Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: Non small cell lung cancer Non small cell lung carcinoma NSCLC INC280 capmatinib MET mutation MET exon14 MET exon14 skipping MET exon14 deletion METex14 METex14del MET∆ex14 EGFRwt Epidermal growth factor receptor wild type ALK negative docetaxel
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 22
Healthy volunteers: no

Brief summary:
The purpose of the study was to learn whether the study drug (capmatinib) helps to control lung cancer better compared to a single agent chemotherapy (docetaxel) and whether it is safe when given to patients suffering from a particular type of lung cancer. This type of cancer is called non-small cell lung cancer (NSCLC) with certain specific genetic alterations (called mutations) of a gene called MET, within a specific part of the gene called exon 14.

Detailed description:
Twenty-two patients with advanced or metastatic lung cancer, with these specific mutations in the MET gene but without changes in their epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genes, were enrolled in this study. Participants were randomly assigned to get either capmatinib or docetaxel in a 2 to 1 ratio. The randomization was stratified by prior lines of systemic therapy received for advanced/metastatic disease (one line vs. two lines).

During treatment, visits were scheduled every 21 days.

For all participants, the respective treatment (either with capmatinib or docetaxel) could be continued beyond initial disease progression as per RECIST 1.1 (as assessed by the investigator and confirmed by BIRC) if, in the judgment of the investigator, there was evidence of clinical benefit, and the participant wished to continue on the study treatment. After treatment discontinuation, all participants were followed for safety evaluations during the safety follow-up period, and the participant's status was collected every 12 weeks as part of the survival follow-up.

Participants randomized to docetaxel treatment were eligible to cross over to receive capmatinib treatment after BIRC-confirmed, RECIST 1.1-defined progressive disease and after meeting the eligibility criteria prior to crossover. This was the extension treatment phase.

Arms:
arm 1: 400 mg, capmatinib tablets, administered orally twice daily arm 2: Docetaxel 75 mg/m\^2 solution administered by intravenous infusion on Day 1 of every 21-day cycle

Interventions: intervention 1: Capmatinib intervention 2: Docetaxel
Intervention descriptions: intervention 1: 400 mg, capmatinib tablets, administered orally twice daily intervention 2: Docetaxel 75 mg/m\^2 by intravenous infusion every 21 days

Protocol document:
Prot_000.pdf: 
Novartis Research and Development 
INC280/Capmatinib 
Clinical Trial Protocol CINC280A2301 / NCT04427072
A phase III, randomized, controlled, open-label, multicenter, 
global study of capmatinib versus SoC docetaxel 
chemotherapy in previously treated patients with EGFR wt, 
ALK negative, locally advanced or metastatic (stage IIIB/IIIC 
or IV) NSCLC harboring MET exon 14 skipping mutation 
(MET∆ex14) 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2020-001578-31 
Version number: 
02 (Clean) 
Clinical Trial Phase: 
III 
Release date: 
24-Feb-2022 (content final)
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 (31-Jan-2020) 


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Table of contents 
Table of contents .................................................................................................................. 2 
List of tables ......................................................................................................................... 6 
List of figures ....................................................................................................................... 7 
List of abbreviations ............................................................................................................. 8 
Glossary of terms ............................................................................................................... 13 
Amendment 2 (24-Feb-2022) ............................................................................................ 16 
Amendment 1 (16-Dec-2020) ............................................................................................ 23 
Protocol summary .............................................................................................................. 28 
1 
Introduction ........................................................................................................................ 31 
1.1 
Background ............................................................................................................ 31 
1.1.1 
Overview of capmatinib (INC280) ........................................................ 32 
1.2 
Purpose ................................................................................................................... 35 
2 
Objectives, endpoints and estimands ................................................................................. 35 
2.1 
Primary estimands .................................................................................................. 36 
2.2 
Secondary estimand ............................................................................................... 37 
3 
Study design ....................................................................................................................... 38 
4 
Rationale ............................................................................................................................ 40 
4.1 
Rationale for study design ...................................................................................... 40 
4.2 
Rationale for dose/regimen and duration of treatment ........................................... 41 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ....................................................................................................................... 42 
4.4 
Purpose and timing of interim analyses/design adaptations ................................... 42 
4.5 
Risks and benefits .................................................................................................. 43 
4.5.1 
Capmatinib ............................................................................................ 44 
4.5.2 
Docetaxel ............................................................................................... 44 
4.6 
Rationale for public health emergency mitigation procedures .............................. 45 
5 
Study Population ................................................................................................................ 45 
5.1 
Inclusion criteria ..................................................................................................... 45 
5.2 
Exclusion criteria ................................................................................................... 47 
6 
Treatment ........................................................................................................................... 50 
6.1 
Study treatment ...................................................................................................... 50 
6.1.1 
Investigational and control drugs ........................................................... 50 
6.1.2 
Additional study treatments ................................................................... 51 
6.1.3 
Treatment arms/group ............................................................................ 51 
6.1.4 
Guidelines for continuation of treatment ............................................... 51 
6.1.5 
Treatment duration ................................................................................ 51 


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6.2 
Other treatment(s) .................................................................................................. 54 
6.2.1 
Concomitant therapy.............................................................................. 54 
6.2.2 
Prohibited medication ............................................................................ 56 
6.3 
Participant numbering, treatment assignment, randomization ............................... 56 
6.3.1 
Participant numbering ........................................................................... 56 
6.3.2 
Treatment assignment, randomization ................................................... 57 
6.4 
Treatment blinding ................................................................................................. 57 
6.5 
Dose escalation and dose modification .................................................................. 58 
6.5.1 
Dose modifications ................................................................................ 58 
6.5.2 
Treatment interruption and treatment discontinuation ........................... 64 
6.5.3 
Follow-up for toxicities ......................................................................... 64 
6.6 
Additional treatment guidance ............................................................................... 70 
6.6.1 
Treatment compliance ........................................................................... 70 
6.6.2 
Emergency breaking of assigned treatment code .................................. 70 
6.7 
Preparation and dispensation .................................................................................. 70 
6.7.1 
Handling of study treatment and other treatment .................................. 71 
6.7.2 
Instruction for prescribing and taking study treatment .......................... 72 
7 
Informed consent procedures ............................................................................................. 73 
8 
Visit schedule and assessments .......................................................................................... 74 
8.1 
Molecular pre-screening ......................................................................................... 84 
8.2 
Screening ................................................................................................................ 85 
8.2.1 
Eligibility screening ............................................................................... 86 
8.2.2 
Information to be collected on screening failures .................................. 86 
8.3 
Participant demographics/other baseline characteristics ........................................ 87 
8.4 
Efficacy .................................................................................................................. 88 
8.4.1 
Tumor imaging assessments .................................................................. 88 
8.4.2 
Appropriateness of efficacy assessments ............................................... 92 
8.4.3 
Overall Survival ..................................................................................... 92 
8.5 
Safety ..................................................................................................................... 93 
8.5.1 
Laboratory evaluations .......................................................................... 94 
8.5.2 
Electrocardiogram (ECG)...................................................................... 96 
8.5.3 
Pregnancy and assessments of fertility .................................................. 97 
8.5.4 
Appropriateness of safety measurements .............................................. 98 
8.6 
Additional assessments .......................................................................................... 98 
8.6.1 
Clinical Outcome Assessments (COAs) ................................................ 98 
8.6.2 
Pharmacokinetics ................................................................................. 100 


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8.6.3 
Biomarkers .......................................................................................... 101 
9 
Discontinuation and completion ...................................................................................... 105 
9.1 
Discontinuation from study treatment and from study ........................................ 105 
9.1.1 
Discontinuation from study treatment ................................................. 105 
9.1.2 
Discontinuation from study ................................................................. 106 
9.1.3 
Lost to follow-up ................................................................................. 106 
9.2 
Withdrawal of informed consent/Opposition to use data/biological samples ..... 107 
9.3 
Study completion and post-study treatment ......................................................... 108 
9.3.1 
Follow-up for safety evaluations ......................................................... 108 
9.3.2 
Efficacy follow-up and PROs .............................................................. 109 
9.3.3 
Survival follow-up ............................................................................... 109 
9.4 
Early study termination by the sponsor ................................................................ 109 
10 Safety monitoring, reporting and committees .................................................................. 110 
10.1 
Definition of adverse events and reporting requirements .................................... 110 
10.1.1 
Adverse events ..................................................................................... 110 
10.1.2 
Serious adverse events ......................................................................... 112 
10.1.3 
SAE reporting ...................................................................................... 113 
10.1.4 
Pregnancy reporting ............................................................................. 114 
10.1.5 
Reporting of study treatment errors including misuse/abuse ............... 114 
10.2 
Additional Safety Monitoring .............................................................................. 115 
10.3 
Committees .......................................................................................................... 115 
10.3.1 
Steering Committee ............................................................................. 115 
11 Data Collection and Database management ..................................................................... 115 
11.1 
Data collection ..................................................................................................... 115 
11.2 
Database management and quality control .......................................................... 116 
11.3 
Site monitoring ..................................................................................................... 116 
12 Data analysis and statistical methods ............................................................................... 117 
12.1 
Analysis sets ......................................................................................................... 117 
12.1.1 
Full analysis set ................................................................................... 117 
12.1.2 
Full analysis set – brain metastases ..................................................... 118 
12.1.3 
Safety set ............................................................................................. 118 
12.1.4 
Pharmacokinetic analysis set ............................................................... 118 
12.2 
Participant demographics and other baseline characteristics ............................... 118 
12.3 
Treatments ............................................................................................................ 118 
12.4 
Primary endpoint(s)/estimand(s) analysis ............................................................ 119 
12.4.1 
Definition of primary endpoint(s) ........................................................ 119 


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12.4.2 
Statistical model, hypothesis, and method of analysis ........................ 119 
12.4.3 
Handling of intercurrent events of primary estimand .......................... 119 
12.4.4 
Handling of missing values not related to intercurrent events ............. 120 
12.4.5 
Sensitivity analyses ............................................................................. 120 
12.4.6 
Supplementary analysis ....................................................................... 120 
12.5 
Secondary endpoint(s)/estimand(s) analysis ........................................................ 121 
12.5.1 
Efficacy endpoints ............................................................................... 121 
12.5.2 
Safety endpoints .................................................................................. 124 
12.5.3 
Pharmacokinetics ................................................................................. 126 
12.5.4 
Patient reported outcomes ................................................................... 127 
12.6 
Analysis of exploratory endpoints ....................................................................... 128 
12.7 
Interim analyses ................................................................................................... 128 
12.8 
Sample size calculation ........................................................................................ 128 
12.8.1 
Primary endpoint(s) ............................................................................. 128 
12.8.2 
Secondary endpoint(s) ......................................................................... 128 
13 Ethical considerations and administrative procedures ..................................................... 129 
13.1 
Regulatory and ethical compliance ...................................................................... 129 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................ 129 
13.3 
Publication of study protocol and results ............................................................. 129 
13.4 
Quality Control and Quality Assurance ............................................................... 130 
14 Protocol adherence ........................................................................................................... 130 
14.1 
Protocol amendments ........................................................................................... 130 
15 References ........................................................................................................................ 131 
16 Appendices ....................................................................................................................... 136 
16.1 
Appendix 1: Guidelines for Response, Duration of Overall Response, TTF, 
TTP, Progression-Free Survival, and Overall Survival (based on RECIST 1.1) 136 
16.1.1 
Introduction ......................................................................................... 138 
16.1.2 
Efficacy assessments ........................................................................... 138 
16.1.3 
Efficacy definitions .............................................................................. 147 
16.1.4 
Data handling and programming rules ................................................ 157 
16.1.5 
References (available upon request) .................................................... 161 
16.2 
Appendix 2: Guidelines for Response Assessment in Neuro-oncology 
(RANO) for Brain Metastases (BM) .................................................................... 162 
16.2.1 
Introduction ......................................................................................... 164 
16.2.2 
Efficacy assessments ........................................................................... 164 
16.2.3 
Efficacy definitions .............................................................................. 173 
16.2.4 
References ........................................................................................... 178 


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16.3 
Appendix 3: List of concomitant medications that require caution or are 
prohibited for patients on capmatinib .................................................................. 179 
 
List of tables 
Table 2-1 
Objectives and related endpoints ........................................................... 35 
Table 4-1 
Rationale for study design ..................................................................... 41 
Table 6-1 
Investigational and control drug ............................................................ 50 
Table 6-2 
Dose reduction steps for capmatinib ..................................................... 59 
Table 6-3 
Criteria for dose reduction / interruption and re-initiation / 
permanent discontinuation of capmatinib treatment for adverse 
drug reactions ........................................................................................ 59 
Table 6-4 
Follow-up evaluations for selected toxicities ........................................ 64 
Table 6-5 
Clinical and diagnostic assessments for LFT abnormalities .................. 69 
Table 6-6 
Dose and treatment schedule ................................................................. 72 
Table 8-1 
Allowable window for participant assessments ..................................... 75 
Table 8-2 
Assessment schedule for capmatinib and docetaxel arms ..................... 76 
Table 8-3 
Assessment schedule for crossover participants .................................... 82 
Table 8-4 
Imaging Assessment Collection Plan .................................................... 89 
Table 8-5 
Physical Assessments ............................................................................ 93 
Table 8-6 
ECOG Performance Status .................................................................... 94 
Table 8-7 
Central clinical laboratory parameters collection plan .......................... 94 
Table 8-8 
Local ECG collection plan .................................................................... 96 
Table 8-9 
Pharmacokinetic blood collection log for capmatinib ......................... 100 
Table 8-10 
Biomarker sample collection plan ....................................................... 103 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ........................................................................................ 115 
Table 16-1 
Response criteria for target lesions ..................................................... 143 
Table 16-2 
Response criteria for non-target lesions .............................................. 145 
Table 16-3 
Overall lesion response at each assessment ......................................... 146 
Table 16-4 
Overall lesion response at each assessment: patients with non- 
target disease only ............................................................................... 154 
Table 16-5 
Options for event dates used in PFS, TTP, DOR ................................. 155 
Table 16-6 
Response assessment of target lesions ................................................ 168 
Table 16-7 
Response assessment of non-target lesions ......................................... 169 
Table 16-8 
Overall Lesion Response at each assessment ...................................... 170 
Table 16-9 
CNS and non-CNS response assessment ............................................. 173 
Table 16-10 
Overall Lesion Response at each assessment: Participant with only 
non-target disease at baseline .............................................................. 176 


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Table 16-11 
Medications that require caution when concomitantly used with 
capmatinib ........................................................................................... 179 
Table 16-12 
Capmatinib: prohibited drugs .............................................................. 180 
List of figures 
Figure 3-1 
Study design .......................................................................................... 39 


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List of abbreviations 
 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AIDS 
Acquired Immunodeficiency Syndrome 
AJCC 
American Joint Committee on Cancer 
ALK 
Anaplastic Lymphoma Kinase 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANA 
Antinuclear Antibodies 
ANC 
Absolute Neutrophil Count 
ART 
Anti-Retroviral Treatment 
ASMA 
Anti-Smooth Muscle Antibody 
AST 
Aspartate Aminotransferase 
ATP 
Adenosine Triphosphate 
AUC 
Area under curve 
AUCinf 
Area under the plasma (serum, or blood) concentration versus time curve from time zero to 
infinity 
b.i.d. 
bis in die/twice a day 
BAL 
Bronchoalveolar Lavage 
BCG 
Bacille Calmette-Guerin 
BCRP 
Breast Cancer Resistance Protein 
BIRC 
Blinded Independent Review Committee 
BOIR 
Best Overall Intracranial Response 
BOR 
Best Overall Response 
BRAF 
v-raf murine sarcoma viral oncogene homolog B1 
BSC 
Best Supportive Care 
BUN 
Blood Urea Nitrogen 
C1D1 
Cycle 1 Day 1 
CDNa 
Complementary Deoxyribonucleic Acid 
CI 
Confidence Interval 
CO 
Country Organization 
COA 
Clinical Outcome Assessment 
COVID-19 
Coronavirus Disease 2019 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum (peak) concentration of drug in plasma 
CMO&PS 
Chief Medical Office and Patient Safety 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
CO 
Country Organization 
CR 
Complete Response 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria Adverse Event 


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CV 
Coefficient of Variation 
CYP1A2 
Cytochrome P450 1A2 
CYP3A 
Cytochrome P450 3A 
DBP 
Diastolic Blood Pressure 
DCR 
Disease Control Rate 
DDE 
Direct Data Entry 
DDI 
Drug-Drug Interaction 
DIDB 
Drug Interaction Database 
DILI 
Drug-Induced Liver Injury 
DLCO 
Diffusing capacity of the Lungs for Carbon monoxide 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DOIR 
Duration Of Intracranial Response 
DOR 
Duration of Response 
EBV 
Epstein-Barr Virus 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EGFR 
Epidermal Growth Factor Receptor 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End Of Treatment 
EQ-5D-5L 
EuroQoL-5 Dimension-5 Level 
ERCP 
Endoscopic retrograde cholangiopancreatography 
eSource 
Electronic Source 
ET 
Extension Treatment 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose- Positron Emission Tomography 
FFPE 
Formalin Fixed Paraffin Embedded 
FPFV 
First Patient First Visit 
FSH 
Follicle Stimulating Hormone 
FUP 
Follow-Up Period 
G-CSF 
Granulocyte Colony-Stimulating Factor 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyl transferase 
GI 
Gastrointestinal 
GLDH 
Glutamate dehydrogenase 
GM-CSF 
Granulocyte-Macrophage Colony-Stimulating Factor 
HAV 
Hepatitis A Virus 
HBsAg 
Hepatitis B virus surface antigen 
HBV 
Hepatitis B Virus 


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HCV 
Hepatitis C Virus 
HEV 
Hepatitis E Virus 
HER2 
Human Epidermal growth factor Receptor 2 
Hgb 
Hemoglobin 
HGF 
Hepatocyte Growth Factor 
HIV 
Human immunodeficiency virus 
hr 
Hour 
HR 
Hazard Ratio 
HRQoL 
Health-Related Quality of Life 
HSV 
Herpes Simplex Virus 
i.v. 
intravenous 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use 
ID 
Identity 
IDCR 
Intracranial disease control rate 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
ILD 
Interstitial Lung Disease 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IO 
Immuno-Oncology 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
KM 
Kaplan-Meier 
KRAS 
Kirsten rat sarcoma viral oncogene homolog 
LFT 
Liver Function Test 
LLN 
Lower Limit of Normal 
LLOQ 
Lower Limit of Quantification 
LPLV 
Last Patient Last Visit 
MAP 
Managed Access Program 
MATE 
Multidrug And Toxin Extrusion 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical dictionary for regulatory activities 
METΔex14 
MET exon 14 skipping 
MET 
Mesenchymal Epithelial Transition factor 
MRI 
Magnetic Resonance Imaging 
NCCN 
National Comprehensive Cancer Network 
 
 
NSCLC 
Non-Small Cell Lung Cancer 
NTI 
Narrow Therapeutic Index 
NTKR 
Neurotrophic Tyrosine Kinase Receptor 


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OIRR 
Overall intracranial response rate 
ORR 
Overall Response Rate 
OS 
Overall Survival 
P-gp 
Permeability-GlycoProtein 
PAS 
Pharmacokinetic Analysis Set 
PD 
Progressive Disease 
PD-1 
Programmed cell Death protein 1 
PD-L1 
Programmed Death-Ligand 1 
PFS 
Progression-Free Survival 
 
 
PFT 
Pulmonary Function Test 
PK 
Pharmacokinetic(s) 
PLT 
Platelet 
PR 
Partial Response 
PRO 
Patient Reported Outcomes 
PS 
Performance Status 
PT 
Prothrombin Time 
QLQ 
Quality of Life Questionnaire 
QMS 
Quality Management System 
QoL 
Quality of Life 
QTcF 
QT interval corrected by Fridericia’s formula 
R value 
ALT/ALP x ULN 
RANO-BM 
Response Assessment in Neuro-Oncology Brain Metastases 
RANKL 
Receptor Activator of Nuclear factor Kappa-Β Ligand 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RET 
Rearranged during transfection 
RNA 
Ribonucleic Acid 
ROS1 
c-ros oncogene 1 
RP2D 
Recommended phase two dose 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SC 
Steering Committee 
SD 
Stable Disease 
SoC 
Standard of Care 
SOP 
Standard Operating Procedures 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBIL 
Total Bilirubin 
TKIs 
Tyrosine Kinase Inhibitors 
TSH 
Thyroid Stimulating Hormone 
TTE 
Time To Event 
TTIR 
Time To Intracranial Response 
TTR 
Time To Response 
Ty21a 
Live-attenuated TY2 strain of Salmonella Typhi 


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ULN 
Upper Limit of Normal 
US 
United States 
VAS 
Visual Analogue Scale 
VATS 
Video-assisted thoracic surgery 
WHS 
White coat Syndrome 
WoC 
Withdrawal of Consent 
wt 
Wildtype 


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Glossary of terms 
 
Additional treatment 
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. any background 
therapy) 
Assessment 
A procedure used to generate data required by the study 
Clinical Outcome 
Assessment (COA) 
A measure that describes or reflects how a participant feels, functions, or 
survives 
Clinical trial team 
A group of people responsible for the planning, execution and reporting of all 
clinical trial activities. Examples of team members include the Study Lead, 
Medical Monitor, Trial Statistician, etc 
Coded Data 
Personal Data which has been de-identified by the investigative center team by 
replacing personal identifiers with a code 
Cohort 
A group of individuals who share a common exposure, experience or 
characteristic, or a group of individuals followed-up or traced over time 
Control drug 
A study intervention (active or placebo) used as a comparator to reduce 
assessment bias, preserve blinding of investigational drug, assess internal 
study validity, and/or evaluate comparative effects of the investigational drug 
Cycles 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g. q21 days) 
Discontinuation from study 
Point/time when the participant permanently stops receiving the study 
treatment and further protocol required assessments or follow-up, for any 
reason. No specific request is made to stop the use of their samples or data. 
Discontinuation from study 
treatment 
Point/time when the participant permanently stops receiving the study 
treatment for any reason (prior to the planned completion of study intervention 
administration, if any). Participant agrees to the other protocol required 
assessments including follow-up. No specific request is made to stop the use 
of their samples or data. 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day) 
Electronic Data Capture 
(EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection systems, such as Web-based applications, interactive 
voice response systems and clinical laboratory interfaces. EDC includes the 
use of Electronic Case Report Forms (eCRFs) which are used to capture data 
transcribed from paper source forms used at the point of care 
End of the study 
The end of the clinical trial is defined as the last visit of the last participant or at 
a later point in time as defined by the protocol 
Enrollment 
Point/time of participant entry into the study at which main informed consent 
must be obtained. The action of enrolling one or more participants. 
eSource (DDE) 
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and case report forms (eCRFs) into one application, 
allowing for the real time collection of clinical trial information to Novartis and 
other oversight authorities, as appropriate 
Estimand 
As defined in the ICH E9(R1) addendum, an estimand is a precise description 
of the treatment effect reflecting the clinical question posed by the trial 
objective. It summarizes at a population-level what the outcomes would be in 
the same participants under different treatment conditions being compared. 
Attributes of an estimand include the population, variable (or endpoint) and 
treatment of interest, as well as the specification of how the remaining 
intercurrent events are addressed and a population-level summary for the 
variable. 
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation or 
the existence of the measurements associated with the clinical question of 
interest. 


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Investigational drug/ 
treatment 
The drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of medication kits 
Mis-randomized participants 
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy) 
Participant 
A trial participant (can be a healthy volunteer or a patient). "Participant" 
terminology is used in the protocol whereas term "Subject" is used in data 
collection. 
Participant number 
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc. 
Patient-Reported Outcome 
(PRO) 
A measurement based on a report that comes directly from the participant 
about the status of a participant's health condition without amendment or 
interpretation of the participant's report by a clinician or anyone else 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis 
Personal data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples. 
Randomization 
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the 
assignments in order to reduce bias. 
Randomization number 
A unique identifier assigned to each randomized participant 
Rescreening 
If a participant fails the initial screening and is considered as a Screen Failure, 
he/she can be invited once for a new Screening visit after medical judgment 
and as specified by the protocol 
Remote 
Describes any trial activities performed at a location that is not the investigative 
site 
Screen Failure 
A participant who did not meet one or more criteria that were required for 
participation in the study 
Source Data/Document 
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has 
spread from the original site to other parts of the body 
Start of the study 
The start of the study is defined as the signature of the informed consent by the 
first participant 
Study treatment 
Any drug or combination of drugs or intervention administered to the study 
participants as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy 
Study treatment 
discontinuation 
When the participant permanently stops taking any of the study drug(s) prior to 
the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation 
Treatment arm/group 
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts. 
Variable (or endpoint) 
The variable (or endpoint) to be obtained for each participant that is required to 
address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event. 


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Withdrawal of consent 
Withdrawal of consent from the study occurs when the participant explicitly 
requests to stop use of their data and/or biological samples AND no longer 
wishes to receive study treatment AND does not agree to further protocol 
required assessments. This request should be in writing (depending on local 
regulations) and recorded in the source documentation. 
This request should be distinguished from a request to discontinue the study. 
Other study participant’s privacy rights are described in the corresponding 
informed consent form. 


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Amendment 2 (24-Feb-2022) 
Amendment rationale 
As of the release date of this amendment, 21 participants have been randomized in this study. 
This amendment addresses the following revisions: 
• MET mutation status: to allow also local results from a validated test according to local 
regulation and documented as part of the participant’s medical record, to be used for 
participant eligibility. 
• SAE reporting: immediate reporting clarified to align with Health Authority (especially with 
Federal Institute for Drugs and Medical Devices (BfArM)) requirements. 
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: 
• List of abbreviations 
• Relevant abbreviations were added or updated. 
• Glossary of terms 
• Relevant terms were added or updated. 
• Protocol summary 
• Updated to reflect the changes made in this protocol amendment. 
• Section 1.1 Background 
• Update of new molecular targets as oncogenic drivers 
• New references added. 
• Section 1.1.1.1 Non-clinical experience 
• New reference added. 
• Section 1.1.1.2 Clinical experience 
• Data from latest [capmatinib Investigator’s Brochure] V.13 included. 
• Information on co-administered MATE substrate exposure added. 
• Section 2 Objectives, endpoints and estimands 
• Secondary objective related to the characterization the pharmacokinetics of capmatinib 
in this study population updated to specify that it will be assessed by plasma 
concentrations at specific time points only. 
• Secondary objective related to the assessment of the effect of capmatinib versus 
docetaxel on patient-reported disease-related symptoms, functioning, and health- 
related quality of life (HRQoL) updated to clarify that time to symptom deterioration 
will be analyzed by treatment group for chest pain, cough and dyspnea scores per QLQ- 
LC13 as well as global health status/QoL per QLQ-C30 questionnaire but not per EQ- 
5D-5L. 


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• Section 3 Study design 
• Sentence added to specify that additional participants may be randomized to support 
the analysis of the second supplementary estimand. 
• Clarification added that all participants will enter in survival follow-up following the 
completion of all study assessments (as applicable). 
• Figure 3-1 study design updated to move the METΔex14 mutation status into the Study 
population / Eligibility box. Patient reworded to participant to align with standard 
language. Extension (E1) typo corrected to Extension (ET). 
• Pre-screening: sentence added to clarify that all participants must sign the molecular 
pre-screening ICF, regardless of if they have a local METΔex14 mutation positive 
result or if they will be submitting a tumor sample for central pre-screening by the 
Novartis-designated laboratory for determination of their METΔex14 mutation status. 
• Survival Follow-up: sentence corrected to clarify that after study treatment 
discontinuation or post-treatment follow-up phase discontinuation (as applicable), 
participant will enter in survival follow-up, irrespective of reasons of discontinuations. 
• Section 4.1 Rationale for study design 
• Clarification added that the study will enroll participants with locally 
advanced/metastatic NSCLC, which are EGFR wt for EGFR mutations that predict 
sensitivity to EGFR therapy, including, but not limited to exon 19 deletions and exon 
21 L858R substitution mutations. 
• Participants must be docetaxel naive and candidates for single agent chemotherapy 
(docetaxel) and progressed on or after the last therapy before study entry. Participants 
with other druggable targetable oncogenic drivers such as BRAF, ROS1, RET, NTRK 
and KRAS will be excluded. 
• Section 4.5 Risks and benefits 
• Paragraph on investigational risk included. 
• Section 4.5.2 Docetaxel 
• Section updated as per latest docetaxel SmPC dated 17-Apr-2020. 
• Section 5.1 Inclusion criteria 
• Inclusion criteria 4: updated to allow MET∆ex14 mutation assessment per a locally 
performed, tissue-based test which is validated according to local regulation, from a 
Clinical Laboratory Improvement Amendments (CLIA)-certified US laboratory or an 
accredited local laboratory outside of the US. The positive MET∆ex14 mutation result 
as determined per local test must be documented in the participant’s source documents 
and in the CRF prior to entering main screening. 
• Inclusion criteria 5: updated to clarify that the tumor tissue sample must be provided 
with sufficient quality (as defined in the study [laboratory manual]) to allow the 
assessment of MET∆ex14 mutation status. The provision of the tumor tissue sample is 


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mandatory for all participants, including those who have a MET∆ex14 mutation result 
from a local test. 
• Inclusion criteria 6: updated to clarify that participants must be docetaxel naive and 
participants must have progressed on or after the last therapy before study entry to be 
eligible. 
• Inclusion criteria 12: new criteria added for participants to have a life expectancy of at 
least 3 months to align with the program standard language. 
• Section 5.2 Exclusion criteria 
• Exclusion criteria 5: list of examples of druggable molecular alterations updated. 
• Exclusion criteria 15: updated to include HIV participants only when the disease is 
under control, the suppressed viral loads as defined by local guidelines and on 
established anti-retroviral treatment (ART) for at least four weeks prior to enrollment 
• Exclusion criteria 18: separation of the definition of post-menopausal women and 
women of no child-bearing potential for more clarity. 
• Exclusion criteria 20: new exclusion criteria added to include requirement for specific 
timing of receiving a live vaccine prior to starting study treatment. 
• Section 6.1.2 Additional study treatments 
• Sentence added to confirm that no other treatment beyond investigational drug 
(capmatinib) and control drug (docetaxel) are included in this trial. 
• Docetaxel administration information removed from this section as already available in 
Section 6.7.2.2. 
• Section 6.1.5.2 Crossover to capmatinib therapy 
• Clarification added that for participants who discontinue docetaxel for reasons other 
than BIRC confirmed disease progression (such as treatment intolerance, AEs…), 
safety and efficacy tumor assessments and PROs collection must continue to be 
performed while waiting to confirm crossover eligibility. 
• Clarification added that participants who crossover from the docetaxel arm to 
capmatinib will have imaging assessments performed according to local practice and 
institutional guidelines; the disease progression on capmatinib treatment in ET will be 
determined based on investigator assessment only. When these participants 
permanently discontinue treatment with capmatinib, they must complete the ET-EOT 
visit and all these participants will then be followed for safety until 30 days after the 
last dose of capmatinib. 
• Section 6.2.1 Concomitant therapy 
• During the entire duration of the study no anticancer therapies other than the study 
medication should be given to participants with the exception of radiation as allowed 
per protocol. 
• Section 6.2.2 Prohibited medication 
• Live vaccines (including Coronavirus Disease 2019 (COVID-19) live vaccine) added 
to the list of prohibited medication. 
• Section 6.5.3.1 Follow-up on potential drug-induced liver injury cases 
• Testing of Glutamate Dehydrogenase (GLDH) changed from required to recommended. 


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• Section 6.7 Preparation and dispensation 
• Updated to mention that during a public health emergency as declared by local or 
regional authorities, i.e. pandemic, epidemic or natural disaster that limits or prevents 
on-site study visits, each capmatinib shipment/provisioning of will be for a maximum 
of 3-month supply. 
• Section 6.7.1.1 Handling of study treatment 
• Sentence added to clarify that the investigator must provide accountability also for 
locally sourced materials used for administration (e.g. i.v. bags). 
• Sentence added to allow flexibility for return or destruction of unused drug at sites. 
• Section 7 Informed consent procedures 
• Updated to clarify that information about common side effects already known about the 
investigational treatment should be discussed with the participant upon obtaining 
consent and also during the study as needed. 
• Section 8 Visit schedule and assessments 
• Table 8-1 Allowable window for participant assessments corrected: windows allowed 
for PROs assessments is within 3 days prior to the visit during the treatment and until 
progression and ±7 days of the visit for EOT and post-progression timepoints. 
• Clarification added that participants who discontinue from study treatment are to return 
for the end of treatment visit as soon as possible, and attend the follow-up visits as 
indicated in the Assessment Schedule. 
• Clarification added that participants who discontinue from study or withdraw their 
consent/oppose the use of their data/biological samples should be scheduled for a final 
evaluation visit if they agree. 
• Table 8-2 Assessment schedule split into 2 separate tables for more clarity: Table 8-2 
for all participants from pre-screening to survival and Table 8-3 for docetaxel 
participants who crossover to capmatinib arm. Collection of PD-L1 status as per 
participant’s record added in Table 8-2. Due to the split of the assessment schedule into 
2 tables, all subsequent table numbers in Section 8 have been updated. 
• Section 8.1 Molecular pre-screening 
• Section updated to allow MET∆ex14 mutation assessment per a locally performed, 
tissue-based test which is validated according to local regulation or per Novartis- 
designated central laboratory test. 
• Clarification added related to tumor sample requirement for METΔex14 testing. The 
quality/quantity of tumor samples will be determined at the Novartis-designated central 
laboratory. Tumor samples must contain at least 10% tumor content and the minimum 
effective tumor area specified in the study [laboratory manual]. 
• Clarification added on the purpose of blood sample collected at pre-screening: potential 
development of liquid biopsy in vitro diagnostic test(s), such as companion diagnostic. 
• Clarification added on tumor requirement in case of ALK testing not available locally. 
• Clarification added on the purpose to retain remaining tissue from all participants: 
potential development of in vitro diagnostic test(s), such as companion diagnostic 
test(s). 


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• Section 8.2 Screening 
• Sentence about central confirmation of MET∆ex14 mutation to be completed prior to 
randomization for all participants removed. 
• Section 8.2.2 Information to be collected on screening failures 
• Collection of PD-L1 status as per participant’s record added to the information to be 
collected on screening failures. 
• Section 8.3 Participant demographics/other baseline characteristics 
• Collection of baseline PD-L1 tumor status added to data to be collected on participant 
characteristics at screening. 
• Section 8.4.1 Tumor imaging assessments 
• Clarifications on data transmitted to the imaging CRO via baseline clinical form and 
cytology form were added. 
• Section 8.4.1.3 Confirmation of disease progression by BIRC 
• Sentence added to clarify that for participants who crossed-over from the docetaxel arm 
to capmatinib arm, capmatinib will count as next-line of therapy. 
• Section 8.4.3 Overall Survival 
• Updated to clarify that all participants will enter the survival follow-up period once 
they complete all study assessments per protocol, as applicable. 
• Section 8.5.1 Laboratory evaluations 
• Sentence added to specify that during a public health emergency as declared by local 
or regional authorities, that limits or prevents on-site study visits, if participants cannot 
visit the site for protocol -specified safety lab assessments, an alternative lab (local) 
collection site may be used. 
• Section 8.6.1 Clinical Outcome Assessments (COAs) 
• Allowable window for participant assessments corrected: windows allowed for PROs 
assessments is within 3 days prior to the visit during the treatment and until progression 
and ±7 days of the visit for EOT and post-progression timepoints. 
• Collection of PROs during treatment and efficacy follow-up, as well as post- 
progression phase was better described. 
• Clarification added that for participants who discontinue docetaxel treatment and enter 
extension treatment, PROs will be collected only at 6, 12 and 18 weeks (±7 days) post- 
docetaxel treatment progression by telephone interview or by face to face interview in 
the event participant is at site to perform other assessments. There won’t be any 
possibility to collect data on electronic device. 
• Section 8.6.3.1 Biomarkers assessments in tumor 
• Clarification added that tumor samples must be provided with sufficient quality and 
quantity to allow the central assessment of MET mutation status for all participants and 
for potential development of in vitro diagnostic test(s), such as companion diagnostic 
test(s).
 
 
 


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• In addition, tumor samples must contain a minimum effective tumor area per slide as 
described in the study [laboratory manual] and as required for the central assessment of 
MET mutation status. Samples obtained from bone metastases and cytology samples 
are not acceptable. 
• Section 9.1.1 Discontinuation from study treatment 
• Discontinuation language updated as per protocol template V5.0. 
• Section 9.1.2 Discontinuation from study 
• New section added for clarity and language updated as per protocol template V5.0. 
• Section 9.2 Withdrawal of informed consent/Opposition to use date/biological samples 
• Withdrawal language updated as per protocol template V5.0. 
• Section 9.3.3 Survival follow-up 
• Updated to clarify that participants will enter the survival follow-up period once they 
complete the 30-day safety follow-up and/or efficacy follow-up (if applicable) after 
treatment discontinuation (whichever is longer) and the post-progression PRO follow- 
up. 
• Section 10.1.3 SAE reporting 
• Immediate reporting clarified and to align with Health Authority requirements and 
especially with Federal Institute for Drugs and Medical Devices (BfArM) requirements. 
• Section 10.1.4 Pregnancy reporting 
• Language regarding Pregnant Participants and Pregnant Partners modified for clarity. 
• Sentence added to clarify that after consent is provided, the pregnancy reporting will 
occur up to one year after the estimated date of delivery. 
• Section 10.1.2 Serious adverse events 
• Sentence added to clarify that all reports of intentional misuse and abuse of the product 
are also considered serious adverse events irrespective of whether a clinical event has 
occurred. 
• Section 10.3 Committees 
• New section created / sections reorganized for clarity. Added an overarching Level 2 
section header for the various study committees. 
• Section 10.1.5 Reporting of study treatment errors including misuse/abuse 
• Updated to clarify that study treatment errors and uses outside of what is foreseen in 
the protocol, misuse or abuse will be collected and reported in the safety database. 
• Section 12.4.3 Handling of intercurrent events of primary estimand 
• Sentence added to clarify that PFS will take into account all PFS events irrespective of 
the start of new anti-cancer therapy (treatment policy strategy). 
• Section 12.4.6 Supplementary analysis 
• Updated to include a further supplementary estimand with a target population of the 
subset of participants for whom the METΔex14 mutation was confirmed by the 
Novartis-designated central laboratory. 
• Section 12.5.1.1 Key secondary estimand/endpoint 


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• Updated to include a further supportive analysis: ORR by BIRC based on the subset of 
participants for whom the METΔex14 mutation was confirmed by the Novartis- 
designated central laboratory. 
• Section 12.5.4 Patient reported outcomes 
• Updated to specify that the distribution of time to symptom deterioration will be 
analyzed by treatment group for chest pain, cough and dyspnea scores per QLQ-LC13 
as well as global health status/QoL per QLQ-C30 questionnaire but not per EQ-5D-5L. 
• Section 12.8.1 Primary endpoint(s) 
• Section updated to align with the wording from the Statistical Analysis Plan (SAP) 
template with standard language for oncology. 
In a concern of homogenization, the wording RECIST 1.1-defined PD has been used 
consistently in the protocol. 
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 1 (16-Dec-2020) 
Amendment rationale 
As of the release date of this amendment, 1 patient has been randomized in this study. 
This amendment addresses the following revisions: 
• Collection of post-progression PROs in order to capture additional cancer related symptoms 
during this period 
• Addition of mitigation procedures to ensure participant safety and trial integrity in relevant 
sections, in the event of Public Event emergencies (e.g., COVID-19 pandemic) 
• The primary scientific question of interest and the primary estimand, especially the estimand 
attributes treatment, variable and intercurrent events, were rephrased to align with the 
capmatinib program protocol standard language 
• The objective to compare the overall response rate of capmatinib and docetaxel has been set 
as key secondary objective. This endpoint would support the assessment of clinical benefit 
and the interpretation of the primary endpoint results. 
• MET (and ALK, if applicable) testing while patient is still receiving anti-cancer therapy at 
pre-screening has been allowed to facilitate recruitment 
• Novartis guidelines on Response Assessment in Neuro-oncology (RANO) for Brain 
Metastases (BM) have been added as Appendix 2 to the protocol to support the secondary 
endpoint assessing intracranial anti-tumor activity of capmatinib in participants with Central 
Nervous System (CNS) lesions by BIRC. The definitions of time to intracranial response 
(TTIR) and duration of intracranial response (DOIR) have been updated accordingly. 
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: 
• List of abbreviations 
• Relevant abbreviations were added 
• Protocol summary 
• Secondary objective summary was updated to reflect changes to key secondary 
objectives and PRO endpoints 
• Section 2 Objectives and endpoints 
• The comparison of the overall response rates per RECIST 1.1 by BIRC of capmatinib 
and docetaxel were moved from a secondary endpoint to the key secondary endpoint 
• Secondary endpoints for Patient Reported Outcome was updated in Table 2-1 
• Section 2.1 Primary estimands 
• The primary scientific question of interest was rephrased to align with the internal 
capmatinib standard protocol language. 
• A justification for targeting the described treatment effect was added. 


