Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: Non Small Cell Lung Non Small Cell Lung Cancer Non-small cell lung cancer NSCLC INC280 EGFR wild-type (wt) advanced non-small cell lung cancer advanced/metastatic disease Non-small cell lung carcinoma (NSCLC) treatment of lung cancer after first metastasis lung cancer lung adenocarcinoma Non small cell lung carcinoma MET exon 14 deletion METex14del MET exon 14 skipping MET exon 14 mutation MET mutation MET amplification MET inhibitor MET dysregulation MET activation MET signaling MET pathway met cMET Geometry mono-1 Geometry
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 373
Healthy volunteers: no

Brief summary:
Study to evaluate the efficacy and safety of capmatinib as a single-agent treatment for subjects with advanced/metastatic (stage IIIB or IV) non-small cell lung cancer (NSCLC) who had wild-type epidermal growth factor receptor (EGFR wt) (for exon 19 deletions and exon 21 L858R substitution mutations), anaplastic lymphoma kinase (ALK)-negative rearrangement, and mesenchymal epithelial transition (MET) mutations leading to exon 14 deletion (referred to as MET mutation hereafter) and/or MET amplification.

Detailed description:
This was a Phase II, multicenter, open-label study. Patients were enrolled in different cohorts based on their MET status (amplification and/or mutation) and prior treatment status: Cohort 1a, Cohort 1b, Cohort 2, Cohort 3, Cohort 4, Cohort 5a, Cohort 5b, Cohort 6, and Cohort 7. MET mutation (by RT-PCR) and/or MET amplification status by gene copy number (GCN, by FISH) was determined by central laboratory.

Patients in Cohorts 1, 2, 3, and 4 had previously failed 1 or 2 prior lines of systemic therapy, while patients enrolled in Cohorts 5 and 7 were treatment-naïve for advanced disease/metastatic disease. Patients enrolled in Cohort 6 had failed 1 prior line of systemic therapy for advanced/ metastatic disease.

Patients with MET mutation were enrolled in Cohort 4 (pre-treated), Cohort 5b (treatment naïve) or Cohort 7 (treatment naïve expansion cohort of Cohort 5b), irrespective of their MET GCN. The enrollment in expansion Cohort 7 started after the completion of enrollment in Cohort 5b.

Patients without MET mutation, were enrolled in Cohorts 1a, 1b, 2, 3 (pre-treated) or 5a (treatment naïve), based on their MET GCN. Patients enrolled in Cohort 6 (expansion cohort of Cohort 1a and Cohort 4) had either MET GCN ≥10 without MET mutation (Cohort 6.1) or MET mutation, irrespective to their MET GCN (Cohort 6.2). The enrollment in Cohort 6 started upon enrollment completion of the respective Cohort 1a or Cohort 4.

All participants in the study received oral capmatinib 400 mg twice daily. A treatment cycle was defined as 21 days. Treatment with capmatinib continued until patient experienced any of the following: disease progression according to RECIST 1.1 as determined by investigator and confirmed by Blinded Independent Review Committee (BIRC), unacceptable toxicity that precluded further treatment, treatment discontinuation at the discretion of the Investigator or patient, lost to follow-up, or death. Treatment with capmatinib was allowed beyond RECIST 1.1-defined disease progression (as determined by investigator and confirmed by BIRC) if, in the judgment of the investigator, there was evidence of clinical benefit and the patient wished to continue on the study treatment. All patients continued to have safety evaluations for 30 days after the last dose of study treatment.

Patients who discontinued treatment with capmatinib for any reason other than disease progression, as determined by the investigator and confirmed by BIRC, death, withdrawal of consent for further assessments, or being lost to follow-up, continued to have tumor assessments (post-treatment efficacy follow-up) until disease progression confirmed by BIRC, death, withdrawal of consent for further assessments, or lost to follow-up.

All patients who discontinued treatment with capmatinib were followed for survival (post-treatment survival follow-up) until death, loss to follow-up, withdrawal of consent to survival follow-up, or the end of the study.

Arms:
arm 1: Pre-treated patients with MET GCN ≥ 10 treated with INC280 at 400mg BID as second or third line (2/3L) arm 2: Pre-treated patients with MET GCN ≥ 6 and \< 10 treated with INC280 at 400 mg BID as second or third line (2/3L) arm 3: Pre-treated patients with MET GCN ≥ 4 and \< 6 treated with INC280 at 400mg BID as second or third line (2/3L) arm 4: Pre-treated patients with MET GCN \< 4 treated with INC280 at 400mg BID as second or third line (2/3L) arm 5: Pre-treated patients with MET mutation regardless of MET GCN treated with INC280 at 400mg BID as second or third line (2/3L) arm 6: Treatment-naïve patients with MET GCN ≥10 treated with INC280 at 400mg BID as first-line (1L) arm 7: Treatment-naïve patients with MET mutation regardless of MET GCN treated with INC280 at 400mg BID as first line (1L) arm 8: Pre-treated patients with MET GCN ≥ 10 without MET mutation treated with INC280 at 400 mg BID as second line (2L) (expansion cohort of Cohort 1a) arm 9: Pre-treated patients with MET mutation regardless of MET GCN treated with INC280 at 400 mg BID as second line (2L)(expansion of Cohort 4) arm 10: Treatment-naïve patients with MET mutation regardless of MET GCN treated with INC280 at 400mg BID as first line (1L) (expansion cohort of Cohort 5b)

Interventions: intervention 1: Capmatinib
Intervention descriptions: intervention 1: Capmatinib was administered orally, at a dose of 400 mg on a continuous twice daily dosing schedule.

Capmatinib was administered to participants in Cohorts 1a, 1b, 2, 3, 4, 5a and 5b in a fasted state. For Cohorts 6.1. 6.2 and 7, capmatinib was administered either with or without food.

Protocol document:
Prot_000.pdf: 


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Table of contents
Table of contents .................................................................................................................2
List of appendices................................................................................................................7
List of figures ......................................................................................................................7
List of tables ........................................................................................................................7
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................11
Amendment 6 (28-Feb-2019)............................................................................................13
Amendment 5 (13-Feb-2018)............................................................................................18
Amendment 4 (17-Nov-2016)...........................................................................................22
Amendment 3 (28-Jul-2016) .............................................................................................27
Amendment 2 ....................................................................................................................32
Amendment 1 ....................................................................................................................38
Protocol summary..............................................................................................................40
1
Background........................................................................................................................48
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............48
1.1.1
Locally advanced unresectable or metastatic non-small cell lung 
cancer (NSCLC)....................................................................................48
1.1.2
Targeted therapies in NSCLC ...............................................................49
1.1.3
cMET in NSCLC...................................................................................50
1.2
Introduction to study treatment..............................................................................51
1.2.1
Overview of INC280.............................................................................51
2
Rationale............................................................................................................................58
2.1
Study rationale and purpose...................................................................................58
2.2
Rationale for the study design ...............................................................................58
2.2.1
Rationale for cMET GCN cohorts ........................................................59
2.2.2
Rationale for cMET mutation cohorts...................................................60
2.2.3
Rationale for treatment-naïve cohort with cMET dysregulation ..........61
2.2.4
Rationale for additional Cohort 6 in pretreated NSCLC with cMET 
dysregulation.........................................................................................62
2.2.5
Rationale for additional Cohort 7 in treatment-naïve NSCLC with 
cMET mutation .....................................................................................62
2.3
Rationale for dose and regimen selection..............................................................62
2.4
Rationale for choice of combination drugs............................................................64
2.5
Rationale for choice of comparators drugs............................................................64
3
Objectives and endpoints...................................................................................................64
4
Study design ......................................................................................................................67


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Description of study design ...................................................................................67
4.1.1
Molecular pre-screening........................................................................71
4.1.2
Main screening......................................................................................72
4.1.3
Treatment ..............................................................................................72
4.1.4
Follow-up ..............................................................................................73
4.1.5
Survival follow-up ................................................................................73
4.2
Timing of interim analyses and design adaptations...............................................73
4.3
Definition of end of the study................................................................................74
4.4
Early study termination..........................................................................................74
5
Population..........................................................................................................................74
5.1
Patient population..................................................................................................74
5.2
Inclusion criteria ....................................................................................................75
5.3
Exclusion criteria...................................................................................................77
6
Treatment...........................................................................................................................80
6.1
Study treatment......................................................................................................80
6.1.1
Dosing regimen.....................................................................................80
6.1.2
Ancillary treatments..............................................................................81
6.1.3
Rescue medication ................................................................................81
6.1.4
Guidelines for continuation of treatment ..............................................81
6.1.5
Treatment duration................................................................................81
6.2
Dose escalation guidelines.....................................................................................81
6.3
Dose modifications................................................................................................81
6.3.1
Dose modification and dose delay ........................................................81
6.3.2
Dose reduction and re-escalation ..........................................................82
6.3.3
Treatment interruption and treatment discontinuation..........................89
6.3.4
Follow-up for toxicities.........................................................................89
6.3.5
Anticipated risks and safety concerns of the study drug.......................94
6.4
Concomitant medications ......................................................................................95
6.4.1
Permitted concomitant therapy .............................................................95
6.4.2
Permitted concomitant therapy requiring caution and/or action...........96
6.4.3
Prohibited concomitant therapy ............................................................97
6.5
Patient numbering and treatment assignment........................................................98
6.5.1
Patient numbering .................................................................................98
6.5.2
Treatment assignment ...........................................................................98
6.5.3
Treatment blinding................................................................................99
6.6
Study drug preparation and dispensation...............................................................99


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6.6.1
Study drug packaging and labeling.......................................................99
6.6.2
Drug supply and storage......................................................................100
6.6.3
Study drug compliance and accountability .........................................100
6.6.4
Disposal and destruction .....................................................................100
7
Visit schedule and assessments .......................................................................................101
7.1
Study flow and visit schedule..............................................................................101
7.1.1
Molecular pre-screening......................................................................108
7.1.2
Screening.............................................................................................109
7.1.3
Treatment period.................................................................................111
7.1.4
Discontinuation of study treatment .....................................................112
7.1.5
Follow-up-period.................................................................................113
7.1.6
Withdrawal of consent ........................................................................114
7.1.7
Lost to follow-up.................................................................................114
7.2
Assessment types.................................................................................................114
7.2.1
Efficacy assessments...........................................................................114
7.2.2
Safety and tolerability assessments.....................................................118
7.2.3
Pharmacokinetics ................................................................................123
124
127
127
8
Safety monitoring and reporting......................................................................................128
8.1
Adverse events.....................................................................................................128
8.1.1
Definitions and reporting ....................................................................128
8.1.2
Laboratory test abnormalities..............................................................130
8.1.3
Adverse events of special interest.......................................................130
8.2
Serious adverse events.........................................................................................131
8.2.1
Definitions...........................................................................................131
8.2.2
Reporting.............................................................................................131
8.3
Emergency unblinding of treatment assignment .................................................132
8.4
Pregnancies..........................................................................................................132
8.5
Warnings and precautions....................................................................................133
8.6
Data Monitoring Committee................................................................................133
8.7
Steering Committee .............................................................................................133
9
Data collection and management.....................................................................................133
9.1
Data confidentiality .............................................................................................133
9.2
Site monitoring ....................................................................................................134


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9.3
Data collection.....................................................................................................134
9.4
Database management and quality control..........................................................135
10 Statistical methods and data analysis ..............................................................................136
10.1
Analysis sets ........................................................................................................137
10.1.1
Full Analysis Set .................................................................................137
10.1.2
Safety Set ............................................................................................137
10.1.3
Per-Protocol Set ..................................................................................137
10.1.4
Pharmacokinetic analysis set...............................................................137
10.2
Patient demographics/other baseline characteristics ...........................................137
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................137
10.4
Primary objective.................................................................................................138
10.4.1
Variable...............................................................................................138
10.4.2
Statistical hypothesis, model, and method of analysis........................138
10.4.3
Handling of missing values/censoring/discontinuations.....................139
10.4.4
Supportive analyses.............................................................................139
10.5
Secondary objectives ...........................................................................................139
10.5.1
Key secondary objective(s).................................................................139
10.5.2
Other secondary efficacy objectives ...................................................140
10.5.3
Safety objectives .................................................................................141
10.5.4
Pharmacokinetics ................................................................................142
143
10.5.6
Resource utilization.............................................................................145
145
145
10.7
Interim analysis....................................................................................................145
10.8
Sample size calculation........................................................................................147
10.9
Power for analysis of key secondary variables....................................................150
11 Ethical considerations and administrative procedures ....................................................150
11.1
Regulatory and ethical compliance......................................................................150
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................150
11.3
Informed consent procedures...............................................................................150
11.4
Discontinuation of the study................................................................................151
11.5
Publication of study protocol and results.............................................................151
11.6
Study documentation, record keeping and retention of documents.....................152
11.7
Confidentiality of study documents and patient records .....................................153
11.8
Audits and inspections.........................................................................................153


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11.9
Financial disclosures............................................................................................153
12 Protocol adherence ..........................................................................................................153
12.1
Amendments to the protocol................................................................................153
13 References (available upon request)................................................................................154
14 Appendices ......................................................................................................................160
14.1
Appendix 1: Harmonization of efficacy analysis of solid tumor studies 
(RECIST 1.1).......................................................................................................160
14.1.1
Introduction.........................................................................................162
14.1.2
Efficacy assessments...........................................................................162
14.1.3
Definitions...........................................................................................162
14.1.4
Disease measurability..........................................................................162
14.1.5
Eligibility based on measurable disease..............................................163
14.1.6
Methods of tumor measurement - general guidelines.........................163
14.1.7
Baseline documentation of target and non-target lesions ...................165
14.1.8
Follow-up evaluation of target and non-target lesions........................165
14.1.9
Follow-up and recording of lesions.....................................................166
14.1.10
Non-nodal lesions................................................................................166
14.1.11
Nodal lesions.......................................................................................166
14.1.12
Determination of target lesion response..............................................167
14.1.13
Determination of non-target lesion response ......................................169
14.1.14
New lesions .........................................................................................169
14.1.15
Evaluation of overall lesion response .................................................170
14.1.16
Efficacy definitions .............................................................................170
14.1.17
Best overall response...........................................................................171
14.1.18
Time to event variables .......................................................................173
14.1.19
Progression-free survival ....................................................................173
14.1.20
Overall survival...................................................................................173
14.1.21
Time to progression.............................................................................173
14.1.22
Time to treatment failure.....................................................................174
14.1.23
Duration of response ...........................................................................174
14.1.24
Time to response .................................................................................175
14.1.25
Definition of start and end dates for time to event variables ..............175
14.1.26
Handling of patients with non-measurable disease only at baseline...176
14.1.27
Sensitivity analyses .............................................................................177
14.1.28
Data handling and programming rules................................................179
14.1.29
Study/project specific decisions..........................................................179


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14.1.30
End of treatment phase completion.....................................................179
14.1.31
End of post-treatment follow-up (study phase completion)................180
14.1.32
Medical validation of programmed overall lesion response ...............180
14.1.33
Programming rules..............................................................................181
14.1.34
Calculation of ‘time to event’ variables..............................................181
14.1.35
Incomplete assessment dates...............................................................181
14.1.36
Incomplete dates for last known date patient alive or death ...............181
14.1.37
Non-target lesion response..................................................................182
14.1.38
Study/project specific programming...................................................182
14.1.39
Censoring reason.................................................................................182
14.1.40
References (available upon request) ...................................................183
List of appendices
Appendix 1: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
List of figures
Figure 4-1
Overall study design..............................................................................71
List of tables
Table 2-1
DLTs experienced with single agent INC280 as of 28-Sep-2014.........62
Table 3-1
Objectives and related endpoints ..........................................................65
Table 6-1
Dose and treatment schedule.................................................................81
Table 6-2
Dose reduction steps for INC280..........................................................82
Table 6-3
Criteria for interruption and re-initiation of INC280 treatment............83
Table 6-4
Follow-up evaluations for selected toxicities*......................................89
Table 6-5
Drugs to be used with caution while on study ......................................96
Table 6-6
Drugs prohibited while on study...........................................................97
Table 6-7
Drugs with a known risk of Torsades des Pointes prohibited while 
on study.................................................................................................97
Table 6-8
Preparation and dispensing ...................................................................99
Table 6-9
Packaging and labeling .........................................................................99
Table 7-1
Visit evaluation schedule ....................................................................102
Table 7-2
Imaging collection plan.......................................................................115
Table 7-3
ECOG performance status scale..........................................................119
Table 7-4
Clinical laboratory parameters collection plan ...................................120


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Table 7-5
ECG collection plan for approximately 30 enrolled patients at 
selected sites........................................................................................121
Table 7-6
ECG collection plan for remaining patients, including patients in 
Cohort 6 and Cohort 7.........................................................................122
Table 7-7
Pharmacokinetic blood collection log for approximately 30 
enrolled patients at selected sites ........................................................123
Table 7-8
Pharmacokinetic blood collection log for remaining patients, 
including patients in Cohort 6 and Cohort 7 .......................................124
126
Table 10-1
Noncompartmental pharmacokinetic parameters................................142
Table 10-2
Probability of Success at the Final Analysis Based on Various 
Number of Responders Observed at IA for Sub-cohort 1a, Sub-
cohort 1b, Cohort 2 and Cohort 4........................................................146
Table 10-3
Number of Responders for Various Number of Evaluable Patients 
at Interim Analyses by Required Probability of Success for Sub-
cohort 1a, Sub-cohort 1b, Cohort 2 and Cohort 4...............................146
Table 10-4
Probability of Success at the Final Analysis Based on Various 
Number of Responders Observed at IA for Cohort 3 .........................147
Table 10-5
Exact Binomial 95 percent Confidence Intervals for Various 
Sample Sizes and Observed ORRs in each Cohort/Sub-cohort 1a, 
1b, 2, 3 and 4.......................................................................................148
Table 10-6
Exact Binomial 95 percent Confidence Intervals for Various 
Sample Sizes and Observed ORRs in each Sub-cohort 5a, 5b and 
Cohort 7...............................................................................................148
Table 10-7
Operating Characteristics for Sub-cohort 1a, Sub-cohort 1b, Cohort 
2 and Cohort 4.....................................................................................148
Table 10-8
Operating Characteristics for Cohort 3 ...............................................149
Table 10-9
Operating Characteristics for Sub-cohort 5a, 5b and Cohort 7...........149
Table 14-1
Response criteria for target lesions .....................................................167
Table 14-2
Response criteria for non-target lesions..............................................169
Table 14-3
Overall lesion response at each assessment ........................................170
Table 14-4
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................177
Table 14-5
Options for event dates used in PFS, TTP, duration of response........178


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List of abbreviations
ADME
Absorption Distribution Metabolism Excretion
AE
Adverse Event
ALKP
Alkaline Phosphatase
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
Area under the curve
AUCinf
Area under the plasma concentration versus time curve from time zero to infinity
BID
bis in diem / twice a day
BLRM
Bayesian Logistic Regression Model
BIRC
Blinded Independent Review Committee
BOR
Best Overall Response
BSC
Best Supportive Care
CxDx
Cycle x Day x
CDx
Companion Diagnostics
CEP7
Centromere of chromosome 7
Cmax
Maximum (peak) concentration of drug
CI
Confidence Interval
CNS
Central Nervous System
CR
Complete Response
CRF/ eCRF
Case Report/Record Form/ electronic Case Report/Record Form
CRO
Contract Research Organization
CSR
Clinical Study Report
CSR addendum
An addendum to Clinical Study Report (CSR) that captures all the additional information that 
is not included in the CSR
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of Variation
CYP
Cytochrome P450 isoenzyme
DCR
Disease Control Rate
DILI
Drug Induced Liver Injury
DOR
Duration of Response
DLT
Dose Limiting Toxicity
DS&E
Drug Safety and Epidemiology
ECG
Electrocardiogram
EGFR
Epidermal Growth Factor Receptor
EOT
End of Treatment
EU
European Union
FAS
Full Analysis Set
FDG-PET
FluoroDeoxyGlucose Positron Emission Tomography
FISH
Fluorescence In Situ Hybridization
FFPE
Formalin Fixed Paraffin Embedded
GCN
Gene Copy Number
Hgb
Hemoglobin
IB
Investigator Brochure
i.v.
intravenous(ly)


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IC50
Half maximal inhibitory concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
ILD
Interstitial Lung Disease
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
NGS
Next Generation Sequencing
NOAEL
No-observed-adverse-effect level
NSCLC
Non-Small Cell Lung Cancer
NTI
Narrow therapeutic index
o.d./QD
omnia die / quaque die / once a day
ORR
Overall response rate
OS
Overall Survival
PD
Progressive Disease
POS
Probability of Success
PFS
Progression Free Survival
p.o.
per os / by mouth / orally
PHI
Protected Health Information
PK
Pharmacokinetics
PPI
Proton Pump Inhibitor
PR
Partial Response
PS
Performance Status
QT interval
A measure of the time between the start of the Q wave and the end of the T wave in the 
heart's electric cycle
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Friderica’s correction
RT-PCR
Reverse Transcription Polymerase Chain Reaction
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses
REB
Research Ethics Board
RECIST
Response Evaluation Criteria In Solid Tumors
RoW
Rest of the World
RP2D
Recommended phase two dose
SAE
Serious Adverse Event
SD
Stable Disease
SDH
Sorbitol Dehydrogenase
SOP
Standard Operating Procedure
TBIL
Total Bilirubin
TKI
Tyrosine Kinase Inhibitor
Tmax
Time of occurrence for maximum (peak) drug concentration
TTP
Time to Progression
TTR
Time to Response
ULN
Upper Limit of Normal
US
United States
wt
Wild-type


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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 or study patient
Control drug
A study treatment used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug
Cohort
A group of newly enrolled patients treated at a specific dose and regimen (i.e.,
treatment group) at the same time
Cycles
Number and timing or recommended repetitions of therapy are usually expressed as
number of days (e.g.,: q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment
Point/time of patient entry into the study; the point at which informed consent must be 
obtained (i.e., prior to starting any of the procedures described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with “investigational 
new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes approved 
drugs used outside of their indication/approved dosage, or that are tested in a fixed 
combination. Investigational treatment generally does not include other study 
treatments administered as concomitant background therapy required or allowed by 
the protocol when used in within approved indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is linked to 
one of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study procedures that 
was not included in the investigational treatment
Subject Number (Subject 
No.)
A unique identifying number assigned to each patient/subject/healthy volunteer who 
enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller functional segments 
such as screening, baseline, titration, washout, etc.
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.
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides 
evidence of preplanned analyses
Randomization number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Stage related to study 
timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of the tumor, 
whether lymph nodes contain cancer, and whether the cancer has spread from the 
original site to other parts of the body
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins.
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this case 
refers to the investigational and non-investigational treatments in combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for any reason


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Supportive treatment
Refers to any treatment required by the exposure to a study treatment, e.g., 
premedication of vitamin supplementation and corticosteroid for pemetrexed 
disodium.
Variable
Identifier used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified timepoints
Withdrawal of consent
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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Protocol No. CINC280A2201

Updated to reflect addition of new Cohort 7
Section 5.1 Patient population

Updated to reflect the addition of Cohort 7 treatment-naïve patients with cMET mutations
regardless of cMET GCN
Section 5.2 Inclusion criteria

Updated Criterion #3 to reflect the inclusion of treatment-naïve patients with cMET 
mutations regardless of cMET GCN in Cohort 7

Fixed a topographical error introduced with Protocol Amendment 5 which leads to 
renumbering of Inclusion Criteria
Section 6.1.1 Dosing regimen

Updated to reflect that similarly to Cohort 6, there will be no food restriction for patients 
enrolled in Cohort 7
Section 6.4 Concomitant medications

Updated presentation of concomitant medications to be listed in only one table with the 
most stringent practice of use  
Section 6.4.2 Permitted concomitant therapy requiring caution and/or action

Updated to reflect latest PK data on studies CINC280A2108 based on final analysis

Table 6-5 updated to reflect general change on concomitant medications listed in only one 
table with the most stringent practice
Section 6.4.2 Prohibited concomitant therapy 

Table 6-6 updated to remove note and align with general change on concomitant 
medications use

Table 6-7 updated to remove note and align with general change on concomitant 
medications use
Section 6.5.2 Treatment assignment

Updated to reflect new Cohort 7 with inclusion of treatment-naïve patients with cMET 
mutations regardless of cMET GCN
Table 7-1 Visit Evaluation Schedule

Updated tumor biopsy requirement at pre-screening

Updated to correct the missing collection of diagnosis and extent of cancer at molecular 
pre-screening
 
Section 7.1.1.1 Tumor sample requirement

Updated to reflect use of tumor biopsy for amplification and/or mutation status

Updated to include a possible request of additional tumor tissue retrospectively, if 
available, for development of future NGS companion diagnostic




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
Updated to clarify PFS definition and censoring

Updated to add that Cohort 7 may also be combined with Sub-cohort 5b 
Section 10.5.5.1 Outline of the data analysis

Updated to remove IHC assessments and related analysis
Section 10.5.5.3.2 Basic tables, figures and listings

Updated to remove IHC assessments and related analysis
Section 10.7 Interim Analysis

Updated to clarify that no interim analysis “for futility” is planned for Sub-cohorts 5a and 
5b, Cohort 6 and 7
Section 10.8 Sample size calculation

Updated to reflect increase in overall patient sample size from 429 to 456 based on new 
Cohort 7 and add number of patients in Cohort 7

Updated Table 10-9 to add Operating Characteristics for Cohort 7

Updated wording to include the utility of Cohort 6
Section 13 References 

Updated for new references used in updated sections
Additional revisions including editorial changes were made throughout the protocol.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Boards
(IRBs)/Independent Ethics Committees (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 5 (13-Feb-2018)
Amendment rationale
As of 09-Feb-2018, a total of 269 patients have been enrolled in the study [54/69 patients in 
Sub-cohort 1a [cMET gene copy number (GCN) ≥10]; 42/69 patients in Sub-cohort 1b 
(cMET GCN ≥ 6 and < 10); 54/69 patients in Cohort 2 (cMET GCN ≥ 4 and < 6); 30/69
patients in Cohort 3 (cMET GCN < 4); 64/69 patients in Cohort 4 (cMET mutations 
regardless of cMET GCN); 6/27 patients in Sub-cohort 5a (treatment naïve and cMET 
GCN≥10); and 19/27 patients in Sub-cohort 5b (treatment naïve and cMET mutations 
regardless of cMET GCN)].
Cohort 3 (as of 31-Aug-2016) and Sub-cohort 1b/Cohort 2 (as of 17-Nov-2016) have been 
closed due to futility based on the planned interim analyses as outlined in the protocol. 
As of 05-Dec-2017 Sub-cohort 1a and Cohort 4 have successfully passed the planned interim 
analysis for futility and enrollment is continuing as planned. 
The main purpose of this amendment is:
1. To update the exclusion criteria, the list of prohibited medications, the list of medications 
to be used with caution and the criteria for dose modifications based on the latest INC280 
clinical data as per [Investigator’s Brochure edition 9] with primary focus on:

Pneumonitis/ILD events that have been reported with INC280 monotherapy

Results from the Clinical Pharmacology Drug-Drug-Interaction studies 
[CINC280A2102], [CINC280A2103] and [CINC280A2105]
2. To introduce a new expansion Cohort 6 for enrollment of approximately additional 30
patients with advanced NSCLC pretreated with one prior line of systemic therapy
harboring either cMET amplification (GCN≥10) or cMET mutations (irrespective of 
cMET GCN). The aim is to generate supportive safety and efficacy data in this second line 
patient population, which currently accounts for the majority of patients enrolled in the 
respective Sub-Cohort 1a and Cohort 4 and therefore Cohort 6 is considered representative 
of the overall eligible patient population of pretreated cMET high amplified and mutated 
NSCLC. 
In light of the food effect study [CINC280A2108] preliminary results, which showed no 
positive food effect of high fat meal on INC280 exposure, INC280 will be given to 
patients enrolled in Cohort 6 irrespective of the food intake. The enrollment in this new 
expansion cohort will only start upon enrollment completion of the respective Sub-cohort 
1a or Cohort 4.
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.
The following sections of the protocol were changed:
Protocol Summary: Updated to align with the amended protocol


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Section 1.2.1.1 Non-clinical experience

Updated “Nonclinical pharmacokinetics (PKs) and metabolism” and “Safety 
pharmacology and toxicology” with the most up to date information 
Section 1.2.1.2 Clinical experience

Updated “Clinical safety and tolerability”, “Clinical pharmacodynamics” and “Clinical 
pharmacokinetics” with the most up to date information following the release of 
[Investigator’s Brochure edition 9]
Section 2.2 Rationale for the study design

Updated to reflect the implementation of Cohort 6
Section 4.1 Description of study design

Updated the patient sample size to 429 from 399 and made changes to the description of 
the study design to reflect the inclusion of Cohort 6

Updated to include a clarification regarding the availability of EGFR and ALK status for 
treatment naïve patients potentially eligible for Sub-cohort 5a and 5b

Updated to include additional analyses planned due to the implementation of Cohort 6
Figure 4-1 Overall study Design

Updated to reflect the implementation of Cohort 6
Section 4.2 Timing of interim analyses and design adaptations

Clarified that no interim analysis will be performed for Cohort 6
Section 5.1 Patient population

Updated to reflect the implementation of Cohort 6 which is to enroll patients who have 
failed 1 prior line of systemic therapy for advanced/metastatic disease
Section 5.2 Inclusion Criteria

Inclusion Criterion #3 – Updated to reflect the implementation of Cohort 6 (inclusion of 
patients with either cMET GCN ≥ 10 without cMET mutation or cMET mutation 
regardless of cMET GCN). Also included a clarification regarding the availability of 
EGFR and ALK status for treatment naïve patients. 

Inclusion Criterion #4 – Clarified that to be eligible for Cohort 6, patients must have failed 
one prior line of systemic therapy for advanced/metastatic disease (stage IIIB or IV 
NSCLC).
Section 5.3 Exclusion Criteria 

Exclusion Criteria #11 – Updated to remove restriction for strong and moderate inhibitors 
of CYP3A4 based on the recent data from Clinical Pharmacology DDI studies.

Exclusion Criteria #16 – Updated to include Cohort 6

Exclusion Criteria #22 – Added a new eligibility criterion to exclude patients with 
presence or history of interstitial lung disease or interstitial pneumonitis, including 
clinically significant radiation pneumonitis (i.e., affecting activities of daily living or 
requiring therapeutic intervention).


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Section 6.1.1 Dosing regimen

Updated to allow administration of INC280 with or without food for patients enrolled in 
Cohort 6 only
Table 6-3 Criteria for interruption and re-initiation of INC280 treatment

Updated to mandate discontinuation of study drug treatment for some adverse events with 
specified severity

Updated to include a section for Respiratory Disorders with more specific guidance on 
management of Interstitial Lung Disease (ILD)/Pneumonitis
Table 6-4 Follow-up evaluations for selected toxicities

Updated to include a section on Respiratory Disorders with more specific guidance on 
follow up of ILD/Pneumonitis
Section 6.4 Concomitant medications

Updated to further stress out that for medications listed in more than one table the more 
stringent practice is to be applied (that is, the medication is prohibited). Drugs that appear 
in more than one table are underlined and bolded.
Section 6.4.2 Permitted concomitant therapy requiring caution and/or action

Updated  permitted concomitant therapy based on most recent data

Table 6-5  Drugs to be used with caution while on study - Updated the list of drugs based 
on most recent data
Section 6.4.3 Prohibited concomitant therapy

Updated section based on most recent data

Table 6-6 Drugs prohibited while on study  - Updated the list of drugs based on most 
recent data

Table 6-7 Drugs with a known risk of Torsades des Pointes - Updated the list of drugs 
based on most recent data
Section 6.5.2 Treatment assignment

Updated to reflect the addition of Cohort 6
Section 7.1.2 Screening

Updated to clarify re-testing and re-screening 
Table 7-6 ECG collection plan for remaining patients, including patients in Cohort 6

Updated to include Cohort 6
Table 7-8 Pharmacokinetic blood collection log for remaining patients, including patients in 
Cohort 6

Updated to include Cohort 6


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Section 8.1.3 Adverse events of special interest

Updated to include adverse events of special interest to be monitored in alignment with 
the recently released [Investigator’s Brochure edition 9]
Section 10 Statistical methods and data analysis

Updated to reflect the inclusion of Cohort 6

Clarified that no interim analysis is planned for Cohort 6
Section 10.4.2 Statistical hypothesis, model, and method of analysis

Provided clarification regarding the null hypothesis rejection
Section 10.4.4 Supportive analyses

Updated to reflect the additional analysis as result of inclusion of Cohort 6
Section 10.5.2 Other secondary efficacy objectives

Updated to reflect the additional analysis as result of inclusion of Cohort 6
Section 10.8 Sample size calculation 

Updated the patient sample size to 429 from 399 to reflect the  inclusion of Cohort 6 

Updated to include Cohort 6 samples size
Section 13 References

Updated the reference list
Additional revisions including editorial changes were made throughout the protocol.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 4 (17-Nov-2016)
Amendment rationale
As of 15-Nov-2016, a total of 157 patients have been enrolled in the study [19 patients in 
Cohort 1a (GCN≥10); 42 patients in Cohort 1b (GCN ≥ 6 and < 10); 54 patients in Cohort 2
(GCN ≥ 4 and < 6); 30 patients in Cohort 3 (GCN < 4); and 12 patients in Cohort 4 (cMET 
exon 14 skipping mutated)].
As of 30-Aug-2016, Cohort 3 has been suspended due to futility based on the planned interim 
analyses as outlined in the protocol. No new safety signal for INC280 has been observed.
The main purpose of this amendment is to implement a new Cohort 5 to investigate the safety 
and antitumor activity of INC280 in treatment-naïve patients for advanced/metastatic disease 
(stage IIIB or IV) NSCLC harboring cMET exon 14 skipping mutations (regardless of cMET 
amplification) or very high cMET gene amplification (GCN ≥ 10 without cMET mutations).
Increasing data confirm that cMET dysregulations such as cMET exon 14 skipping mutations
and high cMET amplification are emerging as independent molecular drivers and predictors
of response to cMET inhibition in NSCLC patients, irrespective of the number of prior lines 
of therapy including some preliminary evidence in the treatment-naïve setting (Frampton 
2015, Jenkins 2015, Mendenhall 2015, Paik 2015, Waqar 2015, Liu 2015, Schuler 2016, 
Drilon 2016).
Promising activity with INC280 in cMET dysregulated (either cMET amplified or cMET 
exon 14 skipping mutated) advanced NSCLC has been observed in the phase I study 
[CINC280X2102] (Schuler 2016). In patients with cMET amplified (GCN ≥6) NSCLC, a 
47% Overall Response Rate (ORR) and a median Progression Free Survival (PFS) of 7.4 
months were reported.
While these promising results were obtained mainly in pretreated patients, three patients (who 
declined chemotherapy) were enrolled as treatment-naïve. Two of these patients harbored 
cMET exon 14 skipping mutation (one had concurrent cMET amplification). Both patients 
gained benefit from INC280 treatment (tumor shrinkage -53.3% and -48.5%), one achieving 
confirmed response. This result was consistent with the overall benefit gained by the other 
two cMET mutated patients enrolled in the study (pretreated with 1 and 3 prior lines of 
systemic therapy, respectively) with 3 out of 4 in cMET mutated patients achieved confirmed 
partial responses. Overall, INC280 was well tolerated in both treatment-naïve and pretreated 
NSCLC patients.
Additional preliminary activity in NSCLC patients harboring cMET mutations, including in 
the treatment-naïve setting, has been reported with another cMET inhibitor (crizotinib). 
Overall 21 cMET mutated patients have been treated and 8 out of 18 evaluable patients (44%) 
achieved a confirmed partial response, including at least 1 of the 3 treatment-naïve patients 
enrolled (Drilon 2016).
While the data are still preliminary, cMET exon 14 skipping mutations and/or high cMET 
gene amplification are emerging as independent tumor drivers. Patients harboring such cMET 
dysregulations can benefit from treatment with cMET inhibitors such as INC280, irrespective 


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of prior lines of therapy, and including treatment-naïve patients, with acceptable safety profile. 
This concept was successfully confirmed in the treatment-naïve advanced NSCLC setting 
with other targeted agents directed against established molecular drivers such as EGFR 
mutation, ALK and ROS1 translocation, which demonstrated greater efficacy when compared 
with platinum-doublet chemotherapy (Rosell 2012, Sequist 2013, Solomon 2014). These data 
also confirmed that the safety profile of such targeted agents does not differ in the treatment-
naïve setting compared to the pretreated setting.
There is no cMET inhibitor currently approved for cMET dysregulated NSCLC and the 
activity of platinum-based chemotherapy in patients with treatment-naïve advanced NSCLC 
harboring cMET exon 14 skipping mutations and/or high level of cMET amplification (GCN 
≥10) is unknown.
In the current [CINC280A2201] study design, NSCLC patients with very high cMET 
amplification (GCN ≥ 10) or cMET exon 14 skipping mutations (regardless of GCN) are 
eligible for enrollment in Cohort 1 (Sub-cohort 1a) and Cohort 4 (respectively), only if 
previously treated with 1 or 2 prior lines of systemic therapies. Therefore, to ensure a proper 
assessment and adequate representation of treatment-naïve NSCLC patients in advanced 
setting harboring very high cMET amplification (GCN ≥10) and/or cMET mutation, an 
additional cohort (Cohort 5) is being implemented as follows:
Cohort 5: Treatment-naïve patients with cMET dysregulation 

Sub-cohort 5a: Patients with a cMET GCN ≥10 (without cMET mutations)

Sub-cohort 5b: Patients with cMET mutations regardless of cMET GCN
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.
The following sections of the protocol were changed:
Protocol Title: updated to reflect the new study design
Protocol Summary: Updated to align with the amended protocol
Section 2.2 Rationale for the study design

Updated to include rationale for changes in study design: the implementation of Cohort 5 
for inclusion of patients who are treatment-naïve for advanced/metastatic disease in 2 Sub-
cohorts (5a - patients with cMET GCN of ≥10, 5b - patients with cMET mutations 
regardless of cMET GCN)
Table 3-1 Objectives and related endpoints

Updated Other secondary objective #4 to align with the inclusion of treatment-naïve 
patients
Section 4.1 Description of study design

Updated the patient sample size to 399 from 345 and made changes to the description of 
the study design to reflect the inclusion of treatment-naïve patients for 
advanced/metastatic disease in Cohort 5 with the 2 Sub-cohorts (5a - patients with cMET 
GCN of ≥10 and 5b - patients with cMET mutations regardless of cMET GCN)


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
Updated to include an option for central pre-screening by NGS, if assay becomes available 

Updated to clarify that EGFR wt must be documented in the patient source documents 
before patient can be consented for molecular pre-screening, except if performed by NGS
at central laboratory and local status is not available

Updated to clarify that patients with previously determined cMET mutation or 
amplification by a Novartis designated central laboratory (as detected by a validated NGS 
assay), will be allowed to enter the screening phase of the INC280A2201 study

Added that all efficacy analyses for Cohort 5 will also be performed separately for each of 
the 2 Sub-cohorts, similar to Cohort 1

Added that no interim analysis will be performed for Cohort 5

Simplified language on when primary analysis will be performed

Updated to include the ORR that will be considered sufficiently efficacious in treatment-
naïve setting (Cohort 5) and included 2 hypotheses testing for Sub-cohorts 5a and 5b
Figure 4-1 Overall study Design

Updated to reflect the implementation of Cohort 5 with Sub-cohorts 5a and 5b
Section 4.2 Timing of interim analyses and design adaptation

Clarified that no interim analysis will be performed for Cohort 5
Section 5.1 Patient Population

Clarified that for eligibility in Cohort 5, patients should not have received systemic 
therapy for advanced/metastatic disease
Section 5.2 Inclusion Criteria

Inclusion Criterion #3 – Updated to reflect the implementation of Cohort 5 to allow 
inclusion of treatment-naïve patients for advanced/metastatic disease as 2 Sub-cohorts (5a 
- patients with cMET GCN of ≥10, 5b - patients with cMET mutations regardless of 
cMET GCN). Updated to clarify that EGFR wt must be documented in the patient source 
documents before patient can be consented for molecular pre-screening, except if 
performed by NGS and local status is not available

Inclusion Criterion #4 – Updated to include criteria for eligibility of the treatment-naïve 
patients for advanced/metastatic disease

Exclusion Criterion #16 – update to clarify that this criterion will apply only for patients in
Cohorts 1-4
Section 6.5.2 Treatment assignment

Updated to reflect the implementation of Cohort 5 for treatment-naïve patients for 
advanced/metastatic disease as 2 Sub-cohorts (5a - patients with cMET GCN of ≥10, 5b -
patients with cMET mutations regardless of cMET GCN)
Table 7-1 Visit evaluation schedule

Updated to clarify that information on prior local testing for cMET amplification and 
cMET mutation may include prior central NGS results, if applicable




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Section 13 References

Updated the reference list
Additional revisions including editorial changes were made throughout the protocol.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 3 (28-Jul-2016)
Amendment rationale
As of 20-Jul-2016, a total of 148 patients have been enrolled in the study.
The main purpose of this amendment is to:

Further investigate and better characterize the optimal GCN as predictor of response to 
INC280 by implementing two sub-cohorts within the high cMET amplified Cohort 1 
[gene copy number (GCN) ≥ 6]

Remove the restrictions on the use of proton pump inhibitors (PPIs) as concomitant 
medications
Changes to implement two sub-cohorts within the high cMET amplified Cohort 1
Emerging data from the ongoing phase I study [CINC280X2102] firmly supports that there is 
activity of single agent INC280 in cMET dysregulated NSCLC, especially in NSCLC patients 
with high cMET amplification and cMET exon 14 skipping mutations (Schuler 2016).
In the 15 patients with cMET GCN ≥6, who had at least one post baseline tumor assessment 
or who had discontinued study treatment early, confirmed partial responses were seen in 7/15 
patients [Overall Response Rate (ORR) 47%, Disease Control Rate (DCR) 80% and Kaplan–
Meier median Progression Free Survival (PFS) 7.39 months (95% CI 3.84–22.11)]. Three out 
of these 7 confirmed responders per local assessment had very high cMET gene amplification 
(GCN ≥10); however, 2 of these responders also harboured a concurrent cMET exon 14 
skipping mutation. Therefore, based on this data generated from the [CINC280X2102] study, 
the single contribution of the very high cMET amplification to the response of INC280 still 
remains to be elucidated and further optimization of appropriate GCN cut off is warranted.
Currently in the CINC280A2201 study, patients with high cMET amplified NSCLC defined 
as GCN ≥ 6 are being enrolled in Cohort 1, while NSCLC patients harboring cMET exon 14 
skipping mutations (irrespective of the level of cMET amplification) are enrolled in Cohort 4. 
While detailed epidemiology data are still lacking, the prevalence of cMET amplification in 
NSCLC is known to diminish with the increase in GCN (Schildhaus 2014). With the 
emerging data, the assumption that patients with higher GCN may derive greater benefit from 
cMET inhibition with higher chance of response to treatment require further more robust 
exploration. To ensure an adequate representation and proper assessment of NSCLC patients 
with very high amplified disease and to avoid the uneven enrichment in the lower GCN range 
of this cohort, the following 2 sub-cohorts are being implemented within Cohort 1:
Cohort 1: Patients with a cMET GCN of ≥ 6

Sub-cohort 1a: Patients with a cMET GCN of ≥ 10, or

Sub-cohort 1b: Patients with a cMET GCN of ≥ 6 and <10
Each of the two sub-cohorts will be tested independently. This change will allow to 
adequately assess the individual contribution of the two GCN ranges to the activity of INC280 
in Cohort 1 patients and to assess the likelihood of differential response at the high amplified 
range as previously suggested by Camidge (2014).


