7. Impaired cardiac function or clinically significant cardiac disease, including any of the 
following:

Clinically significant and/or uncontrolled heart disease such as congestive heart 
failure requiring treatment (NYHA Grade ≥ 2),

Acute myocardial infarction or unstable angina pectoris < 6 months prior to study 
entry

Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg 
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without 
antihypertensive medication. Initiation or adjustment of antihypertensive 
medication(s) is allowed prior to screening.

Ventricular arrhythmias

Supraventricular and nodal arrhythmias not controlled with medication

Other cardiac arrhythmia not controlled with medication

QTcF ≥ 470 msec on the screening ECG (from mean of triplicate ECGs)

Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome
8. Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting study treatment or patients 
who have not recovered from radiotherapy-related toxicities. For all other anatomic sites 
(including radiotherapy to thoracic vertebrae and ribs), radiotherapy ≤ 2 weeks prior to 
starting study treatment or patients who have not recovered from radiotherapy-related 
toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting study 
treatment is allowed.
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9. 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 will not be counted as major surgery and patients can start study 
treatment ≥ 1 week after the procedure.
10. Patients receiving:

strong inducers of CYP3A4 that cannot be discontinued at least 1 week prior to the 
start of study treatment and for the duration of the study,

medications with a “Known Risk of Torsades de Pointes” per www.qtdrugs.org that 
cannot be discontinued or replaced by safe alternative medication,

hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF), 
thrombopoietin mimetics or erythroid stimulating agents in the last 2 weeks prior to 
start of study treatment. If thrombopoietin mimetics or erythroid stimulating agents 
were initiated more than 2 weeks prior to the first dose of study treatment and the 
patient is on a stable dose, they can be maintained.

live vaccines against infectious diseases within 4 weeks of initiation of study 
treatment.

systemic chronic steroid therapy (>10mg/day prednisone or equivalent) or any other 
immunosuppressive therapy within 7 days prior to planned date of first dose of study 
treatment. Note: Topical, inhaled, nasal and ophthalmic steroids are allowed.
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. Unable or unwilling to swallow tablets as per dosing schedule.
13. Active, known or suspected autoimmune disease or a documented history of autoimmune 
disease. Note: Patients with vitiligo, controlled type I diabetes mellitus on stable insulin 
dose, residual autoimmune-related hypothyroidism only requiring hormone replacement or 
psoriasis not requiring systemic treatment are permitted
14. History of allogenic bone marrow or solid organ transplant.
15. Presence or history of interstitial lung disease, non-infectious pneumonitis or interstitial 
pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting 
activities of daily living or requiring therapeutic intervention).
16. Human Immunodeficiency Virus (HIV) infection. Note: Positive HIV test at screening 
where locally required.
17. Active HBV or HCV infection. Patients whose disease is controlled under antiviral 
therapy are eligible.
18. Any condition medical or psychotic conditions or laboratory abnormalities that in the 
opinion of the investigator may increase the risk associated with study participation, or 
that may interfere with the interpretation of study results.
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19. Pregnant or nursing (lactating) women confirmed by a positive hCG laboratory test within 
72 hours prior to initiating study treatment.
Note: Low levels of hCG may also be considered a tumor marker, therefore if low hCG levels 
are detected, another blood sample at least 4 days later must be taken to assess the kinetics of 
the increase and transvaginal ultrasound must be performed to rule out pregnancy.
20. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception while 
taking study treatment and for 150 days after last dose of spartalizumab or placebo or for 
7 days after last dose of capmatinib, whichever is longer. 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 six weeks before 
taking study treatment. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject.

Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example, hormone vaginal ring or transdermal hormone 
contraception.
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal 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, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks 
prior to screening. 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.
21. Sexually active males unless they use a condom during intercourse while taking study 
treatment and for 7 days after stopping treatment and should not father a child in this 
period. A condom is required for all sexually active male participants to prevent them 
from fathering a child. In addition, male participants must not donate sperm for the time 
period specified above.
If local regulations deviate from the contraception methods listed above to prevent pregnancy, 
local regulations apply and will be described in the ICF.
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6
Treatment
6.1
Study treatment
The investigational drugs to be used in this study are capmatinib and spartalizumab, as 
described in Table 6-1. The study treatment is defined as capmatinib plus spartalizumab or 
capmatinib plus placebo.
6.1.1
Investigational drugs
The treatment period begins on Cycle 1 Day 1. In other words, the first dose of study treatment 
(capmatinib plus spartalizumab or capmatinib plus placebo) is given on Day 1 of Cycle 1. 
The duration of each treatment cycle is 28 days.
Refer to Section 6.7.2 for study drug prescribing and administration information.
Spartalizumab will be supplied as concentrate for solution in open label vials and it will be 
diluted in dextrose 5% in water (D5W). Spartalizumab matching placebo will be D5W for 
infusion supplied by the site.
Table 6-1
Investigational drugs
Investigational  
Drugs 
Name and 
Strengths
Pharmaceutical 
Dosage Form
Route of 
Administration
Drug package
Supplier 
(global or 
local) 
Dose and 
Regimen
Capmatinib 
(INC280) 
150 mg or 200 mg
Film-coated tablet
Oral use
Open label, 
patient specific 
bottles
Global 
400 mg BID
Spartalizumab 
(PDR001)
100 mg
Concentrate for 
solution for infusion
Intravenous use
Open label, 
patient specific 
vials
Global 
400 mg 
Q4W
6.1.2
Additional study treatments
No other treatment beyond the investigational drugs described in Section 6.1.1 are included in 
this trial.
6.1.3
Treatment arms
Following the study enrollment halt, spartalizumab treatment has been discontinued and Part 2 
will not be initiated.
Part 1: Single Arm Run-in Part
All eligible subjects enrolled in Part 1 will be treated with capmatinib 400 mg orally twice daily 
(BID) in combination with spartalizumab 400 mg iv every 28 days (Q4W).
A complete cycle of treatment is defined as 28 days of continuous capmatinib treatment and an 
infusion of spartalizumab every 28 days.
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Part 2: Randomized Part
All eligible subjects enrolled in Part 2 will be assigned to one of the following treatment arms 
in a ratio of 2:1 according to stratification factors.

Arm 1: capmatinib 400 mg orally twice daily (BID) plus spartalizumab 400 mg 
intravenously (iv) every 28 days (Q4W).

Arm 2: capmatinib 400 mg orally twice daily (BID) plus spartalizumab matching placebo 
iv every 28 days (Q4W).
A complete cycle of treatment is defined as 28 days of continuous capmatinib treatment and an 
infusion of spartalizumab or placebo every 28 days.
6.1.4
Treatment duration
Subjects will be treated until they experience unacceptable toxicity, disease progression per 
RECIST 1.1 as determined by investigator assessment (with or without confirmation by BIRC), 
and/or treatment is discontinued at the discretion of the investigator or the subject. A complete 
list of the circumstances requiring study treatment discontinuation is provided in Section 9.1.1.
Subjects may continue treatment beyond disease progression if, in the judgment of the 
investigator, there is evidence of clinical benefit and the patient wishes to continue on the study 
treatment. Criteria for treatment beyond progression are described below.
Treatment beyond disease progression
Subjects will be permitted to continue study treatment beyond disease progression per 
RECIST 1.1 as determined by investigator, provided they meet all the following criteria:

Clinical benefit per investigator's judgement

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
The reasons for the subject continuing treatment beyond progression will be documented in the 
eCRF.
Subjects who meet the above criteria and continue study treatment beyond initial disease 
progression per RECIST 1.1 will continue all study procedures as outlined in Table 8-1b and 
Table 8-3.
In addition, subjects enrolled in Part 2, who continue study treatment beyond initial disease 
progression per RECIST 1.1 
. 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)
If a subject experiences an infusion reaction, he/she may receive pre-medication on subsequent 
dosing days. The pre-medication should be chosen per institutional practice at the discretion of 
the treating physician.
Acute allergic reactions should be treated as needed per institutional practice or the dose 
modification guideline (Section 6.5.1). In the event of anaphylactic/anaphylactoid reactions, 
this includes any therapy necessary to restore normal cardiopulmonary status. If a subject 
experiences a Grade ≥3 anaphylactic/anaphylactoid reaction, the subject will be discontinued 
from the study treatment.
The CTCAE category of “Infusion related reaction” should be used to describe study treatment 
related infusion reactions, unless the investigator considers another category, such as “Allergic 
reaction,” “Anaphylaxis,” or “Cytokine release syndrome” more appropriate in a specific 
situation.
6.2.1
Concomitant therapy
In general, concomitant medications and therapies deemed necessary for the supportive care 
(e.g. such as anti-emetics, anti-diarrhea) and safety of the subject are allowed except when 
specifically prohibited (see Section 6.2.2).
The subject must be told to notify the investigational site about any new medications he/she 
takes after the start of the study treatment.  Medications include not only physician prescribed 
medications, but also all over-the counter medications, herbal medications, food supplements 
and vitamins.
All medications (excluding the current study treatment), procedures and significant non-drug 
therapies (including physical therapy and blood transfusions) administered after the subject 
signs the main study ICF and up to 30 days after the last dose of study drugs must be recorded 
in the appropriate eCRF.
Each concomitant drug (or supplement) must be individually assessed against all exclusion 
criteria/prohibited medication. If in doubt, the investigator should contact the Novartis medical 
monitor before enrolling a subject or allowing a new medication to be started. If the subject is 
already enrolled, contact Novartis to determine if the subject should continue participation in 
the study.
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Use of bisphonates or RANKL inhibitor
Treatment with bisphosphonates or receptor activator of nuclear factor kappa-B ligand 
(RANKL) inhibitor for pre-existing bone metastases is permitted, if clinically indicated and at 
the investigator's discretion following existing local guidelines. Treatment with 
bisphosphonates or RANKL inhibitor should preferably begin before the study treatment is 
initiated, but can also be initiated during therapy only if absence of radiological bone disease 
progression is well documented (in this case, the reason for its use must be clearly documented; 
i.e. “pre-existing, non-progressing, bone metastases”).
Permitted radiotherapy
Localized radiotherapy for pre-existing, painful bone metastases is permitted. Local bone 
radiotherapy for analgesic purposes or for lytic lesions at risk of fracture may be carried out if 
required. If palliative radiotherapy is initiated after start of study treatment, the reason for its 
use must be clearly documented and progression as per RECIST 1.1 must be ruled out. 
The study treatment must be interrupted on the days of radiotherapy and can be resumed the 
day after its completion. Caution is advised for radiation to fields that include lung tissue.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
6.2.1.1.1 Capmatinib
Permitted concomitant therapy requiring caution and/or action when co-administered with 
Capmatinib are as follows:

CYP1A2 substrates with narrow therapeutic index (NTI).
Capmatinib is a moderate CYP1A2 inhibitor. Co-administration of capmatinib increased 
sensitive CYP1A2 probe substrate (caffeine) AUC by 134%. CYP1A2 substrates where 
minimal concentration changes may lead to serious adverse reactions. If co-administration 
is unavoidable, decrease the CYP1A2 substrates dosage in accordance with the approved 
prescribing information.

Pgp or BCRP substrates.
Co-adminstration of capmatinib increased Pgp substrate (digoxin) exposure (AUC and 
Cmax by 47% and 74%, respectively) and BCRP substrate (rosuvastatin) exposure 
(AUC and Cmax by 108% and 204%, respectively).  Avoid co-administration of capmatinib 
with P-gp and BCRP substrates where minimal concentration changes may lead to serious 
adverse reactions. If co-administration is unavoidable, decrease the P-gp or BCRP 
substrates dosage in accordance with the approved prescribing information

Strong CYP3A4 inhibitors.
Co-administration of capmatinib with a strong CYP3A4 inhibitor (itraconazole) increased 
capmatinib AUC by 42%. There was no change in capmatinib Cmax. Closely monitor 
subjects for adverse reactions when using strong CYP3A4 inhibitors concurrently with 
capmatinib.
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
Moderate CYP3A4 inducers.
The effect of the moderate CYP3A4 inducer, efavirenz (600 mg once daily for 20 days) 
coadministered with capmatinib was simulated using the physiologically-based 
pharmacokinetic (PBPK) models. The models predicted a weak effect of 44% reduction in 
capmatinib AUC0-12 and 34% reduction in Cmax at steady state compared to 
administration of capmatinib alone. Caution should be exercised during concomitant use of 
capmatinib with moderate CYP3A inducers. Use an alternative medication with no or 
minimal potential to induce CYP3A during co-administration with capmatinib.

Proton Pump Inhibitors (PPIs).
Co-administration of capmatinib with proton pump inhibitor (rabeprazole) decreased 
capmatinib AUCinf by 25% and Cmax by 38%. Exercise caution during concomitant use 
of capmatinib with proton pump inhibitors.

Antacid and H2 receptor antagonists.
As an alternative to proton pump inhibitors, H2-receptor antagonist or antacid can be taken. 
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 Appendix 3 for a list of the medications (presented by mechanism of interaction) that 
require caution when concomitantly used with capmatinib.
6.2.1.1.2 Spartalizumab
Hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF), 
thrombopoietin mimetics or erythroid stimulating agents are allowed as per local or published 
guidelines; in case of anemia, thrombocytopenia or neutropenia, potential immune-mediated 
etiology should be ruled out.
Anticoagulation and anti-aggregation agents are permitted if the subjects are already at stable 
doses for > 2 weeks at time of first dose of spartalizumab/placebo, and International Normalized 
Ratio (INR) should be monitored as clinically indicated per investigator’s discretion.  
However, ongoing anticoagulant therapy should be temporarily discontinued to allow tumor 
sample according to the institutional guidelines.
Subjects with disease metastatic to bone may receive bone-stabilizing agents such as 
bisphosphonates or monoclonal antibodies intended for this purpose.
6.2.2
Prohibited medication
During the course of the study, subjects must not receive other antineoplastic therapies 
(e.g. investigational drugs, devices, chemotherapy, immunotherapies) or any other therapies 
that may be active against cancer or that are intended to modulate an immune response. 
However, limited-field palliative radiotherapy to non-target lesion(s) may be allowed as 
concomitant therapy upon discussion with the Novartis medical monitor. Such local therapies 
administered during the study treatment must be entered into the eCRF. The study treatment 
must be interrupted on the days of radiotherapy and can be resumed the day after its completion.
The use of live vaccines is not allowed during the study and up to 150 days from last dose of 
spartalizumab or 30 days from the last dose of capmatinib, whichever is longer.
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There are no prohibited therapies during the post-treatment follow-up period.
6.2.2.1
Capmatinib: prohibited medication 
Co-administration of capmatinib with a strong CYP3A4 inducer (rifampicin) decreased 
capmatinib AUC by 67% and Cmax by 56% (CINC280A2102), which may decrease 
capmatinib anti-tumor activity. Therefore concurrent use of strong CYP3A inducers is 
prohibited.
Capmatinib prohibited medications are listed in Appendix 3-Table 16-12.
6.2.2.2
Spartalizumab: prohibited medication
The use of systemic steroid therapy (at doses greater than 10 mg/day of prednisone or equivalent) 
and other immunosuppressive drugs is not allowed to subjects receiving spartalizumab, with 
the exception of:

Topical, inhaled, nasal and ophthalmic steroids

prophylactic use for subjects with imaging contrast dye allergy

Replacement-dose steroids (defined as ≤10 mg/day of prednisone or equivalent dose of 
corticosteroids) in the setting of adrenal insufficiency.

Transient exacerbations of other chronic inflammatory conditions, such as chronic 
obstructive pulmonary disease (COPD), requiring treatment. Steroids must be reduced to 
10 mg/day (or lower dose) of prednisone or equivalent dose of corticosteroids prior to the 
next treatment with spartalizumab.

Upon treatment of spartalizumab-related infusion reactions or spartalizumab-related 
irAEs, steroids must be reduced to ≤10 mg/day (or lower dose) of prednisone or 
equivalent dose of corticosteroids prior to the next treatment with spartalizumab. 
Systemic corticosteroids must be tapered, and be at non-immunosuppressive doses, prior 
to the next administration of study treatment. If the dose of prednisone or equivalent 
cannot be reduced to < 10 mg/day before the administration of next dose of study 
treatment then spartalizumab/ placebo must be discontinued (note: next dose of 
spartalizumab/placebo can be delayed up to 12 weeks).
The use of live vaccines is not allowed from 4 weeks prior start of study treatment and up to 
150 days from last dose of spartalizumab/placebo. Inactivated vaccines are allowed.
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 (either at pre-screening or screening) and is retained as the primary 
identifier for the subject throughout his/her entire participation in the trial. A new subject 
number will be assigned at every subsequent enrollment if the subject is re-screened. 
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.
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6.3.2
Treatment assignment, randomization
All subjects entering the main screening phase will be registered in the Interactive Response 
Technology (IRT) system. The investigator or his/her delegate will then contact the IRT once 
all the inclusion/exclusion criteria have been assessed to confirm whether the subject will start 
study treatment or not.
In Part 1, no randomization will be performed. All eligible subjects will be assigned to treatment 
with capmatinib plus spartalizumab.
In Part 2, all eligible subjects will be randomized via IRT in a 2:1 ratio to one of the following 
treatment arms:

Arm 1: capmatinib plus spartalizumab 

Arm 2: capmatinib plus spartalizumab matching placebo
The randomization will be stratified by presence or absence of brain metastasis (as assessed by 
investigator per RECIST 1.1) and PD-L1 expression <1%, or 1-49%, or ≥50%) at baseline 
(either at pre-screening or screening).
The IRT will assign a randomization number to the subject, which will be used to link the 
subject to a treatment arm and will specify the investigational drugs to be dispensed to the 
subject.
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 the IRT provider 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, which in turn are linked to medication 
numbers. A separate medication list will be produced under the responsibility of Novartis 
Global Clinical Supply (GCS) using a validated system that automates the random assignment 
of medication numbers to packs containing the study treatment.
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
Part 1: Single Arm Run-in Part
Not applicable. Treatment will be open to subjects, investigator staff, persons performing the 
assessments, and the clinical trial team (CTT).
Part 2: Randomized Part
Following the study enrollment halt during Part 1, Part 2 will not be initiated.
The CTT will remain blinded to the identity of the treatment from the time of randomization 
until the reporting of primary PFS analysis. Subjects, investigator staff and persons performing 
the assessments will remain blinded to the identity of the treatment from the time of 
randomization until final lock of the study database, using the following methods:
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(1) Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone else involved in the study with the following exceptions: unblinded 
Clinical Research Associates (CRAs), unblinded pharmacist/designee, independent statistician 
and programmer who will perform Data Monitoring Committee (DMC) analysis and the PK 
bioanalyst.  These personnel will not be involved in any other trial activity and treatment 
allocation information will be kept confidential until the final database lock. The randomization 
codes will be disclosed to PK bioanalysts who will keep PK results confidential until the 
database is locked for primary PFS analysis. (2) The identity of the treatments (spartalizumab 
or placebo) will be concealed by the use of a non-translucent, opaque sleeve that will be placed 
on the infusion bag.
Open label or single blinded supply (spartalizumab and placebo) will be provided at sites to the 
unblinded site pharmacist.
IMPORTANT: Due to the difference in preparation methods between the active and placebo 
treatments, an unblinded pharmacist/designee who is independent of the investigational staff 
will be required. The unblinded pharmacist/designee will receive the appropriate treatment 
allocations. Appropriate measures must be taken by the unblinded pharmacist to ensure that the 
investigational staff remains blinded throughout the study. The unblinded pharmacist must not 
administer the drug to the subject nor have any contact with the study participants. Please refer 
to the Pharmacist Instruction Manual.
An independent statistical group (external to and independent of Novartis), not involved in the 
trial conduct, will prepare semi blinded data reports for the DMC. Details will be presented in 
the DMC charter.
Confidentiality of randomization data is required to limit the occurrence of potential bias arising 
from the influence that the knowledge of treatment may have on the recruitment and allocation 
of subjects. Unblinding will only occur in the case of subject emergencies (see Section 6.6.2), 
following the DMC recommendations (e.g. after the interim analyses, see Section 12.7), for 
regulatory reporting purposes or at the end of the study. Except in these cases, documented 
approval by the Novartis study physician is required prior to unblinding a subject's treatment 
assignment. In case of unblinding, all data is required to be captured in the eCRF prior to 
unblinding.  Data after unblinding will continue to be collected as per protocol. The date of any 
unblinding and the reason will also be collected.
In rare cases when unblinding occurs because of emergency subject management, the actual 
treatment arm will not be communicated to any of the Novartis employees involved in running 
the trial in order to remain blinded.
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6.5
Dose modification
6.5.1
Dose modification
For subjects who do not tolerate the protocol-specified dosing schedule, dose adjustments 
(reductions and/or interruptions) are permitted in order to allow subjects to continue the study 
treatment.
The following guidelines should be considered:

Dose reductions are not permitted for spartalizumab/.