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• The attributes of the primary estimand were revised to align with the internal 
capmatinib standard protocol language: 
• Treatment was clarified: treatment includes newly started antineoplastic therapy, 
if any 
• Variable was more precisely defined 
• Intercurrent events were updated (addition of study treatment discontinuation and 
unforeseen intercurrent events, removal of antineoplastic therapy) 
• The summary measure was clarified (removal of confidence interval and addition 
of the test for PFS) 
• Section 2.2 Secondary estimands 
• Scientific question of interest and estimand were formulated for the new key secondary 
endpoint 
• Section 3 Study design 
• Patient-reported outcome modality and duration of collection was updated 
• Section 4.5 Risks and benefits 
• Benefit-risk assessment in the event of a Public Health Emergency was added 
• Section 4.6 Rationale for Public Health Emergency mitigation procedures 
• This new section was added to describe rationale for Public Health Emergency 
mitigation procedures 
• Section 6.2.1.1 Permitted concomitant therapy requiring caution and/or action 
• Formatting was updated 
• “Drugs to be used with caution during coadministration with capmatinib” table was 
removed from this section and embedded in Section 16.3 Appendix 3 
• Section 6.2.1.2 Use of bisphosphonates or RANKL inhibitor 
• Guideline on use of receptor activator of nuclear factor kappa-B ligand (RANKL) 
inhibitor was added 
• Section 6.2.1.3 Permitted radiotherapy 
• Guideline on local bone radiotherapy was added 
• Section 6.2.2 Prohibited medication 
• “Capmatinib: prohibited drugs” table was removed and embedded in Section 16.3 
Appendix 3 
• Section 6.4 Treatment blinding 
• Measures to minimize the potential impact of knowledge of treatment assignment were 
described 
• Section 6.5.1 Dose modifications 
• Exceptions to grade 4 toxicities were defined 
• Grade 4 event was removed for fatigue/asthenia in Table 6-3 to align with CTCAE 
version 5.0 
• Section 6.5.3 Follow-up for toxicities 
• The term “asymptomatic” was removed from the event Amylase or lipase ≥ CTCAE 
grade 3 in Table 6-4 


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• Section 6.7 Preparation and dispensation 
• A paragraph was added to describe home delivery of study drug in the event of a Public 
Health emergency 
• Section 7 Informed consent procedures 
• Home Nursing consent was added, if applicable 
• A paragraph was added to describe alternative methods of conducting informed consent 
discussion in the event of a Public Health emergency 
• Section 8 Visit schedule and assessments 
• A paragraph was added to describe alternatives to on-site visits in the event of a Public 
Health emergency 
• Table 8-2 Assessment schedule was updated: 
• Pregnancy test (urine) was deleted at C1D1 and ET-C1D1 to ensure consistency 
with Section 8.5.3 
• PROs collection was removed from the Extension Treatment period and added to 
the Survival Follow Up period at three time points (6, 12 and 18 weeks post- 
progression) 
• The term “food administration” was replaced by “food consumption” and collection 
for capmatinib arm only was specified. Footnote was added to clarify the 
information on food consumption to be collected. 
• PK blood collection was updated to clarify collection for capmatinib arm only 
• Section 8.1 Molecular pre-screening 
• A paragraph was added to allow MET (and ALK, if applicable) testing while patient is 
still receiving anti-cancer therapy at pre-screening 
• Section 8.2.2 Information to be collected on screening failures 
• A sentence that was repeated by mistake was deleted 
• Section 8.4.1 Tumor imaging assessments 
• Reference to Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) 
criteria was updated to reflect the inclusion of the guideline in the amendment as 
Appendix 2 
• A paragraph was added to describe collection of images in the event of a Public Health 
emergency 
• Section 8.5 Safety 
• A paragraph was added to describe safety monitoring in the event of a Public Health 
emergency 
• Section 8.5.3 Pregnancy and assessments of fertility 
• A paragraph was added to describe alternatives to on-site pregnancy testing in the event 
of a Public Health emergency 
• Section 8.6.1 Clinical Outcome Assessments (COAs) 
• Collection of PROs during treatment and efficacy follow-up was better described 
• Collection of PROs during post-progression period was added and time points were 
defined 
• A paragraph was added to describe alternative methods of PROs collection in the event 
of a Public Health emergency 


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• Section 8.6.3.2 Biomarker assessments in blood 
• Table 8-9 Biomarker sample collection plan was updated 
 
 
 
• Section 9.2.1 Follow-up for safety evaluations 
• 30-day safety follow-up for participants who transfer to another Novartis clinical study 
or Novartis treatment setting was clarified 
• Section 12.1.4 Pharmacokinetic analysis set 
• It was clarified that concentration measurements need to be evaluable for steady state 
• Section 12.4.2 Statistical model, hypothesis, and method of analysis 
• A sentence that was repeated was deleted 
• Section 12.4.3 Handling of remaining intercurrent events of primary estimand 
• Language about discontinuation of study treatment for any reason before a PFS event 
was updated 
• Language about unforeseen intercurrent events (e.g., related to a Public Health 
emergency like the COVID-19 pandemic) was added 
• Start of new anti-cancer therapy was deleted as intercurrent event 
• Section 12.4.6 Supplementary analysis 
• A paragraph to define a supplementary estimand was added to analyze the randomized 
treatment without any antineoplastic therapy post randomization 
• Section 12.5 Analysis of secondary endpoints/estimands 
• Section title was updated 
• Section 12.5.1 Efficacy endpoints 
• The section was split into two subsections. The first subsection describes the analysis 
for the key secondary efficacy endpoint, ORR by BIRC assessment, and includes a 
supportive analysis of ORR by investigator assessment. The second subsection contains 
the analyses for the other secondary endpoints as before. 
• In the definition of duration of response it was clarified that death means death due to 
any cause 
• For the endpoints DOIR and TTIR the event definition was changed to take into 
consideration death due to any cause to align with an updated version of the RANO- 
BM guideline (Appendix 2). The censoring of DOIR for death due to other causes than 
intracranial was deleted. 
• Section 12.5.2 Safety endpoints 
• A paragraph that was repeated by mistake was deleted 
• Section 12.5.4 Patient reported outcomes 
• An analysis of time to deterioration of symptom scores was added 
• Section 12.8.2 Secondary endpoint(s) 
• This section was added to estimate the power for key secondary endpoint for the chosen 
sample size 
• Section 15 References 


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• Two new references were added 
• Section 16.2 Appendix 2: Guidelines for Response Assessment in Neuro-oncology (RANO) 
for Brain Metastases (BM) 
• The Guidelines for RANO-BM was embedded to the protocol as Appendix. 
• Section 16.3 Appendix 3: List of concomitant medications for patients on capmatinib 
• This appendix was added to summarize medications that require caution when used with 
capmatinib and prohibited drugs 
• A footnote related to the dose change required for certain permitted concomitant 
therapies requiring caution when concomitantly used with capmatinib was added 
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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Protocol summary 
 
Protocol number 
CINC280A2301 
Full Title 
A phase III, randomized, controlled, open-label, multicenter, global study of capmatinib 
versus SoC docetaxel chemotherapy in previously treated patients with EGFR wt, ALK 
negative, locally advanced or metastatic (stage IIIB/IIIC or IV) NSCLC harboring MET 
exon 14 skipping mutation (MET∆ex14) 
Brief title 
Study of efficacy of capmatinib in comparison with standard of care docetaxel as a 
second or third line therapy in participants with non-small cell lung cancers harboring 
MET exon 14 skipping mutation. 
Sponsor and 
Clinical Phase 
Novartis, Phase III 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
To date, no approved therapy for advanced MET mutated non-small cell lung cancer 
(NSCLC) pre-treated with one or two prior lines of systemic therapy exists. Capmatinib 
is an orally bioavailable, highly potent and selective MET inhibitor in biochemical and 
cellular assays and capable of blocking MET activation. Clinical data demonstrate that 
capmatinib monotherapy has anti-tumor activity in EGFR wt NSCLC harboring MET 
mutation. Safety data demonstrate that capmatinib is well tolerated by the target 
population at the dose of 400 mg b.i.d. (tablet). 
Primary 
Objective(s) 
The primary objective of this study is to compare the efficacy of capmatinib versus 
docetaxel by comparing progression-free survival (PFS) by blinded independent review 
committee (BIRC) according to Response Evaluation Criteria In Solid Tumors (RECIST) 
1.1 between treatment arms. 
The primary clinical question of interest is: what is the relative effect of the two 
treatment strategies in prolonging time to radiological progression by BIRC per RECIST 
1.1 or death due to any cause in locally advanced or metastatic NSCLC harboring MET 
exon 14 skipping mutation, regardless of study treatment discontinuation or start of new 
antineoplastic therapy? 
Secondary 
Objectives 
Key secondary 
• To compare the overall response rates (ORR) per RECIST 1.1 by BIRC of capmatinib 
and docetaxel 
Secondary 
• To assess the antitumor activity of capmatinib versus docetaxel by evaluating 
duration of response, time to response and disease control rate by both BIRC and 
investigator according to RECIST 1.1 in both treatment arms and by evaluating ORR 
and PFS by investigator according to RECIST 1.1 in both treatment groups 
• To evaluate overall survival in participants treated with capmatinib versus docetaxel 
• To evaluate the safety profile of capmatinib versus docetaxel based on the incidence 
of adverse events and serious adverse events, change in vital signs, laboratory 
results and ECG in both treatment arms 
• To characterize the pharmacokinetics (PK) of capmatinib in this study population by 
assessing plasma concentrations at specific time points. 
• To assess the effect of capmatinib versus docetaxel on patient-reported disease- 
related symptoms, functioning, and health-related quality of life by evaluating the 
change from baseline in European Organization for Research and Treatment of 
Cancer (EORTC) QLQ-LC13, QLQ-C30, EuroQoL-5 Dimension-5 Level/EQ-5D-5L) 
questionnaires and time to symptom deterioration for chest pain, cough and dyspnea 
in the European Organization for Research and Treatment of Cancer (EORTC) QLQ- 
LC13 as well as global health status/QoL per QLQ-C30 questionnaire in both 
treatment groups 
• To assess intracranial anti-tumor activity of capmatinib and docetaxel in participants 
with Central Nervous System (CNS) lesions at baseline by BIRC by evaluating overall 
intracranial response rate, duration of intracranial response, time to intracranial 


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response, intracranial disease control rate by BIRC as per RANO-BM criteria in both 
treatment arms. 
Study design 
This is a multicenter, open-label, randomized, active-controlled, global phase III study 
that will enroll adult participants with EGFR wt, ALK rearrangement negative, NSCLC 
harboring METΔex14 skipping mutations who have progressed on one or two prior lines 
of systemic therapy for locally advanced or metastatic stage and are candidates for 
docetaxel. 
The study will randomize approximately 90 participants globally. Participants eligible for 
the study will be randomized in a 2:1 ratio to one of the two treatment arms: capmatinib 
(investigational therapy) or docetaxel. 
The randomization will be stratified by prior lines of systemic therapy received for 
advanced/metastatic disease (one line vs. two lines). 
Participants randomized to docetaxel treatment will be eligible to crossover to receive 
capmatinib treatment after BIRC-confirmed, RECIST 1.1-defined progressive disease 
(PD) and after meeting the eligibility criteria prior to crossover. 
For all participants, the respective treatment (either with capmatinib or docetaxel) may 
be continued beyond initial disease progression as per RECIST 1.1 (as assessed by 
the investigator and confirmed by BIRC) if, in the judgment of the investigator, there is 
evidence of clinical benefit, and the participant wishes to continue on the study 
treatment. 
After treatment discontinuation, all participants will be followed for safety evaluations 
during the safety follow-up period, and the participant’s status will be collected every 12 
weeks as part of the survival follow-up. 
Study population 
This study will randomize approximately 90 participants, male and female, aged 18 or 
older, with EGFR wt, ALK rearrangement negative, advanced (stage IIIB, IIIC or IV) 
NSCLC harboring METΔex14 mutations and who have progressed on one or two prior 
lines of systemic therapy for advanced/metastatic disease. 
Key Inclusion 
criteria 
• Stage IIIB/IIIC (not amenable to surgery, radiation or multi modality therapy) or IV 
NSCLC at the time of study entry. 
• Histologically or cytologically confirmed diagnosis of NSCLC that is EGFR wt (for 
EGFR mutations that predict sensitivity to EGFR therapy, including, but not limited 
to exon 19 deletions and exon 21 L858R substitution mutations), ALK 
rearrangement negative as assessed by a validated test as part of the participant’s 
standard of care and has MET∆ex14 mutation determined by Novartis-designated 
central laboratory or by a locally performed, tissue-based test, validated according 
to local regulation. 
• At least one measurable lesion as defined by RECIST 1.1. 
• Participants must have progressed on one or two prior lines of systemic therapy for 
advanced/metastatic disease (stage IIIB/IIIC [not candidates for surgery, radiation 
or multi modality therapy] or IV NSCLC) and must be docetaxel naive and be 
candidates for single agent chemotherapy (docetaxel). Participants must have 
progressed on or after the last therapy before study entry 
• ECOG performance status of 0 or 1. 
Key Exclusion 
criteria 
• Prior treatment with any MET inhibitor or HGF-targeting therapy 
• Participants with known druggable molecular alterations (such as ROS1 and RET 
rearrangements, BRAF mutation, KRAS mutation, NTRK fusions, etc.) which might 
be a candidate for alternative targeted therapies. 
• 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). 
• Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome. 
• Clinically significant, uncontrolled heart diseases 
Study treatment 
Capmatinib (INC280) or docetaxel 


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Efficacy 
assessments 
• Tumor assessment by RECIST 1.1 performed every 6 weeks (i.e. every 2 cycles) 
until disease progression as assessed by the investigator and confirmed by BIRC. 
• CNS lesions assessed by BIRC based on Response Assessment in Neuro- 
Oncology Brain Metastases (RANO-BM) criteria. 
• Survival status collected every 12 weeks regardless of treatment discontinuation 
reason (except if consent is withdrawn or participant is lost to follow-up) until death, 
lost to follow-up, or withdrawal of consent for survival follow-up. 
Pharmacokinetic 
assessments 
Capmatinib PK will be assessed in participants who receive capmatinib treatment at the 
following time points: 
• 
Cycle 1 Day 15 
• 
Cycle 3 Day 1 
Key safety 
assessments 
• Laboratory assessments, including hematology, chemistry, urinalysis, coagulation, 
hepatitis markers, HIV testing where locally required, pregnancy testing (for women 
of child-bearing potential) 
• Physical examination 
• Vital signs and body weight 
• Electrocardiogram (ECG) 
• Collection of Adverse Events (AE) and Serious Adverse Events (SAE) 
Other 
assessments 
• Patient Reported Outcomes (PRO): EORTC QLQ-C30, EORTC QLQ-LC13 and 
EQ-5D-5L 
Data analysis 
The primary objective is to evaluate whether capmatinib prolongs PFS by BIRC 
according to RECIST 1.1 compared to docetaxel. 
The following null and alternative hypothesis will be tested to address the primary 
efficacy objective: 
H01: θ1 ≥ 1 vs. HA1: θ1 < 1 
where θ1 is the PFS hazard ratio (capmatinib versus docetaxel). The primary efficacy 
analysis to test these hypotheses and compare the two treatment groups will consist of 
the stratified log-rank test at an overall one-sided 2.5% significance level. 
The stratification will be based on the stratification factor assigned at randomization, i.e. 
the number of prior lines of systemic therapy (one line vs. two lines). The analysis will 
be performed on the Full Analysis Set. 
PFS will be summarized using the Kaplan-Meier method. Median PFS, with 
corresponding 95% CI, and 25th and 75th percentiles will be presented by treatment 
group. The hazard ratio for PFS will be estimated, along with its 95% confidence 
interval, using a stratified Cox proportional hazard model using the same stratification 
factor as for the log-rank test. 
Refer to Section 2.1 for the definition of the primary estimand and to Sections 12.4.1 to 
Section 12.4.6 for details on censoring, intercurrent events, as well as sensitivity and 
supplementary analyses for the primary efficacy endpoint. 
The analyses for secondary objectives are detailed in Section 12.5. 
Key words 
Capmatinib, MET, NSCLC, INC280, docetaxel 


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1 
Introduction 
1.1 
Background 
Lung cancer is the most common cancer type worldwide, with an estimated 2.1 million new 
cases in 2018, representing 11.6% of all new cancers. It is also the most common cause of death 
from cancer, with 1.8 million deaths representing 18.4% of the total deaths from cancer 
(Bray et al 2018). In 2019, approximately 142,670 deaths due to lung cancer are expected in the 
United States (US) (Siegel et al 2019) and 280,000 in the European Union (Malvezzi et al 2019). 
Non-small cell lung cancer (NSCLC) accounts for more than 85% of all lung cancer cases, and 
it includes two major types: (1) non-squamous carcinoma (including adenocarcinoma, large- 
cell carcinoma, other cell types); and (2) squamous cell (epidermoid) carcinoma. 
Adenocarcinoma is the most common type accounting 50% of NSCLC and is also the most 
frequently occurring cell type in non-smokers (Subramanian and Govindan 2007, 
Perez-Moreno et al 2012, Novello et al 2016). 
Mechanisms of oncogenesis in lung cancer have been largely deciphered over the past 20 years. 
The concept of “oncogene addiction” refers to tumor-cell dependence on the specific activity 
of an activated or overexpressed oncogene. The main oncogenic drivers in the field of thoracic 
oncology are mutations of EGFR, and ALK rearrangements. They are most often reported in 
adenocarcinomas. However, new molecular targets have been highlighted recently: e.g. MET, 
KRAS, BRAF, HER2, PIK3CA mutations, translocations, such as ROS1 and RET, NTRK 
fusions, etc. Therapeutic strategies have been designed to inhibit these signaling pathways, 
among which are monoclonal antibodies and tyrosine-kinase inhibitors (TKIs). 
Treatment options for patients with advanced NSCLC with no established and druggable 
molecular driver (e.g. ALK gene rearrangements, ROS1 rearrangements, sensitizing EGFR 
mutations and BRAF V600E point mutations) are based on immunotherapy (immuno-oncology 
[IO]), either as monotherapy or in combination with platinum doublets in the first line setting, 
as well as monotherapy options for patients who progressed to platinum based chemotherapy 
(Planchard et al 2018, NCCN Guidelines Version 1, 2022). Alternatively, systemic 
chemotherapy without the addition of IO is an option for patients not eligible for single agent 
or combination IO therapy (Scagliotti et al 2014, Malhotra et al 2017). Single agent 
chemotherapy remains an established treatment option for pre-treated NSCLC patients. 
Docetaxel monotherapy is approved for all histologic subtypes and has served as a control arm 
for several prospective, randomized trials in second- or third-line settings (Borghaei et al 2015, 
Brahmer et al 2015, Herbst et al 2016, Rittmeyer et al 2017). For docetaxel, please refer to 
Section 4.3 and local prescribing information. Moreover, in some countries also ramucirumab, 
a VEGF receptor antibody, and nintedanib, an anti-angiogenic multi-TKI, are approved for 
second and further line treatment in combination with docetaxel. 
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. Patients often have limited response to third-line therapy, although it 
may have some palliative effect (Shepherd et al 2005, de Marinis and Grossi 2008, 
Eccles et al 2011, Besse et al 2014, Reck et al 2014, Novello et al 2016). 


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MET is a receptor tyrosine kinase involved in embryogenesis, organogenesis and tissue damage 
repair (Birchmeier and Gherardi 1998, Birchmeier et al 2003). MET-pathway dysregulation 
through receptor overexpression, genomic amplification, mutations, autocrine or paracrine 
secretion of its ligand (Hepatic Growth Factor–HGF) has been shown to be oncogenic, 
promoting cell-cell detachment and metastasis, epithelial-mesenchymal transition, invasion, 
angiogenesis, proliferation and survival (Christensen et al 2005). Awad and colleagues showed 
that MET mutation is a negative prognostic factor in advanced NSCLC patients (n=61): 40% 
of the patients included in this retrospective study had brain metastases and median OS (from 
stage IV diagnosis) was 8.1 months and was shorter (5.2 months) when MET amplification and 
mutation were concurrent (Awad et al 2019). MET mutations leading to exon 14 deletion 
(referred to as MET mutation(s) or METΔex14 mutations hereafter) have been identified as an 
additional actionable target for MET inhibition in NSCLC (Kong-Beltran et al 2006). The loss 
of exon 14 deletes the region of the protein required for the CblE3 ligase to bind to MET and 
target it for degradation. This results in extended MET occupancy at the membrane and 
ultimately activation of the receptor. Based on the epidemiology data currently available, MET 
mutations can be detected in 2-4% of NSCLC with adenocarcinoma histology and in ~1% of 
NSCLC with other histologies; notably no overlap between MET mutations and either EGFR 
mutations or ALK translocation is expected (TCGA Research Network 2014, Awad et al 2016, 
Ou et al 2016, Tong et al 2016). Promising efficacy data have also been seen in patients with 
MET mutated NSCLC treated with MET inhibitors, including capmatinib (Frampton et al 2015, 
Jenkins et al 2015, Liu et al 2015, Mendenhall and Goldman 2015, Paik et al 2015, 
Waqar et al 2015, Drilon 2016, Schuler et al 2016, Awad et al 2019, Wolf et al 2019, 
Wolf et al 2020, Paik et al 2020). 
1.1.1 
Overview of capmatinib (INC280) 
Capmatinib (INC280) is a small adenosine triphosphate (ATP) competitive, orally bioavailable, 
highly potent, and selective reversible inhibitor of the MET receptor tyrosine kinase 
(Liu et al 2011, Baltschukat et al 2019). 
1.1.1.1 
Non-clinical experience 
Capmatinib possesses potent inhibitory activity against the MET kinase in vitro [inhibitory 
concentration IC50 = 0.6 nM], and is highly specific for MET with approximately 1,000 times 
or greater selectivity when compared to more than 400 other kinases or mutant kinase variants 
(Fujino et al 2019, Baltschukat et al 2019). Potent activity of blocking MET activation has been 
observed in cell-based biochemical and functional assays that measure MET-mediated signal 
transduction, as well as MET-dependent cell proliferation, survival, and migration. 
In MET–dependent, mouse tumor models (including lung cancer models), capmatinib exhibits 
dose-dependent antitumor activity and causes tumor regression at well-tolerated doses that 
exceeded IC90 coverage (Liu et al 2011). Importantly, plasma levels of capmatinib correlate 
with both the dose administered and the extent of tumor growth inhibition in vivo. 
In MET/HGF-driven tumor models grown as xenografts in mice, oral dosing of capmatinib 
demonstrated significant in vivo activity in blocking both MET phosphorylation and tumor 
growth. Activation of MET in such responsive models is either due to strong MET 


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overexpression (mostly because of gene amplification, e.g. in gastric or hepatocellular 
carcinoma) or HGF secretion resulting in an autocrine loop (e.g. in glioblastoma). 
For further details, please refer to the latest version of the [capmatinib Investigator’s Brochure]. 
1.1.1.2 
Clinical experience 
Capmatinib has been extensively tested in both healthy volunteers and cancer patients. As of 
the safety cut-off date of 28-Sep-2021, 863 participants with solid tumors have been treated 
with capmatinib as a single agent, 810 participants have received capmatinib in combination 
with other therapies and 1246 patients have received capmatinib under Managed Access 
Program (MAP). The recommended phase II dose (RP2D) for capmatinib as a single agent has 
been determined to be 400 mg b.i.d. in tablet formulation [capmatinib Investigator’s Brochure]. 
The most frequent AEs suspected to be related to capmatinib of any grade reported in study 
[CINC280A2201], reference study for the safety profile of capmatinib monotherapy (n=373), 
across study cohorts and irrespective of MET mutational status, were edema peripheral (46.1%), 
nausea (34.3%), blood creatinine increased (19.8%), vomiting (19.0%), fatigue (13.7%), 
decreased appetite (12.6%) and diarrhea (10.7%); the majority were Grade 1/2. 
The Grade 3/4 AEs suspected to be related to capmatinib in the [CINC280A2201] study 
included edema peripheral (8.8%), alanine aminotransferase increased (5.6%), lipase increased 
(5.6%), amylase increased (3.2%), fatigue (2.7%), aspartate aminotransferase increased (2.4%), 
vomiting (1.9%), nausea (1.6%), decreased appetite (0.8%), asthenia (0.8%), constipation 
(0.5%), rash (0.3%) and diarrhea (0.3%) [capmatinib Investigator’s Brochure]. 
Efficacy data for capmatinib single agent in previously treated patients with locally advanced 
or metastatic NSCLC harboring MET 14 exon skipping mutation have been reported in the 
Cohort 4 (2nd/3rd line) and Cohort 6 (2nd line) of phase II GEOMETRY 1 study 
[CINC280A2201]. As of 18-Sep-2020, the ORR by BIRC (95% CI) was 40.6% (28.9, 53.1) for 
Cohort 4 (n=69) and 51.6% (33.1, 69.8) for Cohort 6 patients (n=31) using Response Evaluation 
Criteria In Solid Tumors (RECIST) 1.1. Evaluable patients were defined as those with at least 
one post-baseline tumor assessment or have discontinued treatment at the time of the data cut- 
off. The median DOR (95% CI) by BIRC was 9.72 (5.55, 12.98) months for Cohort 4 patients, 
and 8.38 months (4.17, NE) months for Cohort 6 patients. The median PFS by BIRC (95% CI) 
was 5.42 (4.17, 6.97) months for Cohort 4 patients and 6.93 months (4.17, 13.34) for Cohort 6 
patients. Median OS (95% CI) was 13.57 months (8.61, 22.24) for Cohort 4 patients and not 
reached for Cohort 6 patients. 
Moreover, in a post-hoc analysis, a promising intracranial activity with capmatinib was 
observed in patients with brain metastases based on medical review of central neuroradiologic 
assessment of brain lesions. Of the 28 evaluable patients by BIRC with NSCLC and MET exon 
14 skipping mutation who had brain lesions at baseline and at least one post-baseline tumor 
assessment, 16 subjects showed intracranial lesion shrinkage (9/16 patients had complete 
disappearance of intracranial lesions) and 25 subjects had an intracranial disease control. 
Capmatinib received breakthrough therapy designation for treatment of treatment-naive and 
pre-treated NSCLC patients with METΔex14 mutations from the US Food and Drug 
Administration (FDA). FDA also granted an orphan drug designation to capmatinib for 
treatment of patients with MET dysregulated NSCLC. Subsequently, capmatinib received 


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approval in US, Japan, Switzerland and several other countries for the treatment of adult patients 
with metastatic NSCLC whose tumors have a mutation that leads to MET exon 14 skipping. A 
companion diagnostic approval in tumor and plasma was also granted in US and Japan. 
Capmatinib is rapidly absorbed after oral administration with a median time to reach maximum 
drug concentration (Tmax) ranging from 1 to 2 hours for tablets. The elimination half-life 
estimated from study [CINC280X1101] ranged from 3.5 to 6.3 hours across the cohorts. Steady 
state is achieved by day 3 of 400 mg twice daily dosing. Accumulation in capmatinib exposure 
following repeated administration of 400 mg b.i.d. tablets is low, with geometric mean 
accumulation ratio of 1.39-fold in the single agent [CINC280A2201] study. The mean plasma 
exposure increase is roughly dose proportional for capmatinib tablet from 200 to 400 mg b.i.d. 
Capmatinib may be administered with or without food. The PK and safety of capmatinib 
administered with food has been evaluated in cancer patients in study [CINC280A2108]. No 
significant difference in exposure was seen when capmatinib was given under fasted conditions 
or with food. The safety profile was similar to that of study [CINC280A2201], with no 
dose-limiting toxicities (DLTs) observed. 
Capmatinib is a moderate cytochrome P450 enzyme 1A2 (CYP1A2) inhibitor [CINC280A2103] 
and an inhibitor of P-glycoprotein (P-gp) and breast Cancer Resistance Protein (BCRP) 
transporter [CINC280A2105]. Therefore, CYP1A2 substrates, P-gp substrates, and BCRP 
substrates where minimal concentration changes may lead to serious adverse reactions should 
be avoided. If coadministration is unavoidable, decrease the dosage of CYP1A2 substrates, P- 
gp substrates, or BCRP substrates in accordance with the approved prescribing information. 
Capmatinib is a moderate inhibitor of multidrug and toxic compound extrusion (MATE). Based 
on static DDI risk assessment with Cmax,ss,u/Ki =3, capmatinib is likely a MATE inhibitor at 
therapeutic concentration. Transient serum creatinine increase following capmatinib 
administration in contrast to no change in serum cystatin C level indirectly suggest that the 
transient increase of serum creatinine level may result from reversible inhibition of active renal 
transporters, in this case, likely MATE1 and MATE2K. However, the likely increase in co- 
administered MATE substrate exposure will not lead to safety concern with the following 
evidence: Based on in vitro data from the Drug Interaction Database (DIDB) 
(httpsdidb.druginteractionsolutions.org/) from the University of Washington, MATE inhibitors, 
cimetidine, pyrimethamine, trimethoprim and ondansetron, all have I unbound/Ki >3.2 (range 
from 3.2 to 6.3), greater than the I/Ki value for capmatinib. Yet, the corresponding exposure 
(Cmax or AUC) change in MATE substrates (e.g. metformin, lamivudine and varenicline) when 
co-administered with these MATE inhibitors is unlikely to cause safety concern as identified 
MATE substrates are not narrow therapeutic index drugs (except topotecan, which will not be 
a concomitant medication for capmatinib). 
When coadministered with the strong CYP3A inhibitor itraconazole, capmatinib AUC 
increased by approximately 42% without any change in Cmax. When coadministered with the 
strong CYP3A inducer rifampicin, capmatinib AUC and Cmax decreased by 67% and 56%, 
respectively [CINC280A2102]. Hence, adverse reactions during coadministration of 
capmatinib with strong CYP3A inhibitors should be closely monitored. In addition, strong 
CYP3A inducers should be avoided in participants treated with capmatinib. 
For further details, please refer to the latest version of the [capmatinib Investigator’s Brochure]. 


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1.2 
Purpose 
The rationale for investigating the anti-cancer activity of capmatinib in this study population of 
advanced MET mutated NSCLC pre-treated with one or two prior lines of systemic therapy is 
supported by the following: 
• These patients represent a high unmet medical need as MET dysregulation is considered a 
poor prognostic factor (Dimou et al 2014, Guo et al 2014, Landi et al 2017, Awad et al 2019) 
and to date there are limited treatment options for NSCLC with MET mutation. 
• The evidence of efficacy of standard treatments (either chemotherapy or immunotherapy) 
in this setting is limited. Recent preliminary data showed that, similar to EGFR-mutated and 
ALK-translocated NSCLCs, patients with MET mutated NSCLC do not seem to benefit 
from treatment with immunotherapy (Sabari and Paik 2017, Awad et al 2019). 
• Capmatinib is highly potent in NSCLC in both in vitro and in vivo models [capmatinib 
Investigator’s Brochure]. 
• Clinical data demonstrate that capmatinib monotherapy has anti-tumor activity in EGFR wt 
NSCLC harboring MET mutation [CINC280A2201]. 
• Safety data demonstrate that capmatinib is well tolerated by the target population at the 
RP2D of 400 mg b.i.d. (tablet) [capmatinib Investigator’s Brochure]. 
 
2 
Objectives, endpoints and estimands 
Table 2-1 
Objectives and related endpoints 
 
Objectives 
Endpoints 
Primary objective 
Endpoint for primary objective 
To compare the efficacy of capmatinib versus 
docetaxel 
Progression-free survival (PFS) by BIRC as per 
RECIST 1.1 
See Section 2.1 for Primary Estimand. 
Key secondary objective 
Endpoints for Key secondary objective 
To compare the overall response rate (ORR) of 
capmatinib and docetaxel 
ORR calculated per RECIST 1.1 by BIRC. 
See Section 2.2 for Secondary Estimand. 
Secondary objectives 
Endpoints for secondary objectives 
To assess the antitumor activity of capmatinib versus 
docetaxel 
All calculated per RECIST 1.1, both by BIRC and 
investigator: 
• 
Duration of response (DOR) 
• 
Time to response (TTR) 
• 
Disease control rate (DCR) 
All calculated per RECIST 1.1, by investigator: 
• 
PFS, ORR 
To evaluate overall survival (OS) in participants 
treated with capmatinib versus docetaxel 
Overall survival 
To evaluate the safety profile of capmatinib versus 
docetaxel 
Incidence of adverse events and serious adverse 
events, change in vital signs, laboratory results and 
ECG 
To characterize the pharmacokinetics of capmatinib in 
this study population 
Plasma concentrations at specific time points. 


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Objectives 
Endpoints 
To assess the effect of capmatinib versus docetaxel 
on patient-reported disease-related symptoms, 
functioning, and health-related quality of life (HRQoL) 
• 
Change from baseline in European Organization 
for Research and Treatment of Cancer (EORTC) 
QLQ-LC13, QLQ-C30, EuroQoL-5 Dimension-5 
Level/EQ-5D-5L) questionnaires 
• 
Time to symptom deterioration for chest pain, 
cough and dyspnea in the European Organization 
for Research and Treatment of Cancer (EORTC) 
QLQ-LC13 as well as global health status/QoLper 
QLQ-C30 questionnaire 
To assess intracranial anti-tumor activity of 
capmatinib and docetaxel in participants with Central 
Nervous System (CNS) lesions at baseline by BIRC 
Overall intracranial response rate (OIRR), duration of 
intracranial response (DOIR), time to intracranial 
response (TTIR), intracranial disease control rate 
(IDCR) by BIRC as per RANO-BM criteria 
2.1 
Primary estimands 
The primary scientific question of interest is to estimate the treatment effect based on the 
primary endpoint of PFS for capmatinib compared to the control arm (docetaxel) for the target 
population regardless of study treatment discontinuation or start of new antineoplastic therapy. 
The justification for targeting this treatment effect is that it will help us to understand the 
treatment effect of capmatinib relative to docetaxel regardless of subsequent antineoplastic 
therapy and study treatment discontinuation, which resembles realistic clinical practice. 
The primary estimand is characterized by the following attributes: 
1. Population: adult participants with EGFR wt, ALK rearrangement negative, locally 
advanced or metastatic (stage IIIB/IIIC or IV) NSCLC harboring MET exon 14 skipping 
mutation. Further details on the population are provided in Section 5. 
2. Treatment: randomized treatment capmatinib versus docetaxel with or without any new 
post-treatment antineoplastic therapy as needed. Further details about the treatment are 
provided in Section 6. 
3. Variable: progression free survival (PFS) defined as the time from the date of randomization 
to the date of the first documented disease progression based on BIRC as per RECIST 1.1 
or date of death due to any cause, whichever occurs first. 
4. Intercurrent events: 


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• Discontinuation of study treatment for any reason before PFS event (radiological 
progression or death): 
PFS will take into account all PFS events irrespective of the study treatment 
discontinuation reasons (treatment policy strategy) 
• Any unforeseen intercurrent events (e.g., Coronavirus Disease 2019 (COVID-19) 
pandemic related events): 
PFS will take into account all PFS events irrespective of any unforeseen intercurrent 
events (treatment policy strategy) 
5. Summary measure: PFS hazard ratio (HR) between the two treatment arms (capmatinib 
versus docetaxel). It will be estimated using a Cox proportional hazard model stratified 
by the randomization stratification factor. PFS will be tested using the log-rank test 
stratified by the randomization stratification factor. 
2.2 
Secondary estimand 
The key secondary scientific question of interest is to estimate the treatment effect of capmatinib 
and compared to the control arm (docetaxel) based on ORR for the target population regardless 
of discontinuation of treatments and any unforeseen events resulting from a Public Health 
emergency (e.g. COVID-19). The secondary estimand is defined by the following attributes: 
1. Population: adult participants with EGFR wt, ALK rearrangement negative, locally 
advanced or metastatic (stage IIIB/IIIC or IV) NSCLC harboring MET exon 14 skipping 
mutation. Further details on the population are provided in Section 5. 
2. Treatment: randomized treatment capmatinib versus docetaxel. 
3. Variable: best overall response (BOR) defined as the best response recorded from the date 
of randomization until disease progression/recurrence (taking as reference for disease 
progression the smallest measurements recorded since the treatment started) based on BIRC 
per RECIST 1.1 with responses after the use of new anti-cancer therapy considered as non- 
response. 
4. Intercurrent events 
• Discontinuation of study treatment for any reason: BOR will take into account all 
response assessments irrespective of the study treatment discontinuation reasons 
(treatment policy strategy) 
• Any unforeseen intercurrent events (e.g. related to a Public Health emergency, like the 
COVID-19 pandemic) will be handled by the treatment policy strategy 
5. Summary measure: difference in ORR (defined as the proportion of participants with 
confirmed BOR of complete response or partial response based on BIRC per RECIST 1.1) 
of the two treatments and its 95% confidence interval based on the stratified Miettinen- 
Nurminen method (Miettinen and Nurminen 1985) with randomization strata weighting by 
sample size with a single treatment covariate. 


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3 
Study design 
This is a multicenter, open-label, randomized, active-controlled, global phase III study that will 
enroll adult participants with EGFR wt, ALK rearrangement negative, NSCLC harboring 
METΔex14 skipping mutations who have progressed on one or two prior lines of systemic 
therapy for locally advanced or metastatic stage and are candidates for docetaxel. 
The study will randomize approximately 90 participants globally. Participants eligible for the 
study will be randomized in a 2:1 ratio to one of the two treatment arms: capmatinib 
(investigational therapy) or docetaxel. Additional participants may be randomized to support 
the analysis of the second supplementary estimand (refer to Section 12.4.6). 
The randomization will be stratified by prior lines of systemic therapy received for 
advanced/metastatic disease (one line vs. two lines). 
Participants randomized to docetaxel treatment will be eligible to crossover to receive 
capmatinib treatment after blinded independent review committee (BIRC)-confirmed, RECIST 
1.1-defined progressive disease (PD) and after meeting the eligibility criteria outlined in 
Section 6.1.5.2. 
For all participants, the respective treatment (either with capmatinib or docetaxel) may be 
continued beyond initial disease progression as per RECIST 1.1 (as assessed by the investigator 
and confirmed by BIRC) if, in the judgment of the investigator, there is evidence of clinical 
benefit, and the participant wishes to continue on the study treatment (for additional details 
please refer to Section 6.1.5.1). 
After treatment discontinuation, all participants will be followed for safety evaluations during 
the safety follow-up period. Following completion of all study assessments (as applicable), the 
participant’s status will be collected every 12 weeks as part of the survival follow-up (for 
additional details please refer to Section 9). 
Refer to Figure 3-1 for an overview of the study design. 


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Figure 3-1 
Study design 
 
 
 
Pre-Screening 
Participants must sign a molecular pre-screening Informed Consent Form (ICF) prior to any 
study specific molecular pre-screening evaluations. All participants must sign the molecular 
pre-screening ICF, regardless of if they have a local METΔex14 mutation positive result or if 
they will be submitting a tumor sample for central pre-screening by the Novartis-designated 
laboratory for determination of their METΔex14 mutation status. 
Screening and Randomization 
Participants must sign the main Informed Consent Form (ICF) prior to any study specific 
screening evaluations and as early as 28 days prior to the randomization. 
Following completion of all required screening procedures (refer to Section 8.2) and verifying 
participant eligibility, the participant will be randomized via the Interactive Response 
Technology (IRT) system. 
Treatment 
Study treatment will begin on Cycle 1 Day 1 with the first administration of study treatment. 
Participants will continue treatment until reasons for discontinuation of study treatment are met 
(Section 9.1.1). 


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Participants will be evaluated radiologically at screening/baseline then every 6 weeks to assess 
treatment response until RECIST 1.1-defined PD as assessed by the investigator and confirmed 
by BIRC. 
An end of treatment (EOT) visit will be performed when participants permanently discontinue 
study treatment. 
Participants randomized to the docetaxel arm will be allowed to crossover to receive capmatinib 
therapy after BIRC-confirmed, RECIST 1.1-defined PD. Such participants must complete the 
EOT visit after permanent discontinuation of docetaxel. The subsequent ET-EOT visit will be 
performed for participants who crossover from the docetaxel arm to capmatinib when these 
participants permanently discontinue treatment with capmatinib. 
Post-Treatment Follow-Up (Safety, Efficacy and PRO Follow-Up) 
After treatment discontinuation, all participants will be followed for safety evaluations during 
the safety follow-up period as outlined in details in Section 6.5.2 and Section 9.3.1. Participants 
will be followed for safety up to 30 days after the last dose of study treatment. If a new 
antineoplastic therapy is initiated after end of study treatment, safety follow-up will focus on 
events suspected to be related to study treatment only. 
In addition to the 30-day safety follow-up, participants who discontinue study treatment without 
prior documented BIRC confirmed PD will continue efficacy assessments (Efficacy Follow-up) 
during the post-treatment follow-up until documented RECIST 1.1-defined PD as assessed by 
the investigator and confirmed by BIRC, participant withdrawal of consent, lost to follow-up, 
death or study is terminated by the sponsor as outlined in Section 9. For these participants, 
patient-reported outcomes will also continue to be collected (Efficacy and PRO Follow-up). 
Survival Follow-up 
After study treatment discontinuation or post-treatment follow-up phase discontinuation, as 
applicable, the participant’s survival status will be collected every 12 weeks (via phone calls) 
as part of the survival follow-up phase. 
Every effort should be made to comply with the survival follow-up schedule and ensure 
collection of participant survival. 
 