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The category of GCN ≥ 10 has been recently used to identify the cMET amplified cases in the 
most extensive analysis ever conducted in 11,205 lung cancer specimens (Ou 2016). 
Interestingly, in this study the overlap of amplification with cMET exon 14 skipping mutation, 
which is still a matter of debate, was lower at the GCN ≥ 10 range compared with the one 
observed at the lower GCN cut offs (Awad 2016, Tong 2016). Similarly, very high cMET 
amplified tumor samples are expected to be mutually exclusive to RTK/RAS/PI3K driver 
events (Tong 2016).
Removing restrictions on the concomitant use of proton pump inhibitors (PPIs)
Current clinical data supports the concomitant administration of INC280 with PPIs. 
INC280 is known to exhibit a pH-dependent solubility profile with a low solubility at high pH 
levels (Section 3.1 in the current INC280 Investigator’s Brochure). A study to evaluate the 
effect of a proton pump inhibitor on the PK of a single dose of INC280 tablet (600 mg) was 
completed in healthy volunteers [CINC280A2101]. Daily treatment of 20 mg rabeprazole for 
4 days resulted in a modest reduction in the extent of INC280 absorption with a 25.2% 
decrease in AUCinf and a 37.5% decrease in Cmax. Considering the 42% and 65% variability 
in AUC observed in patients treated in single agent studies [CINC280X2102] and 
[CINC280X1101], respectively, a decrease of approximately 25% in AUC of INC280 when 
administered with a proton pump inhibitor (PPI) is not considered clinically significant. 
Preliminary data in NSCLC patients [CINC280X2202] indicated that maintaining plasma 
trough concentrations above certain threshold over time was required for efficacy. In the 
proton pump inhibitor DDI study, the impact on the 12-hour post-dose concentration of 
INC280 (defined as trough concentration for BID dosing) was minimal with only a ~7% 
reduction after rabeprazole treatment. Therefore, the concomitant use of PPIs is unlikely to 
have an impact on the efficacy of INC280, and the PPI restriction as a concomitant 
medication can be removed from this protocol for patients requiring PPI gastric protection 
treatment. 
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The following sections of the protocol were changed:
List of abbreviations: Updated to align with the amended protocol
Protocol Summary: Updated to align with the amended protocol
Section 1.2.1.1.2 Nonclinical Pharmacokinetics (PKs) and metabolism

Update to include the brain to blood ratio of approximately 0.1
Section 1.2.1.2.1: Clinical Safety and Tolerability

Updated to align with the current INC280 Investigator’s Brochure 
Section 1.2.1.2.2 Clinical Efficacy

Updated to align with most recent data as of 15-Mar-2016 from the INC280X2102 study
Section 1.2.1.2.4: Clinical Pharmacokinetics:


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
Updated with the most recent PK data available as of 28-Sep-2015

Updated with the most recent available clinical data from CINC280A2101 detailing the 
effect of PPIs on the PK of a single dose of INC280 

Updated with the most recent available clinical data from CINC280X2107 detailing the 
food effect on the rate and extent of INC280 exposure. 
Section 2.2. Rational for the study design

Updated to include rationale for the changes in study design: the implementation of 2 sub-
cohorts within Cohort 1 (1a - cMET GCN ≥ 10, 1b - cMET GCN ≥ 6 and < 10)
Table 3-1 Objectives and Endpoint

Updated objectives to include sub-cohorts (where applicable) 
Section 4.1 Description of Study Design

Updated the patient sample size to 345 patients from 276 patients and made changes to the 
description of the study design to reflect the implementation of Sub-cohorts 1a and 1b 
within Cohort 1

Clarified that separate efficacy analyses for Sub-cohort 1a and 1b will be performed

Clarified that the primary analysis for any cohort that was stopped for futility may be 
combined with the primary analyses for other cohorts that were not stopped for futility

Updated hypothesis testing to 5 from 4 to reflect the implementation of Sub-cohorts 1a 
and 1b within Cohort 1
Figure 4-1 Overall study Design

Updated to reflect the implementation of Sub-cohort 1a and 1b within Cohort 1
Section 4.2 Timing of interim analyses and design adaptations

Updated to reflect the implementation of Sub-cohort 1a and 1b within Cohort 1
Section 5.1 Patient Population

Clarified that for eligibility in Cohort 1-4, patients must have failed (versus received) one 
or two prior lines of systemic therapy
Section 5.2 Inclusion Criteria

Inclusion Criterion #3 – Updated to include Sub-cohort 1a and 1b within Cohort 1

Inclusion Criterion #4 – clarified that patients must have failed (versus received) 1 or 2 
lines of prior therapy and added “Treatment failure is defined as documented disease 
progression or intolerance to treatment”

Inclusion Criterion #7 –corrected the conversion of glucose 175mg/mL from 9.8mmol/L 
to 9.7mmol/L.
Section 5.3 Exclusion Criteria

Exclusion Criterion #7 – removed the exception that was allowing patients enrollment 
with indolent malignancies that currently do not require treatment

Exclusion Criteria #11 – removed proton pump inhibitors (PPI) from the list of prohibitive 
medications






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Amendment 2
Amendment rationale
As of 21-Aug-2015, a total of 5 patients have been enrolled in the study with first patient 
treated on 16-Jul-2015. 
The main purpose of this amendment is to implement a fourth cohort (Cohort 4) to the study 
design in light of the emerging data showing that NSCLC patients harboring cMET mutations 
can benefit from the treatment with cMET inhibitors. Moreover the amendment will also 
provide an update on INC280 safety data aligning with the most current edition of the 
Investigator’s Brochure. 
Changes to the study design
Since the release of the last Amendment 1, cMET mutations leading to exon 14 deletion 
[referred to as cMET mutation(s) hereafter] have been identified as an additional actionable 
target for cMET inhibition in NSCLC and promising preliminary efficacy data have been 
published with cMET inhibitors, including INC280, in this setting (Paik 2015, Jenkins 2015, 
Waqar 2015, Mendenhall 2015, Frampton 2015, Liu 2015). With this Amendment 2, Cohort 4 
is added to the study design to allow patients with cMET mutations to be enrolled in the study. 
Prior to enrollment, the cMET mutation status of all patients must be determined at a 
Novartis-designated central laboratory along with their cMET amplification status. Patients 
with cMET mutations will be enrolled in Cohort 4, irrespective of their cMET amplification 
status, while patients without cMET mutations will be enrolled in Cohorts 1-3 based on their 
cMET amplification status. For patients already enrolled in the study prior to the 
implementation of this amendment, the cMET mutation status will be determined 
retrospectively; however these patients will remain in the cohort to which they were initially 
enrolled. Sensitivity analysis on the primary endpoint where patients with cMET mutations 
will be excluded from Cohorts 1, 2 and 3 may also be performed.
Changes related to INC280 safety
Concurrent elevation of ALT and/or AST and total bilirubin: After 28-Sep-2014 (cut-off 
date of the current [Investigator’s Brochure, edition 5.2]), a 
 patient experienced a 
serious, unexpected, possibly related adverse event of abnormal liver function tests during 
treatment with a combination of INC280 and gefitinib while enrolled in the study 
[CINC280X2202]. The investigator assessed the adverse event suspected to be related to the 
combination of INC280 and gefitinib. This adverse event met the criteria of Hy’s Law and the 
hepatotoxicity could not be attributed solely to either drug alone or to the combination.
The protocol is therefore being amended to modify the existing dose modifications guidelines 
for hepatotoxicity in regard to discontinuing study medication(s) with concurrent elevation of 
ALT and/or AST > 3 × ULN and total bilirubin > 2 × ULN with ALP < 2 × ULN, in the 
absence of signs of cholestasis, hemolysis, and alternative causes of the liver injury [e.g., 
concomitant use of hepatotoxic drug(s), alcoholic hepatitis, etc.]. Specific work-up guidelines 
for potential Drug Induced Liver Injury (DILI) cases have also been added to the protocol. 
The dose modification rules as well as the follow-up evaluations for hepatic toxicities have 
also been updated accordingly.












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Amendment 1
Amendment rationale
As of the release date of this amendment, no patients have been screened or treated in this 
study.
This amendment has been implemented to indicate that assessment of ALK rearrangement 
determined with a validated test should be part of the non-squamous NSCLC patient’s 
standard of care, such as the EGFR mutation testing.
Therefore along with the EGFR molecular status, also the ALK rearrangement status should
be documented in the source document of all patients enrolled in this study. The inclusion 
criterion 3 has been amended to include ALK-negative rearrangement status and an exclusion 
criterion has been added to exclude patients with documented ALK-positive rearrangement 
status. If no ALK testing is available locally, the ALK rearrangement status must be 
determined at a Novartis-designated central laboratory.
Changes to the protocol
The following sections of the protocol were changed:
Protocol Summary Table, Section 2.2, Section 4.1, Section 5.1, Section 5.2, Section 5.3, 
Table 7-1, Section 7.1 and Section 7.2.
Section 2.2, updated to indicate that ALK-negative rearrangement patients should be enrolled 
and that crizotinib and ceritinib are approved in ALK-positive rearrangement NSCLC patients.
Section 2.3, updated to provide clarification on difference in exposure between tablet and 
capsule formulation in alignment with the IB.
Section 4.1, updated to indicate that ALK-negative rearrangement patients should be enrolled, 
ALK rearrangement status should be documented and if ALK testing is not available, the 
status will be determined centrally with a validated test along with their cMET amplification 
status.
Figure 4-1, updated to add that ALK-negative rearrangement patients will enter molecular 
pre-screening and that EGFR wt is for exon 19 deletions and exon 21 L858R substitution 
mutation.
Section 4.1.1, updated to indicate that if ALK testing is not available for a patient, the status 
will be determined centrally with a validated test along with their cMET amplification status.
Section 4.1.2, updated to indicate that the ALK rearrangement status will be determined 
centrally, as applicable.
Section 5.1, updated to indicate that patients with ALK-negative rearrangement should be 
enrolled.
Section 5.2, inclusion criterion 3 updated to include that patients with ALK-negative 
rearrangement should be enrolled and ALK rearrangement status should be documented and if 


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local ALK testing is not available, the status will be determined centrally with a validated test 
along with the cMET amplification status.
Section 5.3, exclusion criterion 4 added to indicate that patients with ALK-positive
rearrangement are excluded.
Table 7-1, updated to indicate that confirmation of ALK-negative rearrangement status is 
required at pre-screening and to clarify sample requirement for ALK testing, as applicable.
Section 7.1.1.1, tumor sample requirement added for ALK testing, as applicable.
Section 7.1.2.3, data collection updated to include that ALK rearrangement status will be 
collected.
Section 7.2.4.1, tumor sample requirement added for ALK testing, as applicable.
Table 7-9, updated to indicate sample requirement for ALK testing, as applicable.
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 underlined for insertions.
IRB
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
CINC280A2201
Title
A phase II, multicenter study of oral cMET inhibitor INC280 in adult patients with 
EGFR wild-type (wt), advanced non-small cell lung cancer (NSCLC) 
Brief title
Study of oral cMET inhibitor INC280 in patients with EGFR wild-type (wt), advanced 
non-small cell lung cancer (NSCLC)
Sponsor and Clinical 
Phase
Novartis, Phase II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
Currently, there is no approved therapy for tumors with cMET dysregulations 
(mutations/amplification/overexpression). INC280 is an orally bioavailable, highly 
potent and selective cMET inhibitor in biochemical and cellular assays and capable of 
blocking cMET activation. Pre-clinical and early clinical data showed single-agent 
antitumor activity with a manageable safety profile in NSCLC with cMET mutations 
and/or amplification and/or overexpression.
Primary Objective(s) 
and Key Secondary 
Objective
Primary objective: To demonstrate the antitumor activity of INC280, as measured by 
overall response rate (ORR) by Blinded Independent Review Committee (BIRC) 
assessment, by cohort/sub-cohort
Key secondary objective: To evaluate duration of response (DOR) as assessed by 
BIRC, by cohort/sub-cohort
Secondary Objectives
Objective 1: To evaluate ORR and DOR by investigator assessment, by cohort/sub-
cohort
Objective 2: To evaluate time to response (TTR), disease control rate (DCR) and 
progression-free survival (PFS) by investigator and by BIRC assessment, by 
cohort/sub-cohort
Objective 3: To evaluate overall survival (OS), by cohort/sub-cohort
Objective 4: To evaluate INC280 safety profile as monotherapy in NSCLC patients 
with advanced/metastatic disease
Objective 5: To characterize the pharmacokinetics of INC280 
Study design
This is a prospectively designed, multicenter, open-label, phase II study of single-
agent INC280. Patients with stage IIIB or IV EGFR wt (for exon 19 deletions and exon 
21 L858R substitution mutations) and ALK-negative rearrangement NSCLC will be 
pre-screened for cMET amplification and mutation status. Enrolled patients will be 
assigned to seven cohorts. All patients in Cohorts 1, 2, 3, and 4 must have failed 1 or 
2 prior lines of systemic therapy for advanced/metastatic disease. Patients enrolled in 
Cohort 5 and Cohort 7 must be treatment-naïve for advanced/metastatic disease.
Patients enrolled in Cohort 6 must have failed 1 prior line of systemic therapy for 
advanced/metastatic disease. Patients with cMET mutations will be enrolled in Cohort
4, Sub-cohort 5b, and Cohort 7 irrespective to their cMET GCN. Patients without 
cMET mutations will be enrolled in Cohorts 1-3 and Sub-cohort 5a, based on their 
cMET GCN. Cohort 6 will enroll patients with advanced NSCLC harboring either cMET 
amplification (GCN≥10) or cMET mutations (irrespective of cMET GCN). Patients will 
be eligible for enrollment in Cohort 6 only upon enrollment completion of the 
respective Sub-cohort 1a or Cohort 4.
Study cohort summary:
Cohort 1: Pre-treated patients with cMET gene copy number (GCN) ≥ 6, including:

Sub-cohort 1a: Patients with a cMET GCN ≥10, or

Sub-cohort 1b: Patients with a cMET GCN ≥ 6 and < 10, or
Cohort 2: Pre-treated patients with cMET GCN ≥4 and < 6, or
Cohort 3: Pre-treated patients with cMET GCN < 4, or
Cohort 4: Pre-treated patients with cMET mutations regardless of cMET GCN, or
Cohort 5: Treatment-naïve patients with cMET dysregulation, including:

Sub-cohort 5a: Patients with a cMET GCN ≥10, or




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Association for the Study of Lung Cancer, and Association for Molecular 
Pathology (Lindeman et al 2013). The EGFR wild-type status (for exon 19 
deletions and exon 21 L858R substitution mutations) must be documented in 
the patient source documents before the patient can be consented for pre-
screening for cMET amplification and cMET mutation status (except for 
patients who are treatment-naïve potentially eligible for Sub-Cohorts 5a, 5b
and Cohort 7 or if molecular pre-screening will be performed by NGS and 
local status is not available). Patients with NSCLC of pure squamous cell 
histology can enter pre-screening without EGFR mutation testing or result;
however patients with pure squamous cell histology and are known to have 
EGFR mutations in exons 19 or 21 will be excluded,

AND ALK rearrangement negative. This should have been assessed as part 
of the patient standard of care by a validated test. The ALK rearrangement 
negative status must be documented in the patient source documents before 
the patient can be consented for pre-screening for cMET amplification, 
except for patients who are treatment-naïve potentially eligible for Sub-
Cohorts 5a, 5b and Cohort 7; if local ALK testing is not available, patient 
status will be determined centrally along with the cMET status. Patients with 
NSCLC of pure squamous cell histology can enter pre-screening without ALK 
testing or result, however patients with pure squamous cell histology that are 
known to have ALK rearrangement will be excluded.

AND (as determined by central assessment at a Novartis designated 
laboratory) either: 
Cohort 1: Pre-treated patients with cMET GCN ≥6, including: 
Sub-cohort 1a: Patients with cMET GCN ≥ 10, or
Sub-cohort 1b: Patients with cMET GCN ≥ 6 and < 10, or
Cohort 2: Pre-treated patients with cMET GCN ≥4 and < 6, or
Cohort 3: Pre-treated patients with cMET GCN < 4, or
Cohort 4: Pre-treated patients with cMET mutations regardless of cMET 
GCN, or
Cohort 5: Treatment-naïve patients with cMET dysregulation, including: 
Sub-cohort 5a: Patients with cMET GCN ≥ 10, or
Sub-cohort 5b: Patients with cMET mutations regardless of cMET 
GCN, or
Cohort 6: Pre-treated patients with either cMET GCN ≥ 10 without cMET 
mutations or cMET mutations regardless of cMET GCN
Cohort 7: Treatment-naïve patients with cMET mutations regardless of cMET 
GCN
cMET (and ALK, if applicable) testing may be performed while patient is still 
receiving anti-cancer therapy. However, the patient can only be screened for the 
main study once the patient has discontinued the last prior systemic treatment 
due to either disease progression or intolerance.

To be eligible for Cohorts 1-4, patients must have failed one or two prior lines of 
systemic therapy for advanced/metastatic disease (stage IIIB or IV NSCLC). To 
be eligible for Cohort 6, patients must have failed one prior line of systemic 
therapy for advanced/metastatic disease (stage IIIB or IV NSCLC).
Treatment 
failure is defined as documented disease progression or intolerance to treatment.
Maintenance therapy given after 1st line chemotherapy will be considered as part 
of the 1st line if given to patients with documented response or stable disease 
before starting the maintenance therapy. Neo-adjuvant and adjuvant systemic 
therapies will count as one prior line of treatment if relapse occurred within 12 
months from the end of the neo-adjuvant or adjuvant systemic therapy.
To be eligible for Cohort 5 and Cohort 7, patients must not have received any 
systemic therapy for advanced/metastatic disease (stage IIIB or IV NSCLC). Neo-
adjuvant and adjuvant systemic therapies will not count as one prior line of 
treatment if relapse occurred > 12 months from the end of the neo-adjuvant or 
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
At least one measurable lesion as defined by RECIST 1.1. A previously irradiated 
site lesion may only be counted as a target lesion if there is clear sign of 
progression since the irradiation.

Patients must have recovered from all toxicities related to prior anticancer 
therapies to grade ≤ 1 (CTCAE v 4.03). Patients with any grade of alopecia are 
allowed to enter the study.

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) ≥45 mL/min

Total bilirubin ≤1.5 x ULN

Aspartate transaminase (AST) ≤3 x ULN, except for patients with liver 
metastasis, who may only be included if AST ≤5 x ULN

Alanine transaminase (ALT) ≤3 x ULN, except for patients with liver 
metastasis, who may only be included if ALT ≤5 x ULN

Alkaline phosphatase (ALP) ≤ 5 x ULN

Asymptomatic serum amylase ≤ grade 2. Patients with grade 1 or grade 2 
serum amylase at the beginning of the study must be confirmed to have no 
signs and/or symptoms suggesting pancreatitis or pancreatic injury (e.g.,
elevated P-amylase, abnormal imaging findings of pancreas, etc.)

Serum lipase ≤ULN

Fasting plasma glucose ≤ 175 mg/dL (≤ 9.7 mmol/L)

Patients must have the following laboratory values within the laboratory 
normal limits or corrected to within normal limits with supplements during 
screening:

Potassium

Magnesium 

Phosphorus 

Total calcium (corrected for serum albumin) 

ECOG performance status (PS) of 0 or 1

Willing and able to comply with scheduled visits, treatment plan and laboratory 
tests
Exclusion criteria

Prior treatment with crizotinib, or any other cMET or HGF inhibitor

Patients with known hypersensitivity to any of the excipients of INC280
(crospovidone, mannitol, microcrystalline cellulose, povidone, sodium lauryl 
sulfate, magnesium stearate, colloidal silicon dioxide, and various coating 
premixes)

Patients with characterized EGFR mutations that predict sensitivity to EGFR 
therapy, including, but not limited to exon 19 deletions and exon 21 mutations

Patients with characterized ALK-positive rearrangement

Patients with symptomatic central nervous system (CNS) metastases who are 
neurologically unstable or have required increasing doses of steroids within the 2 
weeks prior to study entry to manage CNS symptoms

Presence or history of carcinomatous meningitis

Presence or history of a malignant disease other than NSCLC that has been 
diagnosed and/or required therapy within the past 3 years. Exceptions to this 
exclusion include the following: completely resected basal cell and squamous cell 
skin cancers, and completely resected carcinoma in situ of any type

Clinically significant, uncontrolled heart diseases such as:

Unstable angina within 6 months prior to screening

Myocardial infarction within 6 months prior to screening


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
History of documented congestive heart failure (New York Heart Association 
functional classification III-IV)

Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 
mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without 
antihypertensive medication. Initiation or adjustment of antihypertensive 
medication (s) is allowed prior to screening

Ventricular arrhythmias

Supraventricular and nodal arrhythmias not controlled with medication

Other cardiac arrhythmia not controlled with medication

QTcF ≥ 450 ms (male patients), ≥ 460 ms (female patients) on the screening 
ECG (as mean of triplicate ECG)

Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting INC280 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 INC280 or patients who have not 
recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone 
lesions ≤ 2 weeks prior to starting INC280 is allowed

Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks 
prior (2 weeks for resection of brain metastases) to starting INC280 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 be enrolled in the study ≥1 week after the procedure

Patients receiving treatment with medications that meet one of the following 
criteria and that cannot be discontinued at least 1 week prior to the start of 
treatment with INC280 and for the duration of the study:

Strong inducers of CYP3A4

Impairment of GI function or GI disease that may significantly alter the absorption 
of INC280 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or 
malabsorption syndrome)

Unable or unwilling to swallow tablets as per dosing schedule

Patients receiving unstable or increasing doses of corticosteroids. If patients are 
on corticosteroids for endocrine deficiencies or tumor-associated symptoms other 
than CNS related, dose must have been stabilized (or decreasing) for at least 5 
days before first dose of INC280

Patients receiving treatment with any enzyme-inducing anticonvulsant that cannot 
be discontinued at least 1 week before first dose of INC280, and for the duration 
of the study. Patients on non-enzyme-inducing anticonvulsants are eligible

Applicable to Cohorts 1-4 and Cohort 6 only: Previous anti-cancer and 
investigational agents within 4 weeks or ≤ 5 x half-life of the agent (whichever is 
longer) before first dose of INC280. If previous treatment is a monoclonal 
antibody, then the treatment must be discontinued at least 4 weeks before first 
dose of INC280. If previous treatment is an oral targeted agent, then the 
treatment must be discontinued at least 5 x half-life of the agent before the first 
dose of INC280

Other severe, acute, or chronic medical or psychotic conditions or laboratory 
abnormalities that in the opinion of the investigator may increase the risk 
associated with study participation, or that may interfere with the interpretation of 
study results

Any other condition that would, in the Investigator’s judgment, contraindicate 
patient’s participation in the clinical study due to safety concerns or compliance 
with clinical study procedures, e.g., infection (including active hepatitis B and C), 
inflammation, intestinal obstruction, unable to swallow medication, social/ 
psychological issues, etc.

Pregnant or nursing (lactating) women

Women of child-bearing potential, defined as all women physiologically capable of 
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Data Analysis to Address Other Objectives:
ORR will be analyzed per investigator assessment by cohort/sub-cohort. 
Other secondary efficacy assessments (DOR, TTR, DCR, PFS) will be analyzed as 
per investigator assessment and as per BIRC by cohort/sub-cohort. Confirmation of 
response is required for all response endpoints, as per RECIST 1.1.
DOR, PFS and OS will be described by cohort using Kaplan-Meier methods, including 
estimated median (in months) with 95% CI, 25th and 75th percentiles and Kaplan-
Meier estimated probabilities with corresponding 95% CIs at several time points. 
The assessment of safety will be based mainly on the frequency of adverse events 
and on the number of laboratory values that fall outside of pre-determined ranges. 
Other safety data (e.g., electrocardiogram, vital signs) will be considered as 
appropriate. The safety summary tables will include only assessments collected no 
later than 30 days after study treatment discontinuation.
Interim analysis for futility assessment:
In Cohort 1, the interim analysis will be performed separately for each of the two sub-
cohorts. 
Interim analyses for each cohort/sub-cohort are planned when at least 28 patients in 
each of Sub-cohort 1a, Sub-cohort 1b, Cohort 2 and Cohort 4 and 20 patients in 
Cohort 3 have completed at least 6 cycles of treatment (18 weeks) or have 
discontinued treatment earlier. The decision to stop for futility for the respective 
cohort/sub-cohort at interim will be based on the probability of success (POS) at the 
end of the study. POS is the probability of a positive conclusion of the study if the 
study continued beyond interim, (i.e., until the final analysis), given the interim 
observed data. The respective cohort/sub-cohort will be stopped for futility at the 
interim analysis if the respective POS is less than 10%. All evaluable patients at the 
time of the data cut-off for the interim analysis will be used to obtain the futility 
boundary using the POS criteria. The interim analysis will be performed by cohort/sub-
cohort in which the patients are enrolled. In addition, for Sub-cohorts 1a and 1b, and 
Cohort 2 and Cohort 3, sensitivity analysis on the primary endpoint may be performed 
excluding patients with cMET mutations.
Sub-cohort 1a, Sub-cohort 1b, Cohort 2 and Cohort 4
With 28 evaluable patients for interim analysis in each of the Sub-cohorts 1a and 1b, 
and Cohorts 2 and 4, if ≤ 7 responses are observed then the respective cohort/sub-
cohort will be stopped for futility. If at the time when the 28th patient is enrolled a 
minimum of 8 responders have not yet been observed, accrual in the cohort/sub-
cohort may be temporarily suspended until either the minimum number of 8 
responders is observed or results of the interim analysis allow the cohort/sub-cohort to 
continue.
Cohort 3 
With 20 evaluable patients for interim analysis in Cohort 3, if ≤ 5 responses are 
observed then the respective cohort will be stopped for futility. If at the time that the 
20th patient is enrolled a minimum of 6 responders have not yet been observed, 
accrual in the cohort may be temporarily suspended until either the minimum number 
of 6 responders are observed or results of the interim analysis allow that cohort to 
continue.
No interim analysis for futility is planned for Sub-cohorts 5a and 5b, Cohort 6 and 
Cohort 7.
Sample size:
Approximately 456 patients (69 patients per Cohort/Sub-cohort 1-4; 27 patients per 
Sub-cohort 5a and 5b; approximately 30 patients in Cohort 6, approximately 27
patients in Cohort 7) will be enrolled in the study if none of the cohorts/sub-cohorts is 
stopped for futility at the time of the interim analysis. For Cohort 2 (cMET GCN ≥4 and 
< 6), the study targets to have at least 40% of patients with cMET GCN ≥ 5 and < 6 at 
the time of the interim analysis, and if Cohort 2 continues to full enrollment, also at the 
final analysis.
With 28 evaluable patients in each of the Sub-cohorts 1a and 1b, and Cohort 2 and
Cohort 4 for interim analysis, there is a > 50% probability of stopping either 
cohort/sub-cohort for futility when the true ORR is < 25%. When the true ORR is 35% 


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then the probability of positive conclusion at the final analysis based on 69 patients is 
≥ 44%. If the true ORR is > 45% or higher, the probability of positive conclusion at the 
final analysis is more than 90%. For Sub-cohorts 1a and 1b, Cohorts 2 and 3, 
sensitivity analysis on the primary endpoint may be performed excluding patients with 
cMET mutations.
With 20 evaluable patients in Cohort 3 for interim analysis, there is a > 90% probability 
of stopping the cohort for futility when the true ORR is 10%. When the true ORR is 
20%, then the probability of stopping for futility at the interim analysis is > 80% and the 
probability of positive conclusion at the final analysis is < 1%.
No interim analysis for futility is planned for Cohort 5, Cohort 6 or Cohort 7.
In expansion Cohort 6, approximately 30 pre-treated patients with cMET GCN of ≥ 10 
and cMET mutations regardless of cMET GCN are expected to be enrolled. Data from 
Cohort 6 will help to further characterize the safety and efficacy of INC280 in the pre-
treated Sub-Cohort 1a and Cohort 4. In addition to presenting the efficacy data of 
Cohort 6, analysis may also be carried out combining the patients with a cMET GCN 
of ≥ 10 from Sub-cohort 1a and Cohort 6 to further evaluate the precision of the 
efficacy estimates. Similar analysis may be carried out for pre-treated patients with 
cMET mutations regardless of cMET GCN combining the patients from Cohort 4 and 
Cohort 6.
In expansion Cohort 7, approximately 27 treatment-naïve patients with cMET 
mutations regardless of cMET GCN are expected to be enrolled. Data from Cohort 7
will help to further characterize the safety and efficacy of INC280 in the treatment-
naïve patient group with cMET mutations regardless of cMET GCN. Analysis may be 
carried out combining the patients from Sub-cohort 5b and Cohort 7.
Key words
cMET, NSCLC, INC280


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
1.1.1
Locally advanced unresectable or metastatic non-small cell lung 
cancer (NSCLC)
Lung cancer has been the most common cancer in the world for several decades. In 2012, 
there were an estimated 1.8 million new cases, representing 12.9% of all new cancers 
worldwide. It was also the most common cause of death from cancer, with 1.6 million deaths 
representing 19.4% of the total deaths from cancer (Globocan 2012). For 2014, approximately 
160,000 deaths are expected in the US (Siegel et al 2014) and 273,000 in the European Union 
(Malvezzi et al 2014).
The World Health Organization (WHO) divides lung cancer into 2 major classes based on its 
biology, therapy, and prognosis: non-small cell lung cancer (NSCLC) and small cell lung 
cancer. NSCLC accounts for more than 85% of all lung cancer cases, and it includes 2 major 
types: (1) non-squamous carcinoma (including adenocarcinoma, large-cell carcinoma, other 
cell types); and (2) squamous cell (epidermoid) carcinoma. Adenocarcinoma (40% of lung 
cancers; 47% in NSCLC) is the most common type of lung cancer seen in the United States 
and is also the most frequently occurring cell type in nonsmokers (NCCN Guidelines 2014).
One reason for the high mortality rate of lung cancer is the advanced stage at diagnosis; only 
25-30% of new NSCLC cases are diagnosed with localized disease that is potentially curable 
with surgery (Nguyen et al 2012). The majority of patients are diagnosed with locally 
advanced or metastatic disease and they are not candidates for surgery.
Platinum-based combination therapy is superior to best supportive care in patients with 
advanced, incurable disease. Platinum-doublet chemotherapy (i.e., cisplatin or carboplatin in 
combination with other chemotherapy agents, with or without bevacizumab) has been the 
standard first-line treatment for patients with locally advanced or metastatic NSCLC (Ettinger 
2010, NCCN Guidelines 2014) unless a patient has a known “druggable” mutation, and is a 
candidate for a targeted therapy (as discussed below). Overall response rate (ORR) with 
chemotherapy in first line has achieved a plateau and most platinum based regimens yield an 
ORR of 25-35% (NCCN Guidelines 2014). For NSCLC patients with non-squamous 
histology, pemetrexed-based platinum doublet therapy is a well-established standard first-line 
treatment option. In a phase III, non-inferiority trial of chemotherapy-naïve patients with 
Stage IIIB or IV NSCLC, pemetrexed plus cisplatin (P/C) has shown to be non-inferior and 
better tolerated than gemcitabine/cisplatin (G/C) with a median overall survival (OS) of 10.3 
months for both combinations (Scagliotti et al 2008). However, with respect to OS in the 
various histological subtypes, P/C was superior to G/C in the subset of patients with 
adenocarcinoma and large-cell carcinoma.
In recent years maintenance therapy has emerged as an approach to try to improve the OS 
rates in patients with advanced NSCLC with tumor response or stable disease after first line 
therapy. Several types of maintenance therapy are available (i.e., continuation with the non-


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platinum portion of the platinum doublet until disease progression or switching to a different 
regimen) and its selection depends on tumor histology, presence of gene mutations or 
rearrangements, and patient performance status. Maintenance therapy is not considered the 
standard of care for all patients (Horn 2014). Outcomes of treatment of advanced/metastatic 
NSCLC in the first-line setting with standard platinum-doublet chemotherapy (with or without 
maintenance) remain poor, with median progression free survival (PFS) and OS of 5-7 months 
and 10-16 months, respectively (Scagliotti 2008, Ciuleanu 2009, Ettinger 2010, Paz-Ares 
2012).
Docetaxel, pemetrexed, erlotinib, or platinum doublets are recommended as second-line 
therapy regimens for unselected patients who have experienced disease progression during or 
after first-line therapy (NCCN Guidelines 2014). The reported response rates to second-line 
chemotherapy have generally been less than 10%, with median PFS and OS generally below 3 
and 8 months respectively (de Marinis 2008, Weiss 2013). Upon progression after second-line 
chemotherapy, patients may be candidates for further treatment, although randomized 
evidence is scarce and most data come from phase II trials or retrospective analyses. 
Pemetrexed, docetaxel, gemcitabine or erlotinib are recommended in third line if they have 
not been already given. Patients have often limited response to third line therapy, although it 
may have a useful palliative effect (Shepherd 2005, de Marinis 2008, Eccles 2011, NCCN 
Guidelines 2014, Reck 2014, Besse 2014).
Overall, current treatments are not considered satisfactory for most NSCLC patients and the 
prognosis continues to be poor despite chemotherapy treatment, with a 5-year overall survival 
rate of only 15% (Nguyen et al 2012).
1.1.2
Targeted therapies in NSCLC
During the last few years, improved knowledge of NSCLC biology has led to the 
identification of aberrant molecular events crucial for malignant transformation and cancer 
cell survival. These aberrant molecular events are critical oncogenic drivers and represent 
potential therapeutic targets (Gettinger and Lynch 2011). As a result, “molecular subsets” of 
NSCLC patients who may be candidates for targeted therapy were defined and new targeted 
treatment options are available. In particular, activating mutations in epidermal growth factor 
receptor (EGFR) and anaplastic lymphoma kinase (ALK) translocations are strong predictors 
of improved efficacy of EGFR and ALK Tyrosine Kinase Inhibitors (TKIs) when compared 
with standard chemotherapy in patients harboring EGFR activating mutations and ALK 
translocations, respectively, and represent a new paradigm in the treatment of NSCLC 
(Fukuoka 2011, Zhou 2011, Sequist 2013, Shaw 2013a, Shaw 2013b). Importantly, due to the 
high oncogenic addiction to the molecular abnormality during the course of the disease, the 
efficacy of these targeted therapies seem to be independent of line of treatment and high 
response rates are still observed in patients who received several treatments (generally 
excluding therapies targeting the same pathway) before receiving the given targeted therapy 
(Camidge et al 2012).
The success of EGFR and ALK TKIs, highlights the importance of identifying specific 
molecular drivers of NSCLC to appropriately direct targeted agents in specific patient 
populations. The landscape of NSCLC treatment is changing and the treatment paradigm of 
“one size fits all” is switching to a personalized therapy.


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1.1.3
cMET in NSCLC
cMET is a receptor tyrosine kinase involved in embryogenesis, organogenesis and tissue 
damage repair (Birchmeier 1998, Birchmeier 2003). cMET-pathway dysregulation through 
genomic amplification, receptor overexpression, mutations, autocrine or paracrine secretion of 
its ligand (hepatic growth factor [HGF]) has shown to be oncogenic, promoting cell-cell 
detachment and metastasis, epithelial-mesenchymal transition, invasion, angiogenesis, 
proliferation and survival (Christensen et al 2005).
1.1.3.1
cMET amplification as an oncogenic driver in NSCLC
cMET dysregulation, in particular gene amplification, leading to increased cMET signaling 
driving cell proliferation and survival, was reported in several human cancers, including lung, 
breast, ovarian and gastrointestinal malignancies. Preclinical findings suggested that lung 
cancer cell lines harboring cMET gene amplification are dependent on cMET for growth and 
survival (Lutterbach et al 2007) and significant growth inhibition and apoptosis are observed 
in cMET overexpressing cell lines when exposed to compounds blocking the cMET pathway 
(Christensen 2005, Liu 2008). Both cMET amplification and overexpression are linked to 
acquired resistance to EGFR inhibitors (EGFRi) in lung cancer in preclinical models and the 
clinical setting (Bean 2007, Engelman 2007, Cappuzzo 2009a). cMET amplification seems to 
correlate with poor prognosis in several tumor types including lung cancer, where it was 
associated with higher grades at diagnosis and poor survival (Cappuzzo et al 2009b). In a 
large retrospective series of 435 surgically resected NSCLC patients, cMET amplification by 
FISH (MET/CEP7 ratio ≥2.2 - average ratio of cMET gene to chromosome 7 centromere 
signals) was reported in ~4% of the patients (Cappuzzo et al 2009b).
cMET amplification is reported in ~4% of NSCLC (TCGA web portal 2015, Schildhaus 
2014). cMET amplification appears to be mutually exclusive with all other oncogenic drivers 
in NSCLC (Cancer Genome Atlas Research Network 2014). Gene amplification is recognized 
to be the main oncogenic driver in NSCLC (Cappuzzo et al 2009a).
1.1.3.2
cMET mutation as an oncogenic driver in NSCLC 
cMET mutations leading to exon 14 deletion [referred to as cMET mutation(s) hereafter] have 
been identified as an additional actionable target for cMET inhibition in NSCLC (Kong-
Beltran et al 2006). The loss of exon 14 deletes the region of the protein required for the Cbl 
E3 ligase to bind to cMET and target it for degradation. This results in extended cMET 
occupancy at the membrane and ultimately activation of the receptor. Based on the limited 
epidemiology data currently available cMET mutations can be detected in 2-4% of NSCLC 
with adenocarcinoma histology and in ~1% of NSCLC with other histologies and the overlap 
between high cMET amplification (GCN>6) and cMET mutations is still to be determined; 
notably no overlap between cMET mutations and either EGFR mutations or ALK 
translocation is expected (TCGA web portal 2015, internal Novartis data). Promising efficacy 
data have been published with cMET inhibitors, including INC280, in this setting (Frampton 
2015, Jenkins 2015, Mendenhall 2015, Paik 2015, Waqar 2015, Liu 2015, Schuler 2016, 
Drilon 2016).


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1.1.3.3
cMET inhibitors in NSCLC
Recent clinical studies suggest that inhibitors of cMET may provide a valuable therapeutic 
option in the treatment of NSCLC and other diseases linked with dysregulated cMET 
signaling. Anti-tumor activity of this class of agents has recently been reported in patients 
with locally advanced or metastatic NSCLC whose tumors contain cMET amplification. In a 
study with crizotinib (inhibitor of ALK and cMET), 5 responses were reported (1 complete 
and 4 partial responses) in 12 patients with cMET FISH intermediate (MET/CEP7 ratio > 2.2 
and < 5) and highly (MET/CEP7 ratio ≥ 5) amplified NSCLC (Camidge 2014). However, 2 
other anti-cMET compounds (onartuzumab and tivantinib) failed to demonstrate any clinical 
benefit when combined with EGFR TKIs in recently reported phase III trials, presumably at 
least in part due to the lack of proper patient selection (Cappuzzo 2014). In the onartuzumab 
phase III study, cMET positive patients were defined as IHC 2+ or 3+ for cMET 
overexpression (Spigel 2014) and in the tivantinib study there was no selection for cMET 
dysregulation (Scagliotti 2015).
Current clinical data on the activity of cMET inhibitors in cMET-mutated NSCLC are still 
very limited as this has not been assessed in any prospective clinical studies. Single institution 
series and single case reports have been published showing preliminary promising efficacy in 
NSCLC patients with cMET mutations irrespective of the histology when treated with either 
crizotinib (9 cases), cabozantinib (1 case) and INC280 (2 cases): 10 patients showed PR, 1 
showed SD and only 1 case experienced PD (even if in the context of a mixed response). 
Activity was observed irrespective of the histology and of the line of therapy. (Frampton 2015, 
Jenkins 2015, Mendenhall 2015, Paik 2015, Waqar 2015; Liu 2015).
1.2
Introduction to study treatment
1.2.1
Overview of INC280
The chemical name of INC280 drug substance is 2-fluoro-N-methyl-4-(7-(quinolin-6-
ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide dihydrochloride monohydrate. 
INC280 dihydrochloride monohydrate is a slightly hygroscopic light yellow powder. The 
solubility of INC280 dihydrochloride at 25°C is approximately 3.47 mg/mL in water; 0.08
mg/mL in pH 6.8 and 0.72 mg/mL in pH 3.0 buffer.
INC280 is an orally bioavailable highly potent and selective cMET inhibitor capable of 
blocking cMET activation. In preclinical studies, INC280 treatment induces regression of 
tumors in lung cancer models with cMET amplification and/or overexpression. Activity in 
these tumor models correlates with inhibition of cMET pathway signaling, as measured by 
phospho-cMET levels. Encouraging early clinical activity has been observed with INC280 as 
single agent in an ongoing phase I trial in patients with metastatic NSCLC (unpublished data 
summarized below). 
These data suggest that INC280 represents a promising therapeutic option in the treatment of 
NSCLC with dysregulated cMET signaling.
For more information, please refer to the current [INC280 Investigator’s Brochure].


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1.2.1.1
Non-clinical experience
1.2.1.1.1 In vitro and in vivo pharmacology
INC280 possesses potent inhibitory activity against the cMET kinase in vitro [inhibitory 
concentration (IC)50 = 0.13 ± 0.05 nM], and is highly specific for cMET with > 10,000-fold 
selectivity over several other human kinases tested. Potent activity of blocking cMET 
activation has been observed in cell-based biochemical and functional assays that measure c-
MET-mediated signal transduction, as well as cMET-dependent cell proliferation, survival, 
and migration.
In cMET–dependent mouse tumor models (including lung cancer models), INC280 exhibits
dose-dependent antitumor activity and causes tumor regression at well tolerated doses that 
exceeded IC90 coverage (Liu et al 2011). Importantly, plasma levels of INC280 correlates 
with both the dose administered and the extent of tumor growth inhibition in vivo.
In cMET/HGF-driven tumor models grown as xenografts in mice, oral dosing of INC280 
demonstrated significant in vivo activity in blocking both c-MET phosphorylation and tumor 
growth. Activation of cMET in such responsive models is either due to strong cMET 
overexpression (mostly as a consequence of gene amplification, e.g. in gastric or 
hepatocellular carcinoma) or HGF secretion resulting in an autocrine loop (e.g. in 
glioblastoma). 
Collectively, the data suggest that INC280 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 cMET dysregulation.
1.2.1.1.2 Nonclinical pharmacokinetics (PKs) and metabolism
INC280 was absorbed rapidly in rats, dogs and monkeys. The absolute oral bioavailability 
following a single low dose was low in dogs (28%), and moderate to complete in rats and 
monkeys (> 66%). Single and multiple dose toxicokinetic studies in rats and monkeys showed 
increase in plasma maximum observed concentration (Cmax) and area under the 
concentration-time curve (AUC) values of INC280 with increased dose, but the increases 
were not always dose-proportional.
INC280 plasma protein binding was moderate to high across species, and was 96% in humans
with no concentration dependency. The in vitro blood-to-plasma ratio in humans was 1.5
(concentration range of 10-1000 ng/mL). After oral dose of [14C]-INC280 in male pigmented 
and albino rats, INC280 and/or its metabolites were widely and rapidly distributed to all 
tissues. Melanin containing structures such as eye (choroid) and eye (ciliary body) appeared to 
show specific uptake and prolonged retention of drug related material. The presence of total 
radiolabeled components in those tissues was at least partly reversible. INC280 can penetrate 
across the blood-brain barrier with a brain to blood ratio of approximately 0.1.
Systemic clearance (CL) was low- to-moderate in mice, rats, dogs and monkeys. The 
estimated terminal half-life (T1/2) was short in mice, rats and dogs but long in monkeys. 
Metabolism is the predominant mechanism of elimination of INC280 in rats and monkeys 
after oral administration. The hydroxylated metabolite M8 and the imidazo-triazinone (lactam) 
M16 were main metabolites observed in plasma and excreta of rats and monkeys. After single 


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oral administration of [14C]INC280 to rats and monkeys, the majority of the radioactivity was 
excreted at the end of the observation period. The major portion of administered radioactivity 
was recovered in feces and only a minor fraction in urine. Direct renal excretion of INC280 
was negligible and biliary excretion/intestinal secretion contributed only to a minor extent to 
the overall elimination of INC280.
INC280 is predominantly metabolized by cytochromes P450 (CYP) 3A4 with a contribution 
by aldehyde oxidase. INC280 showed inhibitory potency in vitro against CYP1A2, 2C8, 2C9, 
2C19 and 3A4/5. INC280 also displayed inhibition of multidrug resistant 1/Permeability 
glycoprotein (P-gp), multi-xenobiotic resistance (MXR)/breast cancer resistant protein 
(BCRP), organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 mediated 
substrate efflux or uptake. Therefore, at clinically relevant doses, potential drug-drug 
interactions are possible due to inhibition of CYP1A2, 2C8, 2C9, 2C19 and 3A4/5 metabolic 
enzymes, and/or due to inhibition of P-gp, BCRP, and OATP1B1/1B3 transporters. The 
clinical DDI study results are presented in Section 1.2.1.2.4.
For more detailed information refer to the current [INC280 Investigator’s Brochure].
1.2.1.1.3 Safety pharmacology and toxicology
A series of preclinical safety studies were completed to support human clinical trials with 
INC280, including safety pharmacology studies, genetic toxicology studies, general 
toxicology studies (single- and repeat-dose studies) in the mouse, rat, and Cynomolgus 
monkey (in rats and monkeys up to 13 weeks in duration), and embryofetal developmental 
studies in rats and rabbits. Additionally, photosensitization potential was also assessed.
Safety pharmacology studies indicate that INC280 had no significant effects on central 
nervous system (CNS) and respiratory functions in rats, and no effects on cardiovascular 
function in monkeys. INC280 inhibited hERG potassium current by 50% at 18.7 M.
Repeat-dose toxicity studies in animals reveal that kidneys, pancreas, CNS/brain, and 
potentially the liver may constitute the target organs or systems. 
Kidney toxicity was observed in the 28-day monkey study where mild-to-moderate deposits 
of amphophilic, crystalline-like material surrounded by multinucleated giant cells within the 
renal interstitium and/or tubular lumen were present in the 75 and 150 mg/kg/day, but not in 
the 30 mg/kg/day groups. It was noted that the results from the 13-week monkey study did not 
reveal any kidney toxicity at doses up to 75 mg/kg/day. INC280 inhibits renal transporter 
MATE1 and MATE2K with a Ki of 0.28 µM in vitro. A small portion of creatinine could be 
cleared via active tubular secretion by renal transporters such as MATE and OAT (Lepist et al 
2014).
The findings in pancreas were observed in rats and monkeys in the 28-day and 13-week 
studies, including pancreatic acinar cell vacuolation and/or apoptosis without inflammation, 
and elevations of amylase or lipase. In the 28-day monkey study, a dose of 30 mg/kg/day was 
identified as a NOAEL because of the low grade and reversible pancreatic findings present at 
that dose. In the 28-day rat study, the mid-dose groups (60 mg/kg/day in males and 30
mg/kg/day in females) also showed reversible low-grade pancreatic changes. Reversibility has 
been clearly demonstrated in both species. Similarly, in the 13-week rat study, reversible 
pancreatic acinar cell vacuolation was observed at the doses of ≥ 60 mg/kg for males and ≥ 30 




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frequent
AEs suspected to be related to INC280 of any grade reported in the 
[CINC280A2201] study, which remains as the reference study for the safety profile of
INC280 monotherapy, were edema peripheral (122 patients, [40.4%]), nausea (99 patients, 
[32.8%]), blood creatinine increased (58 patients, [19.2%]), vomiting (58 patients, [19.2%]), 
decreased appetite (40 patients, [13.2] and fatigue (40 patients, [13.2%]) and diarrhea (35 
patients, [11.6]) and the majority were Grade 1/2. The Grade 3/4 AEs suspected to be related 
to INC280 in the [CINC280A2201] study included edema peripheral (19 patients, [6.3]) and 
lipase increased (15 patients, [5.0%]), fatigue (10 patients, [3.3%]), alanine aminotransferase 
increased (12 patients, [4.0%]), vomiting (6 patients, [2.0%], nausea and hypophosphatemia 
(each in 5 patients, [1.7%], aspartate aminotransferase (5 patients, [1.7%]).
The safety profile of INC280 (capmatinib) has been confirmed to be manageable across all 
cohorts in INC280A2201 and no new safety signals have been observed.
Pneumonitis and ILD have been reported from both INC280 single agent and combination 
studies with the EGFR TKIs, including events with fatal outcome. Investigators are advised to 
carefully monitor patients for signs and symptoms of pneumonitis and implement dose 
modification and follow up evaluations described in the protocol in all INC280 studies, both 
single agent and in combination studies.
The maximum tolerated dose (MTD) for INC280 capsules or tablets as single agent was not 
reached. The RP2D for INC280 as a single agent has been determined to be 600 mg BID in 
capsule formulation and 400 mg BID in tablet formulation. For latest and more information, 
please refer to the current [INC280 Investigator’s Brochure].
1.2.1.2.2 Clinical efficacy
Based on available data as of 15-Mar-2016, from study [INC280X2102] preliminary clinical 
activity has been observed with INC280 as single agent therapy in NSCLC. Confirmed partial 
responses were observed in 11/55 (ORR 20%) evaluable NSCLC patients (defined as those 
with at least one post-baseline tumor assessment or have discontinued treatment at the time of 
the data cut-off) enrolled in the 2 expansion phases (treated at the RP2D of 400 mg BID tablet 
or 600 mg BID capsule) and DCR was 51%. In evaluable patients with cMET IHC 3+
(regardless of GCN), confirmed partial responses were seen in 9/37 patients (ORR 24%) and 
DCR was 60%, while in evaluable patients with cMET GCN ≥6 (IHC 3+, except 2 patients 
with IHC 2+), confirmed partial responses were seen in 7/15 patients (ORR 47%) and DCR 
was 80%. Kaplan–Meier median PFS was 3.55 months (95% CI 1.84–7.33) in the total 
NSCLC population (n=55), while in patients with cMET GCN ≥6 median PFS was extended 
to 7.39 months (95% CI 3.84–22.11). Four NSCLC patients with cMET exon 14 mutations 
were identified by retrospective NGS analysis: all 4 were IHC3+ and 3/4 had a GCN ≥10, 
while the GCN was missing in 1 patient; confirmed PR was achieved in 3 patients (2 with 
GCN >10 and 1 with unknown GCN), while one achieved unconfirmed PR (Schuler et al 
2016). ALK status was available for 51/55 patients and all 51 (100%) were negative for ALK 
rearrangement. EGFR status was available in 50/55 patients and 49 (98%) were EGFR wt.
Thus, the preliminary efficacy data suggest that patients with NSCLC whose tumors are 
EGFR wt and have cMET amplification and/or mutations may obtain therapeutic benefit from 
treatment with single-agent INC280. Based on these preliminary but promising results, a more 


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thorough investigation of the activity of INC280 in patients with EGFR wt NSCLC with 
varying degrees of cMET amplification and/or cMET mutations is warranted in order to 
determine those individuals most likely to benefit from treatment with single-agent INC280.
Promising activity in cMET mutated NSCLC patients with INC280 as single agent therapy 
with INC280 400 mg BID, both in pretreated (Cohort 4) and particularly in treatment naïve
(Sub-cohort 5b) setting was observed as of 09 Aug 2018 cut-off date: ORR by BIRC was 
39.1% (95% CI 27.6–51.6) in 2/3 line patients (n=69, Cohorts 4) and 72.0% (95% CI 50.6–
87.9) in treatment naïve patients (n=25, Sub-cohort 5b) (Wolf et al 2018).
1.2.1.2.3 Clinical pharmacodynamics
In study [CINC280X2102] (with single-agent INC280 in patients with cMET-dependent 
advanced solid tumors), pharmacodynamic effect (inhibition of the phosphorylation of cMET 
in paired biopsies) was observed in one colorectal cancer patient treated at 450 mg BID in 
capsules.
1.2.1.2.4 Clinical pharmacokinetics
As of 28-Sep-2018, INC280 (capsule and tablet) single agent steady state pharmacokinetic 
(PK) data are available from five clinical studies ([CINC280X2101T], [CINC280X2102], 
[CINC280X1101] [CINC280A2201] and [CINC280X2201]), and from four combination 
studies, INC280 plus gefitinib [CINC280X2202], INC280 plus cetuximab [CINC280X2104], 
INC280 plus EGF816 [CINC280X2105C]
and INC280 plus BKM120 (buparlisib) 
[CINC280X2204]. After oral administration, INC280 was rapidly absorbed with the median 
time to reach maximum drug concentration (Tmax) ranging from 1 to 2 hours for tablets and 
from 1 to 4 hours for capsules. The elimination half-life estimated from [CINC280X1101]
ranged from 3.5 to 6.3 hours across the cohorts. Accumulation in INC280 exposure following 
repeated administration of 400 mg BID tablets is low, with geometric mean accumulation 
ratio of 1.4-fold in the single agent [CINC280A2201] study. Steady state INC280 exposure is 
expected to be reached by the third day of consecutive BID dosing. The mean plasma 
exposures (Cmax and AUC) for INC280 generally increased with dose up to 600 mg QD and 
600 mg BID administration with capsule formulation. The mean plasma exposure increase is 
roughly dose proportional for INC280 tablet from 200 to 400 mg BID. 
A relative bioavailability study [CINC280X2103] was conducted to compare the INC280 MF 
(market form) tablet formulation to INC280 capsule formulation. The outcome of this study 
showed that tablets provided higher systemic exposures (Cmax and AUC) and lower inter-
subject variability following a single oral administration of 600 mg INC280 in healthy 
subjects. Tablet PK data are available in cancer patients at different doses (150 mg to 400 mg 
BID) in various INC280 studies. In the study [CINC280X2102], the INC280 MF tablet at 400 
mg BID (N=8) provided comparable mean AUC0-12h,ss (1. 05-fold) and slightly higher 
Cmax,ss (1. 44-fold) compared with the INC280 capsule at 600 mg BID (RP2D, N=45) in the 
limited subjects tested. In the ongoing phase 2 [CINC280A2201] study with FMI tablet, the 
exposures (both Cmax and AUC) were comparable to what was observed in [CINC280X2102]
study at 400 mg BID. Based on the tablet PK and safety data from these studies, the dosage of 
INC280 at 400 mg BID in tablet form has been declared as the RP2D for the single agent 
studies.