Dose reductions are allowed for capmatinib and should follow the dose reduction steps 
described in Table 6-2. For each subject, a maximum of two dose level modifications is 
allowed after which the subject must be discontinued. Dose reductions of capmatinib below 
200 mg BID are not permitted.

Dose re-escalation of capmatinib to the previous dose level is allowed only once, and if no 
AE leading to dose modification is observed after at least 1 cycle (4 weeks) of study 
treatment at the reduced dose.

Dose interruptions due to toxicities are permitted for both spartalizumab and capmatinib. 
Dosing of capmatinib may resume once the adverse event has resolved, as described in 
Table 6-3. All dose modifications, interruptions or discontinuations must be based on the 
worst preceding toxicity graded according to CTCAE v5.0 (http://ctep.cancer.gov).

For clinical management of suspected immune-related events, 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 : https://www.nccn.org/professionals/physician_gls/default.aspx#immunotherapy), 
the American Society for Clinical Oncology clinical practice guideline for Management of 
Immune-Related Adverse Events in Patients 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).  Note that in general, study treatment should be interrupted for grade 3 
and 4 toxicities and for a subset of lower grade toxicities.

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.

Overall, for adverse events of potential immune-related etiology (irAE) that do not recover 
to the extent required in the Table 6-3 at a dose of immunosuppression of ≤ 10 mg/day 
prednisone or equivalent and/or requiring continuation of other immunosuppressive drugs 
within 12 weeks after initiation of immunosuppressive therapy, spartalizumab/placebo must 
be permanently discontinued.

If, due to study drug related toxicity, a subject requires to interrupt capmatinib for > 3 weeks, 
then the subject should be discontinued from study treatment. Exceptions to this 
requirement may be permitted following documented discussion with the Novartis medical 
monitor.

Treatment continuation with spartalizumab alone is not permitted.
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
All interruptions or change to study drug administration must be recorded on the Dose 
Administration Record eCRF.
Table 6-2
Dose reduction steps for capmatinib
Starting dose level 0
Dose level - 1
Dose level - 2
capmatinib
400 mg BID
300 mg BID
200 mg BID
Note: dose reduction should be based on the worst toxicity demonstrated at the last dose.
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Protocol No. CINC280J12201
Table 6-3
Dose modifications of capmatinib and spartalizumab/placebo and recommended clinical management for 
Adverse Events
Worst toxicity
CTCAE grade
Dose Modification
Recommended Clinical Management
Infusion related reaction or hypersensitivity reaction - Note: no action required with capmatinib treatment
Grade 1
Decrease spartalizumab/placebo infusion rate until 
recovery from the symptoms.
Increase monitoring of vital signs as medically indicated until the subject 
is deemed medically stable in the opinion of the investigator.
Grade 2
Stop spartalizumab/placebo infusion immediately, and 
keep line open.
If symptoms resolve, restart infusion at 50% of previous 
rate under continuous observation.
If the AE recurs at the reinitiated slow rate of infusion, and 
despite oral pre-medication, then permanently discontinue 
spartalizumab/placebo treatment.
1. Stop Infusion
2. Treat as per local institutional guidelines, which may include: i.v. fluids, 
antihistamines, NSAIDS, acetaminophen, narcotics, oxygen and 
corticosteroids as indicated
3. Increase monitoring of vital signs/pulse oximetry as medically indicated 
until patient is deemed medically stable
If symptoms resolve, the infusion may be restarted at 50% of the original 
infusion rate.
4. Premedicate patient ~ 1.5h prior to next infusion of 
spartalizumab/placebo with:
● Diphenhydramine 50 mg po (or equivalent dose of antihistamine).
● Acetaminophen 500-1000 mg po (or equivalent dose of analgesic).
● Or as per local institutional guidelines
Grade ≥3 
Stop spartalizumab/placebo infusion immediately, and 
discontinue spartalizumab/placebo treatment permanently.
1. Stop Infusion
2. Treat as per local institutional guidelines, which may include: iv fluids, 
antihistamines, NSAIDs, acetaminophen, narcotics, oxygen, 
corticosteroids, epinephrine
3. Close monitoring of vital signs, pulse oximetry and ECG as medically 
indicated until the patient is deemed medically stable
4. Hospitalization may be indicated.
Fatigue
Grade ≥3 
Hold study treatment.
Upon resolution to ≤ Grade 1 within ≤ 7 days, resume 
study treatment without dose modification,
If resolved in > 7 days, reduce capmatinib ↓ 1 dose level 
and resume spartalizumab/placebo at same dose level.
Treat per local/institutional guidelines
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Worst toxicity
CTCAE grade
Dose Modification
Recommended Clinical Management
Peripheral edema (generalized edema or localized edema)
Grade 3
Hold study treatment.
Upon resolution to ≤ Grade 1, reduce capmatinib ↓ 1 
dose level and resume spartalizumab/placebo at same 
dose level.
Consider conservative measures such as leg elevation, compression 
stockings and dietary salt modification as clinically indicated and treat per 
local/institutional guidelines
Grade 4
Discontinue study treatment.
Intensify as above and treat per local/institutional guidelines
Ocular (uveitis, eye pain, blurred vision) - Note: no action required with capmatinib treatment
Grade 2
Hold spartalizumab/placebo treatment.
Upon resolution to ≤ Grade 1 may consider resuming 
spartalizumab/placebo treatment at same dose level.
Consult with ophthalmologist
Grade ≥3 
Discontinue spartalizumab/placebo treatment.
Pneumonitis/ILD – Note: subjects on combination therapy with capmatinib and spartalizumab/placebo should be monitored for pulmonary symptoms indicative of 
ILD/pneumonitis.
Grade 1
Hold study treatment and perform diagnostic workup for 
ILD/Pneumonitis.
If ILD/Pneumonitis is confirmed, discontinue study treatment.
If ILD/Pneumonitis is not confirmed, upon resolution resume 
study treatment without dose modifications,
At second occurrence, discontinue study treatment.
1. Exclude infections or other etiologies
2. CT scan (high-resolution with lung windows) recommended, with 
serial imaging to monitor for resolution or progression re-image at least 
every 3 weeks
3. Monitor for symptoms every 2-3 days
4. Clinical evaluation and laboratory work-up for infection
5. Monitoring of oxygenation via pulse oximetry recommended
6. Consultation with pulmonologist recommended
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Protocol No. CINC280J12201
Worst toxicity
CTCAE grade
Dose Modification
Recommended Clinical Management
Grade 2
Mandatory: hold study treatment until improvement to ≤ 
Grade 1 and perform diagnostic workup for ILD.
If ILD/Pneumonitis is confirmed, discontinue study treatment.
If ILD/Pneumonitis is not confirmed, study treatment may be 
resumed as follows:

If resolved to ≤ Grade 1 within ≤ 7 days, reduce 
capmatinib ↓ 1 dose level and resume 
spartalizumab/placebo at same dose level