4 
Rationale 
4.1 
Rationale for study design 
The rationale for the study design is described in Table 4-1. 


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Table 4-1 
Rationale for study design 
 
Study Design Aspect 
Rationale 
Study population 
The study will enroll participants with locally advanced/metastatic 
NSCLC, which are EGFR wt (for EGFR mutations that predict 
sensitivity to EGFR therapy, including, but not limited to exon 19 
deletions and exon 21 L858R substitution mutations), ALK 
negative and harbor METΔex14 mutations, after failure of the first 
line treatment for the advanced stage. Participants must be 
docetaxel naive and candidates for single agent chemotherapy 
(docetaxel) and progressed on or after the last therapy before 
study entry. 
Participants with other druggable targetable oncogenic drivers 
(such as BRAF, ROS1, RET, NTRK, KRAS, etc.) will be 
excluded. For more details on participant population, please refer 
to Section 5. 
Comparator treatment 
Docetaxel was selected as the comparator treatment as it is a 
globally established standard of care in this pre-treated setting, 
irrespective of the histology and has been used as a comparator 
in many phase III studies in a similar setting. 
Open-label 
The trial is open-label for the following reasons: effective blinding 
could be difficult given the 1) difference in premedication 
requirements between the two arms, which would pose also an 
unnecessary burden for the participants and 2) varying toxicities 
between the study treatments 
Stratification factors 
Number of prior lines of therapy was chosen as a stratification 
factor due the expected difference in clinical outcome between 
participants based on the number of prior lines of therapy 
received. 
Randomization and 2:1 ratio 
Participants will be randomized with a 2:1 ratio, as the efficacy of 
standard therapies in this setting is currently unknown. 
Therefore, the randomization 2:1 increases the chances for 
participants to receive capmatinib, the innovative MET inhibitor, 
which exhibits meaningful clinical activity. 
Treatment beyond disease progression 
This is to ensure those participants (in either arm) who have 
disease progression per RECIST 1.1 as assessed by the 
investigator and confirmed by BIRC to continue study treatment, 
as long as they are clinically stable, tolerate the treatment, and 
are deriving clinical benefit. Timely follow-up after the initial PD 
will ensure that participants with confirmed/rapid progression will 
be discontinued and can initiate alternative therapies. 
Crossover 
The possibility to crossover increases the chances for 
participants treated with docetaxel to receive the innovative MET 
inhibitor capmatinib, which has shown meaningful clinical activity 
in this patient population of METΔex14 NSCLC. 
4.2 
Rationale for dose/regimen and duration of treatment 
Based on the PK and safety data, capmatinib 400 mg b.i.d. in tablet formulation has been 
declared the recommended phase II dose (RP2D) [CINC280X2102]. Furthermore, robust 
efficacy has been demonstrated in both 2/3L and 1L MET mutant NSCLC patients at this dose 
level [CINC280A2201]. In addition, sustained target coverage was expected at this dose as 96% 
of patients can maintain capmatinib plasma concentration above IC95 for MET inhibition during 
the dosing interval [Population PK report]. For further details, please refer to the latest version 
of the [capmatinib Investigator’s Brochure]. 


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In this study, duration of treatment is continuous until disease progression or other reasons for 
drug discontinuation. Treatment with capmatinib may be continued beyond RECIST 1.1- 
defined PD (as assessed by the investigator and confirmed by BIRC) if considered by the 
investigator to be in the best interest of the participant and as long as no new anticancer 
treatment is initiated. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Docetaxel is a global established treatment option for pre-treated NSCLC patients and has 
served as a control arm for several prospective, randomized trials in the second- or third-line 
setting including the most recent phase III studies with PD-1/PD-L1 inhibitors 
(Borghaei et al 2015, Brahmer et al 2015, Herbst et al 2016, Rittmeyer et al 2017), and it is 
approved for the use in NSCLC irrespective of tumor histology. The combination of 
nintendanib or ramucirumab with docetaxel is also one treatment option for fitting patients 
approved in some countries in the pre-treated NSCLC setting (Janning and Loges 2018). In the 
context of the post-platinum setting, a response rate of approximately 9-10%, median PFS of 2- 
4 months, and median OS of approximately 6-9 months is expected with docetaxel 
(Hanna et al 2004, Borghaei et al 2015, Brahmer et al 2015, Herbst et al 2016, 
Rittmeyer et al 2017). Overall, the reported response rates to second-line chemotherapy 
(including other single agent chemotherapeutics) have generally been less than 10%, with 
median PFS and OS generally below 3 and 8 months, respectively (de Marinis and Grossi 2008, 
Weiss and Stinchcombe 2013, NCCN 2020). 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. Patients often have limited 
response to third-line therapy, although it may have some palliative effect (Shepherd et al 2005, 
de Marinis and Grossi 2008, Eccles et al 2011, Besse et al 2014, Reck et al 2014, 
Novello et al 2016, NCCN 2020). While published data are still lacking, as no sub-analysis for 
MET dysregulated NSCLC have been conducted, poorer outcome is expected in the target 
population due to the negative prognostic impact of MET dysregulation (Dimou et al 2014, 
Guo et al 2014, Landi et al 2017, Awad et al 2019). 
We are expecting that the majority of participants enrolled in the study would have 
adenocarcinoma histology, generally treated with a pemetrexed platinum doublet as first line 
treatment. For those participants who progress, docetaxel would be considered a preferred 
option in the second line setting. 
4.4 
Purpose and timing of interim analyses/design adaptations 
Not applicable. 


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4.5 
Risks and benefits 
The participants enrolled in this study will have stage IIIB/IIIC or stage IV NSCLC. Given the 
clinical and molecular characteristics of METΔex14 mutated NSCLC, participants have fewer 
therapeutic options and the established standard of care has limited benefit in this study 
population. 
Capmatinib is one experimental treatment that has shown an acceptable safety profile and 
clinical meaningful activity in this population (please refer to Section 1.1). Participants enrolled 
in the current study will have the possibility of receiving a potentially efficacious treatment for 
a currently unmet medical need. For this reason, randomization ratio and crossover strategy 
were implemented accordingly to ameliorate patient access to the drug (please refer to 
Section 4.1). 
The protocol includes specific eligibility criteria (Section 5), monitoring visits and assessments, 
dose modification and stopping rules, and recommended guidelines for treatment of expected 
toxicities, including identification and management of study-drug induced adverse events. 
Recommended guidelines for prophylactic or supportive treatment of expected toxicities, 
including the management of study-drug induced AEs, (e.g. infusion reaction, pneumonitis) are 
provided in Section 6.5. 
The central METΔex14 skipping mutation test used for enrollment is investigational and how 
well the test performs to identify patients who are most likely to benefit from capmatinib or 
whether the benefits of capmatinib treatment will outweigh any potential serious side effects or 
risks from the use of the test has not been fully established. However, the test is sufficiently 
validated for the purposes of selecting participants with a MET Δex14 skipping mutation in 
their NSCLC tumor sample for enrollment to this study. 
The risk to participants in this trial will be minimized by compliance with the eligibility criteria 
and study procedures, as well as by close clinical monitoring and oversight. As with any clinical 
study, there may be unforeseen risks with the study treatment, which could be serious. The 
specific risks for each compound are discussed in Section 4.5.1 and Section 4.5.2. For further 
details, refer to the toxicity data provided in the [capmatinib Investigator’s Brochure] and in the 
docetaxel local prescribing information. 
As per Section 4.6, in the event of a public health emergency as declared by local or regional 
authorities i.e. pandemic, epidemic or natural disaster, the risk to participants can be mitigated 
by implementing as appropriate and as permitted by local authorities, the following measures 
(non-exhaustive list): study treatment shipment to participant’s homes, phone calls, virtual 
contacts, home nursing, remote safety monitoring, remote site monitoring. The impact of a 
public health emergency on the study data and participant safety will be assessed, if necessary, 
by collecting protocol deviations and planning additional safety analysis. 
Women of child-bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study and must agree that in order to participate in the study they must adhere to the 
contraception requirements outlined in the exclusion criteria. If there is any question that the 
participant will not reliably comply, they should not be entered or continue in the study. 


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Therefore, the overall safety risk to participants enrolled in this study is considered manageable, 
based on the available clinical safety data for both capmatinib and docetaxel, along with the 
eligibility criteria and monitoring measures implemented in this study. 
4.5.1 
Capmatinib 
Based upon the clinical experience with capmatinib to date, the overall risk-benefit assessment 
of capmatinib is considered favorable. The data from study [CINC280A2201] show that 
capmatinib is generally well tolerated and has a manageable safety profile. The safety profile 
in the METΔex14 mutated NSCLC population is consistent with the safety profile of 
capmatinib across multiple clinical studies. In the context of the significant clinical benefit 
observed for this study population with limited effective therapeutic options, the overall safety 
profile is acceptable, and the benefit/risk favorable (see Section 1.2). 
The most frequent safety findings on treatment with capmatinib monotherapy include peripheral 
edema, nausea, increased blood creatinine, vomiting, fatigue, decreased appetite, and diarrhea. 
In addition, pancreatic events (e.g. amylase and lipase increase), and changes in liver function 
test (LFT): alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) and/or 
bilirubin increase have been observed in participants treated with capmatinib. To date, a direct 
toxic effect of capmatinib on pancreas could not be identified. Caution is recommended when 
capmatinib is administered in combination with other drugs with a known risk of hepatotoxicity. 
Pneumonitis and Interstitial Lung Disease (ILD) have been reported from both capmatinib 
single agent and combination studies with EGFR TKIs, including events with fatal outcomes. 
Investigators are advised to carefully monitor participants for signs and symptoms of 
pneumonitis and implement dose modification and follow-up evaluations described in the 
protocol in all capmatinib studies, both single agent and in combination studies. 
Finally, capmatinib has shown photosensitization potential in in vitro and in vivo assays. The 
investigators should recommend the use of precautionary measures against ultraviolet exposure 
to the participants during treatment with capmatinib (e.g. use of sunscreen, protective clothing 
and avoid sunbathing or using a solarium intensively). 
For further information on potential toxicities and Drug-Drug Interaction (DDI), please refer to 
the current [capmatinib Investigator’s Brochure]. 
4.5.2 
Docetaxel 
Docetaxel as single agent is indicated for the treatment of patients with locally advanced or 
metastatic non-small cell lung cancer after failure of prior platinum chemotherapy. In this 
patient population, its safety and efficacy has been well established since its first approval in 
1996. The median survival was 9.0 months with docetaxel versus 4.6 months for best supportive 
care (BSC) (P = 0.016) (Fossella 2002). Quality-of-life analysis showed significant 
improvement in several disease-related symptoms in patients who received docetaxel. 
The very common adverse reactions to docetaxel are infections, neutropenia, anemia, 
thrombocytopenia, anorexia, peripheral sensory neuropathy, nausea, stomatitis, vomiting, 
diarrhea, alopecia, skin reaction, asthenia, fluid retention and pain. 


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The common adverse reactions to docetaxel are febrile neutropenia, hypersensitivity, peripheral 
motor neuropathy, arrhythmia, hypotension, constipation, nail disorders, myalgia and blood 
bilirubin increased. 
Tumor lysis syndrome (including fatal outcomes) and myositis have been reported from post- 
marketing setting with docetaxel (frequency not known). 
Docetaxel monotherapy is approved worldwide for the treatment of advanced NSCLC and is 
recognized as a standard of care. 
Please refer to the current local prescribing information for docetaxel in this disease setting. 
4.6 
Rationale for public health emergency mitigation procedures 
In the event of a public health emergency as declared by local or regional authorities (i.e. 
pandemic, epidemic or natural disaster), mitigation procedures may be required to ensure 
participant safety and trial integrity, and are listed in relevant sections of the study protocol. 
Notification of public health emergency should be discussed with Novartis prior to 
implementation of mitigation procedures, and permitted/approved by local or regional health 
authorities and ethics committees as appropriate. 
 
5 
Study Population 
This study will enroll adult male and female participants with EGFR wt, ALK rearrangement 
negative, advanced (stage IIIB, IIIC or IV) NSCLC harboring METΔex14 mutations and who 
have progressed on one or two prior lines of systemic therapy for advanced/metastatic disease. 
The study will randomize approximately 90 participants globally. Participants eligible for the 
study will be randomized in a 2:1 ratio to one of the two treatment arms: capmatinib 
(investigational therapy) or docetaxel. 
Participants enrolled in the study are not permitted to participate in additional, parallel, 
investigational drug or device studies. 
The investigator or designee must ensure that only participants who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study. 
2. Adult ≥ 18 years old at the time of informed consent. 
3. Stage IIIB/IIIC (not amenable to surgery, radiation or multi modality therapy) or IV NSCLC 
(according to Version 8 of the American Joint Committee on Cancer (AJCC) Staging 
Manual) at the time of study entry. 
4. Histologically or cytologically confirmed diagnosis of NSCLC that is: 
• EGFR wt. This should have been assessed as part of the participant’s standard of care 
by a validated test for EGFR mutations as per local guidelines. The EGFR wt status 
(for EGFR mutations that predict sensitivity to EGFR therapy, including, but not 
limited to exon 19 deletions and exon 21 L858R substitution mutations) must be 


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documented in the participant source documents before the participant can be consented 
for pre-screening for MET mutation status. Participants with NSCLC of pure squamous 
cell histology can enter pre-screening without EGFR mutation testing or result; 
however, participants with pure squamous cell histology who are known to have EGFR 
activating mutations will be excluded. 
• AND ALK rearrangement negative. This should have been assessed as part of the 
participant’s standard of care by a validated test. The ALK rearrangement negative 
status must be documented in the participant source documents before the participant 
can be consented for pre-screening for MET mutation status; if local ALK testing is not 
available at the time of molecular pre-screening, participant status will be determined 
centrally by Novartis. Participants with NSCLC of pure squamous cell histology can 
enter pre-screening without ALK testing or result, however participants with pure 
squamous cell histology that are known to have ALK rearrangement will be excluded. 
• AND has MET∆ex14 mutation as determined by Novartis-designated central 
laboratory or by locally performed, tissue-based test, validated according to local 
regulation, from a Clinical Laboratory Improvement Amendments (CLIA)-certified US 
laboratory or an accredited local laboratory outside of the US. The positive MET∆ex14 
mutation result as determined per local test must be documented in the participant’s 
source documents and in the CRF prior to entering main screening. 
5. Mandatory provision of a formalin-fixed, paraffin embedded tumor tissue sample (archival 
tumor block or slides, or a newly obtained tumor sample) with quality and quantity 
sufficient to allow assessment of MET∆ex14 mutation status (as defined in the study 
[laboratory manual]). This pertains to all participants, including those who have a 
MET∆ex14 mutation result from a local test. Tumor samples must contain at least 10% 
tumor content. 
6. Participants must have progressed on one or two prior lines of systemic therapy for 
advanced/metastatic disease (stage IIIB/IIIC [not candidates for surgery, radiation or multi- 
modality therapy] or IV NSCLC), and must be docetaxel naive and candidates for single 
agent chemotherapy (docetaxel). Treatment failure is defined as documented disease 
progression or intolerance to treatment, however participants must have progressed on or 
after the last therapy before study entry. Maintenance therapy given after first-line 
chemotherapy will be considered as part of the first-line if given to participants with 
documented response or stable disease before starting the maintenance therapy. 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 neoadjuvant or adjuvant systemic therapy. 
7. Participants must have recovered from all toxicities related to prior systemic therapies to 
grade ≤ 1 (CTCAE version 5.0). Participants with any grade of alopecia and vitiligo are 
allowed to enter the study. 
8. At least one measurable lesion as defined by RECIST 1.1. Any lesions which have been 
subjected to percutaneous therapies or radiotherapy should not be considered measurable, 
unless the lesion has clearly progressed since the procedure. 
9. Participants must have adequate organ function including the following laboratory values 
at the screening visit: 
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without growth factor support 


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• Platelets ≥ 100 x 109/L 
• Hemoglobin (Hgb) ≥ 9 g/dL 
• Calculated creatinine clearance (using Cockcroft-Gault formula) ≥ 45 mL/min 
• Total bilirubin (TBIL) ≤ ULN (upper limit of normal) 
• Aspartate transaminase (AST) ≤ 3 x ULN 
• Alanine transaminase (ALT) ≤ 3 x ULN 
• Asymptomatic serum amylase ≤ 5 x ULN (Grade 2). Participants with Grade 1 or Grade 
2 serum amylase at the beginning of the study must be confirmed to have no signs 
and/or symptoms suggesting pancreatitis or pancreatic injury (e.g. elevated P-amylase, 
abnormal imaging findings of pancreas, etc.) 
• Serum lipase ≤ ULN 
10. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1. 
11. Willing and able to comply with scheduled visits, treatment plan and laboratory tests. 
12. Participants must have a life expectancy of at least 3 months. 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Prior treatment with any MET inhibitor or HGF-targeting therapy. 
2. Participants with symptomatic central nervous system (CNS) metastases who are 
neurologically unstable or have required increasing doses of steroids within the 2 weeks 
prior to study entry to manage CNS symptoms. If participants are 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 Cycle 1 Day 1. 
3. Carcinomatous meningitis. 
4. 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: completely 
resected basal cell and squamous cell skin cancers, and completely resected carcinoma in 
situ of any type. 
5. Participants with known druggable molecular alterations (such as ROS1 and RET 
rearrangement, BRAF mutation, KRAS mutation, NTRK fusion, etc.) which might be a 
candidate for alternative targeted therapies. 
6. 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). 
7. Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome. 
8. Clinically significant, uncontrolled heart diseases such as: 
• Unstable angina within 6 months prior to screening 
• Myocardial infarction within 6 months prior to screening 
• History of documented congestive heart failure (New York Heart Association 
functional classification III-IV) 


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• Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg 
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without antihypertensive 
medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior 
to screening. If white coat syndrome (WHS) is suspected, blood pressure measurements 
may be repeated. 
• Ventricular arrhythmias 
• Supraventricular and nodal arrhythmias not controlled with medication 
• Other cardiac arrhythmia not controlled with medication 
• Fridericia QT correction formula (QTcF) ≥ 470 ms on the screening Electrocardiogram 
(ECG) (as mean of triplicate ECG) 
9. Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting Cycle 1 Day 1 or participants 
who have not recovered from radiotherapy-related toxicities. For all other anatomic sites 
(including radiotherapy to thoracic vertebrae and ribs), radiotherapy ≤ 2 weeks prior to 
Cycle 1 Day 1, or participants who have not recovered from radiotherapy-related toxicities. 
Palliative radiotherapy for bone lesions or radio-surgery for isolated brain lesions ≤ 2 weeks 
prior to Cycle 1 Day 1 is allowed. 
10. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior to 
starting study treatment (2 weeks for resection of brain metastases), or participants who 
have not recovered from the side effects of such procedure. Video-assisted thoracic surgery 
(VATS) and mediastinoscopy will not be counted as major surgery and participants can be 
enrolled in the study ≥1 week after the procedure. 
11. Participants receiving treatment with strong inducers of CYP3A and could not be 
discontinued ≥ 1 week prior to the start of treatment. 
12. Previous anti-cancer and investigational agents within 4 weeks or ≤ 5 x half-life of the agent 
(whichever is longer) before first dose of study treatment. If previous treatment is a 
monoclonal antibody, then the treatment must be discontinued at least 4 weeks before first 
dose of capmatinib. If previous treatment is an oral targeted agent, then the treatment must 
be discontinued at least 5 x half-life of the agent. 
13. Impairment of GI function or GI disease that may significantly alter the absorption of 
capmatinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or 
malabsorption syndrome). 
14. Unable or unwilling to swallow tablets as per dosing schedule. 
15. Substance abuse, active infection or other severe, acute, or chronic medical or psychotic 
conditions or laboratory abnormalities that in the opinion of the investigator may increase 
the risk associated with study participation, or that may interfere with the interpretation of 
study results. 
Active infections include but are not limited to Hepatitis B Virus (HBV), Hepatitis C Virus 
(HCV) and Human Immunodeficiency Virus (HIV). Screening for known chronic 
conditions is not required. Participants with known serologic evidence of chronic HBV or 
HCV infection, whose disease is controlled under antiviral therapy, according to local 
regulations are eligible. 
Participants with known history of testing positive for human immunodeficiency virus (HIV) 
infection, and with a history of acquired immunodeficiency syndrome (AIDS)-defining 


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opportunistic infections in the last 12 months prior to the first dose of study treatment must 
be excluded. HIV participants at high risk or with history of uncontrolled opportunistic 
infection must also be excluded. To ensure that effective anti-retroviral treatment (ART) is 
tolerated and that toxicities are not confused with investigational drug toxicities, trial 
participants should be on established ART for at least four weeks prior to enrollment, they 
should have the disease under control and suppressed viral loads defined as per local 
guideline. HIV participants co-infected with hepatitis virus must also be excluded. 
16. Participants with known hypersensitivity to docetaxel or intolerance to docetaxel excipients 
(as per local prescribing information), polysorbate 80, or to capmatinib and any of the 
excipients of capmatinib (crospovidone, mannitol, microcrystalline cellulose, povidone, 
sodium lauryl sulfate, magnesium stearate, colloidal silicon dioxide, and various coating 
premixes). 
17. Pregnant or nursing (lactating) women. 
18. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception. 
For female participants treated with capmatinib, highly effective contraception must be used 
during capmatinib treatment and for 7 days after stopping study treatment. 
For female participants treated with docetaxel, a highly effective contraception must be used 
during the study. Local prescribing information relating the time limits for such precautions 
and any additional restrictions will be followed. 
Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post- 
ovulation methods) and withdrawal are not acceptable methods of contraception. 
• Female bilateral tubal ligation, female sterilization (have had surgical bilateral 
oophorectomy with or without hysterectomy) or total hysterectomy at least six weeks 
before taking study treatment. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow-up hormone level 
assessment. 
• Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant. 
• Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), 
or other forms of hormonal contraception that have comparable efficacy (failure rate < 
1%), for example hormone vaginal ring or transdermal hormone contraception. 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
Women are considered post-menopausal if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate history 
of vasomotor symptoms). Women are considered not of child-bearing potential if they are 
post-menopausal or have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks prior to 
enrollment on study. In the case of oophorectomy alone, only when the reproductive status 


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of the woman has been confirmed by follow up hormone level assessment is she considered 
to be not of child-bearing potential. 
19. Sexually active males unless they use a condom during intercourse while taking capmatinib 
and for 7 days after stopping treatment and should not father a child in this period. For male 
participants treated with docetaxel, they should not father a child after the last dose of 
treatment for a period defined as per the local prescribing information. A condom is required 
for all sexually active male participants to prevent them from fathering a child AND to 
prevent delivery of study treatment via seminal fluid to their partner. In addition, male 
participants must not donate sperm for the time period specified above. 
If local regulations are more stringent than the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF. 
20. Participants who received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, 
oral polio, BCG, yellow fever, varicella, TY21a typhoid vaccines and COVID-19 vaccines) 
within 30 days prior to the first dose of study treatment. 
 
6 
Treatment 
6.1 
Study treatment 
For this study, the term "investigational or study drug" refers to Novartis study drug capmatinib. 
The comparator drug used in this study is docetaxel. "Study treatment" refers to either 
capmatinib or docetaxel. 
Capmatinib will be labelled and provided to sites by Novartis in compliance with legal 
requirements for each country. Docetaxel will be procured locally as it is commercially 
available in each participating country. 
The general dose and treatment schedule of the study treatments are listed in Table 6-6. 
6.1.1 
Investigational and control drugs 
The study treatment begins on Cycle 1 Day 1 with the first administration of either capmatinib 
or docetaxel. Cycle 1 Day 1 should occur on the day of randomization or no later than 3 days 
after randomization. 
All dosages prescribed and dispensed to the participant and all dose changes during the study 
must be recorded on the dosage administration eCRF. Refer to Section 6.7.2 for study treatment 
prescribing and administration information. 
Table 6-1 
Investigational and control drug 
 
Investigational/ Control 
Drug 
(Name and Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor 
(global or 
local) 
Capmatinib (INC280) 150 
mg or 200 mg 
Film-coated tablet 
Oral use 
Open-label participant 
specific; bottles 
Global 
Docetaxel (as per local 
product available) 
Concentrate for 
solution for infusion 
Intravenous use 
Open-label bulk 
supply; vials 
Local 


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6.1.2 
Additional study treatments 
No other treatment beyond investigational drug (capmatinib) and control drug (docetaxel) are 
included in this trial. 
6.1.3 
Treatment arms/group 
Participants will be randomized to one of the following two treatment arms/groups in a ratio of 
2:1 according to the stratification factor. 
Each treatment cycle is 21 days for both arms. 
• Arm 1: Capmatinib 
• Capmatinib 400 mg (tablets) orally twice daily (b.i.d.) with or without food 
• Capmatinib will be given as continuous daily dosing, and the first dose is administered 
at the study center 
• A complete cycle of treatment is defined as 21 days of continuous capmatinib treatment 
• Arm 2: Docetaxel (reference chemotherapy) 
• Docetaxel 75 mg/m2 intravenously (i.v.) following local guidelines as per standard of 
care and product labels (including steroid premedication) 
• Docetaxel will be administered every 21 days. First infusion day defines Cycle 1 Day 1 
6.1.4 
Guidelines for continuation of treatment 
Participant should continue to receive the study treatment until one or more criteria for treatment 
discontinuation described in Section 9.1.1 are met. Guidelines on the management of common 
capmatinib- and docetaxel-associated toxicities and dose modification instructions are provided 
in Section 6.5. 
6.1.5 
Treatment duration 
Participants will be treated until they experience any of the following: unacceptable toxicity, 
disease progression per RECIST 1.1 as assessed by the investigator and confirmed by BIRC, 
and/or treatment is discontinued at the discretion of the investigator or the participant. A 
complete list of the circumstances requiring study treatment discontinuation is provided in 
Section 9. 
Participants may continue treatment beyond BIRC-confirmed disease progression if, in the 
judgment of the investigator, there is evidence of clinical benefit and the participant wishes to 
continue on the study treatment. Criteria for treatment beyond progression are described in 
Section 6.1.5.1. 
Participants in the docetaxel arm will be allowed to crossover to receive capmatinib therapy 
after BIRC-confirmed, RECIST 1.1-defined PD. Criteria for crossover to capmatinib therapy 
are described in Section 6.1.5.2. 
At the end of the study, every effort will be made to continue provision of study treatment 
outside this study through an alternative setting to participants who in the opinion of the 
investigator are still deriving clinical benefit, where permitted by and in accordance with local 
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6.1.5.1 
Treatment beyond disease progression 
Clinical data indicate that participants may derive benefit from continuing study treatment 
despite initial evidence of disease progression. 
Participants will be permitted to continue study treatment beyond disease progression per 
RECIST 1.1 as assessed by the investigator and confirmed by BIRC, provided they meet all the 
following criteria: 
• Evidence of clinical benefit assessed by investigator 
• No rapid radiological or clinical progression 
• Tolerance to study treatment 
• Should not jeopardize critical interventions to treat/prevent severe complications, or prevent 
participants from receiving adequate care 
• Participant performance status is stable 
• Participant wishes to continue on the study treatment 
• No new antineoplastic therapy has been initiated 
The reasons for the participant continuing treatment beyond progression will be documented in 
the eCRF. 
Participants who meet the above criteria and continue study treatment beyond initial disease 
progression per RECIST 1.1 will continue all study procedures as outlined in Section 8. Clinical 
deterioration or suspicion of further disease progression will require a follow-up imaging 
assessment to be performed promptly rather than waiting for the next scheduled assessment. 
Participants who are no longer deriving clinical benefit, or who meet other protocol 
discontinuation criteria must be discontinued. 
6.1.5.2 
Crossover to capmatinib therapy 
Participants randomized to the docetaxel arm will be allowed to crossover to receive capmatinib 
therapy after BIRC-confirmed, RECIST 1.1-defined PD. 
Participants must complete the EOT visit after permanent discontinuation of docetaxel prior to 
crossing over to capmatinib arm. 
For participants who discontinue docetaxel for reasons other than BIRC-confirmed, RECIST 
1.1-defined PD (such as treatment intolerance, AEs, etc), safety and efficacy follow up 
assessments as well as PROs collection must continue to be performed as outlined in Table 8-2, 
while waiting to confirm crossover eligibility. 
Of note, participants in the docetaxel arm who have RECIST 1.1-defined PD as assessed by the 
investigator and confirmed by BIRC but continue to derive benefit from chemotherapy may 
continue treatment at the investigator’s discretion according to local clinical practice. 
Participants who meet the criteria outlined in Section 6.1.5.1 and continue study treatment 
beyond initial disease progression per RECIST 1.1 will continue all study procedures as 
outlined in Section 8. 


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Participants in the docetaxel arm who elect to crossover to capmatinib therapy must follow the 
study assessments as per visit schedule in Table 8-3 in the Extension Treatment (ET) Phase. 
The following eligibility criteria must be confirmed prior to crossing over to capmatinib arm: 
• Participants must have recovered from all toxicities related to docetaxel to grade ≤ 1 
(CTCAE version 5.0). Exception to this criterion: participants with any grade of alopecia 
and vitiligo. 
• Participants must not have a history or active medical condition of interstitial lung disease 
or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e. 
affecting activities of daily living or requiring therapeutic intervention) 
• Participants must crossover to capmatinib treatment within 84 days of BIRC-confirmed, 
RECIST 1.1-defined PD (imaging date). This window is intended to allow the resolution to 
at least CTCAE grade 1 of the toxicity related to the prior chemotherapy with docetaxel 
• Participants with CNS metastases must be neurologically stable 
• Participants must have an ECOG PS of 0-2 
• Participants must not be pregnant 
• Participants must be compliant with the contraception guidelines outlined in Section 5.2 
• Participants must have adequate organ function including the following laboratory values 
prior to commencing treatment of capmatinib in the ET phase: 
• Calculated creatinine clearance (using Cockcroft-Gault formula) ≥ 45 mL/min 
• Total bilirubin (TBIL) ≤ 1.5 x ULN (upper limit of normal) 
• Aspartate transaminase (AST) ≤ 3 x ULN, except for participants with liver metastases, 
who may only be included if AST ≤ 5 x ULN 
• Alanine transaminase (ALT) ≤ 3 x ULN, except for participants with liver metastases, 
who may only be included if ALT ≤ 5 x ULN 
• Asymptomatic serum amylase ≤ Grade 2. Participants with Grade 1 or Grade 2 serum 
amylase 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 
• If the participant has not undergone these specific assessment 7 days prior to commencing 
treatment of capmatinib in the ET phase, they must complete the following assessments via 
an unscheduled visit prior to the initiation of capmatinib treatment: 
• ECOG-PS 
• Vital signs 
• Hematology labs 
• Chemistry labs 
• ECG 
• Adverse events 
• Concomitant medications 
• Participants must not have started another anti-cancer therapy at the end of the treatment 
phase. 


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Participants who crossover from the docetaxel arm to capmatinib will have imaging 
assessments performed according to local clinical practice and institutional guidelines. The 
disease progression on capmatinib treatment in ET will be determined based on investigator 
assessment only. When these participants permanently discontinue treatment with capmatinib, 
they must complete the ET-EOT visit. All these participants will then be followed for safety 
until 30 days after the last dose of capmatinib. 
6.2 
Other treatment(s) 
No additional treatment beyond investigational drug is provided in this trial. 
6.2.1 
Concomitant therapy 
In general, the use of any concomitant medication/therapy deemed necessary for the care of the 
participant (e.g. such as anti-emetics, anti-diarrhea) is permitted, except when specifically 
prohibited (see Section 6.2.2). 
The participant must be told to notify the investigational site about any new medications he/she 
takes after signing the main study ICF. All medications (excluding study treatment and prior 
antineoplastic treatments), blood transfusions, surgeries and procedures (including physical 
therapy) administered after the participant signs the main study ICF and up to 30 days after the 
last dose of study treatment will be recorded on the appropriate eCRF. For participants with 
brain metastases at baseline, corticosteroid use should be collected on the appropriate eCRF 
until disease progression (as assessed by the investigator and confirmed by BIRC). Medications 
include not only physician prescribed medications, but also all over-the counter medications, 
herbal medications, food supplements and vitamins. 
The following restrictions apply during the entire duration of the study: 
• No other investigational therapy should be given to participants 
• No anticancer therapies (except radiation as allowed per protocol) other than the study 
medication should be given to participants. 
Participants are permitted to use the following medications while taking study treatment: 
• 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. 
• Oxygen therapy and blood products or transfusions 
• Nutritional support or appetite stimulant 
• Pain medication 
Each concomitant drug must be individually assessed against all exclusion criteria and 
prohibited medication. If in doubt, the investigator should contact the Novartis medical monitor 
before randomizing a participant or allowing a new medication to be started. If the participant 
is already enrolled, contact Novartis to determine if the participant should continue participation 
in the study. 


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6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
The following medications should be used with caution when concomitantly used with 
capmatinib treatment in this study: 
• Strong CYP3A inhibitors: Coadministrating capmatinib with strong CYP3A inhibitor 
(itraconazole) increased capmatinib AUCinf by 42%. There was no change in capmatinib 
Cmax. Closely monitor participants for adverse reactions during coadministration of 
capmatinib with strong CYP3A inhibitors. 
• Moderate CYP3A inducers: Simulations using physiologically-based pharmacokinetic 
(PBPK) models predicted that coadministration of capmatinib with the moderate CYP3A 
inducer efavirenz (600 mg once daily for 20 days) would result in a 44% decrease in 
capmatinib AUC0-12h and 34% decrease in Cmax at steady-state compared to administration 
of capmatinib alone. Caution should be exercised during concomitant use of capmatinib 
with moderate CYP3A inducers. Use an alternative medication with no or minimal potential 
to induce CYP3A during coadministration with capmatinib. 
• CYP1A2 substrates with narrow therapeutic index (NTI): Capmatinib is a moderate 
CYP1A2 inhibitor. Coadministration of capmatinib increased sensitive CYP1A2 probe 
substrate (caffeine) AUCinf by 134%. Avoid coadministration of capmatinib with CYP1A2 
substrates where minimal concentration changes may lead to serious adverse reactions. If 
coadministration is unavoidable, decrease the CYP1A2 substrate dosage in accordance with 
the approved prescribing information. 
• P-gp and BCRP substrates: Coadministration of capmatinib increased P-gp substrate 
(digoxin) exposure (AUCinf and Cmax by 47% and 74%, respectively) and BCRP substrate 
(rosuvastatin) exposure (AUCinf and Cmax by 108% and 204%, respectively). Avoid 
coadministration of capmatinib with P gp and BCRP substrates where minimal 
concentration changes may lead to serious adverse reactions. If coadministration is 
unavoidable, decrease the P-gp or BCRP substrate dosage in accordance with the approved 
prescribing information. 
• Proton pump inhibitor: Coadministration of capmatinib with proton pump inhibitor 
(rabeprazole) decreased capmatinib AUCinf by 25% and Cmax by 38%. Exercise caution 
during concomitant use of capmatinib with proton pump inhibitors. 
• H2-receptor antagonists and antacids: As an alternative to proton pump inhibitors, an H2- 
receptor antagonist or antacid can be taken. Capmatinib should be administered at least 3 
hours before or 6 hours after an H2-receptor antagonist. Capmatinib should be administered 
at least 2 hours before or 2 hours after an antacid. 
Refer to Table 16-11 for a list of the medications that require caution when concomitantly used 
with capmatinib. 
For docetaxel, please refer to the local prescribing information with regards to warnings, 
precautions, and contraindications. 
6.2.1.2 
Use of bisphosphonates or RANKL inhibitor 
Treatment with bisphosphonates or receptor activator of nuclear factor kappa-B ligand 
(RANKL) inhibitor for pre-existing bone metastases is permitted, if clinically indicated and at 
the  investigator's  discretion  following  existing  local  guidelines.  Treatment  with 


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bisphosphonates or RANKL inhibitor should preferably begin before the study treatment is 
initiated, but can also be initiated during therapy only if absence of radiological bone disease 
progression is well documented (in this case, the reason for its use must be clearly documented; 
i.e. “pre-existing, non-progressing, bone metastases”). 
6.2.1.3 
Permitted radiotherapy 
Localized palliative radiotherapy for pre-existing, painful bone/liver metastases is permitted. 
Local bone radiotherapy for analgesic purposes or for lytic lesions at risk of fracture may be 
carried out if required. It should not be delivered to a target lesion. If palliative radiotherapy is 
initiated after start of study treatment, the reason for its use must be clearly documented and 
progression as per RECIST 1.1 must be ruled out. The study treatment must be interrupted on 
the days of radiotherapy and can be resumed the day after its completion. Caution is advised 
for radiation to fields that include lung tissue. The radiotherapy must be listed on the 
concomitant antineoplastic therapy – radiotherapy eCRF. After documented BIRC-confirmed, 
RECIST 1.1-defined PD, radiotherapy is allowed following the same dose adjustment guidance 
in case capmatinib is continued beyond PD. 
6.2.2 
Prohibited medication 
Coadministration of capmatinib with strong CYP3A inducer (rifampicin) decreases capmatinib 
AUCinf by 67% and Cmax by 56% [CINC280A2102], which may decrease capmatinib anti-tumor 
activity. Therefore, concurrent use of strong CYP3A inducers are prohibited. Capmatinib 
prohibited medications are listed in Table 16-12. 
For docetaxel, please refer to the local prescribing information with regards to warnings, 
precautions, and contraindications. 
Live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow 
fever, varicella, and TY21a typhoid vaccines and COVID-19 vaccines) must not be 
administered while a participant is on study treatment and for 30 days after the last dose of study 
treatment. 
Participants enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies while on treatment. 
There are no prohibited therapies during the post-treatment follow-up period. 
6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for molecular pre-screening and is retained for the 
participant throughout his/her participation in the trial. A new Participant No. will be assigned 
at every subsequent enrollment if the participant is rescreened. The Participant No. consists of 
the Center Number (Center No.) (as assigned by Novartis to the investigative site) with a 
sequential participant number suffixed to it, so that each participant’s participation is numbered 
uniquely across the entire database. Upon signing the molecular pre-screening informed consent 
form, the participant is assigned to the next sequential Participant No. available. 


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A new ICF will need to be signed if the investigator chooses to rescreen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No. 
6.3.2 
Treatment assignment, randomization 
Following completion of screening procedures, the investigator or his/her delegate will contact 
the IRT after confirming that the participant fulfils all the inclusion/exclusion criteria. All 
eligible participants will be randomized via Interactive Response Technology (IRT) in a 2:1 
ratio to one of the following treatment arms: 
• Arm 1: capmatinib 
• Arm 2: docetaxel 
The randomization will be stratified by the number of prior lines of therapy received (one line 
versus two lines). 
The IRT will assign a randomization number to the participant, which will be used to link the 
participant to a treatment arm and will specify a unique medication number for the first package 
of study treatment to be dispensed to the participant. 
The study treatment phase begins on Cycle 1 Day 1 with the first administration of capmatinib 
or docetaxel. Cycle 1 Day 1 should occur on the day of randomization or no later than 3 days 
after randomization. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Global Clinical Supply (GCS) using a validated system that automates the random 
assignment of medication numbers to packs containing the study treatment. 
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office. 
6.4 
Treatment blinding 
This is an open-label study. Treatment assignment will be open to participants, investigator staff, 
persons performing the assessments, and the Novartis study team. In order to minimize the 
potential impact of knowledge of treatment assignment, the randomization list will be kept 
strictly confidential. No aggregate analyses (efficacy or safety across the study) by treatment 
arm shall be performed prior to the primary analysis. 


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6.5 
Dose escalation and dose modification 
6.5.1 
Dose modifications 
For participants who do not tolerate the protocol-specified dosing schedule, dose interruptions, 
and/or reductions are either recommended or mandated in order to allow participants to continue 
the study treatment. 
The following guidelines should be considered: 
Docetaxel 
Every attempt should be made to maintain the treatment dosing cycle schedule of every 21 days. 
For participants who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted per the local approved label in order to keep the participant on 
treatment. Docetaxel dose reduction will follow the local prescribing information. Participants 
who discontinue docetaxel due to toxicity will have the option to switch to capmatinib therapy 
only after BIRC-confirmed, RECIST 1.1-defined PD. 
Capmatinib 
Dose reductions are allowed for capmatinib and should follow the dose reduction steps 
described in Table 6-2 and Table 6-3. For each participant, a maximum of two consecutive dose 
level reductions is allowed after which the participant must be discontinued. Dose reductions 
of capmatinib below 200 mg b.i.d. are not permitted. The lowest dose allowed, 200 mg b.i.d. in 
tablets is expected to be pharmacologically active, as the observed steady state plasma trough 
concentrations ([CINC280X1101], [CINC280X2202], n=6) were above the concentration 
associated with full MET inhibition in xenograft mice models (IC90, 120 nM total 
concentration). 
For participants who do not tolerate the protocol-specified dosing schedule, dose interruptions 
are permitted in order to allow participants to continue the study treatment. All dose 
modifications, interruptions or discontinuations must be based on the worst preceding toxicity 
as graded by the NCI Clinical Toxicity Criteria (NCI-CTCAE version 5.0). Any changes must 
be recorded on the dosage administration eCRF page. 
A participant must discontinue treatment with capmatinib if, after treatment is resumed at the 
lowest allowed dose (200 mg b.i.d.), the toxicity recurs with the same or worse severity despite 
use of maximal preventive measures as per the institution guidelines for toxicity prevention and 
management. 
Unless otherwise indicated in Table 6-3, for grade 1 and tolerable grade 2 treatment-related 
toxicities, participants may continue full doses of capmatinib. For intolerable grade 2 or grade 
3 treatment-related toxicities, dosing should be interrupted until at least resolution to grade 1 
followed by either dose reduction or re-initiation at the same dose level, depending on the type 
of toxicity as described in Table 6-3. For any grade 4 toxicity, except for neutropenia, febrile 
neutropenia, anemia and thrombocytopenia, participants should interrupt capmatinib until 
resolution to grade 1, followed by either dose reduction or treatment discontinuation (refer to 
Table 6-3). 