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The effect of food on the rate and extent of INC280 exposure was assessed after a single oral 
dose administration of 600 mg INC280 tablet in healthy subjects [CINC280X2107].
Compared to fasting conditions, a low fat meal increased AUCinf and Cmax by 1.20- and 
1.11-fold, respectively; and a high fat meal increased AUCinf and Cmax by 1.46- and 1.15-
fold, respectively. Pharmacokinetics data from study [CINC280A2108] in which INC280 
tablet was administered with food in cancer patients, indicated no clinically relevant food 
effect. At 400 mg BID dose, steady state AUC was similar to the exposure observed in study 
[CINC280A2201], therefore INC280 can be administered without regard to food.
INC280 displayed pH-dependent solubility in vitro. A study to evaluate the effect of a long 
acting proton pump inhibitor on the PK of a single dose of INC280 tablet was completed in 
healthy volunteers [CINC280A2101]. Daily treatment with 20 mg rabeprazole for 4 days 
resulted in a modest reduction in the extent of INC280 absorption with a 25.2% decrease in 
AUCinf and a 37.5% decrease in Cmax. Similarly, PK data from patients on the concurrent 
use of PPI compared to those without PPI (Proton Pump Inhibitor) use from the study 
[CINC280A2108] showed a ~30% lower AUC0-12 at steady state , therefore caution is 
advised on the use of PPI when INC280 is taken with no regards of food.
A study to evaluate the effect of INC280 on the PK of CYP3A4 substrate (midazolam) and 
CYP1A2 substrate (caffeine) in patients with MET dysregulated solid tumors was completed 
[CINC280A2103]. Multiple doses of INC280 tablets at 400 mg BID did not lead to clinically 
significant increase of CYP3A4 substrate (midazolam) exposure. However, AUC of CYP1A2 
substrate (caffeine) increased by 135%. Therefore, INC280 is not a CYP3A4 inhibitor, but a 
moderate CYP1A2 inhibitor. 
A study to evaluate the effect of INC280 on the PK of Pgp substrate (digoxin) and BCRP 
substrate (rosuvastatin) in patients with MET dysregulated solid tumors was completed 
[INC280A2105]. Multiple doses of INC280 tablets at 400 mg BID led to a 74% increase in 
digoxin Cmax and a 47% increase in AUC. Rosuvastatin Cmax and AUC increased 204% and 
108%, respectively. Therefore, INC280 is an inhibitor of P-gp as well as BCRP transporters, 
with clinically relevant DDI potential.
A study to evaluate the effect of itraconazole (strong CYP3A4 inhibitor) and rifampicin 
(strong CYP3A4 inducer) on the single-dose pharmacokinetics of INC280 in healthy subjects 
was completed [CINC280A2102]. When co-administered with itraconazole, INC280 AUC 
increased by approximately 40%. There was no change in Cmax. When co-administered with 
rifampicin, INC280 AUC and Cmax decreased by approximately 66% and 56%, respectively.
The result indicated that INC280 is not a sensitive CYP3A4 substrate. Given that the 
reduction in exposure by strong CYP3A4 inducers could potentially compromise the efficacy, 
the concurrent use of strong CYP3A4 inducers with INC280 should be avoided.
INC280 does not show a risk of QT prolongation. Preliminary analysis on 110 patients in 
study [CINC280A2201] showed that no patients had new post-baseline QTcF values greater 
than 500 ms. Changes from baseline (ΔQTcF) greater than 60 ms were not observed and 
changes greater than 30 ms and below 60 ms were observed in 4 patients (4/110, 3.6%). The 
observed mean QTcF changes from baseline around Tmax (2 hours post-dose) were 5.21 ms 
on Cycle 1 Day 1 and -0.54 ms on Cycle 1 Day 15. Based on the PK/QT analysis, the 
estimated mean ΔQTcF (upper one-sided 95% CI) at mean steady state INC280 concentration 


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2 hours post-dose (4584 ng/mL) was 0.11 ms (1.85 ms) at the recommended phase 2 dose of 
400 mg BID with tablets. The upper one-sided 95% CIs for the estimated mean ΔQTcF at 
clinically relevant INC280 concentrations are below the regulatory threshold of 10 ms. For 
more information, please refer to the current INC280 [Investigator’s Brochure].
2
Rationale
2.1
Study rationale and purpose
cMET dysregulation (amplification, overexpression and mutations) constitutes an oncogenic 
driver in several tumor types, including lung cancer. Currently, there is no approved therapy 
for tumors with cMET dysregulations and therefore there is a high unmet medical need to 
develop therapy capable of cMET inhibition for the treatment of these tumors. INC280 is a 
highly potent and selective cMET inhibitor in biochemical and cellular assays and capable of 
blocking cMET activation. Overall, the emerging preclinical and clinical data suggest that 
INC280 may have a favorable benefit-risk ratio for the treatment of cMET dysregulated 
advanced lung cancer. The definition of cMET amplification and the activity in cMET 
amplified and/or cMET mutated NSCLC is based on limited clinical data and exploration of 
INC280 activity in patients with different levels of gene amplification and with mutation is 
warranted.
2.2
Rationale for the study design
This is a prospectively designed, multicenter, open-label, phase II study to evaluate the 
efficacy and safety of single-agent INC280 in patients with EGFR wt (for exon 19 deletions 
and exon 21 L858R substitution mutations) and ALK-negative rearrangement, advanced 
(stage IIIB or IV) NSCLC harboring cMET amplification and/or cMET mutations with
advanced/metastatic disease. Patients with cMET mutations will be enrolled in Cohort 4, Sub-
cohort 5b and Cohort 7, irrespective to their cMET GCN. Patients without cMET mutations, 
will be enrolled in Cohorts 1-3 and Sub-cohort 5a, based on their cMET GCN. All patients in 
Cohorts 1, 2, 3, and 4 must have failed 1 or 2 prior lines of systemic therapy for 
advanced/metastatic disease, while patients enrolled in Cohort 5 and expansion Cohort 7 must 
be treatment-naïve for advanced/metastatic disease. Expansion Cohort 6 will be opened for 
both cMET high amplified (GCN≥10) and cMET mutated NSCLC patients who have failed 1 
prior line of systemic therapy for advanced/metastatic disease.
The primary objective is to evaluate the antitumor activity of INC280 in the described patient 
population. The primary measure of antitumor activity is ORR according to RECIST 1.1 and 
as determined by blinded independent review committee (BIRC) to ensure unbiased 
assessment of response rate. A supportive analysis will be performed to assess the ORR based 
on investigator assessment. Response rate is an appropriate primary endpoint that can be 
adequately assessed and may predict clinical benefit in the context of this single-agent, phase 
II trial in NSCLC patients with cMET amplification and/or mutations. The suitability of such 
design and ORR end point has been demonstrated by the Health Authorities’ approvals of 
crizotinib and ceritinib in ALK-positive rearrangement NSCLC in studies with similar design.
Data on ORR will be supplemented with data on duration of response (DOR) and time to 
response (TTR).


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The study design will incorporate a Bayesian interim monitoring for Cohorts 1, 2, 3 and 4, 
based on pre-specified response criteria (see Section 10.7) for a decision on whether to 
continue enrollment or stop for futility each of the respective study cohorts.
The study will also monitor and assess safety of INC280 as monotherapy, the disease control 
rate (DCR), progression-free survival (PFS), overall survival (OS) 
 
 of INC280 treatment. These endpoints are considered to be 
important supportive endpoints to better assess the potential clinical benefit of INC280.
2.2.1
Rationale for cMET GCN cohorts
In terms of GCN, any value above 2 can be considered as amplified compared to normal 
tissue when looking across a population of cells. Gene copy numbers in the range of 4-5 are 
commonly considered low level amplification, whereas gene copy numbers of 6 and above are 
considered high (Schildhaus 2014). The use of GCN ≥ 6 as a cut- off to determine high 
amplification is an accepted and routinely used cut-off in pathology labs to determine high 
gene copy number in several settings (Schildhaus 2014). For cMET in NSCLC, of the initial 5
responders observed on the phase I study [CINC280X2102], 3 had GCN higher than 6 while 2
had no FISH result available (Ma et al 2015). 
More recent data from the same study [CINC280X2102] firmly support that there is activity 
of INC280 in patients with cMET amplified NSCLC with cMET GCN ≥6 where confirmed 
partial responses were seen in 7/15 evaluable patients (ORR 47%), DCR was 80% and 
Kaplan–Meier median PFS was 7.39 months (95% CI 3.84–22.11) (Schuler 2016). Of these 7 
responders, 3 patients had a GCN ≥10, however, 2 of these confirmed responders with a GCN 
≥10 also harboured a concurrent cMET exon 14 skipping mutation. Therefore, the 
contribution of the very high cMET amplification to the response of INC280 still remains to 
be elucidated and further optimization of appropriate GCN cut off is warranted. The GCN ≥10 
cut-off has been recently used to identify the cMET amplified cases in the most extensive 
analysis ever conducted in 11,205 lung cancer specimens (Ou 2016). 
Preliminary efficacy data has also been observed with crizotinib in NSCLC patients with 
MET/CEP7 ratio of > 2.2 (Camidge 2014). Four out of six patients with MET/CEP7 ratio of > 
5 achieved response, five responses out of 12 patients with MET/CEP7 ratio of > 2.2 were 
observed and no responses were seen in 2 subjects with low level amplification of 
(MET/CEP7 ratio ≤ 2.2) suggesting a differential gradient of response at higher level of 
amplification.
While detailed epidemiology data are still lacking, the prevalence of cMET amplification in 
NSCLC is known to diminish with the increase in GCN (Schildhaus 2014). With the 
emerging data, the assumption that patients with higher GCN may derive grater benefit from 
cMET inhibition with higher chance of response to treatment require further more robust 
exploration. To characterize the efficacy of INC280 in NSCLC patients with very high 
amplified disease and to ensure an adequate representation of patients with GCN ≥10, 2 sub-
cohorts will be implemented in the high amplified Cohort 1 (cMET GCN of ≥ 6) that will 
enroll either patients with a cMET GCN of ≥ 6 and <10 or patients with a cMET GCN of ≥ 10. 
This will allow for adequate and robust characterization of the individual contribution of the 
two GCN ranges to the activity of INC280 in high amplified patients and to assess the 




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There is a growing body of clinical evidence that shows that cMET mutation, in particular, is
a predictor of response to cMET inhibitors irrespective of the line of treatment (Frampton et al 
2015, Schuler et al 2016, Drilon et al 2016, Awad et al 2017, Drilon et al 2017, Felip et al 
2018, Wolf et al 2018).  
Based on these emerging data, the activity of cMET inhibitors warrants further exploration 
also in cMET-mutated NSCLC.
2.2.3
Rationale for treatment-naïve cohort with cMET dysregulation
Increasing data confirms that cMET dysregulations such as cMET exon 14 skipping mutations 
and high cMET amplification are emerging as independent molecular drivers and predictors 
of response to cMET inhibition in NSCLC patients, irrespective of the number of prior lines 
of therapy including some preliminary evidence in the treatment-naïve setting (Frampton 
2015, Jenkins 2015, Mendenhall 2015, Paik 2015, Waqar 2015, Liu 2015, Schuler 2016, 
Drilon 2016, Felip et al 2018, Drilon et al 2017, Wolf et al 2018).
Promising activity with INC280 in cMET dysregulated (either cMET amplified or cMET 
exon 14 skipping mutated) advanced NSCLC has been observed in the phase I study 
[CINC280X2102] (Schuler 2016). In patients with cMET amplified (GCN ≥6) NSCLC a 
47 % ORR and  median PFS of 7.4 months was reported. While these promising results were 
obtained mainly in pretreated patients, three patients (who declined chemotherapy) were 
enrolled as treatment-naïve. Two of these patients harbored cMET exon 14 skipping mutation 
(one had concurrent cMET amplification). Both patients gained benefit from INC280 
treatment (tumor shrinkage -53.3% and -48.5%) achieving confirmed and unconfirmed partial
responses, respectively. This result was consistent with the overall benefit gained by the other 
two cMET mutated patients enrolled in the study (pretreated with 1 and 3 prior lines of 
systemic therapy, respectively), leading to an ORR of 75% in cMET mutated patients (3 out 
of 4 patients achieved confirmed and durable partial responses). Overall, INC280 was well 
tolerated in both treatment-naïve and pretreated NSCLC patients.
While the data are still preliminary, cMET exon 14 skipping mutations and/or high cMET 
gene amplification are emerging as independent tumor drivers and patients harboring such 
cMET dysregulations can benefit from treatment with cMET inhibitors such as INC280, 
irrespective of prior lines of therapy and including treatment-naïve patients with acceptable 
safety profile. This concept was successfully confirmed in the treatment-naïve advanced 
NSCLC setting with other targeted agents directed against established molecular drivers such 
as EGFR mutation, ALK and ROS1 translocation which showed greater efficacy when 
compared with platinum-doublet chemotherapy (Rosell 2012, Sequist 2013, Solomon 2014). 
These data also confirmed that the safety profile of such targeted agents does not differ in the 
treatment-naïve setting compared to the pretreated setting.
There is no cMET inhibitor currently approved for cMET dysregulated NSCLC and the 
activity of platinum-based chemotherapy in patients with treatment-naïve advanced NSCLC 
harboring cMET exon 14 skipping mutations and/or high level of cMET amplification (GCN 
≥10) is unknown.


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2.2.4
Rationale for additional Cohort 6 in pretreated NSCLC with cMET 
dysregulation
While enrollment in the pretreated cohorts with cMET amplification less than 10 GCN (Sub-
cohort 1b, Cohort 2 and Cohort 3) was stopped following the preplanned interim analyses for
futility, Sub-cohort 1a (GCN ≥10) and Cohort 4 (cMET mutations) passed the futility criteria 
and enrollment is continuing until completion for these 2 cohorts.
In expansion Cohort 6, approximately additional 30 patients with advanced NSCLC pretreated 
with one prior line of systemic therapy harboring either cMET amplification (GCN≥10) or 
cMET mutations (irrespective of cMET GCN) will be enrolled after enrollment of the 
respective Sub-cohort 1a/Cohort 4 is completed.
The main purpose of this additional cohort is to generate supportive safety and efficacy data 
in this second line patient population (which currently accounts for the majority of patients 
enrolled in the respective Sub-cohort 1a and Cohort 4). Therefore Cohort 6 is considered
representative of the overall targeted patient population of pretreated cMET high amplified 
and mutated NSCLC.
2.2.5
Rationale for additional Cohort 7 in treatment-naïve NSCLC with cMET 
mutation
In light of the promising data generated in cMET mutated NSCLC in treatment naive setting 
in Sub-cohort 5b (Wolf et al 2018 - see Section 1.2.1.2.2), the main purpose of Cohort 7 is to 
generate additional supportive safety and efficacy data in this is first line patient population,
which currently accounts for the patients enrolled in Sub-cohort 5b of this study.
2.3
Rationale for dose and regimen selection
As of 28-Sep-2014, the cut-off date of the IB available at the time of preparation of the 
original protocol, a total of 203 patients have been treated with INC280 as a single agent with 
either the capsule formulation (N=192) or tablet formulation (N=11). Five DLTs were 
experienced with INC280 as a single agent with the capsule formulation and no DLTs were 
observed with the tablet formulation (see Table 2-1).
Table 2-1
DLTs experienced with single agent INC280 as of 28-Sep-2014
Study and Treatment
N 
Dose Limiting Toxicities
Study CINC280X1101
INC280 capsules:
100 mg QD
200 mg QD
400 mg QD
500 mg QD
600 mg QD
800 mg QD
400 mg BID
600 mg BID
3
4
3
4
4
4
4
3
None
None
None
None
None
None
None
Grade 2 malaise and suicidal ideation
INC280 tablets:
200 mg BID
3
None


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Study and Treatment
N 
Dose Limiting Toxicities
400 mg BID
3
None
Study CINC280X2101
INC280 capsules:
10 mg QD
20 mg QD
50 mg QD
70 mg QD
50 mg BID
150 mg QD
200 mg QD
300 mg QD
400 mg QD
200 mg BID
300 mg BID
3
4
6
4
3
3
4
4
6
4
4
None
None
Grade 3 AST and ALKP increase
None
None
None
None
None
None
None
None
Study CINC280X2102
INC280 capsules:
100 mg BID
200 mg BID
250 mg BID
350 mg BID
450 mg BID
600 mg BID escalation
600 mg BID expansion
4
5
4
3
9
8
53
None
Grade 3 fatigue
Grade 3 blood bilirubin increased
None
Grade 3 fatigue
None
None
INC280 tablets:
400 mg BID
5
None
Based on the data from study [CINC280X2102], and the observation that exposure did not 
further increase from 600 mg to 800 mg QD dosing, the RP2D of INC280 monotherapy in 
adults (in capsules) is 600 mg BID. Single-agent INC280 is generally tolerable at this dose 
when given twice daily on a continuous dosing schedule, with most adverse events (AEs) 
being manageable and of grade 1 and grade 2 severity.
As of 28-Sep-2014 ([Investigator’s Brochure edition 5.2] data cut-off date), preliminary PK 
data were available from 10 patients treated with the INC280 tablet formulation as single 
agent at 200 mg or 400 mg BID dose. Based on the limited data, mean Cmax at steady-state 
following administration of INC280 tablets at 400 mg BID was 41% higher than that 
following capsules administration at 600 mg BID. Considering the 67% variability (CV%) 
observed with the capsule formulation at 600 mg BID, tablets at 400 mg BID (CV%= 30%) 
provided exposures within the range of exposures observed with capsules at 600 mg BID (the 
RP2D in study [CINC280X2102]).
In study [CINC280X2101] (single agent capsules), dose-dependent inhibition of phospho-
cMET was observed across 11 dose cohorts (10 mg QD up to 400 mg QD or 300 mg BID) 
and complete inhibition was observed at trough concentration on Day 15 at 200 mg BID
single agent capsules. In addition, complete inhibition of tumor cMET phosphorylation in 
patients was observed at 450 mg BID single agent capsules in study [CINC280X2102] and at 
400 mg BID capsules in combination with gefitinib in study [CINC280X2202]. Based on the 
observed 400 mg BID tablet exposure, which appears to be higher in mean level but within 


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the range of 600 mg BID capsule exposure, the 400 mg BID tablet dose and regimen is 
expected to provide high enough inhibition levels to be efficacious. For details, refer to 
Section 1.2.1.2.4 and [Investigator’s Brochure edition 5.2].
Based on the available tablet PK and safety data, the dosage of INC280 at 400 mg BID in 
tablet formulation was found to be tolerable in patients and has been declared as the RP2D 
and is being further evaluated in the ongoing INC280 studies.
2.4
Rationale for choice of combination drugs
Not applicable.
2.5
Rationale for choice of comparators drugs
Not applicable.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
To evaluate the antitumor activity of INC280, as measured 
by overall response rate (ORR) by Blinded Independent 
Review Committee (BIRC) assessment, by cohort/sub-
cohort
ORR, proportion of patients with a best overall response defined as complete 
response or partial response (CR+PR) by BIRC assessment per RECIST 1.1
Refer to Section 10.4
Key secondary
To evaluate duration of response (DOR) as assessed by 
BIRC, by cohort/sub-cohort
DOR, calculated as the time from the date of the first documented CR or PR 
by BIRC per RECIST 1.1 to the first documented progression or death due to 
any cause for patients with PR or CR
Refer to Section 10.5.1
Other secondary
1.
To evaluate ORR and DOR by investigator assessment, 
by cohort/sub-cohort
ORR (CR+PR) and DOR per RECIST 1.1 by investigator assessment
Refer to Section 10.5.2
2.
To evaluate time to response (TTR), disease control 
rate (DCR) and progression-free survival (PFS) by 
investigator and by BIRC assessment, by cohort/sub-
cohort
All calculated per RECIST 1.1, both by BIRC and investigator:

TTR, calculated as the time from first dose of INC280 to first documented 
response (CR+PR) for patients with PR or CR

DCR, calculated as the proportion of patients with best overall response 
of CR, PR, or SD

PFS, defined as time from first dose of INC280 to progression or death 
due to any cause
Refer to Section 10.5.2
3.
To evaluate overall survival (OS), by cohort/sub-cohort
OS, defined as time from first dose of INC280 to death due to any cause
Refer to Section 10.5.2
4.
To evaluate INC280 safety profile as monotherapy in 
NSCLC patients with advanced/metastatic disease
Incidence of adverse events and serious adverse events, change in vital 
signs, laboratory results (hematology, blood chemistry, and urinalysis) and 
ECG.
Refer to Section 10.5.3
5.
To characterize the pharmacokinetics of INC280 and 
metabolite CMN288
Plasma concentration-time profiles and pharmacokinetic parameters estimated 
by non-compartmental analysis or population PK modeling
Refer to Section 10.5.4


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Objective
Endpoint
Analysis


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4
Study design
4.1
Description of study design
This is a prospectively designed, multicenter, open-label, phase II study to evaluate the 
efficacy and safety of single-agent INC280 in patients with EGFR wt (for exon 19 deletions 
and exon 21 L858R substitution mutations), ALK-negative rearrangement, advanced (stage 
IIIB or IV) NSCLC harboring cMET amplification and/or mutations. 
Approximately 456 male and female patients aged 18 or over will be enrolled in this study in 
7 separate cohorts [138 in Cohort 1 (69 patients per each Sub-cohort 1a and 1b) and 69 
patients in each Cohorts 2, 3, and 4; 54 patients in Cohort 5 (27 patients per each Sub-cohort 
5a and 5b); approximately 30 patients in Cohort 6; approximately 27 in Cohort 7] depending 
on their cMET amplification and/or mutation status and prior treatment status. A Bayesian 
interim monitoring for Cohorts 1, 2, 3 and 4, based on pre-specified response criteria is used 
(see Section 10.7) for a decision on whether to continue enrollment or stop for futility in the 
respective cohort. Due to the promising data for the treatment naïve patients from 
[INC280X2102] study, drug tolerability as observed in the other cohorts, and the outcome of 
the futility interim analyses in Sub-cohort 1a and Cohort 4, as well as the small sample size of 
Sub-cohorts 5a and 5b, interim analyses for futility are not being implemented in the 
treatment naïve Sub-cohorts, Cohort 6 and Cohort 7.
For patients with NSCLC, EGFR mutation and ALK rearrangement status should have been 
assessed as part of the patients standard of care using a validated test as per the Molecular 
Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase 
Inhibitors from College of American Pathologists, International Association for the Study of 
Lung Cancer, and Association for Molecular Pathology (Lindeman et al 2013). The EGFR wt
status (for exon 19 deletions and exon 21 L858R substitution mutations) must be documented 
in the patient source documents before patient can be consented for cMET amplification and 
mutation pre-screening (except for patients who are treatment-naïve potentially eligible for
Sub-cohort 5a and 5b or if molecular pre-screening will be performed by NGS and local status 
is not available). ALK rearrangement status, if known, should also be documented in the 
patient’s source documents prior to cMET testing, except for patients who are treatment-naïve 
potentially eligible for Sub-cohorts 5a, and 5b and Cohort 7. If ALK testing is not available
for a patient, their ALK status will be determined centrally with a validated test along with 
their cMET amplification and cMET mutation status. Patients with NSCLC of pure squamous 
cell histology can enter pre-screening without EGFR mutation or ALK testing or result, 
however patients with pure squamous cell histology and are known to have EGFR mutations 
in exons 19 and 21 or ALK-positive rearrangement will be excluded.
Patients will be pre-screened for cMET amplification based on GCN (and ALK rearrangement 
status, if applicable) by FISH and for cMET mutations by RT-PCR at a Novartis-designated 
central laboratory following the signing of the molecular pre-screening Informed Consent 
Form (ICF). Next Generation Sequencing (NGS) may be used as primary pre-screening 
diagnostic, if assay becomes available. Patients with previously determined cMET mutation 
or amplification by a Novartis designated central laboratory (as detected by the same


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validated NGS assay used in this protocol) who have consented for the use of those results,
will be allowed to enter directly the screening phase of the INC280A2201 study. For patients
coming from another Novartis study using the same central lab or being rescreened, repeat 
tumor biopsy or additional archival tumor may not be required provided the central laboratory 
confirms adequate tumor tissue remains for the required study analyses.
All patients in Cohorts 1, 2, 3, and 4 must have failed 1 or 2 prior lines of systemic therapy, 
while patients enrolled in Cohorts 5 and 7 must be treatment-naïve for advanced disease.
Patients enrolled in Cohort 6 must have failed 1 prior line of systemic therapy for 
advanced/metastatic disease.
Patients with cMET mutation will be enrolled based on the prior therapy status in Cohort 4 or 
Sub-cohort 5b or Cohort 7, irrespective of their cMET GCN. Patients without cMET 
mutations, will be enrolled in Cohort 1 (Sub-cohorts 1a or 1b), Cohort 2, and Cohort 3 and 
Sub-cohort 5a, based on their cMET GCN and prior treatment status. Patients enrolled in 
Cohort 6 can be either with cMET GCN ≥10 without cMET mutations or with cMET 
mutation irrespective to their cMET GCN. The enrollment in this Cohort 6 will only start 
upon enrollment completion of the respective Sub-cohort 1a or Cohort 4.
Only the cMET amplification and mutation test results from the pre-screening analysis 
performed by the Novartis-designated laboratory will be used to assign patients into the 
following 7 cohorts:

Cohort 1: Pre-treated patients with cMET GCN ≥6, including: 

Sub-cohort 1a: Patients with a cMET GCN of ≥ 10, or

Sub-cohort 1b: Patients with a cMET GCN of ≥ 6 and < 10, or

Cohort 2: Pre-treated patients with cMET GCN ≥4 and < 6, or

Cohort 3: Pre-treated patients with cMET GCN < 4, or

Cohort 4: Pre-treated patients with cMET mutations regardless of cMET GCN, or

Cohort 5: Treatment-naïve patients with cMET dysregulation, including:

Sub-cohort 5a: Patients with a cMET GCN ≥10, or

Sub-cohort 5b: Patients with cMET mutations regardless of cMET GCN, or

Cohort 6: Pre-treated patients with either cMET GCN ≥ 10 without cMET mutations or 
cMET mutations regardless of cMET GCN or,

Cohort 7: Treatment-naïve patients with cMET mutations regardless of cMET GCN
For the interim and final analyses in Cohort 2 (cMET GCN ≥ 4 and < 6), the study targets to 
have at least 40% of patients with cMET GCN ≥ 5 and < 6. Enrollment in each cohort will be 
controlled via Interactive Response Technology (IRT) system.
Each cohort/sub-cohort of the study will enroll patients in parallel. Patients in all cohorts will 
be treated with 400 mg INC280 twice daily (BID) using the tablet formulation, administered 
orally on a continuous dosing schedule.
Efficacy assessment of tumor response and progression will be performed every 6 weeks (i.e.,
every 2 cycles) from the first day of treatment with INC280 until RECIST 1.1 disease 
progression as determined by investigator and confirmed by Blinded Independent Review 
Committee (BIRC). This schedule must be followed regardless of dose interruptions. 


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Confirmation of response is required for all response endpoints, as per RECIST 1.1. All 
radiological assessments obtained at screening/baseline, during treatment and during the 
follow-up phase should be performed using the same modality (method) and will be submitted 
to the designated independent imaging vendor for review by BIRC.
Approximately 30 enrolled patients at selected sites (regardless of cohort assignment) will 
have full PK samples and ECGs collected. The rest of the patients will have sparse PK 
samples and ECGs collected (see Table 7-6 and Table 7-7). At the time of eligibility 
confirmation, the IRT system will inform the site about which PK and ECG schedule should 
be followed by the patient.
In Cohort 1 and Cohort 5, all of the efficacy analyses will be performed separately for each of 
the two sub-cohorts. 
Interim analyses for futility will be performed separately for Sub-cohorts 1a and 1b and
Cohorts 2 and 4 when there are at least 28 evaluable patients in each cohort/sub-cohort. 
Interim analyses for futility for Cohort 3 will be performed when there are at least 20 
evaluable patients in Cohort 3. Evaluable patients are defined as those patients who have 
completed at least 6 cycles of treatment (18 weeks) or have discontinued the study treatment 
earlier. The decision to stop for futility at interim will be based on the probability of success 
(POS) which will be calculated based on the evaluable patients in each cohort/sub-cohort. One 
(or more) of the cohorts/sub-cohorts will be stopped for futility if the respective POS is less 
than 10% at the interim analysis. In each of Sub-cohorts 1a and 1b and Cohorts 2 and 4, if 7 or 
fewer responses are observed in 28 evaluable patients at interim analysis, then the respective 
cohort/sub-cohort will be stopped for futility. If at the time when the 28th patient is enrolled a 
minimum of 8 responders have not yet been observed, accrual in the cohort/sub-cohort may 
be temporarily suspended until either the minimum number of 8 responders is observed or 
results of the interim analysis allow the cohort/sub-cohort to continue. In Cohort 3, if 5 or 
fewer responses are observed in 20 evaluable patients at interim analysis, then this cohort will 
be stopped for futility. If at the time when the 20th patient is enrolled a minimum of 6
responders have not yet been observed, accrual may be temporarily suspended in the cohort 
until either the minimum number of 6 responders is observed or results of the interim analysis 
allow the cohort to continue. No interim analysis for futility is planned for Cohort 5, Cohort 6
and 7.
The primary analysis will be conducted when all treated patients in their respective 
cohort/sub-cohort (if not stopped for futility at interim analysis) have completed at least 6 
cycles of treatment (18 weeks) or discontinued treatment earlier. Due to the expected 
difference in enrollment rate for each cohort/sub-cohort, the primary analysis for the different 
cohorts/sub-cohorts may occur at different times. The primary analysis for any cohort that was 
stopped for futility may be combined with the primary analyses for other cohorts.
In Cohorts 1, 2, 3 and 4, treatment with INC280 would be considered to have clinically 
relevant efficacy if an ORR of ~35% is observed in that cohort/sub-cohort for the 
corresponding primary analysis. In addition, 5 hypotheses will be tested as following for the 
cohorts/sub-cohorts (Hi0 and Hi1 correspond to cohort/sub-cohort i where i=1a, 1b, 2, 3 or 4):
Hi0: ORR ≤ 25%










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With 20 evaluable patients for interim analysis in Cohort 3, if 5 or fewer responses are 
observed then the respective cohort will be stopped for futility. If at the time that the 20th
patient is enrolled a minimum of 6 responders have not yet been observed, accrual in the 
cohort may be temporarily suspended until either the minimum number of 6 responders are 
observed or results of the interim analysis allow the cohort to continue.
No interim analysis for futility assessment is planned for Cohort 5,Cohort 6 and Cohort 7.
All evaluable patients at the time of the data cut-off for the interim analysis will be used to 
obtain the futility boundary using the POS criteria. The futility boundary will be calculated 
according to the actual number of evaluable patients in the interim analysis.
The statistical considerations for the interim analysis can be found in Section 10.7.
4.3
Definition of end of the study 
Following the cut-off date for the primary analysis reported in the primary Clinical Study 
Reports (CSR)(s), the study will remain open. After all of the primary analyses for the 
different cohorts have been conducted, ongoing patients will continue to receive INC280 
treatment and be followed as per the schedule of assessments, as long as patients derive 
benefit from INC280 or until the end of study defined as the earliest occurrence of one of the 
following:

All patients have died or discontinued from the study

Another clinical study becomes available that can continue to provide INC280 in this 
patient population and all patients ongoing are eligible to be transferred to that clinical 
study

INC280 is commercially available and ongoing patients are able to obtain reimbursement 
of commercial supply
The final analysis will occur at the end of the study. All available data from all patients up to 
this cut-off date will be analyzed and summarized in a final CSR.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7.1.5 for a discontinued or withdrawn patient. 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 patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
This study will enroll adult male and female patients with EGFR wt (for exon 19 deletions 
and exon 21 L858R substitution mutations), ALK-negative rearrangement, advanced (stage 
IIIB or IV) NSCLC who have failed one or two prior lines of systemic therapy (Cohorts 1-4), 


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who have failed one prior line of systemic therapy (Cohort 6), or who have received no 
systemic therapy (Cohort 5 and Cohort 7) for advanced/metastatic disease.
Treatment failure is defined as documented disease progression or intolerance to treatment. 
Patients enrolled in the study are not permitted to participate in additional parallel 
investigational drug or device studies. 
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
Written informed consent must be obtained prior to any screening procedures
1. Age ≥ 18 years
2. Stage IIIB or IV NSCLC (any histology) at the time of study entry
3. Histologically or cytologically confirmed diagnosis of NSCLC that is:
a. EGFR wt. This should have been assessed as part of the patient standard of care by a 
validated test for EGFR mutations, as per the Molecular Testing Guideline for 
Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors 
from College of American Pathologists, International Association for the Study of 
Lung Cancer, and Association for Molecular Pathology (Lindeman et al 2013). The 
EGFR wt status (for exon 19 deletions and exon 21 L858R substitution mutations) 
must be documented in the patient source documents before the patient can be 
consented for pre-screening for cMET amplification and cMET mutation status
(except for patients who are treatment-naïve potentially eligible for Sub-Cohort 5a, 5b
and Cohort 7 or if molecular pre-screening will be performed by NGS and local status 
is not available). Patients with NSCLC of pure squamous cell histology can enter pre-
screening without EGFR mutation testing or result, however patients with pure 
squamous cell histology and are known to have EGFR mutations in exons 19 or 21
will be excluded,
b. AND ALK rearrangement -negative. This should have been assessed as part of the 
patient standard of care by a validated test. The ALK rearrangement-negative status 
must be documented in the patient source documents before the patient can be 
consented for pre-screening for cMET amplification and cMET mutation status,
except for patients who are treatment-naïve potentially eligible for Sub-Cohorts 5a, 5b
and Cohort 7; if local ALK testing is not available, patient status will be determined
centrally along with the cMET status. Patients with NSCLC of pure squamous cell 
histology can enter pre-screening without ALK testing or result, however patients 
with pure squamous cell histology that are known to have ALK rearrangement will be 
excluded.
c. AND (as determined by central assessment at a Novartis designated laboratory) either: 

Cohort 1: Pre-treated patients with cMET GCN ≥6, including:

Sub-cohort 1a: Patients with cMET GCN of ≥10, or

Sub-cohort 1b: Patients with cMET GCN of ≥ 6 and < 10, or


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
Cohort 2: Pre-treated patients with cMET GCN ≥4 and < 6, or

Cohort 3: Pre-treated patients with cMET GCN < 4, or

Cohort 4: Pre-treated patients with cMET mutations regardless of cMET GCN, or

Cohort 5: Treatment-naïve patients with cMET dysregulation, including: 

Sub-cohort 5a: Patients with cMET GCN of ≥10, or

Sub-cohort 5b: Patients with cMET mutations regardless of cMET GCN, or

Cohort 6: Pre-treated patients with either cMET GCN ≥ 10 without cMET 
mutations or cMET mutations regardless of cMET GCN, or

Cohort 7: Treatment-naïve patients with cMET mutations regardless of cMET 
GCN
cMET (and ALK, if applicable) testing may be performed while patient is still 
receiving anti-cancer therapy. However, the patient can only be screened for the main 
study once the patient has discontinued the last prior systemic treatment due to either 
disease progression or intolerance.
4. To be eligible for Cohorts 1-4, patients must have failed one or two prior lines of systemic 
therapy for advanced/metastatic disease (stage IIIB or IV NSCLC). To be eligible for 
Cohort 6, patients must
have failed one prior line of systemic therapy for 
advanced/metastatic disease (stage IIIB or IV NSCLC). Treatment failure is defined as 
documented disease progression or intolerance to treatment. Maintenance therapy given 
after first line chemotherapy will be considered as part of the first line if given to patients 
with documented response or stable disease before starting the maintenance therapy. Neo-
adjuvant and adjuvant systematic therapies will count as one prior line of treatment if 
relapse occurred within 12 months from the end of the neo-adjuvant or adjuvant systemic 
therapy.
To be eligible for Cohort 5 and 7, patients must not have received any systemic therapy 
for advanced/metastatic disease (stage IIIB or IV NSCLC). Neo-adjuvant and adjuvant 
systemic therapies will not count as one prior line of treatment if relapse occurred > 12 
months from the end of the neo-adjuvant or adjuvant systemic therapy.
5. At least one measurable lesion as defined by RECIST 1.1. A previously irradiated site 
lesion may only be counted as a target lesion if there is clear sign of progression since the 
irradiation.
6. Patients must have recovered from all toxicities related to prior anticancer therapies to 
grade ≤ 1 (CTCAE v 4.03). Patients with any grade of alopecia are allowed to enter the 
study.
7. 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) ≥45 mL/min

Total bilirubin ≤1.5 x ULN


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
Aspartate transaminase (AST) ≤ 3 x ULN, except for patients with liver metastasis, 
who may only be included if AST ≤5 x ULN

Alanine transaminase (ALT) ≤ 3 x ULN, except for patients with liver metastasis, 
who may only be included if ALT ≤5 x ULN

Alkaline phosphatase (ALP) ≤ 5 x ULN

Asymptomatic serum amylase ≤ grade 2. Patients with grade 1 or grade 2 serum
amylase at the beginning of the study must be confirmed to have no signs and/or 
symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-amylase, 
abnormal imaging findings of pancreas, etc.)

Serum lipase ≤ULN

Fasting plasma glucose ≤ 175 mg/dL (≤ 9.7 mmol/L)

Patients must have the following laboratory values within the laboratory normal limits 
or corrected to within normal limits with supplements during screening:

Potassium

Magnesium 

Phosphorus 

Total calcium (corrected for serum albumin) 
8. ECOG performance status (PS) of 0 or 1.
9. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Prior treatment with crizotinib, or any other cMET or HGF inhibitor
2. Patients with known hypersensitivity to any of the excipients of INC280 (crospovidone, 
mannitol, microcrystalline cellulose, povidone, sodium lauryl sulfate, magnesium stearate, 
colloidal silicon dioxide, and various coating premixes).
3. Patients with characterized EGFR mutations that predict sensitivity to EGFR therapy, 
including, but not limited to exon 19 deletions and exon 21 mutations.
4. Patients with characterized ALK-positive rearrangement.
5. Patients with symptomatic central nervous system (CNS) metastases who are 
neurologically unstable or have required increasing doses of steroids within the 2 weeks 
prior to study entry to manage CNS symptoms
6. Presence or history of carcinomatous meningitis
7. Presence or history of a malignant disease other than NSCLC that has been diagnosed 
and/or required therapy within the past 3 years. Exceptions to this exclusion include the 
following: completely resected basal cell and squamous cell skin cancers, and completely 
resected carcinoma in situ of any type
8. Clinically significant, uncontrolled heart diseases.

Unstable angina within 6 months prior to screening

Myocardial infarction within 6 months prior to screening


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
History of documented congestive heart failure (New York Heart Association 
functional classification III-IV)

Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg 
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without 
antihypertensive medication. Initiation or adjustment of antihypertensive medication(s) 
is allowed prior to screening

Ventricular arrhythmias

Supraventricular and nodal arrhythmias not controlled with medication

Other cardiac arrhythmia not controlled with medication

QTcF ≥ 450 ms (male patients), ≥ 460 ms (female patients) on the screening ECG (as 
mean of triplicate ECG)
9. Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting INC280 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 INC280 or patients who have not recovered from radiotherapy-related toxicities. 
Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting INC280 is allowed
10. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior (2 
weeks for resection of brain metastases) to starting INC280 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 be enrolled in the 
study ≥1 week after the procedure
11. Patients receiving treatment with medications that meet one of the following criteria and 
that cannot be discontinued at least 1 week prior to the start of treatment with INC280 and 
for the duration of the study:

Strong inducers of CYP3A4
12. Impairment of GI function or GI disease that may significantly alter the absorption of 
INC280 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or 
malabsorption syndrome)
13. Unable or unwilling to swallow tablets as per dosing schedule
14. Patients receiving unstable or increasing doses of corticosteroids. If patients are on 
corticosteroids for endocrine deficiencies or tumor-associated symptoms other than CNS 
related, dose must have been stabilized (or decreasing) for at least 5 days before first dose 
of INC280
15. Patients receiving treatment with any enzyme-inducing anticonvulsant that cannot be 
discontinued at least 1 week before first dose of INC280, and for the duration of the study. 
Patients on non-enzyme-inducing anticonvulsants are eligible
16. Applicable to Cohorts 1-4 and Cohort 6 only: Previous anti-cancer and investigational 
agents within 4 weeks or ≤ 5 x half-life of the agent (whichever is longer) before first dose 
of INC280. If previous treatment is a monoclonal antibody, then the treatment must be 
discontinued at least 4 weeks before first dose of INC280. If previous treatment is an oral 
targeted agent, then the treatment must be discontinued at least 5 x half-life of the agent
before the first dose of INC280.


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17. Other severe, acute, or chronic medical or psychotic
conditions or laboratory 
abnormalities that in the opinion of the investigator may increase the risk associated with 
study participation, or that may interfere with the interpretation of study results
18. Any other condition that would, in the Investigator’s judgment, contraindicate patient’s 
participation in the clinical study due to safety concerns or compliance with clinical study 
procedures, e.g., infection (including active hepatitis B and C), inflammation, intestinal 
obstruction, unable to swallow medication, social/ psychological issues, etc.
19. Pregnant or nursing (lactating) women
20. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 7 days after stopping treatment. Highly effective contraception 
methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
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 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). The vasectomized male 
partner should be the sole partner for that subject

Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate < 1%), for example hormone 
vaginal ring or transdermal hormone contraception.
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of 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 tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child bearing potential
21. Sexually active males unless they use a condom during intercourse while taking drug and 
for 7 days after stopping treatment and should not father a child in this period. A condom 
is required to be used also by vasectomized men as well as during intercourse with a male 
partner in order to prevent delivery of the drug via semen.
22. Presence or history of interstitial lung disease or interstitial pneumonitis, including 
clinically significant radiation pneumonitis (i.e., affecting activities of daily living or 
requiring therapeutic intervention).


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6
Treatment
6.1
Study treatment
For this study, the term “investigational treatment” or “study drug” refers to INC280. The 
dose and treatment schedule are listed in Table 6-1.
The orally administered film-coated tablet formulation will be provided in up to three 
strengths of 100 mg, 150 mg and 200 mg (if available) free base equivalent. For the list of 
excipients, please refer to current [Investigator’s Brochure].
6.1.1
Dosing regimen
INC280 tablet will be administered orally on a continuous twice daily (BID) dosing schedule,
on a flat scale of mg/day and not individually adjusted by weight or body surface area. A 
complete cycle of treatment is defined as 21 days of twice daily treatment with INC280. The 
investigator must instruct the patient to take the study drug exactly as prescribed.

Except on days of PK sampling, patients should take 400 mg INC280 tablets twice daily 
(BID) at approximately the same time each day starting at Cycle 1 Day 1.

Each dose of INC280 is to be taken with a glass of water (at least 8 ounces –
approximately 250 mL) and consumed over as short a time as possible (i.e., not slower 
than 1 tablet every 2 minutes).

Patients should be instructed to swallow the tablets whole and not to chew them.

INC280 should be administered in the fasted state, at least 1 hour before or 2 hours after a 
meal. The morning and the evening doses should be taken 12 (± 4) hours apart, although 
12-hour interval is highly recommended. The morning dose should be taken the same time 
each morning. If a dose is not taken within 4 hours of the planned dosing time, the missed 
dose should not be replaced

Only for Cohort 6 and 7, INC280 can be administered with or without food. 

On days when PK blood samples are to be collected, patients will be instructed to hold 
their dose until arrival at the study center. INC280 will be administered at the site in the 
morning prior to the PK blood draws supervised by a member of the research team. The 
exact time of drug administration should be recorded in the appropriate eCRF. If a patient 
vomits within 4 hours of INC280 dosing, the time of vomiting should be recorded on the 
eCRF.

Patients 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 as a 
case when the full dose is not taken within 4 hours of the scheduled twice daily dosing. If 
that occurs, then the dose (or part 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 INC280, the patient is recommended to use 
precautionary measures against ultraviolet exposure (e.g., use of sunscreen, protective 
clothing, avoid sunbathing or using a solarium).