If resolved in > 7 days, or at second occurrence after 
capmatinib dose reduction, discontinue study 
treatment.
1. Exclude infections or other etiologies
2. CT scan (high-resolution with lung windows)
3. Monitor symptoms daily, consider hospitalization
4. Clinical evaluation and laboratory work up for infection
5. Consult pulmonologist
6. Pulmonary function tests - if normal at baseline, repeat every 8 
weeks
7. Bronchoscopy with biopsy and/or BAL recommended
8. Symptomatic therapy including corticosteroids c if clinically indicated 
(1 to 2 mg/kg/day prednisone or equivalent as clinically indicated).
9. Consider empirical antibiotics
10. If no improvement within 2-3 days, or worsening, treat as grade 3
Grade ≥ 3
Mandatory: Discontinue study treatment
1. CT scan (high-resolution with lung windows)
2. Hospitalization and pulmonary and infectious disease consultation
3. Clinical evaluation and laboratory work-up for infection
4. Commence oxygen therapy
5. Consult pulmonologist
6. Pulmonary function tests*. If < normal, repeat every 8 weeks until ≥ 
normal
7. Bronchoscopy** with biopsy and/or BAL if possible
8. Treat with iv steroids*** (methylprednisolone 125 mg) as indicated. 
When symptoms improve to ≤ Grade 1, switch to high dose oral steroid 
(prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 
4 hours) then slow taper over ≥4-6 weeks
9. If iv steroids followed by high dose oral steroids do not reduce initial 
symptoms within 48 consider non-corticosteroid immunosuppressive 
medication
10 Empiric antibiotics
* 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. 
** 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.
*** Duration and dose of course of corticosteroids will vary according to circumstances but should be as limited as possible. Consider tapering dosage at end. 
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Protocol No. CINC280J12201
Worst toxicity
CTCAE grade
Dose Modification
Recommended Clinical Management
ECG QTc-Interval prolonged 
Grade 3
Hold study treatment.
Upon resolution to ≤ Grade 2 within ≤ 7 days, resume 
study treatment without dose modification,
If resolved in > 7 days, reduce capmatinib ↓ 1 dose 
level and resume spartalizumab/placebo at same dose 
level.
1.Perform an analysis of serum potassium, calcium, phosphorus, and 
magnesium, and if below lower limit of normal, correct with supplements 
to within normal limits.
2.Review concomitant medication usage for the potential to inhibit 
CYP3A4/5 and/or to prolong the QT-interval 
3.Check compliance with correct dose and administration of capmatinib.
4.Repeat ECG within one hour of the first QTcF of ≥501 ms.
5.If QTcF remains ≥ 501 ms, repeat ECG as clinically indicated, but at 
least once daily until the QTcF returns to < 501 ms.
6.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 subject with QTcF 
prolongation should be maintained on study.
Grade 4
Discontinue study treatment.
As for Grade 3 
Myocarditis 
Myocarditis grade
≥2 or other cardiac
event grade ≥3 
Mandatory: permanently discontinue study treatment
Ensure adequate evaluation to confirm etiology and/or exclude other 
causes.
Initiate systemic corticosteroids (prednisone or equivalent) at a dose of 1-2 
mg/kg/d
Consult with specialist; hospitalization as indicated
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Worst toxicity
CTCAE grade
Dose Modification
Recommended Clinical Management
Diarrhea/colitis
Grade 1
May continue study treatment.
Treat symptoms (loperamide*, hydration, diet) and monitor closely
Grade 2 (despite appropriate 
anti-diarrheal medication)
Hold study treatment.
Upon resolution to ≤ Grade 1 resume study treatment without 
dose modification,
At second occurrence of ≥ Grade 2, hold study treatment 
until resolved to ≤ Grade 1, then reduce capmatinib ↓ 1 dose 
level and resume spartalizumab/placebo at same dose level
1. Consult with GI specialist
2. Stool evaluation, imaging and endoscopy as clinically indicated
3. Symptomatic treatment (loperamide*, hydration, diet). 
4. If considered immune-related commence steroids (0.5-1 mg/kg/d 
prednisone or IV equivalent) until recovery to Grade 1, particularly 
in case of persisting/worsening symptoms, ulcerations or bleeding 
seen on endoscopy, or blood in stool. If no improvement within few 
days, manage as per Grade 3.
5. Slowly taper steroids once symptoms improve to Grade 1 (i.e. over 
4-6 weeks)
Grade 3 or (despite 
appropriate anti-diarrheal 
medication)
Hold study treatment.
Upon resolution to ≤ Grade 1 of diarrhea, reduce capmatinib 
↓ 1 dose level and resume spartalizumab/placebo at same 
dose level.
At second occurrence of ≥ Grade 3, discontinue study 
treatment.
1. Consider hospitalization; rule out bowel perforation and initiate IV 
hydration as needed
2. Consultation with GI specialist; consider endoscopy and biopsy
3. If considered immune-related, in addition to symptomatic treatment 
initial treatment with IV steroids (1 to 2 mg/kg/d 
of methylprednisolone or equivalent)
4. Consider antibiotics as appropriate
5. If no improvement in 2-3 days: consider initiating infliximab 5 mg/kg 
and continue steroids. (infliximab is contraindicated in patients with 
sepsis/perforation)
6. Slowly taper steroids once symptoms improve to Grade 1 (4 to 6 
weeks)
7. If symptoms worsen during steroid reduction, re-escalate as needed 
followed by more prolonged taper and consider infliximab
Grade 4
Discontinue study treatment
Urgent hospitalization, supportive care and specialist consultation as 
outlined for Grade 3 toxicity
*Loperamide exposure may be increased in the presence of capmatinib, subjects receiving this treatment should be closely followed. For diarrhea suspected to be 
related to capmatinib, treatment with steroids and/or infliximab is not indicated. For complicated diarrhea associated with capmatinib (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. Note: complicating signs or symptoms include moderate to severe cramping, 
decreased performance status, fever, neutropenia, frank bleeding or dehydration.
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Protocol No. CINC280J12201
Worst toxicity
CTCAE grade
Dose Modification
Recommended Clinical Management
Vomiting
Grade 1 (despite appropriate 
anti-emetics)
Continue study treatment.
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.
Concomitant medication for the treatment of nausea and/or vomiting 
should follow local practice and the investigator`s best judgement*..
Grade ≥3 (despite 
appropriate anti-emetics)
Hold study treatment.
Upon resolution to ≤ Grade 1, reduce capmatinib ↓ 1 dose 
level and resume spartalizumab/placebo at the same dose 
level.
Treat per local/institutional guidelines
*Aprepitant exposure may be increased in the presence of capmatinib, subjects receiving this treatment should be closely followed.
Nausea
Grade 3 (despite appropriate 
anti-emetics)
Hold study treatment.
Upon resolution to ≤ Grade 1, reduce capmatinib ↓ 1 dose 
level and resume spartalizumab/placebo at the same dose 
level.
Treat per local/institutional guidelines
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Protocol No. CINC280J12201
Worst toxicity
CTCAE grade
Dose Modification
Recommended Clinical Management
AST and/or ALT increased
Grade 2 AST and/or ALT
Hold study treatment.
Manage per institutional practice.
Upon resolution to ≤ Grade 1 or baseline, consider resuming 
study treatment without dose modification.
Monitor hepatic laboratory tests more frequently (every 2-3 days) until 
resolved to ≤ grade 1
Rule-out alternative causes (e.g. concomitant medications, infection, 
disease progression)
Consider prednisone (0.5-1 mg/kg/d) if liver tests worsen and/or 
significant symptoms
Grade 3 AST and/or ALT
Hold capmatinib treatment.
Permanently discontinue spartalizumab/placebo
Upon resolution to ≤ Grade 1 or baseline within ≤ 7 days, 
resume capmatinib treatment without dose modification
If resolved in > 7 days, reduce capmatinib ↓ 1 dose level.
1.Monitor hepatic laboratory more frequently (every 2-3 days) until 
returned to ≤ grade 1.
2.Consult with hepatologist; consider hospitalization and liver biopsy to 
establish etiology 
3.Initiate treatment with steroids (prednisone 1-2 mg/kg/d or IV 
equivalent)
4.Add prophylactic antibiotics for opportunistic infections as appropriate
5.Once symptoms/liver tests improve to Grade ≤1, taper steroids over 
at least 4 weeks
6.If no improvement or steroid refractory after 3 days, consider oral 
mycophenolate as per local treatment guidance
7.Infliximab is not recommended due to its potential for hepatotoxicity
Grade 4 AST and/or ALT
Mandatory: permanently discontinue study treatment.
As for Grade 3 toxicity above
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Worst toxicity
CTCAE grade
Dose Modification
Recommended Clinical Management
Isolated total bilirubin increased
Grade 2
Hold study treatment. 
Upon resolution to ≤ Grade 1 or baseline within ≤ 7 days, 
resume study treatment without dose modification,
If resolved in > 7 days, reduce capmatinib ↓ 1 dose level 
and resume spartalizumab/placebo at same dose level.
Frequent monitoring of Liver Function Tests (LFTs), (every 2-3 days) 
until resolved to ≤ grade 1 
Rule-out alternative causes (e.g. concomitant medications, infection, 
disease progression)
Grade 3
Hold study treatment.
Upon resolution to ≤ Grade 1 or baseline, reduce capmatinib 
↓ 1 dose level and resume spartalizumab/placebo at same 
dose level.
If resolved in > 7 days, discontinue study treatment.
Frequent monitoring of LFTs, (every 2-3 days), until resolved to ≤ 
grade 1. 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
Grade 4
Mandatory: Discontinue study treatment.
After permanently discontinuing the subject from study treatment, the 
subject should be monitored weekly (including LFTs), or more 
frequently if clinically indicated, until total bilirubin have resolved to ≤ 
grade 1 or stabilization over 4 weeks. 
Combined elevations of AST or ALT and Total Bilirubin 
Grade 2 AST and/or ALT 
with bilirubin  ≥Grade 2 
(unless Gilbert’s syndrome)
OR
For participants with elevated 
baseline AST or ALT or total 
bilirubin value:
[AST or ALT > 3 x baseline] 
OR [AST or ALT > 8.0 x 
ULN], whichever is lower, 
combined with [total 
bilirubin > 2 x baseline 
AND > 2.0 x ULN] without 
evidence of cholestasis or 
hemolysis
Mandatory: discontinue study treatment.
After permanently discontinuing the subject from study treatment, 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 grade 1 or stabilization over 4 weeks
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Protocol No. CINC280J12201
Worst toxicity
CTCAE grade
Dose Modification
Recommended Clinical Management
Amylase and/or lipase increased
Grade 3 
Hold study treatment.
Upon resolution to ≤ Grade 2 or baseline within ≤ 14 days, 
resume study treatment without dose modification,
If resolved in > 14 days, reduce capmatinib ↓ 1 dose level 
and resume spartalizumab/placebo at same dose level.
Perform CT scan or other imaging study to assess the pancreas, liver, 
and gallbladder must be performed within one week of the first 
occurrence of any ≥ Grade 3 of amylase and/or lipase elevation
Grade 4
Discontinue study treatment
Pancreatitis
Grade 2/radiologic evidence
Hold study treatment.
Upon resolution, may resume study treatment without dose 
modification
Evaluate for pancreatitis (clinical assessment, abdominal imaging 
and/or MRCP as appropriate)
Initiate steroids in case of ≥ grade 2 acute pancreatitis
Grade ≥3
Mandatory: discontinue study treatment.
As for Grade 2
Creatinine increased, nephritis
Grade 1
Continue study treatment
Monitor creatinine weekly
Rule-out other causes (e.g. fluids, medications, IV contrast)
Promote hydration and consider cessation of nephrotoxic drugs
Grade 2
Hold study treatment.
Upon resolution to ≤ Grade 1, resume study treatment 
without dose modification
1. Monitor creatinine every 2 to 3 days
2. Initiate 0.5 to 1 mg/kg/day prednisone or equivalents if other causes 
are ruled-out
3. If worsening or no improvement: 1 to 2 mg/kg/day prednisone or 
equivalents
4. Promote hydration and cessation of nephrotoxic drugs
5. Consult with specialist and consider renal biopsy
Rule-out other causes (e.g. fluids, medications, IV contrast)
If worsening or no improvement: 1 to 2 mg/kg/d prednisone or 
equivalents
Grade 3
Upon resolution to Grade ≤ 1, reduce capmatinib ↓ 1 dose 
level and discontinue spartalizumab/placebo.
1. Monitor creatinine every 1 to 2 days
2. Start 1 to 2 mg/kg/day prednisone or equivalents.
Once event improves to Grade ≤1, slowly taper steroids over at least 
4-6 weeks
3. Promote hydration and cessation of nephrotoxic drugs
4. Consult with specialist and consider renal biopsy
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Protocol No. CINC280J12201
Worst toxicity
CTCAE grade
Dose Modification
Recommended Clinical Management
Grade 4
Discontinue study treatment.
As for Grade 3 toxicity
Immune-related endocrinopathies (e.g. hypophysitis, adrenal insufficiency, hyperthyroidism or hypothyroidism) - Note: no action required with capmatinib 
treatment
Asymptomatic, intervention 
not indicated
Continue study treatment
If Thyroid Stimulating Hormone (TSH) <0.5x LLN, or TSH >2x ULN, or 
consistently out of range in 2 subsequent measurements, include free 
T4 at subsequent cycles as clinically indicated
Consider endocrinologist consult
If hypophysitis is suspected, consider pituitary gland imaging (MRIs 
with gadolinium and sellar cuts); evaluate hormone levels as clinically 
indicated
Repeat labs in 1 to 3 weeks/MRI in 1 month if laboratory abnormalities 
persist but normal lab/pituitary scan
Symptomatic
Hold spartalizumab/placebo until recovery to mild or no 
symptoms, and controlled with hormone replacement therapy
Hypothyroidism may be managed with replacement therapy 
without treatment interruption (unless life-threatening) 
Permanently discontinue spartalizumab/placebo for life-
threatening endocrinopathies (i.e. hyperthyroidism, adrenal 
insufficiency, hypophysitis) or recurring severe/life-
threatening events not controlled by hormone replacement 
therapy.
Endocrinology consultation
Rule out infection/sepsis and other alternative causes with appropriate 
cultures/imaging
Evaluate hormone levels (e.g. ACTH, cortisol FSH/FH, TSH, free T4, 
testosterone/estrogen), metabolic panel (e.g. Na, K, CO2, glucose), 
and imaging (e.g. brain MRI) as clinically indicated
Initiate hormone replacement therapy as appropriate 
Consider steroids (methylprednisolone 1 to 2 mg/kg/d or equivalent) in 
case of severe hypophysitis or thyrotoxicosis
Consider beta-blocker in case of severe hyper-thyroidism
Consider hospitalization (e.g. in case of severe adrenal 
insufficiency/crisis), fluid replacement, and other supportive measures 
as clinically indicated
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Worst toxicity
CTCAE grade
Dose Modification
Recommended Clinical Management
Autoimmune diabetes - Note: no action required with capmatinib treatment
Grade 3 or symptomatic 
hyperglycemia
Hold spartalizumab/placebo until recovery to ≤ Grade 1 or 
baseline
Permanently discontinue spartalizumab/placebo in case of 
recurring severe/life-threatening events not controlled by 
anti-glycemic therapy.
Initiate anti-glycemic therapy (i.e. insulin) as medically indicated
Monitor glucose levels regularly until metabolic control is achieved
Grade 4 hyperglycemia or 
life-threatening complications
Hold spartalizumab/placebo until recovery to grade 1 or 
baseline
Permanently discontinue spartalizumab/placebo in case of 
recurring severe/life-threatening events not controlled by 
anti-glycemic therapy.
Initiate anti-glycemic therapy (i.e. insulin) as medically indicated
Monitor glucose levels regularly until metabolic control is achieved
Consider endocrinology consultation
Evaluate for ketoacidosis as medically indicated
Consider hospitalization (e.g. in case of ketoacidosis)
Encephalitis or aseptic meningitis - Note: no action required with capmatinib treatment
Discontinue spartalizumab/placebo
Rule out infectious or other causes of moderate to severe neurologic 
deterioration, and consult with specialist.
If other etiologies are ruled out, administer corticosteroids at a dose of 
1 to 2 mg/kg/day prednisone equivalents.
Guillain-Barre Syndrome, severe peripheral or autonomic neuropathy, or transverse myelitis - Note: no action required with capmatinib treatment
Discontinue spartalizumab/placebo
Hospitalization and consult with specialist
Other immune-related neuropathies (e.g. autoimmune neuropathy, demyelinating polyneuropathy, etc.) - Note: no action required with capmatinib treatment
Grade 1
Continue study treatment
Provide symptomatic treatment evaluate/monitor adequately
Grade 2
Consider holding spartalizumab/placebo treatment until 
recovery to ≤ Grade 1 or baseline
Ensure adequate evaluation to confirm etiology or exclude other 
causes
Provide symptomatic treatment
Systemic corticosteroids may be indicated
Consider biopsy or additional tests for confirmation of diagnosis
A specialist should be consulted
Grade 3
Hold spartalizumab/placebo until recovery to ≤ Grade 1 or 
baseline
May restart spartalizumab/placebo treatment at the same 
dose and schedule taking into account the risks and benefits
Initiate systemic corticosteroids (prednisone at a dose of 1-2 mg/kg/d 
or equivalent) and other therapies as appropriate
Monitor closely and consult with a specialist
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Protocol No. CINC280J12201
Worst toxicity
CTCAE grade
Dose Modification
Recommended Clinical Management
Grade 4
Discontinue spartalizumab/placebo
Hospitalization and consult with specialist
Initiate systemic corticosteroids (prednisone a dose of 1-2 mg/kg/d or 
equivalent) and other therapies as appropriate
Myasthenia gravis - Note: no action required with capmatinib treatment
Grade 2
Hold spartalizumab/placebo until recovery to ≤ Grade 1 or 
baseline
Grade ≥3
Discontinue spartalizumab/placebo
Consult with specialist
Consider pyridostigmine and systemic corticosteroids (prednisone or 
equivalent) at a dose of 1-2 mg/kg/d; other therapies as appropriate 
(e.g. IVIG)
Hospitalization in case of severe cases
Rash/Photosensitivity – Note: 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).
Grade 1
Continue study treatment without dose modification. 
1. Initiate prophylactic and symptomatic treatment measures.
2. Consider use of antihistamines and /or topical corticosteroids or 
urea containing creams in combination with oral antipruritics or 
moderate strength topical steroid (hydrocortisone 2.5% cream or 
fluticasone propionate 0.5% cream)
3. Reassess after 2 weeks
Grade 2
Consider holding spartalizumab/placebo and continue 
capmatinib treatment
Upon resolution to ≤ Grade 1, resume spartalizumab/placebo 
treatment without dose modification.
In case of bullous dermatitis, acute generalized 
exanthematous pustulosis or DRESS, hold 
spartalizumab/placebo treatment until recovery to Grade ≤1 
or baseline
1. Consider to initiate systemic steroids (e.g. oral prednisolone 0.5-
1mg/kg daily). In addition, treat with topical emollients, oral 
antihistamines, and medium/high-potency topical steroids
2. If symptoms persist or recur consider skin biopsy.
Grade 3 
Hold study treatment.
Upon resolution to Grade 1, reduce capmatinib ↓1 dose 
level and resume spartalizumab/placebo at same dose level.
If resolved in > 7 days, discontinue study treatment.
For patients with severe cutaneous adverse reaction or 
bullous dermatitis, risk/benefit should be carefully considered 
before resuming spartalizumab/placebo treatment.
1. Consult with dermatologist and consider skin biopsy.
2. Initiate systemic steroids (1 mg/kg/d prednisone or IV equivalent); 
consider increasing if no improvement
3. High-potency topical steroids
4. Topical emollients, oral antihistamines as indicated
5. Consider GABA agonists or aprepitant in case of severe pruritus
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Amended Protocol Version v01 (Clean)
Protocol No. CINC280J12201
Worst toxicity
CTCAE grade
Dose Modification
Recommended Clinical Management
Grade 4
Discontinue study treatment
Urgent dermatologic consultation and additional measures as per local 
guidelines
Stevens-Johnson 
syndrome (SJS), or Lyell 
syndrome/toxic epidermal 
necrolysis (TEN)
Discontinue study treatment
Hospitalization and urgent dermatology consultation
Institute supportive care immediately as per local/institutional 
guidelines
Neutrophil count decreased 
Grade ≥3
Hold study treatment.
Upon resolution to ≤ Grade 2 or baseline within ≤ 7 days, 
resume study treatment without dose modification,
If resolved in > 7 days, reduce capmatinib ↓ 1 dose level 
and resume spartalizumab/placebo at same dose level.
Treat per local/institutional guidelines
Febrile neutropenia
Grade ≥3
Hold study treatment.
Upon resolution within ≤ 7 days, reduce capmatinib ↓ 1 
dose level and resume spartalizumab/placebo at same dose 
level,
If resolved in > 7 days, permanently discontinue study 
treatment 
Treat per local/institutional guidelines
Platelets count decreased
Grade 3
Hold study treatment.
Upon resolution to ≤ Grade 2 within ≤ 7 days, resume study 
treatment without dose modification.
If resolved in > 7 days, reduce capmatinib ↓ 1 dose level 
and resume spartalizumab/placebo at same dose level.
Treat per local/institutional guidelines
Grade 4
Hold study treatment.
Upon resolution to ≤ Grade 2 or baseline, reduce 
capmatinib ↓ 1 dose level.
Treat per local/institutional guidelines
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Protocol No. CINC280J12201
Worst toxicity
CTCAE grade
Dose Modification
Recommended Clinical Management
Anemia
Grade 3 
Hold study treatment.
Upon resolution to ≤ Grade 2 or baseline within ≤ 7 days, 
resume study treatment without dose modification.
If resolved in > 7 days, reduce capmatinib ↓ 1 dose level, 
and resume spartalizumab/placebo at same dose level. 
Treat per local/institutional guidelines
Grade 4
Hold study treatment. 
Upon resolution to ≤ Grade 2 or baseline, reduce capmatinib 
↓ 1 dose level and resume spartalizumab/placebo at same 
dose level.
At second occurrence, permanently discontinue study 
treatment. 
Treat per local/institutional guidelines
Autoimmune hemolytic 
anemia, hemolytic uremic 
syndrome, or acquired 
hemophilia grade ≥ 3
Discontinue spartalizumab/placebo
Consult with specialist
Consider systemic corticosteroids and other therapies as appropriate 
(e.g. transfusion) per local institutional guidelines local institutional 
guidelines
Other adverse events
Grade 1 or 2
Maintain dose level, initiate supportive treatment as clinically 
indicated.
For any intolerable grade 2 (e.g. limiting instrumental ADL), 
consider omitting the dose until resolved to ≤ grade 1, then 
then restart either at same dose or ↓ 1 dose level.
Grade 3
Omit dose until resolved to ≤ grade 1, then↓ 1 dose level
Grade 4
Permanently discontinue capmatinib
Note: All dose modifications should be based on the worst preceding toxicity.
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6.5.2
Follow-up for toxicities
All subjects will be followed for safety up to 150 days after last dose of spartalizumab/placebo 
or 30 days after the last dose of capmatinib, whichever is longer. For subjects who are 
transferred to another clinical study or alternative treatment option to continue capmatinib 
treatment at end of study, no further safety data will be collected as part of this study (for details, 
please refer to Section 9.2.1).
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 described in Table 6-3 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.
The emergence of irAE may be anticipated in subjects receiving spartalizumab 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 to 
verify the immune-related nature of the AE and to exclude alternative explanations. 
Recommendations (Section 6.5.1) have been developed to assist investigators in assessing and 
managing the most frequently occurring irAEs.
Patients whose treatment is interrupted or permanently discontinued due to an irAE, AE 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 30 days, and 
subsequently at approximately 30-day intervals (or more frequently if required by institutional 
practices, or if clinically indicated), until resolution or stabilization of the event, whichever 
comes first. Appropriate clinical experts should be consulted as deemed necessary.
If an AE is suspected to be immune-related the relevant immunological assessments 
(e.g. rheumatoid factor, anti-DNA Ab, etc.) should be performed. All subjects receiving 
spartalizumab/placebo must be followed for irAEs, AEs and SAEs for 150 days after the last 
dose of study treatment. Please refer to Section 10 for additional details.
Recommendations for follow-up evaluations of selected toxicities are reported in Table 6-3.
6.5.2.1
Follow up on potential drug-induced liver injury (DILI) cases
Subjects with transaminase increase combined with total bilirubin (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 x 
ULN combined with TBIL > 2.0 x ULN
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
For sub7jects with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed as the cause of liver injury.
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any 
pre-existing liver conditions or risk factors, should be collected.
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, GGT, 
GLDH, prothrombin time (PT)/INR, alkaline phosphatase, albumin, and creatine kinase.
Evaluate status of liver metastasis (new or exacerbation) or vascular occlusion – e.g. using CT, 
MRI, or duplex sonography.
Perform relevant examinations (Ultrasound or MRI, ERCP) as appropriate, to rule out an 
extrahepatic cause of cholestasis (cholestasis is defined as ALP elevation > 2.0 x ULN with R 
value < 2 in subjects without bone metastasis, or elevation of ALP liver fraction in subjects with 
bone metastasis.
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. In clinical 
situations where it is suspected that ALP elevations are from an extrahepatic source, the GGT 
can be used if available. GGT may be less specific than ALP as a marker of cholestatic injury, 
since GGT can also be elevated by enzyme induction or by ethanol consumption. It is more 
sensitive than ALP for detecting bile duct injury (livertox.nih.gov/rucam.html).
Table 6-4 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule out possible alternative causes of observed LFT abnormalities.
Table 6-4
Clinical and diagnostic assessments for LFT abnormalities
Disease
Assessment
Hepatitis A, B, C, E
IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV DNA; anti-HCV, 
HCV RNA, IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV infection
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis
ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis
Ethanol history, GGT, MCV, CD-transferrin
Nonalcoholic steatohepatitis
Ultrasound or MRI
Hypoxic/ischemic hepatopathy
Medical history: acute or chronic CHF, hypotension, hypoxia, 
hepatic venous occlusion. Ultrasound or MRI.
Biliary tract disease
Ultrasound or MRI, ERCP as appropriate.
Wilson disease (if <40 yrs old)
Ceruloplasmin
Hemochromatosis
Ferritin, transferrin
Alpha-1-antitrypsin deficiency
Alpha-1-antitrypsin
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Other causes should also be considered based upon subjects’ medical history (hyperthyroidism/ 
thyrotoxic hepatitis – T3, T4, TSH; CVD / ischemic hepatitis – ECG, prior hypotensive episodes; 
T1D / glycogenic hepatitis).
Obtain PK sample to determine exposure to study treatment.
Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” i.e. >50% likely, if it appears greater than all other possible causes 
of liver injury combined. The term “treatment-induced” indicates probably caused by the 
treatment, not by something else, and only such a case can be considered a DILI case and should 
be reported as an SAE.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” and thus, meet the definition of a serious adverse event (SAE) and should be 
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
The IRT system will be contacted at each study treatment administration/dispensation. 
Additional details are provided in IRT manual.
The investigator must promote compliance by instructing the subject to take the study treatment 
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 the study treatment as prescribed. All dosages prescribed to the 
patient and all dose changes, interruptions during the study must be recorded on the Dosage 
Administration Record eCRFs.
Compliance to capmatinib will be assessed by the investigator and/or study personnel at each 
visit using pill counts and information provided by the subject.
All study treatment dispensed and returned must be recorded in the Drug Accountability Log.
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all treated 
subjects as detailed in Section 8.5.2.
6.6.2
Emergency breaking of assigned treatment code
Part 1: Single Arm Run-in Part
Not applicable.
Part 2: Randomized Part
Following the study enrollment halt, Part 2 will not be initiated.
Emergency code breaks (unblinding decisions) must only be undertaken in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
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treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Blinding codes may also be broken after a subject discontinues treatment due to 
disease progression if deemed essential to allow the investigator to select the patient’s next 
treatment regimen, and after discussion and agreement with the sponsor. Emergency treatment 
code breaks are performed using the IRT.
When the investigator/designee contacts the system to break a treatment code for a subject, 
he/she must provide the requested subject identifying information and confirm the necessity to 
break the treatment code for the subject. The investigator/designee will then receive details of 
the investigational drug treatment for the specified subject and a fax or email confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
study team that the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide:

protocol number

subject number
In addition, the investigator must provide oral and written information to the subject on how to 
contact his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-
blinding can be performed at any time.
Except for medical emergencies, for regulatory reporting purposes, or if it is critical to 
determine subsequent therapy after disease progression, documented approval by the Novartis 
study physician is required prior to unblinding a subject's treatment assignment.
Study treatment must be discontinued once emergency unblinding has occurred. If a subject is 
unblinded, he/she must be discontinued from the study treatment and must be followed for 
efficacy and survival, as applicable per Section 9.2.2.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described in Section 6.1.1.
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). The study medication has a 2-part label 
(base plus tear-off label), immediately before dispensing the medication kit, site personnel will 
detach the outer part of the label from the packaging and affix it to the source document.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the Novartis CO Quality Assurance.
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Note: To maintain the blind in Part 2, study drugs will be kept in a location to which only the 
unblinded pharmacist, unblinded CRA, or unblinded designated staff have access, the 
investigational treatments will be prepared by an unblinded pharmacist/designee, and the bags 
will be covered by a non-translucent, opaque sleeve. Only study personnel blinded to treatment 
allocation must administer spartalizumab or placebo.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. 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.
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, investigator will return all unused study treatment, packaging, 
drug labels, and a copy of the completed drug accountability log to the Novartis monitor or to 
the Novartis address provided in the investigator folder at each site.
6.7.2
Instruction for prescribing and taking study treatment
Following the study enrollment halt, spartalizumab treatment has been discontinued in all 
ongoing subjects.
The dose and treatment schedule of each investigational drug used in this study is described in 
Table 6-5.
All kits of study treatment assigned by the IRT will be recorded in the IRT system.
Table 6-5
Dose and treatment schedule
Investigational Drugs
Dose
Frequency and/or 
Regimen
Capmatinib (INC280)
150 mg or 200 mg
400 mg p.o. (2 x 200 mg) OR
300 mg p.o. (2 x 150 mg) if dose level -1 
is required OR
200 mg p.o. (1 x 200 mg) if dose level -2 
is required
Twice daily 
(28 days cycle)
Spartalizumab (PDR001)
100 mg
400 mg i.v. (4 x 100 mg vials*)
Once every 28 days
* A higher number of vials might be required if closed system drug-transfer devices (CSTDs) are 
used, for more details please refer to the Study Pharmacy manual. 
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6.7.2.1
Capmatinib
Capmatinib tablets will be administered orally on a continuous twice daily (BID) dosing 
schedule, from Day 1 till Day 28 of each 28 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. A complete cycle of treatment is defined as 28 days of twice 
daily treatment with capmatinib. The investigator must instruct the subject to take the study 
drug exactly as prescribed.

Subjects should take capmatinib tablets BID at approximately the same time each day 
starting on Cycle 1 Day 1.

Each dose of capmatinib is to be taken with a glass of water (at least 8 ounces – 
approximately 250 mL) and consumed over as short a time as possible (i.e. not slower 
than approximately 1 tablet every 2 minutes).

Subjects should be instructed to swallow the whole tablets and not to chew them.

Capmatinib can be administered with or without food. The morning and the evening doses 
should be taken 12 (± 4) hours apart, although a 12-hour interval is highly recommended. 
The morning dose should be taken at the same time each morning. If a dose is not taken 
within 4 hours of the planned dosing time, the missed dose should not be replaced.

On days of co-administration of capmatinib with spartalizumab, subjects should be 
instructed to take the morning dose of capmatinib during the clinic visit, when instructed 
by site personnel. Capmatinib will be administered prior to spartalizumab/placebo infusion 
along with its pre-medication (if pre-medication is necessary).

On days when PK blood samples are to be collected, subjects will be instructed to hold 
their dose until arrival at the study center. The pre-dose PK samples will be taken right 
before capmatinib administration. The exact time of drug administration should be 
recorded in the eCRF. If a subject vomits within 4 hours of capmatinib dosing, the time of 
vomiting will also be recorded in the eCRF.

Subjects should be instructed not to make up for missed doses or partial doses (i.e., when 
the entire dose is not taken as instructed). A missed or partial dose will be defined when 
the full dose is not taken within 4 hours of the scheduled twice daily dosing. If that occurs, 
then the dose (or part of the remaining dose) should not be taken and dosing should restart 
with the next scheduled dose. If vomiting occurs, no attempt should be made to replace the 
vomited dose before the next scheduled dose.