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If the treatment with capmatinib or docetaxel is withheld for more than 21 consecutive days 
(counting from the first day when a dose was interrupted), then study treatment should be 
permanently discontinued. Under exceptional circumstance, when the investigator believes that 
continuing treatment may still derive clinical benefit for the participant, study treatment may be 
resumed. However, the investigator must discuss and receive approval from Novartis Medical 
Lead or designee prior to continuing study treatment and rationale should be captured in the 
source documents. 
Permanent treatment discontinuation is mandatory for specific events indicated as such in 
Table 6-3 or listed in Section 6.5.2. Deviations to mandatory dose discontinuations are not 
allowed. 
Dose re/escalation of study treatment to previous dose level is allowed only once, and if no AE 
leading to dose modification is observed after at least 1 cycle (3 weeks) of study treatment at 
the reduced dose. 
Any planned variance from the guidelines in Table 6-3 or Table 6-4, in view of participant 
safety (unless there is an urgent need for action) when in the opinion of the investigator the 
participant continues to experience clinical benefit, should first be discussed and approved by 
the Novartis Medical Lead or designee. 
Events not included in the study protocol or the reference guidance documents should be 
managed according to local practices. 
Table 6-2 
Dose reduction steps for capmatinib 
 
Starting dose level 0 
Dose level -1 
Dose level -2 
Capmatinib 
400 mg b.i.d. 
300 mg b.i.d. 
200 mg b.i.d. 
Note: dose reduction should be based on the worst toxicity demonstrated at the last dose. 
Table 6-3 
Criteria for dose reduction / interruption and re-initiation / permanent 
discontinuation of capmatinib treatment for adverse drug reactions 
 
Worst toxicity CTCAE Gradea during a cycle of therapy 
No toxicity 
Maintain dose level 
HEMATOLOGICAL 
Neutrophil count decreased (ANC) Neutropenia 
Grade 1 (ANC < LLN - 1500/mm3; < LLN - 
1.5 x 109/L) 
Maintain dose level 
Grade 2 (ANC < 1500 - 1000/mm3; < 1.5 - 
1.0 x 109/L) 
Maintain dose level 
Grade 3 (ANC < 1000 - 500/mm3; < 1.0 - 0.5 
x 109/L) 
Omit dose until resolved to ≤ grade 2, then: 
If resolved in ≤ 7 days, resume treatment at the same dose 
level 
If resolved in > 7 days, then ↓ 1 dose level 
Grade 4 (ANC < 500/mm3; < 0.5 x 109/L) 
Omit dose until resolved to ≤ grade 2 and then ↓ 1 dose level 
Platelet count decreased (Thrombocytopenia) 
Grade 1 (PLT < LLN - 75,000/mm3; < LLN - 
75 x 109/L) 
Maintain dose level 


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Grade 2 (PLT < 75,000 - 50,000/mm3; < 75 - 
50 x 109/L) 
Maintain dose level 
Grade 3 (PLT < 50,000 - 25,000/mm3; < 50 - 
25 x 109/L) 
Omit dose until resolved to ≤ grade 2, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then ↓ 1 dose level 
Grade 4 (PLT < 25,000/mm3; < 25 x 109/L) 
Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level 
Febrile neutropenia (ANC < 1000/mm3 (< 
1.0 x 109/L), fever > 38.3°C) 
Omit dose, then: 
If resolved in ≤ 7 days, resume treatment at ↓ 1 dose level 
If resolved in > 7 days, permanently discontinue participant 
from capmatinib treatment 
Hemoglobin decreased (Anemia) 
Grade 1 (Hemoglobin [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; transfusion indicated) 
Omit dose until resolved to ≤ grade 2, then: 
If resolved in ≤ 7 days, resume treatment at the same dose 
level 
If resolved in > 7 days, then ↓ 1 dose level 
Grade 4 (Life-threatening consequences; 
urgent intervention indicated) 
Omit dose until resolved to ≤ grade 2 and then ↓ 1 dose level 
If toxicity recurs, permanently discontinue participant from 
capmatinib treatment. 
RENAL 
Serum creatinine 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level 
Grade 2 (> 1.5 - 3.0 x ULN) 
Omit dose until resolved to ≤ grade 1 or baseline, then resume 
treatment at the same dose level. 
Grade 3 (> 3.0 - 6.0 x ULN) 
Omit dose until resolved to ≤ grade 1 or baseline, then resume 
treatment at ↓ 1 dose level. 
Grade 4 (> 6.0 x ULN) 
Permanently discontinue participant from capmatinib treatment 
HEPATIC 
Isolated Total Bilirubin elevation* 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level 
Grade 2 (> 1.5 - 3.0 x ULN) 
Omit dose until resolved to ≤ grade 1, then 
If resolved in ≤ 7 days, maintain dose level. 
If resolved in > 7 days, ↓1 dose level 
Grade 3 (> 3.0 - 10.0 x ULN) 
Omit dose until resolved to ≤ grade 1, then 
If resolved in ≤ 7 days, ↓ 1 dose level 
If resolved in > 7 days, permanently discontinue participant 
from capmatinib treatment 
Grade 4 (> 10.0 x ULN) 
Mandatory: Permanently discontinue participant from 
capmatinib treatment 
Isolated AST or ALT elevation 
Grade 1 (> ULN - 3 x ULN) 
Maintain dose level 
Grade 2 (> 3.0 - 5.0 x ULN) 
Maintain dose level 
Grade 3 (> 5.0 - 20.0 x ULN) 
Omit dose until resolved to ≤ grade 1 (or ≤ grade 2 if grade 2 
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If resolved in ≤ 7 days, then resume treatment at the same dose 
level 
If resolved in > 7 days, resume treatment at ↓ 1 dose level 
Grade 4 (> 20.0 x ULN) 
Mandatory: Permanently discontinue participant from 
capmatinib treatment 
Combined elevations of AST or ALT and Total Bilirubin b,c,d 
For participants with normal baseline ALT 
and AST and total bilirubin value: 
AST or ALT > 3.0 x ULN combined with total 
bilirubin > 2.0 x ULN without evidence of 
cholestasis or hemolysis 
OR 
For participants with elevated baseline AST 
or ALT or total bilirubin value: 
[AST or ALT > 3 x baseline] OR [AST or 
ALT > 8.0 x ULN], whichever is lower, 
combined with [total bilirubin > 2 x baseline 
AND > 2.0 x ULN] without evidence of 
cholestasis or hemolysis 
Mandatory: Permanently discontinue participant from 
capmatinib treatment 
METABOLIC 
Amylase and/or lipase elevation 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level 
Grade 2 (> 1.5 - 2.0 x ULN; > 2.0 - 5.0 x 
ULN and asymptomatic) 
Maintain dose level 
Grade 3 (> 2.0 - 5.0 x ULN with signs or 
symptoms; > 5.0 x ULN and asymptomatic) 
Omit the dose until resolved to ≤ grade 2, then 
If resolved in ≤ 14 days, resume treatment at the same dose 
level 
If resolved in > 14 days, then ↓ 1 dose level 
Grade 4 (> 5.0 x ULN with signs or 
symptoms) 
Permanently discontinue participant from capmatinib treatment 
CARDIAC 
Electrocardiogram QT corrected (QTc) interval prolonged 
Grade 1 (QTcF 450-480 ms) 
Maintain dose level 
Grade 2 (QTcF 481-500 ms) 
Maintain dose level 
Grade 3 (QTcF ≥ 501 ms on at least two 
separate ECGs) 
Omit dose until resolved to ≤ grade 2, then: 
If resolved in ≤ 7 days, resume treatment at the same dose 
level 
If resolved in > 7 days, then ↓ 1 dose level 
Grade 4 (QTcF ≥ 501 or > 60 ms change 
from baseline and Torsades de pointes or 
polymorphic ventricular tachycardia or 
signs/symptoms of serious arrhythmia) 
Permanently discontinue participant from capmatinib treatment 
GASTROINTESTINAL 
Pancreatitis 
Grade 2 
Maintain dose level 
Grade ≥ 3 
Mandatory: Permanently discontinue participant from 
capmatinib treatment 
Diarrhea** 
Grade 1 (despite appropriate anti-diarrheal 
medication) 
Maintain dose level 


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Grade 2 (despite maximal anti-diarrheal 
medication) 
Omit dose until resolved to ≤ grade 1, then maintain dose level. 
If diarrhea returns as ≥ grade 2, then omit dose until resolved to 
≤ grade 1, then resume treatment at ↓ 1 dose level 
Grade 3 or 4 (despite appropriate anti- 
diarrheal medication) 
Omit dose until resolved to ≤ grade 1, then resume treatment at 
↓ 1 dose level 
Vomiting 
Grade 1 (despite appropriate anti-emetics) 
Maintain dose level 
Grade 2 (despite appropriate anti-emetics) 
Omit dose until resolved to ≤ grade 1, then maintain dose level. 
If vomiting returns as ≥ grade 2, then omit dose until resolved to 
≤ grade 1, then ↓ 1 dose level. 
Grade 3 (despite appropriate anti-emetics) 
Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level 
Grade 4 (despite appropriate anti-emetics) 
Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level 
Nausea 
Grade 1 or 2 (despite appropriate anti- 
emetics) 
Maintain dose level 
Grade 3 (despite appropriate anti-emetics) 
Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Rash/photosensitivity*** 
Grade 1 
Maintain dose level 
Grade 2 
Maintain dose level 
Grade 3, despite skin toxicity therapy 
Omit dose until resolved to grade ≤ 1, then: 
If resolved in ≤ 7 days, then resume treatment at ↓ 1 dose level 
If resolved in > 7 days (despite appropriate skin toxicity 
therapy), then permanently discontinue participant from 
capmatinib treatment 
Grade 4, despite skin toxicity therapy 
Omit dose and permanently discontinue participant from 
capmatinib treatment 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
ILD /Pneumonitis 
Monitor participants for pulmonary symptoms indicative of ILD/pneumonitis. In addition, withhold capmatinib for 
acute onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever and 
during diagnostic workup for ILD/pneumonitis to exclude alternative causes such as, but not limited to 
infections, lymphangitic carcinomatosis, cardiogenic edema, or pulmonary hemorrhage. 
Grade 1 
Interrupt capmatinib during diagnostic workup for 
ILD/Pneumonitis. Exclude infections and other etiologies. 
In presence of diagnosis of ILD/Pneumonitis after diagnostic 
workup, it is mandatory to permanently discontinue capmatinib. 
Only in the absence of a diagnosis of ILD/Pneumonitis, 
capmatinib may be restarted at the same dose. 
If it recurs after resumption of study drug, permanently 
discontinue capmatinib. 
Grade 2 
Mandatory: Interrupt capmatinib dose during diagnostic workup 
for ILD until improvement to ≤ Grade 1. Exclude infections and 
other etiologies. 
In presence of diagnosis of ILD/Pneumonitis after diagnostic 
workup, it is mandatory to permanently discontinue capmatinib. 
Only in the absence of a diagnosis of ILD/Pneumonitis, 
capmatinib may be restarted following these guidelines: 
· If resolves to ≤ Grade 1 in ≤ 7 days reduce study drug by 1 
dose level 


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· If fails to resolve to ≤ Grade 1 within 7 days or recur after 
resumption of study drug at decreased dose, permanently 
discontinue capmatinib 
Grade 3 and Grade 4 
Mandatory: Permanently discontinue capmatinib. 
Treat with IV steroids as clinically indicated. Oxygen therapy as 
indicated 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fatigue/ Asthenia 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ grade 1, then: 
If resolved in ≤ 7 days, resume treatment at same dose level 
If resolved in > 7 days, resume treatment at ↓ 1 dose level 
Peripheral edema 
Grade 1 or 2 
Maintain dose level. 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then ↓1 dose level 
Grade 4 
Permanently discontinue capmatinib 
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 then 
restart either at same dose or ↓ 1 dose level. 
Grade 3 
Omit dose until resolved to ≤ grade 1, then↓ 1 dose level 
Grade 4 
Permanently discontinue capmatinib 
All dose modifications should be based on the worst preceding toxicity. 
a Common Toxicity Criteria for Adverse Events (CTCAE version 5.0). 
b “Combined” defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST increase to 
the defined threshold 
c “Cholestasis” defined as: ALP elevation (> 2.0 x ULN and R value (ALT/ALP in x ULN) < 2.0) in participants 
without bone metastases, or elevation of ALP liver fraction in participants with bone metastases 
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 capmatinib, the participant is recommended to use 
precautionary measures against ultraviolet exposure (e.g., use of sunscreen, protective clothing and avoid 
sunbathing or using a solarium intensively). 
These dose changes must be recorded on the appropriate eCRF. 


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6.5.2 
Treatment interruption and treatment discontinuation 
If the administration of capmatinib is temporarily interrupted for reasons other than toxicity, 
then treatment with capmatinib may be resumed at the same dose. If the treatment with 
capmatinib is withheld due to toxicity, the dose modification guidelines in Table 6-2 should be 
followed. In any case, scheduled visits and all assessments (including tumor assessments) 
should continue to be performed, as described in Table 8-2 and Table 8-3. 
Participants who discontinue the study due to a study treatment related AE or an abnormal 
laboratory value must be followed as described in Section 6.5.3. 
6.5.3 
Follow-up for toxicities 
All participants will be followed for safety until 30 days after the last dose of capmatinib or 
docetaxel. Participants whose treatment is temporarily interrupted or permanently discontinued 
due to an AE or abnormal laboratory value must be followed until resolution or stabilization of 
the event, whichever comes first, including all study assessments appropriate to monitor the 
event. 
An unscheduled assessment should be performed in all cases below where toxicity monitoring 
is recommended more frequently than defined by the schedule of assessments. Subsequent 
monitoring must be performed as per the regular visit schedule. 
Table 6-4 
Follow-up evaluations for selected toxicities 
 
TOXICITY 
FOLLOW-UP EVALUATION 
HEMATOLOGICAL 
Febrile neutropenia, 
Neutropenia ≥ CTCAE grade 3 
Thrombocytopenia ≥ CTCAE grade 3 
Anemia ≥ CTCAE grade 3 
Test weekly (or more frequently if clinically indicated) until ≤ 
CTCAE grade 2. 
Perform physical exam for check on bruising in case of major 
thrombocytopenia. 
RENAL 
Serum creatinine ≥ CTCAE grade 2 
Test weekly (or more frequently if clinically indicated) until ≤ 
CTCAE grade 1 or baseline. 
Participants will be instructed to increase hydration until 
resolution to ≤ CTCAE grade 1 or baseline. 
HEPATIC 
Isolated total bilirubin elevation 
Total bilirubin CTCAE Grade 1: 
Monitor LFTs per protocol or more frequently if clinically 
indicated 
Total bilirubin CTCAE Grade 2: 
Weekly monitoring of LFTs, or more frequently if clinically 
indicated, until resolved to ≤ 1.5 x ULN 
Total bilirubin CTCAE Grade 3: 
Weekly monitoring of LFTs, or more frequently if clinically 
indicated, until resolved to ≤ 1.5 x ULN. If resolved in > 7 days, 
after discontinuing the participant from capmatinib permanently, 
the participant should be monitored weekly (including LFTs), or 
more frequently if clinically indicated, until total bilirubin have 
resolved to baseline or stabilization over 4 weeks 


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TOXICITY 
FOLLOW-UP EVALUATION 
Total bilirubin CTCAE Grade 4: 
After discontinuing the participant from capmatinib 
permanently, the participant should be monitored weekly 
(including LFTs), or more frequently if clinically indicated, until 
total bilirubin have resolved to baseline or stabilization over 4 
weeks 
Isolated AST/ALT elevation 
AST/ALT CTCAE Grade 2 elevation: 
For participants with baseline value ≤ 3.0 x ULN: repeat LFTs 
as soon as possible, preferably within 48-72 hr from awareness 
of the abnormal results; if abnormal lab values are confirmed 
upon the repeat test, then monitor LFTs weekly, or more 
frequently if clinically indicated, until resolved to ≤ 3.0 x ULN 
For participants with baseline value > 3.0 x ULN: monitor LFTs 
per protocol or more frequently if clinically indicated 
AST/ALT CTCAE Grade 3 elevation: 
For AST/ALT elevation > 5.0 - 10.0 x ULN: 
For participants with baseline value ≤ 3.0 x ULN: repeat LFTs 
as soon as possible, preferably within 48-72 hr from awareness 
of the abnormal results; monitor LFTs weekly, or more 
frequently if clinically indicated, until resolved to ≤ 3.0 x ULN 
For participants with baseline value > 3.0 x ULN: repeat LFTs 
as soon as possible, preferably within 48-72 hr 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 hr 
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 hr 
from awareness of the abnormal results; monitor LFTs weekly, 
or more frequently if clinically indicated, until resolved to 
baseline or stabilization over 4 weeks. 
Combined elevations in ALT and/or AST 
with concurrent total bilirubin increase, in the 
absence of cholestasis or hemolysis 
Combined elevations of AST or ALT and total bilirubin: 
After discontinuing the participant from capmatinib 
permanently, repeat LFTs as soon as possible, preferably 
within 48 hr 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.) 
METABOLIC 
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. 


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


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TOXICITY 
FOLLOW-UP EVALUATION 
Individualized supportive and anti-emetic treatment should be 
initiated, as appropriate, at the first signs and/or symptoms of 
these AEs. In participants with vomiting, the participant should 
be monitored for signs of dehydration and instructed to take 
preventive measures against dehydration. 
Concomitant medication for the treatment of nausea and/or 
vomiting should follow local practice and the investigator’s best 
judgment. 
SKIN TOXICITY 
Rash and Photosensitivity 
CTCAE grade 1 
Consider to initiate institute appropriate skin toxicity therapy 
(such as antihistamines, topical corticosteroids and low-dose 
systemic corticosteroids) 
CTCAE grade 2 
Initiate/intensify appropriate skin toxicity therapy (such as 
antihistamines, topical corticosteroids and low-dose systemic 
corticosteroids). 
≥ CTCAE grade 3 
Intensify appropriate skin toxicity therapy and monitor weekly or 
more frequently until resolved to grade ≤ 2 
Peripheral edema 
CTCAE grade≤2 
Consider to initiate conservative measures such as leg 
elevation, compression stockings, and dietary salt modification 
as clinically indicated. 
CTCAE grade≥3 
Initiate/intensify conservative measures 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
ILD/Pneumonitis 
CTCAE Grade 1 
CT scan (high-resolution with lung windows) recommended, 
with serial imaging to monitor for resolution or progression- re- 
image at least every 3 weeks 
Monitor for symptoms every 2-3 days - Clinical evaluation and 
laboratory work-up for infection 
Monitoring of oxygenation via pulse oximetry recommended 
Consultation of pulmonologist recommended 
CTCAE Grade 2 
CT scan (high-resolution with lung windows) 
• Monitor symptoms daily, consider hospitalization 
• Clinical evaluation and laboratory work up for infection 
• Consult pulmonologist 
• Pulmonary function tests a - if normal at baseline, repeat every 
8 weeks 
• Bronchoscopy with biopsy and/or BAL recommended c 
Symptomatic therapy including corticosteroids if clinically 
indicated (1 to 2 mg/kg/day prednisone or equivalent as 
clinically indicated) b 
CTCAE Grade 3 and Grade 4 
CT scan (high-resolution with lung windows) 
Clinical evaluation and laboratory work-up for infection 
Consult pulmonologist 
Pulmonary function testsa-if < normal, repeat every 8 weeks 
until ≥ normal 
Bronchoscopy with biopsy and/or BAL if possiblec 
Treat with IV steroids (methylprednisolone 125 mg) as 
indicated. When symptoms improve to ≤ Grade 1, a high dose 


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TOXICITY 
FOLLOW-UP EVALUATION 
oral steroid (prednisone 1 to 2 mg/kg once per day or 
dexamethasone 4 mg every 4 hr)b. 
If IV steroids followed by high dose oral steroids does not 
reduce initial symptoms within 48 to 72 hours, consider non- 
corticosteroid immunosuppressive medication 
a PFT (Pulmonary function tests) to include: diffusing capacity 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. 
6.5.3.1 
Follow-up on potential drug- induced liver injury cases 
Participants with transaminase increase combined with total bilirubin increase may be 
indicative of potentially severe drug- induced liver injury (DILI), these events should be 
considered as clinically important and assessed appropriately to establish the diagnosis. The 
required clinical information, as detailed below, should be sought to obtain the medical 
diagnosis of the most likely cause of the observed laboratory abnormalities. 
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and total 
bilirubin value; participants meeting any of the following criteria will require further follow-up 
as outlined below: 
• For participants with normal ALT and AST and total bilirubin value at baseline: AST or 
ALT > 3.0 x ULN combined with total bilirubin > 2.0 x ULN 
• For participants with elevated AST or ALT or total bilirubin value at baseline: [AST or 
ALT >3.0 x baseline] OR [ALT or AST > 8.0 x ULN], whichever is lower, combined with 
[total bilirubin > 2.0 x baseline AND > 2.0 x ULN] 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed to be the cause of liver injury. 
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre- 
existing liver conditions or risk factors, should be collected. 
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, GGT, 
prothrombin time (PT)/ International normalized ratio (INR), alkaline phosphatase, albumin, 
and creatine kinase. If available, testing of Glutamate Dehydrogenase (GLDH) is additionally 
recommended. 
Evaluate status of liver metastases (new or exacerbation) or vascular occlusion – e.g. using CT, 
MRI, or duplex sonography. 
Perform 
relevant 
examinations 
(Ultrasound 
or 
MRI, 
Endoscopic 
retrograde 
cholangiopancreatography (ERCP)) as appropriate, to rule out an extrahepatic cause of 
cholestasis. Cholestasis (is defined as an ALP elevation > 2.0 x ULN with R value < 2 in 


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participants without bone metastases, or elevation of the liver-specific ALP isoenzyme in 
participants with bone metastases). 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. In clinical 
situations where it is suspected that ALP elevations are from an extrahepatic source, the GGT 
can be used if available. GGT may be less specific than ALP as a marker of cholestatic injury, 
since GGT can also be elevated by enzyme induction or by ethanol consumption. It is more 
sensitive than ALP for detecting bile duct injury. 
Table 6-5 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule out possible alternative causes of observed LFT abnormalities. 
Table 6-5 
Clinical and diagnostic assessments for LFT abnormalities 
 
Disease 
Assessment 
Hepatitis A, B, C, E 
IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV DNA; anti-HCV, HCV 
RNA, IgM & IgG anti-HEV, HEV RNA 
CMV, HSV, EBV infection 
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV 
Autoimmune hepatitis 
Antinuclear Antibodies (ANA) & Anti-Smooth Muscle Antibody (ASMA) 
titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
Ethanol history, GGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
Medical history: acute or chronic congestive heart failure, hypotension, 
hypoxia, hepatic venous occlusion. Ultrasound or MRI. 
Biliary tract disease 
Ultrasound or MRI, ERCP as appropriate. 
Wilson disease (if <40 yrs old) 
Ceruloplasmin 
Hemochromatosis 
Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
Alpha-1-antitrypsin 
Other causes should also be considered based upon participants’ medical history 
(hyperthyroidism / thyrotoxic hepatitis – T3, T4, TSH; cardiovascular disease / ischemic 
hepatitis – ECG, prior hypotensive episodes; Type 1 diabetes mellitus / glycogenic hepatitis). 
Obtain PK sample to determine exposure to study treatment and metabolites. 
Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” (i.e. >50% likely), if it appears greater than all other possible causes 
of liver injury combined. The term “treatment-induced” indicates probably caused by the 
treatment, not by something else, and only such a case can be considered a DILI case and should 
be reported as an SAE. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” and thus, meet the definition of SAE and should be reported as an SAE using the 
term “potential treatment-induced liver injury.” All events should be followed up with the 
outcome clearly documented. 


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6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
Every time the study treatment is to be administered, IRT needs to be accessed (please refer to 
the IRT manual). The date and time of study treatment administration during the study and any 
deviations from the protocol treatment schedule will be captured on the appropriate study 
treatment dispensing form. The investigator must promote compliance by instructing the 
participant to take the study treatment exactly as prescribed and by stating that compliance is 
necessary for the participant’s safety and the validity of the study. The participant must also be 
instructed to contact the investigator if he/she is unable for any reason to take the study 
treatment as prescribed. 
For treatment with docetaxel: exposure to the study treatment will be based on the number of 
injections administered. 
For treatment with capmatinib: compliance will be assessed by the investigator and/or study 
personnel at each visit using pill counts and information provided by the participant. This 
information should be captured in the source document at each visit. All study treatment 
dispensed and returned must be recorded in a drug accountability log. 
Compliance with the study treatment will be assessed by the Clinical Research Associate (CRA) 
at each visit using vial counts and information provided by the pharmacist or by the investigator. 
All study treatment dispensed and returned must be recorded in a drug accountability log. 
6.6.2 
Emergency breaking of assigned treatment code 
Not applicable. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study treatment in packaging as described under 
investigational and control drugs (Section 6.1.1). 
Capmatinib 
The investigator or responsible site personnel must instruct the participant or caregiver to take 
the study treatment as per protocol. Study treatment will be dispensed to the participant by 
authorized site personnel only. All dosages prescribed to the participant and all dose changes 
during the study must be recorded on the study treatment eCRF. 
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the IRT system and obtaining the medication number(s). The study medication has 
a two-part label (base plus tear-off label). Immediately before dispensing the medication kit to 
the participant, site personnel will detach the outer part of the label from the packaging and 
affix it to the source document. 
As per Section 4.6 during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, delivery 


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of study drug directly to a participant’s home is generally permitted (if allowed by local or 
regional health authorities and ethics committees) in the event the Investigator has decided that 
an on-site visit by the participant is no longer appropriate or possible, and that it is in the interest 
of the participant’s health to administer the study treatment even without performing an on-site 
visit. The dispatch of study drug from the site to the participant’s home remains under the 
accountability of the Investigator. Each shipment/provisioning will be for a maximum of 3- 
month supply. In this case, regular phone calls or virtual contacts (every 3 weeks or more 
frequently, if needed) will occur between the site and the participant for instructional purposes, 
safety monitoring including safety assessments, investigation of any adverse events ensuring 
participants continue to benefit from treatment, and discussion of the participant´s health status 
until the participants can resume visits at the study site. 
Docetaxel 
Preparation and dispensation of docetaxel should follow local guidelines as per standard of care 
and product labels. 
6.7.1 
Handling of study treatment and other treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the docetaxel labels and in the [capmatinib Investigator’s Brochure]. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization (CO) Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The investigator or designated site staff must maintain an accurate record of the shipment and 
dispensing of study treatment in a drug accountability log. Monitoring of drug accountability 
will be performed by monitors during site visits or remotely and at the completion of the trial. 
The investigator must provide accountability also for locally sourced materials used for 
administration (e.g. i.v. bags). 
If study treatment is administered at home (e.g. capmatinib), participants will be asked to return 
all unused study treatment and packaging at the end of the study or at the time of discontinuation 
of study treatment. 
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, the investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to the Novartis 
monitor or to the Novartis address provided in the investigator folder at each site. 


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6.7.1.2 
Handling of other treatment 
Not applicable. 
6.7.2 
Instruction for prescribing and taking study treatment 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. 
Table 6-6 
Dose and treatment schedule 
 
Investigational / Control Drug 
(Name and Strength) 
Dose 
Frequency and/or Regimen 
Capmatinib (INC280) 200 mg or 
150 mg 
400 mg tablet, orally 
(2 x 200 mg or 2 x 150 mg [if dose is 
reduced to 300 mg b.i.d.] or 1 x 200 
mg [if dose is reduced to 200 mg 
b.i.d.], if applicable) 
Twice daily 
Docetaxel (as per local product 
available) 
75 mg/m2 i.v. infusion per product 
label and local guidelines (as per 
standard of care) 
Once every 21 days 
6.7.2.1 
Capmatinib 
Capmatinib tablets will be administered orally on a continuous twice daily (b.i.d.) 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 capmatinib. 
The investigator must instruct the participant to take the study drug exactly as prescribed. All 
dosages prescribed and dispensed to the participant and all dose changes during the study must 
be recorded on the dosage administration eCRF. 
Participants should take 400 mg of capmatinib tablets twice daily (b.i.d.) at approximately the 
same time each day starting at Cycle 1 Day 1. 
Each dose of capmatinib is to be taken with a glass of water (at least 8 ounces – approximately 
250 mL) and consumed over as short a time as possible (i.e., not slower than 1 tablet every 
2 minutes). 
Participants should be instructed to swallow the tablets whole and not to chew them. 
Capmatinib can be administered with or without food. The morning and the evening doses 
should be taken 12 (± 4) hours apart, although a 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. 
On days when PK blood samples are to be collected, participants will be instructed to hold their 
dose until arrival at the study center, unless participant visit is more than 4 hours post-standard 
visit time. Capmatinib will be administered at the site in the morning prior to the post-dose PK 
sample blood draws supervised by a member of the research team. The pre-dose PK samples 
will be taken right before capmatinib administration. The exact time of drug administration 
should be recorded in the appropriate eCRF. Food consumption prior to capmatinib 
administration should be recorded in the appropriate eCRF. If a participant vomits within 4 
hours of capmatinib dosing on the day of post-dose PK blood sampling, PK sample collection 


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is at investigator’s discretion. If PK sample collection is done, the time of vomiting should be 
recorded on the eCRF. 
Participants should be instructed not to make up for missed doses or partial doses (i.e., when 
the entire dose is not taken as instructed). A missed or partial dose will be defined 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 capmatinib, the participant is recommended to use 
precautionary measures against ultraviolet exposure (e.g., use of sunscreen, protective clothing, 
avoid sunbathing or using a solarium). 
6.7.2.2 
Docetaxel 
Docetaxel will be supplied locally as commercially available and labeled accordingly to comply 
with legal requirements of each country. Chemotherapy administration (including related 
steroid pre-medication schemes) should follow local prescribing information. 
 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), Institutional Review Board (IRB) / Independent Ethics 
Committee (IEC)-approved informed consent. 
If applicable, in cases where the participants’ representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her level of understanding. If the participant is capable of doing so, he/she 
must indicate agreement by personally signing and dating the written informed consent 
document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH E6 Good Clinical Practice (GCP) guidelines and regulatory 
requirements and is considered appropriate for this study. Any changes to the proposed consent 
form suggested by the investigator must be agreed by Novartis before submission to the 
IRB/IEC. 
Information about common side effects already known about the investigational treatment can 
be found in the [capmatinib Investigator's Brochure]. This information will be included in the 
participant informed consent and should be discussed with the participant upon obtaining 
consent and also during the study as needed. Any new information regarding the safety profile 
of the investigational drug that is identified between IB updates will be communicated as 
appropriate, for example, via an investigator notification or an aggregate safety finding. New 
information might require an update to the informed consent and then must be discussed with 
the participant. 


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The following informed consents are included in this study: 
• Molecular pre-screening consent 
• Main study consent, which also includes: 
• A subsection that requires a separate signature for the ‘Optional Consent for Additional 
Research’ to allow future research on data/samples collected during this study 
• A subsection that requires a separate signature for the ‘Optional Collection of Tumor 
Biopsy’ to allow for collection of on-treatment biopsy from participants on capmatinib 
treatment 
• As applicable, Pregnancy Outcomes Reporting Consent for female participants or the 
female partners of any male participants who took study treatment 
• Home Nursing consent (if applicable) 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information. As per Section 4.6, during a public health emergency 
as declared by local or regional authorities i.e. pandemic, epidemic or natural disaster, that may 
challenge the ability to obtain a standard written informed consent due to limits that prevent an 
on-site visit, the Investigator may conduct the informed consent discussion remotely (e.g. 
telephone, videoconference) if allowable by a local health authority. 
Guidance issued by local regulatory bodies on this aspect prevails and must be implemented 
and appropriately documented (e.g. the presence of an impartial witness, sign/dating separate 
ICFs by trial participant and person obtaining informed consent, etc.). 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
 
8 
Visit schedule and assessments 
The assessment schedule in Table 8-2 and Table 8-3 lists all of the assessments when they are 
performed. All data obtained from these assessments must be supported in the participant’s 
source documentation. The table indicates which assessments produce data to be entered into 
the database (X) or remain in the source documents only (S). 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 pre-screening and screening. Main screening 
evaluations and baseline radiological tumor assessments should be performed within 28 days 
of treatment start. All visits are to be scheduled according to the appropriate number of calendar 
days from Cycle 1 Day 1 of study treatment administration. 
Please refer to Table 8-1 for allowable visits window. 


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Table 8-1 
Allowable window for participant assessments 
 
Visit Name 
Window allowed 
Screening 
-28 days to -1 day from first dose of study treatment 
Cycle 1 Day 1 
Within 3 days after randomization 
Cycle 1 Day 15 
±3 days 
Day 1 of all subsequent cycles and ET cycles 
±3 days 
Imaging evaluations 
±7 days 
PROs assessments 
• During the treatment and until progression: within 3 days 
prior to the visit 
• For EOT and post progression time points: ±7 days of the 
visit 
EOT and ET-EOT 
≤ 7 days after stopping study treatment for EOT 
30-Day Safety FUP 
+7 days 
Survival FUP 
±14 days 
Laboratory assessments performed as part of the screening evaluations will not be required to 
be repeated on the first day of dosing (Cycle 1 Day 1) (except hematology/chemistry and serum 
pregnancy test if not done within 72 hours prior to treatment start) unless deemed clinically 
necessary by the investigator and/or required as per local institutional policies. 
Every effort must be made to follow the schedule of assessments (Table 8-2 and Table 8-3) 
within the windows outlined in the assessment schedule in Table 8-1 or as close to the 
designated day/time as possible. If a given visit is out of window, the next visit should be 
performed with reference to the day of first dose in order to get the participant back on schedule. 
If an off-schedule imaging assessment is performed, subsequent imaging assessments should 
be performed in accordance with the original imaging schedule. Missed or rescheduled visits 
should not lead to automatic discontinuation. 
Participants who discontinue from study treatment are to return for the end of treatment visit as 
soon as possible, and attend the follow-up visits as indicated in the Assessment Schedule. 
Participants who discontinue from study or withdraw their consent/oppose the use of their 
data/biological samples should be scheduled for a final evaluation visit if they agree, as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and the adverse event and 
concomitant medications not previously reported must be recorded on the eCRF. 
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, alternative 
methods of providing continuing care may be implemented by the Investigator as the situation 
dictates. Depending on local regulations and operational capabilities, phone calls, virtual 
contacts (e.g. tele consult) or visits by site staff/home nursing staff to the participant´s home, 
can replace on-site study visits, for the duration of the disruption until it is safe for the 
participant to visit the site again. 


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Table 8-2 
Assessment schedule for capmatinib and docetaxel arms 
 
Period 
Screening 
Treatment 
Both capmatinib and docetaxel arms 
Post Treatment FUP 
Only if RECIST 1.1-defined PD not 
confirmed by BIRC at EOT. Both 
capmatinib and docetaxel arms 
Survival FUP 
Visit Name 
Molecular 
pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
and 
beyond 
EOT 
30- 
Day 
Safety 
FUP 
Efficacy 
and 
PROs 
FUP 
End of 
Post 
Treatment 
FUP 
Post PD 
PROs FUP 
Survival FUP 
Days 
- 
-28 to -1 
Day1 
Day 15 
Day 1 
- 
- 
- 
- 
- 
Every 12 weeks 
Informed consent for 
molecular pre-screening 
X 
Collection of PD-L1, EGFR 
wt and ALK rearrangement 
negative status 
X 
If ALK local testing not 
available, newly obtained 
tumor biopsy (preferred) or 
archival tumor sample for 
central confirmation of ALK 
negative rearrangement 
status 
X 
Newly obtained tumor 
biopsy (preferred) or 
archival tumor sample for 
central assessment of 
MET∆14 mutation status 
X 
Information on local testing 
for MET∆14 mutation status 
X 
IRT pre-screening 
registration 
X 
Inclusion / Exclusion criteria 
X 
X 
IRT eligibility check 
S 


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Period 
Screening 
Treatment 
Both capmatinib and docetaxel arms 
Post Treatment FUP 
Only if RECIST 1.1-defined PD not 
confirmed by BIRC at EOT. Both 
capmatinib and docetaxel arms 
Survival FUP 
Visit Name 
Molecular 
pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
and 
beyond 
EOT 
30- 
Day 
Safety 
FUP 
Efficacy 
and 
PROs 
FUP 
End of 
Post 
Treatment 
FUP 
Post PD 
PROs FUP 
Survival FUP 
Days 
- 
-28 to -1 
Day1 
Day 15 
Day 1 
- 
- 
- 
- 
- 
Every 12 weeks 
IRT registration 
X 
X 
X 
X 
Main informed consent 
X 
Demography 
X 
Medical history/current 
medical conditions 
X 
Diagnosis and stage of 
cancer 
X 
Smoking history 
X 
Prior antineoplastic therapy 
(meds, surgery, radiation) 
X 
Prior/concomitant 
medications 
Continuously from 28 days prior to first dose until 30 days after 
last dose of study treatment 
X1,2 
IRT randomization 
X 
Physical examination, 
including neurological 
exams 
S 
As clinically indicated 
Targeted physical 
examination 
S 
S 
S 
Performance status (ECOG) 
X 
X 
X 
X 
X1 
Body Height 
X 
Body Weight 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 


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Period 
Screening 
Treatment 
Both capmatinib and docetaxel arms 
Post Treatment FUP 
Only if RECIST 1.1-defined PD not 
confirmed by BIRC at EOT. Both 
capmatinib and docetaxel arms 
Survival FUP 
Visit Name 
Molecular 
pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
and 
beyond 
EOT 
30- 
Day 
Safety 
FUP 
Efficacy 
and 
PROs 
FUP 
End of 
Post 
Treatment 
FUP 
Post PD 
PROs FUP 
Survival FUP 
Days 
- 
-28 to -1 
Day1 
Day 15 
Day 1 
- 
- 
- 
- 
- 
Every 12 weeks 
HIV history (HIV testing 
where locally required) 
S 
Hematology 
X 
X 
X 
X 
X 
Clinical chemistry 
X 
X 
X 
X 
X 
Coagulation panel 
X 
As clinically indicated 
Urinalysis (dipstick) 
X 
As clinically indicated 
Pregnancy Test (serum) 
S (≤72 hr 
before 
C1D1) 
S 
Pregnancy test (urine) 
S 
Tumor evaluation 
X 
Cycle 3 
and then 
every 6 
weeks 
EOT scan 
not 
required if 
previous 
scan was 
performed 
≤28 days 
Every 6 
weeks 
Electrocardiogram (ECG) 
X 
X 
Cycle 2 
and if 
clinically 
indicated 
X 
Adverse Events 
Continuously from signing of main ICF until 30 days after last 
dose of study treatment 


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Period 
Screening 
Treatment 
Both capmatinib and docetaxel arms 
Post Treatment FUP 
Only if RECIST 1.1-defined PD not 
confirmed by BIRC at EOT. Both 
capmatinib and docetaxel arms 
Survival FUP 
Visit Name 
Molecular 
pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
and 
beyond 
EOT 
30- 
Day 
Safety 
FUP 
Efficacy 
and 
PROs 
FUP 
End of 
Post 
Treatment 
FUP 
Post PD 
PROs FUP 
Survival FUP 
Days 
- 
-28 to -1 
Day1 
Day 15 
Day 1 
- 
- 
- 
- 
- 
Every 12 weeks 
Serious Adverse Events 
Continuously from signing of pre-screening ICF until 30 days after last dose 
of study treatment. Before signing of main ICF, only SAEs suspected to be 
related to a study procedure are captured 
SAEs related to study treatment 
SAEs related to 
study treatment 
Pre-dose PROs (EORTC 
QLQ-C30, EORTC LC13, 
EQ-5D-5L) 
Collection on tablet 
X 
Cycle 3 
and then 
every 6 
weeks 
X 
Every 6 
weeks 
Pre-dose PROs (EORTC 
QLQ-C30, EORTC LC13, 
EQ-5D-5L) 
Collection via interview 
mode 
At 6, 12 
and 18 
weeks 
post-BIRC 
progression 
-for all 
capmatinib 
participants 
-only for 
docetaxel 
participants 
if 
participants 
not eligible 
to 
crossover 
or 
recovering 
from 


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Period 
Screening 
Treatment 
Both capmatinib and docetaxel arms 
Post Treatment FUP 
Only if RECIST 1.1-defined PD not 
confirmed by BIRC at EOT. Both 
capmatinib and docetaxel arms 
Survival FUP 
Visit Name 
Molecular 
pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
and 
beyond 
EOT 
30- 
Day 
Safety 
FUP 
Efficacy 
and 
PROs 
FUP 
End of 
Post 
Treatment 
FUP 
Post PD 
PROs FUP 
Survival FUP 
Days 
- 
-28 to -1 
Day1 
Day 15 
Day 1 
- 
- 
- 
- 
- 
Every 12 weeks 
docetaxel 
toxicities 
waiting for 
moving to 
crossover 
Capmatinib administration 
Continuous twice daily dosing [b.i.d.] 
Docetaxel administration 
X 
Every 
cycle 
Mandatory 
Blood sample for 
assessment of MET∆14 
status 
 
X 
X 
X3 
Cycle 3 
and then 
every 3 
cycles3 
X 
Mandatory, if medically 
feasible - Capmatinib arm 
only 
Newly obtained tumor 
biopsy. Archival material 
may be provided instead at 
Cycle 1 Day 1 
X 
X (if 
EOT=PD) 
Optional – Capmatinib 
arm only 


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Period 
Screening 
Treatment 
Both capmatinib and docetaxel arms 
Post Treatment FUP 
Only if RECIST 1.1-defined PD not 
confirmed by BIRC at EOT. Both 
capmatinib and docetaxel arms 
Survival FUP 
Visit Name 
Molecular 
pre- 
screening 
Screening 
Cycle 1 
Cycle 2 
and 
beyond 
EOT 
30- 
Day 
Safety 
FUP 
Efficacy 
and 
PROs 
FUP 
End of 
Post 
Treatment 
FUP 
Post PD 
PROs FUP 
Survival FUP 
Days 
- 
-28 to -1 
Day1 
Day 15 
Day 1 
- 
- 
- 
- 
- 
Every 12 weeks 
Food consumption4 - 
Capmatinib arm only 
X 
PK blood collection - 
Capmatinib arm only 
X 
Cycle 3 
Day 1 
Antineoplastic therapies 
(meds, surgery, radiation) 
since discontinuation of 
study treatment 
X 
X 
X 
X 
X 
Disposition 
X 
X 
X 
Survival (survival 
information can be obtained 
via telephone contact) 
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Only for participants with brain metastases at baseline 
2 Steroids collection only 
3 Capmatinib arm participants only 
4 Collect information on whether capmatinib was taken in fasted condition or with food 


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Table 8-3 
Assessment schedule for crossover participants 
 
Period 
Extension Treatment (ET) 
For docetaxel participants who crossover to capmatinib after BIRC- 
confirmed, RECIST 1.1-defined PD 
Survival FUP 
Visit Name 
ET-Cycle 1 
ET-Cycle 
2 and 
beyond 
ET-EOT 
Post-ET 30- 
Day Safety 
FUP 
Survival FUP 
Days 
Day 1 
Day 15 
Day 1 
- 
- 
Every 12 weeks 
IRT registration 
X 
X 
X 
Prior/concomitant medications 
Continuously from 28 days prior to first dose until 30 days after last dose 
of study treatment 
Physical examination, including neurological exams 
As clinically indicated 
Targeted physical examination 
S 
S 
S 
Performance status (ECOG) 
X 
X 
X 
Body Weight 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
Clinical chemistry 
X 
X 
X 
X 
Coagulation panel 
As clinically indicated 
Urinalysis (dipstick) 
As clinically indicated 
Pregnancy Test (serum) 
S 
Pregnancy test (urine) 
S 
Electrocardiogram (ECG) 
X 
ET-Cycle 
2 and if 
clinically 
indicated 
X 
Adverse Events 
Continuously from signing of main ICF until 30 days after last dose of 
study treatment 
Serious Adverse Events 
Continuously from signing of pre-screening ICF until 30 days after last 
dose of study treatment. Before signing of main ICF, only SAEs suspected 
to be related to a study procedure are captured 
SAEs related to 
study treatment 


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Period 
Extension Treatment (ET) 
For docetaxel participants who crossover to capmatinib after BIRC- 
confirmed, RECIST 1.1-defined PD 
Survival FUP 
Visit Name 
ET-Cycle 1 
ET-Cycle 
2 and 
beyond 
ET-EOT 
Post-ET 30- 
Day Safety 
FUP 
Survival FUP 
Days 
Day 1 
Day 15 
Day 1 
- 
- 
Every 12 weeks 
Pre-dose PROs (EORTC QLQ-C30, EORTC LC13, EQ-5D-5L) 
Collection via interview mode 
At 6, 12 and 18 weeks post-BIRC 
progression (if not collected during 
docetaxel post-treatment FUP) 
Capmatinib administration 
Continuous twice daily dosing [b.i.d.] 
Mandatory 
Blood sample for assessment of MET∆14 status and
 
 
X 
X 
ET- 
Cycle 3 
and then 
every 3 
cycles 
X 
Mandatory, if medically feasible 
Newly obtained tumor biopsy. Archival material may be provided 
instead at Cycle 1 Day 1 
X 
X (if ET-EOT=PD) 
Optional 
 
Antineoplastic therapies (meds, surgery, radiation) since 
discontinuation of study treatment 
X 
X 
Disposition 
X 
Survival (survival information can be obtained via telephone 
contact) 
X 


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8.1 
Molecular pre-screening 
In order to be considered eligible for the study, participants must have written documentation 
of EGFR wt and ALK rearrangements negative NSCLC (not required for participants with pure 
squamous cell histology, for additional details see Section 5.1). The results from procedures 
performed as part of the local standard practices (prior to enrolling in the trial) will satisfy the 
inclusion criteria. 
Additionally, eligible participants must have METΔex14 mutation status determined in their 
tumor tissue sample by the Novartis-designated central laboratory using a validated real time 
Reverse Transcription (RT) Polymerase Chain Reaction (PCR) test that detects exon 14-deleted 
MET mRNA derived from formalin fixed, paraffin-embedded human tissue. The central MET 
Δex14 mutation test is investigational and is sufficiently validated for the purposes of selecting 
participants with a MET Δex14 mutation in their NSCLC tumor sample for enrollment to this 
trial. The central test report must be received to confirm eligibility prior to entering main 
screening. 
In cases where it is medically infeasible for the participant to wait for the central METΔex14 
mutation result, a local test result may be acceptable for METΔex14 mutation status. The local 
test must be validated according to local regulation and detect mutations leading to MET exon 
14 deletions (METΔex14) in DNA or RNA extracted from a tumor tissue sample. Results from 
immunohistochemistry tests are not accepted. Positive METΔ14 mutation status must be 
documented in the participant’s source documents and in the CRF to confirm eligibility prior 
to entering main screening. In cases where there is insufficient evidence that the MET gene 
alteration detected from the local test leads MET exon 14 deletion, central testing should be 
performed to confirm METΔ14 status for eligibility. In addition for eligibility, a tumor tissue 
sample must be submitted with sufficient quality and quantity (as outlined in the study 
[laboratory manual]) to allow for retrospective central assessment of MET∆ex14 mutation 
status using the RT-PCR assay at a Novartis-designated laboratory. If the retrospective central 
result is negative for the presence of a MET∆ex14 mutation, participants will not be excluded 
from the study. 
All participants will be asked to sign and date an IRB/ IEC approved “Molecular pre-screening 
informed consent form” before their tumor sample is sent to the Novartis-designated central 
laboratory. 
A newly obtained tumor biopsy (preferred) or archival tumor tissue (block or slides) must be 
submitted to the Novartis-designated laboratory to test for METΔex14 mutation status for all 
participants. Archival tumor tissue obtained at the time of diagnosis of NSCLC or any time 
prior to patient enrolling in the study is acceptable. If more than one archival tissue sample is 
available, tissue from the most recent biopsy is preferred. The quality/quantity of the tumor 
sample for METΔex14 testing will be determined at the Novartis-designated central laboratory. 
Tumor samples must contain at least 10% tumor content and the minimum effective tumor area 
specified in the study [laboratory manual]. Samples obtained from bone metastases and 
cytology samples are not acceptable. Additionally, a blood sample (2 x 10 mL) will be collected 
at the Pre-screening visit for potential development of liquid biopsy in vitro diagnostic test(s), 
such as companion diagnostic(s). 