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The investigator should instruct the patient to take INC280 exactly as prescribed. All dosages 
prescribed and dispensed to the patient and all dose changes during the study must be 
recorded on the Dosage Administration Record eCRF.
Table 6-1
Dose and treatment schedule
Study 
treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or 
Regimen
INC280
Tablet for oral use
400 mg (4 x 100 mg or 2 x 200 mg, if 
available, or 2 x 150 mg + 1 x 100 mg, if 
applicable)
Twice Daily (BID)
6.1.2
Ancillary treatments
Not applicable.
6.1.3
Rescue medication 
Not applicable.
6.1.4
Guidelines for continuation of treatment
For guidelines for dose modification of treatment, refer to Section 6.3.
6.1.5
Treatment duration
Patients may be discontinued from treatment with INC280 earlier due to:

Disease progression according to RECIST 1.1 as determined by investigator and 
confirmed by BIRC. Patients may continue treatment with INC280 beyond RECIST 1.1-
defined PD (as determined by investigator and confirmed by BIRC) if, in the judgment of 
the investigator, there is evidence of clinical benefit and the patient wishes to continue on 
the study treatment. 

Unacceptable toxicity that precludes further treatment

Discontinued treatment at the discretion of the investigator or the patient 

Death

Patient is lost to follow-up
6.2
Dose escalation guidelines
Not Applicable.
6.3
Dose modifications 
6.3.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. All dose modifications, 
interruptions or discontinuations must be based on the worst preceding toxicity as graded by 
the NCI Clinical Toxicity Criteria (NCI-CTCAE version 4.03). Any changes must be recorded 
on the Dosage Administration Record eCRF page.


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General guidelines for dose modifications are presented in Table 6-3.
Unless otherwise indicated in Table 6-3, for grade 1 and tolerable grade 2 treatment-related 
toxicities, patients may continue full doses of study treatment. For intolerable grade 2 or grade
3 treatment-related toxicities, dosing should be interrupted until at least resolution to grade 1 
followed by either dose reduction or re-initiation at the same dose level, depending on the 
type of toxicity as described in Table 6-3. For any grade 4 toxicity, patients should interrupt 
study treatment until resolution to grade 1, followed by either dose reduction or treatment 
discontinuation (refer to Table 6-3).
Any planned variance from the guidelines in Table 6-3, in view of patient safety (unless there 
is an urgent need for action) when in the opinion of the investigator the patient continues to 
experience clinical benefit, must first be discussed and approved by the Novartis Medical 
Lead or designee.
A patient must discontinue treatment with INC280 if, after treatment is resumed at the lowest 
allowed dose (200 mg BID), the toxicity recurs with the same or worse severity despite use of 
maximal preventive measures as per the institution guidelines for toxicity prevention and 
management. All interruptions or change to study drug administration must be recorded on the 
Dose Administration Record eCRF page.
6.3.2
Dose reduction and re-escalation
An INC280 dose reduction will follow the dose reduction steps described in Table 6-2. For 
each patient, a maximum of 2 dose level modifications is allowed after which the patient must 
be discontinued from treatment with INC280. The lowest dose allowed, 200 mg BID in tablets 
is expected to be pharmacologically active, as the observed steady state plasma trough 
concentrations ([CINC280X1101], [CINC280X2202], n=6) were above the concentration 
associated with full cMET inhibition in xenograft mice models (IC90, 120 nM total 
concentration).
Dose re-escalation of study treatment to the previous dose level is allowed only once, and if 
no AE leading to dose modification is observed after at least 1 cycle (3 weeks) of study 
treatment at the reduced dose.
Table 6-2
Dose reduction steps for INC280
INC280 dose levels*
Starting dose level - 0
Dose level - 1
Dose level - 2
INC280
400 mg BID
300 mg BID
200 mg BID
*Dose reduction should be based on the worst toxicity demonstrated at the last dose.
**Dose reduction below 200 mg is not allowed.


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Table 6-3
Criteria for interruption and re-initiation of INC280 treatment
To be considered recommended dose modifications, unless otherwise specified as mandatory in this Table 6-3. Refer to Table 6-4 for 
follow-up evaluations as applicable.
Refer to Table 6-4 for follow-up evaluations as applicable.
Recommended dose modifications for INC280
Worst toxicity CTCAE Gradea
During a cycle of therapy
No toxicity
Maintain dose level
HEMATOLOGICAL
Neutrophil count decreased (ANC) Neutropenia
Grade 1 (ANC < LLN - 1500/mm3; < LLN - 1.5 x 109/L)
Maintain dose level
Grade 2 (ANC < 1500 - 1000/mm3; < 1.5 - 1.0 x 109/L)
Maintain dose level
Grade 3 (ANC < 1000 - 500/mm3; < 1.0 - 0.5 x 109/L)
Omit dose until resolved to ≤grade 2, then:
If resolved in ≤ 7 days, resume treatment at the same dose level
If resolved in > 7 days, then ↓1 dose level
Grade 4 (ANC < 500/mm3; < 0.5 x 109/L)
Omit dose until resolved to ≤ grade 2 and then ↓1 dose level
Platelet count decreased (Thrombocytopenia)
Grade 1 (PLT < LLN - 75,000/mm3; < LLN - 75 x 109/L)
Maintain dose level
Grade 2 (PLT < 75,000 - 50,000/mm3; < 75 - 50 x 109/L)
Maintain dose level
Grade 3 (PLT < 50,000 - 25,000/mm3; < 50 - 25 x 109/L)
Omit dose until resolved to ≤ grade 2, then:
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then ↓1 dose level 
Grade 4 (PLT < 25,000/mm3; < 25 x 109/L)
Omit dose until resolved to ≤ grade 2, then ↓1 dose level
Febrile neutropenia (ANC < 1000/mm3 (< 1.0 x 109/L), 
fever > 38.3°C)
Omit dose, then:
If resolved in ≤ 7 days, resume treatment at ↓1 dose level
Mandatory: If resolved in > 7 days, discontinue patient from study drug treatment


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Recommended dose modifications for INC280
Worst toxicity CTCAE Gradea
During a cycle of therapy
Hemoglobin decreased (Anemia)
Grade 1 (Hgb < LLN - 10.0 g/dL; < LLN - 6.2 mmol/L; < 
LLN - 100 g/L)
Maintain dose level
Grade 2 (Hgb < 10.0 - 8.0 g/dL; < 6.2 – 4.9 mmol/L; < 100 
- 80 g/L)
Maintain dose level
Grade 3 (Hgb < 8.0 g/dL; < 4.9 mmol/L; < 80 g/L)
Omit dose until resolved to ≤ grade 2, then:
If resolved in ≤ 7 days, resume treatment at the same dose level
If resolved in > 7 days, then ↓1 dose level
Grade 4
Omit dose until resolved to ≤ grade 2 and then ↓1 dose level
Mandatory: If toxicity recurs, discontinue patient from study drug treatment.
RENAL
Serum creatinine
Grade 1 (> ULN - 1.5 x ULN)
Maintain dose level
Grade 2 (> 1.5 - 3.0 x ULN)
Omit dose until resolved to ≤ grade 1 or baseline, then resume treatment at the same dose level. 
Grade 3 (> 3.0 - 6.0 x ULN)
Omit dose until resolved to ≤ grade 1 or baseline, then resume treatment at ↓1 dose level. 
Grade 4 (> 6.0 x ULN)
Mandatory: Permanently discontinue patient from study drug treatment
HEPATIC
Isolated Total Bilirubin elevation*
Grade 1 (> ULN - 1.5 x ULN)
Maintain dose level
Grade 2 (> 1.5 - 3.0 x ULN)
Omit dose until resolved to ≤ grade 1, then 
If resolved in ≤ 7 days, maintain dose level
If resolved in > 7 days, ↓1 dose level
Grade 3 (> 3.0 - 10.0 x ULN)
Omit dose until resolved to ≤ grade 1, then 
If resolved in ≤ 7 days, ↓1 dose level 
If resolved in > 7 days, discontinue INC280 permanently
Grade 4 (> 10.0 x ULN)
Mandatory: Permanently discontinue patient from study drug treatment
Isolated AST or ALT elevation
Grade 1 (> ULN - 3 x ULN)
Maintain dose level
Grade 2 (> 3.0 - 5.0 x ULN)
Maintain dose level 
Grade 3 (> 5.0 - 20.0 x ULN)
Omit dose until resolved to ≤ grade 1 (or ≤ grade 2 if grade 2 elevation at baseline) then


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Recommended dose modifications for INC280
Worst toxicity CTCAE Gradea
During a cycle of therapy
If resolved in ≤ 7 days, then resume treatment at the same dose level
If resolved in > 7 days, resume treatment at ↓1 dose level
Grade 4 (> 20.0 x ULN)
For patients with clinical benefit from INC280 upon investigator’s judgement:

Omit dose until resolved to ≤ grade 1 (or ≤ grade 2 if grade 2 elevation at baseline), then resume 
treatment at ↓1 dose level. Only 1 dose reduction is allowed; if this AE reoccurs at Grade 3 or 
above, discontinue INC280 permanently.
For all other patients: 

Mandatory: Permanently discontinue patient from study drug treatment
Combined elevations of AST or ALT and Total Bilirubinb,d
For patients with normal baseline ALT and AST and total 
bilirubin value:
AST or ALT > 3.0 x ULN combined with total bilirubin > 
2.0 x ULN without evidence of cholestasisc
OR 
For patients with elevated baseline AST or ALT or total 
bilirubin value: 
[AST or ALT > 2 x baseline AND > 3.0 x ULN] OR [AST or 
ALT > 8.0 x ULN], whichever is lower, combined with
[total bilirubin > 2 x baseline AND > 2.0 x ULN]
Mandatory: Permanently discontinue patient from study drug treatment
METABOLIC
Asymptomatic amylase and/or lipase elevation (If symptomatic elevations of any grade, discontinue INC280 permanently)
Grade 1 (> ULN - 1.5 x ULN)
Maintain dose level
Grade 2 (> 1.5 - 2.0 x ULN)
Maintain dose level
Grade 3 (> 2.0 - 5.0 x ULN)
Omit the dose until resolved to ≤ grade 2, then
If resolved in ≤ 14 days, resume treatment at the same dose level
If resolved in > 14 days, then ↓1 dose level
Grade 4 (> 5.0 x ULN)
Mandatory: Permanently discontinue patient from study drug treatment


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Recommended dose modifications for INC280
Worst toxicity CTCAE Gradea
During a cycle of therapy
CARDIAC
Electrocardiogram QT corrected (QTc) interval prolonged
Grade 1 (QTcF 450-480 ms) and
Grade 2 (QTcF 481-500 ms)
Maintain dose level
Grade 3 (QTcF ≥ 501 ms on at least two separate ECGs)
Omit dose until resolved to ≤ grade 2, then:
If resolved in ≤ 7 days, resume treatment at the same dose level
If resolved in > 7 days, then ↓1 dose level
Grade 4 (QTcF ≥ 501 or > 60 ms change from baseline 
and Torsades de pointes or polymorphic ventricular 
tachycardia or signs/symptoms of serious arrhythmia)
Mandatory: Permanently discontinue patient from study drug treatment
GASTROINTESTINAL
Pancreatitis
Grade 2
Maintain dose level
Grade ≥ 3
Mandatory: Permanently discontinue patient from study drug treatment
Diarrhea**
Grade 1 (despite maximal anti-diarrheal medication)
Maintain dose level
Grade 2 (despite maximal anti-diarrheal medication)
Omit dose until resolved to ≤ grade 1, then maintain dose level.
If diarrhea returns as ≥ grade 2, then omit dose until resolved to ≤ grade 1, then resume treatment at↓1 
dose level
Grade 3 or 4 (despite maximal anti-diarrheal medication)
Omit dose until resolved to ≤ grade 1, then resume treatment at ↓1 dose level
Vomiting
Grade 1 (despite appropriate anti-emetics)
Maintain dose level
Grade 2 (despite appropriate anti-emetics)
Omit dose until resolved to ≤ grade 1, then maintain dose level.
If vomiting returns as ≥ grade 2, then omit dose until resolved to ≤ grade 1, then ↓1 dose level.
Grade 3 (despite appropriate anti-emetics)
Omit dose until resolved to ≤ grade 2, then ↓1 dose level
Grade 4 (despite appropriate anti-emetics)
Omit dose until resolved to ≤ grade 2, then ↓1 dose level
Nausea
Grade 1 or 2 (despite appropriate anti-emetics)
Maintain dose level
Grade 3 (despite appropriate anti-emetics)
Omit dose until resolved to ≤ grade 1, then ↓1 dose level


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Recommended dose modifications for INC280
Worst toxicity CTCAE Gradea
During a cycle of therapy
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Rash/photosensitivity***
Grade 1
Maintain dose level.
Grade 2
Maintain dose level.
Grade 3, despite skin toxicity therapy
Omit dose until resolved to grade ≤ 1, then:
If resolved in ≤ 7 days, then↓resume treatment at 1 dose level
If resolved in > 7 days (despite appropriate skin toxicity therapy), then discontinue patient from study drug 
treatment
Grade 4, despite skin toxicity therapy
Mandatory: Omit dose and discontinue patient from study drug treatment
RESPIRATORY DISORDERS
Interstitial Lung Disease (ILD) /Pneumonitis
Monitor patients for pulmonary symptoms indicative of ILD/Pneumonitis. In addition, withhold INC280 for acute onset of new or progressive unexplained pulmonary 
symptoms, such as dyspnea, cough and fever and during diagnostic workup for ILD/Pneumonitis to exclude alternative causes such as, but not limited to infections, 
lymphangitic carcinomatosis, cardiogenic edema, or pulmonary hemorrhage.
Grade 1
Interrupt INC280 during diagnostic workup for ILD/Pneumonitis. Exclude infections and other etiologies.
In presence of diagnosis of ILD/Pneumonitis after diagnostic workup, it is mandatory to permanently 
discontinue INC280.
Only in absence of diagnosis of ILD/Pneumonitis, study drug may be restarted at the same dose.
If it recurs after restarting of study drug, permanently discontinue INC280.
Grade 2
Mandatory: Interrupt INC280 dose during diagnostic workup for ILD until improvement to ≤ Grade 1. Exclude 
infections and other etiologies.
In presence of diagnosis of ILD/Pneumonitis after diagnostic workup, it is mandatory to permanently 
discontinue INC280.
Only in absence of diagnosis of ILD/Pneumonitis, study drug may be restarted following these guidelines:

If resolves to ≤ Grade 1 in ≤ 7 days reduce study drug by 1 dose level

If fails to resolve to ≤ Grade 1 within 7 days or recurs after resumption of study drug at decreased dose, 
permanently discontinue INC280
Grade 3 and Grade 4
Mandatory: Permanently discontinue study drug


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Recommended dose modifications for INC280
Worst toxicity CTCAE Gradea
During a cycle of therapy
Treat with IV steroids as clinically indicated. Oxygen therapy as indicated.
Fatigue/ Asthenia (General disorders and administration site conditions)
Grade 1 or 2
Maintain dose level
Grade 3
Omit dose until resolved to ≤ grade 1, then:
If resolved in ≤ 7 days, resume treatment at same dose level
If resolved in > 7 days, resume treatment at↓1 dose level
Peripheral edema 
Grade 1 or 2
Grade 3
Maintain dose level 
Discontinue dose until resolved to ≤ Grade 1, then ↓1 dose level
Other adverse events
Grade 1 or 2
Maintain dose level, consider to initiate appropriate support medication.
For any intolerable grade 2 (e.g.: limiting instrumental ADL), consider omitting the dose until resolved to ≤
grade 1, then↓1 dose level. 
Grade 3
Omit dose until resolved to ≤ grade 2, then↓1 dose level
Grade 4
Omit dose and then discontinue from study drug treatment
All dose modifications should be based on the worst preceding toxicity.
a Common Toxicity Criteria for Adverse Events (CTCAE Version 4.03).
b “Combined” defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST increase to the defined threshold
c “Cholestasis” defined as: ALP elevation (> 2.0 x ULN and R value (ALT/ALP in x ULN) < 2.0) in patients without bone metastasis, or elevation of ALP liver fraction in 
patients with bone metastasis
d If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the instructions for isolated elevation of total bilirubin and 
isolated elevation of AST/ALT, and take a conservative action based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is needed 
for one parameter and discontinue treatment is required for another parameter). After all elevations resolve to the defined thresholds that allow treatment re-initiation, re-
start the treatment either at the same dose or at one dose lower if meeting a criterion for dose reduction
* Note: If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as the etiology has been ruled out as per institutional guidelines 
(e.g., review of peripheral blood smear and haptoglobin determination), then ↓1 dose level and continue treatment at the discretion of the investigator.
** Note: antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt diarrhea
*** During the whole duration of treatment with INC280, the patient is recommended to use precautionary measures against ultraviolet exposure (e.g., use of sunscreen, 
protective clothing and avoid sunbathing or using a solarium intensively.


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6.3.3
Treatment interruption and treatment discontinuation
If the administration of INC280 is temporarily interrupted for reasons other than toxicity, then 
treatment with INC280 may be resumed at the same dose. If the treatment with INC280 is 
withheld due to toxicity, the dose modification guidelines in Table 6-3 should be followed. In 
any case, scheduled visits and all assessments (including tumor assessments) should continue 
to be performed, as described in Table 7-1.
If the treatment with INC280 is withheld for more than 21 consecutive days (counting from 
the first day when a dose was interrupted), then INC280 should be permanently discontinued. 
Under exceptional circumstance, when the investigator believes that continuing treatment may 
still derive clinical benefit for the patient, study treatment may be resumed. However, the 
investigator must discuss and receive approval from Novartis Medical Lead or designee prior 
to continuing INC280 treatment.
Patients who discontinue the study due to a study drug related AE or an abnormal laboratory 
value must be followed as described in Section 6.3.4.
6.3.4
Follow-up for toxicities
All patients will be followed for safety until 30 days after the last dose of INC280. Patients 
whose treatment is temporarily interrupted or permanently discontinued due to an AE or 
abnormal laboratory value must be followed until resolution or stabilization of the event, 
whichever comes first, including all study assessments appropriate to monitor the event.
An unscheduled assessment should be performed in all cases below where toxicity monitoring 
is recommended more frequently than defined by the schedule of assessments. Subsequent 
monitoring must be performed as per the regular visit schedule.
All patients should receive best supportive care (BSC) as per standard local practice for the 
treatment of pre-existing medical conditions or adverse events that may arise during the study. 
BSC is defined as drug or non-drug therapies, nutritional support, physical therapy, or any 
other treatment alternative that the investigator believes to be in the patient’s best interest, but 
excluding other anti-neoplastic treatments (with the exception of radiotherapy for control of 
bone metastases – see Section 6.4.1).
Table 6-4
Follow-up evaluations for selected toxicities*
TOXICITY
FOLLOW-UP EVALUATION
HEMATOLOGICAL
Febrile neutropenia,
Neutropenia ≥ CTCAE grade 3
Thrombocytopenia ≥ CTCAE grade 3
Anemia ≥ CTCAE grade 3
Test weekly (or more frequently if clinically indicated) until ≤ CTCAE 
grade 2.
Perform physical exam for check on bruising in case of major 
thrombocytopenia.
RENAL
Serum creatinine ≥ CTCAE grade 2
Test weekly (or more frequently if clinically indicated) until ≤ CTCAE 
grade 1 or baseline.
Patients will be instructed to increase hydration until resolution to ≤ 
CTCAE grade 1 or baseline.


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TOXICITY
FOLLOW-UP EVALUATION
HEPATIC
Isolated total bilirubin elevation
Isolated AST/ALT elevation 
Total bilirubin CTCAE Grade 1:
Monitor LFTs per protocol or more frequently if clinically indicated 
Total bilirubin CTCAE Grade 2:
Weekly monitoring of LFTs, or more frequently if clinically indicated, until 
resolved to ≤ 1.5 x ULN
Total bilirubin CTCAE Grade 3:
Weekly monitoring of LFTs, or more frequently if clinically indicated, until 
resolved to ≤ 1.5 x ULN. If resolved in > 7 days, after discontinuing the 
patient from INC280 permanently, the patient should be monitored 
weekly (including LFTs), or more frequently if clinically indicated, until 
total bilirubin have resolved to baseline or stabilization over 4 weeks
Total bilirubin CTCAE Grade 4:
After discontinuing the patient from INC280 permanently, the patient 
should be monitored weekly (including LFTs), or more frequently if 
clinically indicated, until total bilirubin have resolved to baseline or 
stabilization over 4 weeks
AST/ALT CTCAE Grade 2 elevation:
For patients with baseline value ≤ 3.0 x ULN: repeat LFTs as soon as 
possible, preferably within 48-72 hours from awareness of the abnormal 
results; if abnormal lab values are confirmed upon the repeat test, then 
monitor LFTs weekly, or more frequently if clinically indicated, until 
resolved to ≤ 3.0 x ULN
For patients with baseline value > 3.0 - 5.0 x ULN: monitor LFTs per 
protocol or more frequently if clinically indicated
AST/ALT CTCAE Grade 3 elevation:
For AST/ALT elevation > 5.0 - 10.0 x ULN:

For patients with baseline value ≤3.0 x ULN: repeat LFTs as soon as 
possible, preferably within 48-72 hours from awareness of the 
abnormal results; monitor LFTs weekly, or more frequently if clinically 
indicated, until resolved to ≤ 3.0 x ULN 

For patients with baseline value > 3.0 - 5.0 x ULN: repeat LFTs as 
soon as possible, preferably within 48-72 hours from awareness of 
the abnormal results; if abnormal lab values are confirmed upon the 
repeat test, then monitor LFTs, weekly, or more frequently if clinically 
indicated, until resolved to ≤ 5.0 x ULN 
For AST/ALT elevation > 10.0 - 20.0 x ULN: 

Repeat LFTs as soon as possible, preferably within 48-72 hours from 
awareness of the abnormal results; monitor LFTs weekly, or more 
frequently if clinically indicated, until resolved to ≤ baseline
AST/ALT CTCAE Grade 4 elevation:
Repeat LFTs as soon as possible, preferably within 48-72 hours from 
awareness of the abnormal results; monitor LFTs weekly, or more 
frequently if clinically indicated, until resolved to baseline or stabilization 
over 4 weeks.
HEPATIC
Combined AST or ALT and total 
bilirubin elevation
Combined elevations of AST or ALT and total bilirubin:
After discontinuing the patient from INC280 permanently, repeat LFTs as 
soon as possible, preferably within 48 hours from awareness of the 
abnormal results, then with weekly monitoring of LFTs, or more 
frequently if clinically indicated, until AST, ALT, or bilirubin have resolved 
to baseline or stabilization over 4 weeks.
Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated [direct 
and indirect], if total bilirubin > 2.0 x ULN), and alkaline phosphatase 
(fractionated [quantification of isoforms], if alkaline phosphatase > 2.0 x 
ULN.)


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TOXICITY
FOLLOW-UP EVALUATION
METABOLIC
Asymptomatic amylase or lipase ≥ 
CTCAE grade 3
Test weekly (or more frequently) until ≤ CTCAE grade 2.
A CT scan or equivalent imaging procedure to assess the pancreas, 
liver, and gallbladder is recommended within 7 days of the first 
occurrence of any ≥ CTCAE grade 3 result, to exclude disease 
progression or potential other liver or pancreatic disease.
CARDIAC
≥ CTCAE grade 3
QTcF ≥501 ms (CTCAE grade 3)
Test weekly (or more frequently) until ≤CTCAE grade 2.
When QTcF ≥ 501 ms (CTCAE grade 3), perform the following:

Call the study’s central ECG review laboratory immediately and 
request an immediate manual read of the ECG.

Perform an analysis of serum potassium, calcium, phosphorus, and 
magnesium, and if below lower limit of normal, correct with 
supplements to within normal limits.

Review concomitant medication usage for the potential to inhibit 
CYP3A4/5 (Table 6-5) and/or to prolong the QT-interval (Table 6-6).

Check compliance with correct dose and administration of INC280.
Perform a repeat ECG within one hour of the first QTcF of ≥501 ms.

If QTcF remains ≥ 501 ms, repeat ECG as clinically indicated, but at 
least once daily until the QTcF returns to < 501 ms.
Repeat ECGs 7 days and 14 days (and then every 21 days) after dose 
resumption for all patients who had therapy interrupted due to QTcF ≥ 
501 ms.

If QTcF of ≥ 501 ms recurs, repeat ECGs as described above.
Notes:

The investigator should contact the Novartis Medical Lead or 
designee regarding any questions that arise if a patient with QTcF 
prolongation should be maintained on study.

If the central ECG report shows a QTcF ≥ 501 msec (not previously 
documented on the site machine), contact the patient and instruct 
him/her to suspend INC280 and return for a repeat ECG as soon as 
possible. The central ECG reader should be called for a manual read 
of the repeat ECG immediately, and the above guidance followed.


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TOXICITY
FOLLOW-UP EVALUATION
GASTROINTESTINAL
Diarrhea
Nausea and Vomiting
Initiate anti-diarrhea treatment after first signs of abdominal cramping, 
loose stools or overt diarrhea.
Consider/Investigate potential concomitant medication, food or 
comorbidity driven causes of diarrhea (including infectious causes) and 
remedy these causes if possible (e.g. discontinuation of concomitant 
medication, dietary modification, treatment of comorbidity).
The patient should be monitored for signs of dehydration and instructed 
to take preventive measures against dehydration as soon as diarrhea 
occurs. Antidiarrheal medication must be initiated at the first sign of 
abdominal cramping, loose stools or overt diarrhea. Concomitant 
medication for the treatment of diarrhea should follow local practice and 
the investigator’s best judgment and may follow “the recommended 
guidelines for the treatment of cancer treatment-induced diarrhea” 
(Benson et al 2004). For example:

For uncomplicated diarrhea (grade 1 or 2 without complicating signs 
or symptoms), loperamide given at a standard dose (e.g. initial 
administration of 4 mg, then 2 mg every 2-4 hours, maximum of 16 
mg/day), along with oral hydration and dietetic measures should be 
considered. Note: complicating signs or symptoms include: moderate 
to severe cramping, decreased performance status, fever, 
neutropenia, frank bleeding or dehydration.

For complicated diarrhea (all grade 3 or 4, grade 1-2 with 
complicating signs or symptoms), management should involve 
intravenous (IV) fluids, and consider treatment with octreotide (at 
starting dose of 100 to 150 µg sub-cutaneous tid or 25 to 50 µg IV) 
and antibiotics (e.g. fluoroquinolone) should be given.
The investigator should consider/investigate potential concomitant 
medication, food or comorbidity driven causes of nausea and/or vomiting 
and remedy these causes if possible (e.g. discontinuation of concomitant 
medication, dietary modification, treatment of comorbidity).
Individualized supportive and anti-emetic treatment should be initiated, 
as appropriate, at the first signs and/or symptoms of these AEs. In 
patients with vomiting, the patient should be monitored for signs of 
dehydration and instructed to take preventive measures against 
dehydration.
Concomitant medication for the treatment of nausea and/or vomiting 
should follow local practice and the investigator’s best judgment.
SKIN TOXICITY (rash and 
photosensitivity)
CTCAE grade 1
CTCAE grade 2
≥ CTCAE grade 3
Consider to initiate institute appropriate skin toxicity therapy (such as 
antihistamines, topical corticosteroids and low-dose systemic 
corticosteroids)
Initiate/intensify appropriate skin toxicity therapy (such as antihistamines, 
topical corticosteroids and low-dose systemic corticosteroids).
Intensify appropriate skin toxicity therapy and monitor weekly or more 
frequently until resolved to grade ≤ 2


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TOXICITY
FOLLOW-UP EVALUATION
Peripheral edema
≤ CTCAE grade 2
≥ CTCAE grade 3
Consider to initiate conservative measures such as leg elevation, 
compression stockings, and dietary salt modification as clinically 
indicated
Initiate/intensify conservative measures
RESPIRATORY DISORDERS
ILD /Pneumonitis
CTCAE Grade 1
CTCAE Grade 2
CTCAE Grade 3 and Grade 4
CT scan (high-resolution with lung windows) recommended, with serial 
imaging to monitor for resolution or progression - re-image at least every 
3 weeks
Monitor for symptoms every 2-3 days - Clinical evaluation and laboratory 
work-up for infection
Monitoring of oxygenation via pulse oximetry recommended
Consultation of pulmonologist recommended
CT scan (high-resolution with lung windows)

Monitor symptoms daily, consider hospitalization

Clinical evaluation and laboratory work up for infection

Consult pulmonologist

Pulmonary function tests a - if normal at baseline, repeat every 8 
weeks 

Bronchoscopy with biopsy and/or BAL recommended c

Symptomatic therapy including corticosteroids if clinically indicated 
(1 to 2 mg/kg/day prednisone or equivalent as clinically indicated) b
CT scan (high-resolution with lung windows)
Clinical evaluation and laboratory work-up for infection
Consult pulmonologist
Pulmonary function testsa - if < normal, repeat every 8 weeks until ≥ 
normal
Bronchoscopy with biopsy and/or BAL if possiblec
Treat with IV steroids (methylprednisolone 125 mg) as indicated. When 
symptoms improve to ≤ Grade 1, a high dose oral steroid (prednisone 1 
to 2 mg/kg once per day or dexamethasone 4 mg every 4 hours)b.
If IV steroids followed by high dose oral steroids does not reduce initial 
symptoms within 48 to 72 hours, consider non-corticosteroid 
immunosuppressive medication
*Note: this table refers only to the evaluation schedule to monitor selected toxicities. Refer to Table 6-3 for dose 
modifications required for applicable toxicities
**Note: except if the patient is Grade 2 at baseline in which case: it is ≥ CTCAE grade 3
a PFT (Pulmonary function tests) to include: diffusing capacity corrected for hemoglobin (DLCO); spirometry; 
resting oxygen saturation
Guideline for significant deterioration in lung function: Decrease in spirometry and/or DLCO of 30% and/or O2
saturation ≤ 88% at rest on room air.
b Duration and dose of course of corticosteroids will vary according to circumstances but should be as limited as 
possible. Consider tapering dosage at end.
c If bronchoscopy is performed, bronchoalveolar lavage (BAL) should be done where possible to exclude alveolar 
hemorrhage, opportunistic infections, cell count + determination lymphocyte CD4/8 count where possible.


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6.3.4.1
Follow up on potential drug-induced liver injury cases
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events. 
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
values; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 

For patients 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], whichever is lower, 
combined with [TBIL > 2 x baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as: ALP elevation > 2.0 x ULN with R value (ALT/ALP in x ULN) < 2 in patients without 
bone metastasis, or elevation of ALP liver fraction in patients with bone metastasis.
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from 
the awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 

Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase. 

A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected. 

Further testing for acute hepatitis A, B, C or E infection and liver imaging (eg, biliary tract) 
may be warranted. 

Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study. 

Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented.
6.3.5
Anticipated risks and safety concerns of the study drug
Appropriate eligibility criteria as well as specific dose modification and stopping rules are 
included in this protocol. Recommended guidelines for prophylactic or supportive treatment 
for expected toxicities, including management of study-drug induced adverse events, i.e., 


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nausea, vomiting and diarrhea are provided in Section 6.3 and Section 6.4. Refer to preclinical 
toxicity and or clinical data found in the most current [Investigator’s Brochure].
6.4
Concomitant medications
Drugs in Table 6-5 and Table 6-6 are presented by mechanism of interaction. Table 6-7
presents drugs known to cause Torsades des Pointes.
In general, the use of any concomitant medication/therapy deemed necessary for the care of 
the patient (e.g. such as anti-emetics, anti-diarrhea) is permitted (see Section 6.4.1), except 
when specifically prohibited (see Section 6.4.3).
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (excluding study treatment and prior 
antineoplastic treatments), blood transfusions, surgeries and procedures (including physical 
therapy) administered within 28 days prior to the first dose administration of INC280 through 
30 days after the last dose of INC280 will be recorded in the Concomitant Medications or 
Surgical and Medical Procedures eCRF, respectively. Medications include not only physician 
prescribed medications, but also all over-the counter medications, herbal medications, food 
supplements and vitamins.
The following restrictions apply during the entire duration of the study:

No other investigational therapy should be given to patients

No anticancer agents other than the study medication (INC280) should be given to patients.
6.4.1
Permitted concomitant therapy
Patients are permitted to use the following medications while taking INC280:

Oral or topical antibiotics

Medications to prevent or treat nausea, vomiting or diarrhea

Growth factors (e.g. G-CSF, GM-CSF, erythropoietin, platelets growth factors, etc.) are 
allowed per the investigator’s judgement and per local guidelines.

Treatment with bisphosphonates for pre-existing bone metastases is permitted, if clinically 
indicated, and following existing local guidelines. Treatment with bisphosphonates should 
preferably begin before the study treatment is initiated, but can also be initiated during 
therapy only if absence of radiological bone disease progression is well documented (in 
this case, the reason for its use must be clearly documented; i.e. “pre-existing, non-
progressing, bone metastases”).

Oxygen therapy and blood products or transfusions

Nutritional support or appetite stimulants

Pain medication

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.


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6.4.2
Permitted concomitant therapy requiring caution and/or action

INC280 is a moderate CYP1A2 inhibitor. Co-administration of INC280 increased 
sensitive CYP1A2 probe substrate (caffeine) AUC by 135% (see Section 1.2.1.2). The 
dose of CYP1A2 substrates with narrow therapeutic index may need to be reduced when 
used concurrently with INC280 as INC280 may increase their exposure. Consult the 
product information of concomitant drug for dose adjustment.

Co-administration of INC280 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) (see Section 1.2.1.2). Monitor patients closely for 
symptoms of increased exposure to Pgp or BCRP substrates. Consult the concomitant Pgp 
or BCRP substrate product information when considering dose adjustment.

Co-administrating INC280 with strong CYP3A4 inhibitor (itraconazole) increased 
INC280 AUC by 40%. There is no change in INC280 Cmax. Execute caution when using 
a strong CYP3A4 inhibitor concurrently with INC280. 

In healthy subjects, co-administration of PPI decreased INC280 AUCinf by 25% and Cmax
by 38%. In cancer patients [CINC280A2108], ~30% lower AUC,ss was observed in 
patients with concomitant use of PPI compared to that in patients without PPI use. The 
decrease in exposure imposes caution on the use of PPI when INC280 is taken.

Short acting gastric acid modulators containing aluminum hydroxide and magnesium 
hydroxide, or calcium carbonate can be taken with caution. However, it is recommended 
to take these drugs at least 1 hour before or 2 hours after administration of INC280. 

H2 receptor antagonists should be used with caution. If patients are using H2 receptor 
antagonists during the course of this study, INC280 should be administered at least 3 h 
before or 6 h after an H2-receptor antagonist.

INC280 is a weak to moderate inhibitor of CYP2C8, CYP2C9 and CYP2C19 in vitro. 
Substrates of CYP2C8, CYP2C9 and CYP2C19 with a narrow therapeutic index should be 
administered with caution
Refer to Table 6-5 below for a list of the medications that require caution when concomitantly 
used with INC280.
Table 6-5
Drugs to be used with caution while on study
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, elvitegravir/ritonavir, 
saquinavir/ritonavir, lopinavir/ritonavir, itraconazole, voriconazole, mibefradil, , 
posaconazole, telithromycin, grapefruit juice, conivaptan, nefazodone, 
nelfinavir, idelalisib, boceprevir, atazanavir/ritonavir, darunavir/ritonavir
CYP1A2 substrate with NTI
theophylline, tizanidine
CYP2C9 substrate with NTI
warfarin
CYP2C19 substrate with NTI
(S)-mephenytoin
P-gp substrates
afatinib, alfuzosin, aliskiren, alogliptin, ambrisentan, apixaban, apremilast, 
aprepitant, boceprevir, bosentan, carvedilol, carvedilol, caspofungin, ceritinib,  
colchicine, cyclosporine, dabigatran, digoxin, doxepin, doxorubicin, eribulin, 
everolimus, fidaxomicin, fluvastatin, fosamprenavir, idelalisib, iloperidone, 
indacaterol, irbesartan, lacosamide, lapatinib, levetiracetam, linagliptin, 


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Mechanism of Interaction
Drug Name
losartan, maraviroc, mirabegron, naloxegol, nateglinide, nintedanib, 
olodaterol, pantoprazole, paroxetine, pazopanib, posaconazole, pravastatin, 
quinine, ranolazine, riociguat, risperidone, rivaroxaban, saquinavir, silodosin, 
simeprevir, sirolimus, sitagliptin, sorafenib, telaprevir, tenofovir, ticagrelor, 
tipranavir, tolvaptan, topotecan, umeclidinium, valsartan, vardenafil, 
vincristine, voriconazole, atorvastatin, docetaxel, fentanyl, fexofenadine, 
linezolid, loperamide, nadolol, nevirapine, paclitaxel, proguanil, ritonavir, 
simvastatin, sofosbuvir, tacrolimus
BCRP substrates
Atorvastatin, daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, 
imatinib, methotrexate, mitoxantrone, paritaprevir, pitavastatin, rosuvastatin, 
irinotecan, ethinyl estradiol, simvastatin, sofosbuvir, sulfasalazine, tenofovir, 
topotecan, venetoclax
Proton pump inhibitor
Omeprazole, pantoprazole, lansoprazole, esomeprazole, rabeprazole, 
dexlansoprazole
Short acting gastric acid 
modulator and H2 receptor 
antagonist
ranitidine, nizatidine, famotidine, cimetidine, aluminum hydroxide, aluminum 
carbonate, calcium hydroxide, calcium carbonate, bismuth subsalicylate
Source: The list is adapted from the Novartis Institutes for Biomedical PK Sciences internal memorandum (Jan 
2018): drug-drug interactions (DDI) database, which is compiled primarily from the Indiana University School of 
Medicine’s “Clinically Relevant” Table (medicine.iupui.edu/flockhart/table.htm), the University of Washington’s Drug 
Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction Studies”
This may not be an exhaustive list, will be updated periodically.
NTI: narrow therapeutic index
6.4.3
Prohibited concomitant therapy

Co-administrating INC280 with strong CYP3A4 inducer (rifampicin) decreased INC280 
AUC by 66% and Cmax by 56%. Concurrent use of strong CYP3A4 inducers is prohibited 
as decreased INC280 exposure may lead to reduced efficacy.

Drugs with a known risk of Torsades des Pointes (TdP) are prohibited. For identification 
of drugs with known risk of TdP please refer to qtdrugs.org (refer to Table 6-7). 
Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies while on treatment.
The prohibited medications are listed in the Table 6-6 and Table 6-7 below.
Table 6-6
Drugs prohibited while on study
Mechanism of Interaction
Drug Name
Strong CYP3A4 inducer
carbamazepine, enzalutamide, lumacaftor, phenobarbital, phenytoin, 
rifabutin, rifampicin, mitotane, St. John’s wort (Hypericum perforatum)
Source: The list is adapted from the Novartis Institutes for Biomedical PK Sciences internal memorandum (Jan 
2018): drug-drug interactions (DDI) database, which is compiled primarily from the Indiana University School of 
Medicine’s “Clinically Relevant” Table (medicine.iupui.edu/flockhart/table.htm), the University of Washington’s Drug 
Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction Studies” This 
may not be an exhaustive list, will be updated periodically.
Table 6-7
Drugs with a known risk of Torsades des Pointes prohibited while on 
study
Class of medication
Drug Name
With Known risk of Torsades des 
Pointes
amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, 
chloroquine, chlorpromazine, cilostazol, ciprofloxacin, cisapride, citalopram, 
clarithromycin, disopyramide, dofetilide, domperidone, donepezil, dronedarone, 


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Class of medication
Drug Name
droperidol, erythromycin, escitalopram, flecainide, fluconazole, gatifloxacin, 
halofantrine, haloperidol, ibutilide, levofloxacin, levomepromazine, 
levosulpiride, methadone, moxifloxacin, ondansetron, oxaliplatin, papaverine 
HCl (intra-coronary), pentamidine, pimozide, procainamide, propofol, quinidine, 
roxithromycin, sevoflurane, sotalol, sulpiride, sultopride, terlipressin, terodiline, 
thioridazine, vandetanib
This may not be an exhaustive list.
Check:  crediblemeds.org/healthcare-providers/drug-list for the most updated list.
6.5
Patient numbering and treatment assignment
6.5.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned 
when the patient is first enrolled for pre-screening and is retained as the primary identifier for 
the patient throughout his/her entire participation in the trial. The Subject No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a 
sequential patient number suffixed to it, so that each subject is numbered uniquely across the 
entire database. Upon signing the molecular pre-screening informed consent form, the patient 
is assigned to the next sequential Subject No. available to the investigator through the Oracle 
Clinical RDC interface.
At the molecular pre-screening visit, the investigator or designated staff will contact the IRT 
and provide the requested identifying information for the patient to register them into the IRT. 
Once assigned, the Subject No. must not be reused for any other subject and the Subject No. 
for that individual must not be changed, even if the patient is re-screened.
6.5.2
Treatment assignment
At the main screening visit, the investigator or his/her delegate will call or log on to the IRT 
and confirm that the patient fulfills the molecular pre-screening criteria. Prior to dosing he/she 
or delegate will call or log on to the IRT again (at the C1D1 visit) to confirm that the patient 
fulfills all main screening inclusion/exclusion criteria and that the patient can initiate study 
treatment. If the patient fails to start treatment for any reason, the reason will be entered into 
the Screening Disposition eCRF page.
IRT must be notified within 2 days if the patient did not start treatment.
The assignment of a patient to a particular cohort will be coordinated by Novartis via IRT 
based on cMET GCN and cMET mutation pre-screening and prior treatment status results 
either:

Cohort 1: Patients with cMET GCN ≥ 6, including:

Sub-cohort 1a: Patients with cMET GCN of ≥ 10, or

Sub-cohort 1b: Patients with cMET GCN of ≥ 6 and < 10, or

Cohort 2: Pre-treated patients with cMET GCN ≥4 and < 6, or

Cohort 3: Pre-treated patients with cMET GCN < 4, or

Cohort 4: Pre-treated patients with cMET mutations regardless of cMET GCN, or

Cohort 5 treatment-naïve patients with cMET dysregulation, including:  


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
Sub-cohort 5a: Patients with cMET GCN of ≥10, or

Sub-cohort 5b: Patients with cMET mutations regardless of cMET GCN, or

Cohort 6: Pre-treated patients with either cMET GCN ≥ 10 without cMET mutations or 
cMET mutations regardless of cMET GCN, or

Cohort 7: Treatment-naïve patients with cMET mutations regardless of cMET GCN
In addition, in Cohort 2 (if not stopped for futility at the IA), the study enrollment target of 
~40% of patients (i.e. at least 11 patients for the IA and 28 patients for the final enrollment) 
with GCN ≥5 and < 6 at the time of both the interim and the final analysis will be managed 
via IRT. To achieve this target, the IRT system may close the enrollment of patients with 
GCN ≥4 and < 5 when the target of 60% (i.e. at least 17 patients for the IA and 41 patients 
for the final enrollment) of the patients with GCN ≥4 and < 5 is reached.
All patients will receive the same treatment regimen regardless of the cohort to which they are 
allocated.
6.5.3
Treatment blinding
Not applicable.
6.6
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF.
Table 6-8
Preparation and dispensing
Study treatments
Dispensing
Preparation
INC280
Tablets including instructions for administration are 
dispensed by study personnel on an outpatient basis.
Patients will be provided with adequate supply of study 
treatment for self-administration at home until at least their 
next scheduled study visit.
Not applicable
6.6.1
Study drug packaging and labeling
The study medication packaging has a 2-part label. Immediately before dispensing the 
package to the patient, site personnel will detach the outer part of the label from the packaging 
and affix it to the source document (Drug Label Form) for that patient’s unique patient 
number.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug and the medication number 
but no information about the patient.
Table 6-9
Packaging and labeling
Study treatments
Packaging
Labeling
INC280
Tablets in 
bottles
Medication labels comply with the legal requirements of each country and 
will be printed in the local language. They will supply no information about 


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Study treatments
Packaging
Labeling
the patient. The storage conditions for the study drug will be described on 
the medication label.
6.6.2
Drug supply and storage
Study treatments must be received by designated personnel 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, INC280 should be stored according to 
the instructions specified on the drug labels and in the current [Investigator’s Brochure].
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Data for all doses of study medication will be recorded on the Dosage Administration eCRF 
page.
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and 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.
6.6.3.3
Handling of other study treatment
Not applicable.
6.6.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate.
The drug supply can also be destroyed at the site if permitted by local regulations and 
authorized by Novartis in a prior agreement.


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7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. The table indicates which assessments produce data to be entered into the 
database (D) or remain in the source documents only (S) (“Category” column). The eCRF will 
not be used as a source document.
Written informed consent must be obtained before any study specific assessments are 
performed, including those at molecular screening and screening. Main screening evaluations 
and baseline radiological tumor assessments should be performed within 28 days of treatment 
start.
Each treatment cycle is 21 days (the 21 days cycle length is fixed regardless of whether the 
dose of INC280 is withheld).
All visits are to be scheduled according to the appropriate number of calendar days from 
Cycle 1 Day 1 of study drug administration. Every effort must be made to follow the schedule 
of assessments within the windows outlined in the protocol.
After screening:

All assessments have a ±3 day window unless otherwise indicated

Radiological tumor assessments may be performed within a ±4 day window, unless 
otherwise indicated

If a given visit is out of window, the next visit should be performed with reference to the 
day of first dose in order to get the patient back on schedule

If an off-schedule imaging assessment is performed, subsequent imaging assessments 
should be performed in accordance with the original imaging schedule

Laboratory assessments and height/weight performed as part of the screening evaluations 
and within 7 days of the first dose of study drug, will not be required to be repeated on 
Cycle 1, Day 1

All assessments on Cycle 1, Day 1 must be done prior to the first dose unless otherwise 
specified. It is recommended that the investigator checks the pre-dose laboratory results 
prior to starting treatment

Patients who discontinue INC280 treatment must have EOT visit performed ≤7 days after 
stopping study drug

Permitted contact windows for survival follow-up: +/- 7 days
Additional assessments may be performed as clinically indicated.