During the whole duration of treatment with capmatinib, the subject is recommended to 
use precautionary measures against ultraviolet exposure (e.g., use of sunscreen, protective 
clothing, avoid sunbathing or using a solarium).
6.7.2.2
Spartalizumab/placebo
Spartalizumab will be supplied in a vial as concentrate for solution for infusion. Spartalizumab 
(liquid) will be diluted in dextrose 5% in water (D5W). Due to incompatibility, 0.9% sodium 
chloride must not be used. Spartalizumab matching placebo will be a Dextrose 5% in water 
(D5W) infusion supplied by the site.
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Spartalizumab/placebo will be administered intravenously as a 30 minutes infusion (up to 
2 hours, if clinically indicated). Infusion must take place in a facility with appropriate 
resuscitation equipment available at the bedside, and a physician readily available during the 
period of drug administration.
Subjects should be closely observed for potential infusion-related reactions including rigors, 
chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever, and vital signs 
monitored more frequently if clinically indicated, during and for at least 2 hours after the first 
two spartalizumab infusions. The same may apply for the subsequent spartalizumab infusions 
if medically indicated. Subjects should be further provided instructions to notify study 
personnel if symptoms of infusion reaction occur after any spartalizumab infusion.
Further instructions for the preparation and dispensation of spartalizumab are described in the 
Study Pharmacy Manual.
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). 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.
Information about common side effects already known about capmatinib and spartalizumab can 
be found in their respective Investigator's Brochure (IB). 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 Investigator’s Brochure 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.
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.
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A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval.
As per Section 4.6, during a public health emergency as declared by local or regional authorities, 
e.g., 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 
local Health Authority.
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial subject and person obtaining informed consent, etc.).
8
Visit schedule and assessments
The Assessment Schedule (Table 8-1b for Part 1, Table 8-2 for Part 2) lists all 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 8-1b or 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.
As per Section 4.6, during a public health emergency as declared by local or regional authorities, 
e.g., 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 ditactes. If allowed by the local Health Authority and dependent on operational 
capabilities, phone calls, virtual contacts (e.g. teleconsult) can replace on-site study visits, 
during the disruption until it is safe for the subject to visit the site again.
The following time windows are allowed per protocol:

-28 days to -1 day from start of study treatment (Part 1) or from randomization (Part 
2) for screening procedures

Laboratory assessments performed as part of the screening evaluations that are within 
72 hours of the first dose of study treatment are not required to be repeated on the first 
day of dosing (cycle 1 day 1)
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
±3 days for on treatment visits and assessments

±7 days for the 30 days safety follow up visit

±14 days for 60-, 90-, 120-, 150- safety follow up  visits/calls

For imaging evaluations a ± 7 days window is allowed.
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Table 8-1
Assessment Schedule - Part 1 (Single Arm Run-in Part) – obsolete upon approval of protocol amendment 01
Period
Screening
Treatment
Post treatment follow-up
Safety Follow-up
Survival 
Follow-up
Visit Name
Molecular pre-
screening
Main 
screening
C1
C2
C3
C4
C5
C6
Subsequent 
cycles
EOT
30 
day
60 
day
90 
day
120 
day 150 day
Days
-28 to 
-1
D1
D15 D1
D1
D4
D8 D15 D1
D1
D1
D1
-
-
-
-
-
every 12 
weeks
Informed consent for 
molecular pre-screening
X
 
 
 
 
 
 
Confirmation of EGFR wt 
and ALK rearrangement 
negative  status (local 
data)
X
Collection of archival 
tumor sample or newly 
obtained tumor sample 
for central MET testing (if 
no local data available)
X
Informed consent 
X
MET mutation status 
(result of central testing 
or local data if available)
X
Collection of archival 
tumor sample or newly 
obtained tumor sample
X
X (any day from 
C3D1 to C3D15)
X (Optional)
Inclusion / Exclusion 
criteria
X
Demography
X
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Period
Screening
Treatment
Post treatment follow-up
Safety Follow-up
Survival 
Follow-up
Visit Name
Molecular pre-
screening
Main 
screening
C1
C2
C3
C4
C5
C6
Subsequent 
cycles
EOT
30 
day
60 
day
90 
day
120 
day 150 day
Days
-28 to 
-1
D1
D15 D1
D1
D4
D8 D15 D1
D1
D1
D1
-
-
-
-
-
every 12 
weeks
Smoking history
X
Diagnosis and extent of 
cancer
X
Prior antineoplastic 
therapy (meds, surgery, 
radiation)
X
Relevant medical 
history/current medical 
conditions
X
Concomitant medications  
X (from screening up to 150 days from last dose of spartalizumab or 30 days from last dose of capmatinib whichever is 
longer or start of new anti-neoplastic therapy)
 
Adverse Events
X (from screening up to 150 days from last dose of spartalizumab or 30 days from last dose of capmatinib whichever is 
longer, after start of new anti-neoplastic therapy only suspected AEs will be collected). For SAE reporting please refer to 
Section 10.
Physical Examination
S
S
S
S
S
S
S
S
S
S
 
 
 
 
 
Height
X
 
 
 
 
 
Weight
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
 
 
 
 
Chemistry
X
X
X
X
X
X
X
X
X
X
 
 
 
 
Urinalysis
S
S (if clinically indicated)
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Period
Screening
Treatment
Post treatment follow-up
Safety Follow-up
Survival 
Follow-up
Visit Name
Molecular pre-
screening
Main 
screening
C1
C2
C3
C4
C5
C6
Subsequent 
cycles
EOT
30 
day
60 
day
90 
day
120 
day 150 day
Days
-28 to 
-1
D1
D15 D1
D1
D4
D8 D15 D1
D1
D1
D1
-
-
-
-
-
every 12 
weeks
Coagulation 
X
X (if clinically indicated)
 
 
 
 
Serum pregnancy test 
(urine test allowed in 
safety FU)
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Thyroid Stimulating 
Hormone (TSH)
X
X
X
X
X
X
X
X
X
Free T3 and Free T4
X
X (only if TSH is abnormal)
Hepatitis testing
X 
X (if clinically indicated)
HIV History (HIV testing 
where locally required)
S
CT/MRI of chest, 
abdomen, and pelvis with 
i.v. contrast
X
X (every 8 weeks until PD determined by investigator and confirmed by BIRC per RECIST 1.1)
Brain CT/MRI with 
i.v.contrast
X
X (If positive at baseline, follow the same schedule as CT/MRI of chest, abdomen, and pelvis. Or if clinically indicated.)
CT/MRI of other 
metastatic sites (e.g., 
neck, etc.) if suspected
X
X (If positive at baseline, follow the same schedule as CT/MRI of chest, abdomen, and pelvis. Or if clinically indicated.)
Whole body bone scan
X
If clinically indicated
Localized CT, MRI, or X-
Ray
X
X (If positive at baseline, follow the same schedule as CT/MRI of chest, abdomen, and pelvis. Or if clinically indicated.)
Color photographs (with 
metric ruler)
X
X (If positive at baseline, follow the same schedule as CT/MRI of chest, abdomen, and pelvis. Or if clinically indicated.)
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Period
Screening
Treatment
Post treatment follow-up
Safety Follow-up
Survival 
Follow-up
Visit Name
Molecular pre-
screening
Main 
screening
C1
C2
C3
C4
C5
C6
Subsequent 
cycles
EOT
30 
day
60 
day
90 
day
120 
day 150 day
Days
-28 to 
-1
D1
D15 D1
D1
D4
D8 D15 D1
D1
D1
D1
-
-
-
-
-
every 12 
weeks
Electrocardiogram (12-
Lead ECG)
X
X
 
 X
X
 
 
 
X
 
 
 
 
 
Blood sample for 
Capmatinib Extensive 
and non-Extensive PK 
sampling
X
X
Blood sample for 
Spartalizumab 
Extensive PK sampling
 
X
X
X
X
X
X
 
X
X (every 
12 cycles 
from 
C18D1)
X (or at end of 
spartalizumab 
treatment)
 
 
 
X (if visit 
performed 
at site)
 
Blood sample for 
Spartalizumab non-
Extensive PK sampling
X
X
X
X
X (every 
12 cycles 
from 
C18D1)
X (or at end of 
spartalizumab 
treatment)
X (if visit 
performed 
at site)
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Period
Screening
Treatment
Post treatment follow-up
Safety Follow-up
Survival 
Follow-up
Visit Name
Molecular pre-
screening
Main 
screening
C1
C2
C3
C4
C5
C6
Subsequent 
cycles
EOT
30 
day
60 
day
90 
day
120 
day 150 day
Days
-28 to 
-1
D1
D15 D1
D1
D4
D8 D15 D1
D1
D1
D1
-
-
-
-
-
every 12 
weeks
IRT Registration/ 
Treatment Dispensing/
Discontinuation
X
X (study treatment dispensing only)
X
Capmatinib 
administration
 
X (continuous BID dosing)
 
 
 
 
 
 
 
Spartalizumab 
administration
 
X
 
X
X
X
X
X
X
 
 
 
 
 
 
 
Antineoplastic therapies 
since discontinuation of 
study treatment
X
X
X
X 
X 
X
Safety follow-up
 
 
 
 
 
 
 
 
 
 
X
X
X
X 
X 
 
Survival status
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
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Table 8-1b
Assessment Schedule - Part 1 (Single Arm Run-in Part) – applicable upon approval of protocol amendment 01
Period
Treatment
Post treatment follow-up*
Safety Follow-up
Visit Name
C3
C4
Subsequen
t cycles
EOT
30 day
60 day
90 day
120 day
150 day
Days
D1
D1
D1
-
-
-
-
-
Concomitant medications
X (up to 150 days from last dose of spartalizumab or 30 days from last dose of capmatinib whichever is longer or start of new anti-
neoplastic therapy).
Adverse Events
X (up to 150 days from last dose of spartalizumab or 30 days from last dose of capmatinib whichever is longer, after start of new anti-
neoplastic therapy only suspected AEs will be collected). For SAE reporting please refer to Section 10.
Physical Examination
S
S
S
S
 
 
 
Weight
X
X
X
X
Vital signs
X
X
X
X
Performance status
X
X
X
X
Hematology
X
X
X
X
Chemistry
X
X
X
X
Urinanalysis
S (if clinically indicated)
Coagulation
X (if clinically indicated)
Serum pregnancy test 
(urine test allowed in safety 
FU)
S
S
S
S
S
S
S
S
S
Thyroid Stimulating 
Hormone (TSH)
At day 1 of every cycle up to 150 days after the last dose of spartalizumab, then as clinically indicated.
or
as clinically indicated in subjects who have never received spartalizumab treatment).
Free T3 and Free T4
X (only if TSH is abnormal)
Hepatitis testing
X (if clinically indicated)
CT/MRI of chest, abdomen, 
and pelvis with i.v. contrast
X (every 8 weeks until at least 2 post-baseline assessment have been 
obtained then every 12 weeks thereafter
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Period
Treatment
Post treatment follow-up*
Safety Follow-up
Visit Name
C3
C4
Subsequen
t cycles
EOT
30 day
60 day
90 day
120 day
150 day
Days
D1
D1
D1
-
-
-
-
-
Brain CT/MRI with 
i.v.contrast
X (If positive at baseline, follow the same schedule as CT/MRI of chest, 
abdomen, and pelvis. Or if clinically indicated).
CT/MRI of other metastatic 
sites (e.g., neck, etc.) if 
suspected
X (If positive at baseline, follow the same schedule as CT/MRI of chest, 
abdomen, and pelvis. Or if clinically indicated.)
Whole body bone scan
If clinically indicated
Localized CT, MRI, or X-
Ray
X (If positive at baseline, follow the same schedule as CT/MRI of chest, 
abdomen, and pelvis. Or if clinically indicated.)
Color photographs (with 
metric ruler)
X (If positive at baseline, follow the same schedule as CT/MRI of chest, 
abdomen, and pelvis. Or if clinically indicated.)
Electrocardiogram (12-
Lead ECG)
X
  
X
Blood sample for 
Capmatinib Extensive and 
non-Extensive PK 
sampling
X
X
IRT Registration/ 
Treatment Dispensing/
Discontinuation
X (study treatment dispensing only)
X
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Period
Treatment
Post treatment follow-up*
Safety Follow-up
Visit Name
C3
C4
Subsequen
t cycles
EOT
30 day
60 day
90 day
120 day
150 day
Days
D1
D1
D1
-
-
-
-
-
Capmatinib administration
X (continuous BID dosing)
Safety follow-up
 
X
X
X
X 
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.
*Following the approval of protocol amendment 01, tumor assessment follow-up and survival follow-up will not be performed
Table 8-2
Assessment Schedule - Part 2 (Randomized part) - obsolete since Part 2 will not be initiated
Period 
Screening
Treatment
Post treatment follow-up
Safety Follow-up
Survival 
Follow-up
Visit Name
Molecular 
pre
Main 
screening
C1
C2 C3 C4 C5 C6
Subseque
nt cycles
EOT
30 
day
60 
day
90 
day
120 
day
150 day
Days
-28 to -1 D1 D15 D1 D1 D1 D1 D1 D1
-
-
-
-
-
every 12 weeks
Informed consent for molecular pre-
screening
X
 
 
 
 
 
 
Confirmation of EGFR wt and ALK 
rearrangement negative  status 
(local data)
X
Collection of archival tumor sample 
or newly obtained tumor sample for 
central MET testing (if no local data 
available)
X
Informed consent 
X
MET mutation status (result of 
central testing or local data, if 
available)
X
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Period 
Screening
Treatment
Post treatment follow-up
Safety Follow-up
Survival 
Follow-up
Visit Name
Molecular 
pre
Main 
screening
C1
C2 C3 C4 C5 C6
Subseque
nt cycles
EOT
30 
day
60 
day
90 
day
120 
day
150 day
Days
-28 to -1 D1 D15 D1 D1 D1 D1 D1 D1
-
-
-
-
-
every 12 weeks
Inclusion / Exclusion criteria
X
Demography
X
Smoking history
X
 
 
 
 
 
 
Diagnosis and extent of cancer
X
Prior antineoplastic therapy (meds, 
surgery, radiation)
X
 
 
 
 
 
 
Relevant medical history/current 
medical conditions
X
Concomitant medications  
X (from screening until 150 day from last dose of spartalizumab/placebo or 30 days from last dose of 
capmatinib whichever is longer or start of new anti-neoplastic therapy)
 
Adverse Events
X (from screening until 150 day from last dose of spartalizumab/placebo or 30 days from last dose of 
capmatinib whichever is longer, after start of new anti-neoplastic therapy only suspected AEs will be 
collected). For SAE reporting please refer to Section 10.
Physical Examination
S
S
S
S
S
S
S
S
S
S
 
 
 
 
 
 
Height
X
 
 
 
 
 
 
Weight
X
X
X
X
X
X
X
X
X
 
 
 
 
 
 
Vital signs
X
X
X
X
X
X
X
X
X
X
 
 
 
 
 
 
Performance status
X
X
X
X
X
X
X
X
X
 
 
 
 
 
 
Hematology
X
X
X
X
X
X
X
X
X
X
 
 
 
 
 
Chemistry
X
X
X
X
X
X
X
X
X
X
 
 
 
 
 
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Period 
Screening
Treatment
Post treatment follow-up
Safety Follow-up
Survival 
Follow-up
Visit Name
Molecular 
pre
Main 
screening
C1
C2 C3 C4 C5 C6
Subseque
nt cycles
EOT
30 
day
60 
day
90 
day
120 
day
150 day
Days
-28 to -1 D1 D15 D1 D1 D1 D1 D1 D1
-
-
-
-
-
every 12 weeks
Urinalysis
S
S (if clinically indicated)
Coagulation 
X
X (if clinically indicated)
 
 
 
 
 
 
Serum pregnancy test (urine test 
allowed in FU)
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Thyroid Stimulating Hormone (TSH)
X
X
X
X
X
X
X
X
X
 
 
 
 
 
Free T3 and Free T4
X
X (only if TSH is abnormal)
Hepatitis testing
X 
X (if clinically indicated)
HIV History (HIV testing where 
locally required)
S
CT/MRI of chest, abdomen, and 
pelvis with i.v. contrast
X
X (every 8 weeks until PD determined by investigator and confirmed by BIRC per RECIST 1.1 (or until confirmed PD 
by Investigator 
 if subjects meets criteria for treatment beyond progression
Brain CT/MRI with i.v.contrast
X
X (If positive at baseline, follow the same schedule as CT/MRI of chest, abdomen, and pelvis. Or if clinically 
indicated.)
CT/MRI of other metastatic sites 
(e.g., neck, etc.) if suspected
X
X (If positive at baseline, follow the same schedule as CT/MRI of chest, abdomen, and pelvis. Or if clinically 
indicated.)
Whole body bone scan
X
If clinically indicated
Localized CT, MRI, or X-Ray
X
X (If positive at baseline, follow the same schedule as CT/MRI of chest, abdomen, and pelvis. Or if clinically 
indicated.)
Color photographs (with metric 
ruler)
X
X (If positive at baseline, follow the same schedule as CT/MRI of chest, abdomen, and pelvis. Or if clinically 
indicated.)
Electrocardiogram (12-Lead ECG)
X
X
 X
X 
 
 
X
 
 
 
 
 
 
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Period 
Screening
Treatment
Post treatment follow-up
Safety Follow-up
Survival 
Follow-up
Visit Name
Molecular 
pre
Main 
screening
C1
C2 C3 C4 C5 C6
Subseque
nt cycles
EOT
30 
day
60 
day
90 
day
120 
day
150 day
Days
-28 to -1 D1 D15 D1 D1 D1 D1 D1 D1
-
-
-
-
-
every 12 weeks
Blood sample for Capmatinib
non-Extensive PK sampling
X
X
Blood sample for 
Spartalizumab/placebo 
non-Extensive PK sampling
X
X
X
X
X (every 12 
cycles from 
C18D1)
X (or at end of 
spartalizumab 
treatment)
 
 
 
X (if visit 
performed at 
site)
IRT Registration/ Randomization/ 
Treatment 
Dispensing/Discontinuation
X
X (study treatment dispensing only)
X
Capmatinib administration
 
X (continuous BID dosing)
 
 
 
 
 
 
 
Spartalizumab/placebo 
administration
 
X
 
X
X
X
X
X
X
 
 
 
 
 
 
 
Antineoplastic therapies since 
discontinuation of study treatment
X
X
X
X 
X 
X
Safety follow-up
 
 
 
 
 
 
 
 
 
 
X
X
X
X 
X 
 
Survival status
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
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8.1
Screening
8.1.1
Molecular pre-screening
In order to be considered eligible for the study, subjects must have written documentation of 
EGFR wt and ALK rearrangements negative NSCLC (not required for subjects with pure 
squamous cell histology, for additional details see Section 5.1). The results from procedures 
performed as part of the local standard practices (prior to enrolling in the trial) will satisfy the 
inclusion criteria. The results of existing local METΔex14 mutation data (local assays must be 
approved by Novartis) must be captured on the appropriate eCRF upon enrollment onto the 
study after the subject has signed the main study ICF. Evidence of local data must be present in 
the source documentation at the site.
If METΔex14 mutation status is not known at the time of consideration for enrollment or the 
local assay data is not approved by Novartis, a tumor sample will be sent to a 
Novartis-designated central laboratory during the molecular pre-screening period to assess 
METΔex14 mutation (Molecular pre-screening requirements for tumor samples are detailed in 
Section 5.1).
All subjects requiring central MET testing will be asked to sign and date an IRB/IEC approved 
“Molecular pre-screening informed consent form” before their tumor sample is sent for testing 
to the Novartis-designated central laboratory.
The pre-screening results from central testing for all tested subjects (whether the subject is 
eligible or not for the study) will be communicated to the respective study center. If confirmed 
that the subject’s tumor harbors the required mutation(s), the subject will be able to proceed for 
study specific screening procedures following signature of the main ICF.
Remaining tumor material from subjects that do not have METΔex14 mutation may be used for 
companion diagnostic development.
8.1.2
Main screening
The study IRB/IEC approved informed consent form must be signed and dated before any 
screening procedures are performed, except for laboratory and radiological evaluations which 
were performed as part of the 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 8-1 or Table 8-2). Screening assessments must be repeated if performed outside 
of the specified screening window (Section 8). Subjects must meet all inclusion and none of the 
exclusion criteria at screening in order to be eligible for the study.
In Part 2 of the study, PD-L1 status must be established prior to randomization to allow 
appropriate stratification of the subjects. If local PD-L1 expression data is available 
(Dako PD-L1 IHC 22C3 pharmDx assay results only), the results are requested to be entered 
into the eCRF pages and will be used for stratification purposes. If the status is unknown or it 
has been assessed with another assay, Dako PD-L1 IHC 22C3 pharmDx assay will be performed 
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at a local laboratory or at Novartis designated central laboratory and the result will be 
communicated to the site.
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 screening failure.
Re-screening of a subject who has failed screening may be allowed. In such cases, a new ICF 
must be signed. All required screening assessments must be repeated if they do not meet the 
allowed time window for screening when the subject is re-screened for participation in the study. 
An individual subject can only be re-screened once for the study.
8.1.3
Information to be collected on screening failures
Subjects who signed the molecular pre-screening ICF but are considered ineligible after 
molecular pre-screening, as well as subjects who are found ineligible after signing the main ICF 
will be considered as screening failures.
Subjects from Part 2 who are randomized and 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 Case Report Form.
The reason for molecular pre-screening failure or screening failure will be entered on the 
applicable disposition page on the eCRF. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for screening failure subjects.
No other data will be entered into the clinical database for subjects who are screening failures, 
unless the subject experienced a Serious Adverse Event during the screening period 
(see Section 10). For molecular pre-screening failure subjects, only SAEs possibly related to a 
study procedure (i.e. tumor biopsy collection) will be reported to the Novartis safety group. 
For subjects who fail screening, SAEs will be reported in the database up to the screening failure 
date.
8.2
Subject demographics/other baseline characteristics
Data to be collected will include general subject demographics, smoking history, relevant 
medical history and current medical conditions, prior concomitant medications, diagnosis and 
extent of cancer, baseline tumor mutation status (MET, EGFR and ALK) and details of prior 
anti-neoplastic treatments.
Patient 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.
Additionally, the status of PD-L1, if already known and assessed by Dako PD-L1 IHC 22C3 
pharmaDx, will be recorded on the eCRF. If this data is not available, central analysis of PD-L1 
will be performed.
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Country-specific regulations will be considered for the collection of demographic and baseline 
characteristics, in alignment with the eCRF.
8.3
Efficacy
8.3.1
Tumor imaging
Following the approval of protocol amendment 01, the study imaging will no longer be 
collected and reviewed centrally. Centralized assessment of CNS lesions based on RANO BM 
criteria will not be performed.
Tumor response will be assessed locally according to the Novartis guideline version 3.2 
(Appendix 1) based on RECIST 1.1 (Eisenhauer et al 2009) 
 