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If ALK testing is not available locally, confirmation of ALK-negative rearrangement status at 
a Novartis-designated central laboratory using a validated ALK test is required to confirm the 
participant's eligibility. In this case, additional tumor sample slides will be provided (unless a 
tumor block was submitted) and used for METΔex14 mutation testing as well as ALK 
rearrangement testing and should be indicated in the appropriate eCRF and requisition forms. 
If a tumor block or newly obtained biopsy is provided, the remaining tissue from pre-screen 
failure samples will be returned to the site. 
 
 
 
 
 
 
 
 
Where the result is required for eligibility, the results from central testing will be communicated 
to the respective study center by the Novartis-designated central laboratory. Details on the 
collection, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in a separate [laboratory manual]. 
MET∆ex14 mutation (and ALK, if applicable) testing may be performed while participant is 
still receiving anti-cancer therapy. However, the participant can only be screened for the main 
study once the participant has discontinued the last prior systemic treatment due to either disease 
progression or intolerance (Note: participants must have progressed on at least one prior line of 
systemic therapy; for additional details see Section 5.1). 
8.2 
Screening 
The study IRB/IEC approved informed consent form must be signed and dated before any 
screening procedures are performed, except for laboratory and radiological evaluations which 
were performed as part of the participant’s clinical standard of care within the acceptable 
screening window. 
Participants will be evaluated against study inclusion and exclusion criteria and safety 
assessments (refer to Table 8-2). Screening assessments must be repeated if performed outside 
of the specified screening window (Table 8-1). Participants must meet all inclusion and none 
of the exclusion criteria at screening in order to be eligible for the study. 
Laboratory assessments performed as part of the screening evaluations will not be required to 
be repeated prior to dosing (except hematology/chemistry and serum pregnancy test if not done 
within 72 hours prior to treatment start) unless deemed clinically necessary by the investigator 
and/or required as per local institutional policies. 
Laboratory test result(s) or symptoms that do not satisfy the eligibility criteria may be repeated 
or treated during the screening visit window. In the event that the repeated laboratory test(s) 
cannot be performed within 28 days from the original screening visit, or do not meet the 


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eligibility criteria, or other eligibility criteria have changed and are not met anymore, the 
participant is considered a screening failure. 
Re-screening of a participant who has failed screening may be allowed. In such cases, a new 
ICF must be signed. A new participant number will be assigned to the participant. The re-screen 
form will have to be completed in the eCRF and in IRT to provide the original participant 
number. 
All required screening assessments must be repeated if they do not meet the allowed time 
window for screening when the participant is re-screened for participation in the study. An 
individual participant can only be re-screened once for the study. 
Once the number of participants screened and enrolled is likely to ensure target enrollment, the 
Sponsor may close the study to further screening. In this case, the participants who screen failed 
will not be permitted to re-screen. 
Participants who are screened and eligibility confirmed in IRT system, but fail to start treatment, 
e.g. participants confirmed in IRT in error, will be considered as early terminations. The reason 
for early termination should be recorded on the appropriate eCRF. 
8.2.1 
Eligibility screening 
When all screening procedures are completed and once the participant’s eligibility has been 
checked and confirmed (i.e., all inclusion/exclusion criteria have been verified), the key 
eligibility criteria checklist will be completed prior to the first dose of study treatment in the 
IRT system by the investigator or designee. The eligibility check will be embedded in the IRT 
system. Allocation to one of the two study arms will also be registered via IRT. 
Please refer to Section 6.3.2 for further details on treatment assignment/randomization as well 
as comply with detailed guidelines in the IRT manual. 
8.2.2 
Information to be collected on screening failures 
Both participants who sign a molecular pre-screening informed consent form but are a 
molecular pre-screening failure, as well as participants who sign the main informed consent 
form and subsequently found to be ineligible prior to randomization will be considered a screen 
failure and data will be handled in the same manner. The reason for screen failure should be 
recorded on the appropriate eCRF page. 
The following eCRF pages must be completed for screening failure patients: 
• EGFR and ALK status as per participant’s record 
• PD-L1 status as per participant’s record 
• Information on prior local testing for MET mutation status (if available) 
• Tumor samples collection (archival or newly obtained) for central confirmation of MET 
mutation status and ALK (if local ALK status is not available) 
• NSCLC diagnosis and extent of disease 
• Date of diagnosis and stage of NSCLC 
• Site of active disease 
• Characteristics of disease 


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• Screening phase disposition 
• Demography 
• Informed consent 
• Inclusion/Exclusion Criteria 
• Withdrawal of consent (if applicable) 
• Death (if applicable) 
No other data will be entered into the clinical database for participants who are screen failures, 
unless the participant experienced a serious adverse event (SAE) during the screening phase 
(see SAE section for reporting details). For molecular pre-screening failures, only SAEs 
possibly related to a study procedure (i.e. tumor biopsy collection) will be reported to the 
Novartis Safety group. 
The demographic information, informed consent, diagnosis and extent of cancer, and 
Inclusion/Exclusion pages must also be completed for screen failure participants. No other data 
will be entered into the clinical database for participants who are screen failures, unless the 
participant experienced a serious adverse event during the screening phase (see Section 10.1.2 
and Section 10.1.3 for reporting details). If the participant fails to be randomized, the IRT must 
be notified within 2 days of the screen fail that the participant was not randomized. 
Participants who are randomized and fail to start treatment, e.g. participants randomized in error, 
will be considered an early terminator. The reason for early termination should be recorded on 
the appropriate Case Report Form. 
8.3 
Participant demographics/other baseline characteristics 
Data to be collected on participant characteristics at screening include: 
• Demography (age, gender, race and ethnicity, or as allowed by local regulations). 
Participant race and ethnicity are collected and analyzed to identify variations in safety or 
efficacy due to these factors as well as to assess the diversity of the study population as 
required by Health Authorities 
• Other background or relevant medical history (including smoking history) / (serious) 
adverse events 
• Cancer characteristics including diagnosis, history, extent of cancer, baseline tumor 
mutation status (EGFR, ALK and MET), baseline PD-L1 tumor status, prior antineoplastic 
therapies (medications, radiation, surgeries), and date of progression prior to study entry 
• Tumor imaging assessments 
• Other assessments to be completed for the purpose of determining eligibility (ECOG PS, 
complete physical examination, vital signs, hematology, blood chemistry, coagulation 
studies, urinalysis, HIV testing where locally required [only recorded in source 
documentation], serum pregnancy test for women of child-bearing potential [only recorded 
in source documentation], and 12-Lead ECG) 
• Prior and current concomitant medications and surgical and medical procedures 
Data to be collected on Cycle 1 Day 1 (C1D1) pre-dose include: 
• Patient Reported Outcomes (PROs) 


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• 12-Lead ECG 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with the eCRF. 
8.4 
Efficacy 
8.4.1 
Tumor imaging assessments 
Tumor response will be assessed locally and centrally according to the Novartis guideline 
version 3.2 (Section 16.1) based on RECIST 1.1 (Eisenhauer et al 2009). In addition, CNS 
lesions will be assessed by BIRC according to the Novartis guideline version 1 based on 
Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria 
(Section 16.2). 
Participants should have at least one documented measurable lesion at study entry as per 
RECIST 1.1. The imaging assessment collection plan is presented in Table 8-4. The central 
review of the scans will be carried out in a blinded fashion. Further details of the central review 
process will be described in the BIRC charter. 
Imaging data will be centrally collected and checked for quality by an imaging Contract 
Research Organization (CRO) designated by Novartis. The results of the central evaluations 
will be used for primary analysis purposes. The local investigator’s assessment will be used for 
the secondary endpoint analysis and for treatment decision making. 
Information regarding prior interventions (e.g. radiotherapy), pre-existing radiographic findings 
that mimic metastatic disease at baseline/screening and prior interventions should be 
transmitted to the imaging CRO via the Baseline Clinical Form along with the baseline images 
for review by the independent radiologist. Sites must ensure the data entered on the form is 
consistent with the data entered in the clinical database. 
Information regarding cytology results should be transmitted to the imaging CRO via the 
Cytology Form for all visits, when applicable, for review by the independent radiologist. Sites 
must ensure the data entered on the form is consistent with the data entered in the clinical 
database. 
Details regarding collection and shipment of additional information required for imaging 
assessment including RANO-BM assessment by BIRC will be described in the imaging manual 
provided by the designated CRO. 
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, the 
collection of images (e.g. change of imaging center or imaging frequency) may be modified by 
Novartis and will be communicated to the investigator. 


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Table 8-4 
Imaging Assessment Collection Plan 
 
Procedure 
Screening/Baseline 
During Treatment/Follow-up 
Chest and abdomen CT or MRI 
(with intravenous contrast 
enhancement) 
Mandated 
Mandated 
Starting at Cycle 3: every 6 
weeks (+/- 7 days) thereafter until 
RECIST 1.1-defined PD as 
assessed by the investigator and 
confirmed by BIRC. 
At End of Treatment if not done 
within 28 days. 
Post Treatment Follow-Up: for 
participants with EOT reason other 
than disease progression, 
withdrawal of consent, lost to 
follow up, or death will continue 
collect imaging and follow the 
same schedule of every 6 weeks 
(+/- 7 days) thereafter until 
RECIST 1.1-defined PD as 
assessed by the investigator and 
confirmed by BIRC 
Pelvis CT or MRI (with intravenous 
contrast enhancement) 
Mandated 
Only if lesions were documented at 
baseline or if clinically indicated; 
follow the same schedule as 
CT/MRI of chest and abdomen 
Brain MRI (with intravenous 
contrast enhancement) 
Mandated 
Only if lesions were documented at 
baseline or if clinically indicated; 
follow the same schedule as 
CT/MRI of chest and abdomen. 
Whole body bone scan 
Mandated 
If clinically indicated 
Localized bone CT, MRI, or x-ray 
Mandated for any lesions identified 
on the whole body bone scan that 
are not visible on the chest, 
abdomen and pelvis CT or MRI 
Only if lesions were documented at 
baseline or if clinically indicated; 
follow the same schedule as 
CT/MRI of chest and abdomen 
Color photography (with 
scale/ruler) 
Mandated for any skin lesions 
present 
Only if lesions were documented at 
baseline or if clinically indicated; 
follow the same schedule as 
CT/MRI of chest and abdomen 
CT or MRI of other metastatic sites 
(e.g. neck) 
If other metastatic sites are 
suspected 
Only if lesions were documented at 
baseline or if clinically indicated; 
follow the same schedule as 
CT/MRI of chest and abdomen 
8.4.1.1 
Baseline imaging assessments 
Imaging assessments will be performed at screening/baseline within 28 days of start of 
treatment (Day -28 to Day -1 prior to Cycle 1 Day 1) as per Table 8-4. 
Any imaging assessments already completed during the regular work-up of the participant 
within 28 days prior to start of treatment, including before signing the main study ICF, can be 
considered as the baseline images for this study. Any imaging assessments obtained after 
randomization cannot be considered baseline images. 
If a participant is known to have a contraindication to CT intravenous (IV) contrast media or 
develops a contraindication during the trial, a non-contrast CT of the chest (MRI is not 


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recommended due to respiratory artifacts; however, if CT is not feasible per local regulations, 
MRI can be performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen and 
pelvis should be performed. 
Contrast enhanced brain MRI must be completed for all participants unless MRI contrast is 
contraindicated. If MRI contrast is contraindicated, then MRI without contrast or CT 
with/without contrast is acceptable. 
A whole body bone scan should be performed per institutional standard of care [e.g. Tc-99 bone 
scan, whole body bone MRI, Fluorodeoxyglucose positron emission tomography (FDG-PET), 
or sodium fluoride (NaF) PET]. Localized CT, MRI, or X-rays should be acquired for all 
skeletal lesions identified on the screening whole body bone scan, which are not visible on the 
chest, abdomen, and pelvis CT/MRI. 
If clinically indicated, CT or MRI of other areas (e.g. neck) of disease as appropriate should be 
performed. 
If skin lesions are present at screening, color photography should be acquired using a digital 
camera in clear focus, including a scale/ruler, in such a way that the size of the lesion(s) can be 
determined from the photograph. 
Combined PET/CT may be used only if the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of i.v. contrast media. At the discretion of the 
investigators, FDG-PET scans may be performed to document PD per RECIST 1.1 
(Section 16.1). 
Any potentially measurable lesion that has been previously treated with radiotherapy should be 
considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable 
lesion. 
Chest x-rays and ultrasound should not be used to measure tumor lesions. 
8.4.1.2 
Post-baseline imaging assessments 
Imaging assessments as described in Table 8-4 should be performed at the time points specified 
using the same imaging modality used at baseline, irrespective of study treatment interruption 
or actual dosing (see Table 8-1). Imaging assessments for response evaluation will be performed 
starting at Cycle 3 every 6 weeks (+/- 7 days) thereafter until RECIST 1.1-defined PD as 
assessed by the investigator and confirmed by BIRC, death, lost to follow-up, or withdrawal of 
consent. Imaging assessments should be scheduled using the date of first dose of study treatment 
as the reference date (not the date of the previous tumor assessment) and should be respected 
regardless of whether treatment with study treatment is temporarily withheld or unscheduled 
assessments performed. If an unscheduled imaging assessment is performed because 
progression is suspected, subsequent imaging assessments should be performed in accordance 
with the original imaging schedule. 
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a participant, as necessary. 
Clinical suspicion of disease progression at any time requires a physical examination and 


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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. 
All study imaging (including any off-schedule study imaging) should be submitted to the 
designated imaging CRO for quality control and review by BIRC, promptly after acquisition. 
8.4.1.3 
Confirmation of disease progression by BIRC 
Time points at which progression is determined locally 
All participants who have disease progression determined by the local investigator require an 
expedited central review. Rapid image transmission to the imaging CRO may be accomplished 
by transferring the images electronically, e.g. via the Internet. In all instances, the process at the 
imaging CRO will ensure that the central reviewers remain blinded to the results of the local 
assessment and the expedited nature of the review. The investigator seeking an expedited review 
must indicate this request to the imaging CRO on a designated form or by alternative means. 
The imaging will undergo expedited central review (within 5 business days from the time of 
image receipt at the imaging CRO and once all applicable queries are resolved) and the results 
of the central review will be communicated to the site. While the investigator is awaiting the 
results of the central review, it is preferable that the participant continue on study treatment. 
However, during this time, the investigator should do whatever is medically necessary for 
his/her participant. 
If the central review determines disease progression, then the participant will discontinue study 
treatment and subsequent tumor assessments are no longer required. 
If the central review does not determine disease progression, the participant should continue 
receiving the study treatment until disease progression has been determined by the BIRC or, as 
a minimum requirement, until at least one additional tumor assessment has been completed, 
unless there is a medical need (i.e. rapid progression or clinical deterioration) for an immediate 
change in therapy. 
Participants will continue to have imaging performed as per protocol (Table 8-2 and Table 8-4) 
until the central review determines disease progression. 
For participants who crossed-over from the docetaxel arm to capmatinib arm, the disease 
progression on capmatinib treatment will be determined based on investigator assessment. 
Imaging assessment should be performed according to local practice and institutional guidelines. 
Reason for discontinuation and date of disease progression will be captured in the eCRF. 
 
 
 
 


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Time points without locally determined progression 
All imaging time points without locally determined progression will be read on an ongoing, 
non-expedited basis as detailed in the imaging manual to be provided by the designated imaging 
CRO and independent review charter. Results of these readings will not be communicated to 
the sites. 
Treatment beyond disease progression 
Following determination of disease progression, if the investigator believes the participant may 
derive benefit from continuing study treatment, the participant will be permitted to continue 
treatment beyond initial disease progression as per RECIST 1.1. Please see Section 6.1.5.1 for 
additional information. 
8.4.1.4 
Efficacy follow-up imaging assessments 
For participants who discontinue treatment for reasons other than disease progression as 
assessed by the investigator and confirmed by BIRC, tumor assessments must continue to be 
performed as outlined in Table 8-2. Please refer to Section 9.3 for additional information. 
8.4.2 
Appropriateness of efficacy assessments 
Tumor assessments every 6 weeks of chemotherapy are consistent with the standard clinical 
practice. Different guidelines for advanced NSCLC recommend response assessment every 6- 
12 weeks after first line therapy. In participants with NSCLC previously treated with platinum- 
based chemotherapy, the median PFS with docetaxel treatment is approximately 3 months or 
12 weeks. Conducting tumor evaluations more than 6 weeks apart may expose a participant to 
an unnecessary treatment if the disease progression event takes place between the infrequent 
assessments or prevent from early identification of progression lesions and appropriate 
treatment. 
8.4.3 
Overall Survival 
All participants will enter the survival follow-up period once they complete all study 
assessments per protocol, as applicable. Survival status will be collected every 12 weeks 
regardless of treatment discontinuation reason (except if consent is withdrawn or participant is 
lost to follow-up) until death, lost to follow-up, or withdrawal of consent for survival follow- 
up. 
Additional survival assessments may be performed outside the 12 weeks follow-up schedules 
if a survival update is required for an interim assessment to meet safety or regulatory needs. 
Survival information can be obtained via phone, and information will be documented in the 
source documents and relevant eCRFs. At this time, the investigator will record any SAEs that 
may have occurred after discontinuation of study treatment if the investigator suspects a causal 
relationship to study treatment. Information on the therapies received for NSCLC, if any, after 
study treatment has been discontinued will be collected. 


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8.5 
Safety 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, regular 
phone or virtual calls can occur (every 3 weeks or more frequently, if needed) for safety 
monitoring and discussion of the participant´s health status until it is safe for the participant to 
visit the site again. 
For details on AE collection and reporting, refer to AE Section 10.1. 
Table 8-5 
Physical Assessments 
 
Assessments 
Specification 
Physical examination 
Significant findings that were present prior to the signing of informed consent 
must be included as medical history on the participant’s eCRF. Significant new 
findings that begin or worsen after informed consent must be recorded as an 
adverse event on the appropriate eCRF. 
Physical examination 
At screening, a complete physical examination will be performed including the 
examination of general appearance, skin, neck (including thyroid), eyes, ears, 
nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular, 
and neurological systems. More frequent examinations may be performed at 
the discretion of the investigator and if medically indicated. Information about 
the physical examination must be present in the source documentation. 
Targeted physical examination 
A targeted physical exam will be performed at day 1 of each cycle during 
treatment and at EOT as indicated in Table 8-2 and Table 8-3, except where a 
complete physical examination is required (see above). It will include at least 
the examination of general appearance and vital signs (blood pressure [SBP 
and DBP] and pulse). If indicated based on symptoms, additional exams will 
be performed. 
Information for all physical examinations must be included in the source 
documentation at the study site and additionally reported in appropriate eCRF 
pages for blood pressure (SBP and DBP), vital signs, height and weight. For 
participants with brain metastases neurological status will also be evaluated at 
the time of radiological assessments. 
Vital signs 
Vital signs include blood pressure (supine position preferred when ECG is 
collected), pulse measurement, and body temperature. They will be measured 
at screening and at subsequent time points as specified in 
Table 8-2 and Table 8-3. 
Height and weight 
Height will be measured at screening. 
Body weight (in indoor clothing, but without shoes) will be measured at 
screening and at subsequent time points as specified in Table 8-2 and Table 
8-3. 
Performance status 
The performance status will be assessed according to the ECOG Performance 
Status Scale as specified in Table 8-6 following the schedule given in 
Table 8-2 and Table 8-3. 
The ECOG performance status scale will be used as described in Table 8-6 following the 
schedule given in Table 8-2 and Table 8-3. 


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Table 8-6 
ECOG Performance Status 
 
Grade 
ECOG status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
8.5.1 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens collected, except urinalysis, 
pregnancy testing and HIV testing (where locally required), which will be performed locally. 
Details on the collections, shipment of samples and reporting of results by the central laboratory 
are provided to investigators in the [laboratory manual]. 
Local laboratory assessments may be performed instead of central laboratory assessments if 
medically indicated or when the treating physician cannot wait for central laboratory results for 
decision making. In this particular situation, the blood sample obtained at the same time point 
should be submitted to the central laboratory for analysis in parallel with local analysis. 
The results of the local laboratory will be recorded in the CRF if the following criteria are met: 
• a treatment decision was made based on the local results, or 
• there are no concomitant central results available 
As per Section 4.6, during a public health emergency as declared by local or regional authorities, 
i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, if 
participants cannot visit the site for protocol -specified safety lab assessments, an alternative 
lab (local) collection site may be used. 
For assessment of participants’ eligibility to the study, only laboratory results from the central 
laboratory will be used. 
Table 8-7 
Central clinical laboratory parameters collection plan 
 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, White blood cells, Differential [Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands, Other. Absolute value 
preferred, %s are acceptable unless indicated otherwise] 
Chemistry 
Albumin, Alkaline phosphatase, ALT, AST, Gamma-glutamyl-transferase (GGT), 
Calcium, Magnesium, Phosphate, Sodium, Potassium, Creatinine, Creatine kinase, 
Creatinine Clearance, Total Bilirubin, Direct Bilirubin (only if total bilirubin is ≥ grade 
2), Blood Urea Nitrogen (BUN) or Urea. 
Amylase, Lipase, Glucose (fasting) (non-fasting allowed post-baseline). 
Bicarbonate, Chloride, Uric Acid at screening and thereafter if clinically indicated. 
Urinalysis 
Local laboratory: Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, 
Ketones, Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen). 
If dipstick is abnormal then perform local laboratory Microscopic Panel (Red Blood 
Cells, White Blood Cells, Casts, Crystals, Bacteria, Epithelial cells). 


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Test Category 
Test Name 
Coagulation 
Prothrombin time (PT) or Quick Test (QT), INR 
Pregnancy Test 
At screening (and/or Cycle 1 Day 1) a serum pregnancy test is to be performed 
within 72 hr before the first dose (either of capmatinib or docetaxel), while during the 
study (Day 1 of each cycle) urine pregnancy tests are sufficient. An End of 
Treatment serum pregnancy test is also required to be performed. 
For women considered to be post-menopausal and not of child bearing potential, 
pregnancy testing is not required. 
If a serum pregnancy test is required as per local practice at day 1 of every cycle, 
the urine pregnancy test does not need to be repeated. 
Infection markers 
HIV testing (where locally required) 
8.5.1.1 
Hematology 
Hematology tests are to be performed according to the Visit Schedules outlined in 
Table 8-2 and Table 8-3. For details of the hematology panel refer to Table 8-7. Hematology 
should be assessed on the actual scheduled day, even if study treatment is being withheld. 
Laboratory assessment done ≤ 3 days of first dose of study treatment are permitted to be used 
as Cycle 1 Day 1 labs and do not need to be repeated. 
More frequent hematology testing may also be performed as medically necessary. Additional 
results from unscheduled hematology lab evaluations should be recorded on the appropriate 
unscheduled visit eCRF. 
8.5.1.2 
Clinical chemistry 
Clinical chemistry tests are to be performed according to the visit schedule outlined in Table 8-2 
and Table 8-3. For details of the biochemistry panel see Table 8-7. Biochemistry should be 
assessed on the actual scheduled day, even if study treatment is being withheld. 
Chemistry lab tests done as part of screening assessments ≤ 3 days prior to the first dose of 
study treatment do not need to be repeated. 
More frequent chemistry testing may also be performed as medically necessary. Additional 
results from unscheduled chemistry lab evaluations should be recorded on eCRF as unscheduled 
visit. 
8.5.1.3 
Urinalysis 
Urinalysis Dipstick measurements will be performed as per Table 8-7 and according to the 
schedule of assessments (Table 8-2). Any significant findings on dipstick will be followed up 
with microscopic evaluation. 
8.5.1.4 
Coagulation 
Coagulation tests outlined in Table 8-7 will be performed according to the visit schedule 
outlined in Table 8-2 and Table 8-3, as applicable. 


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8.5.2 
Electrocardiogram (ECG) 
Electrocardiograms (ECGs) must be recorded after 10 minutes rest in the supine position to 
ensure a stable baseline/according to the ECG investigator manual. The preferred sequence of 
cardiovascular data collection during study visits is ECG collection first, followed by vital signs, 
and blood sampling. 
Standard triplicate 12 lead ECG recording will be performed at the time points indicated in 
Table 8-8. The individual ECGs should be recorded approximately 2 minutes apart. The 
Fridericia QT correction formula (QTcF) should be used for clinical decisions. The mean QTcF 
value for each visit will be calculated from the triplicate ECGs for each participant. 
For any ECGs with participant safety concerns, two additional ECGs must be performed to 
confirm the safety finding. A monitoring or review process should be in place for clinically 
significant ECG findings throughout the study and especially at baseline before administration 
of study treatment. 
Clinically significant abnormalities must be recorded on the eCRF as either medical 
history/current medical conditions or adverse events as appropriate. 
ECGs are to be collected with machines available at the site. Interpretation of the tracing must 
be made by a qualified physician and documented on the appropriate eCRF. Each ECG tracing 
should be labeled with the study number, participant initials (where regulations permit), 
participant number, date, and kept in the source documents at the study site. Clinically 
significant abnormalities present at screening should be reported on the appropriate eCRF. 
Clinically significant findings must be discussed with Novartis prior to randomizing the 
participant in the study. New or worsened clinically significant findings occurring after 
informed consent must be recorded as adverse events. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically significant 
findings should be collected in triplicate. Local cardiologist ECG assessment may also be 
performed at any time during the study at the discretion of the investigator. 
For all participants (capmatinib, docetaxel, and crossover arms): 
Table 8-8 
Local ECG collection plan 
 
Cycle 
Day 
Time 
ECG Type 
Screening (not required for crossover arm) 
Anytime 
12 Lead, triplicate 
1 
1 
Pre-dose 
12 Lead, triplicate 
2 
1 
Pre-dose 
12 Lead, triplicate 
2 hours post-dose 
12 Lead, triplicate 
End of Treatment 
Anytime 
12 Lead, triplicate 
Unscheduled 
Anytime if clinically 
indicated 
12 Lead, triplicate 


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8.5.3 
Pregnancy and assessments of fertility 
Participants are required to use highly effective methods of contraception during the study and 
for the follow-up time period as specified in Section 5.2. For a definition of highly effective 
contraception, assessment of fertility (males and females), and the definition of post- 
menopausal, please refer to Section 5.2. 
All women of child-bearing potential will have a serum pregnancy test within 72 hours prior to 
the first dose of study treatment. hCG may also be considered a tumor marker, therefore if hCG 
levels are detected, another blood sample at least 4 days later must be taken to assess the kinetics 
of the increase, and a transvaginal ultrasound must be performed to rule out pregnancy. 
Urine pregnancy tests will be required to be performed on Day 1 of every cycle beginning with 
Cycle 2, followed by serum pregnancy test at the end of treatment visit. 
Women of child-bearing potential will be instructed to contact the site immediately at any time 
during the study (on-treatment or during follow-up) should they have a positive pregnancy test. 
In case of positive urine pregnancy testing, additional testing must be performed to confirm the 
pregnancy, and, if confirmed, follow the reporting requirements as described in Section 10.1.4. 
A positive pregnancy test requires immediate discontinuation of study treatment. If a positive 
pregnancy test is performed in between study visits, the participant must immediately notify the 
investigator. Male participants must notify the investigator in case their partner is confirmed 
with positive pregnancy test results during the treatment period. See Section 10.1.4 for 
pregnancy reporting. 
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster that limits or prevents participants from visiting the 
site to have serum pregnancy tests, urine pregnancy test kits may be used. Relevant participants 
can perform the urine pregnancy test at home and report the result to the site. It is important 
that participants are instructed to perform the urine pregnancy test first and only if the test result 
is negative proceed with the administration of the study treatment. A communication process 
should be established with the participant so that the site is informed of the pregnancy test 
results. Country specific measures should be put in place to ensure site verifies the accuracy of 
the reported results. 
Local pregnancy test and associated results will not be collected on the eCRF. 
Assessments of fertility 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child- 
bearing potential must also be available as source documentation in the following cases: 
1. Surgical bilateral oophorectomy without a hysterectomy 
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, Follicle Stimulating Hormone (FSH) 
testing is required of any female participant regardless of reported reproductive/menopausal 
status at screening/baseline. 


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For both treatment arms, when non-child-bearing potential status is determined during the study, 
further pregnancy testing will not be continued. For further details on the assessment of fertility, 
please refer to the study exclusion criteria in Section 5.2. 
If local requirements dictate otherwise, local regulations should be followed. 
8.5.4 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population. 
8.6 
Additional assessments 
8.6.1 
Clinical Outcome Assessments (COAs) 
Patient reported outcomes (PRO) 
A PRO is a measurement based on a report that comes from the participant (i.e., study 
participant) about the status of a participant’s health condition without interpretation of the 
participant’s report by anyone else. A PRO can be administered by self-report or by interview, 
provided that a trained site staff records only the participant’s response. Symptoms or other 
unobservable concepts known only to the participant (e.g., pain severity or nausea) can only be 
captured by PRO measures. PROs can also assess the participant perspective on functioning or 
activities that may also be observable by others. 
The European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire (EORTC-QLQ-C30, and QLQ-LC13) and the EuroQoL 5-level instrument (EQ- 
5D-5L, tablet version) will be used to evaluate patient-reported outcome measures of health- 
related quality-of-life, functioning, disease symptoms, treatment-related adverse experience, 
and global health status. The EORTC QLQ-C30, QLQ-LC13 are frequently used in clinical 
trials of participants with advanced or metastatic lung cancer (Aaronson et al 1993). 
The EORTC QLQ-C30 is a questionnaire developed to assess the quality of life of cancer 
patients which has been translated and validated into 81 languages and has been used in more 
than 3,000 studies worldwide. The questionnaire contains 30 items and is composed of both 
multi-item scales and single-item measures based on the patients experience over the past week. 
These include five scales (physical, role, emotional, cognitive and social functioning), three 
symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, 
appetite loss, constipation, diarrhea and financial impact) and a global health status/QoL scale. 
All of the scales and single-item measures range in score from 0 to 100. A high scale score 
represents a higher response level. Thus a high score for a functional scale represents a high / 
healthy level of functioning; a high score for the global health status / QoL represents a high 
QoL, but a high score for a symptom scale / item represents a high level of 
symptomatology/problems. All scoring will follow the scoring procedures defined by the 
EORTC Scoring Manual (Fayers 2001). 
The QLQ-LC13 is used in conjunction with the EORTC QLQ-C30 and provides information 
on an additional 13 items specifically related to lung cancer. The five domains of the LC13 
include pain, dyspnea, coughing and hemoptysis, and are based on their presence over the past 
week. All but the pain domain are scored on a 4 point Likert scale ranging from “not at all” to 


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“very much”. Pain is score based on its presence, hence yes or no. A higher score indicates a 
higher presence of symptoms (Bergman et al 1994). 
The EQ-5D-5L is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal 
(The EuroQol Group 1990). The EQ-5D 5L is designed for self-completion by respondents and 
takes only a few minutes to complete. Instructions to respondents are included in the 
questionnaire. The EQ-5D-5L consists of 2 pages – the descriptive system and the EQ visual 
analogue scale (EQ VAS) (Herdman et al 2011). The descriptive system comprises 5 
dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each 
with 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme 
problems. The participant is asked to indicate his/her health state by ticking (or placing a cross) 
in the box against the most appropriate statement in each of the 5 dimensions. This decision 
results in a 1-digit number expressing the level selected for that dimension. The EQ VAS 
records the participant’s self-rated health on a 20 cm vertical, visual analogue scale with 
endpoints labeled ‘the best health you can imagine’ and ‘the worst health you can imagine’ 
(Rabin and de Charro 2001). 
PRO data will be collected using an electronic device during treatment and post-treatment 
follow-up period and administered by interview over phone in the post-progression period. All 
PRO assessments should be administered in the participant’s local language and according to 
the visit schedule in Table 8-2 and Table 8-3, prior to any tests, treatments or receipt of results 
from any test to avoid biasing the participant’s perspective. 
The PRO questionnaires should be completed using an electronic device on Cycle 1 Day 1(or 
within 3 days prior to this visit), Cycle 3 Day 1 (≤3 days) and then every 6 weeks (≤3 days) 
until End of Treatment (EOT) visit and then: 
• For participants who discontinue treatment (capmatinib or docetaxel) due to BIRC- 
confirmed, RECIST 1.1-defined PD and enter the safety follow-up period, PROs will be 
collected at EOT (±7 days) and by telephone interview on paper interviewer scripts at 6, 12 
and 18 weeks (±7 days) post-progression. 
• For participants who discontinue study treatment (capmatinib or docetaxel) for any reason 
other than BIRC-confirmed, RECIST 1.1-defined PD and enter the efficacy follow-up 
period, PROs will be collected on electronic device at the same timepoints as the imaging 
assessments (every 6 weeks) until RECIST 1.1-defined PD. Following progression, PROs 
will then be collected within 7 days of the 
• reported progression, by telephone interview on paper interviewer scripts at 6, 12 and 18 
weeks (±7 days) post-progression. 
• For participants who discontinue docetaxel treatment and enter extension treatment, PROs 
will be collected only at 6, 12 and 18 weeks (±7 days) after BIRC-confirmed, RECIST 1.1- 
defined PD on docetaxel treatmentby telephone interview or by face to face interview in the 
event participant is at site to perform other assessments. There won’t be any possibility to 
collect data on electronic device. 
All PRO questionnaires will also be accessible during unscheduled visits and can be 
completed at investigator/site team discretion. 


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The participant must be given the PRO measure(s) to be completed at the scheduled visit before 
any clinical assessments are conducted. Participant’s refusal to complete all or any part of a 
PRO measure should be documented in the study data capture system and should not be 
captured as a protocol deviation. Handling of protocol deviations can be modified if needed per 
study protocol. 
Participant questionnaires should be completed in the language most familiar to the participant. 
The participant should be given sufficient space and time to complete the PRO measure(s). 
The site personnel should check PRO measure(s) for completeness and ask the participant to 
complete any missing responses. The responses stored electronically in the database will be 
considered the source file. 
The participant should be made aware that completed measure(s) are not reviewed by the 
investigator/ study personnel. 
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, Clinical 
Outcome Assessments data may be collected remotely (through interviews via phone) 
depending on local regulations, technical capabilities, and following any applicable training in 
the required process. 
8.6.2 
Pharmacokinetics 
Serial blood samples will be collected from all participants who receive capmatinib treatment 
to assess steady-state plasma PK of capmatinib. Time points of blood sample collection for 
sparse PK analysis are outlined in Table 8-9. 
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 participant experiences an 
AE suspected to be related to study treatment that results in an unscheduled visit or fits the 
criteria of an SAE (unless participant has interrupted capmatinib for 7 days or more). 
 
 
Table 8-9 
Pharmacokinetic blood collection log for capmatinib 
 
Dose ID following 
trough PK 
sampling 
Dose ID prior to 
trough PK 
sampling 
Sample 
number 
Cycle 
Day 
Scheduled time 
(hours) 
Description 
1 
101 a 
11 
1 
15 
0 hr b 
Pre-dose 
1 
- 
12 
1 
15 
0.5-1.5 hr 
Post-dose 
1 
- 
13 
1 
15 
3-5 hr 
Post-dose 
2 
102 a 
21 
3 
1 
0 hr b 
Pre-dose 
- 
1001 + c 
NA 
NA 
Unscheduled c 
Unspecified 


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Dose ID following 
trough PK 
sampling 
Dose ID prior to 
trough PK 
sampling 
Sample 
number 
Cycle 
Day 
Scheduled time 
(hours) 
Description 
a Dose reference IDs with three digits refer to the dose administered and dosing time of the last dose prior to 
collection of the corresponding PK sample b PK samples should be taken immediately prior to the next 
administration of capmatinib. c Sample numbers for any unscheduled blood collection for capmatinib will be 
labeled sequentially starting with 1001. 
8.6.2.1 
Pharmacokinetic blood collection and handling 
Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in 
a forearm vein. At specified time points described in Table 8-9, 3 mL blood draws will be 
collected into tubes containing K2 EDTA and gently inverted several times to thoroughly mix 
the anticoagulant. Tubes will be centrifuged to separate plasma and plasma will immediately be 
transferred into labelled 2 mL polypropylene screw-cap tubes. Plasma samples will be placed 
in a freezer in an upright position until shipment to the bioanalytical laboratory for analysis. 
All sampling is relative to the ingestion of capmatinib. On days and time points where blood 
PK samples are to be drawn, the PK sample must be drawn first. The exact date and time of 
dosing, as well as the date and actual time of blood sampling must be recorded on the 
appropriate eCRF. 
If vomiting occurs within 4 hours following capmatinib administration on Cycle 1 Day 1, PK 
sample collection is at investigator’s discretion. If PK sample collection is done, the clock time 
of vomiting should be recorded in the dosage administration PK eCRF page. 
Refer to the [laboratory manual] for detailed instructions for the collection, handling, and 
shipment of PK samples. 
8.6.2.2 
Analytical method 
Plasma concentrations of capmatinib will be measured using a validated liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) assay with a lower limit of 
quantification (LLOQ) of 1.0 ng/mL by Novartis Bioanalytics. Concentrations below the LLOQ 
will be reported as 0.00 ng/mL and missing samples will be labelled accordingly. 
8.6.3 
Biomarkers 
Biomarker analyses will be used to investigate the effect of capmatinib in the non-small cell 
lung cancer patients within the study and in lung cancer in general.
 