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Table 7-1
Visit evaluation schedule
Category
Protocol 
Section 
reference
Molecular pre-
screening and 
Main Screening 
Phases
Study Treatment Phase
Post-treatment Follow-
Up phase (safety follow-
up within 30d of last dose 
for all patients and
efficacy follow-up every 6 
weeks until BIRC-
confirmed disease 
progression)
Survival 
Follow-up 
Phase
Cycle 1
(21 days)
Subsequent cycles (21 
days per cycle)
End of 
study 
treatment 
(EOT)
Visit Name
Molecular
pre-screen
Screening 
Visit (D-
28 to D-1)
C1
D1
C1
D15
C2
D1
C3
D1
C4D1 
C5D1 
etc…
EOT Visit 
(within 7d of 
last dose)
Tumor 
Follow-Up 
(every 6 wks)
Study 
Evaluation 
Completion
Survival 
Follow-Up 
(every 3 mo)
Pre-Screening
Confirmation of EGFR wild-
type & ALK-negative
rearrangement status
D
5.2
X
Obtain Molecular Pre-
Screening ICF
D
7.1.1
X
Newly obtained tumor biopsy 
(preferred) or archival tumor 
sample to confirm ALK-
negative rearrangement 
status, only if ALK local testing 
not available
D
7.1.1.1
X
Newly obtained tumor biopsy 
(preferred) or archival tumor 
sample to confirm cMET 
amplification and/or mutation
status
D
7.1.1.1
X
Main Screening
Obtain Main ICF 
D
7.1.2
X
IRT Registration
S
6.5.1
X
X
X
X


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Category
Protocol 
Section 
reference
Molecular pre-
screening and 
Main Screening 
Phases
Study Treatment Phase
Post-treatment Follow-
Up phase (safety follow-
up within 30d of last dose 
for all patients and
efficacy follow-up every 6 
weeks until BIRC-
confirmed disease 
progression)
Survival 
Follow-up 
Phase
Cycle 1
(21 days)
Subsequent cycles (21 
days per cycle)
End of 
study 
treatment 
(EOT)
Visit Name
Molecular
pre-screen
Screening 
Visit (D-
28 to D-1)
C1
D1
C1
D15
C2
D1
C3
D1
C4D1 
C5D1 
etc…
EOT Visit 
(within 7d of 
last dose)
Tumor 
Follow-Up 
(every 6 wks)
Study 
Evaluation 
Completion
Survival 
Follow-Up 
(every 3 mo)
Patient History
Demography
D
7.1.2.3
X
Information on prior local 
testing for cMET amplification 
and cMET mutation including
prior central NGS result, if 
applicable 
D
7.1.2.3
X
Inclusion/exclusion criteria
D
5.2; 5.3
X
Eligibility check 
S
7.1.2.1
X
Relevant medical 
history/current medical 
conditions 
D
7.1.2.3
X
Smoking History
D
7.1.2.3
X
Diagnosis and extent of 
cancer 
D
7.1.2.3
X
Prior antineoplastic therapies 
(meds, surgery, radiation)
D
7.1.2.3
X
Prior and current concomitant 
medications (including OTC 
meds); procedures and 
significant non-drug therapies
D
7.1.2.3
Continuous until ≥ 30 days after the last dose of INC280


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Category
Protocol 
Section 
reference
Molecular pre-
screening and 
Main Screening 
Phases
Study Treatment Phase
Post-treatment Follow-
Up phase (safety follow-
up within 30d of last dose 
for all patients and
efficacy follow-up every 6 
weeks until BIRC-
confirmed disease 
progression)
Survival 
Follow-up 
Phase
Cycle 1
(21 days)
Subsequent cycles (21 
days per cycle)
End of 
study 
treatment 
(EOT)
Visit Name
Molecular
pre-screen
Screening 
Visit (D-
28 to D-1)
C1
D1
C1
D15
C2
D1
C3
D1
C4D1 
C5D1 
etc…
EOT Visit 
(within 7d of 
last dose)
Tumor 
Follow-Up 
(every 6 wks)
Study 
Evaluation 
Completion
Survival 
Follow-Up 
(every 3 mo)
Physical Examination
Complete physical 
examination, including 
neurological exams
S
7.2.2.1
X
If clinically indicated
Targeted physical examination
S
7.2.2.1
X
X
X
X
X
X
Height
D
7.2.2.3
X
Weight
D
7.2.2.3
X
X
X
X
X
X
ECOG Performance status
D
7.2.2.4
X
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X
Laboratory assessments
Hematology
D
7.2.2.5
X
X
X
X
X
X
X
Chemistry
D
X
X
X
X
X
X
X
Coagulation
D
X
If clinically indicated
Urinalysis (dipstick) with 
micro-analysis
D
X
If clinically indicated
Serum pregnancy test (if 
applicable)
D
X
X
X
X
X
X
Tumor assessments RECIST 1.1
CT scan or MRI of chest, 
abdomen, pelvis ( EOT scan 
not required if previous scan 
was performed within ≤28 
D
7.2.1
X
X
C5D1 
and 
every 6 
wks
X
X (every 
6wks)


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Category
Protocol 
Section 
reference
Molecular pre-
screening and 
Main Screening 
Phases
Study Treatment Phase
Post-treatment Follow-
Up phase (safety follow-
up within 30d of last dose 
for all patients and
efficacy follow-up every 6 
weeks until BIRC-
confirmed disease 
progression)
Survival 
Follow-up 
Phase
Cycle 1
(21 days)
Subsequent cycles (21 
days per cycle)
End of 
study 
treatment 
(EOT)
Visit Name
Molecular
pre-screen
Screening 
Visit (D-
28 to D-1)
C1
D1
C1
D15
C2
D1
C3
D1
C4D1 
C5D1 
etc…
EOT Visit 
(within 7d of 
last dose)
Tumor 
Follow-Up 
(every 6 wks)
Study 
Evaluation 
Completion
Survival 
Follow-Up 
(every 3 mo)
days)
Whole body bone scan
D
X
Only if clinically indicated
CT scan or MRI of brain
D
X
C3D1 and every 6 wks (if positive at baseline) or if 
clinically indicated
CT scan or MRI of other
metastatic sites (e.g., neck, 
etc)
D
X (if other 
metastatic 
sites)
C3D1 and every 6 wks (if positive at baseline) or if 
clinically indicated
Localized bone CT scan, MRI
or X-ray (for any lesions 
identified on the whole body 
bone scan that are not visible 
on the chest/abdomen/pelvis 
CT scan or MRI)
D
X (only if 
lesions on 
whole 
body scan 
that are 
not visible 
on the 
CAP 
scans)
C3D1 and every 6 wks (if positive at baseline) or if 
clinically indicated
Photography (for skin lesions)
D
X (only if 
skin 
lesions)
C3D1 and every 6 wks (if positive at baseline) or if 
clinically indicated
Safety assessments
Adverse events
D
8.1
Continuous until ≥ 30 days after the last dose of INC280


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Category
Protocol 
Section 
reference
Molecular pre-
screening and 
Main Screening 
Phases
Study Treatment Phase
Post-treatment Follow-
Up phase (safety follow-
up within 30d of last dose 
for all patients and
efficacy follow-up every 6 
weeks until BIRC-
confirmed disease 
progression)
Survival 
Follow-up 
Phase
Cycle 1
(21 days)
Subsequent cycles (21 
days per cycle)
End of 
study 
treatment 
(EOT)
Visit Name
Molecular
pre-screen
Screening 
Visit (D-
28 to D-1)
C1
D1
C1
D15
C2
D1
C3
D1
C4D1 
C5D1 
etc…
EOT Visit 
(within 7d of 
last dose)
Tumor 
Follow-Up 
(every 6 wks)
Study 
Evaluation 
Completion
Survival 
Follow-Up 
(every 3 mo)
Study drug administration
INC280 dosing
D
6.1
Continuous twice daily dosing (BID)


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Category
Protocol 
Section 
reference
Molecular pre-
screening and 
Main Screening 
Phases
Study Treatment Phase
Post-treatment Follow-
Up phase (safety follow-
up within 30d of last dose 
for all patients and
efficacy follow-up every 6 
weeks until BIRC-
confirmed disease 
progression)
Survival 
Follow-up 
Phase
Cycle 1
(21 days)
Subsequent cycles (21 
days per cycle)
End of 
study 
treatment 
(EOT)
Visit Name
Molecular
pre-screen
Screening 
Visit (D-
28 to D-1)
C1
D1
C1
D15
C2
D1
C3
D1
C4D1 
C5D1 
etc…
EOT Visit 
(within 7d of 
last dose)
Tumor 
Follow-Up 
(every 6 wks)
Study 
Evaluation 
Completion
Survival 
Follow-Up 
(every 3 mo)
Pharmacokinetics and ECG assessments
12-Lead ECG
D
7.2.2.6
X
X
X
X
X
Blood for INC280 PK 
D
7.2.3
X
X
X
Other
Antineoplastic therapies 
(medications, surgeries, 
radiotherapies) since 
discontinuation of study drug
D
7.1.4
X (continuous until last follow-up visit)
End of Phase Disposition
D
4.1
X
X
X
Safety Follow-Up
D
7.1.5.1
X
Survival
(survival information can be 
obtained via telephone 
contact)
D
4.1.5
X
Abbreviations: C, cycle; CAP, chest/abdomen/pelvis; CT, computed tomography; D, entered into database; d, day; ECG, electrocardiogram; EOT, end of treatment; EOS, 
end of study; FUp, follow-up; i.v., intravenous; MRI, magnetic resonance imaging; NSCLC, non-small cell lung cancer; PD, progressive disease; PK, pharmacokinetic; S, 
remains in source document only; Tx, treatment; wks, weeks;




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Please refer to Section 6.5 for patient numbering, IRT procedures and cohort assignment.
7.1.2
Screening
Once the cMET amplification and mutation status (and ALK rearrangement status, if 
applicable) is confirmed by the central designated laboratory performing the molecular pre-
screening analysis, patients may enter the screening phase. Written informed consent must be 
obtained before any study specific procedure is performed. Screening assessments to confirm 
eligibility into the main study should be performed as per the schedule of assessments
between Day-28 and Day-1. Laboratory assessments performed as part of the screening 
evaluations will not require to be repeated prior to dosing if performed within 7 days prior to 
the first dose of study treatment. Only laboratory results from the Novartis-designated central 
Laboratory can be used to determine patient’s eligibility for the study. The cardiac eligibility 
criteria should be assessed with the central ECG report.
 
A patient who has a laboratory test result(s) that does not satisfy the entrance criteria may 
have the test(s) repeated within the 28-day screening period. In these cases, the patient is not 
required to sign another ICF and must retain the same Subject No. In the event that the 
laboratory test(s) cannot be performed within the 28 days of the original screening visit, or the 
re-test(s) do not meet the entrance criteria, or other eligibility criteria have changed and are 
not met anymore, the patient is considered a screen failure, and must be discontinued from the 
study. A new ICF will need to be signed if the investigator chooses to re-screen the patient 
after a patient has screen failed, however, the Subject No will remain the same.
Patients who fail screening due to laboratory parameters (inclusion criterion # 7) or baseline 
tumor assessment (inclusion criterion # 5) may be re-screened. Patients who met all eligibility 
criteria but fail to be started on treatment as scheduled may be also re-screened, provided the 
patient was not registered previously in IRT as having entered the Treatment Period. Re-
screening of a patient must be performed within the 28-day re-screening period, and is
allowed only once per patient. All required screening activities must be performed when the 
patient is re-screened for participation in the study.
All eligibility criteria must be re-checked, based on the most recent data available, and met 
prior to enrollment of the patient into the study.
If any cohort/sub-cohort is closed to enrollment, then only patients with the cMET
amplification or mutation status required for the open cohort(s)/sub-cohort(s) will be eligible 
for main screening for study enrollment. Enrollment of patients with GCN ≥4 and < 5 in 
Cohort 2 may be stopped when the target of 60% (i.e. at least 17 patients for the IA and 41 
patients for the final enrollment) with GCN ≥4 and < 5 is reached.
7.1.2.1
Eligibility screening
The main screening period commences as soon as the patient signs the main ICF and ends 
when the patient fails screening or starts treatment. Evaluations will be performed within 4 
weeks (i.e., within 28 calendar days) prior to the first dose of study drug, unless otherwise 
noted. All screening assessments, including laboratory assessments, must be performed as 
described in the protocol (Table 7-1). Any imaging assessments already completed as 




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
Informed consent

Inclusion/Exclusion Criteria

Withdrawal of consent (if applicable)

Death (if applicable)
No other data will be entered into the clinical database for patients who are screen failures, 
unless the patient experienced a Serious Adverse Event during the Screening Phase (see 
Section 8 for SAE reporting details). For molecular pre-screening failures, only SAEs 
possibly related to a study procedure will be reported. 
If the patient fails to be enrolled, the IRT must be notified within 2 days of the screen fail that 
the patient was not enrolled.
7.1.2.3
Patient demographics and other baseline characteristics
Data to be collected include:

EGFR molecular status

ALK rearrangement status

Information on local testing for cMET amplification and cMET mutation prior to patient 
consideration for this study, if available.

Demography (including: date of birth, age, patient initials, gender, childbearing potential, 
race and ethnicity, or as allowed by local regulations)

Relevant medical history

Smoking history

Cohort/sub-cohort assignment

NSCLC diagnosis and extent of disease, including:

Date of diagnosis and stage of NSCLC

Site of active disease

Characteristics of disease

Prior antineoplastic therapies (medications, radiation, surgeries)

Prior and current concomitant medications, surgical and medical procedures
Note: All other medications taken within 28 days before the first dose of study treatment is 
administered must be recorded on the Prior and current concomitant medication eCRF page 
and updated on an ongoing basis if there is new change to the medication.
7.1.3
Treatment period
Following completion of screening procedures and confirmation of patient eligibility, the 
patient will be enrolled via the IRT in one of the cohorts based on the cMET amplification 
status. At the time of eligibility confirmation, the IRT system will inform the site about which
PK and ECG schedule should be followed by the patient.
The study treatment will begin on Cycle 1, Day 1 with the first administration of INC280 and 
does not have fixed treatment duration. Information on drug exposure will be collected on the 
Dosage Administration Record eCRF.


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7.1.4
Discontinuation of study treatment
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a 
patient decides to discontinue from the study treatment, the investigator should make a 
reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for this 
decision and record this information in the patient’s chart and on the appropriate CRF pages. 
They may be considered withdrawn if they state an intention to withdraw, fail to return for 
visits, or become lost to follow-up for any other reason. 
The investigator should discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would be detrimental to the patient’s well-being.
Study treatment must be discontinued under the following circumstances: 

Emergence of specific adverse events or laboratory abnormalities under some 
circumstances as outlined in Section 6

Pregnancy (pregnancy will be followed for outcome)

Use of prohibited treatments (refer to Section 6.4.3)

Any protocol deviation that results in a significant risk to the patient’s safety
Patients who discontinue INC280 treatment should NOT be considered withdrawn from the 
study. They should return for the assessments indicated in Section 7.2.1. If they fail to return 
for these assessments for unknown reasons, every effort (e.g. telephone, email, letter) should 
be made to contact them as specified in Section 7.1.7. 
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
Patients who become pregnant must cease all tumor assessments regardless of whether or not 
they developed Progressive Disease according to BIRC.
Patients who discontinue INC280 should be scheduled for an EOT visit as soon as possible 
and within 7 days of the last dose of INC280, at which time all of the assessments listed for 
the EOT visit will be performed. If a patient is discontinued from treatment at a study visit, 
the assessments performed at that visit will be considered as EOT assessments and do not 
need to be repeated. An End of Treatment Phase Disposition eCRF page should be completed, 
giving the date and reason for stopping treatment.
Patients who discontinue study treatment should enter either the survival follow-up period or 
continue tumor assessments, when appropriate.
Patients who have RECIST-defined Progressive Disease as determined by investigator and 
confirmed by the BIRC, but who, in the judgment of the investigator have evidence of 
continued clinical benefit from INC280 and the patient wishes to continue on the study 
treatment may continue to receive the study drug. These patients will continue assessments as 
detailed in Table 7-1. In such cases, patients must complete the EOT visit only after 
permanent discontinuation of INC280. An End of Treatment Phase Disposition eCRF page 
should be completed, specifying the date of the subject’s last treatment and reason for 
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7.1.5
Follow-up-period
7.1.5.1
Follow-up for Safety Evaluations
All patients must have safety evaluations for 30 days after the last dose of study treatment.
At the end of this period, the investigator should assess and discuss with the patient any AE 
observed/concomitant medication taken since discontinuation of study treatment. This can be
done via a phone contact. 
Data collected should be added to the Adverse Events eCRF and the Concomitant 
Medications eCRF. Antineoplastic therapies will be captured on the 'Antineoplastic therapies 
since discontinuation of study treatment' eCRF page. 
Patients whose treatment is permanently discontinued due to an AE (clinical or based on 
abnormal laboratory value) must be followed until resolution or stabilization of the event, 
whichever comes first. In case of an abnormal laboratory value, blood tests should be repeated 
until resolution or stabilization.
7.1.5.2
Post-Treatment follow-up
All patients who discontinued treatment during the treatment phase for reasons other than 
death, lost to follow-up, pregnancy or disease progression as determined by investigator and 
confirmed by BIRC (Section 7.1.4) should not be considered withdrawn from the study and 
should continue with tumor 
 assessments every 6 weeks from EOT as per Table 7-1
until disease progression is confirmed per BIRC, withdrawal of consent from tumor 
assessments, lost to follow-up, death or study terminated by Sponsor. Once the patient ceases 
tumor follow-up
, the End of Post Treatment Disposition (Study Phase 
Completion) eCRF page should be completed. Antineoplastic therapies since discontinuation 
of study treatment will continue to be collected. If patients refuse to return for these visits or 
are unable to do so, every effort should be made to contact them or a knowledgeable 
informant by telephone to determine the survival status of the patient.
7.1.5.3
Survival follow-up
All patients who had PD determined by investigator and confirmed by BIRC or withdrew 
consent from further study assessments will subsequently be followed for survival 
information every 3 months until death, lost to follow-up or withdrawal of consent for 
survival. The investigator or his designee will collect this survival information and any new 
anti-neoplastic therapies for all patients until the final survival analysis.
Follow-up can be done via a phone contact. Antineoplastic therapies will be captured on the 
'Antineoplastic therapies since discontinuation of study treatment' eCRF page following the 
last dose of the study treatment.
7.1.5.4
Replacement policy
Patients lost to follow-up or withdrawing consent from the study without observed BIRC 
confirmed PD will be censored for the primary analysis and will not be replaced.


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7.1.6
Withdrawal of 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 the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their 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.
7.1.7
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g., dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow-up should be recorded as such on the appropriate 
Disposition eCRF.
7.2
Assessment types
7.2.1
Efficacy assessments
Tumor response will be assessed locally and by BIRC according to the Novartis guideline 
version 3.1 (Appendix 1) based on RECIST 1.1 (Eisenhauer et al 2009). Patients should have 
at least one documented measurable lesion at study entry as per RECIST 1.1. The imaging 


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assessment collection plan is presented in Table 7-2. Details of the central review process will 
be described in the independent review charter.
Imaging data will be centrally collected and checked for quality by an imaging vendor
designated by Novartis. The results of the central BIRC evaluations will be used for primary 
analysis purposes. The local investigator’s assessment will be used for treatment decision 
making.
Table 7-2
Imaging collection plan
Procedure
Screening/Baseline
During Treatment/Follow-Up
CT or MRI (chest, abdomen, 
pelvis) with i.v. contrast
Mandated
Mandated until PD determined by investigator 
and confirmed by BIRC, every 6 weeks
CT or MRI of other metastatic 
sites (e.g., neck, etc.), if 
applicable
Only if other metastatic sites 
are suspected
Mandated if patient has other metastatic sites 
at baseline (following the same schedule as 
CT/MRI of chest/abdomen/pelvis) or 
otherwise, only if clinically indicated
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/pelvis), or otherwise, only if 
clinically indicated
Whole body bone scan
[e.g., Tc-99 bone scan, whole 
body bone MRI, 
fluorodeoxyglucose positron 
emission tomography (FDG-
PET) or sodium fluoride (NaF)-
PET]
Mandated
If clinically indicated
Localized bone CT, MRI or X-
ray
Only if clinically indicated (for 
any lesions identified on the 
whole body bone scan that 
are not visible on the CT/MRI 
of chest/abdomen/pelvis)
Mandated if positive at baseline (following the 
same schedule as CT/MRI of 
chest/abdomen/pelvis), or otherwise, only if 
clinically indicated
Color photographs with a metric 
ruler (only if skin lesions are 
present)
Only if other skin metastases 
are present
Mandated if patient has skin lesions at 
baseline (following the same schedule as 
CT/MRI of chest/abdomen/pelvis) or 
otherwise, only if clinically indicated
7.2.1.1
Baseline imaging assessment
Imaging assessments will be performed at screening/baseline Day -28 to Day -1 prior to Cycle 
1 Day 1.
Any imaging assessments already completed during the regular work-up of the patient within 
28 days prior to start of treatment, including before signing the main study ICF, can be 
considered as the baseline images for this study. Any imaging assessments obtained after first 
dose cannot be considered baseline images.
Imaging requirements at baseline

Patients must have measurable disease as per RECIST 1.1 (Appendix 1). Measurable 
(“target”) lesions include lytic or mixed (lytic + blastic) bone lesions with an identifiable 
soft tissue component that meets the measurability criteria per RECIST 1.1 (Appendix 1).

Patients with only non-measurable lesions are not eligible.


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
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.

Any potentially measurable lesion that has been previously treated with radiotherapy 
should be considered as a non-measurable (“non-target”) lesion. However, if a lesion 
previously treated with radiotherapy has clearly progressed since the radiotherapy, it can 
be considered as a measurable lesion.
All measurable lesions up to a maximum of 5 nodal and/or non-nodal lesions in total (and a 
maximum of 2 lesions per organ), representative of all involved organs, should be identified 
as target lesions and recorded and measured at baseline.
Tumor assessments required at baseline
The following assessments will be performed:

Computed Tomography (CT) with IV contrast or Magnetic Resonance Imaging (MRI) of 
chest, abdomen and pelvis.

The preferred radiologic technique is CT with intravenous (IV) contrast. If a patient is 
known to have a contraindication to CT contrast media or develops a contraindication 
during the trial, a non-contrast CT of the chest (MRI is not recommended due to 
respiratory artifacts) plus a contrast-enhanced MRI (if possible) of the abdomen and 
pelvis should be performed.

A whole body bone scan according to institutional guidelines [e.g. Tc-99 bone scan, whole 
body bone MRI, Fluorodeoxyglucose positron emission tomography (FDG-PET) or 
sodium fluoride positron emission tomography (NaF PET)].

After screening, whole body bone scans is not required, unless clinically indicated. If 
indicated, the same methodology as at screening should be used.

Localized CT, MRI or X-rays of any skeletal lesions identified on the screening whole 
body bone scan, which are not visible on the chest, pelvis and abdomen CT/MRI.

If skeletal lesions are documented at baseline, scans need to be continued following 
the same schedule as CT/MRI of chest, abdomen and pelvis. The same methodology 
as at screening should be used.

Brain CT with IV contrast or MRI scan.

If brain lesions are documented at baseline, scans need to be continued following the 
same schedule as CT/MRI of chest, abdomen and pelvis. The same methodology as at 
screening should be used. Contrast enhanced brain MRI is preferred, however, if MRI 
contrast is contraindicated, then MRI without contrast or CT with/without contrast is 
acceptable.

Color photographs, if skin lesions are present, using a digital camera in clear focus, 
including a scale/ruler, in such a way that the size of the lesion(s) can be determined from 
the photograph.

If skin lesions are documented at baseline, photographies need to be continued 
following the same schedule as CT/MRI of chest, abdomen and pelvis. 

CT or MRI of any other site of disease not captured by any of the above listed images (e.g., 
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
If additional sites of disease are documented at baseline, scans need to be continued 
following the same schedule as CT/MRI of chest, abdomen and pelvis. The same 
methodology as at screening should be used.
Chest x-ray or ultrasound must not be used to measure tumor lesions.
7.2.1.2
Subsequent imaging for response assessment
Imaging assessments as described in Table 7-2 should be performed at the timepoints 
specified using the same imaging modality used at baseline, irrespective of study treatment 
interruption or actual dosing (see Table 7-1). Imaging assessments for response evaluation 
will be performed every 6 weeks starting from Day 1 of cycle 1 (+/- 4 days window).
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a patient, if necessary. Clinical 
suspicion of disease progression at any time requires a physical examination and imaging 
assessments to be performed promptly rather than waiting for the next scheduled imaging
assessment.
Each lesion that is measured at baseline must be measured by the same method (either same 
imaging method or by photography, including a metric ruler) and when possible, the same 
local radiologist/physician throughout the study so that the comparison is consistent. If an off-
schedule imaging assessment is performed because progression is suspected, subsequent 
imaging assessments should be performed in accordance with the original imaging schedule.
Combined PET/CT may be used only if the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of oral and IV contrast media. At the 
discretion of the Investigators, FDG-PET scans may be performed to document PD per 
RECIST 1.1 (Appendix 1).
All study imaging (including any off-schedule imaging studies) performed to evaluate 
progression or response should be submitted to the designated imaging vendor for quality 
control and review by the BIRC, promptly after acquisition. 
7.2.1.3
Transmission of efficacy data to BIRC
All radiological assessments will be read locally and should be submitted promptly after 
acquisition to the imaging vendor designated by Novartis. Rapid image transmission to the 
central imaging vendor will be accomplished by transferring the images acquired by the 
investigator electronically in a secured website (e.g.: via the internet). In all instances, the 
process at the imaging vendor will ensure that the central reviewers remain blinded to the 
results of the local assessment and the expedited nature of the review.
7.2.1.4
Timepoints without locally determined progression
All imaging timepoints without locally determined progression will be read on an ongoing
non-expedited basis as detailed in the imaging manual to be provided by the designated 
imaging vendor and independent review charter. However expedited review may be required 
at the time of the interim analysis. Results of these readings will not be communicated to the 
sites.


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7.2.1.5
Timepoints at which progression is determined locally
All patients who have disease progression determined by the local investigator require an 
expedited tumor response review by the BIRC. If PD has been determined locally at a 
timepoint, the investigator must seek an expedited review and indicate this request to the 
imaging vendor on a designated form or by alternative means identified by the imaging 
vendor. The imaging vendor will ensure that the BIRC reviewers are blinded to BIRC reading 
requests.
Rapid image transmission to the central imaging vendor may be accomplished by uploading 
all digital images acquired by the Investigator to the secure website provided by the imaging 
vendor. The imaging will undergo expedited central review (within 5 business days from the 
time of the receipt of images at the imaging vendor) 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 patient continue on study treatment. However, during this time, 
the investigator should do whatever is medically necessary for his/her patient.
If the central review determines disease progression, then the patient may discontinue study 
treatment and subsequent follow-up tumor assessments are no longer required. Treatment with 
INC280 may be continued beyond RECIST 1.1-defined PD determined by the investigator
and confirmed by BIRC, if, in the judgment of the investigator, there is evidence of clinical 
benefit and the patient wishes to continue on the study treatment. 
If the central review does not determine disease progression, the patient 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 per the investigator’s clinical judgment.
Patients will continue to have imaging performed as per protocol (Table 7-1) until the central 
review determines disease progression.
Note: If an investigator would like to discuss the central review results, there will be an 
independent physician at the imaging vendor who is not part of the central review pool for this 
study. This independent physician will be able to discuss the central review findings with the 
investigator. The central reviewers are completely excluded from such discussion. The contact
at the imaging vendor can arrange such a discussion, as specified in the manual provided by 
the designated imaging vendor.
7.2.2
Safety and tolerability assessments
Safety will be monitored using the following clinical and laboratory assessments: hematology, 
chemistry, coagulation parameters, urinalysis, 12-lead ECG, pregnancy test as well as 
collecting of the adverse events and concomitant medications at every visit. For details on AE 
collection and reporting, refer to Section 8. Significant findings that were present prior to the 
signing of informed consent must be included in the relevant medical history/current medical 
conditions page on the patient’s eCRF. Significant new findings that begin or worsen after 
informed consent must be recorded on the Adverse Event page of the patient’s eCRF.


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7.2.2.1
Physical examination
A complete physical examination must be performed at screening and later as clinically
indicated and will include the examination of general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, 
vascular, and neurological assessments. 
A targeted (short) physical exam will be performed as per schedule in Table 7-1 and will 
include the examination of general appearance and vital signs (blood pressure and pulse).
Information about the physical examination must be present in source documentation at the 
study site. Significant findings that were present prior to the signing of informed consent must 
be included in the Medical History page on the patient’s CRF. Significant new findings that 
begin or worsen after informed consent must be recorded on the Adverse Event page of the 
patient’s CRF.
7.2.2.2
Vital signs
Vital signs include body temperature, blood pressure and pulse measurements and will be 
performed as per schedule in Table 7-1. Blood pressure (systolic and diastolic) and pulse 
should be measured after the patient has been sitting for five minutes.
7.2.2.3
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured. Height will be measured at screening only 
(Refer to Table 7-1).
7.2.2.4
Performance status
Assessment of ECOG performance status (Table 7-3) will be performed as per the assessment 
schedule in Table 7-1, even if study treatment is being interrupted. More frequent 
examinations may be performed at the investigator’s discretion, if medically indicated.
Table 7-3
ECOG performance status scale
Score
Performance 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 housework, 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
7.2.2.5
Laboratory evaluations
Novartis-designated central laboratories will be used for the analysis of scheduled hematology, 
biochemistry and other blood specimens collected as part of safety monitoring (as detailed in
Table 7-4). The frequency of the assessments is indicated in Table 7-1. Dipstick urinalysis 


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will be performed locally, except in the case of any significant findings, a urine sample will be 
sent to central laboratory for further microscopic analysis. Laboratory values obtained prior to 
treatment from central laboratory will be used to assess patient’s eligibility. Only laboratory 
results from the Novartis-designated central Laboratory can be used to determine patient’s 
eligibility for the study. The time windows granted for laboratory evaluations are identical to 
the corresponding visit time windows for each visit (refer to Section 7.1).
Local laboratory assessments may only be performed when an immediate clinical decision 
needs to be made. In those cases locally unscheduled testing may be performed. However 
samples should also be sent to the central lab. In such cases, local laboratories values should 
be recorded on the local laboratory eCRFs as unscheduled visits only if a severity grade 
differs from a severity grade reported by the central laboratory.
Each time local laboratory results are reported on the unscheduled local laboratory eCRF page, 
the study monitor will collect and submit promptly the local laboratory normal ranges and 
local laboratory certification.
Details on the collection, shipment of samples and reporting of results by the Novartis-
designated central laboratory are provided to investigators in a separate [Laboratory Manual].
Table 7-4
Clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, White blood cells, Differentials (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils)
Chemistry
Albumin, Alkaline phosphatase, ALT, Amylase, AST, Calcium, Creatinine, 
Creatinine Clearance, Total Bilirubin, Direct Bilirubin (only if total bilirubin is ≥ 
grade 2), GGT, Lipase, Magnesium, Sodium, Potassium, Phosphate (inorganic 
phosphorus), fasting Glucose (non-fasting allowed post-baseline), Blood Urea 
Nitrogen (BUN) or Urea
Bicarbonate, Chloride and Uric Acid: at screening and thereafter if clinically 
indicated
Urinalysis
(at screening and thereafter if 
clinically indicated)
Macroscopic panel (dipstick) (bilirubin, blood, glucose, WBC, pH, protein,
specific gravity)
Microscopic panel (RBC, WBC, casts)
Coagulation
(at screening and thereafter if 
clinically indicated)
International normalized ratio (INR) and Prothrombin time (PT), or Quick Test 
(QT)
7.2.2.5.1 Hematology
Hematology assessments of the parameters listed in Table 7-4 will be tested as per the 
schedule of assessments (Table 7-1). 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.
7.2.2.5.2 Clinical chemistry
Blood chemistry assessments of the parameters listed in Table 7-4 will be tested as per the 
schedule of assessments (Table 7-1).


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More frequent clinical chemistry testing may also be performed as medically necessary. 
Additional results from unscheduled clinical chemistry lab evaluations should be recorded on 
the appropriate Unscheduled Visit eCRF.
Note: Creatinine clearance should be calculated (e.g Cockcroft-Gault formula) at screening 
and need to be repeated on Cycle 1 Day 1 before first dose, unless screening assessment was 
performed within 7 days prior to the Cycle 1 Day 1 visit.
7.2.2.5.3 Urinalysis
Dipstick measurements will be performed as per Table 7-4 and according to the schedule of 
assessments (Table 7-1). Any significant findings on dipstick will be followed up with 
microscopic evaluation as per Table 7-4 and recorded on the appropriate eCRF page. Dipstick 
urinalysis will be performed locally. In the case of any out of range parameters are noticed on 
local urinalysis, urine sample will be sent to central laboratory for further analysis.
7.2.2.5.4 Pregnancy and assessments of fertility
All women of childbearing potential must complete a serum pregnancy test as per the 
schedule of assessments (Table 7-1). Central laboratories will be used for the analysis of 
serum pregnancy tests.
Women who are determined not to be of child bearing potential before the study will only be 
tested at screening.
For postmenopausal women to be considered “of non-childbearing potential”, patient should 
meet the criteria as outlined in Section 5.3.
Please refer to Section 8.4 for information on reporting any pregnancies that occur while the 
patient is on study.
If a pregnancy test is performed in between study visits by the patient and the result is positive, 
the patient must immediately notify the investigator.
7.2.2.5.5 Coagulation
International normalized ratio (INR) and prothrombin time (PT) or Quick Test will be 
measured according to the schedule of assessment.
7.2.2.6
Cardiac assessments 
7.2.2.6.1 Electrocardiogram (ECG)
Standard triplicate 12 lead ECG assessments will be performed as outlined in Table 7-5 and 
Table 7-6.
Table 7-5
ECG collection plan for approximately 30 enrolled patients at selected 
sites
Cycle
Day
Time
ECG Type
Number of ECGs
Screening
Anytime
12 Lead
3


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Cycle
Day
Time
ECG Type
Number of ECGs
1
1
Pre-dose
Post-dose 1 h (within 15 min prior to PK)
Post-dose 2 h (within 15 min prior to PK)
Post-dose 4 h (within 15 min prior to PK)
Post-dose 8 h (within 15 min prior to PK)
12 Lead
3
1
15
Pre-dose
Post-dose 1 h (within 15 min prior to PK)
Post-dose 2 h (within 15 min prior to PK)
Post-dose 4 h (within 15 min prior to PK)
Post-dose 8 h (within 15 min prior to PK)
12 Lead
3
3
1
Pre-dose (within 15 min prior to PK)
12 Lead
3
EOT
Anytime
12 Lead
3
Unscheduled ECG
Anytime if clinically indicated
12 Lead
3
Table 7-6
ECG collection plan for remaining patients, including patients in 
Cohort 6 and Cohort 7
Cycle
Day
Time
ECG Type
Number of ECGs
Screening
Anytime
12 Lead
3
1
1
Pre-dose
12 Lead
3
1
15
Post-dose 2 h (within 15 min prior to PK)
12 Lead
3
3
1
Pre-dose
12 Lead
3
EOT
Anytime
12 Lead
3
Unscheduled ECG
Anytime if clinically indicated
12 Lead
3
Baseline is defined as the pre-dose assessment on Cycle 1 Day 1 before study drug 
administration.
All ECG assessments will be performed in the supine position. Detailed instructions regarding 
the ECG collection will be provided to the investigators in a separate manual prior to the start 
of the study. INC280 pharmacokinetic evaluation will be conducted in parallel to cardiac 
evaluations (see Section 7.2.3). All ECGs should be performed within 15 minutes prior to the 
collection of PK sample. The triplicate ECGs should be taken approximately 2-4 minutes 
apart. An ECG may be repeated at the discretion of the investigator at any time during the 
study and as clinically indicated.
All ECGs recorded for each time point will be transmitted electronically to a central 
laboratory and will be centrally reviewed by an independent reviewer. Any original ECG not 
transmitted electronically to the central laboratory should be forwarded for central review. 
Review of all ECGs from a particular patient should be performed by a single reader. The 
ECG lead for interval duration measurements should be pre-specified. Baseline and all 
subsequent ECGs should be based on the same lead.
Interpretation of the tracing must be made by a qualified physician. Each ECG tracing should 
be labeled with the study number, patient initials (where regulations permit), patient number, 
ECG nominal day and time, ECG actual date and time (using a 24-hour clock, record up to 
second), ECG replicate number, measured variables (QT, RR, PR, QRS), derived variables 


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(QTcB, QTcF, and HR), ECG lead date, and kept in the source documents at the study site. 
Clinically significant abnormalities present when the patient signed informed consent should 
be reported on the Medical History eCRF page. Clinically significant findings must be 
discussed with Novartis prior to enrolling the patient in the study. New or worsened clinically 
significant findings occurring after informed consent must be recorded on the Adverse Events 
eCRF page.
7.2.3
Pharmacokinetics
Blood samples for PK evaluation will be collected from all enrolled patients participating in 
the study. Time points of blood sample collection for full and sparse PK analyses are outlined 
in Table 7-7 and Table 7-8, respectively.
The study will consist of sparse PK sampling as detailed in Table 7-8 in the majority of the 
patients who receive INC280 treatment. Separate from this, a minimum of 30 patients at 
selected sites will be required to participate in full PK sampling for population PK analysis as 
detailed in Table 7-7.
Complete dosing information, including the date and time of actual blood draw and time of 
the last study drug dose prior to the sampling, should be obtained on all sampling days and 
recorded on the PK eCRF and/or CRO requisition form(s).
An additional unscheduled PK blood sample will be collected if a patient experiences an AE 
suspected to be related to study treatment that results in an unscheduled visit or fits the criteria 
of an SAE (unless patient has interrupted INC280 for 7 days or more).
PK parameters will be estimated from each individual plasma concentration-time profile using 
appropriate methods and software, if possible. A table of PK parameters to be evaluated (e.g., 
Cmax, Tmax, AUC) is to be included in the statistical and data analysis Section 10.5.4 of the 
protocol.
Table 7-7
Pharmacokinetic blood collection log for approximately 30 enrolled
patients at selected sites
Cycle
Day
Scheduled Time Point
Dose Reference ID
PK Sample 
No
Sample 
Volume (mL)
1
1
Pre-dose/0h
1
1
3
1
1
Post-dose 0.5h (± 5min)
1
2
3
1
1
Post-dose 1h (± 10min)
1
3
3
1
1
Post-dose 2h (± 10min)
1
4
3
1
1
Post-dose 4h (± 20min)
1
5
3
1
1
Post-dose 6h (± 20min)
1
6
3
1
1
Post-dose 8h (± 20min)
1
7
3
1
15
Pre-dose/0h
2
201a
8
3
1
15
Post-dose 0.5h (± 5min)
2
9
3
1
15
Post-dose 1h (± 10min)
2
10
3
1
15
Post-dose 2h (± 10min)
2
11
3
1
15
Post-dose 4h (± 20min)
2
12
3
1
15
Post-dose 6h (± 20min)
2
13
3
1
15
Post-dose 8h (± 20min)
2
14
3
3
1
Pre-dose/0h
3
301a
15
3




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8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained.
For patients 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 8.2.2 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 in the Adverse Event eCRF.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms  are considered clinically significant, 


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require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s eCRF. Adverse event monitoring should 
be continued for at least 30 days following the last dose of study treatment. Adverse events 
(including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. When a clear 
diagnosis cannot be identified, each sign or symptom should be reported as a separate 
Adverse Event.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to grades 1 - 4, will be used. CTCAE grade 5 (death) will 
not be used in this study; but is collected as a seriousness criteria; rather, information about 
deaths will be collected though a Death form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine:

The severity grade (CTCAE grade 1-4)

Its duration (Start and end dates)

Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)

Action taken with respect to study (none, dose adjusted, temporarily interrupted, 
permanently discontinued, unknown, not applicable)

Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)

Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown)

Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1
and which seriousness criteria have been met
If the event worsened, the event should be reported a second time in the CRF noting the start 
date when the even worsens in toxicity. For Grade 3 and 4 adverse events only, if 
improvement to a lower grade is determined a new entry for this event should be reported in 
the CRF noting the start date when the event improved from having been Grade 3 or Grade 4.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF.
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 


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necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (RECIST criteria for solid tumors), should not be reported as a serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events eCRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.
8.1.3
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 Investigator Brochure.
8.1.3.1
Definitions and reporting
Adverse events of special interest to be monitored for capmatinib (INC280) include: 

Hepatotoxicity 

Renal dysfunction 

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
Central nervous system toxicity 

Phototoxicity 

Teratogenicity

Pancreatitis

Drug-drug interactions with strong CYP3A4 inhibitors

QTc interval prolongation
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization, 

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

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 patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event.
8.2.2
Reporting
For patients 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 (molecular screen failure), SAE 
collection ends 30 days after the last study related procedure.
For patients who sign the main study ICF, SAE collection starts at time of main study 
informed consent whether the patient is a screen failure or not.
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
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stopped study treatment must be reported to Novartis within 24 hours of learning of its 
occurrence.
Any additional information for the SAE including complications, progression of the initial 
SAE, and recurrent episodes must be reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one 
should be reported separately as a new event.
Any SAE experienced after this 30 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. Instructions regarding the SAE submission process and requirements for 
signatures are to be found in the investigator folder provided to each site. The investigator 
must assess and record the relationship of each SAE to each specific study treatment (if there 
is more than one study treatment), complete the SAE Report Form in English, and submit the 
completed form within 24 hours to Novartis
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.
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 Novartis study treatment, an oncology 
Novartis Drug Safety and Epidemiology (DS&E) 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 drug 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 Directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
8.3
Emergency unblinding of treatment assignment
Since this study is an open-label study, there is no need for treatment unblinding instructions 
or unblinding codes.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
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, 
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Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
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 on the SAE Report Form.
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes
should be obtained from the mother.
Women of childbearing potential should be advised to use highly effective contraception 
methods while they are receiving study treatment and up to 7 days after INC280 treatment has 
been stopped. If a pregnancy occurs while on study treatment, the newborn will be followed 
for at least 3 months.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee
Not applicable.
8.7
Steering Committee
A Steering Committee (SC) will be formed prior to initiation of the trial and will be appointed 
by Novartis. It will consist of investigators participating in the trial and Novartis 
representatives from the Clinical Trial Team. The SC will ensure transparent management of 
the study according to the protocol through recommending and approving modifications as 
circumstances require. The SC will review protocol amendments as appropriate. Together 
with the clinical trial team, the SC will also develop recommendations for publications of 
study results including authorship rules. The details of the role of the Steering Committee will 
be defined in a Steering Committee charter.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information


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
The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements 
and to enable appropriate age-related normal ranges to be used in assessing laboratory test 
results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol 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.
The investigator must maintain source documents for each patient 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 recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria 
and documentation of SAEs. Additional checks of the consistency of the source data with the 
eCRFs are performed according to the study-specific monitoring plan.
9.3
Data collection
The 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 
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10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) includes all patients who receive at least one dose of 
INC280.Unless otherwise specified the FAS will be the default analysis set used for all 
analyses, including the primary analysis.
10.1.2
Safety Set
The Safety Set includes all patients who received at least one dose of INC280. All safety data 
will be analyzed using the Safety Set.
The FAS and Safety Set in this study are identical.
10.1.3
Per-Protocol Set
The Per-Protocol Set (PPS) consists of a subset of patients in the FAS who have no major 
protocol deviations, who have an adequate tumor assessment at baseline and have a follow-up 
tumor assessment > 5 weeks after starting treatment (unless PD is observed before that time).
All major protocol deviations leading to exclusion from the PPS will be detailed in the 
Reporting and Analysis Plan (RAP).
10.1.4
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) consists of all patients who received at least one dose 
of INC280 and had at least one evaluable post-baseline INC280 concentration measurement.
A PK sample is considered as non-evaluable if it is collected after a patient has vomited 
within 4 hours post-dose.
The definition of an evaluable PK concentration profile will be further specified in the RAP.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data including disease characteristics will be summarized 
descriptively by cohort/sub-cohort based on the FAS. Categorical data will be presented as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 
minimum, and maximum will be presented.
10.3
Treatments (study treatment, concomitant therapies, compliance)
The safety set will be used for the analyses below.
The actual dose and duration in days of INC280 as well as the dose intensity (computed as the 
ratio of total dose received and actual duration) and the relative dose intensity (computed as 
the ratio of dose intensity and planned dose received/planned duration), will be listed and 
summarized by cohort/sub-cohort. Dose reductions and dose interruptions (including the 
reasons for these) will be listed and summarized by cohort/sub-cohort.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized by cohort/sub-cohort.