(Seymour et al 2017) for subjects treated beyond initial disease progression as per RECIST 1.1.
The imaging assessment collection plan is presented in Table 8-3.
The central review of the scans will be carried out in a blinded fashion. Further details regarding 
the central review process will be described in the Blinded Independent Review Committee 
(BIRC) charter.
Table 8-3
Imaging Assessment Collection Plan
Procedure
Screening/Baseline
During Treatment/Follow-up
CT or MRI of chest, 
abdomen and pelvis 
with i.v. contrast
Mandated
Mandated every 8 weeks (+/- 7 days) until at least 2 
post-baseline assessments have been obtained, then 
every 12 weeks thereafter until PD determined by 
investigator assessment (with or without confirmation 
by BIRC) or EOT.
Following the approval of protocol amendment 01, 
tumor assessment follow up will not be performed and 
study imaging will no longer be reviewed by BIRC.
CT or MRI of brain 
with i.v. contrast
Mandated
Mandated if positive at baseline following the same 
schedule as CT/MRI of chest, abdomen, and pelvis. Or 
if clinically indicated.
CT or MRI of other 
metastatic sites 
(e.g., neck, etc.)
Mandated if metastatic sites 
are suspected
If other metastatic sites are positive at baseline, follow 
the same schedule as CT/MRI of chest, abdomen, and 
pelvis. Or if clinically indicated.
Whole body bone 
scan*
Mandated
If clinically indicated.
Localized bone CT, 
MRI or X-ray
Mandated for any lesions 
identified on the whole body 
bone scan that are not visible 
on the CT/MRI of chest, 
abdomen, and pelvis or brain
If positive at baseline follow the same schedule as 
CT/MRI of chest, abdomen, and pelvis. Or if clinically 
indicated.
Color photographs 
with a metric ruler
Mandated if skin metastases 
are present.
If positive at baseline follow the same schedule as 
CT/MRI of chest, abdomen, and pelvis. Or if clinically 
indicated. 
*Whole body bone scan according to imaging vendor specifications.
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8.3.1.1
Baseline imaging assessments
Imaging assessments should be performed at screening/baseline within 28 days of start of 
treatment (Day -28 to Day -1 prior to Cycle 1 Day 1) per Table 8-3. Any imaging assessments 
already completed during the regular work-up of the subject within 28 days prior to start of 
treatment (for Part 1) or prior to randomization (Part 2), including before signing the main study 
ICF, can be considered as the baseline images for this study. Any imaging assessments obtained 
after the first dose of treatment cannot be considered baseline images.
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 radiotherapy, it can be considered as a measurable 
lesion.
If a subject is known to have a contraindication to CT 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.
8.3.1.2
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 8-1b or Table 8-2). Imaging assessments for response evaluation 
will be performed every 8 weeks (+/- 7 days) until at least 2 post-baseline imaging assessments 
have been acquired, then every 12 weeks thereafter until disease progression as determined by 
investigator assessment per RECIST 1.1 or until EOT, whichever occurs the earliest.
Note: Imaging assessments should be scheduled using the first dose of study treatment in Part 1 
and the day of randomization for Part 2 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, by 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 disease progression per 
RECIST 1.1 (Appendix 1).
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All complete responses (CRs) and partial responses (PRs) must be confirmed by a second 
assessment. If the second assessment is performed outside the normal window of scans, it 
should not be performed earlier than 4 weeks after the scan where the criteria for response were 
first met.
8.3.1.3
Confirmation of disease progression by BIRC
Following the approval of protocol amendment 01, current section will no longer be applicable.
Timepoints at which progression is determined locally
All subjects who have disease progression determined by the local investigator require an 
expedited central radiological review. Rapid image transmission to the imaging CRO should be 
accomplished by transferring the images electronically promptly after their acquisition. In all 
instances, the process at the imaging CRO will ensure that the central reviewers remain blinded 
to the results of the local assessment and the expedited nature of the review. The investigator 
seeking an expedited review must indicate this request to the imaging CRO on a designated 
form or by alternative means.
The imaging will undergo expedited central review (within 5 business days from the time of 
image receipt at the imaging CRO and once all applicable queries are resolved) and the results 
of the central review will be communicated to the site. While the investigator is awaiting the 
results of the central review, it is preferable that the subject continue on study treatment. 
However, during this time, the investigator should do whatever is medically necessary for 
his/her subject.
If the central review determines disease progression, then the subject will discontinue study 
treatment and subsequent tumor assessments are no longer required. Treatment beyond 
BIRC-confirmed progression can only be provided if the subject meets all requirements in 
Section 6.1.4.
If the central review does not determine disease progression, the subject should continue 
receiving the study treatment unless there is a medical need (i.e., rapid progression or clinical 
deterioration) for an immediate change in therapy.
Subjects will continue to have imaging performed as per protocol (Table 8-1 or Table 8-2, as 
applicable) until the central review determines disease progression.
Time points without locally determined progression
All imaging time points without locally determined progression must be submitted promptly to 
the imaging vendor designated by Novartis. Time points without locally determined progression 
will be read on a non-expedited basis as detailed in the BIRC charter. Results of these readings 
will not be communicated to the sites.
Treatment beyond disease progression
Following determination of disease progression, if the investigator believes the subject may 
derive benefit from continuing study treatment, the subject will be permitted to continue 
treatment beyond initial disease progression as per RECIST 1.1. Subjects enrolled in Part 2 will 
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be followed by the investigator 
. Please see Section 6.1.4 for additional 
information.
Post-Treatment Efficacy Follow-up
Subjects who discontinue treatment for reasons other than disease progression as per RECIST 
1.1 confirmed by BIRC will continue to perform tumor assessments every 8 weeks in parallel 
to the safety and/or survival follow-up until documented disease progression (see Section 9.2.2).
8.3.2
Overall survival
Following the approval of protocol amendment 01, current section is no longer applicable, as 
survival follow up will not be performed.
All subjects will enter the survival follow-up period after completion of the safety follow-up. 
Survival status will be collected every 12 weeks regardless of treatment discontinuation reason 
(except if consent is withdrawn or subject is lost to follow-up) until death, lost to follow-up, or 
withdrawal of consent for survival follow-up. Survival information can be obtained via phone, 
and information will be documented in the source documents and relevant eCRFs.
Additional survival assessments may be performed outside the 12 weeks follow-up schedule if 
a survival update is required for an interim assessment to meet safety or regulatory needs.
8.4
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 Section 10.
8.4.1
Physical examination
Physical examination will be performed according to Table 8-1b or Table 8-2, as applicable.
At screening and Cycle 1 Day 1 prior to treatment (Part 1) or prior randomization (Part 2), 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, vascular, and neurological systems.
From Cycle 1 Day 1 onwards, an abbreviated physical exam will be performed. It will include 
at least the examination of general appearance and vital signs (blood pressure [SBP and DBP] 
and pulse).
More frequent examinations may be performed at the discretion of the investigator and if 
medically indicated. Information about the physical examination must be present in the source 
documentation.
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.
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8.4.2
Vital signs
Vital signs include blood pressure (supine position preferred when ECG is collected), pulse 
measurement, and body temperature.
Vital signs will be measured at screening and at subsequent time points as specified in 
 Table 8-1b or Table 8-2, as applicable.
8.4.3
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 8-1b or Table 8-2, as applicable.
8.4.4
Performance status
The Eastern Cooperative Oncology Group (ECOG) Performance Status Scale will be used as 
described in Table 8-4, following the schedule given in Table 8-1b or Table 8-2, as applicable.
Table 8-4
ECOG Performance Status
Grade
ECOG status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
8.4.5
Laboratory evaluations
The laboratory tests that will be assessed as part of the safety monitoring are listed in 
Table 8-5. For subjects enrolled in Part 1, all parameters will be analyzed locally. For subjects 
enrolled in Part 2, hematology, clinical chemistry, coagulation and thyroid parameters will be 
assessed at a Novartis-designated central laboratory and all other tests will be performed locally.
The frequency of these assessments is indicated in Table 8-1b or Table 8-2, as applicable. 
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.
The site does not need to wait for the results of centrally-analyzed laboratory assessments when 
an immediate clinical decision needs to be made (e.g. confirmation of eligibility, study drug 
interruption, re-initiation, and/or termination) and in those cases locally unscheduled testing 
may be performed and used for eligibility assessments. Details on the collection, shipment of 
samples and reporting of results by the central laboratory are provided to investigators 
separately in the central laboratory manual.
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The results of the laboratory tests performed locally will be recorded in the eCRF, unless 
differently specified in Table 8-1b or Table 8-2. Novartis must be provided with a copy of the 
normal ranges and certification of the all laboratories used to assess subjects’ safety during 
study conduct, when possible. The investigator is responsible for reviewing all laboratory 
reports for subjects in the study and evaluating any abnormalities for clinical significance.
At any time during the study up to safety follow-up, abnormal laboratory parameters which are 
clinically relevant and require an action to be taken with study treatment (e.g., require dose 
modification and/or interruption of study treatment, lead to clinical symptoms or signs, or 
require therapeutic intervention), whether specifically requested in the protocol or not, will be 
recorded on the adverse event eCRF page. The severity of laboratory data will be graded using 
the Common Terminology Criteria for Adverse events (CTCAE) v5.0. (See Section 10.1 for 
additional information). Additional analyses are left to the discretion of the investigator.
Table 8-5
Laboratory Assessments
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets,  White blood cells, , Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils, Other (absolute value 
preferred , %s are acceptable)
Chemistry
Albumin, Alkaline phosphatase, ALT, AST , Gamma-glutamyl-transferase (GGT), 
Lactate dehydrogenase (LDH), Calcium, Magnesium, Phosphorus, Sodium, 
Potassium, Creatinine, Creatine kinase, Total Bilirubin, Direct/Indirect Bilirubin 
(only if total bilirubin is ≥ grade 2), Blood Urea Nitrogen (BUN) or Urea, Amylase, 
Lipase, fasting Glucose (non-fasting glucose allowed post-baseline).
Bicarbonate, Chloride and Uric Acid: at screening and thereafter as clinically 
indicated.
Urinalysis
Local Laboratory: 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)
Coagulation
Prothrombin time (PT) or International normalized ratio [INR]), Activated partial 
thromboplastin time (APTT) 
Thyroid
TSH (Thyroid Stimulation Hormone), Free T3 and Free T4 
Hepatitis 
markers
HBV-DNA*, HBsAg, HBsAb, HBcAb (IgG), HCV Ab,  HCV RNA-PCR* 
Pregnancy Test
A serum pregnancy test must be performed at screening within ≤ 72 hours 
before first dose of study treatment, then the schedule of serum pregnancy tests 
should be performed monthly as indicated in Table 8-1b and Table 8-2. During 
the safety follow-up period, urine pregnancy test can be performed instead of 
serum pregnancy test. If local requirements dictate otherwise, local regulations 
should be followed.
* HBV DNA test not required if HBsAg, HBsAb and HBcAb are all negative; HCV RNA test not 
required if HCV Ab is negative.
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8.4.5.1
Hematology
Hematology tests are to be performed according to the visit schedule outlined in Table 8-1b or 
Table 8-2, as applicable. For details of the hematology panel refer to Table 8-5. Hematology 
should be assessed on the actual scheduled day, even if study drug is being withheld.
Hematology lab tests done as part of screening assessments ≤ 72 hours (3 days) of first dose of 
study treatment do not need to be repeated.
More frequent hematology testing may also be performed as medically necessary. Additional 
results from unscheduled hematology lab evaluations should be recorded on the appropriate 
unscheduled visit eCRF.
8.4.5.2
Clinical chemistry
Clinical chemistry tests are to be performed according to the visit schedule outlined in 
 Table 8-1b or Table 8-2, as applicable. For details of the biochemistry panel see Table 8-5. 
Biochemistry should be assessed on the actual scheduled day, even if study drug is being 
withheld.
Chemistry lab tests done as part of screening assessments ≤ 72 hours (3 days) prior to the first 
dose of study treatment do not need to be repeated.
More frequent chemistry testing may also be performed as medically necessary. 
Additional results from unscheduled chemistry lab evaluations should be recorded on eCRF as 
unscheduled visit.
8.4.5.3
Urinalysis
Urinalysis Dipstick measurements will be performed as per Table 8-5 and according to the 
schedule of assessments (Table 8-1b or Table 8-2, as applicable). Any significant findings on 
dipstick will be followed up with microscopic evaluation.
8.4.5.4
Coagulation
Coagulation tests outlined in Table 8-5 will be performed according to the visit schedule 
outlined in Table 8-1b or Table 8-2, as applicable.
8.4.5.5
Thyroid function
Thyroid function (TSH and Free T3 and T4) will be tested as outlined in Table 8-1b or 
Table 8-2. After screening, Free T3 and T4 will only be tested if TSH is abnormal.
8.4.5.6
Hepatitis marker
Hepatitis panels outlined in Table 8-5 will be performed at screening and as clinically indicated 
while on study treatment and until 30-day safety follow-up (for example to rule out viral 
causality in case of suspected DILI).
HBV and HCV testing will be performed at screening (≤ 28 days prior to start of study treatment) 
and as clinically indicated (hepatitis markers should be evaluated for precautionary safety 
monitoring of viral re-activation while on study treatment).
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During the screening period, subjects must be screened for HBV and HCV (current or past 
history of infection). Careful medical history must be taken for all subjects to look for risk 
factors (family history of HBV and HCV, intravenous drug abuse, unprotected sex, dialysis, 
blood transfusions, etc.), and any past or present HBV symptoms (e.g., jaundice, dark urine, 
light colored stools, right upper quadrant pain).
Hepatitis B:
At screening, all subjects will be tested for:

HBV-DNA level (test not required if HBsAg, HBsAb and HBcAb are all negative.)

Hepatitis B surface antigen (HBsAg)

Hepatitis B core antibody (HBcAb IgG)

Hepatitis B surface antibody (HBsAb)
Hepatitis C:
At screening, all subjects will be tested for HCV Ab and HCV RNA-PCR. If the HCV Ab test 
is negative, HCV RNA test is not required.
8.4.6
Electrocardiogram (ECG)
Electrocardiograms (ECGs) must be recorded after 10 minutes rest in the supine position. 
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, and blood sampling.
Standard triplicate 12 lead ECG recording will be performed at the time points indicated in 
Table 8-6. The individual ECGs should be recorded approximately 2 minutes apart.
The Fridericia QT correction formula (QTcF) should be used for clinical decisions. The mean 
QTcF value for each visit will be calculated from the triplicate ECGs for each subject.
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 baseline before administration of study 
treatment.
Clinically significant abnormalities must be recorded on the eCRF as either medical 
history/current medical conditions or adverse events as appropriate.
ECGs are to be collected with machines available at the site. Interpretation of the tracing must 
be made by a qualified physician and documented on the appropriate eCRF. Each ECG tracing 
should be labeled with the study number, 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 adverse events.
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Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically significant 
findings should be collected in triplicate. Local cardiologist ECG assessment may also be 
performed at any time during the study at the discretion of the investigator.
Table 8-6
Local ECG collection plan
Cycle
Day
Time
ECG Type
Screening
Anytime
12 Lead, triplicate
1
1
Pre-dose
12 Lead, triplicate
2
1
Pre-dose 
12 Lead, triplicate
3
1
Pre-dose 
12 Lead, triplicate
End of treatment
Anytime
12 Lead, triplicate
Unscheduled ECG
Anytime if clinically indicated
12 Lead, triplicate
8.4.7
Pregnancy and assessments of fertility
A condom is required for all sexually active male participants to prevent them from fathering a 
child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, 
male participants should not donate sperm for the time period specified in Section 5.2.
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements. During the 
study, serum pregnancy testing should be done at screening and/or within 72 hours prior to the 
first dose of study treatment and then at monthly intervals until the end of the safety follow-up 
period.
In case the subject is not coming to the clinic during the safety follow-up period, urinary 
pregnancy tests can be performed monthly at home or at a local doctor’s office until 150-day 
after the last dose of spartalizumab/placebo or 30 days after last dose of capmatinib, whichever 
is longer. The results will be communicated to the site staff. These follow-up pregnancy tests 
will be recorded only in the source documentation, not on the eCRF. In case of a positive urine 
pregnancy result, the subject must contact the investigator immediately and the study 
treatment must be stopped until additional tests are performed to confirm pregnancy (including 
a confirmatory serum pregnancy test).
The subject must discontinue his study treatment in case of confirmed pregnancy and the site 
should follow the reporting requirements as described in Section 10.1.4.
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.
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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.
8.4.8
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/subject population.
8.5
Additional assessments
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.5.2
Pharmacokinetics
Blood samples will be collected from all subjects for the analysis of plasma capmatinib and 
serum spartalizumab concentrations, 
.
8.5.2.1
Pharmacokinetic 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 2 mL of blood will be collected for spartalizumab analysis in serum 
 For time points when spartalizumab PK 
 are to be measured, a single blood sample will be collected for 
 spartalizumab 
PK. 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 
 samples.
If subjects experience a SAE or an AE leading to the discontinuation of the study treatment, an 
unscheduled PK blood sample should be obtained whenever possible. The date and time of the 
last dose and the time of PK blood draw should be recorded.
8.5.2.2
Pharmacokinetic sampling for capmatinib
PK blood samples for capmatinib will be collected for all the subjects as outlined in Table 8-7 
and Table 8-8. Extensive PK samples will be collected on cycle 3 day 1 from the first fifteen 
subjects enrolled in Part 1.
Table 8-7
Capmatinib pharmacokinetic blood collection log for extensive PK 
collection (first 15 subjects of Part 1)
Cycle
Day
Scheduled Time (h)
3
1
Pre-dose1
3
1
1h (±10min)
3
1
2h  (±15min)
3
1
4h (±30min)
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Cycle
Day
Scheduled Time (h)
3
1
8h  (±120 min)
4
1
Pre-dose1
4
1
Anytime within 1-4h
Unscheduled 
 
anytime
1 Take samples immediately prior to administration of capmatinib.
Table 8-8
Capmatinib pharmacokinetic blood collection log for non-extensive 
PK collection (remaining subjects of Part 1 and all Part 2 subjects)
Cycle
Day
Scheduled Time (h)
3
1
Pre-dose1
3
1
Anytime within 1-4h
4
1
Pre-dose1
4
1
Anytime within 1-4h
Unscheduled 
 
anytime
1 Take samples immediately prior to administration of capmatinib. 
8.5.2.3
Pharmacokinetic 
 sampling for spartalizumab
Following the approval of protocol amendment 01, PK 
 sampling for spartalizumab will 
not be performed, except in the event of a clinically significant AE or if 
 is suspected up to 
150 days from last dose of spartalizumab.
Blood samples for spartalizumab PK 
 analysis will be collected for all the subjects as 
outlined in Table 8-9 and Table 8-10. PK 
 samples will be collected at the time of study 
treatment discontinuation (EOT visit) or when spartalizumab treatment is discontinued (in case 
spartalizumab is prematurely discontinued due to toxicity). The 150-days safety follow-up 
sample will only be collected if the visit is performed at site. Extensive PK samples will be 
collected in cycle 3 from the first fifteen subjects enrolled in Part 1. PK 
 samples will be 
collected also in the event of a clinically significant AE (such as infusion reaction/anaphylaxis) 
or if 
 is suspected. No additional PK 
 samples will be collected after the cut-off of the 
primary CSR.
Table 8-9
Spartalizumab pharmacokinetic 
 blood collection 
log for extensive PK sample collection (first 15 subjects of Part 1) - 
obsolete upon approval of protocol amendment 01
Cycle
Day
Scheduled Time (h)
Analytes 
1
1
Pre-dose1
PK
3
1
Pre-dose1
PK
3
1
1h (±5min)
PK
3
4
72h (±8h)
PK
3
8
168h (±8h)
PK
3
15
336h (±24h)
PK
4
1
Pre-dose1
PK
6
1
Pre-dose1
PK
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Cycle
Day
Scheduled Time (h)
Analytes 
Every 12 cycles after C6D1 
until discontinuation of 
spartalizumab treatment
1
Pre-dose1
PK/
EOT2
anytime
PK/
150-day safety follow-up3
anytime
PK/
Unscheduled 
 
anytime
1 Take samples immediately prior to infusion of spartalizumab 
2 Samples to be collected at the time of study treatment discontinuation (EOT visit) or when 
spartalizumab treatment is discontinued 
3Only applicable for subjects who return to the site for 150-day safety FU visit
Table 8-10
Spartalizumab/placebo pharmacokinetic 
 blood 
collection log for non-extensive PK collection (remaining subjects of 
Part 1 and all Part 2 subjects) - obsolete upon approval of protocol 
amendment 01
Cycle
Day
Scheduled Time (h)
Analytes 
1
1
Pre-dose1
PK
3
1
Pre-dose1
PK
4
1
Pre-dose1
PK
6
1
Pre-dose1
PK
Every 12 cycles after C6D1 
until discontinuation of 
spartalizumab/placebo 
treatment
1
Pre-dose1
PK
EOT2
anytime
PK
150-day safety follow-up3
anytime
PK
Unscheduled 
 
anytime
1 Take samples immediately prior to infusion of spartalizumab/placebo
2 Samples to be collected at the time of study treatment discontinuation (EOT visit) or when 
spartalizumab/placebo treatment is discontinued 
3 Only applicable for subjects who return to the site for 150-day safety FU visits
8.5.2.4
Analytical method
Pharmacokinetic samples for spartalizumab and capmatinib will be quantified using validated 
liquid chromatography tandem-mass spectrometry (LC/MS/MS) assays. The assay to quantify 
and assess the 
 will be a validated homogeneous ELISA.
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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 occurs when study treatment is stopped, and 
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. An end of treatment visit will 
be performed when subjects permanently discontinue the study treatment to which they were 
assigned at study entry.
Study treatment must be discontinued under the following circumstances:

Disease progression per RECIST 1.1 as determined by investigator assessment (with or 
without confirmation by BIRC). In some circumstances subjects may be allowed to 
continue to receive study treatment beyond disease progression as per RECIST 1.1. These 
subjects will continue assessments as outlined in Table 8-1b and will complete the EOT 
visit only after permanent discontinuation of study treatment (see Section 6.1.4)

Subject/guardian decision

Investigator decision

Any situation in which study participation might result in a safety risk to the subject.