 
While the goal of the biomarker assessments is to provide supportive data for the clinical study, 
there may be circumstances when a decision is made to stop a collection, or not perform or 
discontinue an analysis due to either practical or strategic reasons (e.g., inadequate sample 
number, issues related to the quality of the sample or issues related to the assay that preclude 
analysis, impossibility to perform correlative analyses, etc.). Therefore, depending on the 
results obtained during the study, sample collection analysis may be omitted at the discretion 
of Novartis.
 
Samples and data may be 


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also used to support potential development of in vitro diagnostic test(s), such as companion 
diagnostic test(s). 
The sample collection information must be entered on the appropriate sample collection eCRF 
page(s) and requisition form(s). Detailed instructions for the collection, processing, and 
shipment of biomarker samples are outlined in the [laboratory manual] for the study. Sample(s) 
should be collected at the visit/time point(s) defined in Table 8-2, Table 8-3 and Table 8-10. 
8.6.3.1 
Biomarkers assessments in tumor 
Archival or newly acquired core or excisional biopsy (preferred) are required as part of the 
molecular pre-screening portion of this trial to test for MET∆ex14 mutation and for ALK 
rearrangement status, if ALK local testing is not available (Section 8.1). A formalin-fixed, 
paraffin embedded tumor tissue sample (archival tumor block or slides, or a newly obtained 
tumor sample) must be provided with sufficient quality and quantity to allow the central 
assessment of MET mutation status for all participants and for potential development of in vitro 
diagnostic test(s), such as companion diagnostic test(s).
 
 
umor samples must contain at least 10% tumor content and a 
minimum effective tumor area per slide as described in the study [laboratory manual] and as 
required for the central assessment of MET mutation status. Samples obtained from bone 
metastases and cytology samples are not acceptable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For 
participants randomized to the capmatinib arm or who elect to crossover to capmatinib 
treatment during the ET Phase of the study, newly acquired core or excisional, formalin-fixed 
biopsies should be collected at End of Treatment (at first PD if participant continues on 
treatment post progression and prior to the initiation of any new anticancer therapies), if 
medically feasible. 


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8.6.3.2 
Biomarker assessments in blood 
Blood samples will be collected from all participants at pre-screening, C1D1 (pre-dose) and at 
EOT. For participants randomized to the capmatinib arm or who elect to crossover to 
capmatinib treatment during the ET Phase of the study, blood will also be collected at C1D15, 
C3D1, every third subsequent cycle. Two 10 mL blood samples will be collected f. The blood 
sample collected at pre-screening may be used for development of a potential in vitro diagnostic 
test, such as a companion diagnostic test. 
 
 
 
 
 
 
 
 
Table 8-10    Biomarker sample collection plan 
 
Sample Type 
Volume 
Visit 
Time point 
Tumor samples 
Mandatory for 
eligibility for central 
MET∆ex14 mutation 
testing 
Either newly obtained 
formalin-fixed biopsy 
(preferred) or archival 
tumor block or slides 
from a formalin fixed 
paraffin embedded 
(FFPE) archival biopsy at 
time of diagnosis of 
NSCLC or any time 
since. 
Block or a 
minimum of 13 
slides with at 
least 10% 
tumor content 
and a minimum 
effective tumor 
area per slide 
as described in 
the study 
[laboratory 
manual] 
Pre-Screening 
Requires participant’s written consent on the 
molecular pre-screening ICF. 
Prior to main 
screening (if 
participant has 
local 
MET∆ex14 
mutation testing 
results 
available, tumor 
sample should 
be received 
before 
randomization) 
Mandatory for 
eligibility, if ALK local 
testing is not available. 
Either newly obtained 
formalin-fixed biopsy 
(preferred) or archival 
tumor block or slides 
Block or a 
minimum of 2 
slides 
Pre-Screening 
Requires participant’s written consent on the 
molecular pre-screening ICF. 
Prior to main 
screening 


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Sample Type 
Volume 
Visit 
Time point 
from a formalin fixed 
paraffin embedded 
(FFPE) archival biopsy at 
time of diagnosis of 
NSCLC or any time 
since. Material for this 
test will be taken 
preferably from the same 
tumor sample submitted 
for MET∆ex14 mutation 
testing. 
Mandatory for 
capmatinib or ET- 
capmatinib participants 
only, if medically 
feasible 
Newly obtained tumor 
biopsy (preferred), 
archival material is also 
acceptable. If a newly 
obtained tumor biopsy 
was submitted for 
molecular pre-screening, 
this biopsy is not 
required. 
Newly acquired 
Biopsy or 
archival 
material, block 
(minimum 6-10 
slides) 
Cycle 1 Day 1 
Pre-dose 
Optional for capmatinib 
or ET-capmatinib 
participants only 
 
 
 
 
 
Mandatory for 
capmatinib or ET- 
capmatinib participants 
only, if medically 
feasible 
Newly obtained tumor 
biopsy 
Newly acquired 
biopsy 
(minimum 6-10 
slides) 
End of treatment 
EOT (if 
EOT=PD) or at 
1st PD, if 
participant 
continues 
treatment post 
progression) 
Blood samples 


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Sample Type 
Volume 
Visit 
Time point 
 
 
 
 
8.6.3.4 
Use of residual biological samples 
Optional additional biomarker studies 
If the participant agrees, the biological samples that remain after analysis is completed (tumor, 
blood, plasma, and serum) may be kept for up to 15 years to be used for additional studies 
related to capmatinib or cancer, including research to help develop ways to detect, monitor or 
treat cancer.
 
 
 
9 
Discontinuation and completion 
9.1 
Discontinuation from study treatment and from study 
9.1.1 
Discontinuation from study treatment 
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study treatment administration, if 
any) and can be initiated by either the participant or the investigator. 
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 
Discontinuation from study treatment is required under the following circumstances: 
• Participant/guardian decision 
• Investigator decision 
• Pregnancy (see Section 10.1.4) 
• Any situation in which continued study participation might result in a safety risk to the 
participant 
• Disease progression per RECIST 1.1 as assessed by the investigator and confirmed by BIRC. 
In some circumstances participants may be allowed to continue to receive study treatment 
beyond disease progression as per RECIST 1.1. These participants will continue 
assessments as outlined in Table 8-1 or Table 8-2, as applicable, and will complete the EOT 
visit only after permanent discontinuation of study treatment (see Section 6.1.4) 


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• Adverse event requiring permanent discontinuation of study treatment (see Table 6-3) 
• Protocol deviation that results in a significant risk to participant's safety 
• Withdraw of consent (see Section 9.2) 
• Study is terminated by the sponsor (see Section 9.4) 
• Death 
• Lost to follow-up (see Section 9.1.3) 
If discontinuation from study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation from study treatment and 
record this information. 
Participants who discontinue from study treatment agree to return for the end of treatment and 
follow-up visits indicated in the Assessment Schedule (refer to Section 8). 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule. 
After discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
For participants who discontinue from study treatment for reasons other than documented 
disease progression, death, lost to follow-up, or withdrawal of consent/opposition to use 
data/biological samples, tumor assessments must continue to be performed every 6 weeks until 
documented disease progression per RECIST 1.1 as assessed by the investigator and confirmed 
by BIRC, death, lost to follow-up, or withdrawal of consent/opposition to use data/biological 
samples. 
In some circumstances participants may be allowed to continue to receive study treatment 
beyond disease progression as per RECIST 1.1 criteria. These participants will continue 
assessments as outlined in the assessments section, and will complete the EOT visit only after 
permanent discontinuation of study treatment. 
9.1.2 
Discontinuation from study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. 
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in the assessment table (refer to Section 8). 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits or fail to 
respond to any site attempts to contact them without stating an intention to discontinue from 


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study treatment or discontinue from study or withdraw consent (or exercise other participants’ 
data privacy rights), the investigator must show "due diligence" by documenting in the source 
documents steps taken to contact the participant, e.g. dates of telephone calls, registered letters, 
etc. A participant should not be considered as lost to follow-up until due diligence has been 
completed. 
9.2 
Withdrawal of informed consent/Opposition to use 
data/biological samples 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent/opposition to use of data and/or biological samples occurs in 
countries where the legal justification to collect and process the data is consent and when a 
participant: 
• Explicitly requests to stop use of their data 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be as per local regulations (e.g. in writing) and recorded in the source 
documentation. 
Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g. to respond to data queries) and potentially other country-specific restrictions. It is therefore 
very important to ensure accurate recording of withdrawal vs. discontinuation based on the 
protocol definitions of these terms. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/exercise data privacy rights and record this information. The investigator shall clearly 
document if the participant has withdrawn his/her consent for the use of data in addition to a 
study discontinuation. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/exercise data privacy rights should be made as detailed in the assessment table (refer 
to Section 8). 
Further details on withdrawal of consent or the exercise of participants' data privacy rights are 
included in the corresponding informed consent form. 


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9.3 
Study completion and post-study treatment 
For individual participant 
Study completion is defined when participant completes all post-treatment follow-up (including 
30-day safety follow-up and/or efficacy follow-up until PD, whichever is longer). The 
appropriate disposition eCRF must be completed, giving the date and reason of post-treatment 
follow-up discontinuation. After this, participant can enter survival follow-up. 
For the study 
Study completion is defined as the earliest occurrence of one of the following: 
• All participants have discontinued study treatment and completed the safety follow-up and 
approximately 80% of the participants have died, withdrawn consent or are lost to follow- 
up. 
• Another clinical study becomes available that can continue to provide capmatinib in this 
participant population, and all participants ongoing are transferred to that clinical study. 
Note: For participants who transfer to another clinical study or an alternative treatment 
option to continue provision of study treatment, the follow-up for safety, disease progression 
and survival will not be performed. 
If the primary analysis of PFS does not demonstrate treatment benefit, the follow-up for OS 
will end, in this case the end of the study will be when all participants have discontinued 
treatment and completed the safety follow-up, or have withdrawn consent or are lost to follow- 
up. 
At the end of the study, every effort will be made to continue provision of study treatment 
outside this study through an alternative setting to participants who in the opinion of the 
investigator are still deriving clinical benefit. 
Details on the timing of the primary analysis and final reporting of data are provided in 
Section 12. 
9.3.1 
Follow-up for safety evaluations 
Regardless of the reason for discontinuation from study treatment (see Section 9.1.1), 
participants will be contacted for a safety follow-up 30 days after the last dose of study treatment. 
At this time, the investigator will record any AEs/SAEs that may have occurred after 
discontinuation of study treatment and/or follow on resolution of ongoing AEs. 
If the participant begins any post-treatment antineoplastic medication before the 30-day safety 
follow-up period is complete, the collection of new SAEs and AEs unrelated to study treatment 
will stop, and, thereafter, only suspected AEs and suspected SAEs will continue to be collected 
up to day 30. Suspected SAEs will continue to be collected beyond the 30-day safety follow- 
up. 
AEs, concomitant medications and antineoplastic therapies since discontinuation of study 
treatment will be recorded on the appropriate eCRFs during this follow-up period. 


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


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10 
Safety monitoring, reporting and committees 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
For participants who sign the molecular pre-screening ICF, AEs which occur after signature of 
this consent will only be captured if they meet the definition of serious as outlined in 
Section 10.1.2 and are reported to be causally related with study procedures (e.g. an invasive 
procedure such as biopsy). Once the main study ICF is signed, all AEs per the descriptions 
below will be captured as adverse events. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The Common Toxicity Criteria (CTC) AE grade (version 5.0). 
Adverse events will be assessed and graded according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
life-threatening, and fatal corresponding to grades 1 - 5, will be used. CTCAE grade 5 (death) 
will be used in this study and information about deaths will be collected through a Death 
eCRF. 
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant 
3. Its duration (start and end dates or ongoing) and the outcome must be reported 


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4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment. 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/permanently discontinued 
6. Its outcome 
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be not recovered/not resolved (e.g. continuing at the end of the study), and assessment must be 
made at each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the interventions required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST 1.1 criteria for solid tumors or as per Cheson's guidelines 
for hematological malignancies), should not be reported as a serious adverse event, except if 
the investigator considers that progression of malignancy is related to study treatment. 
Adverse events separate from the progression of malignancy (for example deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
Information about adverse drug reactions for the investigational drug can be found in the 
[capmatinib Investigator's Brochure]. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 


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Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH- 
E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
events irrespective of whether a clinical event has occurred. 


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Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis Patient Safety Department immediately, without undue 
delay, but under no circumstances later than within 24 hours of obtaining knowledge of the 
events (Note: If more stringent, local regulations regarding reporting timelines prevail). 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. Information about all SAEs is collected and recorded 
on the eSAE with paper backup Serious Adverse Event Report Form; all applicable sections of 
the form must be completed in order to provide a clinically thorough report. If a new 
antineoplastic therapy is initiated during the 30-day safety follow-up period, only SAEs 
suspected to be related to the study treatment will be collected in the Adverse Events eCRF. 
• Screen Failures (e.g. a participant who is screened but is not randomized): SAEs occurring 
after the participant has provided informed consent until the time the participant is deemed 
a Screen Failure must be reported to Novartis. 
• Randomized Participants: SAEs suspected to be causally related to a study procedure are 
captured between time participant signs molecular pre-screening ICF and signs main ICF. 
All SAEs collected between time participant signs main ICF until 30 days after the 
participant has permanently stopped study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
If the SAE is not previously documented in the [capmatinib Investigator’s Brochure] or Package 
Insert (new occurrence) and is thought to be related to the study treatment, a CMO & PS 
Department associate may urgently require further information from the investigator for health 
authority reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Collection of SAEs 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 


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investigator (e.g. an invasive procedure such as biopsy). SAEs will be followed until resolution 
or until clinically relevant improvement or stabilization. If the main ICF is not signed (e.g. 
molecular pre-screen failure), SAE collection ends 30 days after the last study related procedure. 
Any SAEs experienced after the 30-day period following the last administration of study 
treatment should only be reported to Novartis Safety if the investigator suspects a causal 
relationship to study treatment, unless otherwise specified by local law/regulations. 
10.1.4 
Pregnancy reporting 
Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the investigator to collect and report information regarding the pregnancy. 
To ensure participant safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up at 1, 3 (for a live birth only) and 12 (for a live birth only) months after the estimated 
date of delivery to determine outcome, including spontaneous or voluntary termination, details 
of the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment and 
pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
If a female partner of a male trial participant who took study treatment in this study becomes 
pregnant, pregnancy outcomes should be collected. Consent to report information regarding 
these pregnancy outcomes should be obtained from the mother. 
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE. Study 
treatment errors and uses outside of what is foreseen in the protocol, misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an AE/SAE 


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within 24 hours of investigator’s awareness. For more information on AE and SAE definition 
and reporting requirements, please see the respective sections. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
 
Treatment error type 
Document in Dosing 
eCRF (Yes/No) 
Document in AE eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with an 
AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
Not applicable 
10.3 
Committees 
10.3.1 
Steering Committee 
A steering committee (SC) will be established comprising investigators participating in the trial 
and/or key opinion leaders in NSCLC and Novartis representatives from the clinical trial team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the steering committee will be defined in the steering committee charter. 
 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web- 
enabled software that conforms to 21 CFR Part 11 requirements, investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (entered into eCRF) is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 


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All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of participant records, the 
accuracy of data capture / data entry, the adherence to the protocol and to GCP, the progress of 
enrollment, and to ensure that study treatment is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor 
during these visits. Continuous remote monitoring of each site’s data may be performed by a 
centralized Novartis CRA organization. Additionally, a central analytics organization may 
analyze data & identify risks & trends for site operational parameters, and provide reports to 
Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 


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participant's file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
 
12 
Data analysis and statistical methods 
The primary efficacy and safety analyses will be performed after observing approximately 62 
PFS events as assessed by BIRC. 
Data from participating centers in this protocol will be combined, so that an adequate number 
of participants will be available for analysis. Data will be summarized using descriptive 
statistics (continuous data) and/or contingency tables (categorical data) for demographic and 
baseline characteristics, and efficacy, safety and pharmacokinetic measurements. 
Study data will be analyzed and reported in a primary clinical study report (CSR) based on all 
participants’ data up to the time of the data cut-off date determined for the primary efficacy 
analysis. Any additional data for participants continuing to receive study treatment past the data 
cut-off date for the primary CSR, as allowed by the protocol, or continuing in the follow-up 
parts will be reported at completion of the study in a final CSR. 
All summaries, listings, figures and analyses will be performed by treatment arms (unless 
otherwise specified). 
Screen failure participants, as described in Section 8.2.2, and the reasons for not being 
randomized will be reported in a listing, but will not be included in any analyses. 
Details of the statistical analysis and data reporting will be provided in the Statistical Analysis 
Plan (SAP). 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
A participant is considered to be enrolled into the study if they have signed the main study 
informed consent. Only participants who have signed main study informed consent will be 
included in the analysis data sets. 
12.1.1 
Full analysis set 
The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned by randomization, regardless of whether or not the treatment was administered. 
According to the intent to treat principle, participants will be analyzed according to the 
treatment and strata they have been assigned to during the randomization procedure. 


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12.1.2 
Full analysis set – brain metastases 
The Full Analysis Set – Brain Metastases (FAS-BM) comprises all participants in the FAS who 
have measurable and/or non-measurable brain metastases at baseline. 
12.1.3 
Safety set 
The Safety Set (SS) includes all participants who received at least one dose of study treatment. 
Participants will be analyzed according to the study treatment received, where treatment 
received is defined as the randomized treatment if the participant took at least one dose of that 
treatment or the first treatment received if the randomized treatment was never received. 
12.1.4 
Pharmacokinetic analysis set 
The Pharmacokinetic Analysis Set (PAS) includes all participants who received at least one 
dose of capmatinib and had at least one steady state evaluable post-baseline capmatinib 
concentration measurement. 
The definition of an evaluable PK concentration profile will be specified in the SAP. 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment arm for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class, preferred term, and by treatment arm. 
12.3 
Treatments 
The Safety Set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
The duration of exposure in weeks to capmatinib and docetaxel as well as the dose intensity 
(computed as the ratio of actual cumulative dose received and actual duration of exposure) and 
the relative dose intensity (computed as the ratio of dose intensity and planned dose intensity) 
will be summarized by means of descriptive statistics using the safety set. 
The number of participants with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by treatment arm, and all dosing data will 
be listed. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment arm. 


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12.4 
Primary endpoint(s)/estimand(s) analysis 
The primary objective is to evaluate whether capmatinib prolongs PFS by BIRC according to 
RECIST 1.1 (see Section 16.1) compared to docetaxel. The analysis will be performed on the 
FAS. 
12.4.1 
Definition of primary endpoint(s) 
PFS is defined as the time from the date of randomization to the date of the first documented 
progression according to RECIST 1.1, or death due to any cause (see Section 2.1 for further 
details). In the primary analysis, PFS will be censored at the date of the last adequate tumor 
assessment if no PFS event is observed prior to the analysis cut-off date (see RECIST 1.1 in 
Section 16.1 for further details). Clinical deterioration without objective radiological evidence 
will not be considered as documented disease progression. PFS will be assessed by BIRC 
according to RECIST 1.1. Censoring conventions (i.e. handling of missing values, censoring, 
and discontinuations) are provided in Section 12.4.3. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The primary efficacy analysis to test these hypotheses and compare the two treatment groups 
will consist of the stratified log-rank test at an overall one-sided 2.5% significance level. The 
following null and alternative hypothesis will be tested to address the primary efficacy objective 
for PFS based on BIRC as per RECIST 1.1: 
H01: θ1 ≥ 1 vs. HA1: θ1 <1 
where θ1 is the PFS hazard ratio (capmatinib versus docetaxel). The stratification will be based 
on the stratification factor assigned at randomization, i.e. the number of prior lines of systemic 
therapy. If there are too few participants/events in one stratum, an unstratified analysis might 
be performed. Further details will be provided in the SAP. 
The PFS will be analyzed at the primary analysis. PFS will be summarized using the Kaplan- 
Meier (KM) method, based on the FAS. Median PFS, with corresponding 95% CI, and 25th and 
75th percentiles (Brookmeyer and Crowley 1982, Klein and Moeschberger 1997) will be 
presented by treatment group. KM estimates for PFS proportions at specific time points, along 
with 95% CI (Greenwood’s formula, Kalbfleisch and Prentice 2002) will also be provided. The 
hazard ratio for PFS will be estimated, along with its 95% confidence interval, using a stratified 
Cox proportional hazard model using the same stratification factor as for the log-rank test. 
12.4.3 
Handling of intercurrent events of primary estimand 
The primary estimand will account for the different intercurrent events as follows: 
Discontinuation of study treatment for any reason before a PFS event (radiological 
progression or death): PFS will take into account all PFS events irrespective of the study 
treatment discontinuation reasons (treatment policy strategy). 
New anti-cancer therapy before a PFS event: PFS will take into account all PFS events 
irrespective of the start of new anti-cancer therapy (treatment policy strategy). 


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Any unforeseen intercurrent events (e.g., resulting from a public health emergency, like the 
COVID-19 pandemic): PFS will take into account all PFS events irrespective of any unforeseen 
intercurrent events (treatment policy strategy). 
12.4.4 
Handling of missing values not related to intercurrent events 
In the primary analysis, PFS will be censored at the date of the last adequate tumor assessment 
if no PFS event is observed prior to the analysis cut-off date. 
Radiological progression or death observed after 2 or more missing tumor assessments will not 
be included in the derivation of the time to event for PFS, and the observation will be censored 
at the time of the last adequate tumor assessment prior to the first missing assessment. 
Participants without a post-baseline tumor assessment (and without death) will be censored at 
the time of randomization. 
12.4.5 
Sensitivity analyses 
As a sensitivity analysis, PFS as per local review will be analyzed using a stratified Cox model, 
with the same analysis conventions as for the primary efficacy analysis. The treatment effect 
will be summarized by the hazard ratio with its 95% confidence interval. Kaplan-Meier curves, 
medians and 95% confidence intervals of the medians will be presented for each treatment 
group. 
The number of participants censored and reasons for censoring will be summarized by treatment 
group using descriptive statistics, presented separately for local review and blinded independent 
central review. 
12.4.6 
Supplementary analysis 
As supplementary analyses performed in the FAS, the hazard ratio and 95% confidence interval 
for PFS per BIRC review will be obtained from: 
1. An unstratified and covariate-unadjusted Cox model. 
2. A stratified and covariate-adjusted Cox model including as potential covariates the 
following: age, gender, ECOG PS (0, 1), smoking status (smoker, non-smokers, ex- 
smokers), race (Asian, other). The final covariates will be pre-specified in the SAP. 
3. If the primary analysis of PFS is statistically significant, sub group analyses to assess the 
homogeneity of the treatment effect across demographics and baseline characteristics will 
be performed. The following subgroups may be considered: gender, age groups (<65, ≥65 
years), ECOG PS (0, 1), histology (squamous, non-squamous), smoking status (smoker, 
non-smokers, ex-smokers), race (Asian, other), and presence or absence of brain metastases 
at baseline (as assessed by the investigator per RECIST 1.1). A final list of subgroups of 
interest will be defined in the SAP. 
A supplementary estimand will be analyzed with the same target population, primary variable, 
intercurrent events and summary measure as for the primary estimand. The treatment of interest 
is the randomized treatment (capmatinib or docetaxel without any antineoplastic therapy post 
randomization). An additional intercurrent event of antineoplastic therapy post randomization 
prior to PFS event will be included and handled using the hypothetical estimand strategy i.e., 


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PFS will be censored at the date of the last adequate tumor assessment prior to the start of new 
anticancer therapy if no PFS event is observed prior to the start of new antineoplastic therapy. 
A further supplementary estimand will be analyzed with the same treatment of interest, primary 
variable, intercurrent events and summary measure as for the primary estimand. The target 
population is the subset of participants for whom the METΔex14 mutation was confirmed by 
the Novartis-designated central laboratory. A subset of the FAS will be used for this analysis. 
12.5 
Secondary endpoint(s)/estimand(s) analysis 
12.5.1 
Efficacy endpoints 
The key secondary estimand is defined in Section 2.2 for the key secondary endpoint of ORR. 
Other secondary efficacy endpoints are the following: 
• ORR by investigator assessment as per RECIST 1.1 
• DOR, time to response (TTR), and disease control rate (DCR), by investigator assessment 
and BIRC as per RECIST 1.1 
• PFS by investigator assessment as per RECIST 1.1 
• Overall Survival 
• Overall intracranial response rate (OIRR), duration of intracranial response (DOIR), time 
to intracranial response (TTIR), and intracranial disease control rate (IDCR) by BIRC as 
per RANO-BM criteria 
12.5.1.1 Key secondary estimand/endpoint 
The secondary estimand for ORR is defined in Section 2.2. ORR is defined as the proportion of 
participants with confirmed best overall response of complete response (CR) or partial response 
(PR), and will be assessed by BIRC review and according to RECIST 1.1. The following null 
and alternative hypothesis will be tested using the stratified Miettinen-Nurminen method 
(Miettinen and Nurminen 1985) to address the key secondary efficacy objective: 
H01: θ1 − θ2 ≤ 30% vs. HA1: θ1 − θ2 >30%, 
where θ1, θ2 are the ORR for the treatment (capmatinib) and control (docetaxel) arms, 
respectively. ORR will be calculated based on the data from the FAS and strata assigned at 
randomization. The stratification will be based on the stratification factor assigned at 
randomization, i.e. the number of prior lines of systemic therapy. A hierarchical testing 
procedure will be adopted and the testing of the ORR difference will be performed only if the 
primary endpoint PFS is statistically significant. 
If there are too few participants/responders in one stratum, an unstratified analysis might be 
performed. In case the primary endpoint analysis is not statistically significant, the ORR will 
be calculated and presented for each treatment group. Further details will be provided in the 
SAP. 
The difference in ORR and its 95% confidence interval based on the stratified 
Miettinen-Nurminen method with strata weighting by sample size with a single treatment 
covariate will be reported. 


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As a supportive analysis, ORR per local investigator assessment will be analyzed using the 
same method as for ORR by BIRC. 
A further supportive analysis will be the ORR by BIRC based on the subset of participants for 
whom the METΔex14 mutation was confirmed by the Novartis-designated central laboratory. 
Further details will be provided in the SAP. 
The intercurrent events for the key secondary estimand and handling strategy are described in 
Section 2.2. The handling of the intercurrent events will allow the inclusion of all BOR in the 
analysis and is targeting the treatment effect based on ORR due to any cause for capmatinib 
compared to docetaxel for the target population irrespective of study treatment discontinuation 
and any unforeseen intercurrent events due to a public health emergency (e.g. COVID-19 
pandemic-related events). 
The BOR assessments after the use of new anti-cancer therapy will be considered as non- 
responses and have been accounted for in the variable attribute using the composite strategy. 
12.5.1.2 Other secondary endpoints 
Duration of response (DOR) 
DOR only applies to participants whose BOR is CR or PR according to RECIST 1.1 based on 
tumor response data. DOR is defined as the time from the date of first documented response 
(CR or PR) to the first documented progression per RECIST 1.1 or death due to any cause. If a 
participant with a CR or PR has no progression or death, the participant is censored at the date 
of last adequate tumor assessment. Definition of last adequate tumor assessment is provided in 
Section 16.1. DOR will be assessed by local review as well as by BIRC. 
DOR will be analyzed based on the data from the FAS. Median DOR, with corresponding 95% 
CI, and 25th and 75th percentiles (Brookmeyer and Crowley 1982, Klein and Moeschberger 1997) 
will be presented. KM estimates for DOR proportions at specific time points, along with 95% 
CI (Greenwood’s formula, Kalbfleisch and Prentice 2002) will also be provided. 
Participants continuing without progression or death due to any cause will be censored at the 
date of their last adequate tumor assessment. 
Time to response (TTR) 
TTR is defined as the time from the date of randomization to the first documented response of 
either CR or PR, which must be subsequently confirmed (date of initial response is used, not 
date of confirmation), according to RECIST 1.1 (see Section 16.1). TTR will be presented by 
local assessment as well as BIRC assessment. 
All participants in the FAS will be included in TTR calculations. Participants without a 
confirmed CR or PR will be censored at the study-maximum follow-up time (i.e. LPLV−FPFV) 
for participants with a PFS event, or at the date of the last adequate tumor assessment for 
participants without a PFS event. TTR will be summarized using the Kaplan-Meier (KM) 
method, based on data from the FAS. Median TTR, with corresponding 95% CI, and 25th and 
75th percentiles (Brookmeyer and Crowley 1982, Klein and Moeschberger 1997) will be 


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presented. KM estimates for TTR proportions at specific time points, along with 95% CI 
(Greenwood’s formula, Kalbfleisch and Prentice 2002) will also be provided. 
Disease control rate (DCR) 
DCR is defined as the proportion of participants with a BOR of confirmed CR, PR and stable 
disease (SD) according to RECIST 1.1 (see Section 16.1). DCR will be assessed by local review 
as well as by BIRC. 
DCR will be calculated based on the data from the FAS and the corresponding 95% confidence 
intervals based on the exact binomial distribution (Clopper and Pearson 1934) will be presented. 
Progression-free survival (PFS) 
The analysis in this section refers to the PFS as per local investigator review. 
PFS is defined as the time from the date of randomization to the date of the first documented 
progression according to RECIST 1.1, or death due to any cause. If a participant has no 
progression or death, the participant is censored at the date of last adequate tumor assessment. 
Definition of last adequate tumor assessment is provided in Section 16.1. 
PFS will be summarized using the Kaplan-Meier (KM) method, based on data from the FAS. 
Median PFS, with corresponding 95% CI, and 25th and 75th percentiles (Brookmeyer and 
Crowley 1982, Klein and Moeschberger 1997) will be presented. KM estimates for PFS 
proportions at specific time points, along with 95% CI (Greenwood’s formula, Kalbfleisch and 
Prentice 2002) will also be provided. 
Overall survival (OS) 
OS is defined as the time from the date of randomization to the date of death due to any cause. 
If a participant 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 summarized using the KM 
method, based on data from the FAS. Median OS with corresponding 95% CI, and 25th and 75th 
percentiles (Brookmeyer and Crowley 1982, Klein and Moeschberger 1997) will be presented. 
KM estimates for OS proportions at specific time points, along with 95% CI (Greenwood’s 
formula, Kalbfleisch and Prentice 2002) will also be provided. 
Overall intracranial response rate (OIRR) 
OIRR is calculated based on response assessments in the brain for participants having 
measurable and/or non-measurable brain metastases at baseline. OIRR is the proportion of 
participants with a confirmed best overall intracranial response (BOIR) of CR or PR per RANO- 
BM criteria as assessed by BIRC review. 
OIRR calculated based on the data from the FAS-BM and the corresponding 95% CI based on 
the exact binomial distribution (Clopper and Pearson 1934) will be presented. 


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Duration of intracranial response (DOIR) 
DOIR only applies to participants whose confirmed BOIR is CR or PR per RANO-BM criteria 
as assessed by BIRC review. DOIR is defined as the time from the date of first documented 
intracranial response of either CR or PR to the date of the first documented intracranial 
progression per RANO-BM criteria as assessed by BIRC review or the date of death due to any 
cause. Participants will be censored if they have disease progression in organs other than brain 
and have no scans in brain after that. The censoring date will be the date of the last adequate 
tumor assessment in brain. 
DOIR will be summarized using the KM method. Median DOIR, with corresponding 95% CI, 
and 25th and 75th percentiles (Brookmeyer and Crowley 1982, Klein and Moeschberger 1997) 
will be presented. KM estimates for DOIR proportions at specific time points, along with 95% 
CI (Greenwood’s formula, Kalbfleisch and Prentice 2002) will also be provided. 
Time to intracranial response (TTIR) 
TTIR is defined as the time from the date of randomization to the date of the first documented 
intracranial response of either CR or PR per RANO-BM criteria as assessed by the BIRC review, 
which must be subsequently confirmed (date of initial response is used, not date of 
confirmation). All participants in the FAS-BM will be included in TTIR calculations. 
Participants without a confirmed intracranial CR or PR will be censored at the study-maximum 
follow-up time (i.e. LPLV−FPFV) for participants with a PFS event (intracranial progression 
or death due to any cause), or at the date of the last adequate tumor assessment in brain for 
participants without a PFS event. 
TTIR will be summarized using the KM method, based on data from the FAS-BM. Median 
TTIR, with corresponding 95% CI, and 25th and 75th percentiles (Brookmeyer and Crowley 
1982, Klein and Moeschberger 1997) will be presented. KM estimates for TTIR proportions at 
specific time points, along with 95% CI (Greenwood’s formula, Kalbfleisch and Prentice 2002) 
will also be provided. 
Intracranial disease control rate (IDCR) 
IDCR is calculated based on response assessments in the brain for participants having 
measurable and/or non-measurable brain metastases at baseline. IDCR is the proportion of 
participants with a confirmed BOIR of CR or PR or SD (or non-CR/non-PD) per RANO-BM 
criteria as assessed by BIRC review. 
IDCR calculated based on the data from the FAS-BM and the corresponding 95% CI based on 
the exact binomial distribution (Clopper and Pearson 1934) will be presented. 
12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 


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treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from date of participant’s first informed consent to the date before 
first administration of study treatment. 
2. On-treatment period: from date of first administration of study treatment to the earlier of 
• 30 days after date of last administration of study treatment (including start and stop 
date), 
• the date prior to start of ET with capmatinib following crossover from docetaxel. 
3. Post-treatment period: starting at day 31 after last administration of study treatment or the 
first day of ET with capmatinib. 
Further details will be included in the SAP. 
Adverse events 
The number (and percentage) of participants with treatment-emergent adverse events (events 
started after the first administration of study treatment or events present prior to start of study 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways: 
• by primary system organ class and preferred term. 
• by primary system organ class, preferred term, and maximum severity. 
Separate summaries will be provided for study treatment related adverse events, deaths, serious 
adverse events, other significant adverse events leading to discontinuation, and adverse events 
leading to dose adjustment. A participant with multiple adverse events within a primary system 
organ class is only counted once towards the total of the primary system organ class. 
The number (and proportion) of participants with adverse events of special interest will be 
summarized. 
Serious adverse events, non-serious adverse events and adverse events of special interest (AESI) 
during the on-treatment period will be tabulated. 
All deaths (on-treatment and post-treatment) will be summarized. 
All AEs, deaths, and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged. 
Vital signs 
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters will be collected: systolic and diastolic blood pressure (mmHg), pulse 
(beats per minute), body temperature (°C), weight (kg), and height (cm). 
All vital signs data will be summarized by treatment arm and visit/time. The number and 
percentage of participants with notable vital sign values will be presented for the safety set. A 


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listing of participants with notable vital signs will be provided and values measured after the 
on-treatment period will be flagged in the listing. Notable criteria for vital sign values will be 
specified in the SAP. 
12-lead ECG 
12-lead ECGs including PR, QRS, QT and QTcF intervals and heart rate will be obtained for 
each participant during the study. ECG data will be read and interpreted centrally. The average 
of the ECG parameters at each assessment should be used in the analyses. ECGs collected 
during the on-treatment period will be summarized. The number and percentage of participants 
with notable ECG values will be presented for the safety set. A listing of participants with 
notable ECGs will be provided and values measured after the on-treatment period will be 
flagged in the listing. Notable ECG value criteria will be specified in the SAP. 
Clinical laboratory evaluations 
All laboratory data will be summarized by treatment arm and visit/time. 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 
For laboratory tests where grades are not defined by CTCAE version 5.0, results will be 
categorized as low/normal/high) based on laboratory normal ranges. 
The following summaries will be generated separately for hematology, and biochemistry tests: 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE version 
5.0 grades, if applicable, and the classifications relative to the laboratory normal ranges. 
For laboratory tests where grades are defined by CTCAE version 5.0: 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each participant will 
be counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE version 5.0 grades to compare baseline to the worst on-treatment 
post-baseline value. 
For laboratory tests where grades are not defined by CTCAE version 5.0: 
• Shift tables using the low/normal/high/ (low and high) classification to compare baseline to 
the worst on-treatment post-baseline value. 
In addition to the above mentioned tables and listings, 
 be specified 
in the SAP. 
12.5.3 
Pharmacokinetics 
The PAS will be used in all pharmacokinetic data analysis and PK summary statistics. 


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Capmatinib plasma concentration data will be listed by participant and visit/sampling time point. 
Descriptive summary statistics will be provided for capmatinib pre-dose (trough) 
concentrations by visit/sampling time point, including the frequency (n, %) of concentrations 
below the LLOQ and reported as zero. 
Descriptive summary statistics will include mean (arithmetic and geometric), SD, CV 
(arithmetic and geometric), median, minimum, and maximum. Concentrations below LLOQ 
will be treated as zero in summary statistics. Zero concentrations will not be included in the 
geometric mean calculation and the CV. 
If there are sufficient data for analysis, the details of the population pharmacokinetic analyses 
will be provided in a separate reporting and analysis plan, and the results may be reported in a 
separate population pharmacokinetic report. Data from this and other studies may be pooled for 
analysis. 
12.5.3.1 Handling of missing values/censoring/discontinuations 
Missing values for any PK concentrations will not be imputed and will be treated as missing. 
Below the limit of quantitation (BLQ) values will be set to zero by the bioanalyst and will be 
displayed in the listings as zero and flagged. BLQ values will be treated as missing for the 
calculation of the geometric means and geometric CV%. 
12.5.4 
Patient reported outcomes 
Three patient-reported outcomes questionnaires will be assessed: EORTC QLQ-C30, QLQ- 
LC13 and EQ-5D-5L. Scoring of PRO data and methods for handling of missing items or 
missing assessments will be handled according to the scoring manual and user guide for each 
respective patient questionnaire (Fayers 2001, Van Reenen et al 2019). Details will be provided 
in the SAP. 
Descriptive statistics will be used to summarize the scored scales and subscales of the EORTC 
QLQ-C30, QLQ-LC13 and EQ-5D-5L at each scheduled assessment time point for each 
treatment group. Additionally, change from baseline in the scale and subscale values at the time 
of each assessment will be summarized. Participants with an evaluable baseline score and at 
least one evaluable post-baseline score during the treatment period will be included in the 
change from baseline analyses. 
The distribution of time to symptom deterioration will be analyzed by treatment group for chest 
pain, cough and dyspnea scores per QLQ-LC13 as well as global health status/QoL per QLQ- 
C30 questionnaire. It will be estimated using the Kaplan-Meier method and the median time 
along with two-sided 95% CIs will be presented. The hazard ratio will be estimated, along with 
its 95% confidence interval, using a stratified Cox proportional hazard model using the 
randomization stratification factor. Further details will be specified in the SAP. 
The number of participants completing each questionnaire and the number of missing or 
incomplete assessments will be summarized by treatment group for each scheduled assessment 
time point. No formal statistical tests will be performed for PRO data and hence no multiplicity 
adjustment will be applied. The FAS will be used for analyzing PRO data. 


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Additional analyses may be performed if deemed necessary. Such analyses will be defined in 
the SAP. 
12.6 
Analysis of exploratory endpoints 
Analysis of exploratory endpoints will be detailed in the SAP. 
12.7 
Interim analyses 
No formal interim analysis is planned for this trial. 
The primary analysis will be performed after approximately 62 PFS BIRC assessed events have 
been documented. Formal testing of the primary endpoint with full level alpha will be 
performed at the primary analysis time point. A final analysis will be performed at the end of 
the study. 
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
The sample size calculation is based on the primary variable PFS. The hypotheses to be tested 
and details of the testing strategy are described in Section 12.4. 
In the planned study, median PFS of 2.5 months was assumed for the control arm in this study 
population (Hanna et al 2004, de Marinis and Grossi 2008, Weiss and Stinchcombe 2013, 
Borghaei et al 2015, Rittmeyer et al 2017) and considering the negative prognostic impact of 
the MET dysregulation (Dimou et al 2014, Guo et al 2014, Landi et al 2017, Awad et al 2019). 
Under the assumption that the median PFS in the control arm is 2.5 months in these participants, 
it is expected that treatment with capmatinib will result in a 58% reduction in the hazard rate 
(corresponding to an increase in median PFS from 2.5 months to 6 months under the exponential 
model assumption). If the true hazard ratio is 0.42 (under the alternative hypothesis), a total of 
62 PFS events are required to have 90% power at a one-sided 2.5% level of significance to 
reject the null hypothesis (HR=1) using a log-rank test. Assuming that enrollment will continue 
for approximately 19 months with a rate of 3 participants/month for the first half year and 6 
participants/months from month 7 onwards, and 20% dropout, approximately 90 participants 
will need to be randomized to reach the required number of events for the two treatment arms 
in a 2:1 ratio, 60 participants in the capmatinib arm and 30 participants in the chemotherapy 
arm. Given the above assumptions, it is estimated that the 62nd PFS event will occur 
approximately 21 months from the date of first participant randomized in the study. No interim 
analysis is planned for PFS. 
These calculations were performed using the software package East (6.4). 
12.8.2 
Secondary endpoint(s) 
ORR, as the key secondary variable, will be formally statistically tested, provided that the 
primary variable PFS is statistically significant. The hypotheses to be tested and details of the 
testing strategy are provided in Section 12.5.1.1. 