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10.4
Primary objective
The primary objective is to demonstrate the antitumor activity of INC280, as measured by 
overall response rate (ORR) to INC280 by Blinded Independent Review Committee (BIRC) 
assessment, by cohort/sub-cohort.
10.4.1
Variable
The primary variable used to evaluate the anti-tumor activity of INC280 is the overall 
response rate (ORR), defined as the proportion of patients with a best overall confirmed 
complete response (CR) or partial response (PR), as assessed per RECIST 1.1 by BIRC.
10.4.2
Statistical hypothesis, model, and method of analysis
The primary analysis will be performed on the FAS. The primary efficacy endpoint ORR will 
be estimated and the exact 95% confidence interval (CI) (Clopper and Pearson 1934) provided 
by cohort/sub-cohort. 
In Cohorts 1-4, treatment with INC280 would be considered to have clinically relevant 
efficacy in a cohort/sub-cohort if an ORR of ~35% is observed in that cohort for the 
corresponding primary analysis.
In addition, 5 hypotheses will be tested as following for the cohorts/sub-cohorts respectively 
(Hi0 and Hi1 correspond to cohort/sub-cohort i where i=1a, 1b, 2, 3 or 4)
Hi0: ORR ≤ 25%
In favor of the alternative
Hi1: ORR > 25%
For Sub-cohorts 5a, 5b and Cohort 7, treatment with INC280 would be considered to have 
clinically relevant efficacy if an ORR of ~55% is observed in that cohort for the 
corresponding primary analysis. In addition, 3 hypotheses will be tested as following for the 
cohorts/sub-cohorts (Hi0 and Hi1 correspond to Sub-cohort i where i=5a, 5b or 7):
Hi0: ORR ≤ 35%
In favor of the alternative
Hi1: ORR > 35%
The tests will be performed based on the exact CI for ORR in each cohort/sub-cohort using a 
one-sided α= 0.025 level. Based on historical data, as referred in Section 1.1.1, a 25% ORR is 
a reasonable threshold to be considered as clinically relevant in this specific setting of second 
and third line advanced NSCLC patients (de Marinis 2008, Weiss 2013, NCCN Guidelines 
2014) in Cohorts/Sub-cohorts 1a, 1b, 2, 3 and 4. Similarly, a 35% ORR is a reasonable 
threshold to be considered as clinically relevant in the treatment-naïve setting for advanced 
NSCLC patients (Zhou 2015, Scagliotti 2008) in Sub-cohorts 5a, 5b and Cohort 7. Since a one 
sided α =0.025 is used for a particular hypothesis testing, the testing will be conducted based 
on two-sided 95% exact confidence interval. The null hypothesis will be rejected if the lower 
bound of the two-sided 95% exact CI is >25% in Cohorts/Sub-cohorts 1a, 1b, 2, 3 and 4. And 


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the null hypothesis will be rejected in Sub-cohorts 5a and 5b if the lower bound of the two-
sided 95% exact CI is >35%.
No hypothesis testing is planned for Cohort 6. 
10.4.3
Handling of missing values/censoring/discontinuations
Confirmed PR or CR reported prior to any additional anticancer therapy will be considered as 
responses in the calculation of the ORR irrespective of the number of missed assessments 
before response.
Patients with a best overall response (BOR) of ‘Unknown’ per RECIST 1.1 will be considered 
as non-responders when estimating ORR.
Patients who have disease progression and continue to receive study drug after progression 
will qualify for PD at the time of progression and will be counted as PD in the derivation of 
efficacy endpoints.
10.4.4
Supportive analyses
The primary analysis on FAS will also be repeated on the PPS.
For Sub-cohorts 1a and 1b, and Cohorts 2 and 3, sensitivity analysis on the primary endpoint 
may be performed excluding patients with cMET mutations.
Data from Cohort 6 will help further characterize the safety and efficacy of INC280 in the 
pre-treated Sub-cohort 1a and Cohort 4. Efficacy and safety data will be presented for Cohort 
6 alone and may also be analyzed for pre-treated patients with cMET GCN ≥ 10 by combining 
the patients from Sub-cohort 1a and Cohort 6. Similar analysis may be carried out for pre-
treated patients with cMET mutations regardless of cMET GCN combining the patients from
Cohort 4 and Cohort 6.
Data from Cohort 7 will help further characterize the safety and efficacy of INC280 in the 
treatment-naïve group with cMET mutations regardless of cMET GCN. Efficacy and safety 
data may also be combined with the patients from Sub-cohort 5b to further increase the 
precision of the efficacy estimates. These analyses will be performed once Cohort 7 enrolment 
is closed and when all treated patients in Cohort 7 have completed at least 6 cycles of 
treatment (18 weeks) or discontinued treatment earlier.  
10.5
Secondary objectives
All secondary analyses will be performed on the FAS, unless otherwise specified.
10.5.1
Key secondary objective(s)
The key secondary objective is to evaluate duration of response (DOR) as assessed by BIRC, 
by cohort/sub-cohort.
Among patients with a confirmed response (PR or CR) per RECIST 1.1, DOR is defined as 
the time from first documented response (PR or CR) to the date of first documented disease 
progression or death due to any cause. If a patient has not had an event, DOR is censored at 
the date of last adequate tumor assessment. DOR will be described in tabular and graphical 


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format, by cohort, using Kaplan-Meier methods. The Kaplan-Meier estimate of the 
distribution function will be constructed. The number of patients at risk at certain time points 
will be shown on the plot. The estimated median (in months) along with 95% CIs, as well as 
25th and 75th percentiles will be reported.
10.5.2
Other secondary efficacy objectives
ORR by investigator assessment, by cohort/sub-cohort: The evaluation of ORR will be 
also conducted based on investigator assessment. ORR will be estimated and the exact 
binomial 95% CI will be provided by cohort/sub-cohort.
DOR by investigator assessment, by cohort/sub-cohort: The evaluation of DOR will be 
conducted based on investigator assessment. DOR will be analyzed as described above for the 
analyses based on BIRC assessment.
Overall survival (OS), by cohort/sub-cohort: OS is defined as the time from the date of first 
dose of INC280 to the date of death due to any cause. If the patient 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. OS will be described in tabular and graphical format, by cohort/sub-cohort, 
using Kaplan-Meier methods, including estimated median (in months) with 95% CI, 25th and 
75th percentiles and Kaplan-Meier estimated probabilities with corresponding 95% CIs at 
several time points. Censoring reasons will also be summarized.
The following secondary efficacy objectives will be assessed separately based on investigator 
assessment and BIRC assessment per RECIST 1.1:
Time to response (TTR), by cohort/sub-cohort: Time to overall response of CR or PR 
(TTR) is defined as the time from start of study drug to first documented response (CR or PR, 
which must be confirmed subsequently) for patients with a confirmed CR or PR. 
TTR will be summarized in 6-week intervals, by cohort/sub-cohort, using descriptive statistics. 
Disease control rate (DCR), by cohort/sub-cohort: DCR is defined as the proportion of 
patients with best overall response of CR, PR, or SD per RECIST 1.1. DCR will be estimated 
and the binomial exact 95% CI will be provided by cohort/sub-cohort. 
Progression-free survival (PFS), by cohort/sub-cohort: PFS is defined as the time from the 
date of first dose of INC280 to the date of first radiologically documented disease progression 
per RECIST 1.1 or death due to any cause. PFS events documented after the initiation of new 
anti-neoplastic therapy (i.e. RECIST 1.1 documented disease progression or death) will be 
considered for the primary analysis provided tumor assessments continue after initiation of the 
new cancer therapy. Clinical deterioration will not be considered as a qualifying event for 
progression. PFS will be censored at the last adequate tumor assessment if one of the 
following occurs: absence of event; the event occurred after two or more missing tumor 
assessments. PFS will be described in tabular and graphical format, by cohort/sub-cohort, 
using Kaplan-Meier methods, including estimated median (in months) with 95% CI, 25th and 
75th percentiles and Kaplan-Meier estimated probabilities with corresponding 95% CIs at 
several time points. Censoring reasons will also be summarized.
Additional analysis of all secondary efficacy objectives in pre-treated patients with a cMET 
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cohort 1a and Cohort 6 to further evaluate the precision of the efficacy estimates. Similar 
analysis will be carried out for pre-treated patients with cMET mutations regardless of cMET 
GCN combining the patients from Cohort 4 and Cohort 6. Cohort 7 may also be combined 
with Sub-cohort 5b.
10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
cohort/sub-cohort for all patients.
The overall observation period will be divided into three mutually exclusive segments:

Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication

On-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication

Post-treatment period: starting at day 31 after last dose of study medication.
The safety summary tables will include only data collected during the on-treatment period. 
However, all safety data will be listed with data collected during the pre-treatment and post-
treatment period flagged.
10.5.3.2 Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs observed during the on-
treatment period. However, all safety data (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and after the on-treatment 
period will be flagged.
The incidence of treatment-emergent AEs (new or worsening from baseline) will be 
summarized by system organ class and/ or preferred term, severity (based on CTCAE grades), 
type of AE, and relation to study treatment by cohort/sub-cohort. Deaths reportable as SAEs 
and non-fatal SAEs will be listed by patient and tabulated by type of AE and cohort/sub-
cohort.
Specific safety event categories (SEC) may be considered. Such categories consist of one or 
more well-defined safety events which are similar in nature and for which there is a specific 
clinical interest in connection with the study treatment.
For each specified category, number and percentage of patients with at least one event per 
category will be summarized by cohort/sub-cohort.
10.5.3.3 Laboratory abnormalities
For laboratory tests covered by the CTCAE version 4.03, the study’s biostatistical and 
reporting team will grade laboratory data accordingly. For laboratory tests covered by 
CTCAE, a grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
Further details will be specified in the reporting analysis plan (RAP). Grade 5 will not be used.


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For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
The following summaries will be generated separately for hematology, biochemistry and 
urinary laboratory tests by cohort/sub-cohort:

shift tables using CTCAE grades to compare baseline to the worst on-treatment value

for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high)
Listing of all laboratory data with values flagged to show the corresponding CTCAE grades 
and the classifications relative to the laboratory normal ranges will be generated.
A separate listing will display notable laboratory abnormalities (i.e., newly occurring CTCAE 
grade 3 or 4 laboratory toxicities).
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the RAP.
10.5.3.4 Other safety data
Data from other tests (including ECGs and vital signs) will be summarized and listed by 
cohort/sub-cohort. Notable values will be flagged, and any other information collected will be 
listed as appropriate. Definitions of notably abnormal results will be provided in the RAP.
10.5.3.5 Tolerability
Tolerability will be summarized in terms of dose reductions or drug interruption due to an AE 
by cohort/sub-cohort.
10.5.4
Pharmacokinetics
The PAS will be used in all pharmacokinetic data analysis and PK summary statistics. 
Summary statistics of plasma concentration of INC280 and its relevant metabolites will be 
reported by visit for all patients that provided at least one evaluable PK sample. Summary 
statistics include n, arithmetic mean, median, SD, geometric mean, coefficient of variation 
(CV) (%) and geometric CV (%), minimum and maximum. PK parameters as listed in Table 
10-1 will be derived using non-compartmental analysis with the aid of WinNonlin Pro 
(Version 5.0 or higher) and reported, if feasible. Graphical presentation will be provided on 
mean concentration at each scheduled time point for PK sub-population where the full PK 
profile is available. In addition, summary statistics on PK parameters will be reported for PAS.
Concentration values below the lower limit of quantitation (LLOQ) will be displayed in 
listings as zero with a flag and handled as zero in any calculations of summary statistics, but 
handled as missing for the calculation of the geometric means and their CV. Any missing PK 
parameter data will not to be imputed.
Table 10-1
Noncompartmental pharmacokinetic parameters
AUCinf
The AUC from time zero to infinity (mass x time x volume-1)
AUC0-t
The AUC from time zero to defined time t (mass x time x volume-1)


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AUCtau
The AUC within the dosing interval (τ) (mass 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)
T1/2
The elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve (time). Use qualifier for other half-lives
CL/F
The apparent total body clearance of drug from the plasma (volume x time-1)
Vz/F
The apparent volume of distribution during terminal phase (associated with z) (volume)
Racc
Accumulation ratio


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study if the study continued beyond interim, (i.e., till the final analysis), given the interim 
observed data (x) and success among n patients. Thus,
POS = Prob[ Final observed ORR ≥ 35% | x,n]
Minimally informative Beta distribution prior (Neuenschwander et al 2008) with prior mean 
equal to 25% will be used, i.e., the prior distribution will be Beta (0.3333, 1) for the POS 
calculations at the interim analysis.
The respective cohort will be stopped for futility at the interim analysis if the respective POS 
< 10%. The interim analysis will be performed by cohort in which the patients are enrolled. In 
addition, for Sub-cohort 1a and 1b, Cohorts 2 and 3, sensitivity analysis on the primary 
endpoint may be performed at interim analysis excluding patients with cMET mutations.
All evaluable patients at the time of the data cut-off for the interim analysis will be used to 
obtain the futility boundary using the POS criteria. The futility boundary will be calculated 
according to the actual number of evaluable patients in the interim analysis.
Sub-cohort 1a, Sub-cohort 1b, Cohort 2 and Cohort 4 
With 28 evaluable patients for interim analysis in each of the Sub-cohorts 1a and 1b, Cohorts
2 and 4, if ≤ 7 responses (POS =0.0543) are observed then the respective cohort/sub-cohort
will be stopped for futility. Further details of POS are provided in With 28 evaluable patients 
for interim analysis in each of the Sub-cohorts 1a and 1b, Cohorts 2 and 4, if ≤ 7 responses 
(POS =0.0543) are observed then the respective cohort/sub-cohort will be stopped for futility. 
Further details of POS are provided in Table 10-2. For each of the Sub-cohorts 1a and 1b, 
Cohorts 2 and 4, if at the time that the 28th patient is enrolled a minimum of 8 responders 
have not yet been observed, accrual in the cohort/sub-cohort may be temporarily suspended 
until either the minimum number of 8 responders are observed or results of the interim 
analysis allow that cohort/sub-cohort to continue. 
Table 10-2
Probability of Success at the Final Analysis Based on Various Number 
of Responders Observed at IA for Sub-cohort 1a, Sub-cohort 1b, 
Cohort 2 and Cohort 4
Responder at IA out of 28 evaluable patients at IA
Probability of Success
≤5
< 0.01
6
0.0164
7
0.0543
8
0.1398
9
0.2863
10
0.4794
11
0.6766
≥12
> 0.83
Table 10-3
Number of Responders for Various Number of Evaluable Patients at 
Interim Analyses by Required Probability of Success for Sub-cohort 
1a, Sub-cohort 1b, Cohort 2 and Cohort 4 
Number of Evaluable patients at IA
Responders at IA
Probability of Success
26
6
0.0368
26
7
0.1050


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Number of Evaluable patients at IA
Responders at IA
Probability of Success
27
7
0.0765
27
8
0.1829
28
7
0.0543
28
8
0.1398
29
7
0.0377
29
8
0.1044
30
8
0.0760
30
9
0.1792
31
8
0.0540
31
9
0.1369
32
8
0.0373
32
9
0.1020
33
9
0.0740
33
10
0.1739
34
9
0.0523
34
10
0.1323
35
10
0.0980
35
11
0.2152
Cohort 3
With 20 evaluable patients for interim analysis in Cohort 3 if ≤ 5 responses (POS=0.0999) are 
observed then the cohort will be stopped for futility. All evaluable patients at the time of the 
data cut-off for the interim analysis will be used to obtain the futility boundary using the POS 
criteria. Further details of POS are provided in Table 10-4. If at the time that the 20th patient is 
enrolled a minimum of 6 responders have not yet been observed, accrual in the cohort may be 
temporarily suspended until either the minimum number of 6 responders are observed or 
results of the interim analysis allow the cohort to continue.
Table 10-4
Probability of Success at the Final Analysis Based on Various Number 
of Responders Observed at IA for Cohort 3 
Responder at IA out of 20 evaluable patients at IA
Probability of Success
1
0.0001
2
0.0009
3
0.0066
4
0.0309
5
0.0999
6
0.2379
7
0.4382
8
0.6533
10.8
Sample size calculation
Approximately 456 patients (69 patients per Sub-cohort in Cohort 1 and 69 patients per cohort 
in Cohorts 2-4, 27 patients per each Sub-cohort in Cohort 5,approximately 30 patients in 
Cohort 6 and approximately 27 in Cohort 7) will be enrolled in the study if none of the four 
cohorts (Cohort 1-4) is stopped for futility at the time of the interim analysis. The exact 95%
CIs for various sample sizes and observed ORRs in each cohort/sub-cohort are shown in 


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Table 10-5 for Sub-cohorts 1a and 1b and Cohorts 2, 3 and 4, and in Table 10-6 for Sub-
cohorts 5a, 5b and Cohort 7.
Table 10-5
Exact Binomial 95 percent Confidence Intervals for Various Sample 
Sizes and Observed ORRs in each Cohort/Sub-cohort 1a, 1b, 2, 3 and 
4
Sample size (N)
Number of 
responders
Observed ORR (%)
95% exact CI (%)
65
23
35.4
23.9
48.2
66
24
36.4
24.9
49.1
67
24
35.8
24.5
48.5
68
24
35.3
24.1
47.8
69
25
36.2
25.0
48.7
70
25
35.7
24.6
48.1
71
25
35.2
24.2
47.5
72
26
36.1
25.1
48.3
Table 10-6
Exact Binomial 95 percent Confidence Intervals for Various Sample 
Sizes and Observed ORRs in each Sub-cohort 5a, 5b and Cohort 7
Sample size (N)
Number of responders
Observed ORR (%)
95% exact CI (%)
25
14
56.0
34.9
75.6
26
15
57.7
36.9
76.6
27
15
55.6
35.3
74.5
28
16
57.1
37.2
75.5
29
16
55.2
35.7
73.6
The operating characteristics (with 69 subjects per cohort/Sub-cohort 1a, 1b, 2, 3 and 4) are 
shown in Table 10-7 and Table 10-8. The tables show probability of stopping at interim, 
probability for positive conclusion (i.e., not stopped at IA for futility and success criteria met 
at final analysis) and negative conclusion (i.e., not stopped at IA for futility but success 
criteria not met at final analysis) under different underlying true ORR. The operating 
characteristics (with 27 subjects per Sub-cohort in 5a, 5b and Cohort 7) are shown in Table 
10-9. The table shows the probability of meeting the success criteria under different 
underlying true ORR.
Sub-cohort 1a, Sub-cohort 1b, Cohort 2 and Cohort 4 
The operating characteristics at this sample size have > 50% probability of stopping the trial 
for futility when the true ORR is < 25%. Also, when the true ORR is 35% then the probability 
of positive conclusion at the final analysis with 69 patients is ≥ 44%. If the true ORR is 45% 
or higher, the probability of positive conclusion at the final analysis with 69 patients is > 90%.
Table 10-7
Operating Characteristics for Sub-cohort 1a, Sub-cohort 1b, Cohort 2 
and Cohort 4
True ORR 
(%)
Probability of a 
cohort to stop at 
IA* (%)
Probability for positive 
conclusion in final 
analysis for a cohort (%)
Probability for negative conclusion in
final analysis for a cohort 
(i.e. not stop at IA* and success criterion 
not met at final analysis) (%)
10
99.50
0.00
0.50


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True ORR 
(%)
Probability of a 
cohort to stop at 
IA* (%)
Probability for positive 
conclusion in final 
analysis for a cohort (%)
Probability for negative conclusion in
final analysis for a cohort 
(i.e. not stop at IA* and success criterion 
not met at final analysis) (%)
20
81.82
0.12
18.06
25
59.97
2.34
37.68
30
36.48
15.01
48.51
35
18.21
44.00
37.79
40
7.40
75.38
17.22
45
2.42
93.11
4.47
50
0.63
98.73
0.64
*Assuming interim analysis at 28 evaluable patients
Cohort 3
The operating characteristics at this sample size have > 60% probability of stopping the trial 
for futility when the true ORR is < 25%. With 69 patients and 20 evaluable patients for 
interim analysis, when the true ORR is 10% then the probability of stopping for futility at the 
interim analysis is > 90%. If the true ORR is 20%, the probability of stopping for futility at 
the interim analysis is > 80% and the probability of positive conclusion at the final analysis is 
< 1%.
Table 10-8
Operating Characteristics for Cohort 3
True ORR (%)
Probability of a 
cohort to stop at 
IA* (%)
Probability of positive
conclusion in final 
analysis for a cohort (%)
Probability of negative conclusion 
in final analysis for a cohort (i.e., 
not stop at IA* and success criterion 
not met at final analysis) (%) 
10
98.87
0
1.13
20
80.42
0.11
19.47
25
61.72
2.17
36.12
30
41.64
13.98
44.39
35
24.54
41.41
34.05
40
12.56
71.99
15.45
45
5.53
90.46
4.01
50
2.07
97.36
0.57
*Assuming interim analysis at 20 evaluable patients
Sub-cohort 5a, 5b and Cohort 7
The operating characteristics at this sample size of 27 have < 36% probability of the trial 
meeting the success criteria when the true ORR is ≤50%. If the true ORR is ≥60%, the 
probability of the trial meeting the success criteria is ≥ 75%.
Table 10-9
Operating Characteristics for Sub-cohort 5a, 5b and Cohort 7
Sample size (N)
True ORR (%)
Probability (%) that ORR>=55% with 
lower 95% CI>35%
27
40
7.4
27
45
18.1
27
50
35.1


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Sample size (N)
True ORR (%)
Probability (%) that ORR>=55% with 
lower 95% CI>35%
27
55
55.6
27
60
75.0
27
65
88.9
Cohort 6 
In expansion Cohort 6, patients with either cMET GCN ≥ 10 without cMET mutations or 
cMET mutations regardless of cMET GCN will be enrolled. Based on the rarity of this patient 
population and considering recruitment within a reasonable timeframe, approximately 30 
patients are expected to be enrolled in Cohort 6.
Data from Cohort 6 will help further characterize the safety and efficacy of INC280 in the 
pre-treated population (from Sub-cohort 1a and Cohort 4). 
10.9
Power for analysis of key secondary variables
Not applicable.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. 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 Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their CRFs.




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For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported 
on the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF 
should be dated, initialed, and explained (if necessary) and should not obscure the original 
entry. For electronic CRFs an audit trail will be maintained by the system. The investigator 
should retain records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.


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11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the 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/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
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/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient 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 (e.g. UK requires the notification of 
urgent safety measures within 3 days) but not later than 10 working days.










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Scagliotti G, Parikh P, von Pawel J et al (2008). Phase III study comparing cisplatin plus 
gemcitabine with cisplatin plus pemetrexed in chemotherapy-naïve patients with advanced-
stage non–small-cell lung cancer. J Clin Oncol. 2008;26:3543–3551.
Scagliotti G, von Pawel J, Novello S et al (2015). Phase III multinational, randomized, 
double-blind, placebo-controlled study of tivantinib (ARQ 197) plus erlotinib versus erlotinib 
alone in previously treated patients with locally advanced or metastatic nonsquamous non–
small-cell lung cancer. J Clin Oncol;33:2667-74. 
Schildhaus HU, Schultheis AM, Ruschoff J, et al (2014). MET amplification status in 
therapy- naïve adeno- and squamous cell carcinomas of the lung. Clin Cancer Res; Dec 9 
(Epub). 
Schuler MH, Berardi R, Lim WT, Van Geel R (2016). Phase I Study of the Safety and 
Efficacy of the cMET Inhibitor Capmatinib (INC280) in Patients With Advanced cMET+ 
Non-small Cell Lung Cancer. J Clin Oncol; (34) (suppl; abstr 9067)
Sequist L, Yang J, Yamamoto N et al (2013). Phase III Study of Afatinib or Cisplatin Plus 
Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. J Clin 
Oncol; 31(27):3327-34.
Shaw AT, Engelman JA (2013a). ALK in lung cancer: past, present, and future. J Clin Oncol; 
31:1105-11.
Shaw AT, Kim D, Nakagawa K et al (2013b). Crizotinib versus Chemotherapy in Advanced 
ALK-Positive Lung Cancer. N Engl J Med; 368:2385-94.
Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al. (2005) Erlotinib in previously treated 
non-small-cell lung cancer. N Engl J Med; 353: 123–132.
Solomon B, Mok T, Kim D et al (2014). First-Line Crizotinib versus Chemotherapy in ALK-
Positive Lung Cancer. N Engl J Med; 371:2167-2177.
Siegel R, Ma J, Zou Z et al (2014). Cancer statistics, 2014. CA Cancer J Clin; 64(1):9-29. 
Spigel D, Edelman M, O’Byrne K et al (2014). Onartuzumab plus erlotinib versus erlotinib in 
previously treated stage IIIb or IV NSCLC: Results from the pivotal phase III randomized, 
multicenter, placebo-controlled METLung (OAM4971g) global trial. J Clin Oncol; (suppl; 
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TCGA web portal (2015). <//tcga-data.nci.nih.gov/tcga/>
Tong JH, Yeung SF, Chan AW 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. May;10(5):e29-31.
Weiss JM, Stinchcombe TE (2013). Second-Line Therapy for Advanced NSCLC. The 
Oncologist;18(8):947-53.
Wolf J, Seto T, Han JY et al (2018). LBA52 Results of the GEOMETRY mono-1 phase II 
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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


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14.1.1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This 
document is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the 
revised RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 14.1.2 and the definition of best response in 
Section 14.1.17 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.1.18 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 14.1.28
of this guideline describes data handling and programming rules. This section is to be referred 
to in the RAP (Reporting and Analysis Plan) to provide further details needed for 
programming.
14.1.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) 
European Journal of Cancer; 45:228-247.
14.1.3
Definitions
14.1.4
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 14.1.26.
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.


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
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions.
Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with 10 to 
< 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging techniques.
14.1.5
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 14.1.26.
14.1.6
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.


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
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 change in technique (e.g. from CT to 
MRI, or vice-versa), or a change in any other imaging modality. A change in methodology 
will result by default in a UNK overall lesion response assessment. However, another 
response assessment than the Novartis calculated UNK response may be accepted from the 
investigator or the central blinded reviewer if a definitive response assessment can be 
justified, based on the available information.

FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.

No FDG-PET at baseline with a positive FDG-PET at follow-up:

If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD.

If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT are needed to determine if there is truly progression occurring at 
that Site (if so, the date of PD will be the date of the initial abnormal CT scan).

If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD.

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.

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. 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 


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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.
14.1.7
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 14.1.4.

Nodal target: See Section 14.1.4.
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.
14.1.8
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 


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for the target (Table 14-1) and non-target lesions (Table 14-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target 
and non-target lesions together (Table 14-3) as well as the presence or absence of new lesions.
14.1.9
Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for 
the evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate 
lesion evaluation data are examined by the investigator in order to derive the overall visit 
response. Therefore all such data applicable to a particular visit should be associated with the 
same assessment number.
14.1.10
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.
14.1.11
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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14.1.12
Determination of target lesion response
Table 14-1
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 mm2.
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. Methodology change See Section 14.1.6.
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 three 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 14-1 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.
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, 


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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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14.1.13
Determination of non-target lesion response
Table 14-2
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 baseline.
1. Although a clear progression of non-target lesions only is exceptional, in such circumstances, the opinion of the 
treating physician does prevail and the progression status should be confirmed later on by the review panel (or 
study chair).
Notes on non-target lesion response
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 any of the lesions was not assessed (in which case response is UNK) or there is 
unequivocal progression of the non-target lesions (in which case response is PD).
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 14.1.12 for assigning PD following a CR for the non-
target lesion response in the presence of non-target lesions nodal lesions should be applied.
14.1.14
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 


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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 14.1.15).

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 14.1.6.
14.1.15
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 14-3.
Table 14-3
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 14.1.8.
If there are no baseline scans available at all, then the overall lesion response at each 
assessment should be considered Unknown (UNK).
If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen.
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.
14.1.16
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.1.26 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.


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14.1.17
Best overall response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). In general, the patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the 
protocol should specifically describe if these will be included in the determination of best 
overall response and/or whether these additional assessments will be required for sensitivity 
or supportive analyses. As a default, any assessments taken more than 30 days after the last 
dose of study treatment will not be included in the best overall response derivation. If any 
alternative cancer therapy is taken while on study any subsequent assessments would 
ordinarily be excluded from the best overall response determination. If response assessments 
taken after withdrawal from study treatment and/or alternative therapy are to be included in 
the main endpoint determination, then this should be described and justified in the protocol.
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met.
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed.

For non-randomized trials where response is the primary endpoint, confirmation is needed.

For trials intended to support accelerated approval, confirmation is needed

For all other trials, confirmation of response may be considered optional.
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required

SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).

PD = progression 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).

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)
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 


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other than a PD, e.g. PR or SD, as this would imply a progression based on one or more 
lesions reappearing, in which case the status would become a PD.
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not 20% increase from previous smallest sum), the objective 
status at that assessment should be SD. Once a confirmed PR was seen, the overall lesion 
response should be considered PR (or UNK) until progression is documented or the lesions 
totally disappear in which case a CR assignment is applicable. In studies where confirmation 
of response is not required after a single PR the overall lesion response should still be 
considered PR (or UNK) until progression is documented or the lesion totally disappears in 
which case a CR assignment is applicable.
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the 
subsequent visits. Assuming that non-target lesions did not progress, the overall lesion 
response would be PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the 
PR for this patient. All subsequent assessments are considered PR even if tumor 
measurements decrease only by 20% compared to baseline (200 mm to 160 mm) at the 
following assessments.
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response.
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources:

Investigator overall lesion response

Central Blinded Review overall lesion response

Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review)
The primary analysis of the best overall response will be based on the sequence of 
investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses.
Based on the patients’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications.
Disease control rate (DCR) is the proportion of patients with a best overall response of CR 
or PR or SD.


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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).
14.1.18
Time to event variables
The protocol should state which of the following variables is used in that study.
14.1.19
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.
14.1.20
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.
14.1.21
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.
14.1.22
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.
14.1.23
Duration of response
The analysis of the following variables should be performed with much caution when 
restricted to responders since treatment bias could have been introduced. There have been 
reports where a treatment with a significantly higher response rate had a significantly shorter 
duration of response but where this probably primarily reflected selection bias which is 
explained as follows: It is postulated that there are two groups of patients: a good risk group 
and a poor risk group. Good risk patients tend to get into response readily (and relatively 
quickly) and tend to remain in response after they have a response. Poor risk patients tend to 
be difficult to achieve a response, may have a longer time to respond, and tend to relapse 
quickly when they do respond. Potent agents induce a response in both good risk and poor 
risk patients. Less potent agents induce a response mainly in good risk patients only. This is 
described in more detail by Morgan (1988).
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then 
interpreted with caution by evaluating the results in the context of the observed response rates. 
If an inferential comparison between treatments is required this should only be performed on 
all patients (i.e. not restricting to “responders” only) using appropriate statistical methods such 
as the techniques described in Ellis et al (2008). It should also be stated in the protocol if 
duration of response is to be calculated in addition for unconfirmed response.
For summary statistics on “responders” only the following definitions are appropriate. 
(Specific definitions for an all-patient analysis of these endpoints are not appropriate since the
status of patients throughout the study is usually taken into account in the analysis).
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end 
date and censoring is defined the same as that for time to progression.


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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.
14.1.24
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 14.1.23. It is 
recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. Where an 
inferential statistical comparison is required, then all patients should definitely be included in 
the analysis to ensure the statistical test is valid. For analysis including all patients, patients 
who did not achieve a response (which may have to be a confirmed response) will be censored 
using one of the following options.

at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV)

at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint.
14.1.25
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 


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assessment date is calculated as the earliest date of all measurement dates at that evaluation 
number.
Start dates
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date.
For the calculation of duration of response the following start date should be used:

Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page).

Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease.

Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used.

Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.1.26).
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.
14.1.26
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 


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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 measurable 
disease is derived slightly differently according to Table 14-4.
Table 14-4
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 14.1.8.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.
For ORR it is recommended that the main (ITT) analysis includes data from patients with 
only non-measurable disease at baseline, handling patients with a best response of CR as 
“responders” with respect to ORR and all other patients as “non-responders”.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses 
which exclude these particular patients. Endpoints such as PFS which are reliant on the 
determination and/or timing of progression can incorporate data from patients with only non-
measurable disease.
14.1.27
Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well as 
addresses the issues of missing tumor assessments during the study. For instance, if one or 
more assessment visits are missed prior to the progression event, to what date should the 
progression event be assigned? And should progression event be ignored if it occurred after a 
long period of a patient being lost to follow-up? It is important that the protocol and RAP 
specify the primary analysis in detail with respect to the definition of event and censoring 
dates and also include a description of one or more sensitivity analyses to be performed.


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Based on definitions outlined in Section 14.1.25, 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 14-5
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) N/A
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
Ignored
Progressed
F
New anticancer therapy given
(1) Date of last adequate assessment
(2) Date of secondary anti-cancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censored
Censored
Event
Ignored
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 14.1.25
2.=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 14.1.25.
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 


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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), i.e. censoring at last adequate assessment may be 
used as a default in this case.
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 14-5 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.
14.1.28
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).
14.1.29
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).
14.1.30
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.


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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

Death

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)
14.1.31
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

New therapy for study indication

Progressive disease

Study terminated by the sponsor
14.1.32
Medical validation of programmed overall lesion response
As RECIST 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), these UNK 


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assessments may be re-evaluated by clinicians 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.
14.1.33
Programming rules
The following should be used for programming of efficacy results:
14.1.34
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.
14.1.35
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 14.1.25). If all measurement dates have no 
day recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
14.1.36
Incomplete dates for last known date patient alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.


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14.1.37
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)’.
14.1.38
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
14.1.39
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 14-5)

Death due to reason other than underlying cancer (only used for TTP and duration of 
response)

Initiation of new anti-cancer therapy
*Adequate assessment is defined in Section 14.1.25. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason 
should also be noted:

This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off).

The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment.

This reason will also be used to censor in case of no baseline assessment.


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14.1.40
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
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumor

SAP_001.pdf: 
Clinical Development
INC280/capmatinib
CINC280A2201/ NCT02414139
A phase II, multicenter, study of oral cMET inhibitor INC280 
in adult patients with EGFR wild-type (wt), advanced non-
small cell lung cancer (NSCLC) 
Statistical Analysis Plan 
for Final CSR (End of Study)
Author:
 Trial Statistician
Document type:
SAP Documentation
Document status:
Final
Release date:
03-Mar-2023
Number of pages:
60
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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CONFIDENTIAL - For Business Use Only
Document History – Changes compared to previous version of SAP.
Version
Date
Main Changes
1.0
03-Mar-2023
Initial version for the final CSR  


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Objectives ................................................................................................................7
1.2.1
Primary objective ....................................................................................7
1.2.2
Secondary objectives...............................................................................7
7
2
Statistical methods...............................................................................................................8
2.1
Data analysis general information ...........................................................................8
2.2
Analysis sets ..........................................................................................................10
2.3
Patient demographics and other baseline characteristics.......................................12
2.4
Protocol deviations ................................................................................................13
2.5
Patient disposition..................................................................................................13
2.6
Treatments (study drug, concomitant therapies, compliance)...............................14
2.7
Analysis of the primary variable............................................................................16
2.7.1
Variable.................................................................................................16
2.7.2
Statistical hypothesis, model, and method of analysis..........................18
2.7.3
Handling of missing values/censoring/discontinuations.......................18
2.7.4
Supportive analyses...............................................................................18
2.8
Analysis of secondary variables ............................................................................19
2.8.1
Efficacy .................................................................................................19
2.8.2
Safety.....................................................................................................22
32
2.8.4
Pharmacokinetics ..................................................................................34
2.8.5
Pharmacogenetics/pharmacogenomics .................................................34
34
2.8.7
PK/PD ...................................................................................................34
2.9
Sample size calculation..........................................................................................34
2.10
Power for analysis of key secondary variables......................................................36
2.11
Interim analysis for futility....................................................................................36
3
Changes to protocol specified analyses.............................................................................38
4
Additional details on implementation of statistical methodology.....................................39
4.1
Data included in the analyses ................................................................................39
4.2
Patient classification into analysis sets..................................................................39


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4.3
Last contact date ....................................................................................................39
4.4
Time unit................................................................................................................40
4.5
Dose interruptions and dose changes.....................................................................40
4.6
Efficacy endpoints .................................................................................................43
4.6.1
Implementation of RECIST guidelines.................................................43
4.6.2
Sources for overall lesion response.......................................................48
4.6.3
Kaplan-Meier estimates ........................................................................48
4.6.4
Confidence interval and p-value for response rate................................49
4.6.5
Baseline.................................................................................................49
4.7
Safety evaluations..................................................................................................49
4.7.1
Multiple assessments within post-baseline visits..................................49
4.7.2
Baseline.................................................................................................50
4.7.3
Laboratory Parameters ..........................................................................51
4.7.4
Time to first occurrence of event and duration.....................................52
4.7.5
Handling of AEs missing grade ............................................................55
4.8
Imputation rules.....................................................................................................55
4.8.1
Study drug.............................................................................................55
4.8.2
AE date imputation ...............................................................................56
4.8.3
Concomitant medication date imputation .............................................57
4.8.4
Other imputations..................................................................................58
59
5
Reference:..........................................................................................................................59


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List of tables
Document History – Changes compared to previous version of SAP........................................2
Table 2-1
Outcome and event dates for DOR and PFS analyses ..........................19
Table 2-2
ECOG performance scale......................................................................32
32
Table 2-4
Exact Binomial 95 percent Confidence Intervals for Various 
Sample Sizes and Observed ORRs in Each Cohort ..............................34
Table 2-5
Exact Binomial 95 percent Confidence Intervals for Various 
Sample Sizes and Observed ORRs in each cohort 5a, 5b and 7 ...........34
Table 2-6
Operating Characteristics for Cohort 1 (MET GCN ≥ 6) and Cohort 
2 (MET GCN ≥ 4 and < 6)....................................................................35
Table 2-7
Operating Characteristics for Cohort 3 (MET GCN < 4) .....................35
Table 2-8
Operating Characteristics for Cohort 5a, 5b and 7................................36
Table 2-9
Probability of Success at the Final Analysis Based on Various 
Number of Responders Observed at IA for Cohort 1a, Cohort 1b, 
Cohort 2 and Cohort 4...........................................................................37
Table 2-10
Number of Responders for Various Number of Evaluable Patients 
at Interim Analyses by Required Probability of Success for Cohort 
1a, Cohort 1b, Cohort 2 and Cohort 4...................................................37
Table 2-11
Probability of Success at the Final Analysis Based on Various 
Number of Responders Observed at IA for Cohort 3 (MET GCN 
less than 4).............................................................................................38
Table 4-1
Patient classification rules.....................................................................39
Table 4-2
Last contact date data sources...............................................................39
Table 4-3
Overall lesion response at each assessment: patients with non-
target disease only.................................................................................46
Table 4-4
Inclusion/exclusion of assessments used in waterfall graph.................47
Table 4-5
Sources for overall lesion response.......................................................48
Table 4-6
Time windows for Labs ........................................................................52
Table 4-7
AE/treatment date abbreviations...........................................................56
Table 4-8
Imputation algorithm.............................................................................56
Table 4-9
Imputation algorithm legend.................................................................56
Table 4-10
Example scenarios.................................................................................57


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1
Introduction
This Statistical Analysis Plan (SAP) describes the planned statistical methods for all safety,
efficacy, pharmacokinetic, 
analyses for study 
CINC280A2201. This SAP refers to study protocol amendment 6. 
1.1
Study design
This is a prospectively designed, multicenter, open-label, phase II study to evaluate the efficacy 
and safety of single-agent INC280. NSCLC patients with stage IIIB or IV that are EGFR wild-
type (for exon 19 deletions and exon 21 L858R substitution mutations) and ALK-negative 
rearrangement will be pre-screened for MET amplification and MET mutation status. Enrolled 
patients will be assigned to the following nine cohorts:

Cohort 1: Pre-treated patients with MET GCN ≥ 6, including: 

Cohort 1a: Patients with a MET GCN of ≥ 10, or

Cohort 1b: Patients with a MET GCN of ≥ 6 and < 10, or

Cohort 2: Pre-treated patients with MET GCN ≥ 4 and < 6, or

Cohort 3: Pre-treated patients with MET GCN < 4, or

Cohort 4: Pre-treated patients with MET mutations regardless of MET GCN, or

Cohort 5: Treatment-naïve patients with MET dysregulation, including:

Cohort 5a: Patients with a MET GCN ≥10, or

Cohort 5b: Patients with MET mutations regardless of MET GCN 

Cohort 6: Pre-treated patients with either MET GCN ≥ 10 without MET mutations or 
MET mutations regardless of MET GCN

Cohort 7: Treatment-naïve patients with MET mutations regardless of MET GCN
Primary diagnostic of MET amplification (and ALK rearrangement, if applicable) will be 
performed using fluorescence in situ hybridization (FISH) and for MET mutations by RT-PCR 
at a Novartis-designated central laboratory. 
 
 
 
 
 
 
 
Enrolled patients will be treated with INC280 tablets at 400 mg twice daily (BID). Treatment 
with INC280 will continue until patient experiences any of the following: disease progression 
according to RECIST 1.1 as determined by investigator and confirmed by BIRC, unacceptable 
toxicity that precludes further treatment, treatment is discontinued at the discretion of the 
Investigator or patient, lost to follow-up, or death. Treatment with INC280 may be continued 
beyond RECIST 1.1-defined PD (as determined by investigator and confirmed by BIRC) if, in 


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the judgment of the investigator, there is evidence of clinical benefit and the patient wishes to 
continue on the study treatment.
Approximately 456 patients (69 patients per each Cohort 1a, 1b, 2, 3, 4; 27 patients per each 
Cohort 5a, 5b; approximately 30 patients in Cohort 6 and approximately 27 patients in Cohort 
7) were to be enrolled in the study if none of the five cohorts (Cohort 1a, 1b, 2, 3, 4) are stopped 
for futility at the time of the interim analysis. No interim analysis is planned for Cohorts 5a, 5b,
6 and 7. 
The primary analysis will be conducted when all treated patients in their respective cohort (if 
not stopped for futility at interim analysis) have completed at least 6 cycles of treatment (18 
weeks) or discontinued treatment earlier. Due to the expected difference in enrollment rate for 
each cohort, the primary analysis for the different cohorts may occur at different times. The 
primary analysis for any cohort that was stopped for futility may be combined with the primary 
analyses for other cohorts. Also, if majority of the patients in a cohort meet the required follow-
up time for primary analysis, the primary analysis of such cohorts may be combined with the 
primary analyses for other cohorts.
1.2
Objectives
1.2.1
Primary objective
The primary objective is to evaluate the antitumor activity of INC280, as measured by overall 
response rate (ORR) by Blinded Independent Review Committee (BIRC) assessment, by cohort.
1.2.2
Secondary objectives
Key secondary objective is to evaluate duration of response (DOR) as assessed by BIRC, by 
cohort.
Other secondary objectives are:

To evaluate ORR and DOR by investigator assessment, by cohort

To evaluate time to response (TTR), disease control rate (DCR) and progression-free 
survival (PFS) by investigator and by BIRC assessment, by cohort

To evaluate overall survival (OS), by cohort

To evaluate INC280 safety profile as monotherapy in NSCLC patients with 
advanced/metastatic setting

To characterize the pharmacokinetics of INC280 and metabolite CMN288


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2
Statistical methods
This section and its subsections will be imported to section 9.7 of the CSR after the analyses 
have been conducted. This section of the SAP follows the CSR template structure of Section 
9.7 as of the release date of this document.
The text will be changed to the past tense when imported into the CSR; references to Section 4
of the SAP, where additional details are provided for programming implementation, may be 
removed in the CSR. 
In what follows, study drug refers to INC280.
2.1
Data analysis general information
Data will be analyzed by Novartis Biostatistics and Statistical Programming personnel 
according to the data analysis section 10 of the CINC280A2201 protocol, which will be 
available in Appendix 16.1.1 of the Clinical Study Report (CSR). Important information is 
given in the following sections and details are provided, as applicable, in Section 4 from which 
Appendix 16.1.9 of the CSR will be extracted.
SAS® version 9.4 (or later version if available at time of database lock) will be used in all 
analyses.
Data from all patients who signed informed consent in centers that participate in this study will 
be used in the analysis. Data collected after withdrawal of informed consent will not be reported. 
Data collected on the same date as withdrawal of informed consent are reported. Due to 
expected small size of enrollment at individual centers, no center effect will be assessed. Each
analysis will use all data in the database up to the analysis cutoff date, determined prior to 
database lock. 
The data from all participating centers in this protocol will be combined. For cohorts 1-4, the 
efficacy data for each cohort will be analyzed separately at the time of the interim analysis and 
one (or more) of the cohorts may be stopped for futility according to the criteria described in 
the Interim Analysis Section of the study protocol (Section 10.7). No interim analysis for futility
is planned for Cohorts 5a, 5b, 6 and 7.  


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Previous reports

The primary analyses for MET mutant patients (Cohort 4, and 5b) and for all closed cohorts 
for futility (Cohorts 1b, 2, and 3) were conducted based on data with a data cut-off date of 
15-Apr-2019. 

The primary analyses for MET amplified patients with a MET GCN ≥ 10 (Cohorts 1a and 
5a) and pre-treated expansion cohort (Cohort 6) were conducted based on data with a data 
cut-off date of 06-Jan-2020. 

A preliminary analysis for MET mutant patients (expansion Cohort 7) along with updated 
results from other MET mutant cohorts (Cohorts 4, 5b and 6) was conducted based on data 
with a data cut-off date of 18-Sep-2020.

The primary analyses for MET mutant patients (expansion Cohort 7) along with updated 
results from other MET mutant cohorts (Cohorts 4, 5b and 6) was conducted based on data 
with a data cut-off date of 30-Aug-2021.
Planned analyses for this report

The updated analyses for all MET mutant patients (Cohorts 4, 5b and 6, and 7) will be 
conducted when Last Patient Last Visit is reached.

Data from cohorts (Cohort 1-7) will be included for patient disposition, baseline 
characteristics and safety analyses. Patient disposition, baseline characteristics and safety 
analyses will also be presented combining the MET mutant patients (pre-treated, treatment-
naïve and all MET mutant patients) and all amplified patients (complementary subgroup to 
MET mutant patients).

Data from MET mutant cohorts (Cohort 4, 5b, 6 and 7) will be included for efficacy a
 
 They will also presented combining the MET mutant patients (pre-treated 
and treatment-naïve MET mutant patients).

No PK analyses will be included in this report as no additional PK samples are analyzed at 
this time.
All available data from all patients will be summarized in the final Clinical Study Report (CSR). 
Section 4.1 provides further details regarding data to be included in the analyses. 
General presentation of descriptive summaries
Qualitative data (e.g., gender, race) will be summarized by frequency counts and percentages. 
Percentages will be calculated using the number of patients in the relevant population or 
subgroup as the denominator.  
Continuous data (e.g., age, body weight) will be summarized by appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum, and maximum).


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2.2
Analysis sets
Screened patients
Patients are considered to be enrolled into the study if they have signed main informed consent. 
Only patients who have signed main informed consent will be included in the analysis data sets.
Patients are considered to be a screen failure if they have signed main informed consent but 
failed to be treated.
Patients are considered to be a pre-screen failure if they have failed to meet pre-screened criteria 
i.e. they have not signed main informed consent.
Full Analysis Set
The Full Analysis Set (FAS) includes all patients who received at least one dose of INC280. 
The FAS will be used for all listings. Unless otherwise specified the FAS will be the default 
analysis set used for all efficacy analyses.
Safety Set
The Safety Set includes all patients who received at least one dose of INC280. All safety data 
will be analyzed using the Safety Set.
The FAS and Safety Set in this study are identical.
Per-Protocol Set
The Per-Protocol Set (PPS) consists of a subset of patients in the FAS who have no major 
protocol deviations, regardless of the adequate tumor assessment.
The major protocol deviations that will lead to removal of patients from the PPS are listed below: 

Patient does not have Stage IIIB or IV NSCLC (any histology) at the time of study entry

Patient does not have a histologically or cytologically confirmed diagnosis of non-squamous 
NSCLC with EGFR wt status (for exon 19 deletions and exon 21 L858R substitution 
mutations)

Patient with NSCLC of pure squamous cell histology that has known EGFR mutations in 
exons 19 or 21 is enrolled

Patient without MET status for eligibility as determined by central assessment at a Novartis 
designated laboratory prior to first dose 

Patient has not received one or two prior lines of systemic therapy for advanced/metastatic 
disease (only for cohorts 1a, 1b, 2, 3 and 4)

Patient has received prior systemic therapy for advanced/metastatic disease (only for 
cohorts 5a and 5b and 7)

Patient has not received one prior line of systemic therapy for advanced/metastatic disease 
(only for cohort 6)

Patients has no measurable lesion from RECIST 1.1 evaluation at baseline or has no baseline 
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
Patient has received crizotinib, or any other MET or HGF inhibitor before entering 
screening

Patient has characterized ALK-positive rearrangement or un-determinant
ALK 
rearrangement status at study entry

ECOG performance status > 1 at study entry

Presence or history of a malignant disease other than NSCLC that has been diagnosed and/or 
required therapy within the past 3 years. Exceptions to this exclusion include the following: 
completely resected basal cell and squamous cell skin cancers, and completely resected 
carcinoma in situ of any type
Combined cohorts 
Patient disposition, baseline characteristics, exposure and safety analyses will be presented 
combining the MET mutant cohorts per line of treatment and regardless of the line of treatment, 
and all amplified cohorts whereas 
 efficacy will be presented combining the MET 
mutant cohorts per line of treatment.
The combined cohorts are defined as follows:

All patients (2/3L, MET mutant) (N=100): Pretreated patients from Cohort 4 and subset of 
MET mutant patients from Cohort 6.

All patients (1L, MET mutant) (N=60): Treatment-naïve patients from Cohort 5b and 7.

All MET mutant patients (N=160): All MET mutant patients regardless of the line of 
treatment i.e. Pre-treated MET mutant patients (2/3L, MET mutant) and treatment-naïve 
MET mutant patients (1L, MET mutant) as defined above.

All Amplified patients (N=213): All patients enrolled in cohorts other than MET mutant 
cohorts (Cohorts 1a, 1b, 2, 3, 5a and subset of amplified patients from Cohort 6).