Protocol deviation that results in a significant safety risk to the subject

Adverse event requiring permanent discontinuation of study treatment (see Table 6-3)

Pregnancy

Death
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 Section 9.1.2). Where possible, they should return for the assessments 
indicated in the assessment schedule. If they fail to return for these assessments for unknown 
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reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact the subject/pre-
designated contact as specified in Section 9.1.3. 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.
9.1.1.1
Replacement policy
Subjects will not be replaced on study. All treated subjects will contribute to the final analyses.
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 only 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  
Table 8-1b or Table 8-2, as applicable.
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.
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.
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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 or until the end of the study.
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 due to safety reasons, subjects must be seen as soon as 
possible 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 Novartis 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
Study completion is defined as when the end of study criteria are met or, in the event of an early 
study termination decision, the date of that decision.
9.2.1
End of Study
The end of study for Part 1 is defined as the earliest occurrence of one of the following:

All subjects have discontinued study treatment and completed the safety follow-up, or have 
died, withdrawn consent or are lost to follow-up.

Another clinical study or an alternative treatment option becomes available to continue the 
provision of campmatinib, and all subjects ongoing are transferred to that clinical study or 
alternative treatment option. For subjects who had received at least one dose of 
spartalizumab, all required safety assessments up to 150 days from the last dose of 
spartalizumab treatment must be completed and at least 2 post-baseline tumor assessments 
are obtained for the purpose of primary outcome measure completion before a transfer to 
another clinical study or alternative treatment option to continue capmatinib treatment may 
be initiated. Note: For subjects who transfer to another clinical study or an alternative 
treatment option to continue provision of study treatment, the follow-up for safety, tumor 
assessment and survival will not be performed. 
At the end of the study, every effort will be made to continue provision of study treatment 
outside this study through an alternative setting to subjects who in the opinion of the 
Investigator are still deriving clinical benefit.
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Details on the timing of the primary analysis and final reporting of data are provided in 
Section 12.
9.2.2
Post treatment follow-up
After treatment discontinuation, all subjects will be followed for safety, as described in 
Section 9.2.2.1.
Note: For subjects who transfer to another clinical study or an alternative treatment option to 
continue provision of study treatment, the follow-up for safety, tumor assessment and survival 
will not be performed.
9.2.2.1
Safety follow-up
All subjects must have safety evaluations for 150 days after the last dose of 
spartalizumab/placebo and 30 days after the last dose of capmatinib, whichever is longer. 
The subject will be followed via telephone call or onsite visit (if patient happens to be visiting 
the site) for the 30-, 60-, 90-, 120- and 150-day follow-up visits. Concomitant medications will 
be collected until the 30-day safety follow-up has been completed or the start of a new anti-
neoplastic therapy, whichever occurs first.
For female subjects of child bearing potential, pregnancy tests will be performed as outlined in 
Section 8.4.7.
The assessments required during safety follow-up are specified in Table 8-1b or Table 8-2.
9.2.2.2
Survival follow up
Following the approval of protocol amendment 01, survival follow up will not be performed.
After completion of the safety follow-up, subjects will enter the survival follow-up period. 
Subjects will be contacted by telephone every 12 weeks to follow-up on their survival status. 
Any new anti-neoplastic therapies that have been started since the last contact date will also be 
collected during these phone calls. Date of progression on new antineoplastic therapies will also 
be collected.
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.
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Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
For subjects whose MET mutation  status is unknown and who sign the molecular pre-screening 
ICF, AEs which occur after signature of this consent will only be captured if they meet the 
definition of serious as outlined in Section 10.1.2 and are reported to be causally related with 
study procedures (e.g. an invasive procedure such as biopsy). Once the main study ICF is signed, 
all AEs per the descriptions below will be captured as adverse events.
Subjects whose MET mutation status is known will sign the main study ICF. AE collection 
starts at time of main study informed consent whether the subject is a screen failure or not.
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. CTCAE (version 5.0) grade. Grade 1 to 5 will be used to characterize the severity of the 
events.
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 a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. action taken regarding with study treatment. All 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 on the eCRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement 
to a lower grade is determined a new entry for this event should be reported on 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.
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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 after the last dose of 
capmatinib or 150 days after the last dose of spartalizumab/placebo, whichever is longer. If a 
patient starts a post treatment anti-neoplastic therapy sooner than the 30/150 days mentioned 
above, then only adverse events suspected to be related to study treatment should be collected.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (i.e. as per RECIST 1.1), should not 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 and spartalizumab Investigator’s Brochure.
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.
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:
1. fatal
2. life-threatening. Life-threatening in the context of a 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).
3. results in persistent or significant disability/incapacity
4. constitutes a congenital anomaly/birth defect
5. requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:
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
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 a SAE given above and not resulting in hospital admission
6. 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
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors) should not be reported as a 
serious adverse event. However, progressive disease should be reported as an SAE if the 
investigator considers that the progression is related to the study treatment (e.g. disease 
progression greater/faster than what would be normally expected for the patients in this setting).
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.
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until the end of the safety follow-up period (i.e. 30 days after 
the last dose of capmatinib or 150 days following the last dose of spartalizumab/placebo, 
whichever is longer), must be reported to Novartis safety immediately, without undue delay, 
but under no circumstances later than within 24 hours of obtaining knowledge of the events 
(Note: If more stringent, local regulations regarding reporting timelines prevail).. If during the 
safety follow-up period, a subject starts a post-treatment antineoplastic therapy, then only SAEs 
suspected to be related to study treatment will be collected.
Any SAEs experienced after the end of the safety follow-up should only be reported to Novartis 
Safety if the investigator suspects a causal relationship to study treatment.
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Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a 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.
For subjects with unknown MET mutation status and who sign the molecular pre-screening 
ICF, SAE collection will start upon signing the molecular pre-screening ICF. SAEs will only 
be reported if the event is suspected to be causally related to a study procedure as assessed by 
the investigator (e.g. an invasive procedure such as biopsy). SAEs will be followed until 
resolution or until clinically relevant improvement or stabilization. If the main ICF is not signed 
(e.g. molecular screen failure), SAE collection ends 30 days after the last study related 
procedure.
For subjects with known MET mutation status who sign the main study ICF, SAE collection 
starts at time of main study informed consent whether the subject is a screen failure or not.
10.1.4
Pregnancy reporting
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 Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported.
Pregnancy outcomes should be collected for the female partners of any male who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. In addition, the newborn will be followed for up to 
12 months after birth.
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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 eCRF 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 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
10.2
Additional Safety Monitoring
10.2.1
Adverse events of special interest
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them.
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the latest capmatinib and spartalizumab Investigator’s 
Brochure.
Adverse events of special interest to be monitored for capmatinib include:

Hepatotoxicity,

Nausea/Vomiting,

Peripheral oedema,

Renal dysfunction,

ILD/pneumonitis,

Central nervous system toxicity,
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
Increased amylase/lipase,

Phototoxicity,

Teratogenicity
Adverse events of special interest to be monitored for spartalizumab include:

Endocrinopathies (i.e. hypothyroidism, hyperthyroidism, diabetes, hypophysitis, 
hypopituitarism, adrenal insufficiency)

Pneumonitis

Colitis

Hepatitis

Nephritis

Skin reactions

Other immune-mediated events

Infusion reactions
10.2.2
Data Monitoring Committee
Following the study enrollment halt during Part 1, Part 2 will not be initiated. This section is no 
longer applicable.
This study will institute 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 constituted after the decision to initiate Part 2 is taken and prior to the 
randomization of the first subject in Part 2.
The DMC will be responsible for reviewing the efficacy results from efficacy interim for PFS 
and the interim analysis for OS, as well as overseeing the safety data accruing in the trial at 
defined intervals. Also, if requested by the DMC Chair, additional safety reviews may be 
performed.
DMC will recommend to the sponsor whether to continue, modify or terminate the trial.
An independent statistical group external to Novartis, not involved in the trial conduct, will 
prepare data reports for the DMC. Details will be presented 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.
10.2.3
Steering Committee
A steering committee (SC) will be established comprising investigators participating in the trial, 
i.e. not members of the DMC, and Novartis representatives from the clinical trial team. The SC 
will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
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develop recommendations for publications of study results including authorship rules. 
The details of the role of the SC will be defined in a SC charter.
11
Data collection and database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the electronic Case 
Report Forms (eCRF). The eCRFs have been built using fully validated secure web-enabled 
software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not be given 
access to the EDC system until they have been trained. Automatic validation programs check 
for data discrepancies in the eCRFs, allow modification and/or verification of the entered data 
by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on eCRFs) (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.
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 adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) terminology.
Randomization codes and data about all study treatment (s) dispensed to the subject and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 
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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’s meeting, a Novartis or a 
designated Clinical Research Organization (CRO) representative will review the protocol and 
data capture requirements (i.e. eSource DDE or eCRFs) with the investigators and their staff. 
During the study, Novartis employs several methods of ensuring protocol and GCP compliance 
and the quality/integrity of the sites’ data. The field monitor will visit the site to check the 
completeness of subject records, the accuracy of data capture / data entry, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. Continuous remote 
monitoring of each site’s data may be performed by a centralized Novartis CRA or a designated 
CRO. 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 demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs 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 eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
12
Data analysis and statistical methods
Following the study enrollment halt during Part 1, Part 2 will not be initiated. Therefore, 
analysis and statistical methods for Part 2 are not applicable.
Data from all participating centers in this protocol will be combined by part, so that an adequate 
number of subjects will be available for analysis. Data will be summarized using descriptive 
statistics (continuous data) and/or contingency tables (categorical data) for demographic and 
baseline 
characteristics, 
efficacy, 
safety, 
pharmacokinetic 
 
 
measurements.
Study data in Part 1 will be reported in the final clinical study report (CSR) based on all subjects’ 
data up to the time of completion of the study. There will be no additional CSR.
All summaries, listings, figures and analyses will be performed for all subjects.
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Screen failure subjects, as described in Section 8.1.3, and the reasons for not starting the study 
treatment (for Part 1) or for not being randomized (for Part 2) 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
Part 1: Single Arm Run-in Part
Full Analysis Set (FAS)
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
and who received at least one dose of study treatment (i.e. at least one dose of any component 
of the study treatment that is capmatinib or spartalizumab (including incomplete infusion)).
Safety Set (SS)
See definition of the FAS.
Pharmacokinetic Analysis Set (PAS)
The capmatinib PAS includes two sets in Part 1, the capmatinib full pharmacokinetic analysis 
set (INC-FPAS) which will be used for NCA analysis and capmatinib pharmacokinetic analysis 
set (INC-PAS).
The INC-FPAS includes all subjects who have provided an evaluable PK profile (only 
applicable to subjects with extensive PK sampling). A profile is considered evaluable if all of 
the following conditions are satisfied:

Subject has received one dose of the planned capmatinib treatment

Subject has provided at least one valid primary PK parameter

Subjects did not vomit within 4 hours after the dosing of capmatinib
The INC-PAS includes all subjects who have provided at least one evaluable PK concentration. 
For a concentration to be evaluable, a subject must:

Have taken a dose of capmatinib prior to sampling

For pre-dose samples, do not vomit within 4 hours after the dosing of capmatinib prior to 
sampling.

For post-dose samples, do not 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 spartalizumab PAS includes two sets in Part 1, spartalizumab full pharmacokinetic analysis 
set (PDR-FPAS) and spartalizumab pharmacokinetic analysis set (PDR-PAS).
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The 
PDR-FPAS 
includes 
all 
subjects 
who 
provide 
an 
evaluable 
PK 
profile 
(Note: Only applicable to subjects with extensive PK sampling). A profile is considered 
evaluable if all of the following conditions are satisfy:

Subject has received one dose (complete infusion) of the planned spartalizumab treatment

Subject has provided at least one valid primary PK parameter

For pre-dose samples, have the sample collected before the next dose administration.
The PDR-PAS includes all subjects who have provided at least one evaluable PK concentration. 
For a concentration to be evaluable, a subject must:

Have received one of the planned doses (complete infusion) of spartalizumab prior to 
sampling.

For pre-dose samples, have the sample collected before the next dose administration.
 
 
Part 2: Randomized Part
Following the study enrollment halt during Part 1, Part 2 will not be initiated.
Full Analysis Set (FAS)
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
by randomization, regardless of whether or not the treatment was administered. According to 
the intention to treat principle, subjects will be analyzed accordingly to the treatment and strata 
they have been assigned during the randomization.
Safety Set (SS)
The Safety Set (SS) comprises all subjects who received at least one dose of the study treatment 
(i.e. at least one dose of any component of the study treatment that is capmatinib or 
spartalizumab/placebo (including incomplete infusion)). Subject will be analyzed according to 
the study treatment received, where treatment received is defined as the randomized treatment 
if the subject took at least one dose of that treatment or the first treatment received if the 
randomized treatment was never received.
Pharmacokinetic Analysis Set (PAS) 
The INC-PAS, PDR-PAS 
 set will be defined in Part 2 and will share the same definition 
of Part 1.
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12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be summarized 
descriptively for the FAS by study part (overall for Part 1; and by treatment group and overall 
for Part 2).
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented.
Relevant medical histories and current medical conditions at baseline will be summarized and 
listed for the FAS by study part.
12.3
Treatments
The Safety Set will be used for the analyses below by study part. Categorical data will be 
summarized as frequencies and percentages. For continuous data, mean, standard deviation, 
median, 25th and 75th percentiles, minimum and maximum will be presented.
The duration of exposure to study treatment 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.
The number of subjects with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized for each study drug (capmatinib or 
spartalizumab/placebo) 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 summarized and listed.
12.4
Analysis of the primary endpoint(s) / estimand(s)
12.4.1
Efficacy endpoint(s) / estimand(s)
Part 1: Single Arm Run-in Part
The primary objective is to evaluate the anti-tumor activity of capmatinib in combination with 
spartalizumab, as measured by overall response rate (ORR) by investigator assessment 
according to RECIST 1.1 (see Appendix 1). The analysis will be performed on the FAS.
Part 2: Randomized Part
Following the study enrollment halt during Part 1, Part 2 will not be initiated.
The primary objective is to evaluate whether spartalizumab in addition to capmatinib prolongs 
progression free survival (PFS) by BIRC according to RECIST 1.1 (see Appendix 1) compared 
to capmatinib plus placebo. The analysis will be performed on the FAS.
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12.4.1.1 Definition of primary endpoint(s) / estimand(s)
Overall response rate (ORR)
ORR is defined as the proportion of subjects with a confirmed best overall response (BOR) of 
complete response (CR) and partial response (PR) as per investigator assessment according to 
RECIST 1.1 (see Appendix 1).
Progression free survival (PFS) 
PFS is defined as the time from the date of randomization to the date of the first documented 
progression according to RECIST 1.1, or death due to any cause. Clinical deterioration without 
objective radiological evidence will not be considered as documented disease progression. PFS 
will be assessed by BIRC according to RECIST 1.1. Censoring conventions (i.e. handling of 
missing values/censoring/discontinuations) are provided in Section 12.4.1.4.
12.4.1.2 Statistical hypothesis, model, and method of analysis 
Part 1: Single Arm Run-in Part
ORR as per investigator assessment calculated based on the data from the FAS and the 
corresponding 95% confidence intervals based on the exact binomial distribution 
(Clopper and Pearson 1934) will be presented.
Participants who had never received one of the investigational drugs will be excluded from the 
efficacy analysis.
Part 2: Randomized Part
Following the study enrollment halt during Part 1, Part 2 will not be initiated.
The primary efficacy analysis to test these hypotheses and compare the two treatment groups 
will be based on a stratified log-rank test at an overall one-sided 2.5% significance level. 
The following null and alternative hypothesis will be tested to address the primary efficacy 
objective for PFS based on BIRC as per RECIST 1.1:
H01: θ1 ≥1 vs H11:  θ1 < 1
Where 𝜃1 is the PFS hazard ratio (HR) (capmatinib in combination with spartalizumab versus 
capmatinib plus placebo). The stratification will be based on the stratification factors assigned 
at randomization (i.e. presence or absence of brain metastasis at baseline [as assessed 
investigator per RECIST 1.1] and PD-L1 expression [<1%, or 1-49%, or ≥50%]).
The PFS will be analyzed at the interim analysis and final analysis of a group sequential design, 
using a Lan-DeMets (O’Brien and Fleming 1979) alpha spending function.
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PFS will be summarized using the Kaplan-Meier (KM) method, based on FAS. Median PFS, 
with corresponding 95% CI, and 25th and 75th percentiles (Brookmeyer and Crowley 1982, 
Klein and Moeschberger 1997) will be presented by treatment group. KM estimates for PFS 
proportions at specific timepoints, along with 95% CI (Greenwood’s formula, Kalbfleisch and 
Prentice 2002) will also be provided. The hazard ratio for PFS will be estimated, along with its 
95% confidence interval, using a stratified Cox proportional hazard model using the same 
stratification factors as for the log-rank test. If there are too few patients/events in a given 
stratum, strata might be grouped for the analysis. Further details will be provided in the SAP.
If PFS is not statistically significant at the PFS interim analysis:
PFS data will be tested at the time of the final PFS analysis.
If PFS is statistically significant at the PFS interim analysis:
The subsequent PFS analysis will still be performed to obtain more PFS data and additional 
follow-up PFS analyses may also be performed earlier than planned primary PFS analysis at 
the request of Health Authorities or to facilitate health authority interactions. Note that in this 
case, the PFS analysis will only be descriptive and no statistical testing will be performed for 
the analysis.
12.4.1.3 Handling of intercurrent events of primary estimand
Part 1: Single Arm run-in Part
The primary estimand will account for the different intercurrent events as follows:

Discontinuation of spartalizumabfor any reason: BOR will take into account all 
available tumor assessments irrespective of spartalizumab discontinuation reasons.

Discontinuation of tumor assessment follow up with approval of protocol 
amendment: BOR will take into account all available tumor assessments up to the last 
valid tumor assessment prior to approval of protocol amendment.