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Based on available data (Borghaei et al 2015, Brahmer et al 2015, Herbst et al 2016, 
Rittmeyer et al 2017) and considering the negative prognostic impact of the MET dysregulation 
in the targeted population, the ORR in the control arm is expected to be around 10%. It is 
hypothesized that treatment with capmatinib will result in a 30% increase in the ORR, i.e., an 
expected ORR of 40% (Wolf et al 2020). The ORR will be tested at the time of the final PFS 
analysis. The sample size calculation is based on the number of participants that are planned to 
be enrolled to provide sufficient power for the primary endpoint (90 participants), the 
randomization ratio of 2:1, and the hypotheses H01: θ1 − θ2 ≤ 30% vs. HA1: θ1 − θ2 >30%. With 
these assumptions, the test for the difference in ORR without the stratification factor and with 
a pooled estimate of variance will have 88.2% power with a one-sided alpha of 0.025. 
The approximate treatment difference (Δ ORR) required to reach the boundary for significance 
(i.e. reject the null hypothesis) is 16.4%. 
 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the IRB/IEC for the trial protocol, written informed consent form, consent form updates, 
participant recruitment procedures (e.g., advertisements) and any other written information to 
be provided to participants. Prior to study start, the investigator is required to sign a protocol 
signature page confirming his/her agreement to conduct the study in accordance with these 
documents and all of the instructions and procedures found in this protocol and to give access 
to all relevant data and records to Novartis monitors, auditors, Novartis Quality Assurance 
representatives, designated agents of Novartis IRBs/IECs, and regulatory authorities as required. 
If an inspection of the clinical site is requested by a regulatory authority, the investigator must 
inform Novartis immediately that this request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 


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13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
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Novello S, Barlesi F, Califano R, et al (2016) Metastatic non-small-cell lung cancer: ESMO 
Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol; 27(5):v1-v27. 
Ou SH, Ahn JS, De Petris L, et al (2016) Alectinib in Crizotinib-Refractory ALK-Rearranged 
Non-Small-Cell Lung Cancer: A Phase II Global Study. J Clin Oncol; 34(7):661-8. 
Paik PK, Drilon A, Fan PD, et al (2015) Response to MET inhibitors in patients with stage IV 
lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov; 
842-9. 
Paik PK, Felip E, Veillon R, et al (2020) Tepotinib in Non–Small-Cell Lung Cancer with MET 
Exon 14 Skipping Mutations. N Engl J Med; 383(10):931-43. 
Perez-Moreno P, Brambilla E, Thomas R, et al (2012) Squamous cell carcinoma of the lung: 
molecular subtypes and therapeutic opportunities. Clin Cancer Res; 18(9):2443-51. 


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Planchard D, Popat S, Kerr K, et al (2018) Metastatic non-small cell lung cancer: ESMO 
Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol; 29 (suppl 
4):iv192-iv237. 
Rabin R, de Charro F (2001) EQ-5D: a measure of health status from the EuroQol Group. Ann 
Med; 33:337-43. 
Reck M, Popat S, Reinmuth N, et al (2014) Metastatic non-small-cell lung cancer (NSCLC): 
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol; 25 
(Suppl 13):iii27-39. 
Rittmeyer A, Barlesi F, Waterkamp D, et al (2017) Atezolizumab versus docetaxel in patients 
with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre 
randomised controlled trial. Lancet; 389:255-65. 
Sabari JK, Paik PK (2017) Relevance of genetic alterations in squamous and small cell lung 
cancer. Ann Transl Med; 5(18):373. 
Scagliotti GV, Gridelli C, de Marinis F, et al (2014) Efficacy and safety of maintenance 
pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following 
pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials. 
Lung Cancer; 85:408-14. 
Schuler MH, Berardi R, Lim WT, et al (2016) Phase I Study of the Safety and Efficacy of the 
cMET Inhibitor Capmatinib (INC280) in Patients With Advanced cMET+ Non-small Cell Lung 
Cancer J Clin Oncol; suppl; abstr 9067-9067. 
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al (2005) Erlotinib in previously treated non- 
small-cell lung cancer. N Engl J Med; 353(2):123-32. 
Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA Cancer J Clin; 70(1):7-34. 
Subramanian J, Govindan R (2007) Lung cancer in never smokers: a review. J Clin Oncol; 
25(5):561-70. 
TCGA Research Network (2014) Comprehensive molecular profiling of lung adenocarcinoma. 
Nature 13385; 543. 
The EuroQol Group (1990) A new facility for the measurement of health-related quality of life. 
Health Policy; 16(3):199-208. 
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. 
Van Reenen M, Janssen B, Stolk E, et al (2019) EQ-5D-5L User Guide, Basic Information on 
how to use the EQ-5D-5L instrument, Version 3.0. EuroQol Research Foundation. 
Waqar SN, Morgensztern D, Sehn J (2015) MET Mutation Associated with Responsiveness to 
Crizotinib. J Thorac Oncol; 10(5):e29-31. 
Weiss JM, Stinchcombe TE (2013) Second-Line Therapy for Advanced NSCLC. Oncologist; 
18:947-53. 


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Wolf J, Seto T, Han J, et al (2019) Capmatinib (INC280) in METΔex14-mutated advanced non- 
small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 study. 
J Clin Oncol 37; suppl; abstr 9004. 
Wolf J, Seto T, Han J-Y, et al (2020) Capmatinib in MET Exon 14-Mutated or MET-Amplified 
Non-Small-Cell Lung Cancer. N Engl J Med; 383(10):944-57. 


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


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


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• Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no septations, 
and low CT density [water-like] content) should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
• Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with ≥ 10 
to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging techniques. 
16.1.2.1.2 
Eligibility based on measurable disease 
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in 
Section 16.1.3.2.8. 
16.1.2.2 Methods of tumor measurement - general guidelines 
In this document, the term “contrast” refers to intravenous (i.v.) contrast. 
The following considerations are to be made when evaluating the tumor: 
• All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment. 
• Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
• For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-up. 
Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed using 
a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan slice 
thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. If, at 
baseline, a patient is known to have a medical contraindication to CT contrast or develops 
a contraindication during the trial, the following change in imaging modality will be 
accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis. 
• A change in methodology can be defined as either a change in contrast use (e.g. keeping the 
same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a major change in technique (e.g. from CT 


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


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


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


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


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


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


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at baseline. If there is unequivocal progression of non-target lesion(s), then at least one of 
the non-target lesions must be assigned a status of “Worsened”. Where possible, similar 
rules to those described in Section 16.1.2.4.2 for assigning PD following a CR for the non- 
target lesion response in the presence of non-target lesions nodal lesions should be applied. 
16.1.2.4.4 
New lesions 
The appearance of a new lesion is always associated with PD and has to be recorded as a new 
lesion in the New Lesion CRF page. 
• If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion 
• If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 16.1.2.5). 
• A lymph node is considered as a “new lesion” and, therefore, indicative of PD if the short 
axis increases in size to ≥ 10 mm for the first time in the study plus 5 mm absolute increase. 
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 16.1.2.2. 
16.1.2.5 Evaluation of overall lesion response 
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in Table 16-3. 
Table 16-3    Overall lesion response at each assessment 
 
Target lesions 
Non-target lesions 
New Lesions 
Overall 
lesion response 
CR 
CR 
No 
CR1 
CR 
Non-CR/Non-PD3 
No 
PR 
CR, PR, SD 
UNK 
No 
UNK 
PR 
SD 
UNK 
Non-PD and not UNK 
Non-PD and not UNK 
Non-PD or UNK 
No 
No 
No 
PR1 
SD1, 2 
UNK1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1. 
This overall lesion response also applies when there are no non-target lesions identified at baseline. 
2. 
Once confirmed PR was achieved, all these assessments are considered PR. 
3. 
As defined in Section 16.1.2.4. 
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK). 


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


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


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• Investigator overall lesion response 
• Central Blinded Review overall lesion response 
• Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review) 
The primary analysis of the BOR will be based on the sequence of central blinded 
review/calculated (central) overall lesion responses. 
Based on the patients’ BOR during the study, the following rates are then calculated: 
Overall response rate (ORR) is the proportion of patients with a BOR of CR or PR. This is 
also referred to as ‘Objective response rate’ in some protocols or publications. 
Disease control rate (DCR) is the proportion of patients with a BOR of CR or PR or SD. The 
objective of this endpoint is to summarize patients with signs of “activity” defined as either 
shrinkage of tumor (regardless of duration) or slowing down of tumor growth. 
Clinical benefit rate (CBR) is the proportion of patients with a BOR of CR or PR, or an overall 
lesion response of SD or Non-CR/Non-PD which lasts for a minimum time duration (with a 
default of at least 24 weeks in breast cancer studies). This endpoint measures signs of activity 
taking into account duration of disease stabilization. 
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used: 
Early progression rate (EPR) is the proportion of patients with PD within 8 weeks of the start 
of treatment. 
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be at 
8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with an 
unknown (UNK) assessment at that time point and no PD before, will not be counted as early 
progressors in the analysis but may be included in the denominator of the EPR rate, depending 
on the analysis population used. Similarly when examining overall response and disease control, 
patients with a BOR assessment of unknown (UNK) will not be regarded as “responders” but 
may be included in the denominator for ORR and DCR calculation depending on the analysis 
population (e.g. populations based on an ITT approach). 
16.1.3.2 Time to event variables 
16.1.3.2.1 
Progression-free survival 
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint. 


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Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, PFS is censored at the date of last adequate tumor assessment. 
PFS rate at x weeks is an additional measure used to quantify PFS endpoint. It is recommended 
that a Kaplan Meier estimate is used to assess this endpoint. 
16.1.3.2.2 
Overall survival 
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”). 
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive. 
16.1.3.2.3 
Time to progression 
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer. 
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment. 
 
 


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


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Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression. 
16.1.3.2.7 
Time to response 
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed. 
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the ORRs, since the same kind of selection bias may be introduced as 
described for DOR in Section 16.1.3.2.5. It is recommended that an analysis of all patients (both 
responders and non-responders) be performed whether or not a “responders only” descriptive 
analysis is presented. Where an inferential statistical comparison is required, then all patients 
should definitely be included in the analysis to ensure the statistical test is valid. For analysis 
including all patients, patients who did not achieve a response (which may have to be a 
confirmed response) will be censored using one of the following options. 
• at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the worst 
possible outcome as it means the patient cannot subsequently respond. Since the statistical 
analysis usually makes use of the ranking of times to response it is sufficient to assign the 
worst possible censoring time which could be observed in the study which is equal to the 
maximum follow-up time (i.e. time from FPFV to LPLV) 
• at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding 
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint. 
16.1.3.2.8 
Definition of start and end dates for time to event variables 
Assessment date 
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number. 
In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations. 


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Start dates 
For all “time to event” variables, other than DOR, the randomization/date of treatment start will 
be used as the start date. 
For the calculation of DOR the following start date should be used: 
• Date of first documented response is the assessment date of the first overall lesion response 
of CR (for duration of overall complete response) or CR / PR (for duration of overall 
response) respectively, when this status is later confirmed. 
End dates 
The end dates which are used to calculate ‘time to event’ variables are defined as follows: 
• Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page). 
• Date of progression is the first assessment date at which the overall lesion response was 
recorded as PD. 
• Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post- 
baseline assessments are available (before an event or a censoring reason occurred) the date 
of randomization/start of treatment is used. 
• Date of next scheduled assessment is the date of the last adequate tumor assessment plus the 
protocol specified time interval for assessments. This date may be used if back-dating is 
considered when the event occurred beyond the acceptable time window for the next tumor 
assessment as per protocol (see Section 16.1.3.2.8). 
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months. 
• Date of discontinuation is the date of the end of treatment visit. 
• Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is used. 
If no survival follow-up is available, the date of discontinuation is used as last contact date. 
• Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery. 
16.1.3.2.9 
Handling of patients with non-measurable disease only at baseline 
It is possible that patients with only non-measurable disease present at baseline are entered 
into the study, either because of a protocol violation or by design (e.g. in Phase III studies 
with PFS as the primary endpoint). In such cases the handling of the response data requires 
special consideration with respect to inclusion in any analysis of endpoints based on the 
overall response evaluations. 


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It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints. 
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with non- 
measurable disease is derived slightly differently according to Table 16-4. 
Table 16-4 
Overall lesion response at each assessment: patients with non-target 
disease only 
 
Non-target lesions 
New Lesions 
Overall lesion response 
CR 
No 
CR 
Non-CR/Non-PD1 
No 
Non-CR/non-PD 
UNK 
No 
UNK 
PD 
Yes or No 
PD 
Any 
Yes 
PD 
1 As defined in Section 16.1.2.4. 
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for BOR patients with only non- 
measurable disease may be highlighted in an appropriate fashion e.g. in particular by displaying 
the specific numbers with the non-CR/non-PD category. 
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account. 
For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease. 
16.1.3.2.10 Sensitivity analyses 
This section outlines the possible event and censoring dates for progression, as well as addresses 
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a patient being lost to follow-up? It is important that the protocol and RAP specify the 
primary analysis in detail with respect to the definition of event and censoring dates and also 
include a description of one or more sensitivity analyses to be performed. 
Based on definitions outlined in Section 16.1.3.2.7, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 2005) 
as a reference, the following analyses can be considered: 


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Table 16-5 
Options for event dates used in PFS, TTP, DOR 
 
Situation 
Options for end-date (progression or 
censoring)1 
(1) = default unless specified differently in the 
protocol or RAP 
Outcome 
A 
No baseline assessment 
(1) Date of randomization/start of treatment3 
Censored 
B 
Progression at or before next scheduled 
assessment 
(1) Date of progression 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C1 
Progression or death after exactly one 
missing assessment 
(1) Date of progression (or death) 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C2 
Progression or death after two or more 
missing assessments 
(1) Date of last adequate assessment2 
(2) Date of next scheduled assessment2 
(3) Date of progression (or death) 
Censored 
Progressed 
Progressed 
D 
No progression 
(1) Date of last adequate assessment 
Censored 
E 
Treatment discontinuation due to ‘Disease 
progression’ without documented 
progression, i.e. clinical progression 
based on investigator claim 
(1) Ignore clinical progression and follow 
situations above 
(2) Date of discontinuation (visit date at which 
clinical progression was determined) 
As per above 
situations 
Progressed 
F 
New anticancer therapy given 
(1) Ignore the new anticancer therapy and follow 
situations above (ITT approach) 
(2) Date of last adequate assessment prior to new 
anticancer therapy 
(3) Date of secondary anti-cancer therapy 
(4) Date of secondary anti-cancer therapy 
As per above 
situations 
Censored 
Censored 
Event 
G 
Deaths due to reason other than 
deterioration of ‘Study indication’ 
(1) Date of last adequate assessment 
Censored 
(only TTP and 
DOR) 
1. 
=Definitions can be found in Section 16.1.3.2.7. 
2. 
=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in 
Section 16.1.3.2.7. 
3. 
=The rare exception to this is if the patient dies no later than the time of the second scheduled assessment 
as defined in the protocol in which case this is a PFS event at the date of death. 
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F. 
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. 


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Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration. 
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1) (ITT) is the recommended approach; events 
documented after the initiation of new cancer therapy will be considered for the primary 
analysis i.e. progressions and deaths documented after the initiation of new cancer therapy 
would be included as events. This will require continued follow-up for progression after the 
start of the new cancer therapy. In such cases, it is recommended that an additional sensitivity 
analysis be performed by censoring at last adequate assessment prior to initiation of new cancer 
therapy. 
Option (2), i.e. censoring at last adequate assessment may be used as a sensitivity analysis. If a 
high censoring rate due to start of new cancer therapy is expected, a window of approximately 
8 weeks performed after the start of new cancer therapy can be used to calculate the date of the 
event or censoring. This should be clearly specified in the analysis plan. 
In some specific settings, local treatments (e.g. radiation/surgery) may not be considered as 
cancer therapies for assessment of event/censoring in PFS/TTP/DoR analysis. For example, 
palliative radiotherapy given in the trial for analgesic purposes or for lytic lesions at risk of 
fracture will not be considered as cancer therapy for the assessment of BOR and PFS analyses. 
The protocol should clearly state the local treatments which are not considered as antineoplastic 
therapies in the PFS/TTP/DoR analysis. 
The protocol should state that tumor assessments will be performed every x weeks until 
radiological progression irrespective of initiation of new antineoplastic therapy. It is strongly 
recommended that a tumor assessment is performed before the patient is switched to a new 
cancer therapy. 
Additional suggestions for sensitivity analyses 
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 16-5 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition: 
• Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly followed 
from baseline, immediately before or on the date of the last adequate tumor assessment. 
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation. 


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16.1.4 
Data handling and programming rules 
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates). 
16.1.4.1 Study/project specific decisions 
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation. 
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock). 
16.1.4.2 End of treatment phase completion 
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow- 
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc. 
The end of treatment visit and its associated assessments should occur within 7 days of the last 
study treatment. 
Patients may discontinue study treatment for any of the following reasons: 
• Adverse event(s) 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Participant/guardian decision 
• Progressive disease 
• Study terminated by the sponsor 
• Non-compliant with study treatment 
• No longer requires treatment 
• Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given) 
Death is a reason which “must” lead to discontinuation of patient from trial. 
16.1.4.3 End of post-treatment follow-up (study phase completion) 
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up. 


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Patients may provide study phase completion information for one of the following reasons: 
• Adverse event 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Participant/guardian decision 
• Death 
• Progressive disease 
• Study terminated by the sponsor 
16.1.4.4 Medical validation of programmed overall lesion response 
In order to be as objective as possible the RECIST programmed calculated response assessment 
is very strict regarding measurement methods (i.e. any assessment with more or less sensitive 
method than the one used to assess the lesion at baseline is considered UNK) and not available 
evaluations (i.e. if any target or non-target lesion was not evaluated the whole overall lesion 
response is UNK unless remaining lesions qualified for PD). This contrasts with the slightly 
more flexible guidance given to local investigators (and to the central reviewers) to use expert 
judgment in determining response in these type of situations, and therefore as a consequence 
discrepancies between the different sources of response assessment often arise. To ensure the 
quality of response assessments from the local site and/or the central reviewer, the responses 
may be re-evaluated by clinicians (based on local investigator data recorded in eCRF or based 
on central reviewer data entered in the database) at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on RECIST 
criteria. This may be queried for clarification. However, the investigator or central reader’s 
response assessment will never be overruled. 
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 
at that specific assessment is to be kept in a dataset. This must be clearly documented in the 
RAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data. 
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation. 
16.1.4.5 Programming rules 
The following should be used for programming of efficacy results: 


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16.1.4.5.1 
Calculation of ‘time to event’ variables 
Time to event = end date - start date + 1 (in days) 
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative. 
16.1.4.5.2 
Incomplete assessment dates 
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year. 
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 16.1.3.2.7). If all measurement dates have 
no day recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation. 
16.1.4.5.3 
Incomplete dates for last known date patient alive or death 
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact. 
16.1.4.5.4 
Non-target lesion response 
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’. 
16.1.4.5.5 
Study/project specific programming 
The standard analysis programs need to be adapted for each study/project. 
16.1.4.5.6 
Censoring reason 
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page. 
For survival the following censoring reasons are possible: 
• Alive 
• Lost to follow-up 
For PFS and TTP (and therefore DORs) the following censoring reasons are possible: 
• Ongoing without event 
• Lost to follow-up 
• Withdrew consent 


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• Adequate assessment no longer available* 
• Event documented after two or more missing tumor assessments (optional, see Table 16-5) 
• Death due to reason other than underlying cancer (only used for TTP and DOR) 
• Initiation of new anti-cancer therapy 
* Adequate assessment is defined in Section 16.1.3.2.7. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted: 
• This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off). 
• The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti- 
cancer therapy) has occurred more than the specified period following the last adequate 
assessment. 
• This reason will also be used to censor in case of no baseline assessment. 


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


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


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


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16.2.1 
Introduction 
This guideline provides the general principles and application of the Response Assessment in 
Neuro-Oncology for Brain Metastases (RANO-BM) criteria to assess tumor response and to 
derive efficacy endpoints in Novartis oncology brain metastases trials. This guideline is based 
on the publication: “Response assessment criteria for brain metastases: proposal from the 
RANO group” (Lin 2015). 
In studies with an endpoint of overall intracranial response rate (OIRR), tumor response will be 
primarily evaluated by the Response Assessment in Neuro-Oncology (RANO) working group 
Brain Metastases criteria, the RANO-BM Criteria (Lin 2015). 
The standard response and progression criteria from RANO-BM are relevant for the assessment 
of parenchymal brain metastases only. Leptomeningeal metastases, which are generally not 
radiographically measurable in a reliable and reproducible manner, will be treated as for non- 
target lesions. 
Similar to RECIST 1.1 (Eisenhauer et al 2009), definitions for radiographical response in 
RANO-BM are based on unidimensional measurements. Participants will undergo gadolinium- 
enhanced MRI* assessments for response evaluation as defined in the protocol. 
The efficacy assessments described in Section 16.2.2 and the definition of best overall 
intracranial response in Section 16.2.3.1 are based on the RANO-BM criteria but also give more 
detailed instructions and rules for determination of best response. Section 16.2.3.2 is 
summarizing the endpoints and related variables. 
The following components will be taken into account when assessing a participant’s overall 
intracranial response at an individual evaluation: 
• Tumor evaluation for gadolinium-enhanced MRI assessments 
• Overall lesion response category (CR/PR/PD/SD (or non-CR/non-PD)/NE) 
• Corticosteroid usage 
• ECOG performance scale and other clinical evaluation findings 
*In this document, the term “MRI” refers to gadolinium-enhanced MRI. 
16.2.2 
Efficacy assessments 
Tumor evaluations are made based on RANO-BM (Lin 2015). 
Tumor assessments will be performed according to assessment schedule described in the 
protocol Section 8.4. 
16.2.2.1 Definitions 
16.2.2.1.1 
Disease measurability 
In order to evaluate CNS tumors throughout a study, definitions of measurability are required 
in order to classify lesions appropriately at baseline. 


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


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


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


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


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Table 16-7 
Response assessment of non-target lesions 
 
Response Criteria 
Evaluation of non-target lesions 
 
Complete response (CR) 
Requires all of the following: disappearance of all enhancing CNS non-target 
lesions, no new CNS lesions. 
Non-complete response 
or non-progressive 
disease (Non-CR/non- 
PD) 
Progressive disease 
(PD) 
Persistence of one or more non-target CNS lesion or lesions. 
 
 
 
Any of the following: unequivocal progression of existing enhancing non-target 
CNS lesions, new lesion(s) (except while on immunotherapy-based treatment), 
CNS lesions. In the case of immunotherapy-based treatment, new lesions alone 
may not constitute progressive disease. 
 
Not evaluable (NE) 
Progression has not been documented and one or more target lesions have not 
been assessed or have been assessed using a different technique than baseline 
New lesions 
New lesions can appear during treatment. The finding of a new CNS lesion should be 
unequivocal and not due to technical or slice variation. A lesion not present at baseline and 
appearing at any follow-up evaluation timepoint is considered a new lesion. 
If the MRI is obtained with slide thickness of 1.5 mm or less, the new lesion should also be 
visible in axial, coronal and sagittal reconstructions of 1.5 mm or thinner projections. If a new 
lesion is equivocal, for example because of its small size (i.e., ≤ 5 mm), continued therapy can 
be considered, and a follow-up assessment will clarify if it really is new disease. If repeated 
scans confirm a new lesion, progression should be declared using the date of the initial scan 
showing the new lesion. In the case of immunotherapy-based treatment, however, new lesions 
alone may not constitute progressive disease. 
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion eCRF page. 
Corticosteroids 
The corticosteroids (including medication name, dose and unit, frequency, route, start and end 
date, indication, ongoing, status compared to baseline) used for response determination have to 
be recorded in the eCRF. 
The corticosteroids dose at the time of the tumor assessment will be compared with the dose 
taken at the time of the baseline tumor assessment. If the participant is not taking corticosteroids 
at baseline, a zero dose will be considered as the baseline value. If corticosteroids dose is not 
available at baseline, then the baseline dose will be considered unknown. Every effort should 
be made to document the baseline and subsequent corticosteroid doses. 
If corticosteroids information is not collected at the intracranial assessment, the most recently 
recorded corticosteroid dose will be considered. 
In the absence of clinical deterioration related to the tumor, an increase in corticosteroid dose 
alone should not be used as a sole determinant of progression. Participants with stable imaging 
results and whose corticosteroid dose has increased for reasons other than clinical deterioration 
related to the tumor do not qualify as having stable disease or progression. These participants 


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should be observed closely, and if their corticosteroid dose can be reduced back to baseline, 
they will be considered as having stable disease, but if further clinical deterioration related to 
the tumor becomes apparent they will be considered as having progression. The date of 
progression should be the first time point at which corticosteroid dose increase was necessary. 
Clinical Status 
Clinical performance status will be evaluated based on the investigators’ opinion and 
complemented by the ECOG performance status scale. At each protocol-specified time point, 
ECOG assessment should occur and intracranial tumor assessment should be coincident with 
ECOG assessment. 
Clinical status based on the investigators’ opinion used for response determination has to be 
recorded in the eCRF page. 
If ECOG is unknown or not done at the intracranial tumor assessment, the previous ECOG 
assessment could be used for determination of the response. 
16.2.2.4.3 
Evaluation of overall lesion response 
The evaluation of overall intracranial lesion response at each assessment is a composite of the 
target lesion response, non-target lesion response, the presence of new lesions, corticosteroid 
use relative to baseline, and clinical status as assessed by investigator and supported by the 
ECOG Performance Scale as shown below in Table 16-8. 
Table 16-8    Overall Lesion Response at each assessment 
 
Criterion 
Complete 
Response 
Partial 
Response 
Stable 
Disease 
Progressive 
Disease 
Target Lesions 
None 
≥ 30% decrease in 
< 30% decrease 
≥ 20% increase in 
sum LD relative to 
relative to baseline 
sum LD relative to 
baseline 
but <20% increase in 
sum LD relative to 
nadir # 
nadir # 
Non-target Lesions § 
None 
Stable or improved 
Stable or improved 
Unequivocal PD* 
New Lesion(s) † 
None 
None 
None 
Present * 
Corticosteroids 
None 
Stable or decreased 
Stable or decreased 
Not applicable ‡ 
compared to baseline 
Clinical Status 
Stable or 
Stable or improved 
Stable or improved 
Worse* 
compared to baseline 
Improved 
Requirement for 
All 
All 
All 
Any ‡ 
Response 
# Nadir: the smallest sum of diameter of all target lesions recorded at or after baseline 
§ Non-target lesions response: stable (Non-CR/Non-PD), improved (CR) 
* progression occurs when this criterion is met 
† A new lesion is one that was not present on prior scans and is visible in minimum two projections. 


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


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


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Table 16-9    CNS and non-CNS response assessment 
 
CNS (RANO-BM) 
Non-CNS (RECIST 1.1) 
Complete response, partial response or stable 
disease (or non-CR/Non-PD) 
Complete response, partial response or stable disease 
(or non-CR/Non-PD) 
Complete response, partial response or stable 
disease (or non-CR/Non-PD) 
Progressive Disease 
Progressive Disease 
Complete response, partial response or stable disease 
(or non-CR/Non-PD) 
Progressive Disease 
Progressive Disease 
16.2.3 
Efficacy definitions 
16.2.3.1 Best overall intracranial response 
The best overall intracranial response (BOIR) is the best intracranial response recorded from 
the randomization/start of treatment until disease progression/recurrence (taking as reference 
for PD the smallest measurements recorded since the randomization/treatment started) and will 
be determined programmatically based on the investigator/local reader’s assessment of 
response at each time point. 
The best overall intracranial response will usually be determined from response assessments 
undertaken while on treatment. However, if any assessments occur after treatment withdrawal 
the protocol should specifically describe if these will be included in the determination of best 
overall intracranial response and/or whether these additional assessments will be required for 
sensitivity or supportive analyses. As a default, any assessments taken more than 30 days after 
the last dose of study treatment will not be included in the best overall intracranial response 
derivation. If any alternative cancer therapy is taken while on study any subsequent assessments 
would ordinarily be excluded from the best overall intracranial response determination. If 
response assessments taken after withdrawal from study treatment and/or alternative therapy 
are to be included in the main endpoint determination, then this should be described and justified 
in the protocol. 
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed. 
• For non-randomized trials in which intracranial response is the primary endpoint, 
confirmation of partial response or complete response at least 4 weeks later is necessary to 
deem either one the best overall intracranial response. 
The best overall intracranial response for each participant is determined from the sequence of 
overall (lesion) responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required 


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


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


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


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Non-CR/Non-PD 
All of the following criteria must be met: 
1. Does not qualify for CR or PD. 
2. No new lesions. 
3. The corticosteroid dose at the time of the scan evaluation is not greater than the 
corticosteroid dose at the time of the baseline MRI scan. 
4. Stable or improved clinical status per investigator supported ECOG performance status 
scale compared to baseline. 
Progressive disease (PD) 
Any of the following criteria must be met: 
1. Unequivocal progression of non-target lesions. To achieve unequivocal progression on the 
basis of non-target disease there must be an overall level of substantial worsening on the 
NT disease. 
2. Any new lesion. 
3. Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. 
seizures, medication side effects, complications of therapy, cerebrovascular events, 
infection etc.). The definition of clinical deterioration is at the discretion of the investigator, 
however, it is recommended that a decline in the ECOG performance status, for at least 7 
days, be considered a clinical deterioration unless attributable to co-morbid events or 
changes in corticosteroid dose. 
a. Increase in corticosteroids alone will not be taken into account in determining 
progression in the absence of persistent clinical deterioration. 
4. Failure to return for evaluation due to death or deteriorating condition unless caused by 
documented non-related disorders. 
16.2.3.4.2 
Best overall intracranial response 
The best overall intracranial response for each participant is determined from the sequence of 
overall (lesion) responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required 
• Non-CR/Non-PD = at least one Non-CR/Non-PD assessment (or better) > 6 weeks after 
randomization/start of treatment (and not qualifying for CR) 
• PD = progression ≤ 12 weeks after randomization/start of treatment (and not qualifying for 
CR or Non-CR/Non-PD). 
• Not evaluable (NE) = all other cases (i.e. not qualifying for confirmed CR and without Non- 
CR/Non-PD after more than 6 weeks or early progression within the first 12 weeks) 


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16.2.4 
References 
Eisenhauer EA, Therasse P, Bogaerts J et al (2009). New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer; 45(2):228-47. 
Lin N et al (2015) Response assessment criteria for brain metastases: proposal from the 
RANO group. Lancet Oncology, 16:e270-278. 


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16.3 
Appendix 3: List of concomitant medications that require caution 
or are prohibited for patients on capmatinib 
Table 16-11 
Medications that require caution when concomitantly used with 
capmatinib 
 
Mechanism of 
Interaction 
Drug Name 
Strong CYP3A 
inhibitor 
ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira Pak), indinavir/ritonavir, 
tipranavir/ritonavir, ritonavir, cobicistat, indinavir, ketoconazole, troleandomycin, 
telaprevir, danoprevir/ritonavir, eltegravir/ritonavir, saquinavir/ritonavir, 
lopinavir/ritonavir, itraconazole, voriconazole, mibefradil,clarithromycin, posaconazole, 
telithromycin, grapefruit juice, conivaptan, nefazodone, nelfinavir, idelalisib, boceprevir, 
atazanavir/ritonavir, darunavir/ritonavir 
Moderate CYP3A 
inducer 
bosentan, dabrafenib, efavirenz, etravirine, genistein, modafinil, nafcillin, 
tipranavir/ritonavir, lopinavir, telotristat, thioridazine 
CYP1A2 substrate 
with NTI 
theophylline, tizanidine 
P-gp substrates 1 
afatinib, alfuzosin, aliskiren, alogliptin, ambrisentan, apixaban, apremilast, aprepitant, 
atorvastatin, azithromycin, boceprevir, bosentan, carvedilol, caspofungin, ceritinib, 
citalopram, colchicine, cyclosporine, dabigatran, digoxin, docetaxel, doxepin, 
doxorubicin, eribulin, everolimus, fentanyl, fexofenadine, fidaxomicin, fluvastatin, 
fosamprenavir, gatifloxacin, idelalisib, iloperidone, indacaterol, irbesartan, lacosamide, 
lapatinib, levetiracetam, linagliptin, linezolid, loperamide, losartan, maraviroc, 
mirabegron, moxifloxacin nadolol, naloxegol, nateglinide, nevirapine, nintedanib, 
olodaterol, paclitaxel, pantoprazole, paroxetine, pazopanib, posaconazole, pravastatin, 
proguanil, quinidine, ranolazine, riociguat, risperidone, ritonavir, rivaroxaban, 
saquinavir, silodosin, simeprevir, simvastatin, sirolimus, sitagliptin, sofosbuvir, 
sorafenib, tacrolimus, telaprevir, tenofovir, ticagrelor, tipranavir, tolvaptan, topotecan, 
umeclidinium, valsartan, vardenafil, vincristine, voriconazole 
BCRP substrates 1 
atorvastatin daunorubicin, dolutegravir, doxorubicin, ethinyl estradiol, hematoporphyrin, 
imatinib, irinotecan, methotrexate, mitoxantrone, paritaprevir, pitavastatin, rosuvastatin, 
simvastatin, sofosbuvir, sulfasalazine, tenofovir, topotecan, venetoclax 
Proton pump 
inhibitor 
dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole 
H2-receptor 
antagonists 
cimetidine, famotidine, nizatidine, ranitidine 
Antacids 
aluminum carbonate, aluminum hydroxide, calcium carbonate, calcium hydroxide, 
bismuth subsalicylate 
Source: The list is adapted from the Novartis Institutes for Biomedical PK Sciences internal memorandum (v01, 
2018): drug-drug interactions (DDI) database, which is compiled primarily from the Indiana University School of 
Medicine’s “Clinically Relevant” Table (drug-interactions.medicine.iu.edu/Main-Table.aspx), the University of 
Washington’s Drug Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug 
Interaction Studies”. This list may not be exhaustive and could be updated periodically. Please refer to the 
above mentioned database for the latest information. NTI: narrow therapeutic index 
1 If coadministration with capmatinib is unavoidable and minimal concentration changes of the drug listed may 
lead to serious adverse reactions, decrease dosage in accordance with the approved prescribing information. 


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Table 16-12 
Capmatinib: prohibited drugs 
 
Mechanism of 
Interaction 
Drug Name (generic) 
Strong CYP3A4 
inducer 
carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin, 
rifabutin, rifampicin, St. John's wort (Hypericum perforatum) 
Live vaccines 
e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, 
varicella, and TY21a typhoid vaccines, COVID-19 vaccines 
Source: The list is adapted from the Novartis Institutes for Biomedical PK Sciences internal memorandum (v01, 
2018): drug-drug interactions (DDI) database, which is compiled primarily from the Indiana University School of 
Medicine’s “Clinically Relevant” Table (drug-interactions.medicine.iu.edu/Main-Table.aspx), the University of 
Washington’s Drug Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug 
Interaction Studies”. This list may not be exhaustive and could be updated periodically. Please refer to the 
above mentioned databases for the latest information. 
 

SAP_001.pdf: 
INC280A/capmatinib/Tabrecta®
CINC280A2301 / NCT04427072
A phase III, randomized, controlled, open-label, multicenter, global 
study of capmatinib versus SoC docetaxel chemotherapy in 
previously treated patients with EGFR wt, ALK negative, locally 
advanced or metastatic (stage IIIB/IIIC or IV) NSCLC harboring MET 
exon 14 skipping mutation (METΔex14)
Statistical Analysis Plan (SAP)
Final analysis
Addendum 1
Author:
Trial statistician
Document type:
SAP Documentation
Document status:
Final 
Release date:
30-Jan-2024
Number of pages:
31
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Template Version 6.0, Effective from 23-Nov-2022


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Document history – Changes compared to previous final version of SAP
Date
Time 
point
Reason for update
Outcome for update
Section and title 
impacted (Current)
06-Oct-2023
Prior to 
DB lock 
for final 
analysis
Creation of final 
version
N/A - First version
NA
29-Nov-2023
Prior to 
DB lock 
for final 
analysis
Amendment 1:
Need for update of 
the derivation of 
censoring reasons 
for duration of 
response
Participants who 
move to capmatinib 
treatment outside of 
the trial are 
presented with the 
correct reason for 
censoring
2.6.1 Secondary 
efficacy endpoint
5.1 Determination of 
missing adequate 
tumor assessments
Abbreviations not 
used in the document 
were removed
List of abbreviations
Addition of 
analyses for 3 
efficacy endpoints 
because late 
updated data have 
an impact on these 
endpoints
Analyses for 
secondary endpoints 
overall response rate, 
disease control rate, 
and time to response 
by investigator 
assessment were 
added back.
Paragraphs for 
ORR/DCR and TTR 
were added to the 
subsection 2.7.1.
2.6 Analysis 
supporting secondary 
objectives
2.7.1 Secondary 
efficacy endpoints
dd-Jan-2024
After DB 
lock
Addendum 1:
Addition of outputs 
to fulfill a HA 
request
Analyses for main 
efficacy endpoints 
performed in the 
primary analysis (not 
planned for re-
analysis with the final 
data (PFS, ORR, 
DCR, TTR, OS, 
) were added 
(excluding sensitivity 
and supportive 
analyses). Estimand-
related text parts 
were removed as 
they are related to 
the primary analysis.
1 Introduction
1.2.1 Primary 
estimand
1.2.2 Secondary 
estimand
2.5 Analysis 
supporting primary 
objective(s)
2.6 Analysis of the 
key secondary 
objective
2.7 Analysis 
supporting secondary 
objectives
 
5
Appendix
5.2 Statistical models
6.1 Published 


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Date
Time 
point
Reason for update
Outcome for update
Section and title 
impacted (Current)
literature
General: correction of 
typos and minor 
wording updates


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Table of contents
Table of contents..................................................................................................................4
List of tables.........................................................................................................................5
List of abbreviations ............................................................................................................6
1
Introduction..........................................................................................................................8
1.1
Study design.............................................................................................................8
1.2
Study objectives, endpoints and estimands..............................................................9
2
Statistical methods .............................................................................................................10
2.1
Data analysis general information..........................................................................10
2.1.1
General definitions ................................................................................10
2.2
Analysis sets...........................................................................................................11
2.3
Patient disposition, demographics, and other baseline characteristics...................11
2.3.1
Patient disposition .................................................................................11
2.3.2
Demographics and other baseline characteristics..................................12
2.4
Treatments (study treatment, concomitant therapies, compliance)........................13
2.4.1
Study treatment / compliance................................................................13
2.4.2
Prior, concomitant and post therapies ...................................................13
2.5
Analysis supporting primary objective(s)..............................................................14
2.5.1
Primary endpoint ...................................................................................14
2.5.2
Statistical hypothesis, model, and method of analysis ..........................15
2.5.3
Handling of missing values ...................................................................15
2.6
Analysis of the key secondary objective................................................................17
2.6.1
Key secondary endpoint ........................................................................17
2.6.2
Statistical hypothesis, model, and method of analysis ..........................18
2.6.3
Handling of missing values ...................................................................18
2.7
Analysis supporting secondary objectives.............................................................19
2.7.1
Secondary efficacy endpoints................................................................19
2.8
Safety analyses.......................................................................................................21
2.8.1
Adverse events (AEs)............................................................................22
2.8.2
Deaths....................................................................................................23
2.8.3
Laboratory data......................................................................................24
2.8.4
Other safety data....................................................................................24
2.9
Pharmacokinetic endpoints ....................................................................................25
2.10
PD and PK/PD analyses.........................................................................................25
2.11
Patient-reported outcomes......................................................................................26


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2.12
Biomarkers.............................................................................................................26
26
26
2.14
Interim analysis......................................................................................................27
3
Sample size calculation......................................................................................................27
4
Change to protocol specified analyses...............................................................................27
5
Appendix............................................................................................................................27
5.1
Determination of missing adequate tumor assessments.........................................28
5.2
Statistical models ...................................................................................................29
5.2.1
Primary analysis ....................................................................................29
5.2.2
Secondary 
 analysis......................................................30
6
References..........................................................................................................................30
6.1
Published literature ................................................................................................30
6.2
Health authority guidance......................................................................................31
List of tables
Table 1-1
Objectives and related endpoints.............................................................9
Table 2-1
Outcome and event/censor dates for PFS analysis................................16
Table 2-2
Outcome and event/censor dates for DOR analysis ..............................20
27


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List of abbreviations
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
BILI
Total Bilirubin
BIRC
Blinded Independent Review Committee
BOR
Best Overall Response
CI
Confidence Interval
CNS
Central Nervous System
COVID-19
Coronavirus Disease 2019
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
DCR
Disease Control Rate
DNA
Deoxyribonucleic Acid
DOIR
Duration Of Intracranial Response
DOR
Duration Of Response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EGFR
Epidermal Growth Factor Receptor; also known as ErbB1
EORTC
European Organization for Research and Treatment of Cancer
EOT
End of Treatment
EQ-5D-5L
EuroQoL-5 Dimension-5 Level
ET
Extension Treatment
FAS
Full Analysis Set
HR
Hazard Ratio
HRQoL
Health-Related Quality of Life
IDCR
Intracranial disease control rate
MedDRA
Medical Dictionary for Drug Regulatory Affairs
METΔex14
MET exon 14 skipping
NCI
National Cancer Institute
NSCLC
Non-Small Cell Lung Cancer
OIRR
Overall intracranial response rate
ORR
Overall Response Rate
OS
Overall Survival
PD
Progressive Disease
PFS
Progression-Free Survival
PK
Pharmacokinetics


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PT
Preferred Term
QLQ
Quality of Life Questionnaire
QoL
Quality of Life
QTcF
Corrected QT interval using Fridericia correction
RANO-BM
Response Assessment in Neuro-Oncology Brain Metastases
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
TTIR
Time to Intracranial Response
TTR
Time to Response
WHO
World Health Organization
wt
Wild type


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1
Introduction
This statistical analysis plan (SAP) describes the planned analyses for the final Clinical Study 
Report (CSR) of the study CINC280A2301, a randomized, controlled, open-label, multicenter, 
global phase III study of capmatinib versus SoC docetaxel chemotherapy in previously treated 
patients with EGFR wt, ALK negative, locally advanced or metastatic (stage IIIB/IIIC or IV) 
NSCLC harboring MET exon 14 skipping mutation (METΔex14).
The content of this SAP is based on the protocol version 02 and the statistical analysis plan 
for the primary analysis, amendment 2, referred to as “primary analysis SAP” 
(CINC280A2301_SAP_CSR_1_primary_amendment2, dated 22-Mar-2023). All decisions 
regarding the final analysis, as defined in the SAP, have been made prior to database lock.
Due to changes in the treatment landscape which have heavily impacted the enrollment of 
new participants into the study, Novartis has taken the decision to permanently halt 
recruitment of participants in September 2022. Based on the primary analysis results of all 
randomized participants available in April 2023 (cut-off date 15-Feb-2023), the decision to 
stop the study prematurely was taken in May 2023. Last participant last visit was achieved on 
31-Oct-2023.
This abbreviated SAP describes the planned analyses for the final CSR and the posting of 
results in registries.
Baseline data will not be summarized again unless data changes after the interim database 
lock necessitate an update. Based on a Heath Authority request to provide the updated results 
for the main efficacy endpoints, the corresponding analyses were added in this SAP 
addendum 1. They had not been planned before because no significant changes were expected.
1.1
Study design
This is a multicenter, open-label, randomized, active-controlled, global phase III study that 
will enroll adult participants with EGFR wt, ALK rearrangement negative, NSCLC harboring 
METΔex14 skipping mutations who have progressed on one or two prior lines of systemic 
therapy for locally advanced or metastatic stage and are candidates for docetaxel.
The study will randomize approximately 90 participants globally. Participants eligible for the 
study will be randomized in a 2:1 ratio to one of the two treatment arms: capmatinib 
(investigational therapy) or docetaxel. The randomization will be stratified by prior lines of 
systemic therapy received for advanced/metastatic disease (one line vs. two lines).
Participants randomized to docetaxel treatment will be eligible to crossover to receive 
capmatinib treatment after BIRC-confirmed, RECIST 1.1-defined progressive disease (PD) 
and after meeting the eligibility criteria outlined in the study protocol.
For all participants, the respective treatment (either with capmatinib or docetaxel) may be 
continued beyond initial disease progression as per RECIST 1.1 (as assessed by the 
investigator and confirmed by BIRC) if, in the judgment of the investigator, there is evidence 
of clinical benefit, and the participant wishes to continue on the study treatment.