All patients (N=373): All patients enrolled in the study.
Subgroup analysis
Efficacy 
ORR, DOR, PFS by BIRC and investigator assessment will be summarized for the following 
subgroups:

age group (< 65 years, ≥65 years)

gender (male, female)

race (Caucasian, Asian, Others)
o
Others: include Black, Other, Unknown, Native American

ECOG performance status (0, ≥1)
Safety
Adverse events (AEs) will be summarized for the following subgroups:


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
age group (< 65 years, ≥65 years)

gender (male, female)

race (Caucasian, Asian, Others) 

ECOG performance status (0, ≥1)

Patients with long exposure of study drug (at least 48, 72, 96 weeks of exposure)
2.3
Patient demographics and other baseline characteristics
The FAS will be used for all patient demographic and baseline characteristic summaries and 
listings.
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed by 
cohort. Categorical data (e.g. gender, race, ethnicity, ECOG performance status) will be 
summarized by frequency count and percentages. Continuous data (e.g. age, weight, height, 
BMI) will be summarized by descriptive statistics (as defined in Section 2.1).
Diagnosis and extent of cancer
Descriptive statistics and frequency counts and percentages will be tabulated by cohort, as 
appropriate, for diagnosis and extent of cancer based on the data collected on the electronic 
Case Report Form (eCRF) including: primary site of cancer, tumor histology/cytology, 
histological grade, time (in months) since initial diagnosis of primary site, stage at initial 
diagnosis, time (in months) from initial diagnosis to first recurrence/progression, time (in 
months) since most recent relapse/progression, current extent of disease (metastatic sites), 
number of metastatic sites at baseline, types of lesions (target and non-target lesions) at baseline, 
number of target lesions at baseline, and disease burden at baseline for target lesion (based on 
the data collected on the RECIST eCRF page).
Medical history
Medical history and ongoing conditions, including cancer-related conditions and symptoms will 
be summarized and listed by cohort. Separate summaries will be presented for ongoing and 
historical medical conditions.  The summaries will be presented by primary system organ class 
and preferred term. Medical history and current medical conditions are coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology.
Prior anti-cancer therapy
Prior anti-neoplastic (anti-cancer) therapy will be listed in three separate categories by cohort: 
1. medications, 2. radiotherapy, and 3. surgery.  
The number and percentage of patients who received any prior anti-neoplastic medications, 
prior anti-neoplastic radiotherapy or prior anti-neoplastic surgery will be summarized by cohort. 
Prior anti-neoplastic medications will be summarized by chemotherapy (medication) setting, 
other therapy (medication) setting, number of prior regimens of anticancer medications and


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prior anticancer medications. Prior antineoplastic medications will also be summarized by ATC 
class, and preferred term. The medication therapy type of any combination therapy will be 
classified based on the following order: immunotherapy, chemotherapy, biologic therapy (other 
than immunotherapy), targeted therapy, hormonal therapy. For example, a combination therapy 
of chemotherapy and immunotherapy will be classified as ‘immunotherapy’. 
Prior anti-neoplastic systemic medications (any line, 1st line, 2nd line) will be summarized by 
line: single agent chemotherapy, Platinum based chemotherapy, immunotherapy.
For radiotherapy, time since last radiotherapy, locations and setting of last therapy will be 
summarized. For prior surgery, time since last surgery, procedure and residual disease of last 
therapy will be summarized.
2.4
Protocol deviations
In addition to the pre-defined standard PD terms, new protocol deviations and the corresponding 
relationship (health status related, lockdown/quarantine of patient, site issues, patient concerns, 
etc.) to the COVID-19 pandemic in line with “FDA Guidance on Conduct of Clinical Trials of 
Medical Products during COVID-19 Public Health Emergency” (March 2020) and “Guidance 
on the management of clinical trials during the COVID-19 (coronavirus) pandemic” (February 
2021) from EMA were defined. 
Frequency counts and percentages of patients in the FAS with any protocol deviations (related 
to study inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be tabulated by deviation category and cohort, broken down by COVID-19 
relationship (COVID-19 related PDs or not). Major protocol deviations will be tabulated 
separately by cohort. A cross-tabulation of COVID-19 related protocol deviations vs. 
corresponding COVID-19 situation will also be produced by cohort. All protocol deviations 
will be listed by cohort. 
2.5
Patient disposition
The FAS will be used for the patient disposition summary tables by cohort.  The FAS will be 
used for the listings by cohort. 
The following will be tabulated:

Number (%) of patients who are still on-treatment (based on the absence of the ‘End of 
Treatment Phase Disposition’ page); 

Number (%) of patients who discontinued  treatment (based on completion of the ‘End of 
Treatment Phase Disposition’ page with date of discontinuation and reason of 
discontinuation/ ‘Subject Status’ entered);

Number (%) of patients who entered post treatment efficacy follow-up (based on ‘Next 
Phase Entered’ is ‘Post-treatment follow-up’ on the ‘End of Treatment Phase Disposition’ 
page for patients who discontinued treatment);

Number (%) of patients who entered survival follow-up (based on ‘Next Phase Entered’ is 
‘Survival follow-up’ on the ‘End of Treatment Phase Disposition’ page for patients who 
discontinued treatment);


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
Number (%) of patients who discontinued from study (based on ‘Will subject continue into 
the next phase of the trial’ is ‘No’ as entered on the ‘End of Treatment Phase Disposition’ 
page for patients who discontinued treatment);

Primary reasons for study treatment discontinuation (based on discontinuation reasons 
entered under ‘Subject Status’ in the ‘End of Treatment Phase Disposition’ page);

Number (%) of patients who are still in the post-treatment study phase (based on presence 
of ‘End of Treatment Phase Disposition’ and absence of ‘Study Phase Disposition’ page);

Number (%) of patients who discontinued from the post-treatment efficacy follow-up (based 
on completion of ‘Study Phase Disposition’ page with date of discontinuation and 
discontinuation reasons entered under ‘Subject Status’);

Number (%) of patients who entered survival follow-up (based on completion of ‘Study 
Phase Disposition’ page with date of discontinuation and discontinuation reasons entered 
under ‘Subject Status’ and ‘Next Phase Entered’ is ‘Survival follow-up’ for patients who 
discontinued from the post-treatment efficacy follow-up);

Number (%) of patients who discontinued from study (based on completion of ‘Study Phase 
Disposition’ page with date of discontinuation and discontinuation reasons entered under 
‘Subject Status’ and ‘Will subject continue into the next phase of the trial’ is ‘No’ for 
patients who discontinued from the post-treatment efficacy follow-up);

Primary reasons for discontinuation from the post-treatment efficacy follow-up (based on 
discontinuation reasons entered under ‘Subject Status’ in the ‘Study Phase Disposition’ 
page).
Note: ‘Study Phase Disposition’ page corresponds to ‘End of Post-Treatment disposition’ CRF 
page.
2.6
Treatments (study drug, concomitant therapies, compliance)
The Safety Set will be used for all medication data summaries and listings unless otherwise 
specified.
Study drug and study treatment
Study drug and study treatment both refer to INC280 and will be used interchangeably.
Date of first/last administration of study drug
The date of first administration of study drug is defined as the first date when a non-zero dose 
of study drug was administered and recorded on the Dosage Administration Record (DAR) 
eCRF. For the sake of simplicity, the date of first administration of study drug will also be 
referred to as start date of study drug.
The date of last administration of study drug is defined as the last date when a non-zero dose of 
study drug was administered and recorded on DAR eCRF. This date will also be referred to as 
last date of study drug.


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Study day
The study day for all assessments (e.g. tumor assessment, death, disease progression, tumor 
response, performance status, adverse event onset, laboratory abnormality occurrence, vital sign 
measurement, dose interruption) will be calculated using the start date of study drug as the 
origin. For assessments occurring after or on the start date of study drug, study day will be 
calculated as:
Study Day =Event date - start date of study drug + 1.
The first day of study drug is therefore study day 1. 
For any assessment or events such as baseline disease characteristics or medical history (e.g., 
time since diagnosis of disease) occurring prior to the start of the study drug, study day will be 
negative and will be calculated as:
Study Day = Event date - start date of study drug.
The study day will be displayed in the relevant data listings.
Dose exposure and intensity
Definitions of duration of exposure, cumulative dose, average daily dose, dose intensity (DI), 
relative dose intensity (RDI), as well as intermediate calculations, include:

Duration of exposure (days):
last date of study drug −first date of study drug + 1
(periods of interruption are not excluded)

Cumulative dose (mg):
total dose of study drug taken by a patient in the study

Number of dosing days (days):
duration of exposure − number of zero dose days

Average daily dose (mg/day):
cumulative dose (mg) ⁄ number of dosing days (days)

DI (mg/day):
cumulative dose (mg) ⁄ duration of exposure (days)

RDI (%):
100 × [DI (mg/day) ⁄ planned dose (800 mg/day)]
Note: Because the planned INC280 dose is 800 mg/day, or the planned dose intensity (PDI) is 
800 mg/day, RDI (%) can be calculated by 100*DI/PDI and simplified as shown above.
Duration of study exposure to study drug, cumulative dose, average daily dose, DI and RDI will 
be summarized by cohort.  In addition, the duration of exposure to study drug will be 
categorized into time intervals and frequency counts and percentages of patients with exposure 
in each time interval will be presented. Frequency counts and percentages of patients who have 
dose changes, reductions or interruptions, and the corresponding reasons, will be summarized
by cohort. 
An analysis of time to first interruption (in weeks) will be presented based on simple descriptive 
statistics (not using time-to event methods). 
Time to first interruption is the time from date of first administration of study drug to the first 
date when a zero dose of study drug is recorded on the DAR eCRF, expressed in weeks. Listings
of all doses of the study drug along with dose change and dose interruption reasons will be 
produced by cohort.  
Section 4.5 provides further details on the definition of dose changes and interruptions.


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Concomitant therapy
Concomitant therapies are defined as any medications (excluding study drug, prior 
antineoplastic treatments and blood transfusions), surgeries or procedures (including physical 
therapy) administered in the study and are recorded in the Prior and Concomitant Medications 
and the Surgical and Medical Procedures eCRF, respectively.
Concomitant medications will be coded using the WHO Drug Reference Listing (WHO DRL) 
dictionary that employs the WHO Anatomical Therapeutic Chemical (WHO ATC) 
classification system. Surgeries or procedures will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology. All summaries will be tabulated using 
frequency counts and percentages.
Concomitant therapies will be summarized by ATC class, preferred term and cohort. Surgical 
and medical procedures will be coded using MedDRA and summarized by SOC and preferred 
term. These summaries will include: 1) medications starting on or after the start of study drug 
but starting no later than 30 days after last dose of study drug and 2) medications starting prior 
to the start of study drug but continuing after the start of study drug.
All concomitant therapies will be listed by cohort. Any concomitant therapies starting and 
ending prior to the start of study drug or starting more than 30 days after the last date of study 
drug will be flagged in the listings. 
Antineoplastic therapy after discontinuation of study drug
The FAS will be used for all listings and summaries of antineoplastic therapies initiated after 
discontinuation of study drug. All summaries will be tabulated using frequency counts and 
percentages by cohort.
Antineoplastic medications initiated after discontinuation of study drug will be summarized and 
listed by Anatomical Therapeutic Chemical (ATC) class, preferred term and cohort.
Antineoplastic radiotherapy since discontinuation of study treatment will be summarized and 
listed by setting and cohort.
Antineoplastic surgery since discontinuation of study treatment will be summarized and listed 
by SOC and preferred term and cohort.
2.7
Analysis of the primary variable
The primary objective is to demonstrate the antitumor activity of INC280, as measured by 
overall response rate (ORR) to INC280 by Blinded Independent Review Committee (BIRC) 
assessment, by cohort.
2.7.1
Variable
The primary variable used to evaluate the anti-tumor activity of INC280 is the overall response 
rate (ORR), defined as the proportion of patients with a best overall response (BOR) as complete 
response (CR) or partial response (PR), as assessed per RECIST 1.1 by BIRC.


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Best overall response (BOR)
The BOR will be assessed based on reported lesion responses at different evaluation time points. 
Both CR and PR must be confirmed by repeat assessments performed not less than 4 weeks 
after the criteria for response are first met. The next scheduled assessment may be used for 
purposes of confirmation of response.  
BOR for each patient is determined from the sequence of overall (lesion) responses according 
to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression 

PR = at least two determinations of PR or better at least 4 weeks apart before progression
(and not qualifying for a CR) 

SD = at least one SD assessment (or better) > 6 weeks after start of study drug (and not 
qualifying for CR or PR).

PD = progression ≤ 12 weeks after start of study drug (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 progression within the first 12 weeks)
Only tumor assessments performed before the start of any further anti-neoplastic therapies (i.e. 
any additional secondary anti-neoplastic therapy or anti-cancer surgery) and within 30 days 
after the last dose of study treatment will be considered in the assessment of BOR. 
Local bone radiotherapy for analgesic purposes or for lytic lesions at risk of fracture are not 
considered secondary anti-neoplastic therapy. If a patient receives any further anti-neoplastic 
therapy while on study, any subsequent assessments will be excluded from the BOR 
determination.  Further anti-neoplastic therapies will be identified via protocol deviations or 
from the data collected on ‘Anti-neoplastic therapies since last date of study drug’ as appropriate. 
Palliative radiotherapy in the bone is the only setting of radiotherapy allowed during the study. 
Therefore palliative radiotherapy in the bone will not be considered as an anti-neoplastic 
therapy for assessment of BOR. 
Clinical deterioration will not be considered as documented disease progression. 
Patients with BOR ‘unknown’ will be summarized by reason for having unknown status. The 
following reasons will be used:

No valid post-baseline assessment

All post-baseline assessments have overall response UNK

New anti-neoplastic therapy started before first post-baseline assessment

Stable disease (SD) too early (≤ 6 weeks after start date of study drug*)

PD too late (> 12 weeks after start date of study drug*)
Special (and rare) cases where BOR is ‘unknown’ due to both early SD and late PD will be 
classified as ‘SD too early’.


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*Thresholds for SD too early and PD too late are defined as the protocol-specified time interval 
+ protocol-allowed time windows (±4 days) around the tumor assessments.
2.7.2
Statistical hypothesis, model, and method of analysis
The primary analysis will be performed on the FAS. The primary efficacy endpoint ORR will 
be estimated and the exact 95% confidence interval (CI) (Clopper and Pearson 1934) provided 
by cohort. 
Treatment with INC280 will be considered to have clinically relevant efficacy in cohort (1-4) 
if an ORR of ~35% is observed in that cohort with lower bound of exact 95% CI greater than 
25%. Whereas, in cohorts (5a and 5b and 7), treatment with INC280 will be considered to have 
clinically relevant efficacy if an ORR of ~55% is observed in that cohort with lower bound of 
exact 95% CI greater than 35%. 
No hypothesis testing is planned for cohort 6. 
2.7.3
Handling of missing values/censoring/discontinuations
Confirmed PR or CR reported prior to any additional anticancer therapy will be considered as 
responses in the calculation of the ORR irrespective of the number of missed assessments before 
response.
Patients with a BOR of ‘Unknown’ per RECIST 1.1 will be considered as non-responders when 
estimating ORR.
Patients with no BIRC data will be considered as non-responders when estimating ORR.
Patients who have disease progression and continue to receive study drug after progression will 
qualify for PD at the time of progression and will be counted as PD in the derivation of ORR 
and any other efficacy endpoints.
2.7.4
Supportive analyses
ORR by BIRC will be presented combining the MET mutant cohorts per line of treatment as 
defined in Section 2.2.
ORR by BIRC will be summarized by subgroup (as defined in Section 2.2). Forest plot 
(including sample size/number of responders and ORR with 95% CI) will be produced to 
graphically depict the treatment effect estimates in different subgroups.
In addition, the primary analysis will be repeated on the PPS.
Waterfall plots representing the best percentage change from baseline in the sum of the tumor
measured diameters for target lesions will be produced by cohort.
ORR by BIRC according to the accepted radiologist who was chosen at the time of the 
submission will be produced as per FDA request (Previous Radiologist Accepted flag: 
PRARDF): radiologist chosen at the data cut-off 15-Apr-2019 for NDA submission in Cohorts
4 and 5b and at the data cut-off 30-Aug-2021 for Post-Marketing Requirements (PMR) in 
Cohorts 6 and 7.


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2.8
Analysis of secondary variables
2.8.1
Efficacy
All secondary endpoint analyses will be performed based on the FAS, unless otherwise 
specified. Efficacy will also be presented combining the MET mutant cohorts per line of 
treatment as defined in Section 2.2.
No adjustment for multiple testing will be made.
Key secondary efficacy endpoints 
The key secondary objective is to evaluate duration of response (DOR) as assessed by BIRC, 
by cohort.
Among patients with a confirmed response (PR or CR), DOR is defined as the time from first 
documented response (PR or CR) to the date of first documented PD or death due to any cause. 
If a patient has not had an event, DOR is censored at the date of last adequate tumor assessment.
The censoring and event date options to be considered for the main analysis are presented in 
Table 2-1.
Table 2-1
Outcome and event dates for DOR and PFS analyses
Situation
Date
Outcome
A
No baseline assessment
Date of first dose of 
study drug a
Censored
B
Progression at or before next scheduled
Assessment
Date of progression
Progressed
C1
Progression or death after exactly one
missing assessment
Date of progression (or 
death)
Progressed
C2
Progression or death after two or more
missing assessments
Date of last adequate 
assessment
Censored
D
No progression
Date of last adequate 
assessment
Censored
E
Treatment discontinuation due to ‘Disease
progression’ without documented
progression, i.e. clinical progression
based on investigator claim
N/A
Information ignored. 
Outcome derived 
based on radiology 
data only.
F
New anticancer therapy given
Ignore the new 
anticancer therapy and 
follow situations above 
As per above situations
G
Deaths due to reason other than 
deterioration of ‘Study indication’
Date of death
Progressed
a 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
DOR will be described in tabular and graphical format using Kaplan-Meier methods. The 
Kaplan-Meier estimate of the distribution function will be constructed. Kaplan-Meier curves 


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will be constructed. The number of patients at risk at certain time points will be shown on the 
plot.  The estimated median (in months) along with 95% CIs, as well as 25th and 75th percentiles 
will be reported (Brookmeyer and Crowley 1982). In addition, Kaplan-Meier estimated 
probabilities with corresponding 95% CIs at several time points (including at least 3, 6, 12, and 
18 months) will be summarized. Refer to Section 4.6.3 for further details regarding derivation 
of Kaplan-Meier estimates.
Supportive analysis
DOR by BIRC will also be presented combining the MET mutant cohorts per line of treatment 
as defined in Section 2.2.
DOR by BIRC assessment will be summarized by subgroup (as described in Section 2.2). 
Supportive analysis of DOR table by BIRC assessment based on the PPS will also be presented. 
DOR by BIRC according to the accepted radiologist who was chosen at the time of the 
submission will be produced as per FDA request (Previous Radiologist Accepted flag: 
PRARDF): radiologist chosen at the data cut-off 15-Apr-2019 for NDA submission in Cohorts
4 and 5b and at the data cut-off 30-Aug-2021 for Post-Marketing Requirements (PMR) in 
Cohorts 6 and 7.
ORR by investigator assessment
The evaluation of ORR will be also conducted based on investigator assessment. ORR will be 
estimated and the exact binomial 95% CI will be provided by cohort.
ORR by investigator will be summarized by subgroup (as defined in Section 2.2) and forest plot 
will be produced.
A summary table will also be produced for BOR based on investigator assessment versus BIRC 
assessment. An assessment of the concordance between BIRC assessment and local assessment 
of the Best Overall Response for each patient will be provided by cohort. Overall concordance 
rate in each cohort is calculated as (number of patients with same BORs per investigator and 
per BIRC)/(total number of patients in that cohort).
DOR by investigator assessment
Among patients with a confirmed response (PR or CR), DOR is defined as the time from first 
documented response (PR or CR) to the date of first documented PD or death due to any cause. 
If a patient has not had an event, DOR is censored at the date of last adequate tumor assessment.
The censoring and event date options to be considered for the main analysis are presented in
Table 2-1.
DOR will be described in tabular and graphical format using Kaplan-Meier methods by cohort. 
The Kaplan-Meier estimate of the distribution function will be constructed. Kaplan-Meier 
curves will be constructed. The number of patients at risk at certain time points will be shown 
on the plot.  The estimated median (in months) along with 95% CIs, as well as 25th and 75th
percentiles will be reported (Brookmeyer and Crowley 1982). In addition, Kaplan-Meier 
estimated probabilities with corresponding 95% CIs at several time points (including at least 3, 
6, 9, 12 and 18 months) will be summarized by cohort. These analyses will be performed 


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separately based on BIRC assessment and based on investigator assessment. Refer to Section 
4.6.3 for further details regarding derivation of Kaplan-Meier estimates.
Disease control rate (DCR)
DCR is defined as the proportion of patients with best overall response of CR, PR, or SD per 
RECIST 1.1. DCR will be estimated and the binomial exact 95% CI will be provided by cohort. 
These analyses will be performed separately based on BIRC assessment and based on 
investigator assessment.
Time to response (TTR)
TTR is defined as the time from start of study drug to first documented response (CR or PR, 
which must be confirmed subsequently) for patients who achieved a confirmed PR or CR. All 
patients in the FAS will be included in time to response calculations. Patients who did not 
achieve a confirmed PR or CR, will be censored at: 

the maximum follow-up time (i.e. first patient first treatment to last patient last treatment 
by cohort used for the analysis) for patients who had a PFS event (i.e. either progressed 
or died due to any cause), or at the date of last adequate tumor assessment date otherwise.
TTR will be summarized in 6-weeks intervals using descriptive statistics. The distribution of 
time to response will be estimated using the Kaplan-Meier method and the median time to 
response will be presented along with 95% confidence interval only if a sufficient number of 
responses is observed. Failure curves (ascending Kaplan-Meier curves) will be constructed. 
These analyses will be performed separately based on BIRC assessment and based on 
investigator assessment.
Progression-free survival (PFS)
PFS is defined as the time from the start date of study drug to the date of the first radiologically 
documented PD or death due to any cause.
If a patient has not progressed or is not known to have died at the date of analysis cut-off, PFS 
will be censored at the date of the last adequate tumor evaluation before the cut-off date. PFS 
events documented after the initiation of new anti-neoplastic therapy (i.e. RECIST 1.1
documented disease progression or death) will be considered for the primary analysis provided 
tumor assessments continue after initiation of the new cancer therapy. Clinical deterioration 
will not be considered as a qualifying event for progression. Refer to Table 2-1 for censoring 
and event date options and outcomes for PFS.
In particular, PFS will be censored at the last adequate tumor assessment if one of the following 
occurs: absence of event; the event occurred after two or more missing tumor assessments (see
Section 4.6.1). See also Section 4.6.1 describing the special case of a missing baseline tumor 
assessment.
Patients with no BIRC data will be considered censored at the start date of study drug.
PFS will be described in tabular and graphical format using Kaplan-Meier methods as described 
for DOR by cohort, including estimated median (in months) with 95% CI, 25th and 75th
percentiles and Kaplan-Meier estimated probabilities with corresponding 95% CIs at several 


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time points. Censoring reasons will also be summarized by cohort. These analyses will be 
performed separately based on BIRC assessment and based on investigator assessment.
In addition, PFS table will be repeated on the PPS.
Overall survival (OS)
OS is defined as the time from the start date of study drug to the date of death due to any cause. 
If the patient 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 cutoff date (see Section 4.3 for further details on 
derivation of last contact date).
OS will be described in tabular and graphical format using Kaplan-Meier methods as described 
for DOR by cohort, including estimated median (in months) with 95% CI, 25th and 75th
percentiles and Kaplan-Meier estimated probabilities with corresponding 95% CIs at several 
time points . Censoring reasons will also be summarized by cohort. 
OS from initial diagnosis to the date of death due to any cause will also be analyzed. Date of 
censoring is the same as defined for OS analysis. 
Duration of Follow-up
Follow-up in the study will be summarized using the following methods to provide a 
comprehensive assessment of follow-up for all patients by cohort. 
Summary of duration between start date of study drug and cut-off date, and follow-up times for 
PFS/OS/DOR, are defined as follows:

Duration between start date of study drug and data cut-off date = (Cut-off date – Start date 
of study drug + 1) / 30.4375 (months).

Follow-up time for PFS/OS = (Date of event or censoring – Start date of study drug + 1) / 
30.4375 (months) regardless of censoring.  Date of censoring is defined as the last adequate 
tumor assessment date for PFS or last contact date (when the patient is known as alive) for 
OS. 

Follow-up time for DOR = (Date of event or censoring – Start date of response + 1) / 
30.4375 (months) regardless of censoring
Quartiles, minimum and maximum as well as the frequency count and percentage of patients in 
each of <1.5, 1.5-<3, 3-<6, 6-<9, 9-<12, ≥12 months will be reported for PFS, OS and DOR. 
All summaries will be reported in months (see Section 4.4). The calculations for DOR and PFS 
will be based on BIRC assessment. Date of censoring is the same as defined for the DOR, PFS 
and OS analysis. 
2.8.2
Safety
All safety analyses will be performed based on the Safety Set by cohort and also for all patients.
Safety will also be presented combining the MET mutant cohorts and amplified cohorts as 
defined in Section 2.2.


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Baseline
Baseline is the result of an investigation describing the “true” uninfluenced state of the patient. 
The last available assessment before or on the start date of study drug is defined as “baseline” 
value or “baseline” assessment. If an assessment is planned to be performed prior to the first 
dose of study drug in the protocol and the assessment is performed on the same day as the first 
administration of study drug, it will be assumed that it was performed prior to study drug 
administration, if assessment time point is not collected or is missing. If assessment time points 
are collected, the observed time point will be used to determine pre-dose on study day 1 for 
baseline calculation. Unscheduled assessments will be used in the determination of baseline. 
See Section 4.7.2 for further details on derivation of baseline for laboratory data and ECGs.
Patients who start treatment and discontinue from the study on the same day may have 2 
different sets of data collected on study day 1, one being reported to the cycle 1 day 1 visit, the 
other reported to the end of treatment (EOT) visit. Data reported at the EOT visit are not eligible 
for baseline selection.
Grouping for the analyses
The overall observation period will be divided into three mutually exclusive segments:

Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study drug

On-treatment period:
o
For discontinued patients, from day of first dose of study drug to 30 days after last 
dose of study drug
o
For ongoing patients, from day of first dose of study drug to the data cut-off date

Post-treatment period: starting at day 31 after last dose of study drug
The safety summary tables will include only assessments collected no later than 30 days after 
study drug discontinuation and assessments prior to the data cut-off date for on-going patients, 
unless otherwise specified. 
For select items, shift tables or change from baseline summaries generated for laboratory, ECG, 
vital signs and change score generation may use data from pre-treatment period for baseline
calculations. 
All data, regardless of observation period, will be listed and assessments collected in the post-
treatment period will be flagged in all the listings.
Adverse events (AEs)
AEs will be coded using MedDRA using the latest version available prior to clinical database 
lock and will be graded using Common Terminology Criteria for Adverse Events (CTCAE)
version 4.03. If CTCAE grading does not exist for an AE, grades 1, 2, 3, or 4 corresponding to 
the severity of mild, moderate, severe, and life-threatening, respectively, will be used. CTCAE 
grade 5 (death) will not be used in this study; rather, this information will be collected on the 
fatal outcome from “Adverse event”, “End of Treatment Phase completion”, “End of post-
treatment phase Completion” or “Death” eCRF pages.


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All AE summaries will be summarized (frequency counts and percentages) by system organ 
class and/or preferred term, and maximum severity grades, except where otherwise noted. A 
patient with multiple CTC grades for an AE will be summarized under the maximum CTC grade 
recorded for the event. 
The following AE summaries will be produced:

AEs regardless of study drug relationship

AEs suspected to be study drug related

On-treatment deaths, by primary system organ class and preferred term

All deaths, by primary system organ class and preferred term

SAEs regardless of study drug relationship

SAEs suspected to be study drug related

AEs leading to permanent discontinuation of study drug regardless of study drug 
relationship

AEs leading to permanent discontinuation of study drug suspected to be study drug related

AEs requiring dose adjustment and/or study drug interruption regardless of study drug 
relationship

AEs requiring dose adjustment and/or study drug interruption suspected to be study drug 
related

AEs requiring dose adjustment regardless of study drug relationship

AEs requiring dose adjustment suspected to be study drug related

AEs requiring study drug interruption regardless of study drug relationship

AEs requiring study drug interruption suspected to be study drug related

AEs requiring significant additional therapy regardless of study drug relationship

AEs requiring significant additional therapy suspected to be study drug related

Non-SAEs (AEs excluding SAEs) regardless of study drug relationship
In addition, a summary of serious adverse events with number of occurrences will be produced 
(an occurrence is defined as >1 day between start and prior end date of record of same preferred 
term).
A listing will be provided to document any terms changed as a result of the re-mapping process 
to the latest MedDRA version available.
All AEs regardless of study drug relationship and all AEs suspected to be study drug related 
will be summarized by cohort and subgroup (as described in Section 2.2) using the safety set. 
Exposure-adjusted overall incidence 
The number and percentage of patients with any AEs along with the 95% confidence interval 
(95% CI) will be presented [Clopper and Pearson 1934]. In order to account for potential 
differences in exposure across groups, incidence rates of adverse events will be presented 
adjusted for Subject-Months exposure. [Sahai and Khurshid, 1993; Ulm 1990].


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The exposure-adjusted overall incidence rate is defined as the number of patients with an event 
divided by the corresponding sum of the exposure duration for all patients, where duration of 
exposure in Subject-Months is counted up to the first qualifying event (or end of time at risk 
for patients without event). AEs missing start date for exposure-adjusted overall incidence 
calculation is handled as follows: Start date of study drug will be considered as the AE start 
date for any AE with missing start date. 
Adverse events of special interest
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound INC280. These groupings are defined using MedDRA 
terms, SMQs (standardized MedDRA queries), HLGTs (high level group terms), HLT (high 
level terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA queries, NMQ) 
may also be used. A NMQ is a customized group of search terms which defines a medical 
concept for which there is no official SMQ available or the available SMQ does not completely 
fit the need. It may include a combination of single terms and/or an existing SMQ, narrow or 
broad.
All AESI definitions or AE grouping are specified in the electronic Case Retrieval Strategy 
(eCRS), in which they are identified by the flag “SP”. Additional AESI may be reported if there 
are any updates to the eCRS at the time of the analyses.
Adverse events of special interest (AESIs) INC280 are:

Hepatotoxicity

Renal dysfunction

ILD/Pneumonitis

Central nervous system toxicity 

Pancreatitis

Photosensitivity 

Teratogenicity

Drug-drug interactions with strong CYP3A4 inducers

QTc interval prolongation
This classification reflects the current version of the eCRS and might be updated based on 
review of accumulating data. 
For each specified AESI, number and percentage of patients with at least one event of the AESI 
occurring during on treatment period will be summarized. 
Summaries of these AESIs will be provided by cohort, (specifying grade, SAE, relationship, 
leading to permanent treatment discontinuation, leading to dose adjustment/interruption, death, 
etc.). 
Analysis of time to first occurrence of any grade AESI will be applied as well as time to first 
occurrence of grade 3/4 AESI using the Kaplan-Meier method (see below the definitions).
Duration of first occurrence of grade 3/4 AESI will also be summarized. These analyses will be 
performed for AESI regardless of study drug relationship and for AESI suspected to be study 
drug related. 


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For time to first occurrence, failure curves (ascending Kaplan-Meier curves) will be constructed
in the combined MET mutant cohorts and all patients. Median together with 95% CI as well as 
25th and 75th percentiles will be presented. In addition, the median time to occurrence for the 
subset of patients who experienced the event of interest will be calculated. Simple descriptive 
statistics (median, min and max, 25th and 75th percentiles) will be presented. The probabilities 
at selected time points and the associate 95% CI will also be summarized.
Duration of first occurrence of grade 3/4 AESI will be presented for the subset of patients who 
experienced the event. Failure curves (ascending Kaplan-Meier curves) will be constructed in 
the combined MET mutant cohorts and all patients. Median together with 95% CI as well as 
25th and 75th percentiles will be presented.
Duration of first occurrence of an event will be presented for the subset of patients of the safety 
set who experienced the event. A patient will be censored for time to resolution, if there is no 
resolution during the on-treatment period. The same censoring rules as described below for time 
to first occurrence apply.
Time to first occurrence

Time to first occurrence of an event is defined as time from start of study treatment to 
the date of first occurrence of this event (or first event within an AE grouping), i.e. time 
in days is calculated as (start date of first occurrence of event) – (start of study treatment) 
+1.

In the absence of an event during the on-treatment period, the censoring date applied 
will be the earliest of the following dates: death date, new anti-neoplastic antineoplastic 
therapy start date, end date of on-treatment, analysis cut-off date, and withdrawal of 
informed consent date. See Section 2.7.1 for the definition of new anti-neoplastic 
antineoplastic therapy.
Duration of first occurrence (i.e. Time to resolution of an event)

Duration of first occurrence of an event is defined as time from onset to the date of 
resolution of the first event: (date of resolution of first event) – (date of onset of event) 
+ 1.

Resolution of the event means that outcome of the Grade 3/4 event is 
“recovered/resolved”, “recovered/resolved with sequelae”, or “recovering/resolving” 
(returning to grade ≤ 2). The same preferred term as the 1st event identified is used to 
determine the resolution. The resolution occurring after end of treatment + 30 days will 
be considered.

The date of resolution of first Grade 3/4 event is derived as follows: 
o
= End date of the first Grade 3/4 event if the first event is resolved (i.e. duration 
of AE). If multiple Grade 3/4 events with the same start date are reported, the 
latest end date will be considered (i.e. the longest duration of AE).
o
= Start date of the 1st Grade ≤ 2 event if the first event is improved. If multiple 
Grade 3/4 events with the same start date are reported, the latest start date of the 


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1st Grade ≤ 2 event will be considered (i.e. the longest duration of first 
occurrence).
o
= Start date of the 1st Grade ≤ 2 event if the first event is worsened and then 
improved, and no Grade 3/4 AE with an outcome “resolved/recovered” reported 
later on. If multiple Grade 3/4 events with the same start date are reported, the 
latest start date of the 1st Grade ≤ 2 event will be considered (i.e. the longest 
duration of first occurrence).
o
= End date of the Grade 3/4 event reported with outcome “recovered/resolved” 
if the first event is worsened and then resolved and Grade 3/4 AE with an 
outcome “resolved/recovered” reported.
With
o
Worsened: Event with a non-missing end date and outcome “not recovered/ not 
resolved”
o
Improved: Event with a non-missing end date and outcome “recovering/not 
resolving”. Event with a lower grade are expected to be reported
o
Resolved: Event with a non-missing end date and outcome “recovered/ not 
resolved” or “resolved/resolved with sequelae”
Section 4.7.4 provides further details on the definition of first occurrence and duration.
Deaths
Separate summaries for on-treatment and all deaths will be produced by cohort, primary system 
organ class and preferred term. 
All deaths will be listed, post treatment deaths will be flagged. 
Laboratory data
For laboratory data assessments, data from all sources (central and local laboratories) will be 
combined. The summaries will include all laboratory assessments collected no later than 30 
days after study drug discontinuation. All laboratory assessments will be listed and those 
collected later than 30 days after study drug discontinuation will be flagged in the listings. 
Laboratory data will be classified (by Novartis Oncology Statistical Programming) into CTC 
grades according to the NCI CTCAE v4.03. For all reports, CTC grade is always obtained on 
the converted measurement in SI unit. Grade 5 will not be used.The CTC grade 0 will be 
assigned as below in different scenarios: 

For lab parameters defined by criteria based on normal range only, a severity grade of 0 will 
be assigned when the value is within normal limits.   

For lab parameters whose grade is defined by criteria based on normal range and absolute 
values (e.g. platelet count decrease). A severity grade of 0 will be assigned when the value 
is within normal limits. 


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
For lab parameters whose grade is defined by criteria based on normal range and the change 
from baseline value, with no other associated clinical criteria such as concomitant 
medication (e.g. creatinine increased) the following will be applied. For the baseline grading 
and for the grading of post-baseline lab values with missing baseline grading, the grade will 
be derived using the criteria based only on the normal range as per CTCAE v4.03. A severity 
grade of 0 will be assigned when the post-baseline value is ≤ ULN (for hyper) or ≥ LLN 
(for hypo).
Parameters for which a grading does not exist will be classified into low/normal/high group by 
means of laboratory normal ranges.
The following summaries will be produced by cohort for the hematology and biochemistry 
laboratory data (by laboratory parameter):

Shift tables using CTC grades to compare baseline to the worst post-baseline value for 
laboratory parameters with CTC grades

Shift tables using low, normal, high (as well as low and high combined) classifications to 
compare baseline to the worst post-baseline value for laboratory parameters where CTC 
grades are not defined.

New or worsened abnormalities for laboratory parameters based on CTC grade 

Trends of renal function parameters (creatinine, BUN) over time (baseline and selected on-
treatment time-points, See Table 4-6) will be displayed via boxplots based on time windows 
and corresponding tables displaying the statistics used for the box plots by the selected time 
points. 
The following lab parameters will be summarized by cohort: 

Hematology: absolute lymphocytes, absolute neutrophils, hemoglobin (anemia), WBC,
platelet counts, absolute basophils, absolute eosinophils, absolute monocytes, hematocrit

Biochemistry: alkaline phosphatase (ALP), SGPT (ALT), SGOT (AST), total bilirubin, 
amylase, potassium, sodium, creatinine, glucose (hypo only), phosphate, albumin, calcium, 
magnesium, creatinine, direct bilirubin, blood urea nitrogen (BUN), GGT, lipase.

For bi-directional parameters, both hyper and hypo summaries will be presented. 
The following laboratory parameters will be presented in listings and will not be summarized: 

Urinalysis: macroscopic panel (dipstick) (bilirubin, blood, glucose, WBC, pH, protein, 
specific gravity), Urinalysis Microscopic panel (RBC, WBC, casts).

Coagulation: INR, pro-thrombin time (PT) or Quick Test
The following listings will be produced for the laboratory data for all laboratory parameters 
where CTC grades are defined:

Listing of patients with laboratory abnormalities of CTC grade 3 or 4

Listing of all laboratory data with values flagged to show the corresponding CTC grades 
and the classifications relative to the laboratory reference ranges.
Liver function parameters of interest are total bilirubin (TBIL), ALT, AST and alkaline 
phosphatase (ALP). The number (%) of patients with worst post-baseline values will be 
summarized by cohort in the following categories:


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
ALT >3×ULN, >5×ULN, >8xULN, >10×ULN, >20×ULN

AST >3×ULN, >5×ULN, >8×ULN, >10xULN, >20×ULN

ALT or AST >3×ULN, >5xULN, >8×ULN, >10xULN, >20×ULN

TBIL > 2xULN, >3×ULN
Combined and concurrent values post-baseline

ALT or AST > 3xULN & TBIL> 2×ULN

ALT or AST > 3×ULN & TBIL> 2×ULN & ALP ≥2×ULN

ALT or AST > 3xULN & TBIL> 2×ULN & ALP < 2×ULN 
Combined elevations values post-baseline (regardless of baseline levels)

ALT or AST > 3xULN & TBIL> 2×ULN

ALT or AST > 3×ULN & TBIL> 2×ULN & ALP ≥ 2×ULN

ALT or AST > 3xULN & TBIL> 2×ULN & ALP < 2×ULN 
Combined elevations values post-baseline by baseline levels
AST/ALT ≤ ULN at baseline

ALT or AST > 3xULN & TBIL> 2×ULN

ALT or AST > 3×ULN & TBIL> 2×ULN & ALP ≥ 2×ULN

ALT or AST > 3xULN & TBIL> 2×ULN & ALP < 2×ULN 
AST/ALT > UNL at baseline

Elevated ALT or AST & TBIL (>2×Baseline and 2×ULN)

Elevated ALT or AST & TBIL (>2×Baseline and 2×ULN) & ALP ≥ 2×ULN

Elevated ALT or AST & TBIL (>2×Baseline and 2×ULN) & ALP <2×ULN
with Elevated AST or ALT defined as: >3×ULN if ≤ULN at baseline, or (>3×Baseline or 
8×ULN) if > ULN at baseline
In addition, a listing of all TBIL, ALT, AST and ALP values for patients with a post-baseline 
TBIL > 2xULN, ALT> 3xULN or AST > 3xULN will be provided.
The relationship between post-baseline increases in ALT/AST and total bilirubin will be shown 
using eDISH plot: peak values of Total bilirubin vs peak values of ALT/AST at any time during 
the course of treatment (not necessarily concurrent).
Analysis of time to first occurrence of grade 3/4 AST/ALT (whichever occurs first) will be done. 
Time to first occurrence of grade 3/4 AST/ALT and duration of the first occurrence of grade 3/4
AST/ALT will be summarized using Kaplan-Meier method. Patients with grade 3/4 AST/ALT 
at baseline will be excluded from the analysis. Median together with 95% CI as well as 25th and 
75th percentiles will be presented. In addition, the median time to occurrence for the subset of 
patients who experienced the event of interest will be calculated. Simple descriptive statistics 


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(median, min and max, 25th and 75th percentiles) will be presented. The probabilities at selected 
time points and the associate 95% CI will also be summarized.
Duration of first occurrence of grade 3/4 AST/ALT will be presented for the subset of patients
who experienced the event. Median together with 95% CI as well as 25th and 75th percentiles 
will be presented.
ECGs
ECG data will be analyzed based on central laboratory reported results by cohort. The 
summaries will include all ECG assessments performed no later than 30 days after the last date 
of study drug.  All ECG assessments will be listed, and those collected later than 30 days after 
study drug discontinuation will be flagged in the listing. 
The number and percentage of patients with notable ECG values will be presented by cohort. 

QTcF and QTcB
-
New value of > 450 and ≤ 480 ms
-
New value of > 480 and ≤ 500 ms
-
New value of > 500 ms
-
Increase from Baseline of > 30 ms to ≤ 60ms
-
Increase from Baseline of > 60 ms

HR
-
Increase from baseline >25% and to a value > 100 bpm
-
Decrease from baseline >25% and to a value < 50 bpm

PR
-
Increase from baseline >25% and  to a value > 200 ms
-
New value of > 200 ms

QRS 
-
Increase from baseline >25% and  to a value > 120 ms
-
New value of > 120 ms
In addition the following analysis will be carried out; 

Descriptive statistical analysis (mean and two-sided 90% confidence interval) by time point 
of assessment for ΔQTcF (QTcF change from baseline).

A graphical presentation of ECG mean change from baseline over time will be produced 
based on time windows.

Shift table based on notable values to compare baseline to the worst post-baseline value for 
QT, QTcF and QTcB.

Summary of newly occurring post-baseline qualitative ECG abnormalities.


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Vital signs
Vital sign assessments will be performed in order to characterize basic body function. The 
parameters collected are weight (kg), body temperature (°C), pulse rate (beats per minute) and
systolic and diastolic blood pressure (mmHg).
Clinically notable elevated values are defined as:

Systolic BP: 180 mmHg and an increase 20 mmHg from baseline

Diastolic BP: 105 mmHg and an increase 15 mmHg from baseline.

Body temperature: 39.1°C

Weight: increase from baseline of 10%

Pulse rate: 100 bpm with increase from baseline of 25%
Clinically notable below normal values are defined as:

Systolic BP: 90 mmHg and a decrease 20 mmHg from baseline

Diastolic BP: 50 mmHg and a decrease 15 mmHg from baseline

Body temperature: 35°C

Weight: decrease from baseline of 10%

Pulse rate: 50 bpm with decrease from baseline of 25%
Vital signs shift table based on values classified as notable low, normal, notable high or notable 
(high and low) at baseline and worst post-baseline will be produced for pulse rate, diastolic BP 
and systolic BP.
Baseline values (Low/high) are defined as:

Systolic BP: 90 mmHg ; Systolic BP: 180 mmHg 

Diastolic BP: 105 mmHg ; Diastolic BP: 50 mmHg 

Body temperature: 35°C ; Body temperature: 39.1°C

Pulse rate: 50 bpm ; Pulse rate: 100 bpm 
Patients with clinically notable vital sign abnormalities will be listed. All vital sign assessments 
will be listed by patient and vital sign parameter by cohort.
In the listings, clinically notable values will also be flagged.
ECOG performance status
The ECOG performance status assessment allows patients to be classified as to their functional 
impairment, the definition of scores in relation to their performance status is provided in Table 
2-2, ranging from 0 (most active) to 5 (dead):


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Table 2-2
ECOG performance scale
Score
Description
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
Shift tables of ECOG performance status at baseline to worst post-baseline ECOG performance 
status by score will be provided by cohort using the safety set; shift tables of ECOG 
performance status at baseline to best post-baseline ECOG performance status by score will 
also be provided. ECOG performance status at each time point will be listed by cohort.


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2.8.4
Pharmacokinetics
Not applicable.
2.8.5
Pharmacogenetics/pharmacogenomics
Not applicable.
 