Any public health emergency as declared by local or regional authorities, e.g., 
pandemic, epidemic or natural disaster: BOR will take into account all tumor 
assessments irrespective of any public health emergency.

New anti-neoplastic therapy: Tumor assessment data collected after starting new anti-
neoplastic therapy will be excluded from the BOR derivation.
Part 2: Randomized Part
Following the study enrollment halt during Part 1, Part 2 will not be initiated.
The primary estimand will account for the different intercurrent events as follows:

Discontinuation of study treatment for any reason before radiological progression or 
death due to any cause: tumor assessment data collected after discontinuation of study 
treatment (or spartalizumab only) will be used for PFS

New anti-cancer therapy before radiological progression or death due to any cause: 
PFS events documented after the start of new anti-cancer therapy will be used to derive 
the time to event for the primary analysis
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
Radiological progression or death observed after 2 or more missing tumor 
assessments: radiological progression or death observed after 2 or more missing tumor 
assessments will not be included in the derivation of the time to event for PFS, and the 
observation will be censored at the time of the last adequate tumor assessment prior to the 
first missing assessment

Lack of post-baseline tumor assessment: Subjects without a post-baseline tumor 
assessment will be censored at the time of the randomization
12.4.1.4 Handling of missing values/censoring/discontinuations
Part 1: Single Arm Run-in Part
Subjects in the FAS with unknown best overall response (BOR) will be noted as such in the 
appropriate tables/listings and counted as non-responders in the ORR calculation.
If there is no baseline tumor assessment, all post-baseline overall lesion responses are expected 
to be ‘Unknown’. If no valid post-baseline tumor assessments are available, the best overall 
response must be “Unknown” unless progression or death is reported.
If any new anti-neoplastic therapy is taken while on study any subsequent assessments would 
be excluded from the BOR derivation.
Subjects without confirmed CR/PR, due to lack of subsequent tumor assessment after one 
CR/PR, will be considered as non-responders.
Part 2: Randomized Part
Following the study enrollment halt during Part 1, Part 2 will not be initiated.
In the primary PFS analysis, PFS will be censored at the last adequate tumor assessment if no 
PFS event is observed prior to the cut-off date.
12.4.1.5 Sensitivity and supplementary analyses
Part 1: Single Arm Run-in Part
A sensitivity analysis may be performed where subjects without a valid post-baseline 
assessment (unless PD or death is reported before that time) are excluded from the calculation 
of the ORR.
Part 2: Randomized Part
Following the study enrollment halt during Part 1, Part 2 will not be initiated.
Sensitivity Analyses
As a sensitivity analysis, PFS as per investigator assessment will be analyzed using a stratified 
Cox proportional hazard model, with the same analysis convention as for the primary analysis. 
The treatment effect will be summarized by the hazard ratio with its 95% confidence interval. 
Kaplan-Meier curves, medians and 95% confidence intervals of these medians will be presented 
for each treatment group.
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Supplementary Analyses
As supplementary analyses performed in the FAS, the hazard ratio and 95% confidence interval 
for PFS per BIRC review will be obtained from:
1. an unstratified and covariate unadjusted Cox model.
2. a stratified and covariate adjusted Cox model including as covariates the following: 
gender, age groups (<65, ≥65 years), ECOG PS (0, 1), histology (squamous, non-
squamous), smoking status (smoker, non-smokers, ex-smokers), race (Asian, other). A list 
of covariates will be defined in the SAP.
3. If the primary analysis of PFS is statistically significant, sub group analysis to assess the 
homogeneity of the treatment effect across demographics and baseline characteristics will 
be performed. The following subgroups may be considered: gender, age groups (<65, 
≥65 years), ECOG PS (0, 1), histology (squamous, non-squamous), smoking status 
(smoker, non-smokers, ex-smokers), race (Asian, other), presence or absence of brain 
metastasis at baseline (as assessed investigator per RECIST 1.1) and PD-L1 expression 
(<1%, or 1-49%, or ≥50%). A final list of subgroups of interest will be defined in the SAP.
Additional key supplementary analysis will be performed to take into account the possible 
delayed immunotherapy response (e.g. weighted log-rank test with Fleming-Harrington class 
of weights) and to assess the robustness of the primary analysis results for PFS. A weighted 
log-rank test using Fleming-Harrington class of weights will be used. Such analyses will be 
detailed in the SAP.
If proportional hazard assumption is violated as a result of a delayed treatment effect, a stratified 
piecewise Cox regression analysis will be performed based on PFS to estimate a hazard ratio 
within pre-specified time periods (0-3 months and >3 months, based on an assumed 3 months 
delay effect for PFS). The analysis will be performed by incorporating a time-dependent 
covariate into the model and estimating the treatment effect for each of the two time periods. 
The hazard ratio, 95% CIs and Wald P-value will be provided for each time period.
12.5
Analysis of secondary endpoints / estimands
12.5.1
Key secondary endpoint (Part 2: Randomized Part)
Following the study enrollment halt during Part 1, Part 2 will not be initiated. Therefore, 
analysis and statistical methods for Part 2 are not applicable.
The key secondary objective is to evaluate whether spartalizumab when added to capmatinib 
prolongs OS compared to capmatinib plus placebo. The analysis will be performed on the FAS.
OS is defined as the time from the date of randomization to the date of death due to any cause. 
If the subject is alive at the date of the analysis cut-off or lost to follow-up, then OS will be 
censored at the last contact date prior to data cut-off date.
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The following null and alternative hypothesis will be tested to address the key secondary 
objective for OS:
H02:θ2 ≥1 vs H12: θ2 < 1
Where 𝜃2 is the OS hazard ratio (capmatinib in combination with spartalizumab versus 
capmatinib plus placebo). The key secondary analysis to test these hypotheses and compare the 
two treatment groups will consist of the stratified log-rank test at an overall one-sided 2.5% 
significance level. The stratification will be based on the stratification factors assigned at 
randomization (i.e. presence or absence of brain metastasis (as assessed by investigator per 
RECIST 1.1) and PD-L1 expression [<1%, or 1-49%, or ≥50%]).
A maximum of four analyses are planned for OS. OS will be hierarchically tested in the 
following way:
1. at the time of the interim analysis for PFS when approximately 49% (96 deaths) are 
expected to occur. If PFS is statistically significant at this stage, OS will also be tested. 
If PFS is not statistically significant at this stage, then OS will not be tested. Note that if 
OS is not  tested a conservative approach is used where some alpha, corresponding to the 
information fraction of OS events available at that time, will be spent.
2. at the time of the final analysis for PFS when approximately 75% (146 deaths) are 
expected to occur. If PFS is statistically significant at this stage, OS will also be tested. 
If PFS is not statistically significant at this stage, then OS will not be tested.
3. When approximately 85% of the deaths have been observed (167 deaths) in case the time 
gap between the final analyses for PFS and for OS is longer than 1 year. If PFS is not 
statistically significant, at the interim or the primary analysis, OS will not be tested.
4. at the final OS analysis of a group sequential design. If PFS is not statistically significant, 
at the interim or the primary analysis, OS will not be tested.
The type I error will be controlled using a Lan-DeMets (O’Brien and Fleming 1979) alpha 
spending function for OS which is independent of the one used for PFS. This guarantees the 
protection of the overall type I error (α = 2.5%) across all hypotheses and the repeated testing 
of the OS hypotheses at the interim and the final analyses (Glimm et al 2010).
OS will be summarized using the KM method, based on FAS. Median OS, with corresponding 
95% CI, and 25th and 75th percentiles (Brookmeyer and Crowley 1982, Klein and 
Moeschberger 1997) will be presented by treatment group. KM estimates for OS proportions at 
specific timepoints, along with 95% CI (Greenwood’s formula, Kalbfleisch and Prentice 2002) 
will also be provided. The hazard ratio for OS will be estimated, along with its 95% confidence 
interval, using a stratified Cox proportional hazard model using the same stratification factors 
as for the log-rank test. If there are too few patients/events in a given stratum, strata might be 
grouped for the analysis. Further details will be provided in the SAP.
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12.5.1.1 Handling of intercurrent events of key secondary estimand
The key secondary estimand will account for the different intercurrent events as follows:

Discontinuation of study for any reason: OS will be analyzed based on the survival 
follow-up irrespective of the study discontinuation. OS will be censored at the last contact 
date if the subject discontinued from study due to lost to follow-up or withdrew consent or 
did not continue to the survival follow up phase.

New anti-cancer therapy: OS will be analyzed regardless of whether new anti-neoplastic 
therapy is initiated. Death collected after the start of new anti-cancer therapy will be used 
for OS analysis.
12.5.1.2 Sensitivity and supplementary analyses
If the OS analysis (either interim or final) is statistically significant, supplementary analyses 
will be performed in the FAS, the hazard ratio and 95% confidence interval for OS will be 
obtained from:

an unstratified and covariate unadjusted Cox model.

a stratified and covariate adjusted Cox model including as covariates the following: 
gender, age groups (<65, ≥65 years), ECOG PS (0, 1), histology (squamous, non-
squamous), smoking status (smoker, non-smokers, ex-smokers), race (Asian, other). 
A final list of covariates will be defined in the SAP.

a sub group analysis to assess the homogeneity of the treatment effect across 
demographics and baseline characteristics will be performed. The following subgroups 
maybe considered: gender, age groups (<65, ≥65 years), ECOG PS (0, 1), histology 
(squamous, non-squamous), smoking status (smoker, non-smokers, ex-smokers), race 
(Asian, other), presence or absence of brain metastasis at baseline (as assessed investigator 
per RECIST 1.1) and PD-L1 expression (<1%, or 1-49%, or ≥50%). A final list of 
subgroups of interest will be defined in the SAP.
12.5.2
Other secondary endpoint(s)
12.5.2.1 Efficacy endpoint(s)
Part 1: Single Arm Run-in Part
The secondary efficacy endpoints are the following:

Disease control rate (DCR) and progression free survival (PFS) by investigator assessment 
as per RECIST 1.1.
Part 2: Randomized Part
Following the study enrollment halt during Part 1, Part 2 will not be initiated. Therefore, the 
analysis for Part 2 are not applicable.
The secondary efficacy endpoints are the following:

Progression free survival (PFS) by investigator assessment as per RECIST 1.1.
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
Disease control rate (DCR), duration of response (DOR), overall response rate (ORR) and 
time to response (TTR) by investigator assessment and BIRC as per RECIST 1.1.
Disease control rate (DCR)
DCR is defined as the proportion of subjects with a confirmed best overall response (BOR) of 
complete response (CR), partial response (PR) and stable disease (SD) according to 
RECIST 1.1 (see Appendix 1).
DCR calculated based on the data from the FAS and the corresponding 95% confidence 
intervals based on the exact binomial distribution (Clopper and Pearson 1934) will be presented.
Participants who had never received one of the investigational drugs will be excluded from the 
DCR analysis.
Progression free survival (PFS)
The analysis in this section refer to the PFS as per local investigator assessment for Part 1.
PFS is defined as the time from the date of start of treatment (Part 1) to the date of the first 
documented progression according to RECIST 1.1, or death due to any cause. If a subject has 
no progression or death, the subject is censored at the date of last adequate tumor assessment. 
Definition of last adequate tumor assessment is provided in Appendix 1.
PFS will be summarized using the KM method, based on FAS. Median PFS, with corresponding 
95% CI, and 25th and 75th percentiles (Brookmeyer and Crowley 1982, Klein and 
Moeschberger 1997) will be presented. KM estimates for PFS proportions at specific timepoints, 
along with 95% CI (Greenwood’s formula, Kalbfleisch and Prentice 2002) will also be provided.
Participants who did not receive one of the investigational drugs will be excluded from the PFS 
analysis.
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), if the event 
occurred after two or more missing tumor assessments, or study treatment discontinuation 
before radiological progression or death. Clinical progression without objective radiological 
evidence will not be considered as documented disease 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 occurred. If no post-baseline assessments are 
available (before an event or a censoring reason occurred), the date of enrollment will be used.
The number of subjects censored and reasons for censoring will be summarized using 
descriptive statistics.
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12.5.2.2 Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented for 
the safety set for each part (overall for Part 1; and by treatment group for Part 2).
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:

from date of first administration of any study drug to 30 days after date of last actual 
administration of study treatment (including start and stop date).
Post-treatment period:

starting at day 31 after the last administration of study treatment.
Safety summaries will primarily be based on all data from the on-treatment period. 
Following last administration of study treatment, adverse events (including serious adverse 
events) will be collected until 150 day from last dose of spartalizumab/placebo or 30 days from 
last dose of capmatinib whichever is longer in subjects receiving both investigational drugs. 
New anti-neoplastic therapies will be collected until subject’s death or lost to follow-up. 
Following start of new anti-neoplastic therapy, only study treatment related adverse events will 
be collected.  Select summaries of related adverse events may be produced for the combined 
on-treatment and post-treatment periods. Details will be specified in the SAP.
Adverse events
All information obtained on adverse events will be displayed for safety set.
The number (and percentage) of subjects with treatment emergent adverse events (events started 
after the first dose of study treatment or events present prior to start of treatment but increased 
in severity based on preferred term) will be summarized in the following ways:

by primary system organ class and preferred term.

by primary system organ class, preferred term and maximum severity.
Separate summaries will be provided for study treatment related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation and adverse events 
leading to dose adjustment. A subject with multiple adverse events within a primary system 
organ class is only counted once towards the total of the primary system organ class.
The number (and percentage) of subjects with adverse events of special interest will be 
summarized.
Serious adverse events, non-serious adverse events and adverse events of special interest (AESI) 
during the on-treatment period will be tabulated.
All deaths and on-treatment deaths will be summarized.
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All AEs, deaths, and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged.
Vital signs
Vital sign assessments are performed in order to characterize basic body function. 
The following parameters will be collected: height (cm), weight (kg), body temperature (°C), 
heart rate (beats per minute), systolic and diastolic blood pressure (mmHg).
Vital signs collected during on-treatment will be summarized. The number and percentage of 
subjects with notable vital sign values will be presented for the safety set. A listing of subjects 
with notable vital signs will be provided and value measure during the post-treatment follow up 
will be flagged in the listing. Notable vital sign values criteria will be specified in the SAP.
12-lead ECG
12-lead ECGs including PR, QRS, QT and QTcF intervals and heart rate will be obtained for 
each subject during the study. ECG data will be read and interpreted locally. The average of the 
ECG parameters at each assessment should be used in the analyses.
ECGs collected during on-treatment will be summarized. The number and percentage of 
subjects with notable ECG values will be presented for the safety set. A listing of subjects with 
notable ECGs will be provided and value measure during the post-treatment follow up will be 
flagged in the listing. Notable ECG values criteria will be specified in the SAP.
Clinical laboratory evaluations
All laboratory data will be summarized by subject and visit/time. 
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,