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After treatment discontinuation, all participants will be followed for safety evaluations during 
the safety follow-up period, and the participant’s status will be collected every 12 weeks as 
part of the survival follow-up.
The primary analysis was performed after enrollment had been closed with 22 randomized 
participants.
1.2
Study objectives, endpoints and estimands
For all detailed objectives and endpoints as well as the primary and secondary estimands of 
the study refer to primary analysis SAP. The following Table 1-1 shows the objectives and 
related endpoints in scope for this final SAP.
Table 1-1
Objectives and related endpoints
Objectives
Endpoints
Primary Objective
Endpoint for primary objective
To compare the efficacy of capmatinib versus 
docetaxel
Progression-free survival (PFS) by BIRC as per 
RECIST 1.1
Key secondary objective
To compare the overall response rate (ORR) of 
capmatinib and docetaxel
Endpoints for key secondary objective
ORR calculated per RECIST 1.1 by BIRC
Secondary Objectives
Endpoints for secondary objectives
To assess the antitumor activity of capmatinib 
versus docetaxel
All calculated per RECIST 1.1, both by BIRC and 
investigator:
•
Duration of response (DOR)
•
Time to response (TTR)
•
Disease control rate (DCR)
All calculated per RECIST 1.1, by investigator:
•
ORR
•
PFS
To evaluate overall survival (OS) in participants 
treated with capmatinib versus docetaxel
Overall survival
To evaluate the safety profile of capmatinib 
versus docetaxel
Incidence of adverse events and serious adverse 
events, change in vital signs, laboratory results 
and ECG


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2
Statistical methods
2.1
Data analysis general information
The final analysis will be performed by Novartis. SAS version 9.4 or later will be used to 
perform all data analyses and to generate tables, figures, and listings.
Data included in the analysis
Data from all participants who signed the main informed consent for this study will be used in 
the analysis. Data collected after participants’ withdrawal of informed consent for further 
participation in the study will not be reported (except for death date, if it is obtained from 
public records).
The analysis cut-off date for the final analysis of study data will be established at the end of 
the study. All statistical analyses will be performed using all data collected in the database up 
to the data cut-off date. All 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 will, be 
included in the analysis. Any data collected beyond the cut-off date will not be included in the 
analysis and will not be used for any derivations.
All events with start date before or on the cut-off date and end date after the cut-off date will 
be reported as ‘ongoing.’ The same rule will be applied to events starting before or on the cut-
off date and not having documented end date. This approach applies, in particular, to adverse 
event and concomitant medication reports. For these cases, the end date will not be imputed 
and therefore will not appear in the listings.
General analysis conventions
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to the expected small number of participants enrolled at each center, no 
center effect will be assessed.
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables 
by treatment arm; a missing category will be included as applicable. Percentages will be 
calculated using the number of participants in the relevant population or subgroup as the 
denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate 
descriptive statistics (e.g., mean, standard deviation, median, percentiles, minimum, and 
maximum) by treatment arm.
2.1.1
General definitions
For general definitions regarding investigational drug and study treatment, date of first/last 
administration of study treatment, last date of exposure to study treatment, baseline, on-
treatment assessments/events and observation period, windows for multiple assessments, last 
contact date, and other specifications please refer to the primary analysis SAP.


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2.2
Analysis sets
Participants are considered to be enrolled into the study if they have signed the main informed 
consent. Only participants who have signed the main informed consent will be included in the 
analysis data sets.
Participants who signed a molecular pre-screening informed consent form but failed to meet 
pre-screening criteria, as well as participants who signed the main informed consent form and 
were subsequently found to be ineligible prior to randomization will be considered screen 
failures. The set of All Screened Participants comprises all those who have signed the main 
informed consent.
Analysis sets will be summarized by treatment arm and stratum.
Full analysis set
The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned by randomization, regardless of whether or not the treatment was administered. 
According to the intent to treat principle, participants will be analyzed according to the 
treatment and strata they have been assigned to during the randomization procedure.
Unless otherwise specified the FAS will be the default analysis set used for all efficacy 
analyses.
Safety set
The Safety Set includes all participants who received at least one dose of study treatment. 
Participants will be analyzed according to the study treatment received, where treatment 
received is defined as the randomized treatment, if the participant took at least one dose of 
that treatment, or the first treatment received if the randomized treatment was never received.
All safety data will be analyzed using the Safety Set.
Crossover analysis set
The crossover analysis set (CAS) consists of participants randomized to the docetaxel arm 
who crossed over to receive at least one dose of capmatinib. This analysis set will be used for 
all analyses pertaining to safety evaluations collected after participants crossed over in the 
extension treatment phase.
2.3
Patient disposition, demographics, and other baseline 
characteristics
The FAS will be used for all participant demographic and baseline characteristic summaries 
and listings.
2.3.1
Patient disposition
The following information will be presented by treatment arm:
Participants randomized:


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•
Number (%) of participants treated
•
Number (%) of participants not treated
•
Reasons for not being treated
Related to the treatment phase (participants randomized):
•
Number (%) of participants who are still on-treatment;
•
Number (%) of participants who discontinued treatment;
•
Reasons for study treatment discontinuation;
Related to the post-treatment follow-up phase (participants who discontinued from 
randomized treatment):
•
Number (%) of participants who did not enter the post-treatment follow-up phase;
•
Number (%) of participants who entered the post-treatment follow-up phase and 
discontinued;
•
Reasons for discontinuation from the post-treatment follow-up phase;
Related to the extension treatment (ET) phase (participants who crossed over to capmatinib):
•
Number (%) of participants who entered the ET phase;
•
Number (%) of participants who discontinued from the ET phase;
•
Reasons for discontinuation from the ET phase;
Related to the ET safety follow-up (participants who discontinued from the ET phase):
•
Number (%) of participants who entered ET safety follow-up and discontinued;
•
Reasons for discontinuation from the ET safety follow-up;
The information will be derived from the applicable ‘Subject status’ and ‘Disposition’ eCRFs.
2.3.2
Demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment arm.
The following age categories will be presented: 18–< 65, ≥ 65–< 85, ≥ 85 years. Categories 
with zero counts will not be included.
Diagnosis and extent of cancer
Summary statistics were prepared in the primary analysis. Data on diagnosis and extent of 
cancer will be listed.
Protocol deviations
Frequency counts and percentages of participants in the FAS with any important protocol 
deviations (eligibility, withdrawal, concomitant medication, study treatment, other) will be 
tabulated by the deviation category by treatment arm. All protocol deviations will be listed.
In addition to the study PD terms, Novartis has defined 6 new protocol deviations related to 
the COVID-19 pandemic and the corresponding relationship (health status related vs. site 
lockdown, patient concerns, drug supply issue, etc.) in line with “FDA Guidance on Conduct 


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of Clinical Trials of Medical Products during COVID-19 Public Health Emergency” 
(FDA 2021) and “Guidance on the management of clinical trials during the COVID-19 
(coronavirus) pandemic” (EMA 2022). One additional study specific PD is also defined to 
capture treatment delay/interruption due to COVID-19. The deviations related to the COVID-
19 pandemic were summarized separately in the primary analysis. Any potential new PDs will 
be included in the main PD summary and listing.
2.4
Treatments (study treatment, concomitant therapies, compliance)
The safety set will be used for all medication data summaries and listings unless otherwise 
specified.
2.4.1
Study treatment / compliance
The exposure related analyses will be presented separately for the investigational drug and the 
control drug, if applicable.
Duration of exposure to study treatment, actual cumulative dose, dose intensity (DI), and 
relative dose intensity (RDI) will be summarized. In addition, a categorical summary of RDI 
will be presented in the respective summaries. The duration of exposure will be categorized 
into time intervals (< 6, ≥ 6–< 12, ≥ 12–< 18, ≥ 18–< 24, ≥ 24–< 36, ≥ 36–< 48, ≥ 48–< 60, 
≥ 60–< 72, ≥ 72–< 84, ≥ 84–< 96, ≥ 96 weeks, or as appropriate); frequency counts and 
percentages will be presented for the number (%) of participants in each interval. The number 
(%) of participants who have dose reductions or interruptions, and the reasons, will be 
summarized.
Participant level listings of all doses administered on treatment along with dose change 
reasons will be produced. Participants who continue treatment beyond disease progression 
will be listed.
Definitions related to the duration of exposure and dose intensity for investigational drug as 
well as for the control drug are specified in the primary analysis SAP.
2.4.2
Prior, concomitant and post therapies
Prior anticancer therapy and concomitant antineoplastic radiotherapy
Prior antineoplastic medications, and radiotherapies were summarized in the primary analysis 
and did not change. Prior antineoplastic surgeries will be listed based on the FAS.
There was no additional data collected on concomitant radiotherapy, therefore no new 
analysis will be done.
Concomitant therapy
Concomitant therapies are defined as any medications (excluding study treatment, prior 
antineoplastic treatments, and blood transfusions), surgeries or procedures (including physical 
therapy) administered in the study and are recorded on the eCRFs for Concomitant 
Medications and Prior or Concomitant non-drug therapies/procedures, respectively.


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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 treatment arm. 
Surgical and medical procedures will be coded using MedDRA and summarized by SOC and 
preferred term. These summaries during the on-treatment period will include: 1) medications 
starting on or after the start of study treatment but starting no later than 30 days after last dose 
of study treatment and 2) medications starting prior to the start of study treatment but 
continuing after the start of study treatment.
All concomitant therapies will be listed by treatment arm. Any concomitant therapies starting 
more than 30 days after the last date of study treatment and collected in the extension-
treatment phase will be flagged in the listings. The safety set will be used for all concomitant 
medication tables and listings.
Antineoplastic therapy after discontinuation of study treatment
The FAS will be used for listings and summaries of antineoplastic therapies initiated after 
discontinuation of study treatment. Summaries will be tabulated using frequency counts and 
percentages by treatment arm.
Antineoplastic medications initiated after discontinuation of study treatment will be 
summarized and listed by Anatomical Therapeutic Chemical (ATC) class, preferred term, and 
treatment arm.
Antineoplastic radiotherapy since discontinuation of study treatment will be listed. 
Antineoplastic surgeries since discontinuation of study treatment did not change, therefore no 
new analysis will be performed.
2.5
Analysis supporting primary objective(s)
The primary objective is to evaluate whether capmatinib prolongs PFS by BIRC according to 
RECIST 1.1 compared to docetaxel. This objective was evaluated in the primary analysis as 
planned in the study protocol and median PFS was reached. No significant change is expected. 
However, to fulfill a HA request, a descriptive summary of the PFS endpoint will be provided 
in the final analysis.
2.5.1
Primary endpoint
Progression-free survival (PFS) based on BIRC assessment as per RECIST 1.1 is the primary 
efficacy endpoint. The analysis will be based on the FAS and will include all data observed 
up-to the cut-off date. Censoring conventions are defined in Section 2.5.3.
PFS is defined as the time from the date of randomization to the date of the first documented 
disease progression based on BIRC assessment as per RECIST 1.1 or date of death due to any 
cause, whichever occurs first.


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The analysis of PFS will be based on the central radiological assessments done until the cut-
off date defined in Section 2.1. The analysis will use the default censoring and event date 
options from table 16-5 of the [Study Protocol Appendix 16.1] based on options A(1), B(1), 
C1(1), C2(1), D(1), E(1), and F(1); option G is not applicable. In particular, PFS will not be 
censored if a new antineoplastic therapy is started; instead, an Intent to treat (ITT) approach 
will be used and this new antineoplastic therapy will be ignored for the purposes of PFS 
derivation (and tumor assessments will continue), i.e., option F(1) in Table 16-5 of the [Study 
Protocol Appendix 16.1] will be used. Discontinuation of study treatment (for any reason 
before a PFS event [radiological progression or death]) will not be considered as a reason for 
censoring. Tumor assessment data collected after discontinuation of study treatment or 
occurrence of any unforeseen intercurrent event (e.g., due to COVID-19 pandemic) but before 
the PFS event will be used for PFS.
2.5.2
Statistical hypothesis, model, and method of analysis 
The confirmatory part of the objective was evaluated in the primary analysis. For the update 
based on final data, the hypothesis test as well as the supportive and sensitivity analyses will 
not be repeated.
The distribution of PFS will be estimated using the Kaplan-Meier method. The results will be 
depicted graphically by treatment arm. The median PFS, 25th and 75th percentiles, and PFS 
rate at different timepoints (e.g., 3, 6, 9, 12, 15 months) along with 95% confidence intervals 
(CIs) will be presented by treatment arm. A Cox regression model stratified by the 
randomization stratification factor will be used to estimate the hazard ratio (HR) of PFS, 
along with 95% CI based on the Wald test.
2.5.3
Handling of missing values
In the primary analysis, PFS will be censored at the date of the last adequate tumor 
assessment performed on or before the cut-off date, if no PFS event (radiological progression 
or death) is observed prior to the analysis cut-off date. Clinical deterioration will not be 
considered as documented disease progression. PFS events will be included in the analysis if 
they occur after one missing assessment.
Radiological progression or death observed after 2 or more missing tumor assessments 
(including missed assessments due to the COVID-19 pandemic) will not be included in the 
derivation of the time to event for PFS, and the observation will be censored at the time of the 
last adequate tumor assessment prior to the first missing assessment. Participants without a 
post-baseline tumor assessment (and without death) will be censored at the time of 
randomization.
The date of last adequate tumor assessment is the date of the last tumor assessment with 
overall lesion response of CR, PR or SD or non-CR/non-PD before an event or a censoring 
reason occurred. In this case the last tumor evaluation date at that assessment will be used. If 
no post-baseline assessments are available (before an event or a censoring reason occurred) 
then the date of randomization will be used.


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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. The term “missing adequate tumor assessment” is defined as a tumor assessment 
(TA) not performed or tumor assessment with overall lesion response of “not evaluable (NE).” 
The rule to determine the number of missing TAs is based on the time interval between the 
date of last adequate tumor assessment and the date of an event. If the interval is greater than 
twice the protocol-specified interval between the TAs and 2 times the protocol-allowed time 
window around assessments, then the number of missing assessments will be 2 or more.
Refer to Table 2-1 for censoring and event date options and outcomes for PFS and Section 5.1 
for details regarding missing adequate tumor assessments.
Table 2-1
Outcome and event/censor dates for PFS analysis
Situation
Date
Outcome
No baseline assessment
Date of randomization1
Censored
Progression or death at or before next 
scheduled assessment
Date of progression (or death)
Progressed
Progression or death after exactly one 
missing assessment
Date of progression (or death)
Progressed
Progression or death after two or more 
missing assessments
Date of last adequate assessment 
prior to missed assessment
Censored
No progression (or death)
Date of last adequate assessment
Censored
Treatment discontinuation due to 
“Disease progression” without 
documented progression, i.e., clinical 
progression based on investigator claim
Date of last adequate assessment
Censored
New anticancer therapy given prior to 
protocol defined progression
Ignore the new anticancer therapy and 
follow situations above
As per above 
situations
Death before first PD assessment
Date of death
Progressed
1 The rare exceptions to this are
(1) if the participant 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,
(2) if baseline target or non-target lesion assessments are unknown or missing, but a new lesion is 
identified post-baseline with overall response of PD, this is a PFS event at the date of PD 
assessment.
Other supportive analyses
Censoring pattern of PFS
The number of participants with a PFS event and number of participants censored for the PFS 
analysis will be summarized. In addition, a summary of reasons for PFS censoring will be 
provided by treatment arm based on the following reasons:
•
Ongoing without event
•
Lost to follow-up
•
Withdrew consent
•
Adequate assessment no longer available


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•
Event after ≥ 2 missing tumor assessments
The PFS censoring reasons are defined in the following way.
If the time interval between the last adequate tumor assessment date and the earliest of the 
following dates is smaller or equal to the interval of 2 missing tumor assessments
1. Analysis cut-off date,
2. Date of consent withdrawal,
3. Visit date of study treatment discontinuation or end of post-treatment follow-up 
discontinuation due to lost to follow-up,
then the PFS censoring reason will be
1. “Ongoing” 
2. “Withdrew consent” 
3. “Lost to follow-up”, respectively
If the time interval is larger than the interval of 2 missing tumor assessments with no event 
observed, then the PFS censoring reason will always default to “Adequate assessment no 
longer available”. If the time interval between the last adequate tumor assessment date and the 
PFS event date is larger than the interval of 2 missing tumor assessments, then the censoring 
reason will be “Event documented after two or more missing tumor assessments”.
These summaries on censoring reasons will be produced for PFS by investigator assessment 
and by BIRC assessment.
2.6
Analysis of the key secondary objective
The key secondary objective is to compare the ORR of capmatinib and docetaxel. This 
objective was evaluated in the primary analysis as planned in the study protocol. No 
significant change in the ORR is expected. However, to fulfill a HA request, a descriptive 
summary of the ORR endpoint will be provided in the final analysis.
2.6.1
Key secondary endpoint
ORR based on BIRC assessment as per RECIST 1.1 is the key secondary efficacy endpoint. 
The analysis will be based on the FAS.
The BOR will be determined from response assessments undertaken while on treatment. In 
addition, only tumor assessments performed before the start of any further anti-neoplastic 
therapy will be considered in the assessment of BOR. Localized palliative radiotherapy for 
pre-existing, painful bone and/or liver metastases is permitted. Local bone radiotherapy for 
analgesic purposes or for lytic lesions at risk of fracture is permitted when not delivered to a 
target lesion. Tumor assessment data collected after occurrence of any unforeseen intercurrent 
event (e.g., due to COVID-19 pandemic) will be included in the BOR assessment.
BOR for each participant is determined from the sequence of overall (lesion) responses 
according to the following rules:
•
CR = at least two determinations of CR at least 4 weeks apart before progression.


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•
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) > 5 weeks after randomization (and not 
qualifying for CR or PR).
•
Non-CR/non-PD* = at least one Non-CR/non-PD assessment > 5 weeks after start of 
treatment (and not qualifying for CR).
•
PD = progression ≤ 13 weeks after randomization (and not qualifying for CR, PR, or SD)
•
NE = all other cases (i.e., not qualifying for confirmed CR or PR and without SD after 
more than 5 weeks or early progression within the first 13 weeks).
* For participants with only non-measurable disease present at baseline. A non-CR/non-PD 
response is considered equivalent to an SD response for the ORR determination and 
participants will be considered “non-responders.”
Complete and partial responses must be confirmed by repeat assessments that should be 
performed not less than 4 weeks after the criteria for response are first met.
The NE BOR status can be due to the following reasons (and was presented in the primary 
CSR):
•
No valid post-baseline assessment
•
All post-baseline assessments have overall lesion response NE
•
New anti-neoplastic therapy started before first post-baseline assessment
•
SD too early (≤ 5 weeks after randomization date)
•
PD too late (> 13 weeks after randomization date)
Note 1: An SD is considered as “SD too early”’ if the SD is documented within the first 
5 weeks after randomization date.
Note 2: A PD is considered as “PD too late” if the first documentation of PD is recorded more 
than 13 weeks after the randomization date with no qualifying CR, PR, or SD in between.
Note 3: Special (and rare) cases where BOR is “NE” due to both too early SD and too late PD 
will be classified as “SD too early”.
2.6.2
Statistical hypothesis, model, and method of analysis
A descriptive summary of the ORR by treatment arm will be provided in the final analysis 
(including 2-sided exact 95% confidence intervals (Clopper and Pearson 1934)).
2.6.3
Handling of missing values
The determination of the BOR incorporates missing values including cases of participants 
with no valid post-baseline assessments.


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2.7
Analysis supporting secondary objectives
Further secondary efficacy objectives, see Table 1-1, were evaluated in the primary analysis. 
There were only 4 participants ongoing on treatment at that time (including 1 participant 
ongoing post BIRC-confirmed progression). Based on the additional data from these 
participants up to the cut-off date (LPLV) at the final database lock, no or only minimal 
changes in the results were expected, except for duration of response, in which some 
improvement might be observed. However, to fulfill a HA request, the RECIST-based 
secondary efficacy analyses, as well as overall survival, will be repeated in the final analysis.
2.7.1
Secondary efficacy endpoints
The secondary efficacy endpoints will be assessed using the FAS. The following analyses will 
be performed based on both local investigator assessment and BIRC per RECIST 1.1 (see 
[Study Protocol Appendix 16.1]).
For analyses of the secondary endpoints there will be no multiplicity adjustment. All results 
will be considered as exploratory.
Overall response rate
ORR per local investigator assessment will be analyzed using the same method as for ORR by 
BIRC, see Section 2.6.
Construction of waterfall graphs
Waterfall graphs will be used to depict the anti-tumor activity based on local investigator or 
based on BIRC assessment. For details please refer to the primary analysis SAP.
Disease control rate
DCR is defined as the proportion of participants with BOR of CR, PR, or SD.
DCR will be estimated and the 95% exact confidence interval (Clopper and Pearson 1934) 
will be provided by treatment arm. These analyses will be performed separately based on 
investigator assessment and based on BIRC assessment.
Duration of response
Among participants with a confirmed response (PR or CR), DOR is defined as the time from 
the first documented response (PR or CR) to the date of the first documented PD or death due 
to any cause. If a participant has not had an event, DOR is censored at the date of last 
adequate tumor assessment using the censoring rules described in Table 2-21. Refer to 
Section 5.1 for details regarding missing adequate tumor assessments.
Please note that the rules to derive the reason for censoring have been adjusted to the situation 
in this early terminated study. Participants who were still receiving study treatment and 
discontinued the study to continue with capmatinib treatment outside of the study could have 
their last visit much earlier than the LPLV due to different regulations and/or possibilities in 
their country. When their last imaging assessment is compared to the global LPLV it might 


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appear as if there were missing assessments. To avoid this, the cut-off date definition in 
Section 5.1 was updated to include study discontinuation due to “study terminated by 
sponsor”.
Table 2-2
Outcome and event/censor dates for DOR analysis
Situation
Date
Outcome
Progression or death at or before next 
scheduled assessment
Date of progression (or death)
Progressed
Progression or death after exactly one 
missing assessment
Date of progression (or death)
Progressed
Progression or death after two or more 
missing assessments
Date of last adequate assessment 
prior to missed assessment
Censored
No progression (or death)
Date of last adequate assessment
Censored
Treatment discontinuation due to 
“Disease progression” without 
documented progression, i.e., clinical 
progression based on investigator claim
Date of last adequate assessment
Censored
Death before first PD assessment
Date of death
Progressed
The distribution function of DOR will be estimated using the Kaplan-Meier method. The 
median DOR along with 95% CIs will be presented by treatment arm. The DOR results will 
also be listed.
These analyses will be performed separately based on investigator assessment and based on 
BIRC assessment.
Time to response
TTR is defined as the time from the date of randomization to the first documented response of 
either CR or PR, which must be confirmed subsequently.
All participants in the FAS will be included in the TTR calculation. Participants without a 
confirmed PR or CR will be censored at
•
the maximum follow-up time (i.e., FPFV − LPLV) for participants with a PFS event (i.e., 
disease progression or death due to any cause), or
•
at the date of the last adequate tumor assessment date for participants without a PFS event.
TTR will be listed and summarized by treatment arm. The distribution function of TTR will 
be estimated using the Kaplan-Meier method. The median TTR along with 95% CIs will be 
presented by treatment arm.
An additional summary of time to response with descriptive statistics based on responders' 
results only will also be prepared.
These analyses will be performed separately based on investigator assessment and based on 
BIRC assessment.


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Overall survival
OS is defined as the time from the date of randomization to the date of death due to any cause. 
If a participant 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 the data cut-off date.
The distribution of OS will be estimated using the Kaplan-Meier method. The median OS and 
25th and 75th percentiles along with 95% CI will be presented by treatment arm. The results 
will also be presented graphically by treatment arm. The survival probabilities at specific time 
points and the associated 95% confidence intervals will be summarized by treatment arm.
Censoring pattern of OS
The pattern of censored data will be examined regarding reasons for censoring (‘Alive’ or 
‘Lost to follow-up’). In addition, survival status, reason for censoring, and cause of death will 
be listed.
Duration of follow-up
Study follow-up will be summarized using the following:
•
Summary of duration between randomization and cut-off date, and follow-up times for 
PFS and OS, which are defined as follows:
•
Duration between randomization and data cut-off date = (cut-off date – date of 
randomization + 1) / 30.4375 (months). This item will be summarized overall.
•
Follow-up time = (date of event or censoring – date of randomization + 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 for OS. This item will be 
summarized by treatment arm.
All summaries will be reported in months. The calculations for PFS will be based on the 
BIRC assessment. Date of censoring is the same as defined for the PFS and OS analysis.
2.8
Safety analyses
For all safety analyses, the safety set will be used unless otherwise specified. All listings and 
tables will be presented by treatment arm.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g., change 
from baseline summaries). In addition, a separate summary for deaths including on-treatment 
and post-treatment deaths will be provided. In particular, summary tables for adverse events 
(AEs) will summarize only on-treatment events, with a start date during the on-treatment 
period (treatment-emergent AEs). The definition of the pre-treatment, on-treatment, and post-
treatment period as well as the crossover period is given in the primary analysis SAP 
(Section 2.1.1.8).
All data, regardless of observation period, will be listed and assessments collected in the post-
treatment period will be flagged in all the listings. Data collected in the extension-treatment 


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phase (including those during and after crossover period) for participants in the crossover 
analysis set will be flagged with a different symbol.
2.8.1
Adverse events (AEs)
AEs will be coded using MedDRA using the latest version available prior to clinical database 
lock and will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0.
AE summaries will include all AEs occurring during the on-treatment period. All AEs 
collected in the AE eCRF page will be listed along with the information collected on those 
AEs e.g., relationship to study treatment, outcome, etc.
Treatment-emergent adverse events (events that started after the first administration of study 
treatment or events present prior to start of study treatment but increased in severity based on 
preferred term) will be summarized by number and percentage of participants having at least 
one AE, having at least one AE in each primary system organ class (SOC) and for each 
preferred term (PT) and maximum grade. A participant with multiple occurrences of an AE 
will be counted only once in the respective AE category. A participant with multiple CTCAE 
grades for the same preferred term will be summarized under the maximum CTCAE grade 
recorded for the event. AE with missing CTCAE grade will be included in the “All grades” 
column of the summary tables.
In AE summaries, the primary system organ class will be presented alphabetically, and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order 
for the preferred term will be based on their frequency in the investigational drug arm.
The following AE summaries will be produced:
•
AEs regardless of study treatment relationship
•
AEs suspected to be study treatment 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 treatment relationship
•
SAEs suspected to be study treatment related
•
AEs leading to permanent discontinuation of study treatment regardless of study treatment 
relationship
•
AEs leading to permanent discontinuation of study treatment suspected to be study 
treatment related
•
AEs requiring dose adjustment and/or study treatment interruption regardless of study 
treatment relationship
•
AEs requiring dose adjustment and/or study treatment interruption suspected to be study 
treatment related
•
AEs excluding SAEs
•
AEs leading to fatal outcome.


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Clinical trial safety disclosure
For the legal requirements of ClinicalTrials.gov and EudraCT, two tables will be provided by 
SOC and PT based on the safety set for randomized phase and extension treatment phases:
•
On-treatment AEs which are not SAEs with an incidence greater than 5%
•
On-treatment SAEs and SAEs suspected to be related to study treatment
If for the same participant, several consecutive AEs (irrespective of study treatment causality, 
seriousness, and severity) occurred with the same SOC and PT,
•
a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE
•
more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE/SAE suspected to be related to study 
treatment/non-SAE has to be checked in a block, e.g., among AEs in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SOC and PT.
2.8.1.1
Adverse events of special interest / grouping of AEs
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to capmatinib. 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. An 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 groupings are specified in the electronic Case Retrieval Strategy 
(eCRS). The latest version of the eCRS available at the time of the analysis will be used.
For each specified AESI, the number and percentage of participants with at least one event of 
the AESI occurring during the on-treatment period will be summarized. The summaries will 
present grade, SAE, relationship to study treatment, leading to treatment discontinuation, 
leading to dose adjustment/interruption, hospitalization, death, etc. A listing of the MedDRA 
terms that define the AESIs will be generated.
2.8.2
Deaths
Separate summaries for on-treatment deaths and all deaths will be produced by treatment arm, 
system organ class and preferred term. All deaths will be listed, and post-treatment deaths will 
be flagged.


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2.8.3
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 in the pre-
treatment (for baseline, if applicable) and on-treatment period. All laboratory assessments will 
be listed and those collected in the post-treatment period will be flagged in the listings.
Grading of laboratory values will be assigned programmatically as per NCI CTCAE 
version 5.0. The calculation of CTCAE grades will be based on the observed laboratory 
values (in SI units) only, clinical assessments will not be taken into account. CTCAE Grade 0 
will be assigned for all non-missing values not graded as 1 or higher. Grade 5 will not be used. 
For laboratory tests where grades are not defined by CTCAE version 5.0, results will be 
categorized as low, normal, or high based on laboratory normal ranges.
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter and treatment arm):
•
Worst post-baseline CTC grade (regardless of the baseline status). Each participant will be 
counted only for the worst grade observed post-baseline.
•
Shift tables using CTC grades to compare baseline to the worst on-treatment value (hypo 
and hyper worst grade will be summarized separately, if applicable)
•
For laboratory tests where CTC grades are not defined, shift tables using low, normal, 
high (as well as low and high combined) classification to compare baseline to the worst 
on-treatment value.
•
Listing of all laboratory data with values flagged to show the corresponding CTCAE 
version 5.0 grades, if applicable, and the classifications relative to the laboratory normal 
ranges.
All laboratory data will be listed by participant and visit/time, and if normal ranges are 
available, abnormalities will be flagged.
Liver function parameters
Liver function parameters of interest are total bilirubin, ALT, AST, and alkaline phosphatase. 
A listing of these parameters will be prepared and participants with combined post-baseline 
peak elevations of AST or ALT and Bilirubin (ALT or AST > 3× ULN and BILI > 2 × ULN) 
will be flagged.
A summary table and/or graph (eDISH plot) will only be prepared if there are new 
observations (after primary database lock) which fulfill the lab criteria of potential Hy’s law 
events. Please refer to the primary analysis SAP for the categories in the summary table.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
12-lead ECGs including PR, QRS, QT, and QTcF intervals and heart rate will be obtained for 
each participant during the study. ECG data will be read and interpreted centrally. The 


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average of the ECG parameters at each assessment should be used in the analyses. ECGs 
collected during the on-treatment period will be summarized.
The number and percentage of participants with notable ECG values will be presented by 
treatment arm. Please refer to the primary analysis SAP regarding the categories.
A listing of all ECG assessments will be produced by treatment arm and notable values will 
be flagged. In the listing, the assessments collected during the post-treatment period and 
during the extension treatment period will be flagged.
2.8.4.2
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: systolic and diastolic blood pressure (mmHg), pulse 
(beats per minute), body temperature (°C), weight (kg), and height (cm).
The number and percentage of participants with notable vital signs values will be presented by 
treatment arm based on the categories described in the primary analysis SAP.
A listing of all vital sign assessments will be produced, and notable values will be flagged. In 
the listing, the assessments collected during the post-treatment period and during the 
extension treatment period will be flagged.
2.8.4.3
ECOG performance status
ECOG performance status at each time point will be listed. Participants with brain metastases 
at baseline will have continued assessments after the end of treatment to assess intracranial 
response per RANO-BM criteria. Post-treatment assessments will be included in the listing 
and flagged (also identifying assessments in the extension treatment period).
The frequency table by timepoint as well as the analysis of definitive deterioration in ECOG 
performance status will not be repeated in the final analysis. The ECOG performance status 
scale is specified in the primary analysis SAP.
2.8.4.4
Safety evaluation after crossover
All participants who had crossed over from the docetaxel arm and received capmatinib had 
discontinued prior to the primary analysis. Their safety data has been reported in the primary 
CSR. No further analysis will be done except including the data in the clinical trial safety 
disclosure tables.
2.9
Pharmacokinetic endpoints
The PK lock at the primary analysis was considered the final lock. No further analysis of 
pharmacokinetic data will be performed.
2.10
PD and PK/PD analyses
No analyses are planned.


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2.11
Patient-reported outcomes
To assess the effect of capmatinib versus docetaxel on patient-reported disease-related 
symptoms, functioning, and health-related quality of life via patient-reported outcomes 
questionnaires is a secondary objective of the study.
The objective was evaluated in the primary analysis. Only minimal changes are expected from 
an analysis based on additional data. A reanalysis will therefore not be performed.
2.12
Biomarkers
Any analysis of biomarker data, if performed, will be outlined in a separate biomarker 
analysis plan with results described in a stand-alone biomarker report.


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2.14
Interim analysis
Not applicable.
3
Sample size calculation
Please refer to the primary analysis SAP regarding the sample size calculation for the primary 
and key secondary endpoint.
4
Change to protocol specified analyses
Not applicable.
5
Appendix
In general, please refer to the primary analysis SAP for the appendices. The following topics 
are covered in the primary analysis SAP appendices. Determination of missing adequate 


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tumor assessments and Statistical models (except the subsection for Patient-reported outcomes) 
are presented again in Section 5.1 and Section 5.2, respectively, below. Not all details in 
Section 5.2 are applicable to the final CSR analysis.
•
Dose interruptions and dose changes
•
Imputation rules
•
AEs coding/grading
•
Laboratory parameters derivations
•
Determination of missing adequate tumor assessments
•
Statistical models
•
Novartis internal criteria for CTC grading of laboratory parameters (based on CTCAE v5 
– Nov 2017)
5.1
Determination of missing adequate tumor assessments
As detailed in the [Study Protocol Appendix 16.1], the PFS and DOR 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/DOR 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/DOR censoring reason.
Possible censoring reasons for PFS/DOR are:
1. Ongoing without event
2. Lost to follow-up
3. Withdrew consent
4. Adequate assessment no longer available
5. Event after ≥ 2 missing tumor assessments
The PFS/DOR censoring reason is then derived by the following sequence of rules.
•
If the participant is considered to have a PFS event, then PFS/DOR censoring reason is set 
to missing.


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•
Else, if the participant has had no baseline assessment then PFS censoring reason = 4 
(not applicable for DOR).
•
Else, if the participant 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/DOR censoring reason = 6.
•
Else, if the participant has no PFS event, and the participant is censored at a date after 
two or more missing assessments ((censoring date − date of LATA) ≥ D2) then 
PFS/DOR censoring reason = 4.
•
Else, if the censoring date equals the date of discontinuation due to consent 
withdrawal then PFS/DOR censoring reason = 3.
•
Else, if the censoring date equals the date of discontinuation due to loss to follow-up 
then PFS/DOR censoring reason = 2.
•
Else, if the censoring date equals the analysis cut-off date and the time between 
LATA and the cut-off date is greater than D2 days then PFS/DOR censoring 
reason = 4.
•
Else, if the censoring date equals the analysis cut-off date and the time between 
LATA and the cut-off date is less than or equal to D2 days then PFS/DOR censoring 
reason = 1
Where censoring date = min (analysis cut-off date, date of discontinuation due to consent 
withdrawal, date of discontinuation due to loss to follow-up, date of discontinuation due to 
study terminated by sponsor).
5.2
Statistical models
5.2.1
Primary analysis
The LIFETEST procedure in SAS with the TIME statement including a variable with survival 
times and a (right) censoring variable, and with a STRATA statement including variables of 
stratification factors, and with a GROUP option in the STRATA statement will be used for 
time-to-event endpoints.
Kaplan-Meier estimates
To analyze time-to-event variables, an estimate of the survival function in each treatment arm 
will be constructed using the Kaplan-Meier (product-limit) method as implemented in PROC 
LIFETEST with the METHOD=KM option. The PROC LIFETEST statement will use the 
option CONFTYPE=LOGLOG (complementary log-log transformation for derivation of CI).
Median survival for each treatment arm will be obtained along with 95% confidence intervals 
calculated from PROC LIFETEST output using the method of Brookmeyer and Crowley 1982. 
Kaplan-Meier estimates of the survival function with 95% confidence intervals at specific 
time points will be summarized. The standard error of the Kaplan-Meier estimate will be 
calculated using Greenwood’s formula (Collett 1994).


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Hazard ratio
The hazard ratio will be estimated by fitting the Cox proportional hazards model using SAS 
procedure PHREG (with TIES=EXACT option in the MODEL statement).
A stratified unadjusted Cox model will be used, i.e., the MODEL statement will include the 
treatment arm variable as the only covariate and the STRATA statement will include the 
stratification variable.
The hazard ratio with two-sided 95% confidence interval will be based on the Wald test.
Treatment of ties
The STRATA statement in the LIFETEST procedure will be used to analyze time to event 
data with ties. The PHREG procedure in SAS with option TIES=EXACT will be used to fit 
the Cox proportional hazards model.
Checking proportionality of hazard assumption
Plots (SURVIVAL, LOGSURV, LOGLOGS) generated by the LIFETEST procedure in SAS 
will be used to provide visual checks of the proportional hazard assumption.
•
SURVIVAL plots the estimated survivor functions. The shape of the curves should be 
basically the same if hazards are proportional.
•
LOGSURV plots the cumulative hazard functions. The larger cumulative hazard should be 
a multiple of the smaller if hazards are proportional.
•
LOGLOGS plots (cumulative hazard) will show parallel curves if the hazards are 
proportional.
5.2.2
Secondary 
 analysis
Confidence interval for response rate
Responses will be summarized in terms of percentage rates with 100 × (1 − α)% confidence 
interval using an exact binomial confidence interval (implemented using SAS procedure 
FREQ with EXACT statement for a one-way table; Clopper and Pearson 1934).
6
References
References are available upon request.
6.1
Published literature
Brookmeyer R and Crowley J (1982) A Confidence Interval for the Median Survival Time. 
Biometrics; 38:29-41.
Clopper C, Pearson ES (1934) The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika; 26(4):404–413.
Collet D (1994) Modelling survival data in medical research. London, Chapman & Hall.
Miettinen O, Nurminen M (1985) Comparative analysis of two rates. Stat Med; 4(2):213-226.


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6.2
Health authority guidance
European Medicines Agency (2022) Guidance on the management of clinical trials during the 
COVID-19 (coronavirus) pandemic. Version 5.0 February 2022. Amsterdam, The 
Netherlands.
Food and Drug Administration (2021) FDA guidance on conduct of clinical trials of medical 
products during COVID-19 pandemic: Guidance for industry, investigators, and institutional 
review boards. August 2021. Silver Spring, MD.