2.8.7
PK/PD
Not applicable.
2.9
Sample size calculation
Approximately 456 patients (69 patients per cohort in Cohorts 1a, 1b, 2, 3, 4 and 27 patients 
per each Cohort 5a, 5b, approximately 30 patients in Cohort 6 and approximately 27 patients in 
Cohort 7) will be enrolled in the study if none of the cohorts 1-4 is stopped for futility at the 
time of the interim analysis. The exact 95% CIs for various sample sizes and observed ORRs 
in each cohort 1-4 are shown in Table 2-4 and in Table 2-5 for cohorts 5a, 5b and 7.
Table 2-4
Exact Binomial 95 percent Confidence Intervals for Various Sample 
Sizes and Observed ORRs in Each Cohort
Sample size (N)
Number of 
responders
Observed ORR (%)
95% exact CI (%)
65
23
35.4
23.9
48.2
66
24
36.4
24.9
49.1
67
24
35.8
24.5
48.5
68
24
35.3
24.1
47.8
69
25
36.2
25.0
48.7
70
25
35.7
24.6
48.1
71
25
35.2
24.2
47.5
72
26
36.1
25.1
48.3
Table 2-5
Exact Binomial 95 percent Confidence Intervals for Various Sample 
Sizes and Observed ORRs in each cohort 5a, 5b and 7
Sample size (N)
Number of responders
Observed ORR (%)
95% exact CI (%)
25
14
56.0
34.9
75.6
26
15
58.0
36.9
76.6
27
15
55.6
35.3
74.5
28
16
57.1
37.2
75.5
29
16
55.2
35.7
73.6


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The operating characteristics (with 69 patients per cohort in 1a, 1b, 2, 3 and 4) are shown in 
Table 2-6 and Table 2-7. The tables show probability of stopping at interim, probability for 
positive conclusion (i.e., not stopped at IA for futility and success criteria met at final analysis) 
and negative conclusion (i.e., not stopped at IA for futility but success criteria not met at final 
analysis) under different underlying true ORR. The operating characteristics (with 27 patients 
per cohort in 5a, 5b and 7) are shown in Table 2-8. The table shows the probability of meeting 
the success criteria under different underlying true ORR.
Cohort 1a, Cohort 1b, Cohort 2 and Cohort 4 
The operating characteristics at this sample size have > 50% probability of stopping the trial for 
futility when the true ORR is < 25%. Also, when the true ORR is 35% then the probability of 
positive conclusion at the final analysis with 69 patients is ≥ 44%. If the true ORR is 45% or 
higher, the probability of positive conclusion at the final analysis with 69 patients is > 90%.
Table 2-6
Operating Characteristics for Cohort 1 (MET GCN ≥ 6) and Cohort 2 
(MET GCN ≥ 4 and < 6)
True ORR 
(%)
Probability of a 
cohort to stop at IA* 
(%)
Probability for positive 
conclusion in final 
analysis for a cohort (%)
Probability for negative conclusion 
in final analysis for a cohort 
(i.e. not stop at IA* and success 
criterion not met at final analysis) (%)
10
99.50
0.00
0.50
20
81.82
0.12
18.06
25
59.97
2.34
37.68
30
36.48
15.01
48.51
35
18.21
44.00
37.79
40
7.40
75.38
17.22
45
2.42
93.11
4.47
50
0.63
98.73
0.64
*Assuming interim analysis at 28 evaluable patients
Cohort 3 (MET GCN < 4)
The operating characteristics at this sample size have > 60% probability of stopping the trial for 
futility when the true ORR is < 25%. With 69 patients and 20 evaluable patients for interim 
analysis, when the true ORR is 10% then the probability of stopping for futility at the interim 
analysis is >90%. If the true ORR is 20%, the probability of stopping for futility at the interim 
analysis is >80% and the probability of positive conclusion at the final analysis is <1%.
Table 2-7
Operating Characteristics for Cohort 3 (MET GCN < 4)
True ORR (%)
Probability of a 
cohort to stop at 
IA* (%)
Probability of positive 
conclusion in final 
analysis for a cohort (%)
Probability of negative conclusion 
in final analysis for a cohort (i.e., 
not stop at IA* and success criterion 
not met at final analysis) (%) 
10
98.87
0
1.13
20
80.42
0.11
19.47
25
61.72
2.17
36.12


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True ORR (%)
Probability of a 
cohort to stop at 
IA* (%)
Probability of positive 
conclusion in final 
analysis for a cohort (%)
Probability of negative conclusion 
in final analysis for a cohort (i.e., 
not stop at IA* and success criterion 
not met at final analysis) (%) 
30
41.64
13.98
44.39
35
24.54
41.41
34.05
40
12.56
71.99
15.45
45
5.53
90.46
4.01
50
2.07
97.36
0.57
*Assuming interim analysis at 20 evaluable patients
Cohort 5a, 5b and 7
The operating characteristics at this sample size of 27 have < 36% probability of the trial 
meeting the success criteria when the true ORR is ≤50%. If the true ORR is ≥ 60%, the 
probability of the trial meeting the success criteria is ≥ 75%.
Table 2-8
Operating Characteristics for Cohort 5a, 5b and 7
Sample size (N)
True ORR (%)
Probability (%) that 
ORR≥55% with lower 95% 
CI>35%
27
40
7.4
27
45
18.1
27
50
35.1
27
55
55.6
27
60
75.0
27
65
88.9
Cohort 6 
In expansion Cohort 6, patients with either MET GCN ≥ 10 without MET mutations or MET 
mutations regardless of MET GCN will be enrolled. Based on the rarity of this patient 
population and considering recruitment within a reasonable timeframe, approximately 30 
patients are expected to be enrolled in Cohort 6.
Data from Cohort 6 will help further characterize the safety and efficacy of INC280 in the pre-
treated population (from Cohort 1a and Cohort 4).
2.10
Power for analysis of key secondary variables
Not applicable.
2.11
Interim analysis for futility
In Cohort 1, the interim analysis for futility will be performed separately for each of the two 
cohorts. Interim analyses for futility for each cohort are planned when at least 28 patients in 
each of Cohorts 1a, 1b, 2 and 4, and 20 patients in Cohort 3 have completed at least 6 cycles of 
treatment (18 weeks) or have discontinued treatment earlier. Due to the expected difference in 
enrollment rate for each cohort, the interim analysis for the different cohorts may occur at 
different times. For the interim analysis and the final analysis in Cohort 2 (MET GCN ≥ 4 and 


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< 6), the study targets to have at least 40% of patients with MET GCN ≥ 5 and < 6. No interim 
analysis is planned for Cohorts 5a, 5b and 6.
The decision to stop for futility for the respective cohort at interim will be based on the 
probability of success (POS). POS is the probability of a positive conclusion of the study if the 
study continued beyond interim, (i.e., till the final analysis), given the interim observed data (x) 
and success among n patients. Thus,
POS = Prob[ Final observed ORR ≥ 35% | x,n]
Minimally informative Beta distribution prior (Neuenschwander 2008) with prior mean equal 
to 25% will be used, i.e., the prior distribution will be Beta (0.3333, 1) for the POS calculations 
at the interim analysis.
The respective cohort will be stopped for futility at the interim analysis if the respective POS < 
10%.
Cohort 1a, Cohort 1b, Cohort 2 and Cohort 4 
With 28 evaluable patients for interim analysis in each of the Cohorts 1a, 1b, 2 and 4, if ≤ 7 
responses (POS =0.0543) are observed then the respective cohort will be stopped for futility. 
Further details of POS are provided in Table 2-9. For each of the Cohorts 1a, 1b, 2 and 4, if at 
the time that the 28th patient is enrolled a minimum of 8 responders have not yet been observed, 
accrual in the cohort may be temporarily suspended until either the minimum number of 8 
responders are observed or results of the interim analysis allow that cohort to continue.
Table 2-9
Probability of Success at the Final Analysis Based on Various Number 
of Responders Observed at IA for Cohort 1a, Cohort 1b, Cohort 2 and 
Cohort 4
Responder at IA out of 28 evaluable patients at IA
Probability of Success
≤ 5
< 0.01
6
0.0164
7
0.0543
8
0.1398
9
0.2863
10
0.4794
11
0.6766
≥ 12
> 0.83
Table 2-10
Number of Responders for Various Number of Evaluable Patients at 
Interim Analyses by Required Probability of Success for Cohort 1a, 
Cohort 1b, Cohort 2 and Cohort 4 
Number of Evaluable patients at IA
Responders at IA
Probability of Success
26
6
0.0368
26
7
0.1050
27
7
0.0765
27
8
0.1829
28
7
0.0543
28
8
0.1398


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Number of Evaluable patients at IA
Responders at IA
Probability of Success
29
7
0.0377
29
8
0.1044
30
8
0.0760
30
9
0.1792
31
8
0.0540
31
9
0.1369
32
8
0.0373
32
9
0.1020
33
9
0.0740
33
10
0.1739
34
9
0.0523
34
10
0.1323
35
10
0.0980
35
11
0.2152
Cohort 3 
With 20 evaluable patients for interim analysis in Cohort 3 if ≤ 5 responses (POS=0.0999) are 
observed then the cohort will be stopped for futility. All evaluable patients at the time of the 
data cut-off for the interim analysis will be used to obtain the futility boundary using the POS 
criteria. Further details of POS are provided in Table 2-11. If at the time that the 20th patient is 
enrolled a minimum of 6 responders have not yet been observed, accrual in the cohort may be 
temporarily suspended until either the minimum number of 6 responders are observed or results 
of the interim analysis allow the cohort to continue.
Table 2-11
Probability of Success at the Final Analysis Based on Various Number 
of Responders Observed at IA for Cohort 3 (MET GCN less than 4)
Responder at IA out of 20 evaluable patients at IA
Probability of Success
1
0.0001
2
0.0009
3
0.0066
4
0.0309
5
0.0999
6
0.2379
7
0.4382
8
0.6533
3
Changes to protocol specified analyses
Not applicable.


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4
Additional details on implementation of statistical 
methodology
The sections below contain additional details on statistical methodology that will be included 
in Appendix 16.1.9 (Documentation of Statistical Methods) of the CSR as well as rules details 
on programing rules that will be followed to implement the analyses described in Section 2.
4.1
Data included in the analyses
This section provides additional details to those included in Section 2.1.
The primary analysis will be conducted when all treated patients in their respective cohort that 
is not stopped for futility have completed at least 6 cycles of treatment (18 weeks) or a patient 
has discontinued treatment earlier. Each analysis will include the data with an assessment date 
or event start date (e.g. vital sign assessment date or start date of an adverse event) prior to or 
on the cut-off date. For example, if the cut-off date is 30-Dec-2008, an AE starting on 30-Dec-
2008 will be reported, whereas an adverse event starting on 31-Dec-2008 will not be reported.
4.2
Patient classification into analysis sets
This section provides additional details to those included in Section 2.2.
Patients are excluded from the analysis populations based on the protocol deviations entered in 
the database and/or on specific patient classification rules as shown in Table 4-1 below. 
Table 4-1
Patient classification rules 
Analysis Population
Additional patient classification rules leading to exclusion
Full Analysis Set
Patients who did not receive at least one dose of study drug
Safety Set
Patients who did not receive at least one dose of study drug.
Per-Protocol Set
Protocol deviations that will lead to removal of patients from Per 
Protocol Set (defined in Section 2.2)
4.3
Last contact date
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the last complete date among the following:
Table 4-2
Last contact date data sources
Source data
Conditions
Last contact date/last date patient was known to 
be alive from Survival Follow-up page 
Patient status is reported to be alive, lost to 
follow-up or unknown
Start/End dates from further antineoplastic 
therapy
Non-missing medication/procedure term.


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Source data
Conditions
Start/End* dates from drug administration record 
Non-missing dose. Doses of 0 are allowed.
End of treatment date from end of treatment page
No condition.
Tumor assessment date
Evaluation is marked as ‘done’.
Laboratory/PK collection dates
Sample collection marked as ‘done’. 
Vital signs date
At least one non-missing parameter value
Performance Status date
Non-missing performance status
Start/End dates of AE 
Non-missing verbatim term
The last contact date is defined as the latest complete date from the above list on or before the 
data cut-off date. The cut-off date will not be used for last contact date, unless the patient was 
seen or contacted on that date. No date post cut-off date will be used. Completely imputed
dates (e.g. the analysis cut-off date programmatically imputed to replace the missing end date
of a dose administration record) will not be used to derive the last contact date. Partial date 
imputation is allowed for event (death)/censoring is coming from ‘Survival information’ eCRF. 
The last contact date will be used for censoring of patients in the analysis of overall survival.
4.4
Time unit
For all derivations, a month will be calculated as (365.25 / 12) = 30.4375 days. 
If duration is to be reported in years, duration in days will be divided by 365.25.
If duration is to be reported in months, duration in days will be divided by 30.4375.
If duration is to be reported in weeks, duration in days will be divided by 7.
4.5
Dose interruptions and dose changes
This section provides additional details to those included in Section 2.6.
All calculations of dose interruptions and dose changes are based on the dose actually taken by 
the patient.
An interruption is defined as a 0 mg dose taken on one or more days between two non-zero 
dosing periods. The last zero dose of INC280 followed by permanent discontinuation are not 
considered as dose interruption. 
What follows defines how dose interruptions will be counted in the case of multiple dose 
interruptions.

If an interruption occurs consecutively for at least two days due to the same reason, then it 
will be counted only once (example: If the actual dose on days 1-3 is 800 mg and actual 
dose on days 4-5 is 0 mg and dose interruption on days 4-5 is due to AE, then the total 
number of dose interruptions is 1).

If an interruption occurs consecutively for at least two days due to different reasons, then it 
will be counted for each reason (example: If the actual dose on days 1-3 is 800 mg and 


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actual dose on days 4-5 is 0 mg and dose interruption on day 4 is due to AE and dose 
interruption on day 5 is due to dosing error, then the total number of dose interruptions is 
2). 

If an interruption occurs for more than one day due to the same reason, but the days are not 
consecutive, i.e. there is at least one dosing day in between, then each dose interruption will 
be counted as a different occurrence (example: if the actual dose on days 1, 3 and 5, is 800
mg and actual dose on days 2 and 4 is 0mg, and dose interruptions on day 2 and 4 are both 
due to dosing error, the total number of dose interruptions is 2). 
A dose change is defined as a change in dosing from one record to the next, however a dose 
interruption will not be counted as a dose change.
Dose reductions are a subset of dose changes where the total daily dose is lower than the 
previous non-zero dose.
Case 1: If a patient did not receive the protocol planned dose for any reason, then this is a dose 
reduction (400 mg, 800 mg).
Patient ID
Start date
End date
Dose
Regimen
Reason
Reduction
(derived)
Comments
0001
22/03/2017
25/03/2017
400
ONCE PER DAY
DOSING ERROR
Y
1st administration 
different from protocol 
planned dose (800 mg)
26/03/2017
26/05/2017
800
2 TIMES PER 
DAY
Case 2: If, due to a dosing error, a patient receives higher than protocol planned dose and moves 
down to the planned dose then this is not a dose reduction ([800 mg, 1000 mg, 800 mg] or [600
mg, 900 mg, 600 mg] ; However if the change is directly from a higher than planned dose down 
to a lower than protocol planned dose, then this is a dose reduction (e.g. In the sequence [800
mg, 1000 mg, 400 mg] or [600 mg, 900 mg, 400 mg], is a dose reduction).
Patient ID
Start date
End date
Dose
Regimen
Reason
Reduction
(derived)
Comments
0002
22/03/2017
21/05/2017
800
2 TIMES PER 
DAY
22/05/2017
23/05/2017
0
ADVERSE EVENT
24/05/2017
01/08/2017
600
2 TIMES PER 
DAY
ADVERSE EVENT
Y
02/08/2017
02/08/2017
700
2 TIMES PER 
DAY
DOSING ERROR
03/08/2017
05/08/2017
800
2 TIMES PER 
DAY
06/08/2017
06/08/2017
1000
2 TIMES PER 
DAY
DOSING ERROR
07/08/2017
12/09/2017
800
2 TIMES PER 
DAY
N
moves down to the 
dose administered just 
before dosing error
0003
22/03/2017
21/05/2017
800
2 TIMES PER 
DAY
22/05/2017
23/05/2017
0
ADVERSE EVENT


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Patient ID
Start date
End date
Dose
Regimen
Reason
Reduction
(derived)
Comments
24/05/2017
01/08/2017
600
2 TIMES PER 
DAY
ADVERSE EVENT
Y
02/08/2017
02/08/2017
700
2 TIMES PER 
DAY
DOSING ERROR
03/08/2017
05/08/2017
800
2 TIMES PER 
DAY
06/08/2017
06/08/2017
1000
2 TIMES PER 
DAY
DOSING ERROR
07/08/2017
12/09/2017
600
2 TIMES PER 
DAY
Y
moves down to a lower 
dose administered just 
before dosing error
Case 3: If due to interruption, a patient receives half of the dose during 1 day and followed by 
an interruption (due to the same reason) then this is not a dose reduction (for ex: 800 mg 2 times 
per day from 27-Dec-2016 to 14-Jan-2018, and 400 mg once per day on 15-Jan-2018 and then 
interruption 16-Jan-2018 to 22-Jan-2018). After interruption, dose reduction will be determined 
using the dose received on a day without interruption (for ex: 600 mg vs 800 mg ignoring 400
mg on 15-Jan given it is related to the interruption). 
Patient ID
Start date
End date
Dose
Regimen
Reason
Reduction
(derived)
Comments
0004
27/12/2017
14/01/2018
800
2 TIMES PER 
DAY
15/01/2018
15/01/2018
400
ONCE PER DAY
ADVERSE EVENT
N
½ dose for 1 day 
same reason than 
interruption
Interruption started on 
15-Jan
16/01/2018
22/01/2018
0
ADVERSE EVENT
23/01/2018
07/02/2018
600
2 TIMES PER 
DAY
ADVERSE EVENT
Y
Dose reduction from 
800 mg to 600 mg
[400 mg on 15Jan 
ignored for reduction 
determination as part of 
the interruption]
08/02/2018
19/02/2018
0
ADVERSE EVENT
0005
25/04/2016
22/05/2016
800
2 TIMES PER 
DAY
23/05/2016
23/05/2016
400
ONCE PER DAY
ADVERSE EVENT
N
½ dose for 1 day 
same reason than 
interruption
Interruption started on 
23-May
24/05/2016
25/05/2016
0
ADVERSE EVENT
26/05/2016
26/05/2016
400
ONCE PER DAY
ADVERSE EVENT
Y
Dose reduction from 
800 mg to 400 mg
[400 mg on 23May 
ignored for reduction 
determination as part of 
the interruption]
27/05/2016
05/06/2016
800
2 TIMES PER 
DAY
06/06/2016
06/06/2016
400
ONCE PER DAY
DOSING ERROR
Y


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Patient ID
Start date
End date
Dose
Regimen
Reason
Reduction
(derived)
Comments
07/06/2016
01/08/2016
800
2 TIMES PER 
DAY
02/08/2016
02/08/2016
400
ONCE PER DAY
DOSING ERROR
Y
½ dose for 1 day 
different reason than 
interruption
03/08/2016
07/08/2016
0
ADVERSE EVENT
Case 4: If due to permanent discontinuation, a patient receives half of the dose the last day of 
treatment then this is not a dose reduction (for ex: 800 mg 2 times per day from 30-May-2016 
to 03-Oct-2016, and 400 mg once per day on 04-Oct-2016). This rule is applied for any dose 
levels (for ex: 600 mg 2 times per day from 15-Dec-2017 to 20-Dec-2017, and 300 mg once 
per day on 04-Oct-2016).
Patient 
ID
Start date
End date
Dose
Regimen
Reason
Permanently 
discontinuation
Reduction
(derived)
0006
30/05/2016
03/10/2016
800
2 TIMES PER 
DAY
04/10/2016
04/10/2016
400
ONCE PER DAY
ADVERSE EVENT
Y
N
4.6
Efficacy endpoints 
For further details on efficacy endpoints, see Section 14 (Appendix II) of the protocol. For the 
evaluation of tumor-response related endpoints, response is assessed by investigator and BIRC 
according to RECIST 1.1.
Response and progression evaluation will be performed according to the Novartis RECIST 1.1 
guidelines, included in Section 14 (Appendix II) of the CINC280A2201 protocol.
The text below gives more detailed instructions and rules needed for programming of the 
analyses described in Sections 2.7 and 2.8.1.
4.6.1
Implementation of RECIST guidelines
Disease progression
PD should only be assigned if it is confirmed by an objective assessment method as per RECIST 
1.1 (e.g. radiologic scan, histology for bronchoscopy, photos for skin lesions). If a new lesion 
is detected using an objective assessment method other than radiologic scan, it should be entered 
on the ‘New lesion’ RECIST eCRF with appropriate method (or method=‘Other’). 
In particular, discontinuation due to disease progression or death due to progressive disease, 
without supporting objective evidence (as defined above), will not be considered as PD in the 
determination of BOR, the derivation of any efficacy endpoint or efficacy analysis.
Change in imaging modality
Per RECIST 1.1, 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-


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versa, regardless of the justification for the change) or a 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 and vice versa while keeping same contrast use (e.g. switching from spiral CT with 
contrast to CT with contrast) is not considered a change in imaging modality. A change in 
methodology will result by default in a UNK (unknown) overall lesion response assessment. 
However, a response assessment other than the Novartis calculated UNK response may be 
accepted from the investigator or BIRC if a definitive response assessment can be justified 
based on the available information. Potential discrepancies between the modality used and 
overall lesion response reported by the investigator (e.g. change in modality but investigator 
assessment of response is different from UNK) will be queried during the data validation 
process.
Determination of missing adequate tumor assessments
For the computation of ORR, patients without any radiological assessment after the start date 
of study drug will be counted as failure.
Partial or complete responses reported prior to any additional anticancer therapy will be 
considered for ORR computation irrespective of the number of missed assessments before 
response. In this section, the ‘missing adequate assessment’ is defined as assessment not done 
or assessment with overall lesion response equal to UNK.  For the sake of simplicity, the 
‘missing adequate assessment’ will also be referred as ‘missing assessment’.
As detailed in Section 14 (Appendix II) of the CINC280A2201 protocol, the PFS censoring and 
event date options depend on the presence and the number of missing tumor assessments. For 
example, an event occurring after two or more missing assessments is censored in the analysis 
of PFS at the last adequate tumor assessment before the event date.
An exact rule to determine whether there is none, one or two missing assessments is therefore 
needed. This rule will be based on the distance between the last adequate tumor assessment date 
and the event date.
If the distance is larger than threshold D1 or D2 then the analysis will assume one or two missing 
assessments, respectively. The threshold D1 will be defined as the protocol specified interval 
between the tumor assessments plus the protocol allowed window around the assessments. 
Similarly, the threshold D2 is defined as two times the protocol specified interval between the 
tumor assessments plus the protocol allowed window around the assessments. In this study, the 
protocol defined schedule of tumor assessment is every 6 weeks and each assessment is 
expected to be performed at the scheduled time point plus or minus 1 week, i.e. the window is 
2 weeks, then any distance larger than D1 = 6+2 = 8 weeks means one missing assessment and 
any distance larger than D2 = (2*6) + 2 = 14 weeks means two missing assessments.
The same definition of D2 will be used to determine the PFS censoring reason. 
Possible censoring reasons for PFS are:
1: Ongoing without event
2: Lost to follow-up
3: Withdrew consent
4: Adequate assessment no longer available


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5: New cancer therapy added
6: Event after >=2 missing tumor assessments
PFS censoring reason is then derived by the following sequence of rules. 
-
If patient is considered to have a PFS event then PFS censoring reason is set to missing.
-
Else if patient has had no baseline assessment then PFS censoring reason = 4.
-
Else if patient has a PFS event after two or more missing assessments [If (PFS Event date 
≤Censoring date and (PFS Event date - Date of last adequate tumor assessment (LATA) ≥
D2)] then PFS censoring reason =6:
-
Else if patient has no PFS event, and patient is censored at a date after two or more missing 
assessments ((Censoring date - Date of LATA) ≥ D2) then PFS censoring reason = 4
-
Else if censoring date equals the start date of further anti-neoplastic therapy then PFS 
censoring reason = 5
-
Else if censoring date equals date of discontinuation due to consent withdrawal then PFS 
censoring reason = 3
-
Else if censoring date equals date of discontinuation due to loss to follow-up then PFS 
censoring reason = 2
-
Else if the censoring date equal the analysis cut-off date and the time between  LATA and 
the cut-off is greater than D2 days then PFS censoring reason = 4
-
Else if the censoring date equal the analysis cut-off date and the time between  LATA and 
the cut-off is less than or equal to D2 days then PFS censoring reason = 1
Where censoring date = minimum(analysis cut-off date, start date of further anti-neoplastic 
therapy, date of discontinuation due to consent withdrawal, date of discontinuation due to loss 
to follow-up).
Non-measurable disease at baseline
As specified in Section 14 (Appendix II) of the CINC280A2201 protocol, the RECIST 1.1 
criteria imply that only patients with measurable disease at baseline should be included in the 
study. If a patient without measurable disease is enrolled, the intent-to-treat (ITT) principle 
requires including these patients in the analyses. Hence, analyses will be based on FAS 
including patients with either measurable or non-measurable disease. Therefore, a rule needs to 
be specified on how to handle these cases.
As specified in Table 3-1 of Section 14 (Appendix II) of the CINC280A2201 protocol, overall 
lesion response can be derived for patients without measurable disease at baseline as follows 
(Table 4-3).


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Table 4-3
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 In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. 
Missing baseline tumor assessment
As specified in Section 14 (Appendix II) of the protocol, since the timing of PD cannot be 
determined for patients with missing baseline tumor assessment, these patients are censored in 
the PFS analysis at the start date of treatment. This rule, however, only applies to the ‘PD 
component’ of the PFS or DOR assessment.  
Patients without baseline tumor assessment who die within D2 distance from start date of 
treatment will be counted as having an event in the primary analysis of PFS.  All deaths will be 
counted in the OS analysis regardless of presence or absence of the baseline tumor assessment.
Construction of waterfall graphs
The waterfall graphs will be used to depict the anti-tumor activity. These plots will display the 
best percentage change from baseline in the sum of the measured diameter of all target lesions 
based on the on-treatment assessments occurring prior to the first PD for each patient with 
measureable disease at baseline. The proportions of patients with various degrees of tumor 
shrinkage or growth can then represent a useful efficacy metric.
However, caution needs to be paid to the assessments, where an occurrence of a new lesion or 
worsening in non-target lesions (resulting in PD as an overall lesion response at given 
assessment) contradicts the measurements obtained on target lesions.  These assessments will 
not be displayed as bars in the graph. If such a “contradicting” assessment represents the only 
post-baseline assessment for a patient, then the patient will be represented by a special symbol 
(e.g. *) in the waterfall graph.
The assessments with unknown target response and also assessments with unknown overall 
response will be excluded. Patients without any valid assessments will be completely excluded 
from the graphs.
The total number of patients displayed in the graph needs to be shown and this number will be 
used as a denominator when calculating the percentages of patients with tumor shrinkage and 
tumor growth.  Footnote will explain the reason for excluding some patients (due to absence of 
any valid assessment).
Patient who have discontinued will be represented by a special symbol in the waterfall graph.


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All possible assessment scenarios are described in Table 4-4.
Table 4-4
Inclusion/exclusion of assessments used in waterfall graph
Criteria for inclusion/exclusion
Possible source of 
contradictions
Target response
Overall lesion 
response
Include in waterfall
Non-target 
response
New lesion?
CR/PR/SD
PD
Yes but as * only
PD
any
CR/PR/SD
PD
Yes but as * only
Any
Yes
UNK
UNK or PD
No
Any
any
CR/PR/SD
UNK
No
UNK
No
CR/PR/SD
CR/PR/SD
Yes as a bar
SD/IR
No
PD
PD
Yes as a bar
Any
any
The following algorithm will be used to construct the graph:
1. Select “valid” post-baseline assessments to be included, i.e. for each patient and each 
assessment repeat the following four steps:
1.1. Check the target lesion response and overall lesion response at each assessment.  If at least 
one of them is UNK then exclude the whole assessment.  Otherwise, go to step 1.2.
1.2. Check the overall lesion response.  If PD, then go to step 1.3. Otherwise, go to step 1.4
1.3. Check target response.  If PD, then go to step 1.4.  Otherwise flag the assessment .
1.4. Calculate the % change from baseline in target lesions. 
2. For each patient, go through all valid assessments identified in step 1 and find the 
assessment with best % change from baseline in target lesions.  The “best” means best for 
the patient, i.e. the largest shrinkage or if a patient only has assessments with tumor growth 
take the assessment where the growth is minimal. (Example 1: Patient 1 has the following % 
changes from baseline at assessments 1, 2, 3, 4 and 5, respectively: -10%; -25%; -13%; -4% 
and +6%. His/her best % change is then -25%. Example 2: Patient 2 has the following % 
changes from baseline at assessments 1, 2 and 3, respectively: +5%; +18% and +35%. 
His/her best % change is then +5%.
3. Construct the waterfall graph displaying the best % change from baseline for each patient. 
Patients having only flagged assessment(s) will be displayed separately. 
Both investigator assessment and BIRC will be used in the construction of waterfall plot.
The recommended way of the display from left to right is:
1. Bars under the horizontal axis representing tumor shrinkage
2. Bars above the horizontal axis representing tumor growth
3. “Zero” bars with symbol representing patients with contradiction


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4.6.2
Sources for overall lesion response
The tumor endpoints derivation is based on the sequence of overall lesion responses at each 
assessment/time point. However, the overall lesion response at a given assessment/time point 
will be provided from different sources as illustrated in Table 4-5.
Table 4-5
Sources for overall lesion response 
Source 1
BIRC (Blinded Independent review committee) reported overall lesion response 
Source 2
Investigator (local radiology) reported overall lesion response
In this study, Source 1 will be used for the primary endpoint derivation and other secondary 
endpoint calculations based on BIRC assessment (ORR, DOR, DCR, TTR and PFS). Source 2 
will be used to calculate ORR, DOR, DCR, TTR and PFS by Investigator assessment.
4.6.3
Kaplan-Meier estimates
To analyze time to event variables (DOR, TTR, OS and PFS) an estimate of the survival 
function will be constructed using Kaplan-Meier (product-limit) method as implemented in 
PROC LIFETEST with METHOD=KM option (see example below).  The median time to event 
and estimated event rates at different time points will be estimated, along with associated 95% 
two-sided CIs derived based on the complementary log-log transformation. This will be 
conducted via the SAS procedure LIFETEST.  The TIME statement will include a variable with 
survival times (survtime in the example below) and a (right) censoring variable (censor in the 
example below) with a value of 1, representing censoring:
PROC LIFETEST data = dataset 
METHOD = KM 
CONFTYPE=LOGLOG;
TIME survtime*censor(1);
RUN;
/* survtime represents variable containing event/censor times;
censor represents censoring variable (1 = censored, 0 = event); */
Kaplan-Meier survival and failure function estimates from this procedure will be used to 
construct the Kaplan-Meier figures.
Median survival will be obtained along with 2-sided 95% CIs calculated from PROC 
LIFETEST output using the method of Brookmeyer & Crowley, 1982.
Kaplan-Meier estimates with 2-sided 95% CIs at specific time points will be summarized.  The 
time points can be expressed in weeks or in months depending on the time-to-event variable.  
The CIs will be constructed using Greenwood’s formula [Collet, 1994, p.23] for the standard 
error of the Kaplan-Meier estimate.
The Kaplan-Meier graphs will be constructed using SAS software.


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4.6.4
Confidence interval and p-value for response rate
ORR will be summarized in terms of percentage rates with 95% CIs. An exact binomial 
confidence interval (implemented using SAS procedure FREQ with EXACT statement for one-
way tables) will be calculated (Clopper & Pearson, 1934).
SAS procedure FREQ will be used to estimate the proportion of responders (binary outcome = 
1 or “Yes”), along with the associated 95% (=100 × (1 – two-sided alpha level)) two-sided 
Pearson-Clopper CI and exact one-sided p-value for the hypothesis test of the null proportion
(0.25). These estimates are obtained as follows:
proc freq data = dataset;
table binary event / 
binomial(
p = null proportion
level = “Yes”)
alpha = two-sided alpha level;
exact binomial;
When there are no responders, SAS does not produce a CI by default. To obtain a CI in this 
situation, PROC FREQ is used as specified above except changing level=”No”. From the results 
of this modified procedure, the values in percent of the LCL and UCL of a 0% response rate are 
calculated as follows:
LCLLEVEL=”Yes” (%) = 100% - UCLLEVEL=”No” (%)
UCLLEVEL=”Yes” (%) = 100% - LCLLEVEL=”No” (%)
4.6.5
Baseline
Baseline is the result of an investigation describing the “true” uninfluenced state of the patient. 
The last available assessment before or on the start date of study drug is defined as “baseline” 
value or “baseline” assessment.
 
4.7
Safety evaluations
The text below gives more detailed instructions and rules needed for programming of the 
analyses described in Section 2.8.2.
4.7.1
Multiple assessments within post-baseline visits
For all analyses regarding abnormal assessments or analyses based on worst or best post-
baseline value (laboratory, ECGs, vital signs, ECOG performance status), all post-baseline 
values will be included (scheduled, unscheduled, repeat). All unscheduled and repeat
measurements will be included in listings.


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Laboratory Data
For laboratory data, assessments can be collected from both local and central laboratory on the 
same date. For shift tables using CTC grades to compare baseline to the worst post-baseline 
value, the assessment with worst post-baseline value is used for analyses irrespective of the 
source. For LFT summaries, where concurrent measurements are used in the calculation of 
number and percentage of patients with worst post-baseline values, the assessment with worst 
post-baseline value is used (since worst values are based on the largest ratio of lab value to its 
ULN for each patient) although the worst values for the different parameters may be coming 
from different laboratories.  
ECGs
For all patients, 3 ECGs are targeted to be measured at the protocol-defined (nominal) time-
points. If a patient has more than one measurement at a nominal scheduled time point, the 
average of all available measurements associated with the nominal time point will be used for 
the analyses. For unscheduled visits, measurements taken within 15 min interval will also be 
averaged and used for analysis.
4.7.2
Baseline
As defined in Section 2.8.2, the last available assessment before or on the date of start of study 
drug is defined as “baseline” value or “baseline” assessment.
Laboratory data 
If both central and local laboratory assessments were performed on the same date and 
corresponding to the baseline assessment date, then the central laboratory assessment will be 
used for the calculation of baseline.
If labs with duplicate laboratory measurements taken at the last assessment date on or before 
the start date of study treatment from the same sources (both from local or central), then the 
rule described below will be applied for the calculation of baseline.

For gradable labs, the value of lower CTCAE grade will be considered as the baseline value. 
If several records have the same absolute grade, but in different directions, 2 baselines 
should be created, the record with grade below 0 should be the baseline of the 'Hypo' 
parameter, and the other record should be the baseline for the 'Hyper' parameters.

For non-gradable labs:

If both within normal range: take average value

If one within normal range and the other outside: take the one within normal range

If both outside normal range: take the one closest to the normal range
ECGs 
Baseline for ECG measurement is the average of the pre-dose replicate measurements on the 
baseline day. Unscheduled assessments will not be included in the calculation of the average. 
Study day 1 scheduled pre-dose ECGs will be considered to have been obtained prior to study 
drug administration if dosing time or ECG time is missing.


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If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement. 
For unscheduled assessments on study day 1, the assessment is classified as post-baseline.
4.7.3
Laboratory Parameters
This section provides further detail on the analysis of laboratory parameters that will be listed 
and summarized as described in Section 2.8.2. 
Hematology
Hematologic tests include: Hemoglobin, platelets, white blood cells (WBC), red blood cells 
(RBC), differential (basophils, eosinophils, lymphocytes, monocytes, neutrophils (% or 
absolute)
The following rules will be applied to derive the WBC differential counts when only 
percentages are available (this is mainly for neutrophils and lymphocytes, because CTC grading 
is based on the absolute counts). 
The method to convert the value is straightforward: for each patient, the original lab value (%) 
is divided by 100 and multiplied by WBC count e.g. for neutrophils (NEU):
NEU count = (WBC count) * (NEU%value/100)
In order to derive the corresponding absolute normal range, the rule to be applied depends on 
the availability of the % range and the absolute range for the differential:

If %  absolute range NOT missing (% range is or isn’t missing), then use the absolute range 
provided by the site

If % range NOT missing and absolute range missing, then the % normal limits (i.e LLN and 
ULN) are divided by 100 and multiplied by the corresponding normal limits of WBC count, 
e.g. for neutrophils NEU):
LLN for NEU count = (LLN for WBC count)* (LLN for NEU%value /100)
ULN for NEU count = (ULN for WBC count)*(ULN for NEU%value/100)
Biochemistry
The following calculation will be applied for corrected calcium in SI unit (if not available in 
the Lab database):
Corrected calcium (mmol/L)=measured total Ca (mmol/L)+0.02 (40-serum albumin[g/L]), 
where 40 represents the average albumin level in g/L.
Time windows will be defined for trends of labs over time.


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Table 4-6
Time windows for Labs   
Time Window
Planned Visit Timing
Time Window Definition
Baseline
On or before Study Day 1
≤ Study Day 1
Cycle 1 Day 15 
(Week 3)
Study Day 15 
Study Days 2 – 18  
Cycle 2 Day 1 
(Week 4)
Study Day 22 
Study Days 19 – 32  
Cycle 3 Day 1 
(Week 7)
Study Day 43 
Study Days 33 – 53  
Cycle 4 Day 1 
(Week 10)
Study Day 64 
Study Days 54 – 74  
Cycle 5 Day 1 
(Week 13)
Study Day 85
Study Days 75 – 95
Cycle 6 Day 1 
(Week 16)
Study Day 106
Study Days 96 – 116
Cycle 7 Day 1 
(Week 19)
Study Day 127
Study Days 117 – 137
Every 6 weeks 
thereafter
Scheduled visit day
(+ 21 days from previous 
cycle)
Scheduled visit day ± 10 days 
centered around the planned 
assessment
Study Day 1 = the first day of dosing
4.7.4
Time to first occurrence of event and duration 
This section provides additional details to those included in Section 2.8.2. For each case, the 
start date and end date for the duration of the 1st occurrence are in bold.
Case 1a: First event resolved with a single event - Outcome = recovered/resolved
Patient ID
Preferred term
Start date
End date
Grade
Outcome
0001
INCREASED LIPASE 
2016-05-31
2016-06-02
3
RECOVERED/RESOLVED
Case 1b: First event resolved with multiple events with the same start date - Outcome =
recovered/ resolved
Patient ID
Preferred term
Start date
End date
Grade
Outcome
0002
INCREASED AMYLASE 
2018-10-01
2018-10-29
3
RECOVERED/RESOLVED
INCREASED LIPASE 
2018-10-01
2018-11-20
3
RECOVERED/RESOLVED


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Case 2a: The first event improved with a single event - Outcome = recovering/resolving
Patient ID
Preferred term
Start date
End date
Grade
Outcome
0003
ILD
2017-08-30
2017-09-20
3
RECOVERING/RESOLVING
ILD
2017-09-21
2017-10-06
2
NOT RECOVERED/NOT 
RESOLVED
ILD
2017-10-07
3
NOT RECOVERED/NOT 
RESOLVED
Case 2b: The first event improved with multiple events with the same start date - Outcome 
=recovering/resolving
Patient ID
Preferred term
Start date
End date
Grade
Outcome
0004
AST INCREASED
2017-11-30
2017-12-06
3
RECOVERING/RESOLVING
HYPOALBUMINEMIA
2017-11-30
2017-12-06
2
RECOVERING/RESOLVING
ALT INCREASED
2017-11-30
2017-12-13
3
RECOVERING/RESOLVING
GGT INCREASED
2017-11-30
2018-01-12
2
RECOVERED/RESOLVED
ALP INCREASED
2017-12-06
2017-12-13
1
RECOVERED/RESOLVED
AST INCREASED
2017-12-06
2017-12-13
2
RECOVERING/RESOLVING
ALT INCREASED
2017-12-13
2017-12-20
2
RECOVERING/RESOLVING
AST INCREASED
2017-12-13
2017-12-20
1
RECOVERED/RESOLVED
ALT INCREASED
2017-12-20
2018-01-12
1
NOT RECOVERED/NOT 
RESOLVED
AST INCREASED
2018-01-12
2018-01-22
3
RECOVERING/RESOLVING
ALT INCREASED
2018-01-12
2018-01-25
4
RECOVERING/RESOLVING


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Case 2c: The first event improved (Gr 4, Gr 3 and Gr <3) - Outcome =recovering/resolving
Patient ID
Preferred term
Start date
End date
Grade
Outcome
0005
HEPATIC 
DYSFUNCTION
2017-01-06
2017-01-11
4
RECOVERING/RESOLVING
HEPATIC 
DYSFUNCTION
2017-01-12
2017-01-18
3
RECOVERING/RESOLVING
HEPATIC 
DYSFUNCTION
2017-01-19
2017-02-06
1
RECOVERED/RESOLVED
Case 3a: The first event worsened and then improved (Gr 3, Gr 4 and Gr <3) - Outcome =not 
recovered/not resolved and then recovering/resolving
Patient ID
Preferred term
Start date
End date
Grade
Outcome
0006
AMYLASE INCREASE
2017-07-13
2017-07-18
2
RECOVERING/RESOLVING
AMYLASE INCREASE
2017-07-19
2017-08-29
1
NOT RECOVERED/NOT 
RESOLVED
AMYLASE INCREASE
2017-08-30
2017-09-05
3
NOT RECOVERED/NOT 
RESOLVED
AMYLASE INCREASE
2017-09-06
2017-09-10
4
RECOVERING/RESOLVING
AMYLASE INCREASE
2017-09-11
2017-09-21
3
RECOVERING/RESOLVING
AMYLASE INCREASE
2017-09-22
1
NOT RECOVERED/NOT 
RESOLVED
Case 3b: The first event worsened with multiple events and then improved (Gr 3, Gr 4 and Gr 
<3) - Outcome =not recovered/not resolved and then recovering/resolving
Patient ID
Preferred term
Start date
End date
Grade
Outcome
0007
AMYLASE INCREASED
2017-09-12
2017-10-05
3
NOT RECOVERED/NOT 
RESOLVED
AMYLASE INCREASED
2017-10-06
2017-10-20
3
RECOVERING/RESOLVING
LIPASE INCREASED
2017-10-06
2017-10-20
1
RECOVERED/RESOLVED
AMYLASE 
INCREASED
2017-10-20
2017-10-26
1
NOT RECOVERED/NOT 
RESOLVED
LIPASE INCREASED
2017-10-26
2017-11-03
3
RECOVERED/RESOLVED
AMYLASE INCREASED
2017-10-27
2017-11-20
3
RECOVERING/RESOLVING
AMYLASE INCREASED
2017-11-20
2017-12-11
2
RECOVERED/RESOLVED
AMYLASE INCREASED
2017-12-11
1
NOT RECOVERED/NOT 
RESOLVED
Case 4: The first event worsened and then resolved - Outcome =not recovered/not resolved and 
then recovered/resolved
Patient ID
Preferred term
Start date
End date
Grade
Outcome
0008
HEPATOTOXICITY
2015-11-17
2015-11-22
3
NOT RECOVERED/NOT 
RESOLVED
HEPATOTOXICITY
2015-11-23
2015-12-02
4
RECOVERING/RESOLVING


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HEPATOXICITY
2015-12-03
2016-01-19
3
RECOVERED/RESOLVED 
WITH SEQUELAE
GGT INCREASED
2016-01-05
2
NOT RECOVERED/NOT 
RESOLVED
4.7.5
Handling of AEs missing grade 

Missing grade will be included under ‘All grades’ column for AE tables displaying ‘Grade 
3/4’ and ‘All grades’. 

Missing grade will be counted twice for AE tables by maximum grade (displaying Total, 
Grade 1–4 and Missing). 
4.8
Imputation rules
4.8.1
Study drug
The following rules should be used for the imputation of the dose end date for a given study 
treatment component:
Scenario 1 
If the dose end date is completely missing and there is no end of treatment (EOT) page and no 
death date, the patient is considered as on-going. 
The patient should be treated as on-going and the cut-off date should be used as the last dosing 
date.
Scenario 2
If the dose end date is completely or partially missing and the EOT page is available:

Case 1: The dose end date is completely missing and the EOT completion date is complete, 
then this latter date should be used.

Case 2: Only year (YYYY) of the dose end date is available and YYYY < the year of EOT 
date, then use 31DECYYYY

Case 3: Only year (YYYY) of the dose end date is available and YYYY = the year of EOT 
date, then use EOT date

Case 4: Both year (YYYY) and month (MMM) are available for dose end date and 
YYYY = the year of EOT date and MMM < the month of EOT date, then use last day of 
the Month (MMM)

Case 5: Both year (YYYY) and month (MMM) are available for dose end date and 
YYYY = the year of EOT date and MMM = the month of EOT date, then use EOT date
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.
After imputation, compare the imputed date with start date of treatment. 

If the imputed date is < start date of treatment, then use the treatment start date

Otherwise, use the imputed date


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Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed.
4.8.2
AE date imputation
The following missing dates will not be imputed

Missing AE start dates

AE start dates missing the year

Partial/missing AE end dates
AE with uncertain relationship will be considered as treatment-emergent AE.
For other types of missing dates, the rules specified in Tables 4-7 to Table 4-10 will be used.
Table 4-7
AE/treatment date abbreviations
Day
Month
Year
Partial Adverse Event Start Date
<not used>
AEM
AEY
Treatment Start Date (TRTSTD)
<not used>
TRTM
TRTY
Table 4-8 describes the possible combinations and their associated imputations. The upper text 
indicates the imputation (NC, A, B, C etc.) and the lower text the relationship of the AE start 
date to the treatment start date (TRTSTD).
Table 4-8
Imputation algorithm
AEM MISSING
AEM < TRTM
AEM = TRTM
AEM > TRTM
AEY MISSING
NC
Uncertain
NC
Uncertain
NC
Uncertain
NC
Uncertain
AEY < TRTY
( D )
Before TRTSTD
( C )
Before TRTSTD
( C )
Before TRTSTD
( C )
Before TRTSTD
AEY = TRTY
( B )
Uncertain
( C )
Before TRTSTD
( B )
Uncertain
( A )
After TRTSTD
AEY > TRTY
( E )
After TRTSTD
( A )
After TRTSTD
( A )
After TRTSTD
( A )
After TRTSTD
The legend to the above table is shown in Table 4-9.
Table 4-9
Imputation algorithm legend
Relationship
Before TRTSTD
Indicates AE start date prior to Treatment Start Date
After TRTSTD
Indicates AE start date after Treatment Start Date
Uncertain
Insufficient to determine the relationship of AE start date 
to Treatment Start Date
Imputation calculation
NC / Blank
No convention/imputation
( A )
01MONYYYY
( B )
TRTSTD+1
( C )
15MONYYYY


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Relationship
( D )
01JULYYYY
( E )
01JANYYYY
A few examples are shown in Table 4-10.
Table 4-10
Example scenarios
Partial
AE start date
Treatment
start date
Relationship 
with TRTSTD
Imputation 
Calculation
Imputed Date
12MMMYYYY
20OCT2001
Uncertain
NC
<blank>
DDMMM2000
20OCT2001
Before
( D )
01JUL2000
DDMMM2002
20OCT2001
After
( E )
01JAN2002
DDMMM2001
20OCT2001
Uncertain
( B )
21OCT2001
DDSEP2001
20OCT2001
Before
( C )
15SEP2001
DDOCT2001
20OCT2001
Uncertain
( B )
21OCT2001
DDNOV2001
20OCT2001
After
( A )
01NOV2001
4.8.3
Concomitant medication date imputation
The imputation of the start date of concomitant medication will follow the same conventions as 
for AE dates. Partial concomitant medication end dates will not be imputed.
4.8.3.1
Prior therapies date imputation
Start date
The same rule which is applied to the imputation of AE/concomitant medication start date will 
be used with the exception that for scenario (B) it will be replaced with “start date of study drug 
−1”.
End date

Imputed date = min (reference end date , last day of the month), if day is missing

Imputed date = min (reference end date , 31DEC), if month and day are missing
Reference end date will be the start date of study drug.
If the end date is not missing and the imputed start date is after the end date, use the end date as 
the imputed start date. If both the start date and the end date are imputed and if the imputed start 
date is after the imputed end date, use the imputed end date as the imputation for the start date.
Incomplete date of progression –Prior antineoplastic therapy-medication
A missing day is defaulted to the 1st of the month. However, date of progression should be 
expected to be after start date of prior antineoplastic therapy.

Imputed date = max (start date of prior antineoplastic therapy, 1st day of the month), if day 
is missing


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4.8.3.2
Post therapies date imputation
Start date

Imputed date = max (reference start date, first day of the month), if day is missing

Imputed date = max (reference start date , 01JAN), if day and month are missing
Reference start date will be the last date of study treatment administration + 1.
End date
No imputation.
4.8.4
Other imputations
Incomplete date of initial diagnosis of cancer and date of most recent recurrence
A missing day is defaulted to the 15th of the month and a missing month and day is defaulted 
to 01JAN.
If because of this imputation the chronology of the events is altered then the imputation should 
be made to the minimum value up to where chronology remains unchanged. E.g. if due to 
imputation the date of most recent recurrence becomes prior to the initial diagnosis date then it 
should be set to initial diagnosis date.
Incomplete assessment dates for tumor assessment
All investigation dates (e.g. MRI scan, CT scan) must be completed with day, month and year. 
If one or more assessment dates are incomplete but other investigation dates are available, the 
incomplete date(s) are not considered for calculation of the assessment date and assessment date 
is calculated as the latest of all investigation dates (e.g. MRI scan, CT-scan) if the overall lesion 
response at that assessment is CR/PR/SD/UNK. Otherwise – if overall response is progression 
– the assessment date is calculated as the earliest date of all investigation dates at that evaluation 
number. If all measurement dates have no day recorded, the 1st of the month is used. If the 
month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between the previous and the following assessment. 
If a previous and following assessment is not available, this assessment will not be used for any 
calculation.
Incomplete or missing death date
For cases when either day is missing or both month and day are missing for the date of death, 
the following imputation rules will be implemented:

If only day is missing, then impute 15th day of the month and year of death.

If both day and month are missing, then impute 01JUL of the year of death.


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Exposure-adjusted overall incidence 

Start date of study treatment will be considered as the AE start date for any AE with missing 
start date for exposure-adjusted overall incidence calculation. 
5
Reference:
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time, 
Biometrics 38, 29 - 41. 
Clopper CJ, Pearson ES (1934).  The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometrika; 26, 404-413.
Collet D (1994). Modelling survival data in medical research. London, Chapman & Hall.


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European Medicines Agency (February 2021). Guidance on the management of clinical trials 
during the COVID-19 (Coronavirus) pandemic
 
 
FDA (2007). Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs 
and Biologics, US Department of Health and Human Services.
Food and Drug Administration (March 2020). FDA Guidance on Conduct of Clinical Trials of 
Medical Products during COVID-19 Pandemic: Guidance for Industry, Investigators, and 
Institutional Review Boards
Neuenschwander B, Branson M, Gsponer T (2008). Critical aspects of the Bayesian approach 
to Phase I cancer trials. Statistics in Medicine; 27:2420-2439
Ulm K (1990) A simple method to calculate the confidence interval of a standard mortality 
ratio. American Journal of Epidemiology, 131(2); 373–375
Sahai H, Khurshid A (1993) Confidence intervals for the mean of a Poisson distribution: a 
review. Biom J, 35 (7); 857–867