Shift tables using low/normal/high (low and high) classification to compare baseline to the 
worst on-treatment value.
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 post-
baseline value.
12.5.2.3 Tolerability
Tolerability of study drug will be assessed by summarizing the number of and reasons for dose 
delays/interruptions and dose reductions. Dose intensity will also be tabulated by treatment 
group for each component of the study treatment.
12.5.2.4 Pharmacokinetics
All PK data analysis and PK summary statistics will be based on the INC-PAS and PDR-PAS. 
PK parameters summary statistics will be based on the INC-FPAS and PDR-FPAS.
Descritpive summary statistics of capmatinib and spartalizumab concentration data will 
beprovided 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 (see Table 12-1) will only be derived from the subjects in the FPAS 
(INC-FPAS and PDR-FPAS). Descriptive summary statistics, for the PK parameters, 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.
Table 12-1
Non-compartmental pharmacokinetic parameters
AUClast
The AUC from time zero to the last measurable analyte (capmatinib or spartalizumab) 
concentration sampling time (tlast) (mass x time x volume-1)
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x 
volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time)
12.5.2.4.1
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%.
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12.5.2.4.2
Population pharmacokinetic analysis
If data permit, a mixed-effects model may be applied to the spartalizumab and/or capmatinib 
concentration-time data to characterize spartalizumab and/or capmatinib exposure. If there are 
sufficient data for analysis, the details of the population pharmacokinetic analyses will be 
provided in a separate reporting and analysis plan, and the results may be reported in a separate 
population pharmacokinetic report. Data from this and other studies may be pooled for analysis.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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12.7
Interim analyses
Part 1: Single Arm Run-in Part
No formal interim analysis is planned for Part 1 of the study. 
Part 2: Randomized Part
Following the study enrollment halt during Part 1, Part 2 will not be initiated. The analysis for 
Part 2 are not applicable.
Progression free survival
One efficacy interim analysis for PFS is planned after approximately 145 PFS events out of 193 
(i.e. at approximately 75% information fraction) have been documented. This analysis is 
expected to occur approximately 39 months after randomization of the first subject. The primary 
intent of this interim analyses is to report early outstanding efficacy results in terms of PFS if 
the pre-specified threshold for significance is crossed.
The interim analysis will only be carried out after all subjects have been randomized. 
A weighted log rank test using Fleming-Harrington class of weights will be used as a 
supplementary analysis to account for the possible delay effect in the capmatinib + 
spartalizumab arm. In addition as a supplementary analysis, if proportional hazard assumption 
is violated as a result of a delayed treatment effect, a stratified piecewise Cox regression analysis 
will be used to estimate the HR after the delay treatment effect.
An alpha spending function according to a two-look (Lan-DeMets) group sequential design 
with (O’Brien-Fleming) type stopping boundary (as implemented in East 6.4) will be used to 
construct the efficacy stopping boundaries (Lan and DeMets 1983).
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The exact nominal p-value that will be needed to declare statistical significance at the time of 
interim analysis will depend on the number of the PFS events that have been observed at the 
interim and for the final analysis. The observed p-value at the time of primary and final will be 
compared to the recalculated boundary.
If the number of PFS events at the interim analysis is exactly 145 then significant results will 
be obtain if the p-value < 0.0096 (or equivalent of the HR < 0.662). Similarly assuming 
145 events have been previously observed at the time of the interim analysis and if there are 
exactly 193 PFS events at the final PFS analysis then significant results will be obtain if the 
p-value < 0.022 (or equivalent of the HR < 0.735). Note that the significance boundaries were 
chosen assuming no delay treatment effect.
The interim analysis for PFS will be performed by an independent external statistician (not 
involved with the conduct of the study). This will include the PFS analysis plus other critical 
efficacy endpoints and safety data. The results will be made available to the DMCs who will 
then make recommendations to Novartis (see Section 10.2.2).
The DMC recommendation at the interim PFS analysis will be based on whether the pre-
specified efficacy threshold for primary endpoint PFS by BIRC was met and will also take into 
account PFS results by local investigator assessment. The details on criteria used will be 
provided in the DMC charter.
If the DMC recommendation is to consider making the unblinded results available, key Novartis 
personnel will review the (unblinded) interim data and make the final decision on what steps to 
take. Full details of this decision-making process including who will have access to the 
unblinded results will be specified in the DMC Charter.
The estimated timing of the interim and final PFS analyses based on current design is 
summarized in Table 12-2.
Table 12-2
Estimated timelines for interim and final PFS analyses an simulated 
power
Analysis
Analysis time (months 
after randomization of 
the first patient)
# PFS events 
(information 
fraction)
Cumulative PFS power against a hazard 
ratio of 1 for first 3 months and a hazard 
ratio of 0.55 after 3 months
Interim
39
145 (75%)
53.6%
Final
59
193 (100%)
85.3%
Calculations using EAST 6.4, Seed =12345, Number of simulations =10,000
Overall survival (OS)
Interim analyses for OS are planned at the time of the interim and final analysis for PFS 
(provided PFS is significant), and when approximately 167 deaths are observed. A hierarchical 
testing procedure will be adopted and the statistical test for OS will be performed only if the 
primary efficacy endpoint PFS is statistically significant.
A maximum of four analyses are planned for OS:
1. At the time of the interim analysis for PFS (provided PFS is significant)
2. At the time of the final analysis for PFS (provided that either interim or final PFS analysis 
is significant)
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3. At an interim analysis for OS when approximately 167 deaths (expected approximately 
74 months after randomization of the first subject) in case the time gap between the final 
analyses for PFS and for OS is longer than 1 year
4. At a final analysis for OS when approximately 197 deaths (expected approximately 
126 months after the randomization of the first subject).
An alpha spending function according to a four-look (Lan-DeMets) group sequential design 
with (O’Brien-Fleming) type stopping boundary (as implemented in East 6.4) will be used to 
construct the efficacy stopping boundaries (Lan and DeMets 1983). This controls 2.5% overall 
level of significance across the repeated testing of the OS hypotheses in the interim and the final 
analyses (Glimm et al 2010).
The trial allows for an early significance claim for efficacy for a superior OS result, provided 
the primary endpoint PFS has already been shown to be statistically significant favoring 
capmatinib in combination with spartalizumab arm. Further, the exact nominal p-values that 
will need to be observed to declare statistical significance at the time of these analyses for OS 
will depend on the number of deaths that have been observed at the time of these analyses and 
the α for OS already spent at the time of earlier analyses.
At the time of final PFS analysis, both PFS and interim OS analyses will be performed by the 
Sponsor's clinical team. Investigators and subjects will remain blinded to study treatment 
(unless OS reaches significance at any of the PFS analyses) and all subjects will continue to be 
followed for OS until study closure.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
Part 1: Single Arm Run-in Part
No formal statistical power calculations to determine sample size were performed for this part 
of the study.
Approximately 30 subjects will be treated in Part 1 of the study. Table 12-3 shows the 
probability to detect a significant effect under different true ORR i.e. Probability to have ORR 
≥ 55% and the lower bound of the 95% CI > 35%. If the true ORR is 67% there is 91.7% 
probability that the single arm run-in part will be declared a success.
Table 12-3
Design operating characteristics
True ORR
N
Minimum number of 
responses to declare 
success
ORR (95% CI)
Probability to 
reject H0
55%
50.2%
60%
71.5%
67%
30
17
56.7% (37.4 - 74.5)
91.7%
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Part 2: Randomized Part
Following the study enrollment halt during Part 1, Part 2 will not be initiated.
The sample size calculation is based on the primary endpoint of PFS. The hypotheses to be 
tested and details of the testing strategy are described in Section 12.4.
Based on available data from the phase II single arm study CINC280A2201 (treatment-naive 
METΔex14 mutated, Cohort 5b), the median PFS in the capmatinib + placebo arm is expected 
to be around 10 months. Ignoring delayed treatment effect, it would be expected that the 
response to capmatinib when combined with spartalizumab would result in a hazard ratio of 
0.55 (which corresponds to an increase in median PFS to 18.182 months under the exponential 
model assumption).
Given knowledge of a potential delayed treatment effect with IO compounds, it is hypothesized 
that there will be no difference between treatment arms until 3 months after the randomization 
date for PFS. Therefore, it is assumed that the HR between the groups will be equal to 1 for the 
first 3 months. Thereafter, exponential survival distributions are assumed, with an HR of 0.55. 
This will result in an overall HR=0.636 (Kalbfleisch and Prentice 1981) at the time of the final 
PFS analysis (given the assumed 3 month delayed treatment effect, this equates to median PFS 
of 15.73 and 10 months in the capmatinib + spartalizumab and capmatinib + placebo, 
respectively).
In order to ensure at least cumulative 85% power for PFS to test the null hypothesis: PFS hazard 
ratio = 1, versus the specific alternative hypothesis: overall PFS hazard ratio = 0.636, using the 
assumptions for HR=1 for the first 3 months and HR=0.55 thereafter, it is calculated that a total 
of 193 PFS events need to be observed. This calculation assumes analysis by a one-sided 
log-rank test at the overall 2.5% level of significance, subjects randomized to the two treatment 
arms in a 2:1 ratio, and a 2-look group sequential design with a Lan-DeMets (O’Brien and 
Fleming) using information fractions of 0.75 and 1.
The total of approximately 193 PFS events targeted for the final PFS analysis represent a large 
percentage of the subjects randomized in the Part 2 of the study (80.4%).
Given the above assumptions, it is estimated that the 193rd PFS event will be observed 
approximately 59 months after first subject randomized in the study.
Assuming that enrollment will continue for 34 months at a uniform rate of 7 subjects per month, 
a total of 240 subjects will need to be randomized to observe the targeted 193 PFS events at 
about 59 months after the randomization date of the first subject. Then assuming losses to 
follow-up for PFS of 5% per year, the required sample size of the study is 240 randomized 
subjects in a 2:1 ratio (160 subjects in the capmatinib plus spartalizumab arm, 80 subjects in the 
capmatinib plus placebo arm). These calculations were made using the software package 
East 6.4.
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12.8.2
Key secondary objective
Following the study enrollment halt during Part 1, Part 2 will not be initiated. The analysis and 
statistical methods for Part 2 are not applicable.
Part 2: Randomized Part
OS, as the key secondary variable, will be formally statistically tested, provided that the primary 
endpoint PFS is statistically significant. The hypothesis to be tested and the details are provided 
in Section 12.5.1.
Based on available data from the phase II single arm study CINC280A2201 (treatment-naive 
METΔex14 mutated, Cohort 5b), the median OS in the capmatinib + placebo arm is expected 
to be around 20 months. It would be expected that the capmatinib in combination with 
spartalizumab response would result in a hazard ratio of 0.65 (which corresponds to an increase 
in median OS to 30.769 months under the exponential model assumption).
In order to ensure at least 80% power for OS to test the null hypothesis: OS hazard ratio = 1, 
versus the specific alternative hypothesis: OS hazard ratio = 0.65, it is calculated that a total of 
197 deaths need to be observed. This calculation assumes analysis by a one-sided log-rank test 
at the overall 2.5% level of significance, subjects are randomized to the two treatments in a 2:1 
ratio and a four-look group sequential design with a Lan-DeMets (O’Brien and Fleming) alpha 
spending function using information fractions of 0.492, 0.741, 0.848, 1.
The type I error probability will be controlled by using a separate Lan-DeMets (O’Brien and 
Fleming) alpha spending function independent of the one used for the primary efficacy analysis 
of PFS at 2.5% level of significance. This guarantees the protection of the overall level α = 
2.5% across the two hypotheses and the repeated testing of the OS hypotheses in the interim 
and the final analyses (Glimm et al 2010).
Based on the same number of subjects that are planned to be enrolled in the Part 2 of this study 
to provide sufficient power for the primary endpoint (i.e. 240 subjects), and assuming losses to 
follow-up for OS of 5% per year, it is estimated that these 197 deaths will be observed 
approximately 126 months after the randomization date of the first subject. Therefore, the 
cut-off date for the third interim analysis of OS, if performed, would be approximately 
15 months after the cut-off date for the final analysis of PFS; and the cut-off date for the final 
OS analysis will be approximately 67 months after the cut-off date for the final analysis of PFS. 
These calculations were made using the software package East 6.4.
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.
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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 (see Section 9.2.1) and finalization 
of the study report the results of this trial will be submitted for publication and posted in a 
publicly accessible database of clinical trial results, such as the Novartis clinical trial results 
website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT, etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
13.5
Participant Engagement
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the timepoints indicated. If compliance is 
impacted by cultural norms or local level laws and regulations, sites may discuss modifications 
to these requirements with Novartis:

Thank You letter

Plain language trial summary – after CSR publication
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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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15
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cMET Inhibitor Capmatinib (INC280) in Patients With Advanced cMET+ Non-small Cell 
Lung Cancer [Abstract]. J Clin Oncol; 34(15_suppl);9067-9067.
Sequist LV, Yang JC, Yamamoto N, et al (2013) Phase III study of afatinib or cisplatin plus 
pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin 
Oncol; 31(27):3327-34.
 
Shaw AT and Engelman JA (2013) ALK in lung cancer: past, present, and future. J Clin 
Oncol; 31(8):1105-11.
Shaw AT, Kim DW, Nakagawa K, et al (2013) Crizotinib versus chemotherapy in advanced 
ALK-positive lung cancer. N Engl J Med; 368(25): 2385-94.
Sheela S, Kim ES, Mileham KF, et al (2018) Moving away (finally) from doublet therapy in 
lung cancer: immunotherapy and KEYNOTE-189. J Thorac Dis; 10(9):5186-5189.
Siegel RL, Miller KD, Jemal A (2019) Cancer Statistics, 2019. CA Cancer J Clin; 69(1):7-34.
Socinski MA, Jotte RM, Cappuzzo F, et al (2018) Atezolizumab for First-Line Treatment of 
Metastatic Nonsquamous NSCLC. N Engl J Med; 378(24):2288-301.
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Solomon BJ, Mok T, Kim DW, et al (2014) First-line crizotinib versus chemotherapy in 
ALK-positive lung cancer. N Engl J Med; 371(23):2167-77.
Spain L, Diem S, Larkin J (2016) Management of toxicities of immune checkpoint inhibitors. 
Cancer Treat Rev; 44:51-60.
TCGA Research Network (2014) Comprehensive molecular profiling of lung 
adenocarcinoma. Nature; 511(7511):543-50.
Tong JH, Yeung SF, Chan AWH, et al (2016) MET Amplification and Exon 14 Splice Site 
Mutation Define Unique Molecular Subgroups of Non–Small Cell Lung Carcinoma with Poor 
Prognosis. Clin Cancer Res; 22(12):3048-56.
Waqar SN, Morgensztern D, Sehn J (2015) MET Mutation Associated with Responsiveness to 
Crizotinib. J Thorac Oncol; 10(5):e29-31.
Wolf J, Baik C, Heist RS, et al (2018) Natural history, treatment (tx) patterns, and outcomes 
in MET dysregulated non-small cell lung cancer (NSCLC) patients (pts). European Journal of 
Cancer 103S1 (2018) e21-e148.
Wolf J, Han J, Nishio M, et al (2017) P2.04-005 GEOMETRY Mono-1: Phase II, Multicenter 
Study of MET Inhibitor Capmatinib (INC280) in EGFR wt, MET dysregulated Advanced 
NSCLC [Abstract]. J Thorac Oncol; 12(11S2):S2399.
Wolf J, Seto T, Han J-Y, et al. (2019) Capmatinib (INC280) in METΔex14-mutated advanced 
non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 
study [Abstract]. J Clin Oncol; 37(15_suppl):9004.
Yang SC, Lai WW, Hsiue TR, et al (2016) Health-related quality of life after first-line anti-
cancer treatments for advanced non-small cell lung cancer in clinical practice. Qual Life Res 
25(6):1441-1449.
Zhou C, Wu YL, Chen G, et al (2011) Erlotinib versus chemotherapy as first-line treatment 
for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, 
CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol; 
12(8):735-42.
Zhou JG, Tian X, Wang X, et al (2015). Treatment on advanced NSCLC: Platinum-based 
chemotherapy plus erlotinib or platinum-based chemotherapy alone? A systematic review and 
meta-analysis of randomized controlled trials. Med Oncol; 32(2):471.
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16
Appendices
16.1
Appendix 1: Guidelines for Response, Duration of Overall 
Response, TTF, TTP, Progression-Free Survival, and Overall 
Survival based on RECIST 1.1
Document type:
TA Specific Guideline
Document status:
Version 3.2: 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).
This document will not address the use of RECIST 1.1 in glioblastoma multiforme (GBM), 
studies in adjuvant setting or immunotherapy.
The efficacy assessments described in Section 16.1.2 and the definition of best response in 
Section 16.1.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 16.1.3.2 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 16.1.4 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the SAP (Statistical Analysis Plan) to provide further details needed for programming.
16.1.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009).
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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 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.

Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 
baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease.

Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions.

Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with 
 10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques..
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16.1.2.1.2
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that patients be excluded from trials where the main focus is on the 
Overall Response Rate (ORR). Guidance on how patients with just non-measurable disease at 
baseline will be evaluated for response and also handled in the statistical analyses is given in 
Section 16.1.3.2.9.
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 10mm size, and can be assessed using calipers.

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions, unless pre-specified by 
the protocol. It is, however, a possible alternative to clinical measurements of 
superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules. US 
might also be useful to confirm the complete disappearance of superficial lesions 
usually assessed by clinical examination.

Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for 
objective tumor evaluation has not yet been fully and widely validated. Their uses in 
this specific context require sophisticated equipment and a high level of expertise that 
may only be available in some centers. Therefore, the utilization of such techniques 
for objective tumor response should be restricted to validation purposes in specialized 
centers. However, such techniques can be useful in confirming complete pathological 
response when biopsies are obtained.

Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian 
cancer, PSA for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) 
can be integrated as non-target disease. If markers are initially above the upper 
normal limit they must normalize for a patient to be considered in complete clinical 
response when all lesions have disappeared.

Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed).

Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
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16.1.2.3 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. 
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Therefore all such data applicable to a particular visit should be associated with the same 
assessment number.
Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement.  This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval.
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated.
Nodal lesions
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist.
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval.
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
1.
SOD for CR may not be zero when nodal lesions are part of target lesions
2.
Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present 
and all nodal lesions are <10 mm in size. In this case, the target lesion response is CR
3.
In exceptional circumstances an UNK response due to change in method could be over-ruled by 
the investigator or central reviewer using expert judgment based on the available information (see 
Notes on target lesion response and methodology change in Section 16.1.2.2).
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following 
possibilities:
The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as 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.
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.
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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 16.1.3.2.9 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 
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cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol.
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met.
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed.

For non-randomized trials where response is the primary endpoint, confirmation is needed.

For trials intended to support accelerated approval, confirmation is needed

For all other trials, confirmation of response may be considered optional.
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required

SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).

PD = progression  12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).

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 
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confirmation of response is required, if a patient has a single PR (30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not 20% increase from previous smallest sum), the objective status 
at that assessment should be SD. Once a confirmed PR was seen, the overall lesion response 
should be considered PR (or UNK) until progression is documented or the lesions totally 
disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable.
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments.
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 central 
blinded review 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.
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Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used:
Early progression rate (EPR) is the proportion of patients with 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.
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.
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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.
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 
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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.
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 16.1.3.2.6. 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.
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
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.
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.
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
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.
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.
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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:
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
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Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently in the 
protocol or RAP
Outcome
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.
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.
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Option (2), i.e. censoring at last adequate assessment may be used as a sensitivity analysis. If a 
high censoring rate due to start of new cancer therapy is expected, a window of approximately 
8 weeks performed after the start of new cancer therapy can be used to calculate the date of the 
event or censoring. This should be clearly specified in the analysis plan. 
In some specific settings, local treatments (e.g. radiation/surgery) may not be considered as 
cancer therapies for assessment of event/censoring in PFS/TTP/DoR analysis. For example, 
palliative radiotherapy given in the trial for analgesic purposes or for lytic lesions at risk of 
fracture will not be considered as cancer therapy for the assessment of BOR and PFS analyses. 
The protocol should clearly state the local treatments which are not considered as antineoplastic 
therapies in the PFS/TTP/DoR analysis.
The protocol should state that tumor assessments will be performed every x weeks until 
radiological progression irrespective of initiation of new antineoplastic therapy. It is strongly 
recommended that a tumor assessment is performed before the patient is switched to a new 
cancer therapy.
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in 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).
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16.1.4.2 End of treatment phase completion
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc.
The end of treatment visit and its associated assessments should occur within 7 days of the last 
study treatment. 
Patients may discontinue study treatment for any of the following reasons:

Adverse event(s)

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

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
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16.1.4.4 Medical validation of programmed overall lesion response
In order to be as objective as possible the RECIST programmed calculated response assessment 
is very strict regarding measurement methods (i.e. any assessment with more or less sensitive 
method than the one used to assess the lesion at baseline is considered UNK) and not available 
evaluations (i.e. if any target or non-target lesion was not evaluated the whole overall lesion 
response is UNK unless remaining lesions qualified for PD). This contrasts with the slightly 
more flexible guidance given to local investigators (and to the central reviewers) to use expert 
judgment in determining response in these type of situations, and therefore as a consequence 
discrepancies between the different sources of response assessment often arise. To ensure the 
quality of response assessments from the local site and/or the central reviewer, the responses 
may be re-evaluated by clinicians (based on local investigator data recorded in eCRF or based 
on central reviewer data entered in the database) at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on RECIST 
criteria. This may be queried for clarification. However, the investigator or central reader’s 
response assessment will never be overruled.
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 
at that specific assessment is to be kept in a dataset. This must be clearly documented in the 
RAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
16.1.4.5 Programming rules
The following should be used for programming of efficacy results:
16.1.4.5.1
Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
16.1.4.5.2
Incomplete assessment dates
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 16.1.3.2.7). If all measurement dates have 
no day recorded, the 1st of the month is used.
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If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
16.1.4.5.3
Incomplete dates for last known date patient alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
16.1.4.5.4
Non-target lesion response
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’.
16.1.4.5.5
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
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 

Initiation of new anti-cancer therapy  
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* 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.
References (available upon request)
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19:785-791.
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29:456-465.
EMA Guidance: 2012 Guideline on the evaluation of anticancer medicinal products in man.
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005. 
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007.
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9:11-18.
Therasse P, Arbuck S, Eisenhauer EEEE, et al (2000) New Guidelines to Evaluate the 
Response to Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16
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16.3
Appendix 3: Drugs that are prohibited or to be used with caution
Table 16-11
Capmatinib: drugs to be used with caution during co-administration
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, nintedanib, 
olodaterol, paclitaxel, pantoprazole, paroxetine, pazopanib, 
posaconazole, pravastatin, proguanil, ranolazine, riociguat, 
risperidone, ritonavir, rivaroxaban, saquinavir, silodosin, simeprevir, 
simvastatin, sirolimus, sitagliptin, sofosbuvir, sorafenib, tacrolimus, 
telaprevir, tenofovir, ticagrelor, tipranavir, tolvaptan, topotecan, 
umeclidinium, valsartan, vardenafil, vincristine, voriconazole
BCRP substrates
atorvastatin daunorubicin, dolutegravir, doxorubicin, ethinyl estradiol, 
hematoporphyrin, imatinib, irinotecan, methotrexate, paritaprevir, 
pitavastatin, rosuvastatin, simvastatin, sofosbuvir, sulfasalazine, 
tenofovir, topotecan, venetoclax
Proton pump inhibitor
Dexlansoprazole, esomeprazole, lansoprazole, omeprazole, 
pantoprazole, rabeprazole
H2-receptor antagonists
cimetidine, famotidine, nizatidine, ranitidine
Antacids
aluminum carbonate, aluminum hydroxide, calcium carbonate, calcium 
hydroxide, bismuth subsalicylate
Source: The list is adapted from the Novartis Institutes for Biomedical PK Sciences internal 
memorandum (v01, 2018): drug-drug interactions (DDI) database, which is compiled primarily from 
the Indiana University School of Medicine’s “Clinically Relevant” Table (https://drug-
interactions.medicine.iu.edu/Main-Table.aspx), the University of Washington’s Drug Interaction 
Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction Studies”.
NTI: narrow therapeutic index
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Table 16-12
Capmatinib: prohibited drugs
Mechanism of 
Interaction
Drug Name
Strong CYP3A4 inducer
carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, 
phenytoin, rifabutin, rifampicin, St. John's wort (Hypericum perforatum)
Source: The list is adapted from the Novartis Institutes for Biomedical PK Sciences internal 
memorandum (v01, 2018): drug-drug interactions (DDI) database, which is compiled primarily from 
the Indiana University School of Medicine’s “Clinically Relevant” Table (https://drug-
interactions.medicine.iu.edu/Main-Table.aspx), the University of Washington’s Drug Interaction 
Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction Studies”
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16.4
Appendix 4: Cockcroft-Gault formula for GRF estimate
Creatinine clearance will be calculated using the following formulas:
Male GFR = (140 - age) x (weight) / (sCr x 72)
Female GFR = (140 - age) x (weight) x 0.85 / (sCr x 72)
GFR is Glomerular Filtration Rate in ml/min; Age is in years; Weight is Lean Body Mass in 
kilograms; sCr: is Serum Creatinine in mg/dl.
The formulas above should be altered in the following cases:

Overweight (GFR >25 kg/m2): Calculate based on adjusted body weight;
Adjusted body weight = wtKgIdeal + 0.4 * (wtKgActual - wtKgIdeal)

Underweight: Use actual weight, Do not round up to Serum Creatinine (significantly 
underestimates GFR)

Elderly: do not round up to Serum Creatinine (significantly underestimates GFR)

Patients who had a limb amputation: measure 24 hour Creatinine Clearance
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Approval Signatures
Compound:
INC280
Document Title:
CINC280J12201: Protocol v01 - Amendment 1 - A double-blind, placebo
controlled, randomized, phase II study evaluating the efficacy and safety
of capmatinib (INC280) and spartalizumab (PDR001) combination therapy
versus capmatinib and placebo as first line treatment for locally advanced or
metastatic non-small cell lung cancer patients with MET exon 14 skipping
mutations
Document Name:
02.01.0201 Protocol - v01
Document Version:
2.0
Username
User ID
Signing Reason
Date
Content Approval
2021-10-27
13:18:12 (UTC)
Document electronically signed
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